Rectal cancer

From HemOnc.org - A Hematology Oncology Wiki
Jump to: navigation, search
Section editor
Nkv.jpg
Neeta K. Venepalli, MD, MBA
University of Illinois at Chicago
Chicago, IL

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

21 regimens on this page
36 variants on this page

Contents


Guidelines

ESMO

Older

NCCN

SIOG

Neoadjuvant therapy

Capecitabine & RT

back to top

RT: Radiation Therapy

Variant #1, continuous capecitabine

Study Evidence Comparator Efficacy Toxicity
Park et al. 2011 Phase III (E) Adjuvant Capecitabine & RT Seems not superior Superior sphincter preservation
Hofheinz et al. 2012 (Rektum-III) Phase III (E) 5-FU & RT Non-inferior OS
O'Connell et al. 2014 (NSABP R-04) Phase III (E) 1. 5-FU & RT Seems not superior Similar toxicity
2. CapeOx & RT
3. FUOX & RT
Seems not superior Superior toxicity

Chemotherapy

Radiotherapy

  • Concurrent radiation therapy, 1.80 Gy for 25 fractions (45 Gy), with boost depending on stage

5-week course

Subsequent treatment

Variant #2, interrupted capecitabine

Study Evidence Comparator Efficacy
Gérard et al. 2010 (ACCORD 12/0405 PRODIGE 2) Phase III (C) CapeOx & RT Might have inferior pCR rate

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

Chemotherapy

7-day cycle for 5 cycles

Radiotherapy

5-week course

Subsequent treatment

References

  1. 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 verified protocol PubMed
    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
  2. 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 protocol PubMed
  3. 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 verified protocol PubMed
  4. 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 verified protocol PubMed
    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

Capecitabine, Sorafenib, RT

back to top

RT: Radiation Therapy

Regimen

Study Evidence
von Moos et al. 2017 (SAKK 41/08) Phase I/II

Note: this regimen was intended for KRAS-mutated rectal cancer.

Chemotherapy

Radiotherapy

5-week course

Subsequent treatment

References

  1. 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 (SAKK). 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

back to top

CapeOX: Capecitabine & OXaliplatin

Regimen

Study Evidence
Chua et al. 2010 Phase II

Chemotherapy

21-day cycle for 4 cycles

Subsequent treatment

References

  1. 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 protocol PubMed

CapeOx, Cetuximab, RT

back to top

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

Regimen

Study Evidence
Leichman et al. 2017 (SWOG S0713) Phase II

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
  • 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

35-day cycle for 2 cycles

Radiotherapy

  • RT 180 cGy in 25 fractions, started with cycle 2

5-week course

Subsequent treatment

References

  1. 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 verified protocol PubMed

Fluorouracil & RT

back to top

RT: Radiation Therapy

Variant #1, continuous

Study Evidence Comparator Efficacy Toxicity
Aschele et al. 2011 (STAR-01) Phase III (C) FUOX & RT Seems not superior (*) Superior toxicity
Ngan et al. 2012 (TTROG 01.014) Phase III (C) Short-course RT Seems not superior Similar toxicity
O'Connell et al. 2014 (NSABP R-04) Phase III (C) 1. Capecitabine & RT Seems not superior Similar toxicity
2. CapeOx & RT
3. FUOX & RT
Seems not superior Superior toxicity

Note: 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, 1.80 Gy for 25 fractions (45 Gy), with boost depending on stage

5-week course

Subsequent treatment

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

Variant #2, intermittent

Study Evidence Comparator Efficacy
Sauer et al. 2004 (CAO/ARO/AIO-94) Phase III (E) Adjuvant 5-FU & RT Superior five-year cumulative incidence of local relapse
Hofheinz et al. 2012 (Rektum-III) Phase III (C) Capecitabine & RT Non-inferior OS
Rödel et al. 2012 (CAO/ARO/AIO-04) Phase III (C) Fluorouracil, Oxaliplatin, RT Seems to have inferior pCR rate

Chemotherapy

  • Fluorouracil (5-FU) 1000 mg/m2/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 5000 mg/m2)

28-day cycle for 2 cycles

Radiotherapy

One course

Subsequent treatment

References

  1. 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 verified protocol 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
  2. 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 verified protocol 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
  3. 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 verified protocol PubMed
  4. 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 protocol PubMed
    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
  5. TTROG 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
  6. 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 PMC article contains verified protocol PubMed
    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

Fluorouracil, Folinic acid, RT

back to top

RT: Radiation Therapy

Variant #1, 800/200 ("Nordic schedule")

Study Evidence Comparator Efficacy
Braendengen et al. 2008 (LARCS) Phase III (E) Radiotherapy Seems not superior (*)

Note: reported efficacy is based on the 2018 update.

