Anal cancer

Page editor		Section editor
	Ari Seifter, MD University of Illinois at Chicago Chicago, IL		Neeta K. Venepalli, MD, MBA University of Illinois at Chicago Chicago, IL

9 regimens on this page 13 variants on this page

Guidelines

ESMO

• Anal cancer: ESMO-ESSO-ESTRO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed

NCCN

• NCCN Guidelines - Anal Carcinoma

Definitive chemoradiotherapy for locally advanced disease

Capecitabine, Mitomycin, RT

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Regimen

Study	Evidence
Glynne-Jones et al. 2008	Phase II

Chemoradiotherapy

• Capecitabine (Xeloda) 825 mg/m² PO twice per day on radiation days
• Mitomycin (Mutamycin) 12 mg/m² IV once on day 1
• Concurrent radiation therapy: 1.8 Gy per day x 28 fractions (total dose: 50.4 Gy)

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 and 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 protocol PubMed

Cisplatin, Fluorouracil, RT

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RT: Radiation Therapy

Regimen

Study	Evidence	Comparator	Efficacy
Ajani et al. 2008 (RTOG 98-11)	Phase III (E)	Fluorouracil, Mitomycin, RT	Seems to have inferior OS (*)
Peiffert et al. 2012 (ACCORD 03)	Non-randomized portion of RCT
James et al. 2013 (ACT II)	Phase III (E)	Fluorouracil, Mitomycin, RT	Seems not superior

Included for reference purposes only. Efficacy for RTOG 98-11 based on the 2012 update.

Chemoradiotherapy

• Cisplatin (Platinol)
• Fluorouracil (5-FU)
• External beam radiotherapy

References

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

Fluorouracil, Mitomycin, RT

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Variant #1, 3750/15/45

Study	Evidence	Comparator	Efficacy
Bartelink et al. 1997	Phase III (E)	Radiation	Superior local failure rate

Note: mitomycin is only given with cycle 1.

Chemoradiotherapy

• Fluorouracil (5-FU) 750 mg/m²/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 3750 mg/m²)
• Mitomycin (Mutamycin) as follows:
  • Cycle 1: 15 mg/m² IV bolus once on day 1
  • Cycle 2: none
• Concurrent radiation therapy: 1.8 Gy x 25 fractions (total dose: 45 Gy)

28-day cycle for 2 cycles

Variant #2, 4000/10/45

Study	Evidence	Comparator	Efficacy
Flam et al. 1996	Phase III (C)	5-FU & RT	Superior DFS
Ajani et al. 2008 (RTOG 98-11)	Phase III (C)	Fluorouracil, Cisplatin, RT	Seems to have superior OS (*)

Note: efficacy for RTOG 98-11 is based on the 2012 update.

Chemoradiotherapy

• Fluorouracil (5-FU) 1000 mg/m²/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 4000 mg/m²)
• Mitomycin (Mutamycin) 10 mg/m² (maximum dose of 20 mg) IV bolus once on day 1
• Concurrent radiation therapy; at a minimum: 1.8 Gy per day x 25 fractions (total dose: 45 Gy), given over 5 weeks; see articles for additional details

28-day cycle for 2 cycles

Variant #3, 4000/12/45

Study	Evidence	Comparator	Efficacy
Northover et al. 1996 (ACT I)	Phase III (E)	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.

Chemoradiotherapy

• Fluorouracil (5-FU) 1000 mg/m²/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 4000 mg/m²), started at least 2 hours before the first radiation fraction
  • Alternate dosing & schedule (per physician discretion): Fluorouracil (5-FU) 750 mg/m²/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 3750 mg/m²)
• Mitomycin (Mutamycin) 12 mg/m² (maximum dose of 20 mg) IV bolus once on day 1
• Concurrent radiation therapy: 1.8 or 2.25 Gy fractions x 20 or 25 fractions (total dose: 45 Gy), given over 4 to 5 weeks; see Northover et al. 2010 for details, including information about boost radiation therapy

28-day cycle for 2 cycles

Variant #4, 4000/12/50.4

Study	Evidence	Comparator	Efficacy
James et al. 2013 (ACT II)	Phase III (C)	Fluorouracil, Cisplatin, RT	Seems not superior

Chemoradiotherapy

• Fluorouracil (5-FU) 1000 mg/m²/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 4000 mg/m²)
• Mitomycin (Mutamycin) 12 mg/m² (maximum dose of 20 mg) IV bolus once on day 1
• Concurrent radiation therapy: 1.8 Gy per day x 28 fractions (total dose: 50.4 Gy), given over 5.5 weeks; see paper for details

