Anal cancer

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 Travis Zack, MD, PhD
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9 regimens on this page
13 variants on this page


Guidelines

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

ESMO

French Intergroup

NCCN

Definitive chemoradiotherapy for locally advanced disease

Capecitabine, Mitomycin, RT

Regimen

Study Dates of enrollment Evidence
Glynne-Jones et al. 2008 (EXTRA) 2004-2006 Phase 2

Chemotherapy

Radiotherapy

  • Concurrent radiation therapy 180 cGy per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33, 35 to 37 (28 fractions; total dose: 5040 cGy)

6-week course

References

  1. EXTRA: Glynne-Jones R, Meadows H, Wan S, Gollins S, Leslie M, Levine E, McDonald AC, Myint S, Samuel L, Sebag-Montefiore D; National Cancer Research Institute Anal Sub Group; NCRI Colorectal Clinical Oncology Group. EXTRA--a multicenter phase II study of chemoradiation using a 5 day per week oral regimen of capecitabine and intravenous mitomycin C in anal cancer. Int J Radiat Oncol Biol Phys. 2008 Sep 1;72(1):119-26. Epub 2008 May 9. link to original article contains dosing details in abstract PubMed

Cisplatin & Fluorouracil (CF) & RT

CF & RT: Cisplatin, Fluorouracil, Radiation Therapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Doci et al. 1996 1991-1995 Phase 2
Ajani et al. 2008 (RTOG 98-11) 1998-2005 Phase 3 (E-switch-ic) Fluorouracil, Mitomycin, RT Seems to have inferior OS1 (secondary endpoint)
Peiffert et al. 2012 (ACCORD 03) 1999-2005 Non-randomized part of phase 3 RCT
James et al. 2013 (ACT II) 2001-2008 Phase 3 (E-switch-ic) Fluorouracil, Mitomycin, RT Did not meet primary endpoint of CR rate at 26 weeks

1Reported efficacy for RTOG 98-11 is based on the 2012 update.
Included for reference purposes only.

Chemotherapy

Radiotherapy

References

  1. Doci R, Zucali R, La Monica G, Meroni E, Kenda R, Eboli M, Lozza L. Primary chemoradiation therapy with fluorouracil and cisplatin for cancer of the anus: results in 35 consecutive patients. J Clin Oncol. 1996 Dec;14(12):3121-5. link to original article PubMed
  2. RTOG 98-11: Ajani JA, Winter KA, Gunderson LL, Pedersen J, Benson AB 3rd, Thomas CR Jr, Mayer RJ, Haddock MG, Rich TA, Willett C. Fluorouracil, mitomycin, and radiotherapy vs fluorouracil, cisplatin, and radiotherapy for carcinoma of the anal canal: a randomized controlled trial. JAMA. 2008 Apr 23;299(16):1914-21. link to original article contains dosing details in manuscript PubMed NCT00003596
    1. Update: Gunderson LL, Winter KA, Ajani JA, Pedersen JE, Moughan J, Benson AB 3rd, Thomas CR Jr, Mayer RJ, Haddock MG, Rich TA, Willett CG. Long-term update of US GI intergroup RTOG 98-11 phase III trial for anal carcinoma: survival, relapse, and colostomy failure with concurrent chemoradiation involving fluorouracil/mitomycin versus fluorouracil/cisplatin. J Clin Oncol. 2012 Dec 10;30(35):4344-51. Epub 2012 Nov 13. link to original article link to PMC article PubMed
  3. ACCORD 03: Peiffert D, Tournier-Rangeard L, Gérard JP, Lemanski C, François E, Giovannini M, Cvitkovic F, Mirabel X, Bouché O, Luporsi E, Conroy T, Montoto-Grillot C, Mornex F, Lusinchi A, Hannoun-Lévi JM, Seitz JF, Adenis A, Hennequin C, Denis B, Ducreux M. Induction chemotherapy and dose intensification of the radiation boost in locally advanced anal canal carcinoma: final analysis of the randomized UNICANCER ACCORD 03 trial. J Clin Oncol. 2012 Jun 1;30(16):1941-8. Epub 2012 Apr 23. Erratum in: J Clin Oncol. 2012 Nov 1;30(31):3903. link to original article PubMed NCT00003652
    1. HRQoL analysis: Tournier-Rangeard L, Mercier M, Peiffert D, Gerard JP, Romestaing P, Lemanski C, Mirabel X, Pommier P, Denis B. Radiochemotherapy of locally advanced anal canal carcinoma: prospective assessment of early impact on the quality of life (randomized trial ACCORD 03). Radiother Oncol. 2008 Jun;87(3):391-7. Epub 2008 Jan 11. link to original article PubMed
  4. ACT II: James RD, Glynne-Jones R, Meadows HM, Cunningham D, Myint AS, Saunders MP, Maughan T, McDonald A, Essapen S, Leslie M, Falk S, Wilson C, Gollins S, Begum R, Ledermann J, Kadalayil L, Sebag-Montefiore D. Mitomycin or cisplatin chemoradiation with or without maintenance chemotherapy for treatment of squamous-cell carcinoma of the anus (ACT II): a randomised, phase 3, open-label, 2×2 factorial trial. Lancet Oncol. 2013 May;14(6):516-24. Epub 2013 Apr 9. link to original article contains dosing details in manuscript PubMed NCT00025090

