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	Travis Zack, MD, PhD University of California San Francisco San Francisco, CA, USA LinkedIn

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22 regimens on this page 48 variants on this page

Note: the page has (neo-)adjuvant regimens specific to rectal cancer. Please see the colon cancer page for adjuvant regimens specific to colon cancer (e.g., adjuvant CapeOx) and the colorectal cancer page for regimens intended more generically for colorectal cancer.

Guidelines

Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.

ESMO

2018: Glynne-Jones et al. Rectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed
- 2017: Glynne-Jones et al. Rectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed
- 2013: Glimelius et al. Rectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed
- 2010: Glimelius et al. Rectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed
- 2009: Glimelius & Oliveira. Rectal cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up PubMed
- 2008: Glimelius & Oliveira. Rectal cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up PubMed
- 2007: Glimelius. Rectal cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up PubMed
- 2005: Tveit & Kataja. ESMO Minimum Clinical Recommendations for diagnosis, treatment and follow-up of rectal cancer PubMed
- 2003: Tveit. ESMO Minimum Clinical Recommendations for diagnosis, treatment and follow-up of rectal cancer PubMed

French Intergroup

2017: Gérard et al. Rectal cancer: French Intergroup clinical practice guidelines for diagnosis, treatments and follow-up (SNFGE, FFCD, GERCOR, UNICANCER, SFCD, SFED, SFRO) PubMed

NCCN

NCCN Guidelines - Rectal Cancer
- 2015: Benson et al. Rectal Cancer, Version 2.2015 PubMed
- 2009: Engstrom et al. NCCN Clinical Practice Guidelines in Oncology: rectal cancer. PubMed

SIOG

2018: Montroni et al. Personalized management of elderly patients with rectal cancer: Expert recommendations of the European Society of Surgical Oncology, European Society of Coloproctology, International Society of Geriatric Oncology, and American College of Surgeons Commission on Cancer PubMed

Neoadjuvant therapy

Capecitabine & RT

Capecitabine & RT: Capecitabine & Radiation Therapy

Regimen variant #1, interrupted capecitabine, 1600 mg/m²/day, 4500 cGy

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Gérard et al. 2010 (ACCORD 12/0405 PRODIGE 2)	2005-2008	Phase 3 (C)	CapeOx & RT	Might have inferior pCR rate

Note: adjuvant therapy was not specified. Treatment is assumed to start on a Monday.

Chemotherapy

Capecitabine (Xeloda) 800 mg/m² PO twice per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33

Radiotherapy

Concurrent radiation therapy 180 cGy per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33 (4500 cGy total in 25 fractions)

5-week course

Subsequent treatment

Surgery

Regimen variant #2, interrupted capecitabine, 1600 mg/m²/day, 5000 cGy

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Conroy et al. 2021 (UNICANCER-PRODIGE 23)	2012-2017	Non-randomized part of phase 3 RCT
François et al. 2022	2016-2019	Phase 3 (C)	RT; 5 x 5	Inconclusive whether non-inferior R0 resection rate

Note: Treatment is assumed to start on a Monday.

Preceding treatment

UNICANCER-PRODIGE 23: Neoadjuvant FOLFIRINOX versus no neoadjuvant chemotherapy

Chemotherapy

Capecitabine (Xeloda) 800 mg/m² PO twice per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33

Radiotherapy

Concurrent radiation therapy 200 cGy per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33 (5000 cGy total in 25 fractions)

5-week course

Subsequent treatment

UNICANCER-PRODIGE 23: TME, then adjuvant mFOLFOX6
François et al. 2022: Surgery

Regimen variant #3, interrupted capecitabine, 1650 mg/m²/day, 4500 cGy

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Schmoll et al. 2020 (PETACC 6)	2008-2011	Phase 3 (C)	CapeOx & RT	Did not meet primary endpoint of DFS36

Chemotherapy

Capecitabine (Xeloda) 825 mg/m² PO twice per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33

Radiotherapy

Concurrent radiation therapy 180 cGy per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33 (4500 cGy total in 25 fractions)

5-week course

Subsequent treatment

Surgery, then adjuvant capecitabine

Regimen variant #4, continuous capecitabine, 1650 mg/m²/day, 4500 cGy

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Hofheinz et al. 2012 (Rektum-III)	2002-2007	Phase 3 (E-RT-switch-ic)	5-FU & RT	Non-inferior OS (primary endpoint) OS60: 76% vs 67%
Park et al. 2011 (AMC Rectal Pre Vs Post 2004)	2004-2006	Phase 3 (E-switch-ic)	Capecitabine & RT; adjuvant	Did not meet primary endpoint of DFS36	Superior sphincter preservation
O'Connell et al. 2014 (NSABP R-04)	2004-2010	Phase 3 (E-switch-ic)	1. 5-FU & RT	Did not meet primary endpoint of LRC	Similar toxicity
O'Connell et al. 2014 (NSABP R-04)	2004-2010	Phase 3 (E-switch-ic)	2. CapeOx & RT 3. FUOX & RT	Did not meet primary endpoint of LRC	Superior toxicity
Valentini et al. 2016 (INTERACT)	2005-2013	Phase 3 (C)	CapeOx & RT	Did not meet efficacy endpoints	Superior toxicity

Chemotherapy

Capecitabine (Xeloda) 825 mg/m² PO twice per day on days 1 to 38

Radiotherapy

Concurrent radiation therapy 180 cGy per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33 (25 fractions/4500 cGy), with boost depending on stage

5.5-week course

Subsequent treatment

Surgery, then adjuvant capecitabine

Regimen variant #5, interrupted capecitabine, 1650 mg/m²/day, 5000 cGy

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Zhu et al. 2020 (CinClare)	2015-2017	Phase 3 (C)	See link	See link

Note: Treatment is assumed to start on a Monday. Surgery is to take place 8 weeks after completion of chemoradiotherapy.

Chemotherapy

Capecitabine (Xeloda) 825 mg/m² PO twice per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33

Radiotherapy

Concurrent radiation therapy 200 cGy per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33 (5000 cGy total in 25 fractions)

5-week course

Subsequent treatment

Neoadjuvant CapeOx x 1, then TME, then adjuvant CapeOx x 5

Regimen variant #6, interrupted capecitabine, 1650 mg/m²/day, 5040 cGy

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Schmoll et al. 2020 (PETACC 6)	2008-2011	Phase 3 (C)	CapeOx & RT	Did not meet primary endpoint of DFS36

Note: Treatment starts on a Monday.

Chemotherapy

Capecitabine (Xeloda) 825 mg/m² PO twice per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33, 36 to 38

Radiotherapy

Concurrent radiation therapy 180 cGy per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33, 36 to 38 (5040 cGy total in 28 fractions)

5.5-week course

Subsequent treatment

Surgery, then adjuvant capecitabine

References

ACCORD 12: Gérard JP, Azria D, Gourgou-Bourgade S, Martel-Laffay I, Hennequin C, Etienne PL, Vendrely V, François E, de La Roche G, Bouché O, Mirabel X, Denis B, Mineur L, Berdah JF, Mahé MA, Bécouarn Y, Dupuis O, Lledo G, Montoto-Grillot C, Conroy T. Comparison of two neoadjuvant chemoradiotherapy regimens for locally advanced rectal cancer: results of the phase III trial ACCORD 12/0405-PRODIGE 2. J Clin Oncol. 2010 Apr 1;28(10):1638-44. Epub 2010 Mar 1. link to original article contains dosing details in manuscript PubMed NCT00227747
1. Update: Gérard JP, Azria D, Gourgou-Bourgade S, Martel-Lafay I, Hennequin C, Etienne PL, Vendrely V, François E, de La Roche G, Bouché O, Mirabel X, Denis B, Mineur L, Berdah JF, Mahé MA, Bécouarn Y, Dupuis O, Lledo G, Seitz JF, Bedenne L, Juzyna B, Conroy T. Clinical outcome of the ACCORD 12/0405 PRODIGE 2 randomized trial in rectal cancer. J Clin Oncol. 2012 Dec 20;30(36):4558-65. Epub 2012 Oct 29. link to original article PubMed
AMC Rectal Pre Vs Post 2004: Park JH, Yoon SM, Yu CS, Kim JH, Kim TW, Kim JC. Randomized phase 3 trial comparing preoperative and postoperative chemoradiotherapy with capecitabine for locally advanced rectal cancer. Cancer. 2011 Aug 15;117(16):3703-12. Epub 2011 Feb 15. link to original article contains dosing details in abstract PubMed NCT01186081
Rektum-III: Hofheinz RD, Wenz F, Post S, Matzdorff A, Laechelt S, Hartmann JT, Müller L, Link H, Moehler M, Kettner E, Fritz E, Hieber U, Lindemann HW, Grunewald M, Kremers S, Constantin C, Hipp M, Hartung G, Gencer D, Kienle P, Burkholder I, Hochhaus A. Chemoradiotherapy with capecitabine versus fluorouracil for locally advanced rectal cancer: a randomised, multicentre, non-inferiority, phase 3 trial. Lancet Oncol. 2012 Jun;13(6):579-88. Epub 2012 Apr 12. link to original article contains dosing details in manuscript PubMed NCT01500993
NSABP R-04: O'Connell MJ, Colangelo LH, Beart RW, Petrelli NJ, Allegra CJ, Sharif S, Pitot HC, Shields AF, Landry JC, Ryan DP, Parda DS, Mohiuddin M, Arora A, Evans LS, Bahary N, Soori GS, Eakle J, Robertson JM, Moore DF Jr, Mullane MR, Marchello BT, Ward PJ, Wozniak TF, Roh MS, Yothers G, Wolmark N. Capecitabine and oxaliplatin in the preoperative multimodality treatment of rectal cancer: surgical end points from National Surgical Adjuvant Breast and Bowel Project trial R-04. J Clin Oncol. 2014 Jun 20;32(18):1927-34. Epub 2014 May 5. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00058474
1. Update: Allegra CJ, Yothers G, O'Connell MJ, Beart RW, Wozniak TF, Pitot HC, Shields AF, Landry JC, Ryan DP, Arora A, Evans LS, Bahary N, Soori G, Eakle JF, Robertson JM, Moore DF Jr, Mullane MR, Marchello BT, Ward PJ, Sharif S, Roh MS, Wolmark N. Neoadjuvant 5-FU or capecitabine plus radiation with or without oxaliplatin in rectal cancer patients: a phase III randomized clinical trial. J Natl Cancer Inst. 2015 Sep 14;107(11). Erratum in: J Natl Cancer Inst. 2016 Apr;108(4). link to original article link to PMC article PubMed
INTERACT: Valentini V, Gambacorta MA, Cellini F, Aristei C, Coco C, Barbaro B, Alfieri S, D'Ugo D, Persiani R, Deodato F, Crucitti A, Lupattelli M, Mantello G, Navarria F, Belluco C, Buonadonna A, Boso C, Lonardi S, Caravatta L, Barba MC, Vecchio FM, Maranzano E, Genovesi D, Doglietto GB, Morganti AG, La Torre G, Pucciarelli S, De Paoli A. The INTERACT Trial: Long-term results of a randomised trial on preoperative capecitabine-based radiochemotherapy intensified by concomitant boost or oxaliplatin, for cT2 (distal)-cT3 rectal cancer. Radiother Oncol. 2019 May;134:110-118. Epub 2019 Feb 7. link to original article PubMed NCT01653301
CinClare: Zhu J, Liu A, Sun X, Liu L, Zhu Y, Zhang T, Jia J, Tan S, Wu J, Wang X, Zhou J, Yang J, Zhang C, Zhang H, Zhao Y, Cai G, Zhang W, Xia F, Wan J, Zhang H, Shen L, Cai S, Zhang Z. Multicenter, Randomized, Phase III Trial of Neoadjuvant Chemoradiation With Capecitabine and Irinotecan Guided by UGT1A1 Status in Patients With Locally Advanced Rectal Cancer. J Clin Oncol. 2020 Dec 20;38(36):4231-4239. Epub 2020 Oct 29. link to original article link to PMC article contains dosing details in manuscript PubMed NCT02605265
PETACC 6: Schmoll HJ, Stein A, Van Cutsem E, Price T, Hofheinz RD, Nordlinger B, Daisne JF, Janssens J, Brenner B, Reinel H, Hollerbach S, Caca K, Fauth F, Hannig CV, Zalcberg J, Tebbutt N, Mauer ME, Marreaud S, Lutz MP, Haustermans K. Pre- and Postoperative Capecitabine Without or With Oxaliplatin in Locally Advanced Rectal Cancer: PETACC 6 Trial by EORTC GITCG and ROG, AIO, AGITG, BGDO, and FFCD. J Clin Oncol. 2021 Jan 1;39(1):17-29. Epub 2020 Oct 1. link to original article contains dosing details in manuscript PubMed NCT00766155
UNICANCER-PRODIGE 23: Conroy T, Bosset JF, Etienne PL, Rio E, François É, Mesgouez-Nebout N, Vendrely V, Artignan X, Bouché O, Gargot D, Boige V, Bonichon-Lamichhane N, Louvet C, Morand C, de la Fouchardière C, Lamfichekh N, Juzyna B, Jouffroy-Zeller C, Rullier E, Marchal F, Gourgou S, Castan F, Borg C; Unicancer Gastrointestinal Group and Partenariat de Recherche en Oncologie Digestive (PRODIGE) Group. Neoadjuvant chemotherapy with FOLFIRINOX and preoperative chemoradiotherapy for patients with locally advanced rectal cancer (UNICANCER-PRODIGE 23): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2021 May;22(5):702-715. Epub 2021 Apr 13. link to original article contains dosing details in abstract PubMed NCT01804790
STELLAR_rectal: Jin J, Tang Y, Hu C, Jiang LM, Jiang J, Li N, Liu WY, Chen SL, Li S, Lu NN, Cai Y, Li YH, Zhu Y, Cheng GH, Zhang HY, Wang X, Zhu SY, Wang J, Li GF, Yang JL, Zhang K, Chi Y, Yang L, Zhou HT, Zhou AP, Zou SM, Fang H, Wang SL, Zhang HZ, Wang XS, Wei LC, Wang WL, Liu SX, Gao YH, Li YX. Multicenter, Randomized, Phase III Trial of Short-Term Radiotherapy Plus Chemotherapy Versus Long-Term Chemoradiotherapy in Locally Advanced Rectal Cancer (STELLAR). J Clin Oncol. 2022 May 20;40(15):1681-1692. Epub 2022 Mar 9. link to original article link to PMC article NCT02533271 PubMed
CONVERT_rectal: Mei WJ, Wang XZ, Li YF, Sun YM, Yang CK, Lin JZ, Wu ZG, Zhang R, Wang W, Li Y, Zhuang YZ, Lei J, Wan XB, Ren YK, Cheng Y, Li WL, Wang ZQ, Xu DB, Mo XW, Ju HX, Ye SW, Zhao JL, Zhang H, Gao YH, Zeng ZF, Xiao WW, Zhang XP, Zhang X, Xie E, Feng YF, Tang JH, Wu XJ, Chen G, Li LR, Lu ZH, Wan DS, Bei JX, Pan ZZ, Ding PR. Neoadjuvant Chemotherapy With CAPOX Versus Chemoradiation for Locally Advanced Rectal Cancer With Uninvolved Mesorectal Fascia (CONVERT): Initial Results of a Phase III Trial. Ann Surg. 2023 Apr 1;277(4):557-564. Epub 2022 Dec 20. link to original article link to PMC article PubMed NCT02288195
François E, De Bari B, Ronchin P, Nouhaud E, Martel-Lafay I, Artru P, Clavere P, Vendrely V, Boige V, Gargot D, Lemanski C, De Sousa Carvalho N, Gal J, Pernot M, Magné N. Comparison of short course radiotherapy with chemoradiotherapy for locally advanced rectal cancers in the elderly: A multicentre, randomised, non-blinded, phase 3 trial. Eur J Cancer. 2023 Feb;180:62-70. Epub 2022 Nov 28. link to original article PubMed
PROSPECT_rectal: Schrag D, Shi Q, Weiser MR, Gollub MJ, Saltz LB, Musher BL, Goldberg J, Al Baghdadi T, Goodman KA, McWilliams RR, Farma JM, George TJ, Kennecke HF, Shergill A, Montemurro M, Nelson GD, Colgrove B, Gordon V, Venook AP, O'Reilly EM, Meyerhardt JA, Dueck AC, Basch E, Chang GJ, Mamon HJ. Preoperative Treatment of Locally Advanced Rectal Cancer. N Engl J Med. 2023 Jul 27;389(4):322-334. Epub 2023 Jun 4. link to original article PubMed NCT01515787
1. PRO analysis: Basch E, Dueck AC, Mitchell SA, Mamon H, Weiser M, Saltz L, Gollub M, Rogak L, Ginos B, Mazza GL, Colgrove B, Chang G, Minasian L, Denicoff A, Thanarajasingam G, Musher B, George T, Venook A, Farma J, O'Reilly E, Meyerhardt JA, Shi Q, Schrag D. Patient-Reported Outcomes During and After Treatment for Locally Advanced Rectal Cancer in the PROSPECT Trial (Alliance N1048). J Clin Oncol. 2023 Jul 20;41(21):3724-3734. Epub 2023 Jun 4. link to original article link to PMC article PubMed

Capecitabine, Sorafenib, RT

Capecitabine, Sorafenib, RT: Capecitabine, Sorafenib, Radiation Therapy

Regimen

Study	Evidence
von Moos et al. 2017 (SAKK 41/08)	Phase 1/2

Biomarker eligibility criteria

KRAS-mutation

Chemotherapy

Capecitabine (Xeloda) 825 mg/m² PO twice per day on days 1 to 33

Targeted therapy

Sorafenib (Nexavar) 400 mg PO once per day

Radiotherapy

Concurrent radiation therapy, 4500 cGy total

5-week course

Subsequent treatment

Surgery

References

SAKK 41/08: von Moos R, Koeberle D, Schacher S, Hayoz S, Winterhalder RC, Roth A, Bodoky G, Samaras P, Berger MD, Rauch D, Saletti P, Plasswilm L, Zwahlen D, Meier UR, Yan P, Izzo P, Klingbiel D, Bärtschi D, Zaugg K; Swiss Group for Clinical Cancer Research. Neoadjuvant radiotherapy combined with capecitabine and sorafenib in patients with advanced KRAS-mutated rectal cancer: A phase I/II trial (SAKK 41/08). Eur J Cancer. 2018 Jan;89:82-89. Epub 2017 Dec 11. link to original article PubMed

CapeOx

CapeOX: Capecitabine & OXaliplatin

Regimen variant #1, 4 cycles

Study	Dates of enrollment	Evidence
Chua et al. 2010	2001-2005	Phase 2

Chemotherapy

Capecitabine (Xeloda) 1000 mg/m² PO twice per day on days 1 to 14
Oxaliplatin (Eloxatin) 130 mg/m² IV once on day 1

21-day cycle for 4 cycles

Subsequent treatment

Neoadjuvant Capecitabine & RT, then TME

Regimen variant #2, 6 cycles

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Bahadoer et al. 2020 (RAPIDO)	2011-2016	Phase 3 (E-switch-ic)	See link	See link

Preceding treatment

Neoadjuvant RT; 5 x 500 cGy

Chemotherapy

Capecitabine (Xeloda) 1000 mg/m² PO twice per day on days 1 to 14
Oxaliplatin (Eloxatin) 130 mg/m² IV once on day 1

21-day cycle for 6 cycles

Subsequent treatment

TME

References

Chua YJ, Barbachano Y, Cunningham D, Oates JR, Brown G, Wotherspoon A, Tait D, Massey A, Tebbutt NC, Chau I. Neoadjuvant capecitabine and oxaliplatin before chemoradiotherapy and total mesorectal excision in MRI-defined poor-risk rectal cancer: a phase 2 trial. Lancet Oncol. 2010 Mar;11(3):241-8. Epub 2010 Jan 25. link to original article contains dosing details in abstract PubMed NCT00220051
RAPIDO: Bahadoer RR, Dijkstra EA, van Etten B, Marijnen CAM, Putter H, Kranenbarg EM, Roodvoets AGH, Nagtegaal ID, Beets-Tan RGH, Blomqvist LK, Fokstuen T, Ten Tije AJ, Capdevila J, Hendriks MP, Edhemovic I, Cervantes A, Nilsson PJ, Glimelius B, van de Velde CJH, Hospers GAP; RAPIDO collaborative investigators. Short-course radiotherapy followed by chemotherapy before total mesorectal excision (TME) versus preoperative chemoradiotherapy, TME, and optional adjuvant chemotherapy in locally advanced rectal cancer (RAPIDO): a randomised, open-label, phase 3 trial. Lancet Oncol. 2021 Jan;22(1):29-42. Epub 2020 Dec 7. link to original article contains dosing details in manuscript PubMed NCT01558921

CapeOx, Cetuximab, RT

CapeOX, Cetuximab, RT: Capecitabine, OXaliplatin, Cetuximab, Radiation Therapy

Regimen

Study	Dates of enrollment	Evidence
Leichman et al. 2017 (SWOG S0713)	2009-02 to 2013-04	Phase 2

Chemotherapy

Capecitabine (Xeloda) 825 mg/m² PO twice per day on Monday to Friday
Oxaliplatin (Eloxatin) as follows:
- Cycle 1: 50 mg/m² IV once per day on days 1, 8, 15, 22, 29
- Cycle 2: 50 mg/m² IV once per day on days 1, 8, 22, 29

Targeted therapy

Cetuximab (Erbitux) as follows:
- Cycle 1: 400 mg/m² IV once on day 1, then 250 mg/m² IV once per day on days 8, 15, 22, 29
- Cycle 2: 250 mg/m² IV once per day on days 1, 8, 15, 22, 29

Radiotherapy

RT as follows:
- Cycle 2: 180 cGy per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33 (25 fractions)

35-day cycle for 2 cycles

Subsequent treatment

TME

References

SWOG S0713: Leichman CG, McDonough SL, Smalley SR, Billingsley KG, Lenz HJ, Beldner MA, Hezel AF, Velasco MR, Guthrie KA, Blanke CD, Hochster HS. Cetuximab Combined With Induction Oxaliplatin and Capecitabine, Followed by Neoadjuvant Chemoradiation for Locally Advanced Rectal Cancer: SWOG 0713. Clin Colorectal Cancer. 2018 Mar;17(1):e121-e125. Epub 2017 Oct 24. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00686166

CapIriRT

CapIriRT: Capecitabine, Irinotecan, Radiation Therapy

Regimen variant #1, 65 mg/m²

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Zhu et al. 2020 (CinClare)	2015-2017	Phase 3 (E-switch-ic)	See link	See link

Note: Treatment is assumed to start on a Monday. Surgery is to take place 8 weeks after completion of chemoradiotherapy.

Biomarker eligibility criteria

UGT1A1*1*28 genotype

Chemotherapy

Capecitabine (Xeloda) 625 mg/m² PO twice per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33
Irinotecan (Camptosar) 65 mg/m² IV once per day on days 1, 8, 15, 22, 29

Radiotherapy

Concurrent radiation therapy 200 cGy per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33 (5000 cGy total in 25 fractions)

5-week course

Subsequent treatment

Neoadjuvant CAPIRI x 1, then TME, then adjuvant CapeOx x 5

Regimen variant #2, 80 mg/m²

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Zhu et al. 2020 (CinClare)	2015-2017	Phase 3 (E-switch-ic)	See link	See link

Note: Treatment is assumed to start on a Monday. Surgery is to take place 8 weeks after completion of chemoradiotherapy.

Biomarker eligibility criteria

UGT1A1*1*1 genotype

Chemotherapy

Capecitabine (Xeloda) 625 mg/m² PO twice per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33
Irinotecan (Camptosar) 80 mg/m² IV once per day on days 1, 8, 15, 22, 29

Radiotherapy

Concurrent radiation therapy 200 cGy per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33 (5000 cGy total in 25 fractions)

5-week course

Subsequent treatment

Neoadjuvant CAPIRI x 1, then TME, then adjuvant CapeOx x 5

References

CinClare: Zhu J, Liu A, Sun X, Liu L, Zhu Y, Zhang T, Jia J, Tan S, Wu J, Wang X, Zhou J, Yang J, Zhang C, Zhang H, Zhao Y, Cai G, Zhang W, Xia F, Wan J, Zhang H, Shen L, Cai S, Zhang Z. Multicenter, Randomized, Phase III Trial of Neoadjuvant Chemoradiation With Capecitabine and Irinotecan Guided by UGT1A1 Status in Patients With Locally Advanced Rectal Cancer. J Clin Oncol. 2020 Dec 20;38(36):4231-4239. Epub 2020 Oct 29. link to original article link to PMC article contains dosing details in manuscript PubMed NCT02605265

Fluorouracil & RT

Fluorouracil & RT: Fluorouracil & Radiation Therapy

Regimen variant #1, continuous

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Ngan et al. 2012 (TROG 01.014)	2001-2006	Phase 3 (C)	Short-course RT	Did not meet primary endpoint of LR rate at 36 mo	Similar toxicity
Aschele et al. 2011 (STAR-01)	2003-2008	Phase 3 (C)	FUOX & RT	Did not meet primary endpoint of OS¹	Less toxic
O'Connell et al. 2014 (NSABP R-04)	2004-2010	Phase 3 (C)	1. Capecitabine & RT	Did not meet primary endpoint of LRC	Similar toxicity
O'Connell et al. 2014 (NSABP R-04)	2004-2010	Phase 3 (C)	2. CapeOx & RT 3. FUOX & RT	Did not meet primary endpoint of LRC	Superior toxicity

¹Reported efficacy for STAR-01 is based on the 2016 update.

Chemotherapy

Fluorouracil (5-FU) 225 mg/m²/day IV continuous infusion until the end of radiation, started on day 1

Radiotherapy

Concurrent radiation therapy, 180 cGy for 25 fractions (4500 cGy), with boost depending on stage

5-week course

Subsequent treatment

STAR-01: Surgery, preferably TME, then adjuvant fluourouracil-based therapy
NSABP R-04: Surgery

Regimen variant #2, intermittent

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Sauer et al. 2004 (CAO/ARO/AIO-94)	1995-2002	Phase 3 (E-switch-ic)	5-FU & RT; adjuvant	Superior five-year cumulative incidence of local relapse (secondary endpoint)
Hofheinz et al. 2012 (Rektum-III)	2002-2007	Phase 3 (C)	Capecitabine & RT	Non-inferior OS
Rödel et al. 2012 (CAO/ARO/AIO-04)	2006-2010	Phase 3 (C)	FUOX & RT	Seems to have inferior pCR rate

Chemotherapy

Fluorouracil (5-FU) 1000 mg/m²/day IV continuous infusion over 120 hours, started on days 1 & 29 (total dose: 10,000 mg/m²)

Radiotherapy

Concurrent radiation therapy, 5040 cGy total

One course

Subsequent treatment

CAO/ARO/AIO-94: TME, then adjuvant 5-FU

References

CAO/ARO/AIO-94: Sauer R, Becker H, Hohenberger W, Rödel C, Wittekind C, Fietkau R, Martus P, Tschmelitsch J, Hager E, Hess CF, Karstens JH, Liersch T, Schmidberger H, Raab R; German Rectal Cancer Study Group. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med. 2004 Oct 21;351(17):1731-40. link to original article contains dosing details in manuscript PubMed
1. Update: Sauer R, Liersch T, Merkel S, Fietkau R, Hohenberger W, Hess C, Becker H, Raab HR, Villanueva MT, Witzigmann H, Wittekind C, Beissbarth T, Rödel C. Preoperative versus postoperative chemoradiotherapy for locally advanced rectal cancer: results of the German CAO/ARO/AIO-94 randomized phase III trial after a median follow-up of 11 years. J Clin Oncol. 2012 Jun 1;30(16):1926-33. Epub 2012 Apr 23. link to original article PubMed
STAR-01: Aschele C, Cionini L, Lonardi S, Pinto C, Cordio S, Rosati G, Artale S, Tagliagambe A, Ambrosini G, Rosetti P, Bonetti A, Negru ME, Tronconi MC, Luppi G, Silvano G, Corsi DC, Bochicchio AM, Chiaulon G, Gallo M, Boni L. Primary tumor response to preoperative chemoradiation with or without oxaliplatin in locally advanced rectal cancer: pathologic results of the STAR-01 randomized phase III trial. J Clin Oncol. 2011 Jul 10;29(20):2773-80. Epub 2011 May 23. link to original article contains dosing details in manuscript PubMed
1. Update: Abstract: Carlo Aschele, Sara Lonardi, Luca Cionini, Carmine Pinto, Stefano Sergio Cordio, Gerardo Rosati, Andrea Sartore Bianchi, Angiolo Tagliagambe, Michela Frisinghelli, Vittorina Zagonel, Paola Rosetti, Maria Emanuela Negru, Andrea Bonetti, Maria Chiara Tronconi, Gabriele Luppi, Anna Rita Marsella, Domenico C. Corsi, Anna Maria Bochicchio, Nicoletta Pella, and Luca Boni. Final results of STAR-01: A randomized phase III trial comparing preoperative chemoradiation with or without oxaliplatin in locally advanced rectal cancer. Journal of Clinical Oncology 2016 34:15_suppl, 3521-3521 link to abstract
Rektum-III: Hofheinz RD, Wenz F, Post S, Matzdorff A, Laechelt S, Hartmann JT, Müller L, Link H, Moehler M, Kettner E, Fritz E, Hieber U, Lindemann HW, Grunewald M, Kremers S, Constantin C, Hipp M, Hartung G, Gencer D, Kienle P, Burkholder I, Hochhaus A. Chemoradiotherapy with capecitabine versus fluorouracil for locally advanced rectal cancer: a randomised, multicentre, non-inferiority, phase 3 trial. Lancet Oncol. 2012 Jun;13(6):579-88. Epub 2012 Apr 12. link to original article contains dosing details in manuscript PubMed NCT01500993
CAO/ARO/AIO-04: Rödel C, Liersch T, Becker H, Fietkau R, Hohenberger W, Hothorn T, Graeven U, Arnold D, Lang-Welzenbach M, Raab HR, Sülberg H, Wittekind C, Potapov S, Staib L, Hess C, Weigang-Köhler K, Grabenbauer GG, Hoffmanns H, Lindemann F, Schlenska-Lange A, Folprecht G, Sauer R; German Rectal Cancer Study Group. Preoperative chemoradiotherapy and postoperative chemotherapy with fluorouracil and oxaliplatin versus fluorouracil alone in locally advanced rectal cancer: initial results of the German CAO/ARO/AIO-04 randomised phase 3 trial. Lancet Oncol. 2012 Jul;13(7):679-87. Epub 2012 May 23. link to original article contains dosing details in abstract PubMed NCT00349076
1. Update: Rödel C, Graeven U, Fietkau R, Hohenberger W, Hothorn T, Arnold D, Hofheinz RD, Ghadimi M, Wolff HA, Lang-Welzenbach M, Raab HR, Wittekind C, Ströbel P, Staib L, Wilhelm M, Grabenbauer GG, Hoffmanns H, Lindemann F, Schlenska-Lange A, Folprecht G, Sauer R, Liersch T; German Rectal Cancer Study Group. Oxaliplatin added to fluorouracil-based preoperative chemoradiotherapy and postoperative chemotherapy of locally advanced rectal cancer (the German CAO/ARO/AIO-04 study): final results of the multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2015 Aug;16(8):979-89. Epub 2015 Jul 15. link to original article PubMed
TROG 01.014: Ngan SY, Burmeister B, Fisher RJ, Solomon M, Goldstein D, Joseph D, Ackland SP, Schache D, McClure B, McLachlan SA, McKendrick J, Leong T, Hartopeanu C, Zalcberg J, Mackay J. Randomized trial of short-course radiotherapy versus long-course chemoradiation comparing rates of local recurrence in patients with T3 rectal cancer: Trans-Tasman Radiation Oncology Group trial 01.04. J Clin Oncol. 2012 Nov 1;30(31):3827-33. Epub 2012 Sep 24. Erratum in: J Clin Oncol. 2013 Jan 20;31(3):399. link to original article PubMed NCT00351598
NSABP R-04: O'Connell MJ, Colangelo LH, Beart RW, Petrelli NJ, Allegra CJ, Sharif S, Pitot HC, Shields AF, Landry JC, Ryan DP, Parda DS, Mohiuddin M, Arora A, Evans LS, Bahary N, Soori GS, Eakle J, Robertson JM, Moore DF Jr, Mullane MR, Marchello BT, Ward PJ, Wozniak TF, Roh MS, Yothers G, Wolmark N. Capecitabine and oxaliplatin in the preoperative multimodality treatment of rectal cancer: surgical end points from National Surgical Adjuvant Breast and Bowel Project trial R-04. J Clin Oncol. 2014 Jun 20;32(18):1927-34. Epub 2014 May 5. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00058474
1. Update: Allegra CJ, Yothers G, O'Connell MJ, Beart RW, Wozniak TF, Pitot HC, Shields AF, Landry JC, Ryan DP, Arora A, Evans LS, Bahary N, Soori G, Eakle JF, Robertson JM, Moore DF Jr, Mullane MR, Marchello BT, Ward PJ, Sharif S, Roh MS, Wolmark N. Neoadjuvant 5-FU or capecitabine plus radiation with or without oxaliplatin in rectal cancer patients: a phase III randomized clinical trial. J Natl Cancer Inst. 2015 Sep 14;107(11). Erratum in: J Natl Cancer Inst. 2016 Apr;108(4). link to original article link to PMC article PubMed
PROSPECT_rectal: Schrag D, Shi Q, Weiser MR, Gollub MJ, Saltz LB, Musher BL, Goldberg J, Al Baghdadi T, Goodman KA, McWilliams RR, Farma JM, George TJ, Kennecke HF, Shergill A, Montemurro M, Nelson GD, Colgrove B, Gordon V, Venook AP, O'Reilly EM, Meyerhardt JA, Dueck AC, Basch E, Chang GJ, Mamon HJ. Preoperative Treatment of Locally Advanced Rectal Cancer. N Engl J Med. 2023 Jul 27;389(4):322-334. Epub 2023 Jun 4. link to original article PubMed NCT01515787
1. PRO analysis: Basch E, Dueck AC, Mitchell SA, Mamon H, Weiser M, Saltz L, Gollub M, Rogak L, Ginos B, Mazza GL, Colgrove B, Chang G, Minasian L, Denicoff A, Thanarajasingam G, Musher B, George T, Venook A, Farma J, O'Reilly E, Meyerhardt JA, Shi Q, Schrag D. Patient-Reported Outcomes During and After Treatment for Locally Advanced Rectal Cancer in the PROSPECT Trial (Alliance N1048). J Clin Oncol. 2023 Jul 20;41(21):3724-3734. Epub 2023 Jun 4. link to original article link to PMC article PubMed

FOLFIRINOX

FOLFIRINOX: FOLinic acid (Leucovorin), Fluorouracil, IRINotecan, OXaliplatin

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Conroy et al. 2021 (UNICANCER-PRODIGE 23)	2012-2017	Phase 3 (E-esc)	No neoadjuvant chemotherapy	Seems to have superior DFS36 (primary endpoint) DFS36: 76% vs 69% (sHR 0.69, 95% CI 0.49-0.97)

Chemotherapy

Leucovorin (Folinic acid) 400 mg/m² IV once on day 1
Fluorouracil (5-FU) 2400 mg/m² IV continuous infusion (duration not specified)
Irinotecan (Camptosar) 180 mg/m² IV once on day 1
Oxaliplatin (Eloxatin) 85 mg/m² IV once on day 1

14-day cycle for 6 cycles

Subsequent treatment

Neoadjuvant Capecitabine & RT

References

UNICANCER-PRODIGE 23: Conroy T, Bosset JF, Etienne PL, Rio E, François É, Mesgouez-Nebout N, Vendrely V, Artignan X, Bouché O, Gargot D, Boige V, Bonichon-Lamichhane N, Louvet C, Morand C, de la Fouchardière C, Lamfichekh N, Juzyna B, Jouffroy-Zeller C, Rullier E, Marchal F, Gourgou S, Castan F, Borg C; Unicancer Gastrointestinal Group and Partenariat de Recherche en Oncologie Digestive (PRODIGE) Group. Neoadjuvant chemotherapy with FOLFIRINOX and preoperative chemoradiotherapy for patients with locally advanced rectal cancer (UNICANCER-PRODIGE 23): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2021 May;22(5):702-715. Epub 2021 Apr 13. link to original article contains dosing details in abstract PubMed NCT01804790

mFOLFOX6

mFOLFOX6: FOLinic acid (Leucovorin), Fluorouracil, OXaliplatin

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Schrag et al. 2023 (PROSPECT_rectal)	2012-06 to 2018-12	Phase 3 (E-switch-ooc)	1a. Capecitabine & RT 1b. 5-FU & RT	Non-inferior DFS (primary endpoint) DFS60: 80.8% vs 78.6% (HR 0.92, 90.2% CI 0.74-1.14)

Note: this trial should not be confused with the one by the same name in prostate cancer.

