Rectal cancer

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Section editor
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Neeta K. Venepalli, MD, MBA
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).

15 regimens on this page
24 variants on this page

Contents


Guidelines

ESMO

NCCN

Neoadjuvant chemoradiotherapy

Capecitabine & RT

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RT: Radiation Therapy

Variant #1, continuous capecitabine

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

Chemoradiotherapy

One 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.

Chemoradiotherapy

One course

Subsequent treatment

  • Surgery

References

  1. 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. 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. 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 PubMed

Fluorouracil & RT

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RT: Radiation Therapy

Variant #1, continuous

Study Evidence Comparator Efficacy Toxicity
Aschele et al. 2011 (STAR-01) Phase III (C) Fluorouracil, Oxaliplatin, RT Seems not superior (*) Superior toxicity

Note: efficacy is based on the 2016 update.

Chemoradiotherapy

One course

Subsequent treatment

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

Variant #2, intermittent

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

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. 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 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

Variant #1, 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.

Chemoradiotherapy

6-week course

Subsequent treatment

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

Variant #2, 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

Chemoradiotherapy

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 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 monotherapy

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Regimen

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

Preceding treatment

Chemotherapy

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

Fluorouracil monotherapy

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Variant #1

Study Evidence Comparator Efficacy
Hofheinz et al. 2012 Phase III 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 FOLFOX Not reported

Preceding treatment

Chemotherapy

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

Preceding treatment

  • Fluoropyrimidine-based chemoradiation and total mesorectal excision

Chemotherapy

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

Variant #1

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

Preceding treatment

  • Fluoropyrimidine-based chemoradiation and total mesorectal excision

Chemotherapy

14-day cycle for 8 cycles

Variant #2

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

Note: it is unclear from the abstract whether the intent is for 8 cycles (16 doses of oxaliplatin) or 8 doses of oxaliplatin.

Preceding treatment

Chemotherapy

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

S-1 monotherapy

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Regimen

Study Evidence Comparator Efficacy
Oki et al. 2016 (ACTS-RC) Phase III 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 BID on days 1 to 28
    • BSA 1.25 to 1.50 m2: 50 mg PO BID on days 1 to 28
    • BSA 1.50 or greater m2: 60 mg PO BID on days 1 to 28

42-day cycles for 12 months

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 articlelink to PMC article contains verified protocol PubMed

UFT monotherapy

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Regimen

Study Evidence Comparator Efficacy
Oki et al. 2016 (ACTS-RC) Phase III 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 BID on days 1 to 5
    • BSA 1.25 or greater m2: 300 mg PO BID on days 1 to 5

7-day cycles for 12 months

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 articlelink to PMC article contains verified protocol PubMed

Adjuvant chemoradiotherapy

Capecitabine, then Capecitabine & RT, then Capecitabine

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RT: Radiation Therapy

Regimen

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

Chemotherapy, part 1

21-day cycle for 2 cycles, followed by:

Chemoradiotherapy

Followed by:

Chemotherapy, part 2

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, then Fluorouracil & RT, then Fluorouracil

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RT: Radiation Therapy

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

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

Chemotherapy, part 1

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

28-day cycle for 2 cycles

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

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

Chemotherapy, part 1

28-day cycle for 2 cycles, followed by:

Chemoradiotherapy

Followed by:

Chemotherapy, part 2

28-day cycle for 2 cycles

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

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

Chemotherapy, part 1

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

56-day course

Variant #4

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

Chemotherapy, part 1

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

28-day cycle for 2 cycles

Variant #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, then 5-FU, Leucovorin, RT, then 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, then 5-FU & RT, then 5-FU Seems not superior
Levamisole combination #1 Seems not superior
Levamisole combination #2 Seems not superior

Chemotherapy, part 1

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

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, then 5-FU & RT, then 5-FU Seems not superior
5-FU & Leucovorin, then 5-FU, Leucovorin, RT, then 5-FU & Leucovorin Seems not superior

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

Chemotherapy

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 the colon cancer page for colorectal cancer regimens.