Fluorouracil, Mitomycin, RT

Regimen variant #1, 3750/12/45

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Northover et al. 1996 (ACT I) 1987-1994 Phase 3 (E-esc) Radiation Superior local failure rate

Because there were a few different schedules used in UKCCCR Anal Cancer Trial Working Party 1996 and the update (Northover et al. 2010), there is some variability in potential schedules.

Chemotherapy

  • Fluorouracil (5-FU) 750 mg/m2/day IV continuous infusion over 120 hours, started on days 1 & 29 (total dose: 7500 mg/m2)
  • Mitomycin (Mutamycin) 12 mg/m2 (maximum dose of 20 mg) IV bolus once per day on days 1 & 29

Radiotherapy

  • Concurrent radiation therapy 1.8 or 225 cGy fractions x 20 or 25 fractions (total dose: 4500 cGy), given over 4 to 5 weeks; see Northover et al. 2010 for details, including information about boost radiation therapy

8-week course


Regimen variant #2, 3750/15/45

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Bartelink et al. 1997 (EORTC 22861) 1987-1994 Phase 3 (E-esc) Radiation Superior local failure rate

Note: mitomycin is only given with cycle 1.

Chemotherapy

Radiotherapy

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

5-week course


Regimen variant #3, 4000/10/45

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Flam et al. 1996 (ECOG E1289) 1988-1991 Phase 3 (C) 5-FU & RT Superior DFS
Ajani et al. 2008 (RTOG 98-11) 1998-2005 Phase 3 (C) CF & RT Seems to have superior OS1

1Reported efficacy for RTOG 98-11 is based on the 2012 update.

Chemotherapy

  • Fluorouracil (5-FU) 1000 mg/m2/day IV continuous infusion over 96 hours, started on days 1 & 29 (total dose: 8000 mg/m2)
  • Mitomycin (Mutamycin) 10 mg/m2 (maximum dose of 20 mg) IV bolus once per day on days 1 & 29

Radiotherapy

  • Concurrent radiation therapy at a minimum, 180 cGy per day x 25 fractions (total dose: 4500 cGy), given over 5 weeks; see articles for additional details

5-week course


Regimen variant #4, 4000/12/45

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Northover et al. 1996 (ACT I) 1987-1994 Phase 3 (E-esc) Radiation Superior local failure rate

Because there were a few different schedules used in UKCCCR Anal Cancer Trial Working Party 1996 and the update (Northover et al. 2010), there is some variability in potential schedules.