Chemotherapy

Fluorouracil (5-FU) 400 mg/m² IV bolus on day 1, then 2400 mg/m² IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m²)
Leucovorin (Folinic acid) 200 mg/m² IV once on day 1
Oxaliplatin (Eloxatin) 85 mg/m² IV once on day 1

14-day cycle for 6 cycles

Subsequent treatment

Surgery, then optional adjuvant mFOLFOX6 x 6

References

PROSPECT_rectal: Schrag D, Shi Q, Weiser MR, Gollub MJ, Saltz LB, Musher BL, Goldberg J, Al Baghdadi T, Goodman KA, McWilliams RR, Farma JM, George TJ, Kennecke HF, Shergill A, Montemurro M, Nelson GD, Colgrove B, Gordon V, Venook AP, O'Reilly EM, Meyerhardt JA, Dueck AC, Basch E, Chang GJ, Mamon HJ. Preoperative Treatment of Locally Advanced Rectal Cancer. N Engl J Med. 2023 Jul 27;389(4):322-334. Epub 2023 Jun 4. link to original article PubMed NCT01515787
1. PRO analysis: Basch E, Dueck AC, Mitchell SA, Mamon H, Weiser M, Saltz L, Gollub M, Rogak L, Ginos B, Mazza GL, Colgrove B, Chang G, Minasian L, Denicoff A, Thanarajasingam G, Musher B, George T, Venook A, Farma J, O'Reilly E, Meyerhardt JA, Shi Q, Schrag D. Patient-Reported Outcomes During and After Treatment for Locally Advanced Rectal Cancer in the PROSPECT Trial (Alliance N1048). J Clin Oncol. 2023 Jul 20;41(21):3724-3734. Epub 2023 Jun 4. link to original article link to PMC article PubMed

FULV & RT

FULV & RT: FluoroUracil, LeucoVorin, Radiation Therapy

Regimen variant #1, 800/200 ("Nordic schedule")

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Braendengen et al. 2008 (LARCS)	1996-2003	Phase 3 (E-esc)	Radiotherapy	Might have superior OS60 (primary endpoint) OS60: 66% vs 53%

Note: reported efficacy is based on the 2018 update.

Chemotherapy

Fluorouracil (5-FU) 400 mg/m² IV once per day on days 1, 2, 15, 16, 29, 30 given first, prior to RT
Leucovorin (Folinic acid) 100 mg IV once per day on days 1 & 2, given second

Radiotherapy

Concurrent radiation therapy 200 cGy per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33 (25 fractions, total of 5000 cGy)

5-week course

Subsequent treatment

Surgery, then adjuvant FULV x 8

Regimen variant #2, 1625/100

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Roh et al. 2009 (NSABP R-03)	1993-1999	Phase 3 (E-esc)	Adjuvant 5-FU & RT	Might have superior OS (co-primary endpoint) OS60: 74.5% vs 65.6% (HR 0.69, 95% CI 0.47-1.03)

Preceding treatment

Neoadjuvant FULV x 1

Chemotherapy

Fluorouracil (5-FU) 325 mg/m² IV once per day on days 1 to 5, 29 to 33
Leucovorin (Folinic acid) 20 mg/m² IV once per day on days 1 to 5, 29 to 33

Radiotherapy

Concurrent radiation therapy, 5040 cGy

5-week course

Subsequent treatment

Surgery, then adjuvant FULV x 4

Regimen variant #3, 1750/100

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Sainato et al. 2014 (I-CNR-RT)	1992-2001	Non-randomized part of phase 3 RCT
Bosset et al. 2006 (EORTC 22921)	1993-2003	Phase 3 (E-esc)	Radiotherapy	Did not meet primary endpoint of OS¹
Gérard et al. 2006 (FFCD 9203)	1993-2003	Phase 3 (E-esc)	Radiotherapy	Did not meet primary endpoint of OS¹

¹These trials were negative for the primary endpoint of overall survival, but had much improved local control for the experimental arm.

Chemotherapy

Fluorouracil (5-FU) 350 mg/m² IV once per day on days 1 to 5, 29 to 33
Leucovorin (Folinic acid) 20 mg/m² IV once per day on days 1 to 5, 29 to 33

Radiotherapy

Concurrent radiation therapy, 4500 cGy

5-week course

Subsequent treatment

FFCD 9203 & EORTC 22921: Surgery, then adjuvant FULV x 2
I-CNR-RT: Surgery, then adjuvant FULV versus no further treatment

Regimen variant #4, 2800/400

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Deng et al. 2016 (FOWARC)	2010-2015	Phase 3 (C)	1. mFOLFOX6	Did not meet primary endpoint of DFS36¹
Deng et al. 2016 (FOWARC)	2010-2015	Phase 3 (C)	2. mFOLFOX6 & RT	Did not meet primary endpoint of DFS36¹

¹Reported efficacy is based on the 2019 update.
Note: this regimen is stated to be based on the de Gramont regimen in the manuscript, although the details are different than those in de Gramont et al. 2000.

Chemotherapy

Fluorouracil (5-FU) 400 mg/m² IV bolus once on day 1, then 1200 mg/m²/day IV continuous infusion over 48 hours (total dose per cycle: 2800 mg/m²)
Leucovorin (Folinic acid) 400 mg/m² IV once on day 1

14-day cycle for 5 cycles

Radiotherapy

Concurrent radiation therapy given during cycles 2 to 4: 1.8 to 200 cGy once per day Monday through Friday for a total of 23 to 28 fractions over 5 to 6 weeks and a total dose of 4600 to 5040 cGy

6-week course

Subsequent treatment

Surgery, then adjuvant FULV x 7

References

FFCD 9203: Gérard JP, Conroy T, Bonnetain F, Bouché O, Chapet O, Closon-Dejardin MT, Untereiner M, Leduc B, Francois E, Maurel J, Seitz JF, Buecher B, Mackiewicz R, Ducreux M, Bedenne L. Preoperative radiotherapy with or without concurrent fluorouracil and leucovorin in T3-4 rectal cancers: results of FFCD 9203. J Clin Oncol. 2006 Oct 1;24(28):4620-5. link to original article contains dosing details in manuscript PubMed NCT00296608
EORTC 22921: Bosset JF, Collette L, Calais G, Mineur L, Maingon P, Radosevic-Jelic L, Daban A, Bardet E, Beny A, Ollier JC; EORTC Radiotherapy Group. Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med. 2006 Sep 14;355(11):1114-23. Erratum in: N Engl J Med. 2007 Aug 16;357(7):728. link to original article contains dosing details in manuscript PubMed NCT00002523
1. Update: Bosset JF, Calais G, Mineur L, Maingon P, Stojanovic-Rundic S, Bensadoun RJ, Bardet E, Beny A, Ollier JC, Bolla M, Marchal D, Van Laethem JL, Klein V, Giralt J, Clavère P, Glanzmann C, Cellier P, Collette L; EORTC Radiation Oncology Group. Fluorouracil-based adjuvant chemotherapy after preoperative chemoradiotherapy in rectal cancer: long-term results of the EORTC 22921 randomised study. Lancet Oncol. 2014 Feb;15(2):184-90. Epub 2014 Jan 17. link to original article PubMed
LARCS: Braendengen M, Tveit KM, Berglund A, Birkemeyer E, Frykholm G, Påhlman L, Wiig JN, Byström P, Bujko K, Glimelius B. Randomized phase III study comparing preoperative radiotherapy with chemoradiotherapy in nonresectable rectal cancer. J Clin Oncol. 2008 Aug 1;26(22):3687-94. link to original article PubMed
1. Update: Brændengen M, Glimelius B. Preoperative radiotherapy or chemoradiotherapy in rectal cancer - Is survival improved? An update of the "Nordic" LARC study in non-resectable cancers. Radiother Oncol. 2018 Jun;127(3):392-395. Epub 2018 May 16. link to original article PubMed
NSABP R-03: Roh MS, Colangelo LH, O'Connell MJ, Yothers G, Deutsch M, Allegra CJ, Kahlenberg MS, Baez-Diaz L, Ursiny CS, Petrelli NJ, Wolmark N. Preoperative multimodality therapy improves disease-free survival in patients with carcinoma of the rectum: NSABP R-03. J Clin Oncol. 2009 Nov 1;27(31):5124-30. Epub 2009 Sep 21. link to original article link to PMC article contains dosing details in manuscript PubMed
I-CNR-RT: Sainato A, Cernusco Luna Nunzia V, Valentini V, De Paoli A, Maurizi ER, Lupattelli M, Aristei C, Vidali C, Conti M, Galardi A, Ponticelli P, Friso ML, Iannone T, Osti FM, Manfredi B, Coppola M, Orlandini C, Cionini L. No benefit of adjuvant Fluorouracil Leucovorin chemotherapy after neoadjuvant chemoradiotherapy in locally advanced cancer of the rectum (LARC): Long term results of a randomized trial (I-CNR-RT). Radiother Oncol. 2014 Nov;113(2):223-9. Epub 2014 Nov 14. link to original article contains dosing details in abstract PubMed
FOWARC: Deng Y, Chi P, Lan P, Wang L, Chen W, Cui L, Chen D, Cao J, Wei H, Peng X, Huang Z, Cai G, Zhao R, Huang Z, Xu L, Zhou H, Wei Y, Zhang H, Zheng J, Huang Y, Zhou Z, Cai Y, Kang L, Huang M, Peng J, Ren D, Wang J. Modified FOLFOX6 with or without radiation versus fluorouracil and leucovorin with radiation in neoadjuvant treatment of locally advanced rectal cancer: initial results of the Chinese FOWARC multicenter, open-label, randomized three-arm phase III trial. J Clin Oncol. 2016 Sep 20;34(27):3300-7. Epub 2016 Aug 1. link to original article contains dosing details in manuscript PubMed NCT01211210
1. Update: Deng Y, Chi P, Lan P, Wang L, Chen W, Cui L, Chen D, Cao J, Wei H, Peng X, Huang Z, Cai G, Zhao R, Huang Z, Xu L, Zhou H, Wei Y, Zhang H, Zheng J, Huang Y, Zhou Z, Cai Y, Kang L, Huang M, Wu X, Peng J, Ren D, Wang J. Neoadjuvant Modified FOLFOX6 With or Without Radiation Versus Fluorouracil Plus Radiation for Locally Advanced Rectal Cancer: Final Results of the Chinese FOWARC Trial. J Clin Oncol. 2019 Dec 1;37(34):3223-3233. Epub 2019 Sep 26. link to original article link to PMC article PubMed

FUOX & RT

FUOX & RT: FluoroUracil, OXaliplatin, Radiation Therapy

Regimen variant #1, 225/50

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
O'Connell et al. 2014 (NSABP R-04)	2004-2010	Phase 3 (E-esc)	1. 5-FU & RT 2. Capecitabine & RT	Did not meet primary endpoint of LRC	Inferior toxicity
O'Connell et al. 2014 (NSABP R-04)	2004-2010	Phase 3 (E-esc)	3. CapeOx & RT	Did not meet primary endpoint of LRC	Similar toxicity

Note: This was an experimental arm that did not meet its primary endpoint; included here because other variants of this regimen have demonstrated comparative superiority.

Chemotherapy

Fluorouracil (5-FU) 225 mg/m²/day IV continuous infusion over 120 hours, started on days 1, 8, 15, 22, 29 (total dose: 5625 mg/m²)
Oxaliplatin (Eloxatin) 50 mg/m² IV once per day on days 1, 8, 15, 22, 29

Radiotherapy

Concurrent radiation therapy, 5040 cGy total

5.5-week course

Subsequent treatment

Surgery

Regimen variant #2, 225/60

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Aschele et al. 2011 (STAR-01)	2003-2008	Phase 3 (E-esc)	Fluorouracil & RT	Did not meet primary endpoint of OS¹	More toxic

¹Reported efficacy is based on the 2016 update.
Note: This was an experimental arm that did not meet its primary endpoint; included here because other variants of this regimen have demonstrated comparative superiority.

Chemotherapy

Fluorouracil (5-FU) 225 mg/m²/day IV continuous infusion over approximately 6 weeks, started on day 1
Oxaliplatin (Eloxatin) 60 mg/m² IV once per day on days 1, 8, 15, 22, 29, 36

Radiotherapy

Concurrent radiation therapy, 5040 cGy total

6-week course

Subsequent treatment

Surgery, preferably TME, then adjuvant fluourouracil-based therapy

Regimen variant #3, 250/50

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Rödel et al. 2012 (CAO/ARO/AIO-04)	2006-2010	Phase 3 (E-esc)	Fluorouracil & RT	Seems to have superior pCR rate (secondary endpoint)

Chemotherapy

Fluorouracil (5-FU) 250 mg/m²/day IV continuous infusion over 14 days, started on days 1 & 22 (total dose: 7000 mg/m²)
Oxaliplatin (Eloxatin) 50 mg/m² IV once per day on days 1, 8, 22, 29

Radiotherapy

Concurrent radiation therapy, 5040 cGy total

One course

Subsequent treatment

Surgery, then adjuvant FOLFOX

References

STAR-01: Aschele C, Cionini L, Lonardi S, Pinto C, Cordio S, Rosati G, Artale S, Tagliagambe A, Ambrosini G, Rosetti P, Bonetti A, Negru ME, Tronconi MC, Luppi G, Silvano G, Corsi DC, Bochicchio AM, Chiaulon G, Gallo M, Boni L. Primary tumor response to preoperative chemoradiation with or without oxaliplatin in locally advanced rectal cancer: pathologic results of the STAR-01 randomized phase III trial. J Clin Oncol. 2011 Jul 10;29(20):2773-80. Epub 2011 May 23. link to original article contains dosing details in manuscript PubMed
1. Update: Abstract: Carlo Aschele, Sara Lonardi, Luca Cionini, Carmine Pinto, Stefano Sergio Cordio, Gerardo Rosati, Andrea Sartore Bianchi, Angiolo Tagliagambe, Michela Frisinghelli, Vittorina Zagonel, Paola Rosetti, Maria Emanuela Negru, Andrea Bonetti, Maria Chiara Tronconi, Gabriele Luppi, Anna Rita Marsella, Domenico C. Corsi, Anna Maria Bochicchio, Nicoletta Pella, and Luca Boni. Final results of STAR-01: A randomized phase III trial comparing preoperative chemoradiation with or without oxaliplatin in locally advanced rectal cancer. Journal of Clinical Oncology 2016 34:15_suppl, 3521-3521 link to abstract
CAO/ARO/AIO-04: Rödel C, Liersch T, Becker H, Fietkau R, Hohenberger W, Hothorn T, Graeven U, Arnold D, Lang-Welzenbach M, Raab HR, Sülberg H, Wittekind C, Potapov S, Staib L, Hess C, Weigang-Köhler K, Grabenbauer GG, Hoffmanns H, Lindemann F, Schlenska-Lange A, Folprecht G, Sauer R; German Rectal Cancer Study Group. Preoperative chemoradiotherapy and postoperative chemotherapy with fluorouracil and oxaliplatin versus fluorouracil alone in locally advanced rectal cancer: initial results of the German CAO/ARO/AIO-04 randomised phase 3 trial. Lancet Oncol. 2012 Jul;13(7):679-87. Epub 2012 May 23. link to original article contains dosing details in abstract PubMed NCT00349076
1. Update: Rödel C, Graeven U, Fietkau R, Hohenberger W, Hothorn T, Arnold D, Hofheinz RD, Ghadimi M, Wolff HA, Lang-Welzenbach M, Raab HR, Wittekind C, Ströbel P, Staib L, Wilhelm M, Grabenbauer GG, Hoffmanns H, Lindemann F, Schlenska-Lange A, Folprecht G, Sauer R, Liersch T; German Rectal Cancer Study Group. Oxaliplatin added to fluorouracil-based preoperative chemoradiotherapy and postoperative chemotherapy of locally advanced rectal cancer (the German CAO/ARO/AIO-04 study): final results of the multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2015 Aug;16(8):979-89. Epub 2015 Jul 15. link to original article PubMed
NSABP R-04: O'Connell MJ, Colangelo LH, Beart RW, Petrelli NJ, Allegra CJ, Sharif S, Pitot HC, Shields AF, Landry JC, Ryan DP, Parda DS, Mohiuddin M, Arora A, Evans LS, Bahary N, Soori GS, Eakle J, Robertson JM, Moore DF Jr, Mullane MR, Marchello BT, Ward PJ, Wozniak TF, Roh MS, Yothers G, Wolmark N. Capecitabine and oxaliplatin in the preoperative multimodality treatment of rectal cancer: surgical end points from National Surgical Adjuvant Breast and Bowel Project trial R-04. J Clin Oncol. 2014 Jun 20;32(18):1927-34. Epub 2014 May 5. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00058474
1. Update: Allegra CJ, Yothers G, O'Connell MJ, Beart RW, Wozniak TF, Pitot HC, Shields AF, Landry JC, Ryan DP, Arora A, Evans LS, Bahary N, Soori G, Eakle JF, Robertson JM, Moore DF Jr, Mullane MR, Marchello BT, Ward PJ, Sharif S, Roh MS, Wolmark N. Neoadjuvant 5-FU or capecitabine plus radiation with or without oxaliplatin in rectal cancer patients: a phase III randomized clinical trial. J Natl Cancer Inst. 2015 Sep 14;107(11). Erratum in: J Natl Cancer Inst. 2016 Apr;108(4). link to original article link to PMC article PubMed

mFOLFOX6 & RT

mFOLFOX6 & RT: modified FOLinic acid (Leucovorin), Fluorouracil, OXaliplatin and Radiation Therapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Deng et al. 2016 (FOWARC)	2010-2015	Phase 3 (E-esc)	1. FULV & RT	Did not meet primary endpoint of DFS36¹
Deng et al. 2016 (FOWARC)	2010-2015	Phase 3 (E-esc)	2. mFOLFOX6	Did not meet primary endpoint of DFS36¹

¹Reported efficacy is based on the 2019 update.

Chemotherapy

Leucovorin (Folinic acid) 400 mg/m² IV once on day 1
Fluorouracil (5-FU) 400 mg/m² IV bolus once on day 1, then 1200 mg/m²/day IV continuous infusion over 48 hours (total dose per cycle: 2800 mg/m²)
Oxaliplatin (Eloxatin) 85 mg/m² IV once on day 1

14-day cycle for 4 to 6 cycles

Radiotherapy

Concurrent radiation therapy given before or after surgery at physician discretion: 180 to 200 cGy once per day Monday through Friday for a total of 23 to 28 fractions, for a total dose of 4600 to 5040 cGy

5- to 6-week course

Subsequent treatment

Surgery, then adjuvant mFOLFOX6 x 6 to 8

References

FOWARC: Deng Y, Chi P, Lan P, Wang L, Chen W, Cui L, Chen D, Cao J, Wei H, Peng X, Huang Z, Cai G, Zhao R, Huang Z, Xu L, Zhou H, Wei Y, Zhang H, Zheng J, Huang Y, Zhou Z, Cai Y, Kang L, Huang M, Peng J, Ren D, Wang J. Modified FOLFOX6 with or without radiation versus fluorouracil and leucovorin with radiation in neoadjuvant treatment of locally advanced rectal cancer: initial results of the Chinese FOWARC multicenter, open-label, randomized three-arm phase III trial. J Clin Oncol. 2016 Sep 20;34(27):3300-7. Epub 2016 Aug 1. link to original article contains dosing details in manuscript PubMed NCT01211210
1. Update: Deng Y, Chi P, Lan P, Wang L, Chen W, Cui L, Chen D, Cao J, Wei H, Peng X, Huang Z, Cai G, Zhao R, Huang Z, Xu L, Zhou H, Wei Y, Zhang H, Zheng J, Huang Y, Zhou Z, Cai Y, Kang L, Huang M, Wu X, Peng J, Ren D, Wang J. Neoadjuvant Modified FOLFOX6 With or Without Radiation Versus Fluorouracil Plus Radiation for Locally Advanced Rectal Cancer: Final Results of the Chinese FOWARC Trial. J Clin Oncol. 2019 Dec 1;37(34):3223-3233. Epub 2019 Sep 26. link to original article link to PMC article PubMed

Radiation therapy

RT: Radiation Therapy

Regimen variant #1, 2500 cGy

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Cedermark et al. 1997 (Swedish Rectal Cancer Trial)	1987-1990	Phase 3 (E-esc)	Surgery alone	Superior OS
Kapiteijn et al. 2001	1996-1999	Phase 3 (E-esc)	Surgery alone	Superior local recurrence rate
Sebag-Montefiore et al. 2009 (MRC CR07; NCIC-CTG CO.16)	1998-2005	Phase 3 (C)	Selective postoperative 5-FU & RT	Seems to have superior DFS
Bujko et al. 2016 (Polish II)	2008-2014	Phase 3 (E-switch-ic)	FULV & RT	Might have superior R0 resection rate (primary endpoint)
Bahadoer et al. 2020 (RAPIDO)	2011-2016	Phase 3 (E-switch-ic)	See link	See link

Radiotherapy

Radiation therapy, 500 cGy once per day for a total of 5 fractions (total dose: 2500 cGy)

5-day course

Subsequent treatment

Swedish Rectal Cancer Trial, Kapiteijn et al. 2001, NCIC-CTG CO.16: Surgery
Polish II: Neoadjuvant FOLFOX4 x 3, then Surgery
RAPIDO: Neoadjuvant CapeOx x 6 or FOLFOX4 x 9, then Surgery

Regimen variant #2, 4000 cGy

Historic variant

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Oates et al. 1996	1981-1989	Phase 3 (E-esc)	Surgery alone	Seems to have superior DFS

Radiotherapy

Radiation therapy, 200 cGy x 20 fractions (total dose: 4000 cGy)

4-week course

Subsequent treatment

Surgery

Regimen variant #3, 5000 cGy

Historic variant

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Braendengen et al. 2008 (LARCS)	1996-2003	Phase 3 (C)	FULV/FULV & RT	Might have inferior OS60

Radiotherapy

Radiation therapy, 200 cGy x 25 fractions (total dose: 5000 cGy)

5-week course

Subsequent treatment

Surgery

References

Oates GD, Stenning SP, Hardcastle JD; Medical Research Council Rectal Cancer Working Party. Randomised trial of surgery alone versus radiotherapy followed by surgery for potentially operable locally advanced rectal cancer. Lancet. 1996 Dec 14;348(9042):1605-10. link to original article contains dosing details in abstract PubMed
Swedish Rectal Cancer Trial: Cedermark B, Dahlberg M, Glimelius B, Påhlman L, Rutqvist LE, Wilking N; Swedish Rectal Cancer Trial investigators. Improved survival with preoperative radiotherapy in resectable rectal cancer. N Engl J Med. 1997 Apr 3;336(14):980-7. Erratum in: N Engl J Med 1997 May 22;336(21):1539. link to original article PubMed
1. Update: Folkesson J, Birgisson H, Pahlman L, Cedermark B, Glimelius B, Gunnarsson U. Swedish Rectal Cancer Trial: long lasting benefits from radiotherapy on survival and local recurrence rate. J Clin Oncol. 2005 Aug 20;23(24):5644-50. link to original article PubMed
Kapiteijn E, Marijnen CA, Nagtegaal ID, Putter H, Steup WH, Wiggers T, Rutten HJ, Pahlman L, Glimelius B, van Krieken JH, Leer JW, van de Velde CJ; Dutch Colorectal Cancer Group. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med. 2001 Aug 30;345(9):638-46. link to original article PubMed
LARCS: Braendengen M, Tveit KM, Berglund A, Birkemeyer E, Frykholm G, Påhlman L, Wiig JN, Byström P, Bujko K, Glimelius B. Randomized phase III study comparing preoperative radiotherapy with chemoradiotherapy in nonresectable rectal cancer. J Clin Oncol. 2008 Aug 1;26(22):3687-94. link to original article PubMed
1. Update: Brændengen M, Glimelius B. Preoperative radiotherapy or chemoradiotherapy in rectal cancer - Is survival improved? An update of the "Nordic" LARC study in non-resectable cancers. Radiother Oncol. 2018 Jun;127(3):392-395. Epub 2018 May 16. link to original article PubMed
MRC CR07; NCIC-CTG CO.16: Sebag-Montefiore D, Stephens RJ, Steele R, Monson J, Grieve R, Khanna S, Quirke P, Couture J, de Metz C, Myint AS, Bessell E, Griffiths G, Thompson LC, Parmar M. Preoperative radiotherapy versus selective postoperative chemoradiotherapy in patients with rectal cancer (MRC CR07 and NCIC-CTG C016): a multicentre, randomised trial. Lancet. 2009 Mar 7;373(9666):811-20. link to original article link to PMC article contains dosing details in abstract PubMed NCT00003422
Polish II: Bujko K, Wyrwicz L, Rutkowski A, Malinowska M, Pietrzak L, Kryński J, Michalski W, Olędzki J, Kuśnierz J, Zając L, Bednarczyk M, Szczepkowski M, Tarnowski W, Kosakowska E, Zwoliński J, Winiarek M, Wiśniowska K, Partycki M, Bęczkowska K, Polkowski W, Styliński R, Wierzbicki R, Bury P, Jankiewicz M, Paprota K, Lewicka M, Ciseł B, Skórzewska M, Mielko J, Bębenek M, Maciejczyk A, Kapturkiewicz B, Dybko A, Hajac Ł, Wojnar A, Leśniak T, Zygulska J, Jantner D, Chudyba E, Zegarski W, Las-Jankowska M, Jankowski M, Kołodziejski L, Radkowski A, Żelazowska-Omiotek U, Czeremszyńska B, Kępka L, Kolb-Sielecki J, Toczko Z, Fedorowicz Z, Dziki A, Danek A, Nawrocki G, Sopyło R, Markiewicz W, Kędzierawski P, Wydmański J; Polish Colorectal Study Group. Long-course oxaliplatin-based preoperative chemoradiation versus 5 x 5 Gy and consolidation chemotherapy for cT4 or fixed cT3 rectal cancer: results of a randomized phase III study. Ann Oncol. 2016 May;27(5):834-42. Epub 2016 Feb 15. link to original article contains dosing details in abstract PubMed NCT00833131
1. Update: Ciseł B, Pietrzak L, Michalski W, Wyrwicz L, Rutkowski A, Kosakowska E, Cencelewicz A, Spałek M, Polkowski W, Jankiewicz M, Styliński R, Bębenek M, Kapturkiewicz B, Maciejczyk A, Sadowski J, Zygulska J, Zegarski W, Jankowski M, Las-Jankowska M, Toczko Z, Żelazowska-Omiotek U, Kępka L, Socha J, Wasilewska-Tesluk E, Markiewicz W, Kładny J, Majewski A, Kapuściński W, Suwiński R, Bujko K; Polish Colorectal Study Group. Long-course preoperative chemoradiation vs 5 x 5 Gy and consolidation chemotherapy for clinical T4 and fixed clinical T3 rectal cancer: long-term results of the randomized Polish II study. Ann Oncol. 2019 Aug 1;30(8):1298-1303. Epub 2019 Jun 13. link to original article PubMed
RAPIDO: Bahadoer RR, Dijkstra EA, van Etten B, Marijnen CAM, Putter H, Kranenbarg EM, Roodvoets AGH, Nagtegaal ID, Beets-Tan RGH, Blomqvist LK, Fokstuen T, Ten Tije AJ, Capdevila J, Hendriks MP, Edhemovic I, Cervantes A, Nilsson PJ, Glimelius B, van de Velde CJH, Hospers GAP; RAPIDO collaborative investigators. Short-course radiotherapy followed by chemotherapy before total mesorectal excision (TME) versus preoperative chemoradiotherapy, TME, and optional adjuvant chemotherapy in locally advanced rectal cancer (RAPIDO): a randomised, open-label, phase 3 trial. Lancet Oncol. 2021 Jan;22(1):29-42. Epub 2020 Dec 7. link to original article contains dosing details in manuscript PubMed NCT01558921

Adjuvant chemotherapy

Capecitabine monotherapy

Regimen variant #1, 2000 mg/m²/day x 6

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Schmoll et al. 2020 (PETACC 6)	2008-2011	Phase 3 (C)	CapeOx	Did not meet primary endpoint of DFS36

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Preceding treatment

Neoadjuvant capecitabine & RT, then surgery

Chemotherapy

Capecitabine (Xeloda) 1000 mg/m² PO twice per day on days 1 to 15

21-day cycle for 6 cycles

Regimen variant #2, 2500 mg/m²/day x 5

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Hofheinz et al. 2012 (Rektum-III)	2002-2007	Phase 3 (E-RT-switch-ic)	Fluorouracil	Non-inferior OS (primary endpoint) OS60: 76% vs 67%

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Preceding treatment

Neoadjuvant capecitabine & RT, then surgery

Chemotherapy

Capecitabine (Xeloda) 1250 mg/m² PO twice per day on days 1 to 14

21-day cycle for 5 cycles

Regimen variant #3, 2500 mg/m²/day x 8

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Breugom et al. 2014 (SCRIPT)	2000-2013	Phase 3 (E-esc)	Observation	Did not meet primary endpoint of OS

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Preceding treatment

Neoadjuvant 5-FU-based chemoradiotherapy or RT, then surgery

Chemotherapy

Capecitabine (Xeloda) 1250 mg/m² PO twice per day on days 1 to 14

21-day cycle for 8 cycles

References

Rektum-III: Hofheinz RD, Wenz F, Post S, Matzdorff A, Laechelt S, Hartmann JT, Müller L, Link H, Moehler M, Kettner E, Fritz E, Hieber U, Lindemann HW, Grunewald M, Kremers S, Constantin C, Hipp M, Hartung G, Gencer D, Kienle P, Burkholder I, Hochhaus A. Chemoradiotherapy with capecitabine versus fluorouracil for locally advanced rectal cancer: a randomised, multicentre, non-inferiority, phase 3 trial. Lancet Oncol. 2012 Jun;13(6):579-88. Epub 2012 Apr 12. link to original article contains dosing details in manuscript PubMed NCT01500993
SCRIPT: Breugom AJ, van Gijn W, Muller EW, Berglund Å, van den Broek CB, Fokstuen T, Gelderblom H, Kapiteijn E, Leer JW, Marijnen CA, Martijn H, Meershoek-Klein Kranenbarg E, Nagtegaal ID, Påhlman L, Punt CJ, Putter H, Roodvoets AG, Rutten HJ, Steup WH, Glimelius B, van de Velde CJ; Dutch Colorectal Cancer Group; Nordic Gastrointestinal Tumour Adjuvant Therapy Group. Adjuvant chemotherapy for rectal cancer patients treated with preoperative (chemo)radiotherapy and total mesorectal excision: a Dutch Colorectal Cancer Group (DCCG) randomized phase III trial. Ann Oncol. 2015 Apr;26(4):696-701. Epub 2014 Dec 5. link to original article contains dosing details in manuscript PubMed ISRCTN36266738
PETACC 6: Schmoll HJ, Stein A, Van Cutsem E, Price T, Hofheinz RD, Nordlinger B, Daisne JF, Janssens J, Brenner B, Reinel H, Hollerbach S, Caca K, Fauth F, Hannig CV, Zalcberg J, Tebbutt N, Mauer ME, Marreaud S, Lutz MP, Haustermans K. Pre- and Postoperative Capecitabine Without or With Oxaliplatin in Locally Advanced Rectal Cancer: PETACC 6 Trial by EORTC GITCG and ROG, AIO, AGITG, BGDO, and FFCD. J Clin Oncol. 2021 Jan 1;39(1):17-29. Epub 2020 Oct 1. link to original article contains dosing details in manuscript PubMed NCT00766155

Fluorouracil monotherapy

Regimen variant #1

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Hofheinz et al. 2012 (Rektum-III)	2002-2007	Phase 3 (C)	Capecitabine	Non-inferior OS

Preceding treatment

Neoadjuvant 5-FU & RT, then surgery

Chemotherapy

Fluorouracil (5-FU) 500 mg/m² IV bolus once per day on days 1 to 5

28-day cycle for 4 cycles

Regimen variant #2

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Rödel et al. 2012 (CAO/ARO/AIO-04)	2006-2010	Phase 3 (C)	FOLFOX	Seems to have inferior DFS¹

¹Reported efficacy is based on the 2015 update.

Preceding treatment

Neoadjuvant 5-FU & RT, then surgery

Chemotherapy

Fluorouracil (5-FU) 500 mg/m² IV bolus once per day on days 1 to 5, 29

4 cycles (length not specified)

References

Rektum-III: Hofheinz RD, Wenz F, Post S, Matzdorff A, Laechelt S, Hartmann JT, Müller L, Link H, Moehler M, Kettner E, Fritz E, Hieber U, Lindemann HW, Grunewald M, Kremers S, Constantin C, Hipp M, Hartung G, Gencer D, Kienle P, Burkholder I, Hochhaus A. Chemoradiotherapy with capecitabine versus fluorouracil for locally advanced rectal cancer: a randomised, multicentre, non-inferiority, phase 3 trial. Lancet Oncol. 2012 Jun;13(6):579-88. Epub 2012 Apr 12. link to original article contains dosing details in manuscript PubMed NCT01500993
CAO/ARO/AIO-04: Rödel C, Liersch T, Becker H, Fietkau R, Hohenberger W, Hothorn T, Graeven U, Arnold D, Lang-Welzenbach M, Raab HR, Sülberg H, Wittekind C, Potapov S, Staib L, Hess C, Weigang-Köhler K, Grabenbauer GG, Hoffmanns H, Lindemann F, Schlenska-Lange A, Folprecht G, Sauer R; German Rectal Cancer Study Group. Preoperative chemoradiotherapy and postoperative chemotherapy with fluorouracil and oxaliplatin versus fluorouracil alone in locally advanced rectal cancer: initial results of the German CAO/ARO/AIO-04 randomised phase 3 trial. Lancet Oncol. 2012 Jul;13(7):679-87. Epub 2012 May 23. link to original article contains dosing details in abstract PubMed NCT00349076
1. Update: Rödel C, Graeven U, Fietkau R, Hohenberger W, Hothorn T, Arnold D, Hofheinz RD, Ghadimi M, Wolff HA, Lang-Welzenbach M, Raab HR, Wittekind C, Ströbel P, Staib L, Wilhelm M, Grabenbauer GG, Hoffmanns H, Lindemann F, Schlenska-Lange A, Folprecht G, Sauer R, Liersch T; German Rectal Cancer Study Group. Oxaliplatin added to fluorouracil-based preoperative chemoradiotherapy and postoperative chemotherapy of locally advanced rectal cancer (the German CAO/ARO/AIO-04 study): final results of the multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2015 Aug;16(8):979-89. Epub 2015 Jul 15. link to original article PubMed

FULV

FULV: 5-FU & LeucoVorin

Regimen variant #1, 500/500

Historic variant

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Wolmark et al. 2000 (NSABP R-02)	1987-1992	Phase 3 (C)	FULV & RT	Did not meet primary endpoint of OS60

Note: male patients were also randomized to MOF or MOF & RT.