Chemotherapy

14-day cycle for 3 cycles

Radiotherapy

5-week course

Subsequent treatment

Variant #2, 1625/100

Study Evidence Comparator Efficacy
Roh et al. 2009 (NSABP R-03) Phase III (E) Postoperative chemoradiotherapy Might have superior OS

Preceding treatment

  • 5-FU & Leucovorin x 1

Chemotherapy

28-day cycle for 2 cycles

Radiotherapy

5-week course

Subsequent treatment

Variant #3, 1750/100

Study Evidence Comparator Efficacy
Gérard et al. 2006 (FFCD 9203) Phase III (E) Radiotherapy Seems not superior (*)
Bosset et al. 2006 (EORTC 22921) Phase III (E) Radiotherapy Seems not superior (*)
Sainato et al. 2014 (I-CNR-RT) Non-randomized portion of RCT

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

Chemotherapy

28-day cycle for 2 cycles

Radiotherapy

5-week course

Subsequent treatment

Variant #4, 2800/400

Study Evidence Comparator Efficacy
Deng et al. 2016 (FOWARC) Phase III (C) 1. mFOLFOX6 Not superior DFS (though superior pCR)
2. mFOLFOX6 & RT Not superior DFS (though inferior pCR)

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

14-day cycle for 5 cycles

Radiotherapy

  • Concurrent radiation therapy given during cycles 2 to 4: 1.8 to 2.0 Gy once per day Monday through Friday for a total of 23 to 28 fractions over 5 to 6 weeks and a total dose of 46.0 to 50.4 Gy

6-week course

Subsequent treatment

References

  1. 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 verified protocol PubMed
  2. 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 Trial 22921. 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 verified protocol PubMed
    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
  3. 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
  4. 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 verified protocol PubMed
  5. 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 protocol PubMed
  6. 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 verified protocol PubMed

Fluorouracil, Oxaliplatin, RT

back to top

FUOX & RT: FluoroUracil, OXaliplatin, Radiation Therapy

Variant #1, 225/50

Study Evidence Comparator Efficacy Toxicity
O'Connell et al. 2014 (NSABP R-04) Phase III (E) 1. 5-FU & RT
2. Capecitabine & RT
Seems not superior Inferior toxicity
3. CapeOx & RT Seems not superior Similar toxicity

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

Chemotherapy

7-day cycle for 5 cycles

Radiotherapy

5.5-week course

Subsequent treatment

Variant #2, 225/60

Study Evidence Comparator Efficacy Toxicity
Aschele et al. 2011 (STAR-01) Phase III (E) Fluorouracil & RT Seems not superior (*) Inferior toxicity

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

Chemotherapy

Radiotherapy

6-week course

Subsequent treatment

  • Surgery, preferably TME, then fluourouracil-based adjuvant therapy

Variant #3, 250/50

Study Evidence Comparator Efficacy
Rödel et al. 2012 (CAO/ARO/AIO-04) Phase III (E) Fluorouracil & RT Seems to have superior pCR rate

Chemotherapy

21-day cycle for 2 cycles

Radiotherapy

One course

Subsequent treatment

References

  1. 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 verified protocol 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
  2. 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 protocol PubMed
    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
  3. 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 PMC article contains verified protocol PubMed
    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

back to top

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

Regimen

Study Evidence Comparator Efficacy
Deng et al. 2016 (FOWARC) Phase III (E) 1. Fluorouracil, Folinic acid, RT not superior DFS (though superior pCR rate)
2. mFOLFOX6 not superior DFS

Chemotherapy

14-day cycle for 4 to 6 cycles

Radiotherapy

  • Concurrent radiation therapy given before or after surgery at physician discretion: 1.8 to 2.0 Gy once per day Monday through Friday for a total of 23 to 28 fractions, for a total dose of 46 to 50.4 Gy

5- to 6-week course

Subsequent treatment

  • Surgery, then 6 to 8 more cycles of mFOLFOX6

References

  1. 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 verified protocol PubMed

Radiation therapy

back to top

RT: Radiation Therapy

Variant #1, 25 Gy

Study Evidence Comparator Efficacy
Cedermark et al. 1997 (Swedish Rectal Cancer Trial) Phase III (E) Surgery alone Superior OS
Kapiteijn et al. 2001 Phase III (E) Surgery alone Superior local recurrence rate
Sebag-Montefiore et al. 2009 (MRC CR07; NCIC CTG CO.16) Phase III (C) Selective postoperative 5-FU & RT Seems to have superior DFS
Bujko et al. 2016 (Polish II) Phase III (E) 5-FU, LV, RT, +/- oxaliplatin Seems not superior

Radiotherapy

  • Radiation therapy, 5.0 Gy once per day for a total of 5 fractions (total dose: 25 Gy)

5-day course

Subsequent treatment

Variant #2, 40 Gy

Study Evidence Comparator Efficacy
Oates et al. 1996 Phase III (E) Surgery alone Seems to have superior DFS

Of historic interest.