28-day cycle for 2 cycles

Subsequent treatment

• CF maintenance versus no further treatment

References

1. Flam M, John M, Pajak TF, Petrelli N, Myerson R, Doggett S, Quivey J, Rotman M, Kerman H, Coia L, Murray K. 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 verified protocol 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 verified protocol 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 verified protocol PubMed content property of HemOnc.org
3. Bartelink H, Roelofsen F, Eschwege F, Rougier P, Bosset JF, Gonzalez DG, Peiffert D, van Glabbeke M, Pierart M. 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 Organization 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 protocol 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 verified protocol PubMed
   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. link to original article contains verified protocol PubMed

Radiation therapy

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Regimen

Study	Evidence	Comparator	Efficacy
Northover et al. 1996 (ACT I)	Phase III (C)	Fluorouracil, Mitomycin, radiation	Inferior local failure rate

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

Radiotherapy

• External beam 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 verified protocol 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 verified protocol PubMed content property of HemOnc.org

Metastatic disease, first-line therapy

Cisplatin & Fluorouracil

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Variant #1, 100/5000 every 4 weeks

Study	Evidence
Faivre et al. 1999	Pilot, <20 patients reported

Chemotherapy

• Cisplatin (Platinol) 100 mg/m² IV once on day 2
• 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 cycles

Variant #2, 60/4000 every 3 weeks

Study	Evidence	Comparator	Efficacy
Sclafani et al. 2017	Randomized Phase II (C)	Carboplatin & Paclitaxel	Not reported

Chemotherapy

• Cisplatin (Platinol) 60 mg/m² IV once on day 1
• Fluorouracil (5-FU) 1000 mg/m²/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 4000 mg/m²)

21-day 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 protocol PubMed
2. Abstract: Sclafani F et al. [InterAACT: An international multicenter open label randomized phase II advanced anal cancer trial comparing cisplatin (CDDP) plus 5-fluorouracil (5-FU) versus carboplatin (CBDCA) plus weekly paclitaxel (PTX) in patients with inoperable locally recurrent (ILR) or metastatic disease]. Journal of Clinical Oncology. 2015 33:3_suppl, TPS792-TPS792. link to abstract contains protocol clinicaltrials.gov

Carboplatin & Paclitaxel

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• Carboplatin (Paraplatin) AUC 5 IV once on day 1
• Paclitaxel (Taxol) 80 mg/m² IV on days 1, 8, 15

28-day cycles

Study	Evidence	Comparator	Efficacy
Sclafani et al. 2017	Randomized Phase II (C)	Cisplatin & 5-FU	Not reported

References

1. Abstract: Sclafani F et al. [InterAACT: An international multicenter open label randomized phase II advanced anal cancer trial comparing cisplatin (CDDP) plus 5-fluorouracil (5-FU) versus carboplatin (CBDCA) plus weekly paclitaxel (PTX) in patients with inoperable locally recurrent (ILR) or metastatic disease]. Journal of Clinical Oncology. 2015 33:3_suppl, TPS792-TPS792. link to abstract contains protocol clinicaltrials.gov

mDCF

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mDCF: modified Docetaxel, Cisplatin, Fluorouracil

Regimen

Study	Evidence
Kim et al. 2018 (Epitopes-HPV02)	Phase II

Chemotherapy

• Docetaxel (Taxotere) 40 mg/m² IV once on day 1
• Cisplatin (Platinol) 40 mg/m² IV once on day 1
• Fluorouracil (5-FU) 1200 mg/m²/day IV continuous infusion over 48 hours, started on day 1 (total dose per cycle: 2400 mg/m²)

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

Metastatic disease, subsequent lines of therapy

Nivolumab monotherapy

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Regimen

Study	Evidence
Morris et al. 2017 (NCI9673)	Phase II

Immunotherapy

• Nivolumab (Opdivo) 3 mg/kg IV once on day 1

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 PubMed

Pembrolizumab monotherapy

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Regimen

Study	Evidence
Ott et al. 2017 (KEYNOTE-028)	Phase Ib, >20 pts in this subgroup

Immunotherapy

• Pembrolizumab (Keytruda) 10 mg/kg IV once on day 1

14-day cycle for up to 2 years

References

1. KEYNOTE-028: 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 protocol PubMed