Preceding treatment

Surgery

Chemotherapy

Fluorouracil (5-FU) 500 mg/m² IV once per day on days 1, 8, 15, 22, 29, 36, given 1 hour after leucovorin
Leucovorin (Folinic acid) 500 mg/m² IV once per day on days 1, 8, 15, 22, 29, 36, given first

8-week cycle for 6 cycles

Regimen variant #2, 1000/120 ("Nordic regimen")

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Breugom et al. 2014 (PROCTOR)	2000-2013	Phase 3 (E-esc)	Observation	Did not meet primary endpoint of OS

Note: This was an experimental arm that did not meet its primary endpoint; included here because other variants of this regimen have been used as a standard comparator. This is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Preceding treatment

Neoadjuvant 5-FU-based chemoradiotherapy or RT, then surgery

Chemotherapy

Fluorouracil (5-FU) 500 mg/m² IV once per day on days 1 & 2, given first (total dose per cycle: 1000 mg/m²)
Leucovorin (Folinic acid) 60 mg/m² IV once per day on days 1 & 2, given second (total dose per cycle: 120 mg/m²)

14-day cycle for 12 cycles

Regimen variant #3, 1900/100

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Hong et al. 2014 (ADORE)	2008-2012	Randomized Phase 2 (C)	FOLFOX	Seems to have inferior DFS36

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Preceding treatment

Neoadjuvant fluoropyrimidine-based chemoradiation, then TME

Chemotherapy

Fluorouracil (5-FU) 380 mg/m² IV once per day on days 1 to 5 (total dose per cycle: 1900 mg/m²)
Leucovorin (Folinic acid) 20 mg/m² IV once per day on days 1 to 5 (total dose per cycle: 100 mg/m²)

28-day cycle for 4 cycles

Regimen variant #4, 2125/100 ("Mayo regimen")

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Delbaldo et al. 2015 (R98)	1999-2005	Phase 3 (C)	FOLFIRI	Did not meet primary endpoint of DFS
Breugom et al. 2014 (PROCTOR)	2000-2013	Phase 3 (E-esc)	Observation	Did not meet primary endpoint of OS

Note: This was an experimental arm that did not meet its primary endpoint; included here because it was eventually used to establish this regimen as a standard comparator. This is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Preceding treatment

PROCTOR: Neoadjuvant 5-FU-based chemoradiotherapy or RT, then surgery

Chemotherapy

Fluorouracil (5-FU) 425 mg/m² IV once per day on days 1 to 5 (total dose per cycle: 2125 mg/m²)
Leucovorin (Folinic acid) 20 mg/m² IV once per day on days 1 to 5 (total dose per cycle: 100 mg/m²)

4- to 5-week cycle for 6 cycles

References

NSABP R-02: Wolmark N, Wieand HS, Hyams DM, Colangelo L, Dimitrov NV, Romond EH, Wexler M, Prager D, Cruz AB Jr, Gordon PH, Petrelli NJ, Deutsch M, Mamounas E, Wickerham DL, Fisher ER, Rockette H, Fisher B. Randomized trial of postoperative adjuvant chemotherapy with or without radiotherapy for carcinoma of the rectum: National Surgical Adjuvant Breast and Bowel Project Protocol R-02. J Natl Cancer Inst. 2000 Mar 1;92(5):388-96. link to original article contains dosing details in manuscript PubMed
ADORE: Hong YS, Nam BH, Kim KP, Kim JE, Park SJ, Park YS, Park JO, Kim SY, Kim TY, Kim JH, Ahn JB, Lim SB, Yu CS, Kim JC, Yun SH, Kim JH, Park JH, Park HC, Jung KH, Kim TW. Oxaliplatin, fluorouracil, and leucovorin versus fluorouracil and leucovorin as adjuvant chemotherapy for locally advanced rectal cancer after preoperative chemoradiotherapy (ADORE): an open-label, multicentre, phase 2, randomised controlled trial. Lancet Oncol. 2014 Oct;15(11):1245-53. Epub 2014 Sep 4. link to original article contains dosing details in abstract PubMed NCT00807911
1. Update: Hong YS, Kim SY, Lee JS, Nam BH, Kim KP, Kim JE, Park YS, Park JO, Baek JY, Kim TY, Lee KW, Ahn JB, Lim SB, Yu CS, Kim JC, Yun SH, Kim JH, Park JH, Park HC, Jung KH, Kim TW. Oxaliplatin-Based Adjuvant Chemotherapy for Rectal Cancer After Preoperative Chemoradiotherapy (ADORE): Long-Term Results of a Randomized Controlled Trial. J Clin Oncol. 2019 Nov 20;37(33):3111-3123. Epub 2019 Oct 8. link to original article PubMed
PROCTOR: Breugom AJ, van Gijn W, Muller EW, Berglund Å, van den Broek CB, Fokstuen T, Gelderblom H, Kapiteijn E, Leer JW, Marijnen CA, Martijn H, Meershoek-Klein Kranenbarg E, Nagtegaal ID, Påhlman L, Punt CJ, Putter H, Roodvoets AG, Rutten HJ, Steup WH, Glimelius B, van de Velde CJ; Dutch Colorectal Cancer Group; Nordic Gastrointestinal Tumour Adjuvant Therapy Group. Adjuvant chemotherapy for rectal cancer patients treated with preoperative (chemo)radiotherapy and total mesorectal excision: a Dutch Colorectal Cancer Group (DCCG) randomized phase III trial. Ann Oncol. 2015 Apr;26(4):696-701. Epub 2014 Dec 5. link to original article contains dosing details in manuscript PubMed ISRCTN36266738
R98: Delbaldo C, Ychou M, Zawadi A, Douillard JY, André T, Guerin-Meyer V, Rougier P, Dupuis O, Faroux R, Jouhaud A, Quinaux E, Buyse M, Piedbois P; AERO; GERCOR; FNCLCC; FFCD. Postoperative irinotecan in resected stage II-III rectal cancer: final analysis of the French R98 Intergroup trial. Ann Oncol. 2015 Jun;26(6):1208-15. Epub 2015 Mar 3. link to original article PubMed

mFOLFOX6

mFOLFOX6: FOLinic acid (Leucovorin), Fluorouracil, OXaliplatin

Regimen variant #1, with 5-FU bolus, 8 cycles

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Hong et al. 2014 (ADORE)	2008-2012	Randomized Phase 2 (E-esc)	FULV	Seems to have superior DFS36 (primary endpoint) DFS36: 71.6% vs 62.9% (HR 0.66, 95% CI 0.43-0.994)

Preceding treatment

Neoadjuvant fluoropyrimidine-based chemoradiation, then TME

Chemotherapy

Fluorouracil (5-FU) 400 mg/m² IV bolus on day 1, then 2400 mg/m² IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m²)
Leucovorin (Folinic acid) 200 mg/m² IV once on day 1
Oxaliplatin (Eloxatin) 85 mg/m² IV once on day 1

14-day cycle for 8 cycles

Regimen variant #2, no 5-FU bolus, 8 cycles

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Rödel et al. 2012 (CAO/ARO/AIO-04)	2006-2010	Phase 3 (E-esc)	Fluorouracil	Seems to have superior DFS¹ (primary endpoint) DFS36: 75.95% vs 71.2% (HR 0.79, 95% CI 0.64-0.98)

¹Reported efficacy is based on the 2015 update.

Preceding treatment

Neoadjuvant FUOX & RT, then surgery

Chemotherapy

Fluorouracil (5-FU) 2400 mg/m² IV continuous infusion over 46 hours, started on day 1, given third (total dose per cycle: 2400 mg/m²)
Leucovorin (Folinic acid) 400 mg/m² IV over 2 hours once on day 1, given second
Oxaliplatin (Eloxatin) 100 mg/m² IV over 2 hours once on day 1, given first

14-day cycle for 8 cycles

Regimen variant #3, 12 cycles

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Chakravarthy et al. 2019 (ECOG E5204)	2006-2009	Phase 3 (C)	mFOLFOX6-B	Did not meet primary endpoint of OS OS60: 88.3% vs 83.7%

Preceding treatment

Neoadjuvant fluoropyrimidine-based chemoradiation, then TME

Chemotherapy

Fluorouracil (5-FU) 400 mg/m² IV bolus on day 1, then 2400 mg/m² IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m²)
Leucovorin (Folinic acid) 400 mg/m² IV over 2 hours once on day 1
Oxaliplatin (Eloxatin) 85 mg/m² IV over 2 hours once on day 1

14-day cycle for 12 cycles

References

ADORE: Hong YS, Nam BH, Kim KP, Kim JE, Park SJ, Park YS, Park JO, Kim SY, Kim TY, Kim JH, Ahn JB, Lim SB, Yu CS, Kim JC, Yun SH, Kim JH, Park JH, Park HC, Jung KH, Kim TW. Oxaliplatin, fluorouracil, and leucovorin versus fluorouracil and leucovorin as adjuvant chemotherapy for locally advanced rectal cancer after preoperative chemoradiotherapy (ADORE): an open-label, multicentre, phase 2, randomised controlled trial. Lancet Oncol. 2014 Oct;15(11):1245-53. Epub 2014 Sep 4. link to original article contains dosing details in abstract PubMed NCT00807911
1. Update: Hong YS, Kim SY, Lee JS, Nam BH, Kim KP, Kim JE, Park YS, Park JO, Baek JY, Kim TY, Lee KW, Ahn JB, Lim SB, Yu CS, Kim JC, Yun SH, Kim JH, Park JH, Park HC, Jung KH, Kim TW. Oxaliplatin-Based Adjuvant Chemotherapy for Rectal Cancer After Preoperative Chemoradiotherapy (ADORE): Long-Term Results of a Randomized Controlled Trial. J Clin Oncol. 2019 Nov 20;37(33):3111-3123. Epub 2019 Oct 8. link to original article PubMed
CAO/ARO/AIO-04: Rödel C, Liersch T, Becker H, Fietkau R, Hohenberger W, Hothorn T, Graeven U, Arnold D, Lang-Welzenbach M, Raab HR, Sülberg H, Wittekind C, Potapov S, Staib L, Hess C, Weigang-Köhler K, Grabenbauer GG, Hoffmanns H, Lindemann F, Schlenska-Lange A, Folprecht G, Sauer R; German Rectal Cancer Study Group. Preoperative chemoradiotherapy and postoperative chemotherapy with fluorouracil and oxaliplatin versus fluorouracil alone in locally advanced rectal cancer: initial results of the German CAO/ARO/AIO-04 randomised phase 3 trial. Lancet Oncol. 2012 Jul;13(7):679-87. Epub 2012 May 23. link to original article contains dosing details in manuscript PubMed NCT00349076
1. Update: Rödel C, Graeven U, Fietkau R, Hohenberger W, Hothorn T, Arnold D, Hofheinz RD, Ghadimi M, Wolff HA, Lang-Welzenbach M, Raab HR, Wittekind C, Ströbel P, Staib L, Wilhelm M, Grabenbauer GG, Hoffmanns H, Lindemann F, Schlenska-Lange A, Folprecht G, Sauer R, Liersch T; German Rectal Cancer Study Group. Oxaliplatin added to fluorouracil-based preoperative chemoradiotherapy and postoperative chemotherapy of locally advanced rectal cancer (the German CAO/ARO/AIO-04 study): final results of the multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2015 Aug;16(8):979-89. Epub 2015 Jul 15. link to original article PubMed
ECOG E5204: Chakravarthy AB, Zhao F, Meropol NJ, Flynn PJ, Wagner LI, Sloan J, Diasio RB, Mitchell EP, Catalano P, Giantonio BJ, Catalano RB, Haller DG, Awan RA, Mulcahy MF, O'Brien TE, Santala R, Cripps C, Weis JR, Atkins JN, Leichman CG, Petrelli NJ, Sinicrope FA, Brierley JD, Tepper JE, O'Dwyer PJ, Sigurdson ER, Hamilton SR, Cella D, Benson AB 3rd. Intergroup Randomized Phase III Study of Postoperative Oxaliplatin, 5-Fluorouracil, and Leucovorin Versus Oxaliplatin, 5-Fluorouracil, Leucovorin, and Bevacizumab for Patients with Stage II or III Rectal Cancer Receiving Preoperative Chemoradiation: A Trial of the ECOG-ACRIN Research Group (E5204). Oncologist. 2020 May;25(5):e798-e807. Epub 2019 Dec 18. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00303628

S-1 monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Oki et al. 2016 (ACTS-RC)	2006-2009	Phase 3 (E-switch-ic)	UFT	Seems to have superior RFS (primary endpoint) RFS60: 66.4% vs 61.7% (HR 0.77, 95% CI 0.63-0.96)

Note: these patients did not receive preoperative therapy.

Preceding treatment

Curative resection for stage II or stage III rectal cancer, within 49 days

Chemotherapy

Tegafur, gimeracil, oteracil (S-1) by the following BSA-based criteria:
- Less than 1.25 m²: 40 mg PO twice per day on days 1 to 28
- BSA 1.25 to 1.5 m²: 50 mg PO twice per day on days 1 to 28
- BSA 1.5 or greater m²: 60 mg PO twice per day on days 1 to 28

42-day cycle for 9 cycles (1 year)

References

ACTS-RC: Oki E, Murata A, Yoshida K, Maeda K, Ikejiri K, Munemoto Y, Sasaki K, Matsuda C, Kotake M, Suenaga T, Matsuda H, Emi Y, Kakeji Y, Baba H, Hamada C, Saji S, Maehara Y. A randomized phase III trial comparing S-1 versus UFT as adjuvant chemotherapy for stage II/III rectal cancer (JFMC35-C1: ACTS-RC). Ann Oncol. 2016 Jul;27(7):1266-72. Epub 2016 Apr 7. link to original article link to PMC article contains dosing details in manuscript PubMed UMIN C000000385

UFT monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Hamaguchi et al. 2010 (NSAS-CC)	1996-2001	Phase 3 (E-esc)	Observation	Seems to have superior OS (secondary endpoint)
Oki et al. 2016 (ACTS-RC)	2006-2009	Phase 3 (C)	S-1	Seems to have inferior RFS

Note: these patients did not receive preoperative therapy.

Preceding treatment

Curative resection for stage II or stage III rectal cancer, within 49 days

Chemotherapy

Tegafur and uracil (UFT) by the following BSA-based criteria:
- Less than 1.25 m²: 250 mg PO twice per day on days 1 to 5
- 1.25 m² or more: 300 mg PO twice per day on days 1 to 5

7-day cycle for 52 cycles

References

NSAS-CC: Hamaguchi T, Shirao K, Moriya Y, Yoshida S, Kodaira S, Ohashi Y; NSAS-CC Group. Final results of randomized trials by the National Surgical Adjuvant Study of Colorectal Cancer (NSAS-CC). Cancer Chemother Pharmacol. 2011 Mar;67(3):587-96. Epub 2010 May 19. link to original article PubMed NCT00152230
ACTS-RC: Oki E, Murata A, Yoshida K, Maeda K, Ikejiri K, Munemoto Y, Sasaki K, Matsuda C, Kotake M, Suenaga T, Matsuda H, Emi Y, Kakeji Y, Baba H, Hamada C, Saji S, Maehara Y. A randomized phase III trial comparing S-1 versus UFT as adjuvant chemotherapy for stage II/III rectal cancer (JFMC35-C1: ACTS-RC). Ann Oncol. 2016 Jul;27(7):1266-72. Epub 2016 Apr 7. link to original article link to PMC article contains dosing details in manuscript PubMed UMIN C000000385

Adjuvant chemoradiotherapy

Capecitabine & RT

Capecitabine & RT: Capecitabine & Radiation Therapy

Regimen variant #1, fully concurrent

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Feng et al. 2016 (CAMS rectal cancer 01)	2008-2014	Phase 3 (C)	CapeOx & RT	Did not meet primary endpoint of DFS DFS36: 71.6% vs 73.9%

Preceding treatment

Surgery

Chemotherapy

Capecitabine (Xeloda) 800 mg/m² PO twice per day on days 1 to 14, 22 to 36

Radiotherapy

Concurrent radiation therapy, 4500 to 5040 cGy total in 25 to 28 fractions

5- to 5.5-week course

Regimen variant #2, sandwich

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Hofheinz et al. 2012 (Rektum-III)	2002-2007	Phase 3 (E-RT-switch-ic)	5-FU & RT	Non-inferior OS (primary endpoint) OS60: 76% vs 67%

Preceding treatment

Surgery

Chemotherapy

Capecitabine (Xeloda) as follows:
- Cycles 1 & 2: 1250 mg/m² PO twice per day on days 1 to 14
- Cycle 3 (chemoradiation): 825 mg/m² PO twice per day on days 1 to 38
- Cycles 4 to 6: 1250 mg/m² PO twice per day on days 1 to 14

Radiotherapy

Concurrent radiation therapy as follows:
- Cycle 3: 5040 cGy total

21-day cycle for 2 cycles, then 38-day course, then 21-day cycle for 3 cycles

References

Rektum-III: Hofheinz RD, Wenz F, Post S, Matzdorff A, Laechelt S, Hartmann JT, Müller L, Link H, Moehler M, Kettner E, Fritz E, Hieber U, Lindemann HW, Grunewald M, Kremers S, Constantin C, Hipp M, Hartung G, Gencer D, Kienle P, Burkholder I, Hochhaus A. Chemoradiotherapy with capecitabine versus fluorouracil for locally advanced rectal cancer: a randomised, multicentre, non-inferiority, phase 3 trial. Lancet Oncol. 2012 Jun;13(6):579-88. Epub 2012 Apr 12. link to original article contains dosing details in manuscript PubMed NCT01500993
CAMS rectal cancer 01: Feng YR, Zhu Y, Liu LY, Wang WH, Wang SL, Song YW, Wang X, Tang Y, Liu YP, Ren H, Fang H, Zhang SP, Liu XF, Yu ZH, Li YX, Jin J. Interim analysis of postoperative chemoradiotherapy with capecitabine and oxaliplatin versus capecitabine alone for pathological stage II and III rectal cancer: a randomized multicenter phase III trial. Oncotarget. 2016 May 3;7(18):25576-84. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00714077

Fluorouracil & RT

Fluorouracil & RT: Fluorouracil & Radiation Therapy

Regimen variant #1, Bolus 5-FU (500 mg/m²), then CI 5-FU & RT, then Bolus 5-FU (450 mg/m²)

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
O'Connell et al. 1994 (INT 864751)	1986-1990	Phase 3 (E-switch-ic)	5-FU & RT; bolus	Superior OS
Smalley et al. 2006 (GI INT 0144)	1994-2000	Phase 3 (E-switch-ic)	1. 5-FU & RT; bolus	Not compared
Smalley et al. 2006 (GI INT 0144)	1994-2000	Phase 3 (E-switch-ic)	2. 5-FU & RT; CI	Did not meet co-primary endpoints of OS/DFS

Note: INT 864751 also included a randomization to add semustine, which is only of historic interest.

Preceding treatment

Surgery

Chemotherapy

Fluorouracil (5-FU) as follows:
- Cycles 1 & 2: 500 mg/m² IV bolus once per day on days 1 to 5
- Cycle 3 (chemoradiation): 225 mg/m²/day IV continuous infusion while radiation is being given
- Cycles 4 & 5: 450 mg/m² IV bolus once per day on days 1 to 5

Radiotherapy

Concurrent radiation therapy as follows:
- Cycle 3: 180 cGy fractions x 25 fractions for an initial dose of 4500 cGy, which is followed by a 180 cGy x 3 fraction (540 cGy total) boost to the tumor bed and adjacent lymph nodes, and then optionally a 180 cGy x 2 fraction (360 cGy total) boost to the tumor bed and a 2 cm margin if the small bowel could be avoided

28-day cycle for 2 cycles, then 8-week course, then 28-day cycle for 2 cycles

Regimen variant #2, Bolus 5-FU (500 mg/m²), then CI 5-FU & RT, then Bolus 5-FU (500 mg/m²)

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Hofheinz et al. 2012 (Rektum-III)	2002-2007	Phase 3 (C)	Capecitabine & RT	Non-inferior OS

Preceding treatment

Surgery

Chemotherapy

Fluorouracil (5-FU) as follows:
- Cycles 1, 2, 4, 5: 500 mg/m² IV bolus once per day on days 1 to 5
- Cycle 3 (chemoradiation): 225 mg/m²/day IV continuous infusion while radiation is being given

Radiotherapy

Concurrent radiation therapy as follows:
- Cycle 3: 5040 cGy total

28-day cycle for 2 cycles, then one course, then 28-day cycle for 2 cycles

Regimen variant #3, CI 5-FU, then CI 5-FU & RT, then CI 5-FU

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Smalley et al. 2006 (GI INT 0144)	1994-2000	Phase 3 (E-switch-ic)	1. 5-FU & RT; bolus	Did not meet co-primary endpoints of DFS/OS
Smalley et al. 2006 (GI INT 0144)	1994-2000	Phase 3 (E-switch-ic)	2. 5-FU & RT; fully concurrent	Not compared

Preceding treatment

Surgery

Chemotherapy

Fluorouracil (5-FU) as follows:
- Cycle 1: 300 mg/m²/day IV continuous infusion over 42 days, started on day 1 (total dose: 12,600 mg/m²)
- Cycle 2 (chemoradiation): 225 mg/m²/day IV continuous infusion while radiation is being given
- Cycle 3: 300 mg/m²/day IV continuous infusion over 56 days, started on day 1 (total dose: 16,800 mg/m²)

Radiotherapy

Concurrent radiation therapy as follows:
- Cycle 2: 180 cGy fractions x 25 fractions for an initial dose of 4500 cGy, which is followed by a 180 cGy x 3 fraction (540 cGy total) boost to the tumor bed and adjacent lymph nodes, and then optionally a 180 cGy x 2 fraction (360 cGy total) boost to the tumor bed and a 2 cm margin if the small bowel could be avoided

10-week cycle for 3 cycles

Regimen variant #4, bolus 5-FU, then bolus 5-FU & RT, then bolus 5-FU

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
O'Connell et al. 1994 (INT 864751)	1986-1990	Phase 3 (C)	5-FU & RT; bolus/CI	Inferior OS
Tepper et al. 1997 (GI INT 0114)	1990-1992	Phase 3 (C)	1. FULV/FULV & RT	Did not meet primary endpoint of DFS36
			2. Levamisole combination #1	Did not meet primary endpoint of DFS36
			3. Levamisole combination #2	Did not meet primary endpoint of DFS36

Note: INT 864751 also included a randomization to add semustine, which is only of historic interest.

Preceding treatment

Surgery

Chemotherapy

Fluorouracil (5-FU) as follows:
- Cycles 1 & 2: 500 mg/m² IV bolus once per day on days 1 to 5
- Cycle 3 (chemoradiation): 500 mg/m² IV bolus 3 days per week during weeks 1 & 5 of radiation, preferably within 2 hours after the day's radiation
- Cycles 4 & 5: 450 mg/m² IV bolus once per day on days 1 to 5

Radiotherapy

Concurrent radiation therapy as follows:
- Cycle 3: 180 cGy fractions x 25 fractions for an initial dose of 4500 cGy, which is followed by a 180 cGy x 3 fraction (540 cGy total) boost to the tumor bed and adjacent lymph nodes, and then optionally a 180 cGy x 2 fraction (360 cGy total) boost to the tumor bed and a 2 cm margin if the small bowel could be avoided

28-day cycle for 2 cycles, then 10-week course, then 28-day cycle for 2 cycles

Regimen variant #5, fully concurrent

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Fountzilas et al. 1999	1989-1997	Phase 3 (C)	FULV/5-FU & RT	Did not meet primary endpoint of OS36

Chemotherapy

Fluorouracil (5-FU)

Radiotherapy

Radiation therapy

References

INT 864751: O'Connell MJ, Martenson JA, Wieand HS, Krook JE, Macdonald JS, Haller DG, Mayer RJ, Gunderson LL, Rich TA. Improving adjuvant therapy for rectal cancer by combining protracted-infusion fluorouracil with radiation therapy after curative surgery. N Engl J Med. 1994 Aug 25;331(8):502-7. link to original article contains dosing details in manuscript PubMed
GI INT 0114: Tepper JE, O'Connell MJ, Petroni GR, Hollis D, Cooke E, Benson AB 3rd, Cummings B, Gunderson LL, Macdonald JS, Martenson JA. Adjuvant postoperative fluorouracil-modulated chemotherapy combined with pelvic radiation therapy for rectal cancer: initial results of intergroup 0114. J Clin Oncol. 1997 May;15(5):2030-9. link to original article contains dosing details in manuscript PubMed
1. Update: Tepper JE, O'Connell M, Niedzwiecki D, Hollis DR, Benson AB 3rd, Cummings B, Gunderson LL, Macdonald JS, Martenson JA, Mayer RJ. Adjuvant therapy in rectal cancer: analysis of stage, sex, and local control--final report of intergroup 0114. J Clin Oncol. 2002 Apr 1;20(7):1744-50. link to original article contains dosing details in manuscript PubMed content property of HemOnc.org
Fountzilas G, Zisiadis A, Dafni U, Konstantaras C, Hatzitheoharis G, Liaros A, Athanassiou E, Dombros N, Dervenis C, Basdanis G, Gamvros O, Souparis A, Briasoulis E, Samantas E, Kappas A, Kosmidis P, Skarlos D, Pavlidis N; Hellenic Cooperative Oncology Group. Postoperative radiation and concomitant bolus fluorouracil with or without additional chemotherapy with fluorouracil and high-dose leucovorin in patients with high-risk rectal cancer: a randomized phase III study conducted by the Hellenic Cooperative Oncology Group. Ann Oncol. 1999 Jun;10(6):671-6. link to original article PubMed
GI INT 0144: Smalley SR, Benedetti JK, Williamson SK, Robertson JM, Estes NC, Maher T, Fisher B, Rich TA, Martenson JA, Kugler JW, Benson AB 3rd, Haller DG, Mayer RJ, Atkins JN, Cripps C, Pedersen J, Periman PO, Tanaka MS Jr, Leichman CG, Macdonald JS. Phase III trial of fluorouracil-based chemotherapy regimens plus radiotherapy in postoperative adjuvant rectal cancer: GI INT 0144. J Clin Oncol. 2006 Aug 1;24(22):3542-7. link to original article contains dosing details in manuscript PubMed NCT00002551
Rektum-III: Hofheinz RD, Wenz F, Post S, Matzdorff A, Laechelt S, Hartmann JT, Müller L, Link H, Moehler M, Kettner E, Fritz E, Hieber U, Lindemann HW, Grunewald M, Kremers S, Constantin C, Hipp M, Hartung G, Gencer D, Kienle P, Burkholder I, Hochhaus A. Chemoradiotherapy with capecitabine versus fluorouracil for locally advanced rectal cancer: a randomised, multicentre, non-inferiority, phase 3 trial. Lancet Oncol. 2012 Jun;13(6):579-88. Epub 2012 Apr 13. link to original article contains dosing details in manuscript PubMed NCT01500993

FULV/FULV & RT

FULV/FULV & RT: FluoroUracil & LeucoVorin alternating with FluoroUracil, LeucoVorin, Radiation Therapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Tepper et al. 1997 (GI INT 0114)	1990-1992	Phase 3 (E-esc)	1. 5-FU & RT	Did not meet primary endpoint of DFS36
			2. Levamisole combination #1	Did not meet primary endpoint of DFS36
			3. Levamisole combination #2	Did not meet primary endpoint of DFS36
Kalofonos et al. 2008	1999-2004	Phase 3 (C)	IFL & RT	Did not meet primary endpoint of OS36

Preceding treatment

Surgery

Chemotherapy

Fluorouracil (5-FU) as follows:
- Cycles 1 & 2: 425 mg/m² IV bolus once per day on days 1 to 5, given second
- Cycle 3 (chemoradiation): 400 mg/m² IV bolus 4 days per week during weeks 1 & 5 of radiation, preferably within 2 hours after the day's radiation
- Cycles 4 & 5: 380 mg/m² IV bolus once per day on days 1 to 5, given second
Leucovorin (Folinic acid) as follows:
- Cycles 1, 2, 4, 5: 20 mg/m² IV bolus once per day on days 1 to 5, given first
- Cycle 3 (chemoradiation): 20 mg/m² IV bolus 4 days per week during weeks 1 & 5 of radiation, preferably within 2 hours after the day's radiation

Radiotherapy

Concurrent radiation therapy as follows:
- Cycle 3: 180 cGy fractions x 25 fractions for an initial dose of 4500 cGy, which is followed by a 180 cGy x 3 fraction (540 cGy total) boost to the tumor bed and adjacent lymph nodes, and then optionally a 180 cGy x 2 fraction (360 cGy total) boost to the tumor bed and a 2 cm margin if the small bowel could be avoided

28-day cycle for 2 cycles, then 10-week course, then 28-day cycles for 2 cycles

References

GI INT 0114: Tepper JE, O'Connell MJ, Petroni GR, Hollis D, Cooke E, Benson AB 3rd, Cummings B, Gunderson LL, Macdonald JS, Martenson JA. Adjuvant postoperative fluorouracil-modulated chemotherapy combined with pelvic radiation therapy for rectal cancer: initial results of intergroup 0114. J Clin Oncol. 1997 May;15(5):2030-9. link to original article contains dosing details in manuscript PubMed
1. Update: Tepper JE, O'Connell M, Niedzwiecki D, Hollis DR, Benson AB 3rd, Cummings B, Gunderson LL, Macdonald JS, Martenson JA, Mayer RJ. Adjuvant therapy in rectal cancer: analysis of stage, sex, and local control--final report of intergroup 0114. J Clin Oncol. 2002 Apr 1;20(7):1744-50. link to original article contains dosing details in manuscript PubMed
Kalofonos HP, Bamias A, Koutras A, Papakostas P, Basdanis G, Samantas E, Karina M, Misailidou D, Pisanidis N, Pentheroudakis G, Economopoulos T, Papadimitriou C, Skarlos DV, Pectasides D, Stavropoulos M, Bafaloukos D, Kardamakis D, Karanikiotis C, Vourli G, Fountzilas G; Hellenic Cooperative Oncology Group. A randomised phase III trial of adjuvant radio-chemotherapy comparing Irinotecan, 5FU and Leucovorin to 5FU and Leucovorin in patients with rectal cancer: a Hellenic Cooperative Oncology Group Study. Eur J Cancer. 2008 Aug;44(12):1693-700. Epub 2008 Jul 17. link to original article PubMed

Radiation therapy

RT: Radiation Therapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Fisher et al. 1988 (NSABP R-01)	1977-1986	Phase 3 (E-esc)	1. MOF	Not reported
Fisher et al. 1988 (NSABP R-01)	1977-1986	Phase 3 (E-esc)	2. Observation	Did not meet efficacy endpoints of DFS/OS
Krook et al. 1991	1980-1986	Phase 3 (C)	Fluorouracil & RT	Inferior RFS
Amott et al. 1996	1984-1989	Phase 3 (E-esc)	Observation	Superior local recurrence rate

Note: this regimen in this context is of historic interest.

Preceding treatment

Surgery

Radiotherapy

Radiation therapy, 4000 to 5040 cGy

4-week course

References

NSABP R-01: Fisher B, Wolmark N, Rockette H, Redmond C, Deutsch M, Wickerham DL, Fisher ER, Caplan R, Jones J, Lerner H, Gordon P, Feldman M, Cruz A, Legault-Poisson S, Wexler M, Lawrence W, Robidoux A. Postoperative adjuvant chemotherapy or radiation therapy for rectal cancer: results from NSABP protocol R-01. J Natl Cancer Inst. 1988 Mar 2;80(1):21-9. link to original article PubMed
Krook JE, Moertel CG, Gunderson LL, Wieand HS, Collins RT, Beart RW, Kubista TP, Poon MA, Meyers WC, Mailliard JA, Twito DI, Morton RF, Veeder MH, Witzig TE, Cha S, Vidyarthi SC. Effective surgical adjuvant therapy for high-risk rectal carcinoma. N Engl J Med. 1991 Mar 14;324(11):709-15. link to original article PubMed
Amott SJ, Stenning SP, Hardcastle JD; Medical Research Council Rectal Cancer Working Party. Randomised trial of surgery alone versus surgery followed by radiotherapy for mobile cancer of the rectum. Lancet. 1996 Dec 14;348(9042):1610-4. link to original article contains dosing details in abstract PubMed
TROG 01.014: Ngan SY, Burmeister B, Fisher RJ, Solomon M, Goldstein D, Joseph D, Ackland SP, Schache D, McClure B, McLachlan SA, McKendrick J, Leong T, Hartopeanu C, Zalcberg J, Mackay J. Randomized trial of short-course radiotherapy versus long-course chemoradiation comparing rates of local recurrence in patients with T3 rectal cancer: Trans-Tasman Radiation Oncology Group trial 01.04. J Clin Oncol. 2012 Nov 1;30(31):3827-33. Epub 2012 Sep 24. Erratum in: J Clin Oncol. 2013 Jan 20;31(3):399. link to original article PubMed NCT00351598

Advanced or metastatic disease

See the colorectal cancer page for colorectal cancer regimens.