Chemotherapy

  • Fluorouracil (5-FU) 1000 mg/m2/day IV continuous infusion over 96 hours, started on days 1 & 29, initiated at least 2 hours before the first radiation fraction (total dose: 8000 mg/m2)
  • Mitomycin (Mutamycin) 12 mg/m2 (maximum dose of 20 mg) IV bolus once per day on days 1 & 29

Radiotherapy

  • Concurrent radiation therapy 1.8 or 225 cGy fractions x 20 or 25 fractions (total dose: 4500 cGy), given over 4 to 5 weeks; see Northover et al. 2010 for details, including information about boost radiation therapy

8-week course


Regimen variant #5, 4000/12/50.4

Study Dates of enrollment Evidence Comparator Comparative Efficacy
James et al. 2013 (ACT II) 2001-2008 Phase 3 (C) Cisplatin, Fluorouracil, RT Did not meet primary endpoint of CR rate at 26 weeks

Chemotherapy

  • Fluorouracil (5-FU) 1000 mg/m2/day IV continuous infusion over 96 hours, started on days 1 & 29 (total dose: 8000 mg/m2)
  • Mitomycin (Mutamycin) 12 mg/m2 (maximum dose of 20 mg) IV bolus once per day on days 1 & 29

Radiotherapy

  • Concurrent radiation therapy 180 cGy per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33, 35 to 37 (28 fractions; total dose: 5040 cGy); see paper for details

6-week course

Subsequent treatment

References

  1. ECOG E1289: Flam M, John M, Pajak TF, Petrelli N, Myerson R, Doggett S, Quivey J, Rotman M, Kerman H, Coia L, Murray K; RTOG; ECOG. Role of mitomycin in combination with fluorouracil and radiotherapy, and of salvage chemoradiation in the definitive nonsurgical treatment of epidermoid carcinoma of the anal canal: results of a phase III randomized intergroup study. J Clin Oncol. 1996 Sep;14(9):2527-39. link to original article contains dosing details in manuscript PubMed
  2. ACT I: Northover JMA, Arnott SJ, Cunningham D, Gallagher J, Gray R, Hardcastle J, Houghton J, James RD, Lennon TA, Meadows HM, Mossman J, Morgan DAL, Plowman PN, Slevin M; UKCCCR Anal Cancer Trial Working Party; UK Co-ordinating Committee on Cancer Research. Epidermoid anal cancer: results from the UKCCCR randomised trial of radiotherapy alone versus radiotherapy, 5-fluorouracil, and mitomycin. Lancet. 1996 Oct 19;348(9034):1049-54. link to original article contains dosing details in manuscript PubMed
    1. Update: Northover J, Glynne-Jones R, Sebag-Montefiore D, James R, Meadows H, Wan S, Jitlal M, Ledermann J. Chemoradiation for the treatment of epidermoid anal cancer: 13-year follow-up of the first randomised UKCCCR Anal Cancer Trial (ACT I). Br J Cancer. 2010 Mar 30;102(7):1123-8. Epub 2010 Mar 16. link to original article contains dosing details in manuscript link to PMC article PubMed content property of HemOnc.org
  3. EORTC 22861: Bartelink H, Roelofsen F, Eschwege F, Rougier P, Bosset JF, Gonzalez DG, Peiffert D, van Glabbeke M, Pierart M; European Organisation for Research and Treatment of Cancer Radiotherapy Group; EORTC Gastrointestinal Cooperative Group. Concomitant radiotherapy and chemotherapy is superior to radiotherapy alone in the treatment of locally advanced anal cancer: results of a phase III randomized trial of the European Organisation for Research and Treatment of Cancer Radiotherapy and Gastrointestinal Cooperative Groups. J Clin Oncol. 1997 May;15(5):2040-9. link to original article contains dosing details in abstract PubMed
  4. RTOG 98-11: Ajani JA, Winter KA, Gunderson LL, Pedersen J, Benson AB 3rd, Thomas CR Jr, Mayer RJ, Haddock MG, Rich TA, Willett C. Fluorouracil, mitomycin, and radiotherapy vs fluorouracil, cisplatin, and radiotherapy for carcinoma of the anal canal: a randomized controlled trial. JAMA. 2008 Apr 23;299(16):1914-21. link to original article contains dosing details in manuscript PubMed NCT00003596
    1. Update: Gunderson LL, Winter KA, Ajani JA, Pedersen JE, Moughan J, Benson AB 3rd, Thomas CR Jr, Mayer RJ, Haddock MG, Rich TA, Willett CG. Long-term update of US GI intergroup RTOG 98-11 phase III trial for anal carcinoma: survival, relapse, and colostomy failure with concurrent chemoradiation involving fluorouracil/mitomycin versus fluorouracil/cisplatin. J Clin Oncol. 2012 Dec 10;30(35):4344-51. Epub 2012 Nov 13. link to original article link to PMC article PubMed
  5. ACT II: James RD, Glynne-Jones R, Meadows HM, Cunningham D, Myint AS, Saunders MP, Maughan T, McDonald A, Essapen S, Leslie M, Falk S, Wilson C, Gollins S, Begum R, Ledermann J, Kadalayil L, Sebag-Montefiore D. Mitomycin or cisplatin chemoradiation with or without maintenance chemotherapy for treatment of squamous-cell carcinoma of the anus (ACT II): a randomised, phase 3, open-label, 2×2 factorial trial. Lancet Oncol. 2013 May;14(6):516-24. Epub 2013 Apr 9. link to original article contains dosing details in manuscript PubMed NCT00025090