Radiotherapy

4-week course

Subsequent treatment

Variant #3, 50 Gy

Study Evidence Comparator Efficacy
Braendengen et al. 2008 (LARCS) Phase III (C) 5-FU, LV, RT Seems not superior (*)

Of historic interest. Reported efficacy is based on the 2018 update.

Radiotherapy

5-week course

Subsequent treatment

References

  1. 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 protocol PubMed
  2. 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
  3. 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
  4. 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
  5. 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 protocol PubMed
  6. 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 × 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 protocol PubMed
    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 Jun 13. [Epub ahead of print] link to original article PubMed

Adjuvant chemotherapy

Capecitabine monotherapy

back to top

Regimen

Study Evidence Comparator Efficacy
Hofheinz et al. 2012 (Rektum-III) Phase III (E) Fluorouracil Non-inferior OS
Breugom et al. 2014 (SCRIPT) Phase III (E) Observation Seems not superior

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

Chemotherapy

21-day cycle for 5 (Rektum-III) or 8 (SCRIPT) cycles

References

  1. 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 verified protocol PubMed
  2. 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; Cooperative Investigators of Dutch Colorectal Cancer Group and 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 verified protocol PubMed

Fluorouracil monotherapy

back to top

Variant #1

Study Evidence Comparator Efficacy
Hofheinz et al. 2012 (Rektum-III) Phase III (C) Capecitabine Non-inferior OS

Preceding treatment

Chemotherapy

28-day cycle for 4 cycles

Variant #2

Study Evidence Comparator Efficacy
Rödel et al. 2012 (CAO/ARO/AIO-04) Phase III (C) FOLFOX Not reported

Preceding treatment

Chemotherapy

4 cycles (length not specified)

References

  1. 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 verified protocol PubMed
  2. 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 protocol PubMed
    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

Fluorouracil & Folinic acid

back to top

Variant #1, 500/500

Study Evidence Comparator Efficacy
Wolmark et al. 2000 (NSABP R-02) Phase III (C) Chemoradiation Seems not superior

Preceding treatment

Chemotherapy

8-week cycle for 6 cycles

Variant #2, 1000/120 ("Nordic regimen")

Study Evidence Comparator Efficacy
Breugom et al. 2014 (PROCTOR) Phase III (E) Observation Seems not superior

Note: this is 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

  • 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)
  • Folinic acid (Leucovorin) 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

Variant #3, 1900/100

Study Evidence Comparator Efficacy
Hong et al. 2014 (ADORE) Randomized Phase II (C) FOLFOX Seems to have inferior DFS

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

  • Fluoropyrimidine-based chemoradiation, then TME

Chemotherapy

28-day cycle for 4 cycles

Variant #4, 2125/100 ("Mayo regimen")

Study Evidence Comparator Efficacy
Breugom et al. 2014 (PROCTOR) Phase III (E) Observation Seems not superior
Delbaldo et al. 2015 (R98) Phase III (C) FOLFIRI Seems not superior

Note: this is 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: 5-FU-based chemoradiotherapy or RT, then surgery

Chemotherapy

4- to 5-week cycle for 6 cycles

References

  1. 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 verified protocol PubMed
  2. 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 protocol PubMed
  3. 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; Cooperative Investigators of Dutch Colorectal Cancer Group and 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 verified protocol PubMed
  4. 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, FNLCC and 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

FOLFOX

back to top

FOLFOX: FOLinic acid, Fluorouracil, OXaliplatin

Variant #1, week-based cycles

Study Evidence Comparator Efficacy
Hong et al. 2014 (ADORE) Randomized Phase II (E) Fluorouracil & Leucovorin Seems to have superior DFS

Preceding treatment

  • Fluoropyrimidine-based chemoradiation, then TME

Chemotherapy

14-day cycle for 8 cycles

Variant #2, month-based cycles

Study Evidence Comparator Efficacy
Rödel et al. 2012 (CAO/ARO/AIO-04) Phase III (E) Fluorouracil Not reported