@@ Line 1: / Line 1: @@
-'''Use of this site is subject to you reading and agreeing with the terms set forth in the [[HemOnc.org_-_A_Hematology_Oncology_Wiki:General_disclaimer|disclaimer]].'''
+<span id="BackToTop"></span>
+<div class="noprint" style="background-color:LightGray; position:fixed; bottom:2%; right:0.25%; padding-left:5px; padding-right:5px; margin: 15px; opacity:0.8; border-style: solid; border-color:DarkGray; border-width: 1px">
-Is there a regimen missing from this list?  Would you like to share a different dosage/schedule or an additional reference for a regimen?  Have you noticed an error?  Do you have an idea that will help the site grow to better meet your needs and the needs of many others?  You are [[How_to_contribute|invited to contribute to the site]].
+[[#top|Back to Top]]
+</div>
-'''Please be aware that some regimens listed here are studies for colon cancer.'''  These regimens were listed as options by the NCCN, Rectal Cancer version 3.2012, and their inclusion here reflects the overlap between treatments of colon and rectal cancer.
+{{#lst:Editorial board transclusions|gi}}
+''Are you looking for a regimen but can't find it here? For placebo or observational studies in this condition, please visit [[Rectal cancer - null regimens|this page]]. If you still can't find it, please let us know so we can add it!''
 {| class="wikitable" style="float:right; margin-right: 5px;"
 |-
-|<div style="background-color: #66FF66; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]]  |?Regimen |limit=10000|format=sum}} regimens on this page</b></font></div>
+|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div>
-<div style="background-color: #66CCFF; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]]  |?Variant |limit=10000|format=sum}} variants on this page</b></font></div>
+<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div>
 |}
+<big>Note: the page has (neo-)adjuvant regimens specific to rectal cancer. Please see the [[Colon_cancer|'''colon cancer page''']] for adjuvant regimens specific to colon cancer (e.g., adjuvant [[Colon_cancer#CapeOx|CapeOx]]) and the [[Colorectal_cancer|'''colorectal cancer page''']] for regimens intended more generically for colorectal cancer.</big>
 {{TOC limit|limit=3}}
+=Guidelines=
+'''Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.'''
+==[https://www.esmo.org/ ESMO]==
+*'''2018:''' Glynne-Jones et al. [https://doi.org/10.1093/annonc/mdy161 Rectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/29741565/ PubMed]
+**'''2017:''' Glynne-Jones et al. [https://doi.org/10.1093/annonc/mdx224 Rectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/28881920/ PubMed]
+**'''2013:''' Glimelius et al. [https://doi.org/10.1093/annonc/mdt240 Rectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/24078665/ PubMed]
+**'''2010:''' Glimelius et al. [https://doi.org/10.1093/annonc/mdq170 Rectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/20555109/ PubMed]
+**'''2009:''' Glimelius & Oliveira. [https://doi.org/10.1093/annonc/mdp128 Rectal cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/19454463/ PubMed]
+**'''2008:''' Glimelius & Oliveira. [https://doi.org/10.1093/annonc/mdn078 Rectal cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/18456759/ PubMed]
+**'''2007:''' Glimelius. [https://doi.org/10.1093/annonc/mdm022 Rectal cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/17491031/ PubMed]
+**'''2005:''' Tveit & Kataja. [https://doi.org/10.1093/annonc/mdi827 ESMO Minimum Clinical Recommendations for diagnosis, treatment and follow-up of rectal cancer] [https://pubmed.ncbi.nlm.nih.gov/15888739/ PubMed]
+**'''2003:''' Tveit. [https://doi.org/10.1093/annonc/mdg297 ESMO Minimum Clinical Recommendations for diagnosis, treatment and follow-up of rectal cancer] [https://pubmed.ncbi.nlm.nih.gov/12853337/ PubMed]
+==French Intergroup==
+*'''2017:''' Gérard et al. [https://doi.org/10.1016/j.dld.2017.01.152 Rectal cancer: French Intergroup clinical practice guidelines for diagnosis, treatments and follow-up (SNFGE, FFCD, GERCOR, UNICANCER, SFCD, SFED, SFRO)] [https://pubmed.ncbi.nlm.nih.gov/28179091/ PubMed]
+==NCCN==
+*[https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1461 NCCN Guidelines - Rectal Cancer]
+**'''2015:''' Benson et al. [https://doi.org/10.6004/jnccn.2015.0087 Rectal Cancer, Version 2.2015] [https://pubmed.ncbi.nlm.nih.gov/26085388/ PubMed]
+**'''2009:''' Engstrom et al. [https://doi.org/10.6004/Jnccn.2009.0057 NCCN Clinical Practice Guidelines in Oncology: rectal cancer.] [https://pubmed.ncbi.nlm.nih.gov/19755047/ PubMed]
+==SIOG==
+*'''2018''': Montroni et al. [https://doi.org/10.1016/j.ejso.2018.08.003 Personalized management of elderly patients with rectal cancer: Expert recommendations of the European Society of Surgical Oncology, European Society of Coloproctology, International Society of Geriatric Oncology, and American College of Surgeons Commission on Cancer] [https://pubmed.ncbi.nlm.nih.gov/30150158/ PubMed]
-=Adjuvant chemotherapy=
+=Neoadjuvant therapy=
-==Capecitabine (Xeloda) {{#subobject:161f3c|Regimen=1}}==
+==Capecitabine & RT {{#subobject:1887b9|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+Capecitabine & RT: Capecitabine & '''<u>R</u>'''adiation '''<u>T</u>'''herapy
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #1, interrupted capecitabine, 1600 mg/m<sup>2</sup>/day, 4500 cGy {{#subobject:19cc2a|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://doi.org/10.1200/JCO.2009.25.8376 Gérard et al. 2010 (ACCORD 12/0405 PRODIGE 2)]
+|2005-2008
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#CapeOx_.26_RT_333|CapeOx & RT]]
+| style="background-color:#fee08b" |Might have inferior pCR rate
+|-
+|}
+''Note: adjuvant therapy was not specified. Treatment is assumed to start on a Monday.''
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Capecitabine (Xeloda)]] 800 mg/m<sup>2</sup> PO twice per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33
+====Radiotherapy====
+*Concurrent [[External_beam_radiotherapy|radiation therapy]] 180 cGy per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33 (4500 cGy total in 25 fractions)
+'''5-week course'''
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
+====Subsequent treatment====
+*[[Surgery#Rectal_cancer_surgery|Surgery]]
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #2, interrupted capecitabine, 1600 mg/m<sup>2</sup>/day, 5000 cGy {{#subobject:19ff2a|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://doi.org/10.1016/s1470-2045(21)00079-6 Conroy et al. 2021 (UNICANCER-PRODIGE 23)]
+|2012-2017
+| style="background-color:#91cf61" |Non-randomized part of phase 3 RCT
+| style="background-color:#d3d3d3" |
+| style="background-color:#d3d3d3" |
+|-
+|[https://doi.org/10.1016/j.ejca.2022.11.020 François et al. 2022]
+|2016-2019
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#Radiation_therapy|RT]]; 5 x 5
+| style="background-color:#ffffbf" |Inconclusive whether non-inferior R0 resection rate
 |-
-|[[#toc|back to top]]
 |}
-===Regimen {{#subobject:481fb|Variant=1}}===
+''Note: Treatment is assumed to start on a Monday.''
-Level of Evidence:
+<div class="toccolours" style="background-color:#cbd5e8">
-<span
+====Preceding treatment====
-style="background:#00CD00;
+*UNICANCER-PRODIGE 23: Neoadjuvant [[#FOLFIRINOX|FOLFIRINOX]] versus [[Rectal_cancer_-_null_regimens#No_neoadjuvant_therapy|no neoadjuvant chemotherapy]]
-padding:3px 6px 3px 6px;
+</div>
-border-color:black;
+<div class="toccolours" style="background-color:#b3e2cd">
-border-width:2px;
+====Chemotherapy====
-border-style:solid;">Phase III</span>
+*[[Capecitabine (Xeloda)]] 800 mg/m<sup>2</sup> PO twice per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33
+====Radiotherapy====
+*Concurrent [[External_beam_radiotherapy|radiation therapy]] 200 cGy per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33 (5000 cGy total in 25 fractions)
+'''5-week course'''
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
+====Subsequent treatment====
+*UNICANCER-PRODIGE 23: [[Surgery#Total_mesorectal_excision|TME]], then adjuvant [[#mFOLFOX6_2|mFOLFOX6]]
+*François et al. 2022: [[Surgery#Rectal_cancer_surgery|Surgery]]
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
-*[[Capecitabine (Xeloda)]] 1250 mg/m2 PO BID on days 1 to 14
+===Regimen variant #3, interrupted capecitabine, 1650 mg/m<sup>2</sup>/day, 4500 cGy {{#subobject:19c7tg|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://doi.org/10.1200/jco.20.01740 Schmoll et al. 2020 (PETACC 6)]
+|2008-2011
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#CapeOx_.26_RT_999|CapeOx & RT]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS36
+|-
+|}
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Capecitabine (Xeloda)]] 825 mg/m<sup>2</sup> PO twice per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33
+====Radiotherapy====
+*Concurrent [[External_beam_radiotherapy|radiation therapy]] 180 cGy per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33 (4500 cGy total in 25 fractions)
+'''5-week course'''
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
+====Subsequent treatment====
+*[[Surgery#Rectal_cancer_surgery|Surgery]], then adjuvant [[#Capecitabine_monotherapy|capecitabine]]
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #4, continuous capecitabine, 1650 mg/m<sup>2</sup>/day, 4500 cGy {{#subobject:a05392|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 17%"|Study
+!style="width: 15%"|Dates of enrollment
+!style="width: 17%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 17%"|Comparator
+!style="width: 17%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+!style="width: 17%"|[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
+|-
+|[https://doi.org/10.1016/S1470-2045%2812%2970116-X Hofheinz et al. 2012 (Rektum-III)]
+|2002-2007
+| style="background-color:#1a9851" |Phase 3 (E-RT-switch-ic)
+|[[#Fluorouracil_.26_RT|5-FU & RT]]
+| style="background-color:#eeee01" |Non-inferior OS (primary endpoint)<br>OS60: 76% vs 67%
+|
+|-
+|[https://doi.org/10.1002/cncr.25943 Park et al. 2011 (AMC Rectal Pre Vs Post 2004)]
+|2004-2006
+| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
+|[[#Capecitabine_.26_RT_2|Capecitabine & RT]]; adjuvant
+| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS36
+| style="background-color:#1a9850" |Superior sphincter preservation
+|-
+| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4050205/ O'Connell et al. 2014 (NSABP R-04)]
+|rowspan=2|2004-2010
+| rowspan="2" style="background-color:#1a9851" |Phase 3 (E-switch-ic)
+|1. [[#Fluorouracil_.26_RT|5-FU & RT]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of LRC
+| style="background-color:#eeee01" |Similar toxicity
+|-
+|2. [[#CapeOx_.26_RT_999|CapeOx & RT]]<br> 3. [[#FUOX_.26_RT|FUOX & RT]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of LRC
+| style="background-color:#1a9850" |Superior toxicity
+|-
+|[https://doi.org/10.1016/j.radonc.2018.11.023 Valentini et al. 2016 (INTERACT)]
+|2005-2013
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#CapeOx_.26_RT_999|CapeOx & RT]]
+| style="background-color:#ffffbf" |Did not meet efficacy endpoints
+| style="background-color:#1a9850" |Superior toxicity
+|-
+|}
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Capecitabine (Xeloda)]] 825 mg/m<sup>2</sup> PO twice per day on days 1 to 38
+====Radiotherapy====
+*Concurrent [[External_beam_radiotherapy|radiation therapy]] 180 cGy per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33 (25 fractions/4500 cGy), with boost depending on stage
+'''5.5-week course'''
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
+====Subsequent treatment====
+*[[Surgery#Rectal_cancer_surgery|Surgery]], then adjuvant [[#Capecitabine_monotherapy|capecitabine]]
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #5, interrupted capecitabine, 1650 mg/m<sup>2</sup>/day, 5000 cGy {{#subobject:19ihaa|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768334/ Zhu et al. 2020 (CinClare)]
+|2015-2017
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[Complex_multipart_regimens#CinClare|See link]]
+| style="background-color:#d73027" |[[Complex_multipart_regimens#CinClare|See link]]
+|-
+|}
+''Note: Treatment is assumed to start on a Monday. Surgery is to take place 8 weeks after completion of chemoradiotherapy.''
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Capecitabine (Xeloda)]] 825 mg/m<sup>2</sup> PO twice per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33
+====Radiotherapy====
+*Concurrent [[External_beam_radiotherapy|radiation therapy]] 200 cGy per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33 (5000 cGy total in 25 fractions)
+'''5-week course'''
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
+====Subsequent treatment====
+*Neoadjuvant [[#CapeOx|CapeOx]] x 1, then [[Surgery#Total_mesorectal_excision|TME]], then adjuvant [[#CapeOx|CapeOx]] x 5
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #6, interrupted capecitabine, 1650 mg/m<sup>2</sup>/day, 5040 cGy {{#subobject:17tatg|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://doi.org/10.1200/jco.20.01740 Schmoll et al. 2020 (PETACC 6)]
+|2008-2011
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#CapeOx_.26_RT_888|CapeOx & RT]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS36
+|-
+|}
+''Note: Treatment starts on a Monday.''
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Capecitabine (Xeloda)]] 825 mg/m<sup>2</sup> PO twice per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33, 36 to 38
+====Radiotherapy====
+*Concurrent [[External_beam_radiotherapy|radiation therapy]] 180 cGy per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33, 36 to 38 (5040 cGy total in 28 fractions)
+'''5.5-week course'''
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
+====Subsequent treatment====
+*[[Surgery#Rectal_cancer_surgery|Surgery]], then adjuvant [[#Capecitabine_monotherapy|capecitabine]]
+</div></div>
+===References===
+# '''ACCORD 12:''' Gérard JP, Azria D, Gourgou-Bourgade S, Martel-Laffay I, Hennequin C, Etienne PL, Vendrely V, François E, de La Roche G, Bouché O, Mirabel X, Denis B, Mineur L, Berdah JF, Mahé MA, Bécouarn Y, Dupuis O, Lledo G, Montoto-Grillot C, Conroy T. Comparison of two neoadjuvant chemoradiotherapy regimens for locally advanced rectal cancer: results of the phase III trial ACCORD 12/0405-PRODIGE 2. J Clin Oncol. 2010 Apr 1;28(10):1638-44. Epub 2010 Mar 1. [https://doi.org/10.1200/JCO.2009.25.8376 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/20194850/ PubMed] [https://clinicaltrials.gov/study/NCT00227747 NCT00227747]
+## '''Update:''' Gérard JP, Azria D, Gourgou-Bourgade S, Martel-Lafay I, Hennequin C, Etienne PL, Vendrely V, François E, de La Roche G, Bouché O, Mirabel X, Denis B, Mineur L, Berdah JF, Mahé MA, Bécouarn Y, Dupuis O, Lledo G, Seitz JF, Bedenne L, Juzyna B, Conroy T. Clinical outcome of the ACCORD 12/0405 PRODIGE 2 randomized trial in rectal cancer. J Clin Oncol. 2012 Dec 20;30(36):4558-65. Epub 2012 Oct 29. [https://doi.org/10.1200/JCO.2012.42.8771 link to original article] [https://pubmed.ncbi.nlm.nih.gov/23109696/ PubMed]
+# '''AMC Rectal Pre Vs Post 2004:''' Park JH, Yoon SM, Yu CS, Kim JH, Kim TW, Kim JC. Randomized phase 3 trial comparing preoperative and postoperative chemoradiotherapy with capecitabine for locally advanced rectal cancer. Cancer. 2011 Aug 15;117(16):3703-12. Epub 2011 Feb 15. [https://doi.org/10.1002/cncr.25943 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/21328328/ PubMed] [https://clinicaltrials.gov/study/NCT01186081 NCT01186081]
+# '''Rektum-III:''' Hofheinz RD, Wenz F, Post S, Matzdorff A, Laechelt S, Hartmann JT, Müller L, Link H, Moehler M, Kettner E, Fritz E, Hieber U, Lindemann HW, Grunewald M, Kremers S, Constantin C, Hipp M, Hartung G, Gencer D, Kienle P, Burkholder I, Hochhaus A. Chemoradiotherapy with capecitabine versus fluorouracil for locally advanced rectal cancer: a randomised, multicentre, non-inferiority, phase 3 trial. Lancet Oncol. 2012 Jun;13(6):579-88. Epub 2012 Apr 12. [https://doi.org/10.1016/S1470-2045%2812%2970116-X link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/22503032/ PubMed] [https://clinicaltrials.gov/study/NCT01500993 NCT01500993]
+# '''NSABP R-04:''' O'Connell MJ, Colangelo LH, Beart RW, Petrelli NJ, Allegra CJ, Sharif S, Pitot HC, Shields AF, Landry JC, Ryan DP, Parda DS, Mohiuddin M, Arora A, Evans LS, Bahary N, Soori GS, Eakle J, Robertson JM, Moore DF Jr, Mullane MR, Marchello BT, Ward PJ, Wozniak TF, Roh MS, Yothers G, Wolmark N. Capecitabine and oxaliplatin in the preoperative multimodality treatment of rectal cancer: surgical end points from National Surgical Adjuvant Breast and Bowel Project trial R-04. J Clin Oncol. 2014 Jun 20;32(18):1927-34. Epub 2014 May 5. [https://doi.org/10.1200/JCO.2013.53.7753 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4050205/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/24799484/ PubMed] [https://clinicaltrials.gov/study/NCT00058474 NCT00058474]
+## '''Update:''' Allegra CJ, Yothers G, O'Connell MJ, Beart RW, Wozniak TF, Pitot HC, Shields AF, Landry JC, Ryan DP, Arora A, Evans LS, Bahary N, Soori G, Eakle JF, Robertson JM, Moore DF Jr, Mullane MR, Marchello BT, Ward PJ, Sharif S, Roh MS, Wolmark N. Neoadjuvant 5-FU or capecitabine plus radiation with or without oxaliplatin in rectal cancer patients: a phase III randomized clinical trial. J Natl Cancer Inst. 2015 Sep 14;107(11). Erratum in: J Natl Cancer Inst. 2016 Apr;108(4). [https://academic.oup.com/jnci/article/107/11/djv248/2457689 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4849360/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26374429/ PubMed]
+#'''INTERACT:''' Valentini V, Gambacorta MA, Cellini F, Aristei C, Coco C, Barbaro B, Alfieri S, D'Ugo D, Persiani R, Deodato F, Crucitti A, Lupattelli M, Mantello G, Navarria F, Belluco C, Buonadonna A, Boso C, Lonardi S, Caravatta L, Barba MC, Vecchio FM, Maranzano E, Genovesi D, Doglietto GB, Morganti AG, La Torre G, Pucciarelli S, De Paoli A. The INTERACT Trial: Long-term results of a randomised trial on preoperative capecitabine-based radiochemotherapy intensified by concomitant boost or oxaliplatin, for cT2 (distal)-cT3 rectal cancer. Radiother Oncol. 2019 May;134:110-118. Epub 2019 Feb 7. [https://doi.org/10.1016/j.radonc.2018.11.023 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31005204/ PubMed] [https://clinicaltrials.gov/study/NCT01653301 NCT01653301]
+#'''CinClare:''' Zhu J, Liu A, Sun X, Liu L, Zhu Y, Zhang T, Jia J, Tan S, Wu J, Wang X, Zhou J, Yang J, Zhang C, Zhang H, Zhao Y, Cai G, Zhang W, Xia F, Wan J, Zhang H, Shen L, Cai S, Zhang Z. Multicenter, Randomized, Phase III Trial of Neoadjuvant Chemoradiation With Capecitabine and Irinotecan Guided by UGT1A1 Status in Patients With Locally Advanced Rectal Cancer. J Clin Oncol. 2020 Dec 20;38(36):4231-4239. Epub 2020 Oct 29. [https://doi.org/10.1200/jco.20.01932 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768334/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/33119477/ PubMed] [https://clinicaltrials.gov/study/NCT02605265 NCT02605265]
+# '''PETACC 6:''' Schmoll HJ, Stein A, Van Cutsem E, Price T, Hofheinz RD, Nordlinger B, Daisne JF, Janssens J, Brenner B, Reinel H, Hollerbach S, Caca K, Fauth F, Hannig CV, Zalcberg J, Tebbutt N, Mauer ME, Marreaud S, Lutz MP, Haustermans K. Pre- and Postoperative Capecitabine Without or With Oxaliplatin in Locally Advanced Rectal Cancer: PETACC 6 Trial by EORTC GITCG and ROG, AIO, AGITG, BGDO, and FFCD. J Clin Oncol. 2021 Jan 1;39(1):17-29. Epub 2020 Oct 1. [https://doi.org/10.1200/jco.20.01740 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/33001764/ PubMed] [https://clinicaltrials.gov/study/NCT00766155 NCT00766155]
+# '''UNICANCER-PRODIGE 23:''' Conroy T, Bosset JF, Etienne PL, Rio E, François É, Mesgouez-Nebout N, Vendrely V, Artignan X, Bouché O, Gargot D, Boige V, Bonichon-Lamichhane N, Louvet C, Morand C, de la Fouchardière C, Lamfichekh N, Juzyna B, Jouffroy-Zeller C, Rullier E, Marchal F, Gourgou S, Castan F, Borg C; Unicancer Gastrointestinal Group and Partenariat de Recherche en Oncologie Digestive (PRODIGE) Group. Neoadjuvant chemotherapy with FOLFIRINOX and preoperative chemoradiotherapy for patients with locally advanced rectal cancer (UNICANCER-PRODIGE 23): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2021 May;22(5):702-715. Epub 2021 Apr 13. [https://doi.org/10.1016/s1470-2045(21)00079-6 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/33862000/ PubMed] [https://clinicaltrials.gov/study/NCT01804790 NCT01804790]
+# '''STELLAR<sub>rectal</sub>:''' Jin J, Tang Y, Hu C, Jiang LM, Jiang J, Li N, Liu WY, Chen SL, Li S, Lu NN, Cai Y, Li YH, Zhu Y, Cheng GH, Zhang HY, Wang X, Zhu SY, Wang J, Li GF, Yang JL, Zhang K, Chi Y, Yang L, Zhou HT, Zhou AP, Zou SM, Fang H, Wang SL, Zhang HZ, Wang XS, Wei LC, Wang WL, Liu SX, Gao YH, Li YX. Multicenter, Randomized, Phase III Trial of Short-Term Radiotherapy Plus Chemotherapy Versus Long-Term Chemoradiotherapy in Locally Advanced Rectal Cancer (STELLAR). J Clin Oncol. 2022 May 20;40(15):1681-1692. Epub 2022 Mar 9. [https://doi.org/10.1200/jco.21.01667 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc9113208/ link to PMC article] [https://clinicaltrials.gov/study/NCT02533271 NCT02533271] [https://pubmed.ncbi.nlm.nih.gov/35263150/ PubMed]
+#'''CONVERT<sub>rectal</sub>:''' Mei WJ, Wang XZ, Li YF, Sun YM, Yang CK, Lin JZ, Wu ZG, Zhang R, Wang W, Li Y, Zhuang YZ, Lei J, Wan XB, Ren YK, Cheng Y, Li WL, Wang ZQ, Xu DB, Mo XW, Ju HX, Ye SW, Zhao JL, Zhang H, Gao YH, Zeng ZF, Xiao WW, Zhang XP, Zhang X, Xie E, Feng YF, Tang JH, Wu XJ, Chen G, Li LR, Lu ZH, Wan DS, Bei JX, Pan ZZ, Ding PR. Neoadjuvant Chemotherapy With CAPOX Versus Chemoradiation for Locally Advanced Rectal Cancer With Uninvolved Mesorectal Fascia (CONVERT): Initial Results of a Phase III Trial. Ann Surg. 2023 Apr 1;277(4):557-564. Epub 2022 Dec 20. [https://doi.org/10.1097/SLA.0000000000005780 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9994847/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/36538627/ PubMed] [https://clinicaltrials.gov/study/NCT02288195 NCT02288195]
+# François E, De Bari B, Ronchin P, Nouhaud E, Martel-Lafay I, Artru P, Clavere P, Vendrely V, Boige V, Gargot D, Lemanski C, De Sousa Carvalho N, Gal J, Pernot M, Magné N. Comparison of short course radiotherapy with chemoradiotherapy for locally advanced rectal cancers in the elderly: A multicentre, randomised, non-blinded, phase 3 trial. Eur J Cancer. 2023 Feb;180:62-70. Epub 2022 Nov 28. [https://doi.org/10.1016/j.ejca.2022.11.020 link to original article] [https://pubmed.ncbi.nlm.nih.gov/36535196/ PubMed]
+#'''PROSPECT<sub>rectal</sub>:''' Schrag D, Shi Q, Weiser MR, Gollub MJ, Saltz LB, Musher BL, Goldberg J, Al Baghdadi T, Goodman KA, McWilliams RR, Farma JM, George TJ, Kennecke HF, Shergill A, Montemurro M, Nelson GD, Colgrove B, Gordon V, Venook AP, O'Reilly EM, Meyerhardt JA, Dueck AC, Basch E, Chang GJ, Mamon HJ. Preoperative Treatment of Locally Advanced Rectal Cancer. N Engl J Med. 2023 Jul 27;389(4):322-334. Epub 2023 Jun 4. [https://doi.org/10.1056/nejmoa2303269 link to original article] [https://pubmed.ncbi.nlm.nih.gov/37272534/ PubMed] [https://clinicaltrials.gov/study/NCT01515787 NCT01515787]
+##'''PRO analysis:''' Basch E, Dueck AC, Mitchell SA, Mamon H, Weiser M, Saltz L, Gollub M, Rogak L, Ginos B, Mazza GL, Colgrove B, Chang G, Minasian L, Denicoff A, Thanarajasingam G, Musher B, George T, Venook A, Farma J, O'Reilly E, Meyerhardt JA, Shi Q, Schrag D. Patient-Reported Outcomes During and After Treatment for Locally Advanced Rectal Cancer in the PROSPECT Trial (Alliance N1048). J Clin Oncol. 2023 Jul 20;41(21):3724-3734. Epub 2023 Jun 4. [https://doi.org/10.1200/jco.23.00903 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10351948/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/37270691/ PubMed]
-'''21-day cycles x 8 cycles'''
+==Capecitabine, Sorafenib, RT {{#subobject:1812b9|Regimen=1}}==
+Capecitabine, Sorafenib, RT: Capecitabine, Sorafenib, '''<u>R</u>'''adiation '''<u>T</u>'''herapy
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:a01232|Variant=1}}===
+{| class="wikitable" style="width: 40%; text-align:center;"
+! style="width: 50%" |Study
+! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
+|-
+|[https://doi.org/10.1016/j.ejca.2017.11.005 von Moos et al. 2017 (SAKK 41/08)]
+| style="background-color:#91cf61" |Phase 1/2
+|-
+|}
+<div class="toccolours" style="background-color:#fdcdac">
+====Biomarker eligibility criteria====
+*KRAS-mutation
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Capecitabine (Xeloda)]] 825 mg/m<sup>2</sup> PO twice per day on days 1 to 33
+====Targeted therapy====
+*[[Sorafenib (Nexavar)]] 400 mg PO once per day
+====Radiotherapy====
+*Concurrent [[External_beam_radiotherapy|radiation therapy]], 4500 cGy total
+'''5-week course'''
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
+====Subsequent treatment====
+*[[Surgery#Rectal_cancer_surgery|Surgery]]
+</div></div>
+===References===
+# '''SAKK 41/08:''' von Moos R, Koeberle D, Schacher S, Hayoz S, Winterhalder RC, Roth A, Bodoky G, Samaras P, Berger MD, Rauch D, Saletti P, Plasswilm L, Zwahlen D, Meier UR, Yan P, Izzo P, Klingbiel D, Bärtschi D, Zaugg K; Swiss Group for Clinical Cancer Research. Neoadjuvant radiotherapy combined with capecitabine and sorafenib in patients with advanced KRAS-mutated rectal cancer: A phase I/II trial (SAKK 41/08). Eur J Cancer. 2018 Jan;89:82-89. Epub 2017 Dec 11. [https://doi.org/10.1016/j.ejca.2017.11.005 link to original article] [https://pubmed.ncbi.nlm.nih.gov/29241084/ PubMed]
+==CapeOx {{#subobject:cf9acc|Regimen=1}}==
+CapeOX: '''<u>Cape</u>'''citabine & '''<u>OX</u>'''aliplatin
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #1, 4 cycles {{#subobject:205ad6|Variant=1}}===
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
+!style="width: 33%"|Study
+!style="width: 33%"|Dates of enrollment
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
+|-
+|[https://doi.org/10.1016/s1470-2045(09)70381-x Chua et al. 2010]
+|2001-2005
+| style="background-color:#91cf61" |Phase 2
+|-
+|}
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14
+*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV once on day 1
+'''21-day cycle for 4 cycles'''
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
+====Subsequent treatment====
+*Neoadjuvant [[#Capecitabine_.26_RT|Capecitabine & RT]], then [[Surgery#Total_mesorectal_excision|TME]]
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #2, 6 cycles {{#subobject:9a1iog|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://doi.org/10.1016/s1470-2045(20)30555-6 Bahadoer et al. 2020 (RAPIDO)]
+|2011-2016
+| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
+|[[Complex_multipart_regimens#RAPIDO|See link]]
+| style="background-color:#91cf60" |[[Complex_multipart_regimens#RAPIDO|See link]]
+|-
+|}
+<div class="toccolours" style="background-color:#cbd5e8">
+====Preceding treatment====
+*Neoadjuvant [[#Radiation_therapy|RT]]; 5 x 500 cGy
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14
+*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV once on day 1
+'''21-day cycle for 6 cycles'''
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
+====Subsequent treatment====
+*[[Surgery#Total_mesorectal_excision|TME]]
+</div></div>
+===References===
+# Chua YJ, Barbachano Y, Cunningham D, Oates JR, Brown G, Wotherspoon A, Tait D, Massey A, Tebbutt NC, Chau I. Neoadjuvant capecitabine and oxaliplatin before chemoradiotherapy and total mesorectal excision in MRI-defined poor-risk rectal cancer: a phase 2 trial. Lancet Oncol. 2010 Mar;11(3):241-8. Epub 2010 Jan 25. [https://doi.org/10.1016/s1470-2045(09)70381-x link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/20106720/ PubMed] [https://clinicaltrials.gov/study/NCT00220051 NCT00220051]
+#'''RAPIDO:''' Bahadoer RR, Dijkstra EA, van Etten B, Marijnen CAM, Putter H, Kranenbarg EM, Roodvoets AGH, Nagtegaal ID, Beets-Tan RGH, Blomqvist LK, Fokstuen T, Ten Tije AJ, Capdevila J, Hendriks MP, Edhemovic I, Cervantes A, Nilsson PJ, Glimelius B, van de Velde CJH, Hospers GAP; RAPIDO collaborative investigators. Short-course radiotherapy followed by chemotherapy before total mesorectal excision (TME) versus preoperative chemoradiotherapy, TME, and optional adjuvant chemotherapy in locally advanced rectal cancer (RAPIDO): a randomised, open-label, phase 3 trial. Lancet Oncol. 2021 Jan;22(1):29-42. Epub 2020 Dec 7. [https://doi.org/10.1016/s1470-2045(20)30555-6 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/33301740/ PubMed] [https://clinicaltrials.gov/study/NCT01558921 NCT01558921]
+==CapeOx, Cetuximab, RT {{#subobject:2d68ed|Regimen=1}}==
+CapeOX, Cetuximab, RT: '''<u>Cape</u>'''citabine, '''<u>OX</u>'''aliplatin, Cetuximab, '''<u>R</u>'''adiation '''<u>T</u>'''herapy
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:5a3ef0|Variant=1}}===
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
+!style="width: 33%"|Study
+!style="width: 33%"|Dates of enrollment
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
+|-
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6598683/ Leichman et al. 2017 (SWOG S0713)]
+|2009-02 to 2013-04
+| style="background-color:#91cf61" |Phase 2
+|-
+|}
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Capecitabine (Xeloda)]] 825 mg/m<sup>2</sup> PO twice per day on Monday to Friday
+*[[Oxaliplatin (Eloxatin)]] as follows:
+**Cycle 1: 50 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22, 29
+**Cycle 2: 50 mg/m<sup>2</sup> IV once per day on days 1, 8, 22, 29
+====Targeted therapy====
+*[[Cetuximab (Erbitux)]] as follows:
+**Cycle 1: 400 mg/m<sup>2</sup> IV once on day 1, then 250 mg/m<sup>2</sup> IV once per day on days 8, 15, 22, 29
+**Cycle 2: 250 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22, 29
+====Radiotherapy====
+*[[External_beam_radiotherapy|RT]] as follows:
+**Cycle 2: 180 cGy per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33 (25 fractions)
+'''35-day cycle for 2 cycles'''
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
+====Subsequent treatment====
+*[[Surgery#Total_mesorectal_excision|TME]]
+</div></div>
+===References===
+# '''SWOG S0713:''' Leichman CG, McDonough SL, Smalley SR, Billingsley KG, Lenz HJ, Beldner MA, Hezel AF, Velasco MR, Guthrie KA, Blanke CD, Hochster HS. Cetuximab Combined With Induction Oxaliplatin and Capecitabine, Followed by Neoadjuvant Chemoradiation for Locally Advanced Rectal Cancer: SWOG 0713. Clin Colorectal Cancer. 2018 Mar;17(1):e121-e125. Epub 2017 Oct 24. [https://doi.org/10.1016/j.clcc.2017.10.008 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6598683/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29233486/ PubMed] [https://clinicaltrials.gov/study/NCT00686166 NCT00686166]
+==CapIriRT {{#subobject:115th9|Regimen=1}}==
+CapIriRT: '''<u>Cap</u>'''ecitabine, '''<u>Iri</u>'''notecan, '''<u>R</u>'''adiation '''<u>T</u>'''herapy
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #1, 65 mg/m<sup>2</sup> {{#subobject:19ugak|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768334/ Zhu et al. 2020 (CinClare)]
+|2015-2017
+| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
+|[[Complex_multipart_regimens#CinClare|See link]]
+| style="background-color:#1a9850" |[[Complex_multipart_regimens#CinClare|See link]]
+|-
+|}
+''Note: Treatment is assumed to start on a Monday. Surgery is to take place 8 weeks after completion of chemoradiotherapy.''
+<div class="toccolours" style="background-color:#fdcdac">
+====Biomarker eligibility criteria====
+*''UGT1A1*1*28'' genotype
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Capecitabine (Xeloda)]] 625 mg/m<sup>2</sup> PO twice per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33
+*[[Irinotecan (Camptosar)]] 65 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22, 29
+====Radiotherapy====
+*Concurrent [[External_beam_radiotherapy|radiation therapy]] 200 cGy per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33 (5000 cGy total in 25 fractions)
+'''5-week course'''
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
+====Subsequent treatment====
+*Neoadjuvant [[#CAPIRI_888|CAPIRI]] x 1, then [[Surgery#Total_mesorectal_excision|TME]], then adjuvant [[#CapeOx|CapeOx]] x 5
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #2, 80 mg/m<sup>2</sup> {{#subobject:t81bak|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768334/ Zhu et al. 2020 (CinClare)]
+|2015-2017
+| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
+|[[Complex_multipart_regimens#CinClare|See link]]
+| style="background-color:#1a9850" |[[Complex_multipart_regimens#CinClare|See link]]
+|-
+|}
+''Note: Treatment is assumed to start on a Monday. Surgery is to take place 8 weeks after completion of chemoradiotherapy.''
+<div class="toccolours" style="background-color:#fdcdac">
+====Biomarker eligibility criteria====
+*''UGT1A1*1*1'' genotype
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Capecitabine (Xeloda)]] 625 mg/m<sup>2</sup> PO twice per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33
+*[[Irinotecan (Camptosar)]] 80 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22, 29
+====Radiotherapy====
+*Concurrent [[External_beam_radiotherapy|radiation therapy]] 200 cGy per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33 (5000 cGy total in 25 fractions)
+'''5-week course'''
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
+====Subsequent treatment====
+*Neoadjuvant [[#CAPIRI_888|CAPIRI]] x 1, then [[Surgery#Total_mesorectal_excision|TME]], then adjuvant [[#CapeOx|CapeOx]] x 5
+</div></div>
 ===References===
-# Twelves C, Wong A, Nowacki MP, Abt M, Burris H 3rd, Carrato A, Cassidy J, Cervantes A, Fagerberg J, Georgoulias V, Husseini F, Jodrell D, Koralewski P, Kröning H, Maroun J, Marschner N, McKendrick J, Pawlicki M, Rosso R, Schüller J, Seitz JF, Stabuc B, Tujakowski J, Van Hazel G, Zaluski J, Scheithauer W. Capecitabine as adjuvant treatment for stage III colon cancer. N Engl J Med. 2005 Jun 30;352(26):2696-704. [http://www.nejm.org/doi/full/10.1056/NEJMoa043116 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/15987918 PubMed]
+#'''CinClare:''' Zhu J, Liu A, Sun X, Liu L, Zhu Y, Zhang T, Jia J, Tan S, Wu J, Wang X, Zhou J, Yang J, Zhang C, Zhang H, Zhao Y, Cai G, Zhang W, Xia F, Wan J, Zhang H, Shen L, Cai S, Zhang Z. Multicenter, Randomized, Phase III Trial of Neoadjuvant Chemoradiation With Capecitabine and Irinotecan Guided by UGT1A1 Status in Patients With Locally Advanced Rectal Cancer. J Clin Oncol. 2020 Dec 20;38(36):4231-4239. Epub 2020 Oct 29. [https://doi.org/10.1200/jco.20.01932 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768334/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/33119477/ PubMed] [https://clinicaltrials.gov/study/NCT02605265 NCT02605265]
+==Fluorouracil & RT {{#subobject:bffc7f|Regimen=1}}==
+Fluorouracil & RT: Fluorouracil & '''<u>R</u>'''adiation '''<u>T</u>'''herapy
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #1, continuous {{#subobject:5801b6|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 17%"|Study
+!style="width: 15%"|Dates of enrollment
+!style="width: 17%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 17%"|Comparator
+!style="width: 17%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+!style="width: 17%"|[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
+|-
+|[https://doi.org/10.1200/JCO.2012.42.9597 Ngan et al. 2012 (TROG 01.014)]
+|2001-2006
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#Radiation_therapy|Short-course RT]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of LR rate at 36 mo
+| style="background-color:#eeee01" |Similar toxicity
+|-
+|[https://doi.org/10.1200/JCO.2010.34.4911 Aschele et al. 2011 (STAR-01)]
+|2003-2008
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#FUOX_.26_RT|FUOX & RT]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<sup>1</sup>
+| style="background-color:#1a9850" |Less toxic
+|-
+| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4050205/ O'Connell et al. 2014 (NSABP R-04)]
+|rowspan=2|2004-2010
+| rowspan="2" style="background-color:#1a9851" |Phase 3 (C)
+|1. [[#Capecitabine_.26_RT|Capecitabine & RT]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of LRC
+| style="background-color:#eeee01" |Similar toxicity
+|-
+|2. [[#CapeOx_.26_RT_999|CapeOx & RT]]<br> 3. [[#FUOX_.26_RT|FUOX & RT]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of LRC
+| style="background-color:#1a9850" |Superior toxicity
+|-
+|}
+''<sup>1</sup>Reported efficacy for STAR-01 is based on the 2016 update.''
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Fluorouracil (5-FU)]] 225 mg/m<sup>2</sup>/day IV continuous infusion until the end of radiation, started on day 1
+====Radiotherapy====
+*Concurrent [[External_beam_radiotherapy|radiation therapy]], 180 cGy for 25 fractions (4500 cGy), with boost depending on stage
+'''5-week course'''
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
+====Subsequent treatment====
+*STAR-01: [[Surgery#Rectal_cancer_surgery|Surgery]], preferably [[Surgery#Total_mesorectal_excision|TME]], then adjuvant [[Regimen_classes#5-FU-based_regimen|fluourouracil-based therapy]]
+*NSABP R-04: [[Surgery#Rectal_cancer_surgery|Surgery]]
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #2, intermittent {{#subobject:3c5452|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://doi.org/10.1056/NEJMoa040694 Sauer et al. 2004 (CAO/ARO/AIO-94)]
+|1995-2002
+| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
+|[[#Fluorouracil_.26_RT_2|5-FU & RT]]; adjuvant
+| style="background-color:#1a9850" |Superior five-year cumulative incidence of local relapse (secondary endpoint)
+|-
+|[https://doi.org/10.1016/S1470-2045%2812%2970116-X Hofheinz et al. 2012 (Rektum-III)]
+|2002-2007
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#Capecitabine_.26_RT|Capecitabine & RT]]
+| style="background-color:#eeee01" |Non-inferior OS
+|-
+|[https://doi.org/10.1016/S1470-2045(12)70187-0 Rödel et al. 2012 (CAO/ARO/AIO-04)]
+|2006-2010
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#FUOX_.26_RT|FUOX & RT]]
+| style="background-color:#fc8d59" |Seems to have inferior pCR rate
+|-
+|}
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Fluorouracil (5-FU)]] 1000 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on days 1 & 29 (total dose: 10,000 mg/m<sup>2</sup>)
+====Radiotherapy====
+*Concurrent [[External_beam_radiotherapy|radiation therapy]], 5040 cGy total
+'''One course'''
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
+====Subsequent treatment====
+*CAO/ARO/AIO-94: [[Surgery#Total_mesorectal_excision|TME]], then adjuvant [[#Fluorouracil_monotherapy|5-FU]]
+</div></div>
+===References===
+# '''CAO/ARO/AIO-94:''' Sauer R, Becker H, Hohenberger W, Rödel C, Wittekind C, Fietkau R, Martus P, Tschmelitsch J, Hager E, Hess CF, Karstens JH, Liersch T, Schmidberger H, Raab R; German Rectal Cancer Study Group. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med. 2004 Oct 21;351(17):1731-40. [https://doi.org/10.1056/NEJMoa040694 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15496622/ PubMed]