Radiation therapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Northover et al. 1996 (ACT I) 1987-1994 Phase 3 (C) Fluorouracil, Mitomycin, RT Inferior local failure rate

Inferior to combined modality therapy; included for reference purposes only.

Radiotherapy

References

  1. ACT I: Northover JMA, Arnott SJ, Cunningham D, Gallagher J, Gray R, Hardcastle J, Houghton J, James RD, Lennon TA, Meadows HM, Mossman J, Morgan DAL, Plowman PN, Slevin M; UKCCCR Anal Cancer Trial Working Party; UK Co-ordinating Committee on Cancer Research. Epidermoid anal cancer: results from the UKCCCR randomised trial of radiotherapy alone versus radiotherapy, 5-fluorouracil, and mitomycin. Lancet. 1996 Oct 19;348(9034):1049-54. link to original article contains dosing details in manuscript PubMed
    1. Update: Northover J, Glynne-Jones R, Sebag-Montefiore D, James R, Meadows H, Wan S, Jitlal M, Ledermann J. Chemoradiation for the treatment of epidermoid anal cancer: 13-year follow-up of the first randomised UKCCCR Anal Cancer Trial (ACT I). Br J Cancer. 2010 Mar 30;102(7):1123-8. Epub 2010 Mar 16. link to original article contains dosing details in manuscript link to PMC article PubMed content property of HemOnc.org

Metastatic disease, first-line therapy

Cisplatin & Fluorouracil (CF)

Regimen variant #1, 100/5000 every 4 weeks

Study Dates of enrollment Evidence
Faivre et al. 1999 NR in abstract Pilot, fewer than 20 patients reported

Chemotherapy

28-day cycles


Regimen variant #2, 60/4000 every 3 weeks

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Rao et al. 2020 (InterAACT) 2013-2017 Randomized Phase 2 (C) Carboplatin & Paclitaxel Did not meet primary endpoint of ORR

Chemotherapy

21-day cycle for 8 cycles

References

  1. Faivre C, Rougier P, Ducreux M, Mitry E, Lusinchi A, Lasser P, Elias D, Eschwege F. [5-fluorouracile and cisplatinum combination chemotherapy for metastatic squamous-cell anal cancer]. Bull Cancer. 1999 Oct;86(10):861-5. link to original article & English summary contains dosing details in abstract PubMed
  2. InterAAct: Rao S, Sclafani F, Eng C, Adams RA, Guren MG, Sebag-Montefiore D, Benson A, Bryant A, Peckitt C, Segelov E, Roy A, Seymour MT, Welch J, Saunders MP, Muirhead R, O'Dwyer P, Bridgewater J, Bhide S, Glynne-Jones R, Arnold D, Cunningham D. International Rare Cancers Initiative Multicenter Randomized Phase II Trial of Cisplatin and Fluorouracil Versus Carboplatin and Paclitaxel in Advanced Anal Cancer: InterAAct. J Clin Oncol. 2020 Aug 1;38(22):2510-2518. Epub 2020 Jun 12. link to original article link to PMC article contains dosing details in manuscript PubMed NCT02051868