Preceding treatment

Chemotherapy

1-month cycle for 4 cycles

References

  1. 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 protocol PubMed
  2. 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 verified protocol PubMed
    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

Observation

back to top

Regimen

Study Evidence Comparator Efficacy
Mittelman et al. 1985 Phase III (C) 5-FU & Semustine Not reported
5-FU, Semustine, RT Inferior RFS
RT Not reported
Glynne-Jones et al. 2014 (Chronicle) Phase III (C) XELOX Seems not superior
Sainato et al. 2014 (I-CNR-RT) Phase III (C) 5-FU & LV Seems not superior
Breugom et al. 2014 (PROCTOR) Phase III (C) 5-FU & LV Seems not superior
Breugom et al. 2014 (SCRIPT) Phase III (C) Capecitabine Seems not superior

No further treatment after (neoadjuvant therapy) and surgery.

Preceding treatment

References

  1. Mittelman A, Holyoke ED, Stablein DM, Novak JW, Thomas PRM, Moertel CG, Weiland LH, Livstone EM, Bruckner HW, Knowlton AH; Gastrointestinal Tumor Study Group. Prolongation of the disease-free interval in surgically treated rectal carcinoma. N Engl J Med. 1985 Jun 6;312(23):1465-72. link to original article PubMed
  2. Chronicle: Glynne-Jones R, Counsell N, Quirke P, Mortensen N, Maraveyas A, Meadows HM, Ledermann J, Sebag-Montefiore D. Chronicle: results of a randomised phase III trial in locally advanced rectal cancer after neoadjuvant chemoradiation randomising postoperative adjuvant capecitabine plus oxaliplatin (XELOX) versus control. Ann Oncol. 2014 Jul;25(7):1356-62. Epub 2014 Apr 8. link to original article PubMed
  3. 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 protocol PubMed
  4. PROCTOR/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; Cooperative Investigators of Dutch Colorectal Cancer Group and 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 verified protocol PubMed

S-1 monotherapy

back to top

Regimen

Study Evidence Comparator Efficacy
Oki et al. 2016 (ACTS-RC) Phase III (E) UFT Seems to have superior 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, gimeracil, oteracil (S-1) as follows:
    • BSA less than 1.25 m2: 40 mg PO twice per day on days 1 to 28
    • BSA 1.25 to 1.50 m2: 50 mg PO twice per day on days 1 to 28
    • BSA 1.50 or greater m2: 60 mg PO twice per day on days 1 to 28

42-day cycle for 9 cycles (1 year)

References

  1. 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 verified protocol PubMed

UFT monotherapy

back to top

Regimen

Study Evidence Comparator Efficacy
Hamaguchi et al. 2010 (NSAS-CC) Phase III (E) Surgery alone Seems to have superior OS (*)
Oki et al. 2016 (ACTS-RC) Phase III (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) as follows:
    • BSA less than 1.25 m2: 250 mg PO twice per day on days 1 to 5
    • BSA 1.25 or greater m2: 300 mg PO twice per day on days 1 to 5

7-day cycle for 52 cycles

References

  1. 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
  2. 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 verified protocol PubMed

Adjuvant chemoradiotherapy

Capecitabine, then Capecitabine & RT, then Capecitabine

back to top

RT: Radiation Therapy

Regimen

Study Evidence Comparator Efficacy
Hofheinz et al. 2012 (Rektum-III) Phase III (E) 5-FU, then 5-FU & RT, then 5-FU Non-inferior OS

Preceding treatment

Chemotherapy, part 1

21-day cycle for 2 cycles, followed by:

Chemotherapy, part 2

Radiotherapy

Followed by:

Chemotherapy, part 3

21-day cycle for 3 cycles

References

  1. 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 verified protocol PubMed

Capecitabine & RT

back to top

RT: Radiation Therapy

Regimen

Study Evidence Comparator Efficacy
Feng et al. 2016 (CAMS_rectal cancer_01) Phase III (C) CapeOx & RT Seems not superior

Preceding treatment

Chemotherapy

21-day cycle for 2 cycles

Radiotherapy

5- to 5.5-week course

References

  1. 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 verified protocol PubMed

Fluorouracil & RT

back to top

RT: Radiation Therapy

Regimen

Study Evidence Comparator Efficacy
Fountzilas et al. 1999 Phase III (C) 5-FU & LV, then 5-FU & RT, then 5-FU & LV Seems not superior

Chemotherapy

Radiotherapy

References

  1. 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. 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