+## '''Update:''' Sauer R, Liersch T, Merkel S, Fietkau R, Hohenberger W, Hess C, Becker H, Raab HR, Villanueva MT, Witzigmann H, Wittekind C, Beissbarth T, Rödel C. Preoperative versus postoperative chemoradiotherapy for locally advanced rectal cancer: results of the German CAO/ARO/AIO-94 randomized phase III trial after a median follow-up of 11 years. J Clin Oncol. 2012 Jun 1;30(16):1926-33. Epub 2012 Apr 23. [https://doi.org/10.1200/jco.2011.40.1836 link to original article] [https://pubmed.ncbi.nlm.nih.gov/22529255/ PubMed]
+# '''STAR-01:''' Aschele C, Cionini L, Lonardi S, Pinto C, Cordio S, Rosati G, Artale S, Tagliagambe A, Ambrosini G, Rosetti P, Bonetti A, Negru ME, Tronconi MC, Luppi G, Silvano G, Corsi DC, Bochicchio AM, Chiaulon G, Gallo M, Boni L. Primary tumor response to preoperative chemoradiation with or without oxaliplatin in locally advanced rectal cancer: pathologic results of the STAR-01 randomized phase III trial. J Clin Oncol. 2011 Jul 10;29(20):2773-80. Epub 2011 May 23. [https://doi.org/10.1200/JCO.2010.34.4911 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21606427/ PubMed]
+## '''Update: Abstract:''' Carlo Aschele, Sara Lonardi, Luca Cionini, Carmine Pinto, Stefano Sergio Cordio, Gerardo Rosati, Andrea Sartore Bianchi, Angiolo Tagliagambe, Michela Frisinghelli, Vittorina Zagonel, Paola Rosetti, Maria Emanuela Negru, Andrea Bonetti, Maria Chiara Tronconi, Gabriele Luppi, Anna Rita Marsella, Domenico C. Corsi, Anna Maria Bochicchio, Nicoletta Pella, and Luca Boni. Final results of STAR-01: A randomized phase III trial comparing preoperative chemoradiation with or without oxaliplatin in locally advanced rectal cancer. Journal of Clinical Oncology 2016 34:15_suppl, 3521-3521 [https://doi.org/10.1200/JCO.2016.34.15_suppl.3521 link to abstract]
+# '''Rektum-III:''' Hofheinz RD, Wenz F, Post S, Matzdorff A, Laechelt S, Hartmann JT, Müller L, Link H, Moehler M, Kettner E, Fritz E, Hieber U, Lindemann HW, Grunewald M, Kremers S, Constantin C, Hipp M, Hartung G, Gencer D, Kienle P, Burkholder I, Hochhaus A. Chemoradiotherapy with capecitabine versus fluorouracil for locally advanced rectal cancer: a randomised, multicentre, non-inferiority, phase 3 trial. Lancet Oncol. 2012 Jun;13(6):579-88. Epub 2012 Apr 12. [https://doi.org/10.1016/S1470-2045%2812%2970116-X link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/22503032/ PubMed] [https://clinicaltrials.gov/study/NCT01500993 NCT01500993]
+# '''CAO/ARO/AIO-04:''' Rödel C, Liersch T, Becker H, Fietkau R, Hohenberger W, Hothorn T, Graeven U, Arnold D, Lang-Welzenbach M, Raab HR, Sülberg H, Wittekind C, Potapov S, Staib L, Hess C, Weigang-Köhler K, Grabenbauer GG, Hoffmanns H, Lindemann F, Schlenska-Lange A, Folprecht G, Sauer R; German Rectal Cancer Study Group. Preoperative chemoradiotherapy and postoperative chemotherapy with fluorouracil and oxaliplatin versus fluorouracil alone in locally advanced rectal cancer: initial results of the German CAO/ARO/AIO-04 randomised phase 3 trial. Lancet Oncol. 2012 Jul;13(7):679-87. Epub 2012 May 23. [https://doi.org/10.1016/S1470-2045(12)70187-0 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/22627104/ PubMed] [https://clinicaltrials.gov/study/NCT00349076 NCT00349076]
+## '''Update:''' Rödel C, Graeven U, Fietkau R, Hohenberger W, Hothorn T, Arnold D, Hofheinz RD, Ghadimi M, Wolff HA, Lang-Welzenbach M, Raab HR, Wittekind C, Ströbel P, Staib L, Wilhelm M, Grabenbauer GG, Hoffmanns H, Lindemann F, Schlenska-Lange A, Folprecht G, Sauer R, Liersch T; German Rectal Cancer Study Group. Oxaliplatin added to fluorouracil-based preoperative chemoradiotherapy and postoperative chemotherapy of locally advanced rectal cancer (the German CAO/ARO/AIO-04 study): final results of the multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2015 Aug;16(8):979-89. Epub 2015 Jul 15. [https://doi.org/10.1016/S1470-2045(15)00159-X link to original article] [https://pubmed.ncbi.nlm.nih.gov/26189067/ PubMed]
+# '''TROG 01.014:''' Ngan SY, Burmeister B, Fisher RJ, Solomon M, Goldstein D, Joseph D, Ackland SP, Schache D, McClure B, McLachlan SA, McKendrick J, Leong T, Hartopeanu C, Zalcberg J, Mackay J. Randomized trial of short-course radiotherapy versus long-course chemoradiation comparing rates of local recurrence in patients with T3 rectal cancer: Trans-Tasman Radiation Oncology Group trial 01.04. J Clin Oncol. 2012 Nov 1;30(31):3827-33. Epub 2012 Sep 24. Erratum in: J Clin Oncol. 2013 Jan 20;31(3):399. [https://doi.org/10.1200/JCO.2012.42.9597 link to original article] [https://pubmed.ncbi.nlm.nih.gov/23008301/ PubMed] [https://clinicaltrials.gov/study/NCT00351598 NCT00351598]
+# '''NSABP R-04:''' O'Connell MJ, Colangelo LH, Beart RW, Petrelli NJ, Allegra CJ, Sharif S, Pitot HC, Shields AF, Landry JC, Ryan DP, Parda DS, Mohiuddin M, Arora A, Evans LS, Bahary N, Soori GS, Eakle J, Robertson JM, Moore DF Jr, Mullane MR, Marchello BT, Ward PJ, Wozniak TF, Roh MS, Yothers G, Wolmark N. Capecitabine and oxaliplatin in the preoperative multimodality treatment of rectal cancer: surgical end points from National Surgical Adjuvant Breast and Bowel Project trial R-04. J Clin Oncol. 2014 Jun 20;32(18):1927-34. Epub 2014 May 5. [https://doi.org/10.1200/JCO.2013.53.7753 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4050205/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/24799484/ PubMed] [https://clinicaltrials.gov/study/NCT00058474 NCT00058474]
+## '''Update:''' Allegra CJ, Yothers G, O'Connell MJ, Beart RW, Wozniak TF, Pitot HC, Shields AF, Landry JC, Ryan DP, Arora A, Evans LS, Bahary N, Soori G, Eakle JF, Robertson JM, Moore DF Jr, Mullane MR, Marchello BT, Ward PJ, Sharif S, Roh MS, Wolmark N. Neoadjuvant 5-FU or capecitabine plus radiation with or without oxaliplatin in rectal cancer patients: a phase III randomized clinical trial. J Natl Cancer Inst. 2015 Sep 14;107(11). Erratum in: J Natl Cancer Inst. 2016 Apr;108(4). [https://academic.oup.com/jnci/article/107/11/djv248/2457689 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4849360/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26374429/ PubMed]
+#'''PROSPECT<sub>rectal</sub>:''' Schrag D, Shi Q, Weiser MR, Gollub MJ, Saltz LB, Musher BL, Goldberg J, Al Baghdadi T, Goodman KA, McWilliams RR, Farma JM, George TJ, Kennecke HF, Shergill A, Montemurro M, Nelson GD, Colgrove B, Gordon V, Venook AP, O'Reilly EM, Meyerhardt JA, Dueck AC, Basch E, Chang GJ, Mamon HJ. Preoperative Treatment of Locally Advanced Rectal Cancer. N Engl J Med. 2023 Jul 27;389(4):322-334. Epub 2023 Jun 4. [https://doi.org/10.1056/nejmoa2303269 link to original article] [https://pubmed.ncbi.nlm.nih.gov/37272534/ PubMed] [https://clinicaltrials.gov/study/NCT01515787 NCT01515787]
+##'''PRO analysis:''' Basch E, Dueck AC, Mitchell SA, Mamon H, Weiser M, Saltz L, Gollub M, Rogak L, Ginos B, Mazza GL, Colgrove B, Chang G, Minasian L, Denicoff A, Thanarajasingam G, Musher B, George T, Venook A, Farma J, O'Reilly E, Meyerhardt JA, Shi Q, Schrag D. Patient-Reported Outcomes During and After Treatment for Locally Advanced Rectal Cancer in the PROSPECT Trial (Alliance N1048). J Clin Oncol. 2023 Jul 20;41(21):3724-3734. Epub 2023 Jun 4. [https://doi.org/10.1200/jco.23.00903 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10351948/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/37270691/ PubMed]
+==FOLFIRINOX {{#subobject:aaa3c4|Regimen=1}}==
+FOLFIRINOX: '''<u>FOL</u>'''inic acid (Leucovorin), '''<u>F</u>'''luorouracil, '''<u>IRIN</u>'''otecan, '''<u>OX</u>'''aliplatin
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:e140cb|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://doi.org/10.1016/s1470-2045(21)00079-6 Conroy et al. 2021 (UNICANCER-PRODIGE 23)]
+|2012-2017
+| style="background-color:#1a9851" |Phase 3 (E-esc)
+|[[Rectal_cancer_-_null_regimens#No_neoadjuvant_therapy|No neoadjuvant chemotherapy]]
+| style="background-color:#91cf60" |Seems to have superior DFS36 (primary endpoint)<br>DFS36: 76% vs 69%<br>(sHR 0.69, 95% CI 0.49-0.97)
+|-
+|}
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Leucovorin (Folinic acid)]] 400 mg/m<sup>2</sup> IV once on day 1
+*[[Fluorouracil (5-FU)]] 2400 mg/m<sup>2</sup> IV continuous infusion (duration not specified)
+*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV once on day 1
+*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV once on day 1
+'''14-day cycle for 6 cycles'''
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
+====Subsequent treatment====
+*Neoadjuvant [[#Capecitabine_.26_RT|Capecitabine & RT]]
+</div></div>
+===References===
+# '''UNICANCER-PRODIGE 23:''' Conroy T, Bosset JF, Etienne PL, Rio E, François É, Mesgouez-Nebout N, Vendrely V, Artignan X, Bouché O, Gargot D, Boige V, Bonichon-Lamichhane N, Louvet C, Morand C, de la Fouchardière C, Lamfichekh N, Juzyna B, Jouffroy-Zeller C, Rullier E, Marchal F, Gourgou S, Castan F, Borg C; Unicancer Gastrointestinal Group and Partenariat de Recherche en Oncologie Digestive (PRODIGE) Group. Neoadjuvant chemotherapy with FOLFIRINOX and preoperative chemoradiotherapy for patients with locally advanced rectal cancer (UNICANCER-PRODIGE 23): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2021 May;22(5):702-715. Epub 2021 Apr 13. [https://doi.org/10.1016/s1470-2045(21)00079-6 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/33862000/ PubMed] [https://clinicaltrials.gov/study/NCT01804790 NCT01804790]
+==mFOLFOX6 {{#subobject:faig8v|Regimen=1}}==
+mFOLFOX6: '''<u>FOL</u>'''inic acid (Leucovorin), '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:ckvfc0|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://doi.org/10.1056/nejmoa2303269 Schrag et al. 2023 (PROSPECT<sub>rectal</sub>)]
+|2012-06 to 2018-12
+| style="background-color:#1a9851" |Phase 3 (E-switch-ooc)
+|1a. [[#Capecitabine_.26_RT|Capecitabine & RT]]<br>1b. [[#Fluorouracil_.26_RT|5-FU & RT]]
+| style="background-color:#eeee01" |Non-inferior DFS (primary endpoint)<br>DFS60: 80.8% vs 78.6%<br>(HR 0.92, 90.2% CI 0.74-1.14)
+|-
+|}
+''Note: this trial should not be confused with the one by the same name in prostate cancer.''
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m<sup>2</sup>)
+*[[Leucovorin (Folinic acid)]] 200 mg/m<sup>2</sup> IV once on day 1
+*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV once on day 1
+'''14-day cycle for 6 cycles'''
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
+====Subsequent treatment====
+*[[Surgery#Rectal_cancer_surgery|Surgery]], then optional adjuvant [[#mFOLFOX6_2|mFOLFOX6]] x 6
+</div></div>
+===References===
+#'''PROSPECT<sub>rectal</sub>:''' Schrag D, Shi Q, Weiser MR, Gollub MJ, Saltz LB, Musher BL, Goldberg J, Al Baghdadi T, Goodman KA, McWilliams RR, Farma JM, George TJ, Kennecke HF, Shergill A, Montemurro M, Nelson GD, Colgrove B, Gordon V, Venook AP, O'Reilly EM, Meyerhardt JA, Dueck AC, Basch E, Chang GJ, Mamon HJ. Preoperative Treatment of Locally Advanced Rectal Cancer. N Engl J Med. 2023 Jul 27;389(4):322-334. Epub 2023 Jun 4. [https://doi.org/10.1056/nejmoa2303269 link to original article] [https://pubmed.ncbi.nlm.nih.gov/37272534/ PubMed] [https://clinicaltrials.gov/study/NCT01515787 NCT01515787]
+##'''PRO analysis:''' Basch E, Dueck AC, Mitchell SA, Mamon H, Weiser M, Saltz L, Gollub M, Rogak L, Ginos B, Mazza GL, Colgrove B, Chang G, Minasian L, Denicoff A, Thanarajasingam G, Musher B, George T, Venook A, Farma J, O'Reilly E, Meyerhardt JA, Shi Q, Schrag D. Patient-Reported Outcomes During and After Treatment for Locally Advanced Rectal Cancer in the PROSPECT Trial (Alliance N1048). J Clin Oncol. 2023 Jul 20;41(21):3724-3734. Epub 2023 Jun 4. [https://doi.org/10.1200/jco.23.00903 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10351948/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/37270691/ PubMed]
+==FULV & RT {{#subobject:fbe1a7|Regimen=1}}==
+FULV & RT: '''<u>F</u>'''luoro'''<u>U</u>'''racil, '''<u>L</u>'''euco'''<u>V</u>'''orin, '''<u>R</u>'''adiation '''<u>T</u>'''herapy
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #1, 800/200 ("Nordic schedule") {{#subobject:3780c0|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://doi.org/10.1200/JCO.2007.15.3858 Braendengen et al. 2008 (LARCS)]
+|1996-2003
+| style="background-color:#1a9851" |Phase 3 (E-esc)
+|[[#Radiation_therapy|Radiotherapy]]
+| style="background-color:#d9ef8b" |Might have superior OS60 (primary endpoint)<br>OS60: 66% vs 53%
+|-
+|}
+''Note: reported efficacy is based on the 2018 update.''
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV once per day on days 1, 2, 15, 16, 29, 30 '''given first, prior to RT'''
+*[[Leucovorin (Folinic acid)]] 100 mg IV once per day on days 1 & 2, '''given second'''
+====Radiotherapy====
+*Concurrent [[External_beam_radiotherapy|radiation therapy]] 200 cGy per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33 (25 fractions, total of 5000 cGy)
+'''5-week course'''
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
+====Subsequent treatment====
+*[[Surgery#Rectal_cancer_surgery|Surgery]], then adjuvant [[#FULV|FULV]] x 8
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #2, 1625/100 {{#subobject:0160e1|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2773471/ Roh et al. 2009 (NSABP R-03)]
+|1993-1999
+| style="background-color:#1a9851" |Phase 3 (E-esc)
+|Adjuvant [[#Fluorouracil_.26_RT_2|5-FU & RT]]
+| style="background-color:#d9ef8b" |Might have superior OS (co-primary endpoint)<br>OS60: 74.5% vs 65.6%<br>(HR 0.69, 95% CI 0.47-1.03)
+|-
+|}
+<div class="toccolours" style="background-color:#cbd5e8">
+====Preceding treatment====
+*Neoadjuvant [[#FULV_888|FULV]] x 1
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Fluorouracil (5-FU)]] 325 mg/m<sup>2</sup> IV once per day on days 1 to 5, 29 to 33
+*[[Leucovorin (Folinic acid)]] 20 mg/m<sup>2</sup> IV once per day on days 1 to 5, 29 to 33
+====Radiotherapy====
+*Concurrent [[External_beam_radiotherapy|radiation therapy]], 5040 cGy
+'''5-week course'''
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
+====Subsequent treatment====
+*[[Surgery#Rectal_cancer_surgery|Surgery]], then adjuvant [[#FULV|FULV]] x 4
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #3, 1750/100 {{#subobject:7d3ec1|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://doi.org/10.1016/j.radonc.2014.10.006 Sainato et al. 2014 (I-CNR-RT)]
+|1992-2001
+| style="background-color:#91cf61" |Non-randomized part of phase 3 RCT
+| style="background-color:#d3d3d3" |
+| style="background-color:#d3d3d3" |
+|-
+|[https://doi.org/10.1056/NEJMoa060829 Bosset et al. 2006 (EORTC 22921)]
+|1993-2003
+| style="background-color:#1a9851" |Phase 3 (E-esc)
+|[[#Radiation_therapy|Radiotherapy]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<sup>1</sup>
+|-
+|[https://doi.org/10.1200/JCO.2006.06.7629 Gérard et al. 2006 (FFCD 9203)]
+|1993-2003
+| style="background-color:#1a9851" |Phase 3 (E-esc)
+|[[#Radiation_therapy|Radiotherapy]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<sup>1</sup>
+|-
+|}
+''<sup>1</sup>These trials were negative for the primary endpoint of overall survival, but had much improved local control for the experimental arm.''
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Fluorouracil (5-FU)]] 350 mg/m<sup>2</sup> IV once per day on days 1 to 5, 29 to 33
+*[[Leucovorin (Folinic acid)]] 20 mg/m<sup>2</sup> IV once per day on days 1 to 5, 29 to 33
+====Radiotherapy====
+*Concurrent [[External_beam_radiotherapy|radiation therapy]], 4500 cGy
+'''5-week course'''
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
+====Subsequent treatment====
+*FFCD 9203 & EORTC 22921: [[Surgery#Rectal_cancer_surgery|Surgery]], then adjuvant [[#FULV|FULV]] x 2
+*I-CNR-RT: [[Surgery#Rectal_cancer_surgery|Surgery]], then adjuvant [[#FULV|FULV]] versus [[Rectal_cancer_-_null_regimens#Observation|no further treatment]]
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
-==CapeOx (XELOX) {{#subobject:85a4fd|Regimen=1}}==
+===Regimen variant #4, 2800/400 {{#subobject:98d3ca|Variant=1}}===
-{| class="wikitable" style="float:right; margin-left: 5px;"
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+| rowspan="2" |[https://doi.org/10.1200/jco.2016.66.6198 Deng et al. 2016 (FOWARC)]
+|rowspan=2|2010-2015
+| rowspan="2" style="background-color:#1a9851" |Phase 3 (C)
+|1. [[#mFOLFOX6|mFOLFOX6]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS36<sup>1</sup>
+|-
+|2. [[#mFOLFOX6_.26_RT|mFOLFOX6 & RT]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS36<sup>1</sup>
+|-
+|}
+''<sup>1</sup>Reported efficacy is based on the 2019 update.''<br>
+''Note: this regimen is stated to be based on the de Gramont regimen in the manuscript, although the details are different than those in de Gramont et al. 2000.''
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 1200 mg/m<sup>2</sup>/day IV continuous infusion over 48 hours (total dose per cycle: 2800 mg/m<sup>2</sup>)
+*[[Leucovorin (Folinic acid)]] 400 mg/m<sup>2</sup> IV once on day 1
+'''14-day cycle for 5 cycles'''
+====Radiotherapy====
+*Concurrent [[External_beam_radiotherapy|radiation therapy]] given during cycles 2 to 4: 1.8 to 200 cGy once per day Monday through Friday for a total of 23 to 28 fractions over 5 to 6 weeks and a total dose of 4600 to 5040 cGy
+'''6-week course'''
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
+====Subsequent treatment====
+*[[Surgery#Rectal_cancer_surgery|Surgery]], then adjuvant [[#FULV|FULV]] x 7
+</div></div>
+===References===
+# '''FFCD 9203:''' Gérard JP, Conroy T, Bonnetain F, Bouché O, Chapet O, Closon-Dejardin MT, Untereiner M, Leduc B, Francois E, Maurel J, Seitz JF, Buecher B, Mackiewicz R, Ducreux M, Bedenne L. Preoperative radiotherapy with or without concurrent fluorouracil and leucovorin in T3-4 rectal cancers: results of FFCD 9203. J Clin Oncol. 2006 Oct 1;24(28):4620-5. [https://doi.org/10.1200/JCO.2006.06.7629 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17008704/ PubMed] [https://clinicaltrials.gov/study/NCT00296608 NCT00296608]
+# '''EORTC 22921:''' Bosset JF, Collette L, Calais G, Mineur L, Maingon P, Radosevic-Jelic L, Daban A, Bardet E, Beny A, Ollier JC; [[Study_Groups#EORTC|EORTC]] Radiotherapy Group. Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med. 2006 Sep 14;355(11):1114-23. Erratum in: N Engl J Med. 2007 Aug 16;357(7):728. [https://doi.org/10.1056/NEJMoa060829 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16971718/ PubMed] [https://clinicaltrials.gov/study/NCT00002523 NCT00002523]
+## '''Update:''' Bosset JF, Calais G, Mineur L, Maingon P, Stojanovic-Rundic S, Bensadoun RJ, Bardet E, Beny A, Ollier JC, Bolla M, Marchal D, Van Laethem JL, Klein V, Giralt J, Clavère P, Glanzmann C, Cellier P, Collette L; [[Study_Groups#EORTC|EORTC]] Radiation Oncology Group. Fluorouracil-based adjuvant chemotherapy after preoperative chemoradiotherapy in rectal cancer: long-term results of the EORTC 22921 randomised study. Lancet Oncol. 2014 Feb;15(2):184-90. Epub 2014 Jan 17. [https://doi.org/10.1016/S1470-2045(13)70599-0 link to original article] [https://pubmed.ncbi.nlm.nih.gov/24440473/ PubMed]
+# '''LARCS:''' Braendengen M, Tveit KM, Berglund A, Birkemeyer E, Frykholm G, Påhlman L, Wiig JN, Byström P, Bujko K, Glimelius B. Randomized phase III study comparing preoperative radiotherapy with chemoradiotherapy in nonresectable rectal cancer. J Clin Oncol. 2008 Aug 1;26(22):3687-94. [https://doi.org/10.1200/JCO.2007.15.3858 link to original article] [https://pubmed.ncbi.nlm.nih.gov/18669453/ PubMed]
+## '''Update:''' Brændengen M, Glimelius B. Preoperative radiotherapy or chemoradiotherapy in rectal cancer - Is survival improved? An update of the "Nordic" LARC study in non-resectable cancers. Radiother Oncol. 2018 Jun;127(3):392-395. Epub 2018 May 16. [https://doi.org/10.1016/j.radonc.2018.05.004 link to original article] [https://pubmed.ncbi.nlm.nih.gov/29778486/ PubMed]
+# '''NSABP R-03:''' Roh MS, Colangelo LH, O'Connell MJ, Yothers G, Deutsch M, Allegra CJ, Kahlenberg MS, Baez-Diaz L, Ursiny CS, Petrelli NJ, Wolmark N. Preoperative multimodality therapy improves disease-free survival in patients with carcinoma of the rectum: NSABP R-03. J Clin Oncol. 2009 Nov 1;27(31):5124-30. Epub 2009 Sep 21. [https://doi.org/10.1200/JCO.2009.22.0467 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2773471/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19770376/ PubMed]
+# '''I-CNR-RT:''' Sainato A, Cernusco Luna Nunzia V, Valentini V, De Paoli A, Maurizi ER, Lupattelli M, Aristei C, Vidali C, Conti M, Galardi A, Ponticelli P, Friso ML, Iannone T, Osti FM, Manfredi B, Coppola M, Orlandini C, Cionini L. No benefit of adjuvant Fluorouracil Leucovorin chemotherapy after neoadjuvant chemoradiotherapy in locally advanced cancer of the rectum (LARC): Long term results of a randomized trial (I-CNR-RT). Radiother Oncol. 2014 Nov;113(2):223-9. Epub 2014 Nov 14. [https://doi.org/10.1016/j.radonc.2014.10.006 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/25454175/ PubMed]
+<!-- Presented at the 51st Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 29-June 2, 2015, and 18th Annual Meeting of the Chinese Society of Clinical Oncology, Xiamen, China, September 16-20, 2015. -->
+# '''FOWARC:''' Deng Y, Chi P, Lan P, Wang L, Chen W, Cui L, Chen D, Cao J, Wei H, Peng X, Huang Z, Cai G, Zhao R, Huang Z, Xu L, Zhou H, Wei Y, Zhang H, Zheng J, Huang Y, Zhou Z, Cai Y, Kang L, Huang M, Peng J, Ren D, Wang J. Modified FOLFOX6 with or without radiation versus fluorouracil and leucovorin with radiation in neoadjuvant treatment of locally advanced rectal cancer: initial results of the Chinese FOWARC multicenter, open-label, randomized three-arm phase III trial. J Clin Oncol. 2016 Sep 20;34(27):3300-7. Epub 2016 Aug 1. [https://doi.org/10.1200/jco.2016.66.6198 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/27480145/ PubMed] [https://clinicaltrials.gov/study/NCT01211210 NCT01211210]
+## '''Update:''' Deng Y, Chi P, Lan P, Wang L, Chen W, Cui L, Chen D, Cao J, Wei H, Peng X, Huang Z, Cai G, Zhao R, Huang Z, Xu L, Zhou H, Wei Y, Zhang H, Zheng J, Huang Y, Zhou Z, Cai Y, Kang L, Huang M, Wu X, Peng J, Ren D, Wang J. Neoadjuvant Modified FOLFOX6 With or Without Radiation Versus Fluorouracil Plus Radiation for Locally Advanced Rectal Cancer: Final Results of the Chinese FOWARC Trial. J Clin Oncol. 2019 Dec 1;37(34):3223-3233. Epub 2019 Sep 26. [https://doi.org/10.1200/JCO.18.02309 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6881102/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31557064/ PubMed]
+==FUOX & RT {{#subobject:b3761c|Regimen=1}}==
+FUOX & RT: '''<u>F</u>'''luoro'''<u>U</u>'''racil, '''<u>OX</u>'''aliplatin, '''<u>R</u>'''adiation '''<u>T</u>'''herapy
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #1, 225/50 {{#subobject:66269c|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 17%"|Study
+!style="width: 15%"|Dates of enrollment
+!style="width: 17%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 17%"|Comparator
+!style="width: 17%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+!style="width: 17%"|[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
+|-
+| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4050205/ O'Connell et al. 2014 (NSABP R-04)]
+|rowspan=2|2004-2010
+| rowspan="2" style="background-color:#1a9851" |Phase 3 (E-esc)
+|1. [[#Fluorouracil_.26_RT|5-FU & RT]]<br>2. [[#Capecitabine_.26_RT|Capecitabine & RT]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of LRC
+| style="background-color:#d73027" |Inferior toxicity
+|-
+|3. [[#CapeOx_.26_RT_999|CapeOx & RT]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of LRC
+| style="background-color:#eeee01" |Similar toxicity
+|-
+|}
+''Note: This was an experimental arm that did not meet its primary endpoint; included here because other variants of this regimen have demonstrated comparative superiority.''
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Fluorouracil (5-FU)]] 225 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on days 1, 8, 15, 22, 29 (total dose: 5625 mg/m<sup>2</sup>)
+*[[Oxaliplatin (Eloxatin)]] 50 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22, 29
+====Radiotherapy====
+*Concurrent [[External_beam_radiotherapy|radiation therapy]], 5040 cGy total
+'''5.5-week course'''
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
+====Subsequent treatment====
+*[[Surgery#Rectal_cancer_surgery|Surgery]]
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #2, 225/60 {{#subobject:0b1c02|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 17%"|Study
+!style="width: 15%"|Dates of enrollment
+!style="width: 17%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 17%"|Comparator
+!style="width: 17%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+!style="width: 17%"|[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
+|-
+|[https://doi.org/10.1200/JCO.2010.34.4911 Aschele et al. 2011 (STAR-01)]
+|2003-2008
+| style="background-color:#1a9851" |Phase 3 (E-esc)
+|[[#Fluorouracil_.26_RT|Fluorouracil & RT]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<sup>1</sup>
+| style="background-color:#d73027" |More toxic
+|-
+|}
+''<sup>1</sup>Reported efficacy is based on the 2016 update.''<br>
+''Note: This was an experimental arm that did not meet its primary endpoint; included here because other variants of this regimen have demonstrated comparative superiority.''
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Fluorouracil (5-FU)]] 225 mg/m<sup>2</sup>/day IV continuous infusion over approximately 6 weeks, started on day 1
+*[[Oxaliplatin (Eloxatin)]] 60 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22, 29, 36
+====Radiotherapy====
+*Concurrent [[External_beam_radiotherapy|radiation therapy]], 5040 cGy total
+'''6-week course'''
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
+====Subsequent treatment====
+*[[Surgery#Rectal_cancer_surgery|Surgery]], preferably [[Surgery#Total_mesorectal_excision|TME]], then adjuvant [[Regimen_classes#5-FU-based_regimen|fluourouracil-based therapy]]
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #3, 250/50 {{#subobject:858489|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://doi.org/10.1016/S1470-2045(12)70187-0 Rödel et al. 2012 (CAO/ARO/AIO-04)]
+|2006-2010
+| style="background-color:#1a9851" |Phase 3 (E-esc)
+|[[#Fluorouracil_.26_RT|Fluorouracil & RT]]
+| style="background-color:#91cf60" |Seems to have superior pCR rate (secondary endpoint)
+|-
+|}
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Fluorouracil (5-FU)]] 250 mg/m<sup>2</sup>/day IV continuous infusion over 14 days, started on days 1 & 22 (total dose: 7000 mg/m<sup>2</sup>)
+*[[Oxaliplatin (Eloxatin)]] 50 mg/m<sup>2</sup> IV once per day on days 1, 8, 22, 29
+====Radiotherapy====
+*Concurrent [[External_beam_radiotherapy|radiation therapy]], 5040 cGy total
+'''One course'''
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
+====Subsequent treatment====
+*[[Surgery#Rectal_cancer_surgery|Surgery]], then adjuvant [[#FOLFOX|FOLFOX]]
+</div></div>
+===References===
+# '''STAR-01:''' Aschele C, Cionini L, Lonardi S, Pinto C, Cordio S, Rosati G, Artale S, Tagliagambe A, Ambrosini G, Rosetti P, Bonetti A, Negru ME, Tronconi MC, Luppi G, Silvano G, Corsi DC, Bochicchio AM, Chiaulon G, Gallo M, Boni L. Primary tumor response to preoperative chemoradiation with or without oxaliplatin in locally advanced rectal cancer: pathologic results of the STAR-01 randomized phase III trial. J Clin Oncol. 2011 Jul 10;29(20):2773-80. Epub 2011 May 23. [https://doi.org/10.1200/JCO.2010.34.4911 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21606427/ PubMed]
+## '''Update: Abstract:''' Carlo Aschele, Sara Lonardi, Luca Cionini, Carmine Pinto, Stefano Sergio Cordio, Gerardo Rosati, Andrea Sartore Bianchi, Angiolo Tagliagambe, Michela Frisinghelli, Vittorina Zagonel, Paola Rosetti, Maria Emanuela Negru, Andrea Bonetti, Maria Chiara Tronconi, Gabriele Luppi, Anna Rita Marsella, Domenico C. Corsi, Anna Maria Bochicchio, Nicoletta Pella, and Luca Boni. Final results of STAR-01: A randomized phase III trial comparing preoperative chemoradiation with or without oxaliplatin in locally advanced rectal cancer. Journal of Clinical Oncology 2016 34:15_suppl, 3521-3521 [https://doi.org/10.1200/JCO.2016.34.15_suppl.3521 link to abstract]
+# '''CAO/ARO/AIO-04:''' Rödel C, Liersch T, Becker H, Fietkau R, Hohenberger W, Hothorn T, Graeven U, Arnold D, Lang-Welzenbach M, Raab HR, Sülberg H, Wittekind C, Potapov S, Staib L, Hess C, Weigang-Köhler K, Grabenbauer GG, Hoffmanns H, Lindemann F, Schlenska-Lange A, Folprecht G, Sauer R; German Rectal Cancer Study Group. Preoperative chemoradiotherapy and postoperative chemotherapy with fluorouracil and oxaliplatin versus fluorouracil alone in locally advanced rectal cancer: initial results of the German CAO/ARO/AIO-04 randomised phase 3 trial. Lancet Oncol. 2012 Jul;13(7):679-87. Epub 2012 May 23. [https://doi.org/10.1016/S1470-2045(12)70187-0 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/22627104/ PubMed] [https://clinicaltrials.gov/study/NCT00349076 NCT00349076]
+## '''Update:''' Rödel C, Graeven U, Fietkau R, Hohenberger W, Hothorn T, Arnold D, Hofheinz RD, Ghadimi M, Wolff HA, Lang-Welzenbach M, Raab HR, Wittekind C, Ströbel P, Staib L, Wilhelm M, Grabenbauer GG, Hoffmanns H, Lindemann F, Schlenska-Lange A, Folprecht G, Sauer R, Liersch T; German Rectal Cancer Study Group. Oxaliplatin added to fluorouracil-based preoperative chemoradiotherapy and postoperative chemotherapy of locally advanced rectal cancer (the German CAO/ARO/AIO-04 study): final results of the multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2015 Aug;16(8):979-89. Epub 2015 Jul 15. [https://doi.org/10.1016/S1470-2045(15)00159-X link to original article] [https://pubmed.ncbi.nlm.nih.gov/26189067/ PubMed]
+# '''NSABP R-04:''' O'Connell MJ, Colangelo LH, Beart RW, Petrelli NJ, Allegra CJ, Sharif S, Pitot HC, Shields AF, Landry JC, Ryan DP, Parda DS, Mohiuddin M, Arora A, Evans LS, Bahary N, Soori GS, Eakle J, Robertson JM, Moore DF Jr, Mullane MR, Marchello BT, Ward PJ, Wozniak TF, Roh MS, Yothers G, Wolmark N. Capecitabine and oxaliplatin in the preoperative multimodality treatment of rectal cancer: surgical end points from National Surgical Adjuvant Breast and Bowel Project trial R-04. J Clin Oncol. 2014 Jun 20;32(18):1927-34. Epub 2014 May 5. [https://doi.org/10.1200/JCO.2013.53.7753 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4050205/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/24799484/ PubMed] [https://clinicaltrials.gov/study/NCT00058474 NCT00058474]
+## '''Update:''' Allegra CJ, Yothers G, O'Connell MJ, Beart RW, Wozniak TF, Pitot HC, Shields AF, Landry JC, Ryan DP, Arora A, Evans LS, Bahary N, Soori G, Eakle JF, Robertson JM, Moore DF Jr, Mullane MR, Marchello BT, Ward PJ, Sharif S, Roh MS, Wolmark N. Neoadjuvant 5-FU or capecitabine plus radiation with or without oxaliplatin in rectal cancer patients: a phase III randomized clinical trial. J Natl Cancer Inst. 2015 Sep 14;107(11). Erratum in: J Natl Cancer Inst. 2016 Apr;108(4). [https://academic.oup.com/jnci/article/107/11/djv248/2457689 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4849360/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26374429/ PubMed]
+==mFOLFOX6 & RT {{#subobject:4ffffc|Regimen=1}}==
+mFOLFOX6 & RT: '''<u>m</u>'''odified '''<u>FOL</u>'''inic acid (Leucovorin), '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin and '''<u>R</u>'''adiation '''<u>T</u>'''herapy
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:9bf2ab|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+| rowspan="2" |[https://doi.org/10.1200/jco.2016.66.6198 Deng et al. 2016 (FOWARC)]
+|rowspan=2|2010-2015
+| rowspan="2" style="background-color:#1a9851" |Phase 3 (E-esc)
+|1. [[#FULV_.26_RT|FULV & RT]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS36<sup>1</sup>
+|-
+|2. [[#mFOLFOX6|mFOLFOX6]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS36<sup>1</sup>
+|-
+|}
+''<sup>1</sup>Reported efficacy is based on the 2019 update.''
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Leucovorin (Folinic acid)]] 400 mg/m<sup>2</sup> IV once on day 1
+*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 1200 mg/m<sup>2</sup>/day IV continuous infusion over 48 hours (total dose per cycle: 2800 mg/m<sup>2</sup>)
+*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV once on day 1
+'''14-day cycle for 4 to 6 cycles'''
+====Radiotherapy====
+*Concurrent [[External_beam_radiotherapy|radiation therapy]] given before or after surgery at physician discretion: 180 to 200 cGy once per day Monday through Friday for a total of 23 to 28 fractions, for a total dose of 4600 to 5040 cGy
+'''5- to 6-week course'''
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
+====Subsequent treatment====
+*[[Surgery#Rectal_cancer_surgery|Surgery]], then adjuvant [[#mFOLFOX6_2|mFOLFOX6]] x 6 to 8
+</div></div>
+===References===
+<!-- Presented at the 51st Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 29-June 2, 2015, and 18th Annual Meeting of the Chinese Society of Clinical Oncology, Xiamen, China, September 16-20, 2015. -->
+# '''FOWARC:''' Deng Y, Chi P, Lan P, Wang L, Chen W, Cui L, Chen D, Cao J, Wei H, Peng X, Huang Z, Cai G, Zhao R, Huang Z, Xu L, Zhou H, Wei Y, Zhang H, Zheng J, Huang Y, Zhou Z, Cai Y, Kang L, Huang M, Peng J, Ren D, Wang J. Modified FOLFOX6 with or without radiation versus fluorouracil and leucovorin with radiation in neoadjuvant treatment of locally advanced rectal cancer: initial results of the Chinese FOWARC multicenter, open-label, randomized three-arm phase III trial. J Clin Oncol. 2016 Sep 20;34(27):3300-7. Epub 2016 Aug 1. [https://doi.org/10.1200/jco.2016.66.6198 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/27480145/ PubMed] [https://clinicaltrials.gov/study/NCT01211210 NCT01211210]
+## '''Update:''' Deng Y, Chi P, Lan P, Wang L, Chen W, Cui L, Chen D, Cao J, Wei H, Peng X, Huang Z, Cai G, Zhao R, Huang Z, Xu L, Zhou H, Wei Y, Zhang H, Zheng J, Huang Y, Zhou Z, Cai Y, Kang L, Huang M, Wu X, Peng J, Ren D, Wang J. Neoadjuvant Modified FOLFOX6 With or Without Radiation Versus Fluorouracil Plus Radiation for Locally Advanced Rectal Cancer: Final Results of the Chinese FOWARC Trial. J Clin Oncol. 2019 Dec 1;37(34):3223-3233. Epub 2019 Sep 26. [https://doi.org/10.1200/JCO.18.02309 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6881102/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31557064/ PubMed]
+==Radiation therapy {{#subobject:41234c|Regimen=1}}==
+RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #1, 2500 cGy {{#subobject:9abcab|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://doi.org/10.1056/NEJM199704033361402 Cedermark et al. 1997 (Swedish Rectal Cancer Trial)]
+|1987-1990
+| style="background-color:#1a9851" |Phase 3 (E-esc)
+|[[Rectal_cancer_-_null_regimens#No_neoadjuvant_therapy|Surgery alone]]
+| style="background-color:#1a9850" |Superior OS
+|-
+|[https://doi.org/10.1056/NEJMoa010580 Kapiteijn et al. 2001]
+|1996-1999
+| style="background-color:#1a9851" |Phase 3 (E-esc)
+|[[Rectal_cancer_-_null_regimens#No_neoadjuvant_therapy|Surgery alone]]
+| style="background-color:#1a9850" |Superior local recurrence rate
+|-
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2668947/ Sebag-Montefiore et al. 2009 (MRC CR07; NCIC-CTG CO.16)]
+|1998-2005
+| style="background-color:#1a9851" |Phase 3 (C)
+|Selective postoperative [[#Fluorouracil_.26_RT_2|5-FU & RT]]
+| style="background-color:#91cf60" |Seems to have superior DFS
+|-
+|[https://doi.org/10.1093/annonc/mdw062 Bujko et al. 2016 (Polish II)]
+|2008-2014
+| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
+|[[#FULV_.26_RT|FULV & RT]]
+| style="background-color:#d9ef8b" |Might have superior R0 resection rate (primary endpoint)
+|-
+|[https://doi.org/10.1016/s1470-2045(20)30555-6 Bahadoer et al. 2020 (RAPIDO)]
+|2011-2016
+| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
+|[[Complex_multipart_regimens#RAPIDO|See link]]
+| style="background-color:#91cf60" |[[Complex_multipart_regimens#RAPIDO|See link]]
+|-
+|}
+<div class="toccolours" style="background-color:#b3e2cd">
+====Radiotherapy====
+*[[External_beam_radiotherapy|Radiation therapy]], 500 cGy once per day for a total of 5 fractions (total dose: 2500 cGy)
+'''5-day course'''
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
+====Subsequent treatment====
+*Swedish Rectal Cancer Trial, Kapiteijn et al. 2001, NCIC-CTG CO.16: [[Surgery#Rectal_cancer_surgery|Surgery]]
+*Polish II: Neoadjuvant [[#FOLFOX4_888|FOLFOX4]] x 3, then [[Surgery#Rectal_cancer_surgery|Surgery]]
+*RAPIDO: Neoadjuvant [[#CapeOx|CapeOx]] x 6 or [[#FOLFOX4_888|FOLFOX4]] x 9, then [[Surgery#Rectal_cancer_surgery|Surgery]]
+</div></div><br>
+<div class="toccolours" style="background-color:#ee6b6e">
+===Regimen variant #2, 4000 cGy {{#subobject:8b0799|Variant=1}}===
+{| class="wikitable" style="color:white; background-color:#f01e2c"
+|<small><span style="color:white;">'''Historic variant'''</span></small>
 |-
-|[[#toc|back to top]]
 |}
-CapeOX: '''<u>Cape</u>'''citabine, '''<u>OX</u>'''aliplatin <br>
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-XELOX: '''<u>XEL</u>'''oda (Capecitabine), '''<u>OX</u>'''aliplatin
+!style="width: 20%"|Study
-===Regimen {{#subobject:34b870|Variant=1}}===
+!style="width: 20%"|Dates of enrollment
-{| border="1" style="text-align:center;" !align="left"
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-|'''Study'''
+!style="width: 20%"|Comparator
-|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|'''Comparator'''
+|-
+|[https://doi.org/10.1016/S0140-6736(96)05348-2 Oates et al. 1996]
+|1981-1989
+| style="background-color:#1a9851" |Phase 3 (E-esc)
+|[[Rectal_cancer_-_null_regimens#No_neoadjuvant_therapy|Surgery alone]]
+| style="background-color:#91cf60" |Seems to have superior DFS
 |-
-|[http://jco.ascopubs.org/content/25/1/102.long Schmoll et al. 2007]
+|}
-|<span
+<div class="toccolours" style="background-color:#b3e2cd">
-style="background:#00CD00;
+====Radiotherapy====
-padding:3px 6px 3px 6px;
+*[[External_beam_radiotherapy|Radiation therapy]], 200 cGy x 20 fractions (total dose: 4000 cGy)
-border-color:black;
+'''4-week course'''
-border-width:2px;
+</div>
-border-style:solid;">Phase III</span>
+<div class="toccolours" style="background-color:#cbd5e7">
-|[[Rectal_cancer#Fluorouracil_.285-FU.29_.26_Folinic_acid_.28Leucovorin.29|Fluorouracil & Folinic acid]]
+====Subsequent treatment====
+*[[Surgery#Rectal_cancer_surgery|Surgery]]
+</div></div><br>
+<div class="toccolours" style="background-color:#ee6b6e">
+===Regimen variant #3, 5000 cGy {{#subobject:159853|Variant=1}}===
+{| class="wikitable" style="color:white; background-color:#f01e2c"
+|<small><span style="color:white;">'''Historic variant'''</span></small>
 |-
 |}
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://doi.org/10.1200/JCO.2007.15.3858 Braendengen et al. 2008 (LARCS)]
