Rectal cancer

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Please be aware that there are overlaps for protocols used in the treatment of colon and rectal cancer. We have tried to only include rectal cancer-specific protocols here, with links to the colon cancer page for non-specific colorectal cancer protocols.

22 regimens on this page 48 variants on this page

Guidelines

ESMO

• Rectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. (2013) PubMed

NCCN

• NCCN Guidelines - Rectal Cancer

Neoadjuvant chemoradiation

Capecitabine & RT

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RT: Radiation Therapy

Regimen

Study	Evidence	Comparator	Efficacy
Hofheinz et al. 2012	Phase III	5-FU & RT	Non-inferior OS

Chemoradiotherapy

• Capecitabine (Xeloda) 825 mg/m² PO BID (1650 mg/m²/day) on days 1 to 38
• Concurrent radiation therapy, 50.4 Gy total

One course

After surgery, patients proceeded to receive adjuvant capecitabine.

References

1. 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. 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 PubMed

Fluorouracil & RT

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RT: Radiation Therapy

Regimen

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

Chemoradiotherapy

• Fluorouracil (5-FU) 1000 mg/m²/day IV continuous infusion on days 1 to 5, 29 to 33
• Concurrent radiation therapy, 50.4 Gy total

One course

After surgery, patients proceeded to receive adjuvant fluorouracil.

References

1. 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 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. 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
3. 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
4. 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 PubMed

Fluorouracil, Folinic acid, RT

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RT: Radiation Therapy

Regimen

Study	Evidence	Comparator	Efficacy
Deng et al. 2016 (FOWARC)	Phase III	mFOLFOX6	Seems to have superior pCR rate
		mFOLFOX6 & RT	Inferior pCR rate

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.

Chemoradiotherapy

• Folinic acid (Leucovorin) 400 mg/m² IV once on day 1
• Fluorouracil (5-FU) 400 mg/m² IV bolus, then 2400 mg/m²/day IV continuous infusion over 48 hours starting on day 1
• Concurrent radiotherapy 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

14-day cycle for 5 cycles

Treatment followed by surgery and then 7 more cycles of fluorouracil & folinic acid.

References

1. 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

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RT: Radiation Therapy

Regimen

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

Chemoradiotherapy

• Fluorouracil (5-FU) 250 mg/m²/day IV continuous infusion on days 1 to 14, 22 to 35
• Oxaliplatin (Eloxatin) 50 mg/m² IV once per day on days 1, 8, 22, 29
• Concurrent radiation therapy, 50.4 Gy total

One course

After surgery, patients proceeded to receive adjuvant FOLFOX.

References

1. 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
2. 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 PubMed

mFOLFOX6 & RT

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

Regimen

Study	Evidence	Comparator	Efficacy
Deng et al. 2016 (FOWARC)	Phase III	Fluorouracil, Folinic acid, RT	Superior pCR rate
		mFOLFOX6	Not reported

Chemoradiotherapy

• Folinic acid (Leucovorin) 400 mg/m² IV once on day 1
• Fluorouracil (5-FU) 400 mg/m² IV bolus, then 2400 mg/m²/day IV continuous infusion over 48 hours starting on day 1
• Oxaliplatin (Eloxatin) 85 mg/m² IV once on day 1
• Concurrent radiotherapy 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 over 5 to 6 weeks and a total dose of 46.0 to 50.4 Gy

14-day cycle for 4 to 6 cycles

Treatment followed by surgery and then 6 to 8 more cycles of mFOLFOX6.

References

1. 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

Adjuvant chemotherapy

Capecitabine (Xeloda)

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Regimen

Study	Evidence	Comparator	Efficacy
Hofheinz et al. 2012	Phase III	Fluorouracil	Non-inferior OS

Treatment preceded by neoadjuvant capecitabine & RT and surgery.

Chemotherapy

• Capecitabine (Xeloda) 1250 mg/m² PO BID (2500 mg/m²/day) on days 1 to 14

21-day cycle for 5 cycles

References

1. 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

CapeOx (XELOX)

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CapeOX: Capecitabine, OXaliplatin
XELOX: XELoda (Capecitabine), OXaliplatin

Regimen

See CapeOx for adjuvant treatment of colon cancer.

References

1. 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. link to original article contains verified protocol PubMed
   1. 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. link to original article PubMed
2. 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. link to original article contains verified protocol PubMed

FLOX

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FLOX: Fluorouracil, Leucovorin, OXaliplatin

Regimen

See FLOX for adjuvant treatment of colon cancer.

References

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. link to original article contains verified protocol PubMed

Fluorouracil (5-FU)

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Regimen #1

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

Treatment preceded by neoadjuvant fluorouracil & RT and 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 #2

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

Treatment preceded by neoadjuvant fluorouracil & RT and 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

1. 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. 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

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Regimen

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

Treatment preceded by fluoropyrimidine-based chemoradiation and total mesorectal excision.

Chemotherapy

• Fluorouracil (5-FU) 380 mg/m² IV once per day on days 1 to 5
• Folinic acid (Leucovorin) 20 mg/m² IV once per day on days 1 to 5

28-day cycle for 4 cycles

References

1. 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

FOLFOX

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FOLFOX: FOLinic acid, Fluorouracil, OXaliplatin

Regimen #1

Study	Evidence	Comparator	Efficacy
Hong et al. 2014 (ADORE)	Randomized Phase II	Fluorouracil & 5-FU	Seems to have superior DFS

Treatment preceded by fluoropyrimidine-based chemoradiation and total mesorectal excision.