Carboplatin & Paclitaxel (CP)

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Rao et al. 2020 (InterAACT) 2013-2017 Randomized Phase 2 (E-switch-ic) CF Did not meet primary endpoint of ORR

Chemotherapy

28-day cycle for 6 cycles

References

  1. InterAAct: Rao S, Sclafani F, Eng C, Adams RA, Guren MG, Sebag-Montefiore D, Benson A, Bryant A, Peckitt C, Segelov E, Roy A, Seymour MT, Welch J, Saunders MP, Muirhead R, O'Dwyer P, Bridgewater J, Bhide S, Glynne-Jones R, Arnold D, Cunningham D. International Rare Cancers Initiative Multicenter Randomized Phase II Trial of Cisplatin and Fluorouracil Versus Carboplatin and Paclitaxel in Advanced Anal Cancer: InterAAct. J Clin Oncol. 2020 Aug 1;38(22):2510-2518. Epub 2020 Jun 12. link to original article link to PMC article contains dosing details in manuscript PubMed NCT02051868
  2. ECOG-ACRIN EA2176: NCT04444921

mDCF

mDCF: modified Docetaxel, Cisplatin, Fluorouracil

Regimen

Study Dates of enrollment Evidence
Kim et al. 2018 (Epitopes-HPV02) 2014-2016 Phase 2

Chemotherapy

14-day cycle for 8 cycles

References

  1. Epitopes-HPV02: Kim S, François E, André T, Samalin E, Jary M, El Hajbi F, Baba-Hamed N, Pernot S, Kaminsky MC, Bouché O, Desrame J, Zoubir M, Ghiringhelli F, Parzy A, De La Fouchardiere C, Smith D, Deberne M, Spehner L, Badet N, Adotevi O, Anota A, Meurisse A, Vernerey D, Taieb J, Vendrely V, Buecher B, Borg C. Docetaxel, cisplatin, and fluorouracil chemotherapy for metastatic or unresectable locally recurrent anal squamous cell carcinoma (Epitopes-HPV02): a multicentre, single-arm, phase 2 study. Lancet Oncol. 2018 Aug;19(8):1094-1106. Epub 2018 Jul 2. link to original article PubMed NCT02402842

Metastatic disease, subsequent lines of therapy

Nivolumab monotherapy

Regimen

Study Dates of enrollment Evidence
Morris et al. 2017 (NCI9673) 2015-05-14 to 2015-11-11 Phase 2

Immunotherapy

14-day cycles

References

  1. NCI9673: Morris VK, Salem ME, Nimeiri H, Iqbal S, Singh P, Ciombor K, Polite B, Deming D, Chan E, Wade JL, Xiao L, Bekaii-Saab T, Vence L, Blando J, Mahvash A, Foo WC, Ohaji C, Pasia M, Bland G, Ohinata A, Rogers J, Mehdizadeh A, Banks K, Lanman R, Wolff RA, Streicher H, Allison J, Sharma P, Eng C. Nivolumab for previously treated unresectable metastatic anal cancer (NCI9673): a multicentre, single-arm, phase 2 study. Lancet Oncol. 2017 Apr;18(4):446-453. Epub 2017 Feb 18. link to original article link to PMC article contains dosing details in manuscript PubMed NCT02314169

Pembrolizumab monotherapy

Regimen

Study Dates of enrollment Evidence
Ott et al. 2017a (KEYNOTE-028anal) 2014 Phase 1b, >20 pts in this subgroup

Immunotherapy

14-day cycle for up to 52 cycles (2 years)

References

  1. KEYNOTE-028anal: Ott PA, Piha-Paul SA, Munster P, Pishvaian MJ, van Brummelen EMJ, Cohen RB, Gomez-Roca C, Ejadi S, Stein M, Chan E, Simonelli M, Morosky A, Saraf S, Emancipator K, Koshiji M, Bennouna J. Safety and antitumor activity of the anti-PD-1 antibody pembrolizumab in patients with recurrent carcinoma of the anal canal. Ann Oncol. 2017 May 1;28(5):1036-1041. link to original article link to PMC article contains dosing details in abstract PubMed NCT02054806
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