+|1996-2003
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#FULV.2FFULV_.26_RT|FULV/FULV & RT]]
+| style="background-color:#fee08b" |Might have inferior OS60
+|-
+|}
+<div class="toccolours" style="background-color:#b3e2cd">
+====Radiotherapy====
+*[[External_beam_radiotherapy|Radiation therapy]], 200 cGy x 25 fractions (total dose: 5000 cGy)
+'''5-week course'''
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
+====Subsequent treatment====
+*[[Surgery#Rectal_cancer_surgery|Surgery]]
+</div></div>
+===References===
+# Oates GD, Stenning SP, Hardcastle JD; Medical Research Council Rectal Cancer Working Party. Randomised trial of surgery alone versus radiotherapy followed by surgery for potentially operable locally advanced rectal cancer. Lancet. 1996 Dec 14;348(9042):1605-10. [https://doi.org/10.1016/S0140-6736(96)05348-2 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/8961989/ PubMed]
+# '''Swedish Rectal Cancer Trial:''' Cedermark B, Dahlberg M, Glimelius B, Påhlman L, Rutqvist LE, Wilking N; Swedish Rectal Cancer Trial investigators. Improved survival with preoperative radiotherapy in resectable rectal cancer. N Engl J Med. 1997 Apr 3;336(14):980-7. Erratum in: N Engl J Med 1997 May 22;336(21):1539. [https://doi.org/10.1056/NEJM199704033361402 link to original article] [https://pubmed.ncbi.nlm.nih.gov/9091798/ PubMed]
+## '''Update:''' Folkesson J, Birgisson H, Pahlman L, Cedermark B, Glimelius B, Gunnarsson U. Swedish Rectal Cancer Trial: long lasting benefits from radiotherapy on survival and local recurrence rate. J Clin Oncol. 2005 Aug 20;23(24):5644-50. [https://doi.org/10.1200/JCO.2005.08.144 link to original article] [https://pubmed.ncbi.nlm.nih.gov/16110023/ PubMed]
+# Kapiteijn E, Marijnen CA, Nagtegaal ID, Putter H, Steup WH, Wiggers T, Rutten HJ, Pahlman L, Glimelius B, van Krieken JH, Leer JW, van de Velde CJ; Dutch Colorectal Cancer Group. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med. 2001 Aug 30;345(9):638-46. [https://doi.org/10.1056/NEJMoa010580 link to original article] [https://pubmed.ncbi.nlm.nih.gov/11547717/ PubMed]
+# '''LARCS:''' Braendengen M, Tveit KM, Berglund A, Birkemeyer E, Frykholm G, Påhlman L, Wiig JN, Byström P, Bujko K, Glimelius B. Randomized phase III study comparing preoperative radiotherapy with chemoradiotherapy in nonresectable rectal cancer. J Clin Oncol. 2008 Aug 1;26(22):3687-94. [https://doi.org/10.1200/JCO.2007.15.3858 link to original article] [https://pubmed.ncbi.nlm.nih.gov/18669453/ PubMed]
+## '''Update:''' Brændengen M, Glimelius B. Preoperative radiotherapy or chemoradiotherapy in rectal cancer - Is survival improved? An update of the "Nordic" LARC study in non-resectable cancers. Radiother Oncol. 2018 Jun;127(3):392-395. Epub 2018 May 16. [https://doi.org/10.1016/j.radonc.2018.05.004 link to original article] [https://pubmed.ncbi.nlm.nih.gov/29778486/ PubMed]
+# '''MRC CR07; NCIC-CTG CO.16:''' Sebag-Montefiore D, Stephens RJ, Steele R, Monson J, Grieve R, Khanna S, Quirke P, Couture J, de Metz C, Myint AS, Bessell E, Griffiths G, Thompson LC, Parmar M. Preoperative radiotherapy versus selective postoperative chemoradiotherapy in patients with rectal cancer (MRC CR07 and NCIC-CTG C016): a multicentre, randomised trial. Lancet. 2009 Mar 7;373(9666):811-20. [https://doi.org/10.1016/s0140-6736(09)60484-0 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2668947/ link to PMC article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/19269519/ PubMed] [https://clinicaltrials.gov/study/NCT00003422 NCT00003422]
+# '''Polish II:''' Bujko K, Wyrwicz L, Rutkowski A, Malinowska M, Pietrzak L, Kryński J, Michalski W, Olędzki J, Kuśnierz J, Zając L, Bednarczyk M, Szczepkowski M, Tarnowski W, Kosakowska E, Zwoliński J, Winiarek M, Wiśniowska K, Partycki M, Bęczkowska K, Polkowski W, Styliński R, Wierzbicki R, Bury P, Jankiewicz M, Paprota K, Lewicka M, Ciseł B, Skórzewska M, Mielko J, Bębenek M, Maciejczyk A, Kapturkiewicz B, Dybko A, Hajac Ł, Wojnar A, Leśniak T, Zygulska J, Jantner D, Chudyba E, Zegarski W, Las-Jankowska M, Jankowski M, Kołodziejski L, Radkowski A, Żelazowska-Omiotek U, Czeremszyńska B, Kępka L, Kolb-Sielecki J, Toczko Z, Fedorowicz Z, Dziki A, Danek A, Nawrocki G, Sopyło R, Markiewicz W, Kędzierawski P, Wydmański J; Polish Colorectal Study Group. Long-course oxaliplatin-based preoperative chemoradiation versus 5 x 5 Gy and consolidation chemotherapy for cT4 or fixed cT3 rectal cancer: results of a randomized phase III study. Ann Oncol. 2016 May;27(5):834-42. Epub 2016 Feb 15. [https://doi.org/10.1093/annonc/mdw062 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/26884592/ PubMed] [https://clinicaltrials.gov/study/NCT00833131 NCT00833131]
+## '''Update:''' Ciseł B, Pietrzak L, Michalski W, Wyrwicz L, Rutkowski A, Kosakowska E, Cencelewicz A, Spałek M, Polkowski W, Jankiewicz M, Styliński R, Bębenek M, Kapturkiewicz B, Maciejczyk A, Sadowski J, Zygulska J, Zegarski W, Jankowski M, Las-Jankowska M, Toczko Z, Żelazowska-Omiotek U, Kępka L, Socha J, Wasilewska-Tesluk E, Markiewicz W, Kładny J, Majewski A, Kapuściński W, Suwiński R, Bujko K; Polish Colorectal Study Group. Long-course preoperative chemoradiation vs 5 x 5 Gy and consolidation chemotherapy for clinical T4 and fixed clinical T3 rectal cancer: long-term results of the randomized Polish II study. Ann Oncol. 2019 Aug 1;30(8):1298-1303. Epub 2019 Jun 13.  [https://doi.org/10.1093/annonc/mdz186 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31192355/ PubMed]
+#'''RAPIDO:''' Bahadoer RR, Dijkstra EA, van Etten B, Marijnen CAM, Putter H, Kranenbarg EM, Roodvoets AGH, Nagtegaal ID, Beets-Tan RGH, Blomqvist LK, Fokstuen T, Ten Tije AJ, Capdevila J, Hendriks MP, Edhemovic I, Cervantes A, Nilsson PJ, Glimelius B, van de Velde CJH, Hospers GAP; RAPIDO collaborative investigators. Short-course radiotherapy followed by chemotherapy before total mesorectal excision (TME) versus preoperative chemoradiotherapy, TME, and optional adjuvant chemotherapy in locally advanced rectal cancer (RAPIDO): a randomised, open-label, phase 3 trial. Lancet Oncol. 2021 Jan;22(1):29-42. Epub 2020 Dec 7. [https://doi.org/10.1016/s1470-2045(20)30555-6 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/33301740/ PubMed] [https://clinicaltrials.gov/study/NCT01558921 NCT01558921]
-*[[Capecitabine (Xeloda)]] 1000 mg/m2 PO BID, starting the evening of day 1, to continue through the morning of day 15 (28 total doses)
+=Adjuvant chemotherapy=
-*[[Oxaliplatin (Eloxatin)]] 130 mg/m2 IV over 2 hours once on day 1
+==Capecitabine monotherapy {{#subobject:38d595|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
-'''21-day cycle x 8 cycles'''
+===Regimen variant #1, 2000 mg/m<sup>2</sup>/day x 6 {{#subobject:48gua4|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://doi.org/10.1200/jco.20.01740 Schmoll et al. 2020 (PETACC 6)]
+|2008-2011
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#CapeOx_999|CapeOx]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS36
+|-
+|}
+''Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.''
+<div class="toccolours" style="background-color:#cbd5e8">
+====Preceding treatment====
+*Neoadjuvant [[#Capecitabine_.26_RT|capecitabine & RT]], then [[Surgery#Rectal_cancer_surgery|surgery]]
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 15
+'''21-day cycle for 6 cycles'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #2, 2500 mg/m<sup>2</sup>/day x 5 {{#subobject:4e5ce4|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://doi.org/10.1016/S1470-2045%2812%2970116-X Hofheinz et al. 2012 (Rektum-III)]
+|2002-2007
+| style="background-color:#1a9851" |Phase 3 (E-RT-switch-ic)
+|[[#Fluorouracil_monotherapy|Fluorouracil]]
+| style="background-color:#eeee01" |Non-inferior OS (primary endpoint)<br>OS60: 76% vs 67%
+|-
+|}
+''Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.''
+<div class="toccolours" style="background-color:#cbd5e8">
+====Preceding treatment====
+*Neoadjuvant [[#Capecitabine_.26_RT|capecitabine & RT]], then [[Surgery#Rectal_cancer_surgery|surgery]]
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Capecitabine (Xeloda)]] 1250 mg/m<sup>2</sup> PO twice per day on days 1 to 14
+'''21-day cycle for 5 cycles'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #3, 2500 mg/m<sup>2</sup>/day x 8 {{#subobject:4e9jn4|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://doi.org/10.1093/annonc/mdu560 Breugom et al. 2014 (SCRIPT)]
+|2000-2013
+| style="background-color:#1a9851" |Phase 3 (E-esc)
+|[[Rectal_cancer_-_null_regimens#Observation|Observation]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
+|-
+|}
+''Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.''
+<div class="toccolours" style="background-color:#cbd5e8">
+====Preceding treatment====
+*Neoadjuvant [[Regimen_classes#5-FU-based_chemoradiotherapy|5-FU-based chemoradiotherapy]] or [[#Radiation_therapy|RT]], then [[Surgery#Rectal_cancer_surgery|surgery]]
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Capecitabine (Xeloda)]] 1250 mg/m<sup>2</sup> PO twice per day on days 1 to 14
+'''21-day cycle for 8 cycles'''
+</div></div>
+===References===
+# '''Rektum-III:''' Hofheinz RD, Wenz F, Post S, Matzdorff A, Laechelt S, Hartmann JT, Müller L, Link H, Moehler M, Kettner E, Fritz E, Hieber U, Lindemann HW, Grunewald M, Kremers S, Constantin C, Hipp M, Hartung G, Gencer D, Kienle P, Burkholder I, Hochhaus A. Chemoradiotherapy with capecitabine versus fluorouracil for locally advanced rectal cancer: a randomised, multicentre, non-inferiority, phase 3 trial. Lancet Oncol. 2012 Jun;13(6):579-88. Epub 2012 Apr 12. [https://doi.org/10.1016/S1470-2045%2812%2970116-X link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/22503032/ PubMed] [https://clinicaltrials.gov/study/NCT01500993 NCT01500993]
+# '''SCRIPT:''' Breugom AJ, van Gijn W, Muller EW, Berglund Å, van den Broek CB, Fokstuen T, Gelderblom H, Kapiteijn E, Leer JW, Marijnen CA, Martijn H, Meershoek-Klein Kranenbarg E, Nagtegaal ID, Påhlman L, Punt CJ, Putter H, Roodvoets AG, Rutten HJ, Steup WH, Glimelius B, van de Velde CJ; Dutch Colorectal Cancer Group; Nordic Gastrointestinal Tumour Adjuvant Therapy Group. Adjuvant chemotherapy for rectal cancer patients treated with preoperative (chemo)radiotherapy and total mesorectal excision: a Dutch Colorectal Cancer Group (DCCG) randomized phase III trial. Ann Oncol. 2015 Apr;26(4):696-701. Epub 2014 Dec 5. [https://doi.org/10.1093/annonc/mdu560 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/25480874/ PubMed] ISRCTN36266738
+# '''PETACC 6:''' Schmoll HJ, Stein A, Van Cutsem E, Price T, Hofheinz RD, Nordlinger B, Daisne JF, Janssens J, Brenner B, Reinel H, Hollerbach S, Caca K, Fauth F, Hannig CV, Zalcberg J, Tebbutt N, Mauer ME, Marreaud S, Lutz MP, Haustermans K. Pre- and Postoperative Capecitabine Without or With Oxaliplatin in Locally Advanced Rectal Cancer: PETACC 6 Trial by EORTC GITCG and ROG, AIO, AGITG, BGDO, and FFCD. J Clin Oncol. 2021 Jan 1;39(1):17-29. Epub 2020 Oct 1. [https://doi.org/10.1200/jco.20.01740 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/33001764/ PubMed] [https://clinicaltrials.gov/study/NCT00766155 NCT00766155]
+==Fluorouracil monotherapy {{#subobject:adc56e|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #1 {{#subobject:66d35a|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://doi.org/10.1016/S1470-2045%2812%2970116-X Hofheinz et al. 2012 (Rektum-III)]
+|2002-2007
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#Capecitabine_monotherapy|Capecitabine]]
+| style="background-color:#eeee01" |Non-inferior OS
+|-
+|}
+<div class="toccolours" style="background-color:#cbd5e8">
+====Preceding treatment====
+*Neoadjuvant [[#Fluorouracil_.26_RT|5-FU & RT]], then [[Surgery#Rectal_cancer_surgery|surgery]]
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5
+'''28-day cycle for 4 cycles'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #2 {{#subobject:38a90a|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://doi.org/10.1016/S1470-2045(12)70187-0 Rödel et al. 2012 (CAO/ARO/AIO-04)]
+|2006-2010
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#FOLFOX|FOLFOX]]
+| style="background-color:#fc8d59" |Seems to have inferior DFS<sup>1</sup>
+|-
+|}
+''<sup>1</sup>Reported efficacy is based on the 2015 update.''
+<div class="toccolours" style="background-color:#cbd5e8">
+====Preceding treatment====
+*Neoadjuvant [[#Fluorouracil_.26_RT|5-FU & RT]], then [[Surgery#Rectal_cancer_surgery|surgery]]
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5, 29
+'''4 cycles (length not specified)'''
+</div></div>
 ===References===
-# Schmoll HJ, Cartwright T, Tabernero J, Nowacki MP, Figer A, Maroun J, Price T, Lim R, Van Cutsem E, Park YS, McKendrick J, Topham C, Soler-Gonzalez G, de Braud F, Hill M, Sirzén F, Haller DG. Phase III trial of capecitabine plus oxaliplatin as adjuvant therapy for stage III colon cancer: a planned safety analysis in 1,864 patients. J Clin Oncol. 2007 Jan 1;25(1):102-9. [http://jco.ascopubs.org/content/25/1/102.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/17194911 PubMed]
+# '''Rektum-III:''' Hofheinz RD, Wenz F, Post S, Matzdorff A, Laechelt S, Hartmann JT, Müller L, Link H, Moehler M, Kettner E, Fritz E, Hieber U, Lindemann HW, Grunewald M, Kremers S, Constantin C, Hipp M, Hartung G, Gencer D, Kienle P, Burkholder I, Hochhaus A. Chemoradiotherapy with capecitabine versus fluorouracil for locally advanced rectal cancer: a randomised, multicentre, non-inferiority, phase 3 trial. Lancet Oncol. 2012 Jun;13(6):579-88. Epub 2012 Apr 12. [https://doi.org/10.1016/S1470-2045%2812%2970116-X link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/22503032/ PubMed] [https://clinicaltrials.gov/study/NCT01500993 NCT01500993]
-## '''Update:''' Haller DG, Tabernero J, Maroun J, de Braud F, Price T, Van Cutsem E, Hill M, Gilberg F, Rittweger K, Schmoll HJ. Capecitabine plus oxaliplatin compared with fluorouracil and folinic acid as adjuvant therapy for stage III colon cancer. J Clin Oncol. 2011 Apr 10;29(11):1465-71. Epub 2011 Mar 7. [http://jco.ascopubs.org/content/29/11/1465.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/21383294 PubMed]
+# '''CAO/ARO/AIO-04:''' Rödel C, Liersch T, Becker H, Fietkau R, Hohenberger W, Hothorn T, Graeven U, Arnold D, Lang-Welzenbach M, Raab HR, Sülberg H, Wittekind C, Potapov S, Staib L, Hess C, Weigang-Köhler K, Grabenbauer GG, Hoffmanns H, Lindemann F, Schlenska-Lange A, Folprecht G, Sauer R; German Rectal Cancer Study Group. Preoperative chemoradiotherapy and postoperative chemotherapy with fluorouracil and oxaliplatin versus fluorouracil alone in locally advanced rectal cancer: initial results of the German CAO/ARO/AIO-04 randomised phase 3 trial. Lancet Oncol. 2012 Jul;13(7):679-87. Epub 2012 May 23. [https://doi.org/10.1016/S1470-2045(12)70187-0 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/22627104/ PubMed] [https://clinicaltrials.gov/study/NCT00349076 NCT00349076]
+## '''Update:''' Rödel C, Graeven U, Fietkau R, Hohenberger W, Hothorn T, Arnold D, Hofheinz RD, Ghadimi M, Wolff HA, Lang-Welzenbach M, Raab HR, Wittekind C, Ströbel P, Staib L, Wilhelm M, Grabenbauer GG, Hoffmanns H, Lindemann F, Schlenska-Lange A, Folprecht G, Sauer R, Liersch T; German Rectal Cancer Study Group. Oxaliplatin added to fluorouracil-based preoperative chemoradiotherapy and postoperative chemotherapy of locally advanced rectal cancer (the German CAO/ARO/AIO-04 study): final results of the multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2015 Aug;16(8):979-89. Epub 2015 Jul 15. [https://doi.org/10.1016/S1470-2045(15)00159-X link to original article] [https://pubmed.ncbi.nlm.nih.gov/26189067/ PubMed]
-==FLOX {{#subobject:27341b|Regimen=1}}==
+==FULV {{#subobject:d6c3bd|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+FULV: 5-'''<u>FU</u>''' & '''<u>L</u>'''euco'''<u>V</u>'''orin
+<div class="toccolours" style="background-color:#ee6b6e">
+===Regimen variant #1, 500/500 {{#subobject:cc7508|Variant=1}}===
+{| class="wikitable" style="color:white; background-color:#f01e2c"
+|<small><span style="color:white;">'''Historic variant'''</span></small>
+|-
+|}
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://academic.oup.com/jnci/article/92/5/388/2606692 Wolmark et al. 2000 (NSABP R-02)]
+|1987-1992
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#FULV_.26_RT_999|FULV & RT]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS60
+|-
+|}
+''Note: male patients were also randomized to MOF or MOF & RT.''
+<div class="toccolours" style="background-color:#cbd5e8">
+====Preceding treatment====
+*[[Surgery#Rectal_cancer_surgery|Surgery]]
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22, 29, 36, '''given 1 hour after leucovorin'''
+*[[Leucovorin (Folinic acid)]] 500 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22, 29, 36, '''given first'''
+'''8-week cycle for 6 cycles'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #2, 1000/120 ("Nordic regimen") {{#subobject:9df33b|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://doi.org/10.1093/annonc/mdu560 Breugom et al. 2014 (PROCTOR)]
+|2000-2013
+| style="background-color:#1a9851" |Phase 3 (E-esc)
+|[[Rectal_cancer_-_null_regimens#Observation|Observation]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
+|-
+|}
+''Note: This was an experimental arm that did not meet its primary endpoint; included here because other variants of this regimen have been used as a standard comparator. This is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.''
+<div class="toccolours" style="background-color:#cbd5e8">
+====Preceding treatment====
+*Neoadjuvant [[Regimen_classes#5-FU-based_chemoradiotherapy|5-FU-based chemoradiotherapy]] or [[#Radiation_therapy|RT]], then [[Surgery#Rectal_cancer_surgery|surgery]]
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV once per day on days 1 & 2, '''given first''' (total dose per cycle: 1000 mg/m<sup>2</sup>)
+*[[Leucovorin (Folinic acid)]] 60 mg/m<sup>2</sup> IV once per day on days 1 & 2, '''given second''' (total dose per cycle: 120 mg/m<sup>2</sup>)
+'''14-day cycle for 12 cycles'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #3, 1900/100 {{#subobject:9df33b|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://doi.org/10.1016/S1470-2045(14)70377-8 Hong et al. 2014 (ADORE)]
+|2008-2012
+| style="background-color:#1a9851" |Randomized Phase 2 (C)
+|[[#FOLFOX|FOLFOX]]
+| style="background-color:#fc8d59" |Seems to have inferior DFS36
+|-
+|}
+''Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.''
+<div class="toccolours" style="background-color:#cbd5e8">
+====Preceding treatment====
+*Neoadjuvant [[Regimen_classes#Fluoropyrimidine-based_chemoradiotherapy|fluoropyrimidine-based chemoradiation]], then [[Surgery#Total_mesorectal_excision|TME]]
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Fluorouracil (5-FU)]] 380 mg/m<sup>2</sup> IV once per day on days 1 to 5 (total dose per cycle: 1900 mg/m<sup>2</sup>)
+*[[Leucovorin (Folinic acid)]] 20 mg/m<sup>2</sup> IV once per day on days 1 to 5 (total dose per cycle: 100 mg/m<sup>2</sup>)
+'''28-day cycle for 4 cycles'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #4, 2125/100 ("Mayo regimen") {{#subobject:9df33b|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://doi.org/10.1093/annonc/mdv135 Delbaldo et al. 2015 (R98)]
+|1999-2005
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#FOLFIRI_999|FOLFIRI]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
+|-
+|[https://doi.org/10.1093/annonc/mdu560 Breugom et al. 2014 (PROCTOR)]
+|2000-2013
+| style="background-color:#1a9851" |Phase 3 (E-esc)
+|[[Rectal_cancer_-_null_regimens#Observation|Observation]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
-|[[#toc|back to top]]
 |}
-FLOX: '''<u>F</u>'''luorouracil, '''<u>L</u>'''eucovorin, '''<u>OX</u>'''aliplatin
+''Note: This was an experimental arm that did not meet its primary endpoint; included here because it was eventually used to establish this regimen as a standard comparator. This is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.''
-===Regimen {{#subobject:75f6f2|Variant=1}}===
+<div class="toccolours" style="background-color:#cbd5e8">
-Level of Evidence:
+====Preceding treatment====
-<span
+*PROCTOR: Neoadjuvant [[Regimen_classes#5-FU-based_chemoradiotherapy|5-FU-based chemoradiotherapy]] or [[#Radiation_therapy|RT]], then [[Surgery#Rectal_cancer_surgery|surgery]]
-style="background:#00CD00;
+</div>
-padding:3px 6px 3px 6px;
+<div class="toccolours" style="background-color:#b3e2cd">
-border-color:black;
+====Chemotherapy====
-border-width:2px;
+*[[Fluorouracil (5-FU)]] 425 mg/m<sup>2</sup> IV once per day on days 1 to 5 (total dose per cycle: 2125 mg/m<sup>2</sup>)
-border-style:solid;">Phase III</span>
+*[[Leucovorin (Folinic acid)]] 20 mg/m<sup>2</sup> IV once per day on days 1 to 5 (total dose per cycle: 100 mg/m<sup>2</sup>)
+'''4- to 5-week cycle for 6 cycles'''
-*[[Fluorouracil (5-FU)]] 500 mg/m2 IV bolus on days 1, 8, 15, 22, 29, 36, to start 1 hour after start of leucovorin
+</div></div>
-*[[Folinic acid (Leucovorin)]] 500 mg/m2 IV over 2 hours on days 1, 8, 15, 22, 29, 36, given before Fluorouracil (5-FU)
-*[[Oxaliplatin (Eloxatin)]] 85 mg/m2 IV over 2 hours on days 1, 15, 29, given prior to 5-FU and leucovorin
-'''8-week cycles x 3 cycles'''
 ===References===
-# Kuebler JP, Wieand HS, O'Connell MJ, Smith RE, Colangelo LH, Yothers G, Petrelli NJ, Findlay MP, Seay TE, Atkins JN, Zapas JL, Goodwin JW, Fehrenbacher L, Ramanathan RK, Conley BA, Flynn PJ, Soori G, Colman LK, Levine EA, Lanier KS, Wolmark N. Oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer: results from NSABP C-07. J Clin Oncol. 2007 Jun 1;25(16):2198-204. Epub 2007 Apr 30. [http://jco.ascopubs.org/content/25/16/2198.full link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/17470851 PubMed]
+# '''NSABP R-02:''' Wolmark N, Wieand HS, Hyams DM, Colangelo L, Dimitrov NV, Romond EH, Wexler M, Prager D, Cruz AB Jr, Gordon PH, Petrelli NJ, Deutsch M, Mamounas E, Wickerham DL, Fisher ER, Rockette H, Fisher B. Randomized trial of postoperative adjuvant chemotherapy with or without radiotherapy for carcinoma of the rectum: National Surgical Adjuvant Breast and Bowel Project Protocol R-02. J Natl Cancer Inst. 2000 Mar 1;92(5):388-96. [https://academic.oup.com/jnci/article/92/5/388/2606692 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/10699069/ PubMed]
+# '''ADORE:''' Hong YS, Nam BH, Kim KP, Kim JE, Park SJ, Park YS, Park JO, Kim SY, Kim TY, Kim JH, Ahn JB, Lim SB, Yu CS, Kim JC, Yun SH, Kim JH, Park JH, Park HC, Jung KH, Kim TW. Oxaliplatin, fluorouracil, and leucovorin versus fluorouracil and leucovorin as adjuvant chemotherapy for locally advanced rectal cancer after preoperative chemoradiotherapy (ADORE): an open-label, multicentre, phase 2, randomised controlled trial. Lancet Oncol. 2014 Oct;15(11):1245-53. Epub 2014 Sep 4. [https://doi.org/10.1016/S1470-2045(14)70377-8 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/25201358/ PubMed] [https://clinicaltrials.gov/study/NCT00807911 NCT00807911]
-==Fluorouracil (5-FU) & Folinic acid (Leucovorin) {{#subobject:d6c3bd|Regimen=1}}==
+## '''Update:''' Hong YS, Kim SY, Lee JS, Nam BH, Kim KP, Kim JE, Park YS, Park JO, Baek JY, Kim TY, Lee KW, Ahn JB, Lim SB, Yu CS, Kim JC, Yun SH, Kim JH, Park JH, Park HC, Jung KH, Kim TW. Oxaliplatin-Based Adjuvant Chemotherapy for Rectal Cancer After Preoperative Chemoradiotherapy (ADORE): Long-Term Results of a Randomized Controlled Trial. J Clin Oncol. 2019 Nov 20;37(33):3111-3123. Epub 2019 Oct 8. [https://doi.org/10.1200/JCO.19.00016 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31593484/ PubMed]
-{| class="wikitable" style="float:right; margin-left: 5px;"
+# '''PROCTOR:''' Breugom AJ, van Gijn W, Muller EW, Berglund Å, van den Broek CB, Fokstuen T, Gelderblom H, Kapiteijn E, Leer JW, Marijnen CA, Martijn H, Meershoek-Klein Kranenbarg E, Nagtegaal ID, Påhlman L, Punt CJ, Putter H, Roodvoets AG, Rutten HJ, Steup WH, Glimelius B, van de Velde CJ; Dutch Colorectal Cancer Group; Nordic Gastrointestinal Tumour Adjuvant Therapy Group. Adjuvant chemotherapy for rectal cancer patients treated with preoperative (chemo)radiotherapy and total mesorectal excision: a Dutch Colorectal Cancer Group (DCCG) randomized phase III trial. Ann Oncol. 2015 Apr;26(4):696-701. Epub 2014 Dec 5. [https://doi.org/10.1093/annonc/mdu560 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/25480874/ PubMed] ISRCTN36266738
+# '''R98:''' Delbaldo C, Ychou M, Zawadi A, Douillard JY, André T, Guerin-Meyer V, Rougier P, Dupuis O, Faroux R, Jouhaud A, Quinaux E, Buyse M, Piedbois P; AERO; GERCOR; FNCLCC; FFCD. Postoperative irinotecan in resected stage II-III rectal cancer: final analysis of the French R98 Intergroup trial. Ann Oncol. 2015 Jun;26(6):1208-15. Epub 2015 Mar 3. [https://doi.org/10.1093/annonc/mdv135 link to original article] [https://pubmed.ncbi.nlm.nih.gov/25739671/ PubMed]
+==mFOLFOX6 {{#subobject:fad3f|Regimen=1}}==
+mFOLFOX6: '''<u>FOL</u>'''inic acid (Leucovorin), '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #1, with 5-FU bolus, 8 cycles {{#subobject:f31fc0|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://doi.org/10.1016/S1470-2045(14)70377-8 Hong et al. 2014 (ADORE)]
+|2008-2012
+| style="background-color:#1a9851" |Randomized Phase 2 (E-esc)
+|[[#FULV|FULV]]
+| style="background-color:#91cf60" |Seems to have superior DFS36 (primary endpoint)<br>DFS36: 71.6% vs 62.9%<br>(HR 0.66, 95% CI 0.43-0.994)
+|-
+|}
+<div class="toccolours" style="background-color:#cbd5e8">
+====Preceding treatment====
+*Neoadjuvant [[Regimen_classes#Fluoropyrimidine-based_chemoradiotherapy|fluoropyrimidine-based chemoradiation]], then [[Surgery#Total_mesorectal_excision|TME]]
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m<sup>2</sup>)
+*[[Leucovorin (Folinic acid)]] 200 mg/m<sup>2</sup> IV once on day 1
+*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV once on day 1
+'''14-day cycle for 8 cycles'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #2, no 5-FU bolus, 8 cycles {{#subobject:f3300f|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://doi.org/10.1016/S1470-2045(12)70187-0 Rödel et al. 2012 (CAO/ARO/AIO-04)]
+|2006-2010
+| style="background-color:#1a9851" |Phase 3 (E-esc)
+|[[#Fluorouracil_monotherapy|Fluorouracil]]
+| style="background-color:#91cf60" |Seems to have superior DFS<sup>1</sup> (primary endpoint)<br>DFS36: 75.95% vs 71.2%<br>(HR 0.79, 95% CI 0.64-0.98)
+|-
+|}
+''<sup>1</sup>Reported efficacy is based on the 2015 update.''
+<div class="toccolours" style="background-color:#cbd5e8">
+====Preceding treatment====
+*Neoadjuvant [[#FUOX_.26_RT|FUOX & RT]], then [[Surgery#Rectal_cancer_surgery|surgery]]
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Fluorouracil (5-FU)]] 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours, started on day 1, '''given third''' (total dose per cycle: 2400 mg/m<sup>2</sup>)
+*[[Leucovorin (Folinic acid)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given second'''
+*[[Oxaliplatin (Eloxatin)]] 100 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first'''
+'''14-day cycle for 8 cycles'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #3, 12 cycles {{#subobject:f3hg10|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7216434/ Chakravarthy et al. 2019 (ECOG E5204)]
+|2006-2009
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#mFOLFOX6-B_999|mFOLFOX6-B]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br>OS60: 88.3% vs 83.7%
 |-
-|[[#toc|back to top]]
 |}
-===Regimen #1, simplified biweekly (sLV5FU2), André et al. 1999 {{#subobject:9df33b|Variant=1}}===
+<div class="toccolours" style="background-color:#cbd5e8">
-Level of Evidence:
+====Preceding treatment====
-<span
+*Neoadjuvant [[Regimen_classes#Fluoropyrimidine-based_chemoradiotherapy|fluoropyrimidine-based chemoradiation]], then [[Surgery#Total_mesorectal_excision|TME]]
-style="background:#EEEE00;
+</div>
-padding:3px 6px 3px 6px;
+<div class="toccolours" style="background-color:#b3e2cd">
-border-color:black;
+====Chemotherapy====
-border-width:2px;
+*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m<sup>2</sup>)
-border-style:solid;">Phase II</span>
+*[[Leucovorin (Folinic acid)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1
+*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1
-''Note: The reference cited by the NCCN, Rectal Cancer version 3.2012, is for patients with metastatic disease. No primary reference for adjuvant use of these dosages could be found.''
+'''14-day cycle for 12 cycles'''
-*[[Folinic acid (Leucovorin)]] 400 mg/m2 IV over 2 hours day 1 (administer first)
+</div></div>
-*[[Fluorouracil (5-FU)]] 400 mg/m2 IV bolus after leucovorin, then 1200 mg/m2/day IV continuous infusion over 46-48 hours
-'''14-day cycles x 12 cycles'''
-===Regimen #2, Van Cutsem et al. 2009 (PETACC-3) & Baumgaertner et al. 2010 (GERCOR C96.1) {{#subobject:996b06|Variant=1}}===
-Level of Evidence:
-<span
-style="background:#00CD00;
-padding:3px 6px 3px 6px;
-border-color:black;
-border-width:2px;
-border-style:solid;">Phase III</span>
-*[[Fluorouracil (5-FU)]] 400 mg/m2 IV bolus, then 600 mg/m2/day IV continuous infusion over 22 hours; both bolus and continuous infusion given on days 1 & 2
-*[[Folinic acid (Leucovorin)]] 200 mg/m2 IV over 2 hours before 5-FU on days 1 and 2
-'''14-day cycles x 12 cycles'''
-===Regimen #3, 5-FU & high-dose Leucovorin (Roswell Park regimen/HDLV); Haller et al. 2005; Lembersky et al. 2006; Schmoll et al. 2007 {{#subobject:dd01b5|Variant=1}}===
-Level of Evidence:
-<span
-style="background:#00CD00;
-padding:3px 6px 3px 6px;
-border-color:black;
-border-width:2px;
-border-style:solid;">Phase III</span>
-''Note: The Petrelli et al. 1989 reference cited by the NCCN, Rectal Cancer version 3.2012, is for patients with metastatic disease, and the regimen differs from what is listed by the NCCN.  The other references contain the correct regimen.  The NCCN lists a 6-month course of therapy, whereas the other references list either a 6 to 8-month course of therapy.''
-*[[Folinic acid (Leucovorin)]] 500 mg/m2 IV over 2 hours weekly x 6 weeks
-*[[Fluorouracil (5-FU)]] 500 mg/m2 IV push 1 hour after start of leucovorin weekly x 6 weeks
-'''8-week cycles x 3-4 cycles'''
 ===References===
-# Petrelli N, Douglass HO Jr, Herrera L, Russell D, Stablein DM, Bruckner HW, Mayer RJ, Schinella R, Green MD, Muggia FM et al. The modulation of fluorouracil with leucovorin in metastatic colorectal carcinoma: a prospective randomized phase III trial. Gastrointestinal Tumor Study Group. J Clin Oncol. 1989 Oct;7(10):1419-26. [http://jco.ascopubs.org/content/7/10/1419.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/2674331 PubMed]
+# '''ADORE:''' Hong YS, Nam BH, Kim KP, Kim JE, Park SJ, Park YS, Park JO, Kim SY, Kim TY, Kim JH, Ahn JB, Lim SB, Yu CS, Kim JC, Yun SH, Kim JH, Park JH, Park HC, Jung KH, Kim TW. Oxaliplatin, fluorouracil, and leucovorin versus fluorouracil and leucovorin as adjuvant chemotherapy for locally advanced rectal cancer after preoperative chemoradiotherapy (ADORE): an open-label, multicentre, phase 2, randomised controlled trial. Lancet Oncol. 2014 Oct;15(11):1245-53. Epub 2014 Sep 4. [https://doi.org/10.1016/S1470-2045(14)70377-8 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/25201358/ PubMed] [https://clinicaltrials.gov/study/NCT00807911 NCT00807911]
-# André T, Louvet C, Maindrault-Goebel F, Couteau C, Mabro M, Lotz JP, Gilles-Amar V, Krulik M, Carola E, Izrael V, de Gramont A. CPT-11 (irinotecan) addition to bimonthly, high-dose leucovorin and bolus and continuous-infusion 5-fluorouracil (FOLFIRI) for pretreated metastatic colorectal cancer. GERCOR. Eur J Cancer. 1999 Sep;35(9):1343-7. [http://www.ejcancer.info/article/S0959-8049%2899%2900150-1/fulltext link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/10658525 PubMed]
+## '''Update:''' Hong YS, Kim SY, Lee JS, Nam BH, Kim KP, Kim JE, Park YS, Park JO, Baek JY, Kim TY, Lee KW, Ahn JB, Lim SB, Yu CS, Kim JC, Yun SH, Kim JH, Park JH, Park HC, Jung KH, Kim TW. Oxaliplatin-Based Adjuvant Chemotherapy for Rectal Cancer After Preoperative Chemoradiotherapy (ADORE): Long-Term Results of a Randomized Controlled Trial. J Clin Oncol. 2019 Nov 20;37(33):3111-3123. Epub 2019 Oct 8. [https://doi.org/10.1200/JCO.19.00016 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31593484/ PubMed]
-# Twelves C, Wong A, Nowacki MP, Abt M, Burris H 3rd, Carrato A, Cassidy J, Cervantes A, Fagerberg J, Georgoulias V, Husseini F, Jodrell D, Koralewski P, Kröning H, Maroun J, Marschner N, McKendrick J, Pawlicki M, Rosso R, Schüller J, Seitz JF, Stabuc B, Tujakowski J, Van Hazel G, Zaluski J, Scheithauer W. Capecitabine as adjuvant treatment for stage III colon cancer. N Engl J Med. 2005 Jun 30;352(26):2696-704. [http://www.nejm.org/doi/full/10.1056/NEJMoa043116 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/15987918 PubMed]
+# '''CAO/ARO/AIO-04:''' Rödel C, Liersch T, Becker H, Fietkau R, Hohenberger W, Hothorn T, Graeven U, Arnold D, Lang-Welzenbach M, Raab HR, Sülberg H, Wittekind C, Potapov S, Staib L, Hess C, Weigang-Köhler K, Grabenbauer GG, Hoffmanns H, Lindemann F, Schlenska-Lange A, Folprecht G, Sauer R; German Rectal Cancer Study Group. Preoperative chemoradiotherapy and postoperative chemotherapy with fluorouracil and oxaliplatin versus fluorouracil alone in locally advanced rectal cancer: initial results of the German CAO/ARO/AIO-04 randomised phase 3 trial. Lancet Oncol. 2012 Jul;13(7):679-87. Epub 2012 May 23. [https://doi.org/10.1016/S1470-2045(12)70187-0 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/22627104/ PubMed] [https://clinicaltrials.gov/study/NCT00349076 NCT00349076]
-# Haller DG, Catalano PJ, Macdonald JS, O'Rourke MA, Frontiera MS, Jackson DV, Mayer RJ. Phase III study of fluorouracil, leucovorin, and levamisole in high-risk stage II and III colon cancer: final report of Intergroup 0089. J Clin Oncol. 2005 Dec 1;23(34):8671-8. [http://jco.ascopubs.org/content/23/34/8671.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/16314627 PubMed]
+## '''Update:''' Rödel C, Graeven U, Fietkau R, Hohenberger W, Hothorn T, Arnold D, Hofheinz RD, Ghadimi M, Wolff HA, Lang-Welzenbach M, Raab HR, Wittekind C, Ströbel P, Staib L, Wilhelm M, Grabenbauer GG, Hoffmanns H, Lindemann F, Schlenska-Lange A, Folprecht G, Sauer R, Liersch T; German Rectal Cancer Study Group. Oxaliplatin added to fluorouracil-based preoperative chemoradiotherapy and postoperative chemotherapy of locally advanced rectal cancer (the German CAO/ARO/AIO-04 study): final results of the multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2015 Aug;16(8):979-89. Epub 2015 Jul 15. [https://doi.org/10.1016/S1470-2045(15)00159-X link to original article] [https://pubmed.ncbi.nlm.nih.gov/26189067/ PubMed]
-# Lembersky BC, Wieand HS, Petrelli NJ, O'Connell MJ, Colangelo LH, Smith RE, Seay TE, Giguere JK, Marshall ME, Jacobs AD, Colman LK, Soran A, Yothers G, Wolmark N. Oral uracil and tegafur plus leucovorin compared with intravenous fluorouracil and leucovorin in stage II and III carcinoma of the colon: results from National Surgical Adjuvant Breast and Bowel Project Protocol C-06. J Clin Oncol. 2006 May 1;24(13):2059-64. [http://jco.ascopubs.org/content/24/13/2059.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/16648506 PubMed]
+#'''ECOG E5204:''' Chakravarthy AB, Zhao F, Meropol NJ, Flynn PJ, Wagner LI, Sloan J, Diasio RB, Mitchell EP, Catalano P, Giantonio BJ, Catalano RB, Haller DG, Awan RA, Mulcahy MF, O'Brien TE, Santala R, Cripps C, Weis JR, Atkins JN, Leichman CG, Petrelli NJ, Sinicrope FA, Brierley JD, Tepper JE, O'Dwyer PJ, Sigurdson ER, Hamilton SR, Cella D, Benson AB 3rd. Intergroup Randomized Phase III Study of Postoperative Oxaliplatin, 5-Fluorouracil, and Leucovorin Versus Oxaliplatin, 5-Fluorouracil, Leucovorin, and Bevacizumab for Patients with Stage II or III Rectal Cancer Receiving Preoperative Chemoradiation: A Trial of the ECOG-ACRIN Research Group (E5204). Oncologist. 2020 May;25(5):e798-e807. Epub 2019 Dec 18. [https://doi.org/10.1634/theoncologist.2019-0437 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7216434/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/31852811/ PubMed] [https://clinicaltrials.gov/study/NCT00303628 NCT00303628]
-# Schmoll HJ, Cartwright T, Tabernero J, Nowacki MP, Figer A, Maroun J, Price T, Lim R, Van Cutsem E, Park YS, McKendrick J, Topham C, Soler-Gonzalez G, de Braud F, Hill M, Sirzén F, Haller DG. Phase III trial of capecitabine plus oxaliplatin as adjuvant therapy for stage III colon cancer: a planned safety analysis in 1,864 patients. J Clin Oncol. 2007 Jan 1;25(1):102-9. [http://jco.ascopubs.org/content/25/1/102.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/17194911 PubMed]
+==S-1 monotherapy {{#subobject:ec10ef|Regimen=1}}==
-# Kuebler JP, Wieand HS, O'Connell MJ, Smith RE, Colangelo LH, Yothers G, Petrelli NJ, Findlay MP, Seay TE, Atkins JN, Zapas JL, Goodwin JW, Fehrenbacher L, Ramanathan RK, Conley BA, Flynn PJ, Soori G, Colman LK, Levine EA, Lanier KS, Wolmark N. Oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer: results from NSABP C-07. J Clin Oncol. 2007 Jun 1;25(16):2198-204. Epub 2007 Apr 30. [http://jco.ascopubs.org/content/25/16/2198.full link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/17470851 PubMed]
+<div class="toccolours" style="background-color:#eeeeee">
-# Van Cutsem E, Labianca R, Bodoky G, Barone C, Aranda E, Nordlinger B, Topham C, Tabernero J, André T, Sobrero AF, Mini E, Greil R, Di Costanzo F, Collette L, Cisar L, Zhang X, Khayat D, Bokemeyer C, Roth AD, Cunningham D. Randomized phase III trial comparing biweekly infusional fluorouracil/leucovorin alone or with irinotecan in the adjuvant treatment of stage III colon cancer: PETACC-3. J Clin Oncol. 2009 Jul 1;27(19):3117-25. Epub 2009 May 18. [http://jco.ascopubs.org/content/27/19/3117.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/19451425 PubMed]
+===Regimen {{#subobject:0ee98c|Variant=1}}===
-# Baumgaertner I, Quinaux E, Khalil A, Louvet C, Buyse M, de Gramont A, André T; GERCOR Group. Comparison of the levogyre and dextro-levogyre forms of leucovorin in a phase III trial of bimonthly LV5FU2 versus monthly 5-fluorouracil and high-dose leucovorin for patients with stage II and III colon cancer (GERCOR C96.1). Clin Colorectal Cancer. 2010 Apr;9(2):E5-10. [http://www.sciencedirect.com/science/article/pii/S1533002811700470 link to original article] '''contains protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/20378497 PubMed]
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
-==Fluorouracil, Folinic acid, Levamisole {{#subobject:45b35a|Regimen=1}}==
+!style="width: 20%"|Dates of enrollment
-{| class="wikitable" style="float:right; margin-left: 5px;"
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4922318/ Oki et al. 2016 (ACTS-RC)]
+|2006-2009
+| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
+|[[#UFT_monotherapy|UFT]]