Fluorouracil, then Fluorouracil & RT, then Fluorouracil

back to top

RT: Radiation Therapy

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

Study Evidence Comparator Efficacy
O'Connell et al. 1994 (INT 864751) Phase III (E) Bolus 5-FU, then bolus 5-FU & RT, then bolus 5-FU Superior OS
Smalley et al. 2006 (GI INT 0144) Phase III (E) 1. Bolus 5-FU, then RT, then Bolus 5-FU Seems not superior
2. CI 5-FU, then 5-FU & RT, then CI 5-FU Seems not superior

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

Preceding treatment

Chemotherapy, part 1

28-day cycle for 2 cycles, followed immediately by:

Chemotherapy, part 2

Radiotherapy

  • 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

6-week course, followed 28 days later by:

Chemotherapy, part 3

28-day cycle for 2 cycles

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

Study Evidence Comparator Efficacy
Hofheinz et al. 2012 (Rektum-III) Phase III (C) Capecitabine, then Capecitabine & RT, then Capecitabine Non-inferior OS

Preceding treatment

Chemotherapy, part 1

28-day cycle for 2 cycles, followed by:

Chemotherapy, part 2

Radiotherapy

Followed by:

Chemotherapy, part 3

28-day cycle for 2 cycles

Variant #3, CI 5-FU, then CI 5-FU & RT, then CI 5-FU

Study Evidence Comparator Efficacy
Smalley et al. 2006 (GI INT 0144) Phase III (E) 1. Bolus 5-FU, then 5-FU & RT, then Bolus 5-FU Seems not superior
2. Bolus 5-FU, then RT, then Bolus 5-FU Seems not superior

Preceding treatment

Chemotherapy, part 1

  • Fluorouracil (5-FU) 300 mg/m2/day IV continuous infusion over 42 days, started on day 1 (total dose: 12,600 mg/m2)

8-week course, followed in 2 weeks by:

Chemotherapy, part 2

Radiotherapy

  • 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

Followed in 28 days by:

Chemotherapy, part 3

56-day course

Variant #4, bolus 5-FU, then bolus 5-FU & RT, then bolus 5-FU

Study Evidence Comparator Efficacy
O'Connell et al. 1994 (INT 864751) Phase III (C) Bolus 5-FU, then CI 5-FU & RT, then bolus 5-FU Inferior OS
Tepper et al. 1997 (GI INT 0114) Phase III (C) 1. 5-FU & Leucovorin, then 5-FU, Leucovorin, RT, then 5-FU & Leucovorin Seems not superior
2. Levamisole combination #1 Seems not superior
3. Levamisole combination #2 Seems not superior

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

Preceding treatment

Chemotherapy, part 1

28-day cycle for 2 cycles, followed by:

Chemotherapy, part 2

  • 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

Radiotherapy

  • 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

Followed in 28 days by:

Chemotherapy, part 3

28-day cycle for 2 cycles

References

  1. 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 verified protocol PubMed
  2. 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 verified protocol 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 verified protocol PubMed content property of HemOnc.org
  3. 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 verified protocol PubMed
  4. 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 verified protocol PubMed

5-FU & Leucovorin, then 5-FU, Leucovorin, RT, then 5-FU & Leucovorin

back to top

RT: Radiation Therapy

Regimen

Study Evidence Comparator Efficacy
Tepper et al. 1997 (GI INT 0114) Phase III (E) 1. 5-FU, then 5-FU & RT, then 5-FU Seems not superior
2. Levamisole combination #1 Seems not superior
3. Levamisole combination #2 Seems not superior

Preceding treatment

Chemotherapy, part 1

28-day cycle for 2 cycles, followed by:

Chemotherapy, part 2

  • 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

Radiotherapy

  • 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

Followed in 28 days by:

Chemotherapy, part 3

28-day cycle for 2 cycles

References

  1. 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 verified protocol 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 verified protocol PubMed

Radiation therapy

back to top

RT: Radiation Therapy

Regimen

Study Evidence Comparator Efficacy
Fisher et al. 1988 (NSABP R-01) Phase III (E) 1. MOF Not reported
2. Surgery alone Seems not superior
Krook et al. 1991 Phase III (C) Fluorouracil & RT Inferior RFS
Amott et al. 1996 Phase III (E) Surgery alone Superior local recurrence rate

Of historic interest.

Preceding treatment

Radiotherapy

4-week course

References

  1. 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
  2. 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
  3. 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 protocol PubMed
  4. TTROG 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

Advanced or metastatic disease

See the colon cancer page for colorectal cancer regimens.