Chemotherapy

• Fluorouracil (5-FU) 400 mg/m² IV bolus on day 1, then 1200 mg/m²/day IV continuous infusion over 46 hours (total dose: 2800 mg/m²)
• Folinic acid (Leucovorin) 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 #2

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

Treatment preceded by neoadjuvant fluorouracil, oxaliplatin, RT and surgery. Note: it is unclear from the abstract whether the intent is for 8 cycles (16 doses of oxaliplatin) or 8 doses of oxaliplatin.

Chemotherapy

• Fluorouracil (5-FU) 2400 mg/m² IV continuous infusion over 48 hours twice per cycle on days 1 & 2, 15 & 16
• Folinic acid (Leucovorin) 400 mg/m² IV once per day on days 1 & 15
• Oxaliplatin (Eloxatin) 100 mg/m² IV once per day on days 1 & 15

8 cycles

References

1. 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. 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

Adjuvant chemoradiation

Capecitabine -> Capecitabine & RT -> Capecitabine

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RT: Radiation Therapy

Regimen

Study	Evidence	Comparator	Efficacy
Hofheinz et al. 2012	Phase III	5-FU -> 5-FU & RT -> 5-FU	Non-inferior OS

Chemotherapy, part 1

• Capecitabine (Xeloda) 1250 mg/m² PO BID (2500 mg/m²/day) on days 1 to 14

21-day cycle for 2 cycles, followed by:

Chemoradiotherapy

• Capecitabine (Xeloda) 825 mg/m² PO BID (1650 mg/m²/day) on days 1 to 38
• Concurrent radiation therapy, 50.4 Gy total

Followed by:

Chemotherapy, part 2

• Capecitabine (Xeloda) 1250 mg/m² PO BID (2500 mg/m²/day) on days 1 to 14

21-day cycle for 3 cycles

References

1. 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

Fluorouracil -> Fluorouracil & RT -> Fluorouracil

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RT: Radiation Therapy

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

Study	Evidence	Comparator	Efficacy
Smalley et al. 2006 (GI INT 0144)	Phase III	Bolus 5-FU -> RT -> Bolus 5-FU	Seems not superior
		Continuous 5-FU -> 5-FU & RT -> Continuous 5-FU	Seems not superior

Chemotherapy, part 1

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

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

Chemoradiotherapy

• 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

One course, followed 28 days later by:

Chemotherapy, part 2

• Fluorouracil (5-FU) 450 mg/m² IV bolus once per day on days 1 to 5

28-day cycle for 2 cycles

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

Study	Evidence	Comparator	Efficacy
Hofheinz et al. 2012	Phase III	Capecitabine -> Capecitabine & RT -> Capecitabine	Non-inferior OS

Chemotherapy, part 1

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

28-day cycle for 2 cycles, followed by:

Chemoradiotherapy

• Fluorouracil (5-FU) 225 mg/m²/day IV continuous infusion while radiation is being given
• Concurrent radiation therapy, 50.4 Gy total

Followed by:

Chemotherapy, part 2

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

28-day cycle for 2 cycles

Regimen #3, Continuous 5-FU -> 5-FU & RT -> Continuous 5-FU

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

Chemotherapy, part 1

• Fluorouracil (5-FU) 300 mg/m²/day IV continuous infusion on days 1 to 42

8-week course, followed in 2 weeks by:

Chemoradiotherapy

• 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

Followed in 28 days by:

Chemotherapy, part 2

• Fluorouracil (5-FU) 300 mg/m²/day IV continuous infusion on days 1 to 56

56-day course

Regimen #4

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

Chemotherapy, part 1

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

28-day cycle for 2 cycles, followed by:

Chemoradiotherapy

• 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

Followed in 28 days by:

Chemotherapy, part 2

• Fluorouracil (5-FU) 450 mg/m² IV bolus once per day on days 1 to 5

28-day cycle for 2 cycles

Regimen #5

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

1. 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 PubMed
2. 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. 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. 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 -> 5-FU, Leucovorin, RT -> 5-FU & Leucovorin

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RT: Radiation Therapy

Regimen

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

Chemotherapy, part 1

• Fluorouracil (5-FU) 425 mg/m² IV bolus once per day on days 1 to 5, given after Folinic acid (Leucovorin)
• Folinic acid (Leucovorin) 20 mg/m² IV bolus once per day on days 1 to 5, given before Fluorouracil (5-FU)

28-day cycle for 2 cycles, followed by:

Chemoradiotherapy

• 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

Followed in 28 days by:

Chemotherapy, part 2

• Fluorouracil (5-FU) 380 mg/m² IV bolus once per day on days 1 to 5
• Folinic acid (Leucovorin) 20 mg/m² IV bolus once per day on days 1 to 5

28-day cycle for 2 cycles

References

1. 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

Fluorouracil, Folinic acid, Levamisole, RT

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RT: Radiation Therapy

Regimen

Study	Evidence	Comparator	Efficacy
Tepper et al. 1997 (GI INT 0114)	Phase III	5-FU -> 5-FU & RT -> 5-FU	Seems not superior
		5-FU & Leucovorin -> 5-FU, Leucovorin, RT -> 5-FU & Leucovorin	Seems not superior

Two levamisole combinations were evaluated and neither were superior; here for reference purposes only.

Chemotherapy

• Folinic acid (Leucovorin)
• Fluorouracil (5-FU)
• Levamisole (Ergamisol)

References

1. 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

Advanced or metastatic disease

See Colon cancer - Advanced or metastatic disease.