+| style="background-color:#91cf60" |Seems to have superior RFS (primary endpoint)<br>RFS60: 66.4% vs 61.7%<br>(HR 0.77, 95% CI 0.63-0.96)
 |-
-|[[#toc|back to top]]
 |}
+''Note: these patients did not receive preoperative therapy.''
-===Regimen, Haller et al. 2005 (Intergroup 0089) {{#subobject:dda8f4|Variant=1}}===
+<div class="toccolours" style="background-color:#cbd5e8">
-Level of Evidence:
+====Preceding treatment====
-<span
+*Curative [[Surgery#Rectal_cancer_surgery|resection]] for stage II or stage III rectal cancer, within 49 days
-style="background:#00CD00;
+</div>
-padding:3px 6px 3px 6px;
+<div class="toccolours" style="background-color:#b3e2cd">
-border-color:black;
+====Chemotherapy====
-border-width:2px;
+*[[Tegafur, gimeracil, oteracil (S-1)]] by the following BSA-based criteria:
-border-style:solid;">Phase III</span>
+**Less than 1.25 m<sup>2</sup>: 40 mg PO twice per day on days 1 to 28
+**BSA 1.25 to 1.5 m<sup>2</sup>: 50 mg PO twice per day on days 1 to 28
-''Not in routine use; used as a comparator arm and here for reference purposes only.''
+**BSA 1.5 or greater m<sup>2</sup>: 60 mg PO twice per day on days 1 to 28
+'''42-day cycle for 9 cycles (1 year)'''
-*[[Folinic acid (Leucovorin)]] 20 mg/m2 IV push before 5-FU on days 1 to 5
+</div></div>
-*[[Fluorouracil (5-FU)]] 425 mg/m2 IV push on days 1 to 5
-*[[Levamisole (Ergamisol)]]
-'''28-day cycles x 3 cycles, then 35-day cycles x 3 cycles'''
 ===References===
-# Haller DG, Catalano PJ, Macdonald JS, O'Rourke MA, Frontiera MS, Jackson DV, Mayer RJ. Phase III study of fluorouracil, leucovorin, and levamisole in high-risk stage II and III colon cancer: final report of Intergroup 0089. J Clin Oncol. 2005 Dec 1;23(34):8671-8. [http://jco.ascopubs.org/content/23/34/8671.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/16314627 PubMed]
+# '''ACTS-RC:''' Oki E, Murata A, Yoshida K, Maeda K, Ikejiri K, Munemoto Y, Sasaki K, Matsuda C, Kotake M, Suenaga T, Matsuda H, Emi Y, Kakeji Y, Baba H, Hamada C, Saji S, Maehara Y. A randomized phase III trial comparing S-1 versus UFT as adjuvant chemotherapy for stage II/III rectal cancer (JFMC35-C1: ACTS-RC). Ann Oncol. 2016 Jul;27(7):1266-72. Epub 2016 Apr 7. [https://doi.org/10.1093/annonc/mdw162 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4922318/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/27056996/ PubMed] UMIN C000000385
+==UFT monotherapy {{#subobject:0c1194|Regimen=1}}==
-==mFOLFOX 6 {{#subobject:fad3f|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
-{| class="wikitable" style="float:right; margin-left: 5px;"
+===Regimen {{#subobject:7dc55c|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://doi.org/10.1007/s00280-010-1358-1 Hamaguchi et al. 2010 (NSAS-CC)]
+|1996-2001
+| style="background-color:#1a9851" |Phase 3 (E-esc)
+|[[Rectal_cancer_-_null_regimens#Observation|Observation]]
+| style="background-color:#91cf60" |Seems to have superior OS (secondary endpoint)
+|-
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4922318/ Oki et al. 2016 (ACTS-RC)]
+|2006-2009
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#S-1_monotherapy|S-1]]
+| style="background-color:#fc8d59" |Seems to have inferior RFS
 |-
-|[[#toc|back to top]]
 |}
-===Regimen {{#subobject:f31fc0|Variant=1}}===
+''Note: these patients did not receive preoperative therapy.''
-Level of Evidence:
+<div class="toccolours" style="background-color:#cbd5e8">
-<span
+====Preceding treatment====
-style="background:#00CD00;
+*Curative [[Surgery#Rectal_cancer_surgery|resection]] for stage II or stage III rectal cancer, within 49 days
-padding:3px 6px 3px 6px;
+</div>
-border-color:black;
+<div class="toccolours" style="background-color:#b3e2cd">
-border-width:2px;
+====Chemotherapy====
-border-style:solid;">Phase III</span>
+*[[Tegafur and uracil (UFT)]] by the following BSA-based criteria:
+**Less than 1.25 m<sup>2</sup>: 250 mg PO twice per day on days 1 to 5
+**1.25 m<sup>2</sup> or more: 300 mg PO twice per day on days 1 to 5
+'''7-day cycle for 52 cycles'''
+</div></div>
+===References===
+# '''NSAS-CC:''' Hamaguchi T, Shirao K, Moriya Y, Yoshida S, Kodaira S, Ohashi Y; NSAS-CC Group. Final results of randomized trials by the National Surgical Adjuvant Study of Colorectal Cancer (NSAS-CC). Cancer Chemother Pharmacol. 2011 Mar;67(3):587-96. Epub 2010 May 19. [https://doi.org/10.1007/s00280-010-1358-1 link to original article] [https://pubmed.ncbi.nlm.nih.gov/20490797/ PubMed] [https://clinicaltrials.gov/study/NCT00152230 NCT00152230]
+# '''ACTS-RC:''' Oki E, Murata A, Yoshida K, Maeda K, Ikejiri K, Munemoto Y, Sasaki K, Matsuda C, Kotake M, Suenaga T, Matsuda H, Emi Y, Kakeji Y, Baba H, Hamada C, Saji S, Maehara Y. A randomized phase III trial comparing S-1 versus UFT as adjuvant chemotherapy for stage II/III rectal cancer (JFMC35-C1: ACTS-RC). Ann Oncol. 2016 Jul;27(7):1266-72. Epub 2016 Apr 7. [https://doi.org/10.1093/annonc/mdw162 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4922318/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/27056996/ PubMed] UMIN C000000385
-*[[Fluorouracil (5-FU)]] 400 mg/m2 IV bolus on day 1, then 1200 mg/m2/day IV continuous infusion over 46-48 hours
+=Adjuvant chemoradiotherapy=
-*[[Folinic acid (Leucovorin)]] 400 mg/m2 IV over 2 hours day 1
-*[[Oxaliplatin (Eloxatin)]] 85 mg/m2 IV over 2 hours day 1
-'''14-day cycles x 12 cycles'''
+==Capecitabine & RT {{#subobject:3cec7f|Regimen=1}}==
+Capecitabine & RT: Capecitabine & '''<u>R</u>'''adiation '''<u>T</u>'''herapy
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #1, fully concurrent {{#subobject:5ea375|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5041927/ Feng et al. 2016 (CAMS rectal cancer 01)]
+|2008-2014
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#CapeOx_.26_RT_999|CapeOx & RT]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS<br>DFS36: 71.6% vs 73.9%
+|-
+|}
+<div class="toccolours" style="background-color:#cbd5e8">
+====Preceding treatment====
+*[[Surgery#Rectal_cancer_surgery|Surgery]]
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Capecitabine (Xeloda)]] 800 mg/m<sup>2</sup> PO twice per day on days 1 to 14, 22 to 36
+====Radiotherapy====
+*Concurrent [[External_beam_radiotherapy|radiation therapy]], 4500 to 5040 cGy total in 25 to 28 fractions
+'''5- to 5.5-week course'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #2, sandwich {{#subobject:2028c1|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://doi.org/10.1016/S1470-2045%2812%2970116-X Hofheinz et al. 2012 (Rektum-III)]
+|2002-2007
+| style="background-color:#1a9851" |Phase 3 (E-RT-switch-ic)
+|[[#Fluorouracil_.26_RT_2|5-FU & RT]]
+| style="background-color:#eeee01" |Non-inferior OS (primary endpoint)<br>OS60: 76% vs 67%
+|-
+|}
+<div class="toccolours" style="background-color:#cbd5e8">
+====Preceding treatment====
+*[[Surgery#Rectal_cancer_surgery|Surgery]]
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Capecitabine (Xeloda)]] as follows:
+**Cycles 1 & 2: 1250 mg/m<sup>2</sup> PO twice per day on days 1 to 14
+**Cycle 3 (chemoradiation): 825 mg/m<sup>2</sup> PO twice per day on days 1 to 38
+**Cycles 4 to 6: 1250 mg/m<sup>2</sup> PO twice per day on days 1 to 14
+====Radiotherapy====
+*Concurrent [[External_beam_radiotherapy|radiation therapy]] as follows:
+**Cycle 3: 5040 cGy total
+'''21-day cycle for 2 cycles, then 38-day course, then 21-day cycle for 3 cycles'''
+</div></div>
 ===References===
-# Kojima S, Ina K, Futamura Y, Ito Y, Hibi S, Nagaoka M, Yuasa S, Kawai M, Nagao S, Kataoka T. A phase I study of modified FOLFOX 6 therapy for advanced colorectal cancer. Gan To Kagaku Ryoho. 2007 Feb;34(2):203-6. [http://www.pieronline.jp/content/article/0385-0684/34020/203 link to original article (Japanese)] [http://www.ncbi.nlm.nih.gov/pubmed/17301527 PubMed]
+# '''Rektum-III:''' Hofheinz RD, Wenz F, Post S, Matzdorff A, Laechelt S, Hartmann JT, Müller L, Link H, Moehler M, Kettner E, Fritz E, Hieber U, Lindemann HW, Grunewald M, Kremers S, Constantin C, Hipp M, Hartung G, Gencer D, Kienle P, Burkholder I, Hochhaus A. Chemoradiotherapy with capecitabine versus fluorouracil for locally advanced rectal cancer: a randomised, multicentre, non-inferiority, phase 3 trial. Lancet Oncol. 2012 Jun;13(6):579-88. Epub 2012 Apr 12. [https://doi.org/10.1016/S1470-2045%2812%2970116-X link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/22503032/ PubMed] [https://clinicaltrials.gov/study/NCT01500993 NCT01500993]
-# Allegra CJ, Yothers G, O'Connell MJ, Sharif S, Colangelo LH, Lopa SH, Petrelli NJ, Goldberg RM, Atkins JN, Seay TE, Fehrenbacher L, O'Reilly S, Chu L, Azar CA, Wolmark N. Initial safety report of NSABP C-08: A randomized phase III study of modified FOLFOX6 with or without bevacizumab for the adjuvant treatment of patients with stage II or III colon cancer. J Clin Oncol. 2009 Jul 10;27(20):3385-90. Epub 2009 May 4. [http://jco.ascopubs.org/content/27/20/3385.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/19414665 PubMed]
+# '''CAMS rectal cancer 01:''' Feng YR, Zhu Y, Liu LY, Wang WH, Wang SL, Song YW, Wang X, Tang Y, Liu YP, Ren H, Fang H, Zhang SP, Liu XF, Yu ZH, Li YX, Jin J. Interim analysis of postoperative chemoradiotherapy with capecitabine and oxaliplatin versus capecitabine alone for pathological stage II and III rectal cancer: a randomized multicenter phase III trial. Oncotarget. 2016 May 3;7(18):25576-84. [https://doi.org/10.18632/oncotarget.8226 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5041927/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/27014909/ PubMed] [https://clinicaltrials.gov/study/NCT00714077 NCT00714077]
-=Adjuvant chemoradiation=
+==Fluorouracil & RT {{#subobject:25293e|Regimen=1}}==
-==Capecitabine (Xeloda) {{#subobject:4c3312|Regimen=1}}==
+Fluorouracil & RT: Fluorouracil & '''<u>R</u>'''adiation '''<u>T</u>'''herapy
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #1, Bolus 5-FU (500 mg/m<sup>2</sup>), then CI 5-FU & RT, then Bolus 5-FU (450 mg/m<sup>2</sup>) {{#subobject:d06581|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://doi.org/10.1056/NEJM199408253310803 O'Connell et al. 1994 (INT 864751)]
+|1986-1990
+| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
+|[[#Fluorouracil_.26_RT_2|5-FU & RT]]; bolus
+| style="background-color:#1a9850" |Superior OS
+|-
+| rowspan="2" |[https://doi.org/10.1200/jco.2005.04.9544 Smalley et al. 2006 (GI INT 0144)]
+|rowspan=2|1994-2000
+| rowspan="2" style="background-color:#1a9851" |Phase 3 (E-switch-ic)
+|1. [[#Fluorouracil_.26_RT_2|5-FU & RT]]; bolus
+| style="background-color:#d3d3d3" |Not compared
+|-
+|2. [[#Fluorouracil_.26_RT_2|5-FU & RT]]; CI
+| style="background-color:#ffffbf" |Did not meet co-primary endpoints of OS/DFS
+|-
+|}
+''Note: INT 864751 also included a randomization to add semustine, which is only of historic interest.''
+<div class="toccolours" style="background-color:#cbd5e8">
+====Preceding treatment====
+*[[Surgery#Rectal_cancer_surgery|Surgery]]
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Fluorouracil (5-FU)]] as follows:
+**Cycles 1 & 2: 500 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5
+**Cycle 3 (chemoradiation): 225 mg/m<sup>2</sup>/day IV continuous infusion while radiation is being given
+**Cycles 4 & 5: 450 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5
+====Radiotherapy====
+*Concurrent [[External_beam_radiotherapy|radiation therapy]] as follows:
+**Cycle 3: 180 cGy fractions x 25 fractions for an initial dose of 4500 cGy, which is followed by a 180 cGy x 3 fraction (540 cGy total) boost to the tumor bed and adjacent lymph nodes, and then optionally a 180 cGy x 2 fraction (360 cGy total) boost to the tumor bed and a 2 cm margin if the small bowel could be avoided
+'''28-day cycle for 2 cycles, then 8-week course, then 28-day cycle for 2 cycles'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #2, Bolus 5-FU (500 mg/m<sup>2</sup>), then CI 5-FU & RT, then Bolus 5-FU (500 mg/m<sup>2</sup>) {{#subobject:23bcde|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://doi.org/10.1016/S1470-2045%2812%2970116-X Hofheinz et al. 2012 (Rektum-III)]
+|2002-2007
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#Capecitabine_.26_RT_2|Capecitabine & RT]]
+| style="background-color:#eeee01" |Non-inferior OS
+|-
+|}
+<div class="toccolours" style="background-color:#cbd5e8">
+====Preceding treatment====
+*[[Surgery#Rectal_cancer_surgery|Surgery]]
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Fluorouracil (5-FU)]] as follows:
+**Cycles 1, 2, 4, 5: 500 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5
+**Cycle 3 (chemoradiation): 225 mg/m<sup>2</sup>/day IV continuous infusion while radiation is being given
+====Radiotherapy====
+*Concurrent [[External_beam_radiotherapy|radiation therapy]] as follows:
+**Cycle 3: 5040 cGy total
+'''28-day cycle for 2 cycles, then one course, then 28-day cycle for 2 cycles'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #3, CI 5-FU, then CI 5-FU & RT, then CI 5-FU {{#subobject:da8c0d|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+| rowspan="2" |[https://doi.org/10.1200/jco.2005.04.9544 Smalley et al. 2006 (GI INT 0144)]
+|rowspan=2|1994-2000
+| rowspan="2" style="background-color:#1a9851" |Phase 3 (E-switch-ic)
+|1. [[#Fluorouracil_.26_RT_2|5-FU & RT]]; bolus
+| style="background-color:#ffffbf" |Did not meet co-primary endpoints of DFS/OS
+|-
+|2. [[#Fluorouracil_.26_RT_2|5-FU & RT]]; fully concurrent
+| style="background-color:#d3d3d3" |Not compared
 |-
-|[[#toc|back to top]]
 |}
-===Regimen {{#subobject:2028c1|Variant=1}}===
+<div class="toccolours" style="background-color:#cbd5e8">
-Level of Evidence:
+====Preceding treatment====
-<span
+*[[Surgery#Rectal_cancer_surgery|Surgery]]
-style="background:#00CD00;
+</div>
-padding:3px 6px 3px 6px;
+<div class="toccolours" style="background-color:#b3e2cd">
-border-color:black;
+====Chemotherapy====
-border-width:2px;
+*[[Fluorouracil (5-FU)]] as follows:
-border-style:solid;">Phase III</span>
+**Cycle 1: 300 mg/m<sup>2</sup>/day IV continuous infusion over 42 days, started on day 1 (total dose: 12,600 mg/m<sup>2</sup>)
+**Cycle 2 (chemoradiation): 225 mg/m<sup>2</sup>/day IV continuous infusion while radiation is being given
-Prior to chemoradiation:
+**Cycle 3: 300 mg/m<sup>2</sup>/day IV continuous infusion over 56 days, started on day 1 (total dose: 16,800 mg/m<sup>2</sup>)
-*[[Capecitabine (Xeloda)]] 1250 mg/m2 PO BID (2500 mg/m2/day) on days 1 to 14
+====Radiotherapy====
+*Concurrent [[External_beam_radiotherapy|radiation therapy]] as follows:
-'''21-day cycles x 2 cycles'''
+**Cycle 2: 180 cGy fractions x 25 fractions for an initial dose of 4500 cGy, which is followed by a 180 cGy x 3 fraction (540 cGy total) boost to the tumor bed and adjacent lymph nodes, and then optionally a 180 cGy x 2 fraction (360 cGy total) boost to the tumor bed and a 2 cm margin if the small bowel could be avoided
+'''10-week cycle for 3 cycles'''
-Chemoradiation:
+</div></div><br>
-*[[Capecitabine (Xeloda)]] 825 mg/m2 PO BID (1650 mg/m2/day) on days 1 to 38
+<div class="toccolours" style="background-color:#eeeeee">
-*Concurrent radiation therapy, 50.4 Gy total
-After chemoradiation:
-*[[Capecitabine (Xeloda)]] 1250 mg/m2 PO BID (2500 mg/m2/day) on days 1 to 14
-'''21-day cycles x 3 cycles'''
+===Regimen variant #4, bolus 5-FU, then bolus 5-FU & RT, then bolus 5-FU {{#subobject:3d1b7b|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://doi.org/10.1056/NEJM199408253310803 O'Connell et al. 1994 (INT 864751)]
+|1986-1990
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#Fluorouracil_.26_RT_2|5-FU & RT]]; bolus/CI
+| style="background-color:#d73027" |Inferior OS
+|-
+| rowspan="3" |[https://doi.org/10.1200/jco.1997.15.5.2030 Tepper et al. 1997 (GI INT 0114)]
+|rowspan=3|1990-1992
+| rowspan="3" style="background-color:#1a9851" |Phase 3 (C)
+|1. [[#FULV.2FFULV_.26_RT_2|FULV/FULV & RT]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS36
+|-
+|2. Levamisole combination #1
+| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS36
+|-
+|3. Levamisole combination #2
+| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS36
+|-
+|}
+''Note: INT 864751 also included a randomization to add semustine, which is only of historic interest.''
+<div class="toccolours" style="background-color:#cbd5e8">
+====Preceding treatment====
+*[[Surgery#Rectal_cancer_surgery|Surgery]]
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Fluorouracil (5-FU)]] as follows:
+**Cycles 1 & 2: 500 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5
+**Cycle 3 (chemoradiation): 500 mg/m<sup>2</sup> IV bolus 3 days per week during weeks 1 & 5 of radiation, preferably within 2 hours after the day's radiation
+**Cycles 4 & 5: 450 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5
+====Radiotherapy====
+*Concurrent [[External_beam_radiotherapy|radiation therapy]] as follows:
+**Cycle 3: 180 cGy fractions x 25 fractions for an initial dose of 4500 cGy, which is followed by a 180 cGy x 3 fraction (540 cGy total) boost to the tumor bed and adjacent lymph nodes, and then optionally a 180 cGy x 2 fraction (360 cGy total) boost to the tumor bed and a 2 cm margin if the small bowel could be avoided
+'''28-day cycle for 2 cycles, then 10-week course, then 28-day cycle for 2 cycles'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #5, fully concurrent {{#subobject:e903ad|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://doi.org/10.1023/a:1008357609434 Fountzilas et al. 1999]
+|1989-1997
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#FULV.2FFluorouracil_.26_RT_999|FULV/5-FU & RT]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS36
+|-
+|}
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Fluorouracil (5-FU)]]
+====Radiotherapy====
+*[[External_beam_radiotherapy|Radiation therapy]]
+</div></div>
 ===References===
-# Hofheinz RD, Wenz F, Post S, Matzdorff A, Laechelt S, Hartmann JT, Müller L, Link H, Moehler M, Kettner E, Fritz E, Hieber U, Lindemann HW, Grunewald M, Kremers S, Constantin C, Hipp M, Hartung G, Gencer D, Kienle P, Burkholder I, Hochhaus A. Chemoradiotherapy with capecitabine versus fluorouracil for locally advanced rectal cancer: a randomised, multicentre, non-inferiority, phase 3 trial. Lancet Oncol. 2012 Apr 12. [Epub ahead of print] [http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045%2812%2970116-X/fulltext link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/22503032 PubMed]
+# '''INT 864751:''' O'Connell MJ, Martenson JA, Wieand HS, Krook JE, Macdonald JS, Haller DG, Mayer RJ, Gunderson LL, Rich TA. Improving adjuvant therapy for rectal cancer by combining protracted-infusion fluorouracil with radiation therapy after curative surgery. N Engl J Med. 1994 Aug 25;331(8):502-7. [https://doi.org/10.1056/NEJM199408253310803 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/8041415/ PubMed]
+# '''GI INT 0114:''' Tepper JE, O'Connell MJ, Petroni GR, Hollis D, Cooke E, Benson AB 3rd, Cummings B, Gunderson LL, Macdonald JS, Martenson JA. Adjuvant postoperative fluorouracil-modulated chemotherapy combined with pelvic radiation therapy for rectal cancer: initial results of intergroup 0114. J Clin Oncol. 1997 May;15(5):2030-9. [https://doi.org/10.1200/jco.1997.15.5.2030 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/9164215/ PubMed]
+## '''Update:''' Tepper JE, O'Connell M, Niedzwiecki D, Hollis DR, Benson AB 3rd, Cummings B, Gunderson LL, Macdonald JS, Martenson JA, Mayer RJ. Adjuvant therapy in rectal cancer: analysis of stage, sex, and local control--final report of intergroup 0114. J Clin Oncol. 2002 Apr 1;20(7):1744-50. [https://doi.org/10.1200/jco.2002.07.132 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/11919230/ PubMed] content property of [https://hemonc.org HemOnc.org]
+# Fountzilas G, Zisiadis A, Dafni U, Konstantaras C, Hatzitheoharis G, Liaros A, Athanassiou E, Dombros N, Dervenis C, Basdanis G, Gamvros O, Souparis A, Briasoulis E, Samantas E, Kappas A, Kosmidis P, Skarlos D, Pavlidis N; Hellenic Cooperative Oncology Group. Postoperative radiation and concomitant bolus fluorouracil with or without additional chemotherapy with fluorouracil and high-dose leucovorin in patients with high-risk rectal cancer: a randomized phase III study conducted by the Hellenic Cooperative Oncology Group. Ann Oncol. 1999 Jun;10(6):671-6. [https://doi.org/10.1023/a:1008357609434 link to original article] [https://pubmed.ncbi.nlm.nih.gov/10442189/ PubMed]
+# '''GI INT 0144:''' Smalley SR, Benedetti JK, Williamson SK, Robertson JM, Estes NC, Maher T, Fisher B, Rich TA, Martenson JA, Kugler JW, Benson AB 3rd, Haller DG, Mayer RJ, Atkins JN, Cripps C, Pedersen J, Periman PO, Tanaka MS Jr, Leichman CG, Macdonald JS. Phase III trial of fluorouracil-based chemotherapy regimens plus radiotherapy in postoperative adjuvant rectal cancer: GI INT 0144. J Clin Oncol. 2006 Aug 1;24(22):3542-7. [https://doi.org/10.1200/jco.2005.04.9544 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16877719/ PubMed] [https://clinicaltrials.gov/study/NCT00002551 NCT00002551]
+# '''Rektum-III:''' Hofheinz RD, Wenz F, Post S, Matzdorff A, Laechelt S, Hartmann JT, Müller L, Link H, Moehler M, Kettner E, Fritz E, Hieber U, Lindemann HW, Grunewald M, Kremers S, Constantin C, Hipp M, Hartung G, Gencer D, Kienle P, Burkholder I, Hochhaus A. Chemoradiotherapy with capecitabine versus fluorouracil for locally advanced rectal cancer: a randomised, multicentre, non-inferiority, phase 3 trial. Lancet Oncol. 2012 Jun;13(6):579-88. Epub 2012 Apr 13. [https://doi.org/10.1016/S1470-2045%2812%2970116-X link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/22503032/ PubMed] [https://clinicaltrials.gov/study/NCT01500993 NCT01500993]
-==Fluorouracil (5-FU) & RT {{#subobject:423753|Regimen=1}}==
+==FULV/FULV & RT {{#subobject:e9de02|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+FULV/FULV & RT: '''<u>F</u>'''luoro'''<u>U</u>'''racil & '''<u>L</u>'''euco'''<u>V</u>'''orin alternating with '''<u>F</u>'''luoro'''<u>U</u>'''racil, '''<u>L</u>'''euco'''<u>V</u>'''orin, '''<u>R</u>'''adiation '''<u>T</u>'''herapy
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:cd06ac|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+| rowspan="3" |[https://doi.org/10.1200/jco.1997.15.5.2030 Tepper et al. 1997 (GI INT 0114)]
+|rowspan=3|1990-1992
+| rowspan="3" style="background-color:#1a9851" |Phase 3 (E-esc)
+|1. [[#Fluorouracil_.26_RT_2|5-FU & RT]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS36
+|-
+|2. Levamisole combination #1
+| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS36
+|-
+|3. Levamisole combination #2
+| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS36
+|-
+|[https://doi.org/10.1016/j.ejca.2008.05.025 Kalofonos et al. 2008]
+|1999-2004
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#IFL_.26_RT_999|IFL & RT]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS36
 |-
-|[[#toc|back to top]]
 |}
-===Regimen #1, Smalley et al. 2006 {{#subobject:d06581|Variant=1}}===
+<div class="toccolours" style="background-color:#cbd5e8">
-Level of Evidence:
+====Preceding treatment====
-<span
+*[[Surgery#Rectal_cancer_surgery|Surgery]]
-style="background:#00CD00;
+</div>
-padding:3px 6px 3px 6px;
+<div class="toccolours" style="background-color:#b3e2cd">
-border-color:black;
+====Chemotherapy====
-border-width:2px;
+*[[Fluorouracil (5-FU)]] as follows:
-border-style:solid;">Phase III</span>
+**Cycles 1 & 2: 425 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5, '''given second'''
+**Cycle 3 (chemoradiation): 400 mg/m<sup>2</sup> IV bolus 4 days per week during weeks 1 & 5 of radiation, preferably within 2 hours after the day's radiation
-Prior to chemoradiation:
+**Cycles 4 & 5: 380 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5, '''given second'''
-*[[Fluorouracil (5-FU)]] 500 mg/m2 IV bolus on days 1 to 5
+*[[Leucovorin (Folinic acid)]] as follows:
+**Cycles 1, 2, 4, 5: 20 mg/m<sup>2</sup> IV bolus once per day on days 1 to 5, '''given first'''
-'''28-day cycles x 2 cycles'''
+**Cycle 3 (chemoradiation): 20 mg/m<sup>2</sup> IV bolus 4 days per week during weeks 1 & 5 of radiation, preferably within 2 hours after the day's radiation
+====Radiotherapy====
-Chemoradiation starting on day 57:
+*Concurrent [[External_beam_radiotherapy|radiation therapy]] as follows:
-*[[Fluorouracil (5-FU)]] 225 mg/m2/day IV continuous infusion while radiation is being given
+**Cycle 3: 180 cGy fractions x 25 fractions for an initial dose of 4500 cGy, which is followed by a 180 cGy x 3 fraction (540 cGy total) boost to the tumor bed and adjacent lymph nodes, and then optionally a 180 cGy x 2 fraction (360 cGy total) boost to the tumor bed and a 2 cm margin if the small bowel could be avoided
-*Concurrent radiation therapy, 1.8 Gy fractions x 25 fractions for an initial dose of 45 Gy, which is followed by a 1.8 Gy x 3 fraction (5.4 Gy total) boost to the tumor bed and adjacent lymph nodes, and then optionally a 1.8 Gy x 2 fraction (3.6 Gy total) boost to the tumor bed and a 2 cm margin if the small bowel could be avoided
+'''28-day cycle for 2 cycles, then 10-week course, then 28-day cycles for 2 cycles'''
+</div></div>
-After chemoradiation:
-*[[Fluorouracil (5-FU)]] 450 mg/m2 IV bolus on days 1 to 5
-'''28-day cycles x 2 cycles, to start 28 days after completion of chemoradiation'''
-===Regimen #2, Hofheinz et al. 2012 {{#subobject:23bcde|Variant=1}}===
-Level of Evidence:
-<span
-style="background:#00CD00;
-padding:3px 6px 3px 6px;
-border-color:black;
-border-width:2px;
-border-style:solid;">Phase III</span>
-Prior to chemoradiation:
-*[[Fluorouracil (5-FU)]] 500 mg/m2 IV bolus on days 1 to 5
-'''28-day cycles x 2 cycles'''
-Chemoradiation:
-*[[Fluorouracil (5-FU)]] 225 mg/m2/day IV continuous infusion while radiation is being given
-*Concurrent radiation therapy, 50.4 Gy total
-After chemoradiation:
-*[[Fluorouracil (5-FU)]] 500 mg/m2 IV bolus on days 1 to 5
-'''28-day cycles x 2 cycles'''
-===Regimen #3, Smalley et al. 2006 {{#subobject:da8c0d|Variant=1}}===
-Level of Evidence:
-<span
-style="background:#00CD00;
-padding:3px 6px 3px 6px;
-border-color:black;
-border-width:2px;
-border-style:solid;">Phase III</span>
-Prior to chemoradiation:
-*[[Fluorouracil (5-FU)]] 300 mg/m2/day IV continuous infusion on days 1 to 42
-'''8-week course''' (2 weeks off of chemotherapy prior to chemoradiation)
-Chemoradiation starting on day 57:
-*[[Fluorouracil (5-FU)]] 225 mg/m2/day IV continuous infusion while radiation is being given
-*Concurrent radiation therapy, 1.8 Gy fractions x 25 fractions for an initial dose of 45 Gy, which is followed by a 1.8 Gy x 3 fraction (5.4 Gy total) boost to the tumor bed and adjacent lymph nodes, and then optionally a 1.8 Gy x 2 fraction (3.6 Gy total) boost to the tumor bed and a 2 cm margin if the small bowel could be avoided
-After chemoradiation:
-*[[Fluorouracil (5-FU)]] 300 mg/m2/day IV continuous infusion on days 1 to 56
-'''56-day course, to start 28 days after completion of chemoradiation'''
-===Regimen #4, Tepper et al. 1997 & Tepper et al. 2002 {{#subobject:3d1b7b|Variant=1}}===
-Level of Evidence:
-<span
-style="background:#00CD00;
-padding:3px 6px 3px 6px;
-border-color:black;
-border-width:2px;
-border-style:solid;">Phase III</span>
-Prior to chemoradiation:
-*[[Fluorouracil (5-FU)]] 500 mg/m2 IV bolus on days 1 to 5
-'''28-day cycles x 2 cycles'''
-Chemoradiation:
-*[[Fluorouracil (5-FU)]] 500 mg/m2 IV bolus 3 days per week during weeks 1 & 5 of radiation, preferably within 2 hours after the day's radiation
-*Concurrent radiation therapy, 1.8 Gy fractions x 25 fractions for an initial dose of 45 Gy, which is followed by a 1.8 Gy x 3 fraction (5.4 Gy total) boost to the tumor bed and adjacent lymph nodes, and then optionally a 1.8 Gy x 2 fraction (3.6 Gy total) boost to the tumor bed and a 2 cm margin if the small bowel could be avoided
-After chemoradiation:
-*[[Fluorouracil (5-FU)]] 450 mg/m2 IV bolus on days 1 to 5
-'''28-day cycles x 2 cycles, to start 28 days after completion of chemoradiation'''
-===Regimen #5 {{#subobject:4b7461|Variant=1}}===
-Level of Evidence:
-<span
-style="background:#EEEE00;
-padding:3px 6px 3px 6px;
-border-color:black;
-border-width:2px;
-border-style:solid;">Non-randomized</span>
-''Note: The O'Connell et al. 1994 reference cited by the NCCN, Rectal Cancer version 3.2012, contains a different regimen than what is listed by the NCCN.  No primary reference could be found for this exact regimen as listed by the NCCN.''
-*[[Fluorouracil (5-FU)]] 225 mg/m2/day IV continuous infusion either 5 or 7 days per week during radiation therapy
 ===References===
-# O'Connell MJ, Martenson JA, Wieand HS, Krook JE, Macdonald JS, Haller DG, Mayer RJ, Gunderson LL, Rich TA. Improving adjuvant therapy for rectal cancer by combining protracted-infusion fluorouracil with radiation therapy after curative surgery. N Engl J Med. 1994 Aug 25;331(8):502-7. [http://www.nejm.org/doi/full/10.1056/NEJM199408253310803 link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/8041415 PubMed]
+# '''GI INT 0114:''' Tepper JE, O'Connell MJ, Petroni GR, Hollis D, Cooke E, Benson AB 3rd, Cummings B, Gunderson LL, Macdonald JS, Martenson JA. Adjuvant postoperative fluorouracil-modulated chemotherapy combined with pelvic radiation therapy for rectal cancer: initial results of intergroup 0114. J Clin Oncol. 1997 May;15(5):2030-9. [https://doi.org/10.1200/jco.1997.15.5.2030 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/9164215/ PubMed]
-# Tepper JE, O'Connell MJ, Petroni GR, Hollis D, Cooke E, Benson AB 3rd, Cummings B, Gunderson LL, Macdonald JS, Martenson JA. Adjuvant postoperative fluorouracil-modulated chemotherapy combined with pelvic radiation therapy for rectal cancer: initial results of intergroup 0114. J Clin Oncol. 1997 May;15(5):2030-9. [http://jco.ascopubs.org/content/15/5/2030.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/9164215 PubMed]
+## '''Update:''' Tepper JE, O'Connell M, Niedzwiecki D, Hollis DR, Benson AB 3rd, Cummings B, Gunderson LL, Macdonald JS, Martenson JA, Mayer RJ. Adjuvant therapy in rectal cancer: analysis of stage, sex, and local control--final report of intergroup 0114. J Clin Oncol. 2002 Apr 1;20(7):1744-50. [https://doi.org/10.1200/jco.2002.07.132 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/11919230/ PubMed]
-# '''Update:''' Tepper JE, O'Connell M, Niedzwiecki D, Hollis DR, Benson AB 3rd, Cummings B, Gunderson LL, Macdonald JS, Martenson JA, Mayer RJ. Adjuvant therapy in rectal cancer: analysis of stage, sex, and local control--final report of intergroup 0114. J Clin Oncol. 2002 Apr 1;20(7):1744-50. [http://jco.ascopubs.org/content/20/7/1744.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/11919230 PubMed] content property of [http://hemonc.org HemOnc.org]
+# Kalofonos HP, Bamias A, Koutras A, Papakostas P, Basdanis G, Samantas E, Karina M, Misailidou D, Pisanidis N, Pentheroudakis G, Economopoulos T, Papadimitriou C, Skarlos DV, Pectasides D, Stavropoulos M, Bafaloukos D, Kardamakis D, Karanikiotis C, Vourli G, Fountzilas G; Hellenic Cooperative Oncology Group. A randomised phase III trial of adjuvant radio-chemotherapy comparing Irinotecan, 5FU and Leucovorin to 5FU and Leucovorin in patients with rectal cancer: a Hellenic Cooperative Oncology Group Study. Eur J Cancer. 2008 Aug;44(12):1693-700. Epub 2008 Jul 17. [https://doi.org/10.1016/j.ejca.2008.05.025 link to original article] [https://pubmed.ncbi.nlm.nih.gov/18639450/ PubMed]
-# Smalley SR, Benedetti JK, Williamson SK, Robertson JM, Estes NC, Maher T, Fisher B, Rich TA, Martenson JA, Kugler JW, Benson AB 3rd, Haller DG, Mayer RJ, Atkins JN, Cripps C, Pedersen J, Periman PO, Tanaka MS Jr, Leichman CG, Macdonald JS. Phase III trial of fluorouracil-based chemotherapy regimens plus radiotherapy in postoperative adjuvant rectal cancer: GI INT 0144. J Clin Oncol. 2006 Aug 1;24(22):3542-7. [http://jco.ascopubs.org/content/24/22/3542.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/16877719 PubMed]
-# Hofheinz RD, Wenz F, Post S, Matzdorff A, Laechelt S, Hartmann JT, Müller L, Link H, Moehler M, Kettner E, Fritz E, Hieber U, Lindemann HW, Grunewald M, Kremers S, Constantin C, Hipp M, Hartung G, Gencer D, Kienle P, Burkholder I, Hochhaus A. Chemoradiotherapy with capecitabine versus fluorouracil for locally advanced rectal cancer: a randomised, multicentre, non-inferiority, phase 3 trial. Lancet Oncol. 2012 Apr 12. [Epub ahead of print] [http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045%2812%2970116-X/fulltext link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/22503032 PubMed]
-==Fluorouracil (5-FU), Folinic acid (Leucovorin), RT {{#subobject:e9de02|Regimen=1}}==
+==Radiation therapy {{#subobject:3f3b45|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+RT: '''<u>R</u>'''adiation '''<u>T</u>'''herapy
+<div class="toccolours" style="background-color:#ee6b6e">
+===Regimen {{#subobject:f7cd24|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+| rowspan="2" |[https://academic.oup.com/jnci/article-abstract/80/1/21/886000 Fisher et al. 1988 (NSABP R-01)]
+|rowspan=2|1977-1986
+| rowspan="2" style="background-color:#1a9851" |Phase 3 (E-esc)
+|1. [[#MOF_888|MOF]]
+| style="background-color:#d3d3d3" |Not reported
+|-
+|2. [[Rectal_cancer_-_null_regimens#Observation|Observation]]
+| style="background-color:#ffffbf" |Did not meet efficacy endpoints of DFS/OS
+|-
+|[https://doi.org/10.1056/NEJM199103143241101 Krook et al. 1991]
+|1980-1986
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#Fluorouracil_.26_RT_2|Fluorouracil & RT]]
+| style="background-color:#d73027" |Inferior RFS
+|-
+|[https://doi.org/10.1016/S0140-6736(96)05349-4 Amott et al. 1996]
+|1984-1989
+| style="background-color:#1a9851" |Phase 3 (E-esc)
+|[[Rectal_cancer_-_null_regimens#Observation|Observation]]
+| style="background-color:#1a9850" |Superior local recurrence rate
 |-
-|[[#toc|back to top]]
 |}
-===Regimen {{#subobject:cd06ac|Variant=1}}===
+''Note: this regimen in this context is of historic interest.''
-Level of Evidence:
+<div class="toccolours" style="background-color:#cbd5e8">
-<span
+====Preceding treatment====
-style="background:#00CD00;
+*[[Surgery#Rectal_cancer_surgery|Surgery]]
-padding:3px 6px 3px 6px;
+</div>
-border-color:black;
+<div class="toccolours" style="background-color:#b3e2cd">
-border-width:2px;
+====Radiotherapy====
-border-style:solid;">Phase III</span>
+*[[External_beam_radiotherapy|Radiation therapy]], 4000 to 5040 cGy
+'''4-week course'''
-Prior to chemoradiation:
+</div></div>
-*[[Fluorouracil (5-FU)]] 425 mg/m2 IV bolus on days 1 to 5, given after Folinic acid (Leucovorin)
-*[[Folinic acid (Leucovorin)]] 20 mg/m2 IV bolus on days 1 to 5, given before Fluorouracil (5-FU)
-'''28-day cycles x 2 cycles'''
-Chemoradiation:
-*[[Fluorouracil (5-FU)]] 400 mg/m2 IV bolus 4 days per week during weeks 1 & 5 of radiation, preferably within 2 hours after the day's radiation
-*[[Folinic acid (Leucovorin)]] 20 mg/m2 IV bolus 4 days per week during weeks 1 & 5 of radiation, preferably within 2 hours after the day's radiation
-*Concurrent radiation therapy, 1.8 Gy fractions x 25 fractions for an initial dose of 45 Gy, which is followed by a 1.8 Gy x 3 fraction (5.4 Gy total) boost to the tumor bed and adjacent lymph nodes, and then optionally a 1.8 Gy x 2 fraction (3.6 Gy total) boost to the tumor bed and a 2 cm margin if the small bowel could be avoided
-After chemoradiation:
-*[[Fluorouracil (5-FU)]] 380 mg/m2 IV bolus on days 1 to 5
-*[[Folinic acid (Leucovorin)]] 20 mg/m2 IV bolus on days 1 to 5
-'''28-day cycles x 2 cycles, to start 28 days after completion of chemoradiation'''
 ===References===
-# Tepper JE, O'Connell MJ, Petroni GR, Hollis D, Cooke E, Benson AB 3rd, Cummings B, Gunderson LL, Macdonald JS, Martenson JA. Adjuvant postoperative fluorouracil-modulated chemotherapy combined with pelvic radiation therapy for rectal cancer: initial results of intergroup 0114. J Clin Oncol. 1997 May;15(5):2030-9. [http://jco.ascopubs.org/content/15/5/2030.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/9164215 PubMed]
+# '''NSABP R-01:''' Fisher B, Wolmark N, Rockette H, Redmond C, Deutsch M, Wickerham DL, Fisher ER, Caplan R, Jones J, Lerner H, Gordon P, Feldman M, Cruz A, Legault-Poisson S, Wexler M, Lawrence W, Robidoux A. Postoperative adjuvant chemotherapy or radiation therapy for rectal cancer: results from NSABP protocol R-01. J Natl Cancer Inst. 1988 Mar 2;80(1):21-9. [https://academic.oup.com/jnci/article-abstract/80/1/21/886000 link to original article] [https://pubmed.ncbi.nlm.nih.gov/3276900/ PubMed]
-# '''Update:''' Tepper JE, O'Connell M, Niedzwiecki D, Hollis DR, Benson AB 3rd, Cummings B, Gunderson LL, Macdonald JS, Martenson JA, Mayer RJ. Adjuvant therapy in rectal cancer: analysis of stage, sex, and local control--final report of intergroup 0114. J Clin Oncol. 2002 Apr 1;20(7):1744-50. [http://jco.ascopubs.org/content/20/7/1744.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/11919230 PubMed]
+# Krook JE, Moertel CG, Gunderson LL, Wieand HS, Collins RT, Beart RW, Kubista TP, Poon MA, Meyers WC, Mailliard JA, Twito DI, Morton RF, Veeder MH, Witzig TE, Cha S, Vidyarthi SC. Effective surgical adjuvant therapy for high-risk rectal carcinoma. N Engl J Med. 1991 Mar 14;324(11):709-15. [https://doi.org/10.1056/NEJM199103143241101 link to original article] [https://pubmed.ncbi.nlm.nih.gov/1997835/ PubMed]
+# Amott SJ, Stenning SP, Hardcastle JD; Medical Research Council Rectal Cancer Working Party. Randomised trial of surgery alone versus surgery followed by radiotherapy for mobile cancer of the rectum. Lancet. 1996 Dec 14;348(9042):1610-4. [https://doi.org/10.1016/S0140-6736(96)05349-4 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/8961990/ PubMed]
+# '''TROG 01.014:''' Ngan SY, Burmeister B, Fisher RJ, Solomon M, Goldstein D, Joseph D, Ackland SP, Schache D, McClure B, McLachlan SA, McKendrick J, Leong T, Hartopeanu C, Zalcberg J, Mackay J. Randomized trial of short-course radiotherapy versus long-course chemoradiation comparing rates of local recurrence in patients with T3 rectal cancer: Trans-Tasman Radiation Oncology Group trial 01.04. J Clin Oncol. 2012 Nov 1;30(31):3827-33. Epub 2012 Sep 24. Erratum in: J Clin Oncol. 2013 Jan 20;31(3):399. [https://doi.org/10.1200/JCO.2012.42.9597 link to original article] [https://pubmed.ncbi.nlm.nih.gov/23008301/ PubMed] [https://clinicaltrials.gov/study/NCT00351598 NCT00351598]
 =Advanced or metastatic disease=
-See [[Colon cancer#Advanced_or_metastatic_disease|Colon cancer - Advanced or metastatic disease]].  The regimens listed by the NCCN, Rectal Cancer version 3.2012, are identical to the list for Colon Cancer version 2.2012, with the same references.
+''See the [[Colorectal cancer|colorectal cancer page]] for colorectal cancer regimens.''
+[[Category:Rectal cancer regimens]]
-[[Category:Chemotherapy regimens]]
+[[Category:Disease-specific pages]]
-[[Category:Solid oncology regimens]]
+[[Category:Colorectal cancers]]
-[[Category:Gastrointestinal (GI) oncology regimens]]

Difference between revisions of "Rectal cancer"

Latest revision as of 19:28, 23 June 2024

Guidelines

ESMO

French Intergroup

NCCN

SIOG

Neoadjuvant therapy

Capecitabine & RT

Regimen variant #1, interrupted capecitabine, 1600 mg/m2/day, 4500 cGy

Chemotherapy

Radiotherapy

Subsequent treatment

Regimen variant #2, interrupted capecitabine, 1600 mg/m2/day, 5000 cGy

Preceding treatment

Chemotherapy

Radiotherapy

Subsequent treatment

Regimen variant #3, interrupted capecitabine, 1650 mg/m2/day, 4500 cGy

Chemotherapy

Radiotherapy

Subsequent treatment

Regimen variant #4, continuous capecitabine, 1650 mg/m2/day, 4500 cGy

Chemotherapy

Radiotherapy

Subsequent treatment

Regimen variant #5, interrupted capecitabine, 1650 mg/m2/day, 5000 cGy

Chemotherapy

Radiotherapy

Subsequent treatment

Regimen variant #6, interrupted capecitabine, 1650 mg/m2/day, 5040 cGy

Chemotherapy

Radiotherapy

Subsequent treatment

References

Capecitabine, Sorafenib, RT

Regimen

Biomarker eligibility criteria

Chemotherapy

Targeted therapy

Radiotherapy

Subsequent treatment

References

CapeOx

Regimen variant #1, 4 cycles

Chemotherapy

Subsequent treatment

Regimen variant #2, 6 cycles

Preceding treatment

Chemotherapy

Subsequent treatment

References

CapeOx, Cetuximab, RT

Regimen

Chemotherapy

Targeted therapy

Radiotherapy

Subsequent treatment

References

CapIriRT

Regimen variant #1, 65 mg/m2

Biomarker eligibility criteria

Chemotherapy

Radiotherapy

Subsequent treatment

Regimen variant #2, 80 mg/m2

Biomarker eligibility criteria

Chemotherapy

Radiotherapy

Subsequent treatment

References

Fluorouracil & RT

Regimen variant #1, continuous

Chemotherapy

Radiotherapy

Subsequent treatment

Regimen variant #2, intermittent

Chemotherapy

Radiotherapy

Subsequent treatment

Regimen variant #1, interrupted capecitabine, 1600 mg/m²/day, 4500 cGy

Regimen variant #2, interrupted capecitabine, 1600 mg/m²/day, 5000 cGy

Regimen variant #3, interrupted capecitabine, 1650 mg/m²/day, 4500 cGy

Regimen variant #4, continuous capecitabine, 1650 mg/m²/day, 4500 cGy

Regimen variant #5, interrupted capecitabine, 1650 mg/m²/day, 5000 cGy

Regimen variant #6, interrupted capecitabine, 1650 mg/m²/day, 5040 cGy

Regimen variant #1, 65 mg/m²

Regimen variant #2, 80 mg/m²

Regimen variant #1, 2000 mg/m²/day x 6

Regimen variant #2, 2500 mg/m²/day x 5