Anal Cancer Treatment Regimens

Days 1-5, 8-12, 15-19, 22-26, 29-33, 36-38: Capecitabine 825mg/m2 orally twice daily

Days 1,29: Mitomycin 10mg/m2 IV (max 20 mg) push.

Administer for one 6-week cycle with radiation.

OR

Days 1-5, 8-12, 15-19, 22-26, 29-33, 36-40: Capecitabine 825mg/m2 orally twice daily

Day 1: Mitomycin 12mg/m2 (max 20mg) IV push.

Administer for one 6-week cycle with radiation.

Days 1-4, 29-32: Fluorouracil 1,000mg/m2 IV continuous infusion over 24 hours

Days 1,29: Mitomycin 10mg/m2 (max 20mg) IV push.

Administer for one 5-week cycle with radiation.

OR

Days 1-4, 29-32: Fluorouracil 1,000mg/m2 IV continuous infusion over 24 hours

Day 1: Mitomycin 12mg/m2 (max 20mg) IV push, with radiation.

Administer for one 5-week cycle with radiation.

Days 1-4, 29-32: Fluorouracil 1,000mg/m2 IV continuous infusion over 24 hours

Days 1,29: Cisplatin 75mg/m2 IV over 2 hours.

Administer for one 8-week cycle without radiation, followed by:

one cycle with radiation.

Day 1: Paclitaxel 175mg/m2 IV over 3 hours, followed by:

Day 1: Carboplatin AUC 5 IV over 30 minutes.

Repeat cycle every 3 weeks.

OR

Day 1,8,15: Paclitaxel 80mg/m2 IV over 1 hour, followed by:

Day 1: Carboplatin AUC 5 IV over 30 minutes.

Repeat cycle every 4 weeks.

Day 1: Cisplatin 60mg/m2 IV over 1 hour

Days 1-4: Fluorouracil 1,000mg/m2 IV continuous infusion over 24 hours daily.

Repeat cycle every 3 weeks.

OR

Day 1: Cisplatin 75mg/m2 IV over 2 hours

Days 1-5: Fluorouracil 750mg/m2 IV continuous infusion over 24 hours daily.

Repeat cycle every 4 weeks.

Day 1: Cisplatin 40mg/m2 IV over 30 minutes, with:

Day 1: Leucovorin 400mg/m2 IV over 30 minutes, followed by:

Day 1: Fluorouracil 400mg/m2 IV push, followed by:

Days 1-2: Fluorouracil 1000mg/m2 IV continuous infusion daily (2,000mg/m2 IV over 46-48 hours).

Repeat cycle every 2 weeks.

Day 1: Oxaliplatin 85mg/m2 IV over 2 hours, with:

Day 1: Leucovorin 400mg/m2 IV over 2 hours, followed by:

Day 1: Fluorouracil 400mg/m2 IV push, followed by:

Days 1-2: Fluorouracil 1,200mg/m2 IV continuous infusion daily (2,400 mg/m2 IV over 46-48 hours).

Repeat cycle every 2 weeks.

Day 1: Cisplatin 40mg/m2 IV over 1 hour

Day 1: Docetaxel 40mg/m2 IV over 1 hour

Days 1-2: Fuorouracil 1,200mg/m2 IV continuous infusion daily (2,400 mg over 46-48 hours).

Repeat cycle every 2 weeks for maximum of 8 cycles.

Day 1: Nivolumab 240mg IV over 30 minutes.

Repeat cycle every 2 weeks.

OR

Day 1: Nivolumab 3mg/kg IV over 30 minutes.

Repeat cycle every 2 weeks.

OR

Day 1: Nivolumab 480mg IV over 30 minutes.

Repeat cycle every 4 weeks.

Day 1: Pembrolizumab 200mg IV over 30 minutes.

Repeat cycle every 3 weeks up to 2 years.

OR

Day 1: Pembrolizumab 2mg/kg IV over 30 minutes.

Repeat cycle every 3 weeks.

OR

Day 1: Pembrolizumab 400mg IV over 30 minutes.

Repeat cycle every 6 weeks up to 2 years.

a  Patients with dihydropyrimidine dehydrogenase (DPD) deficiency are unable to metabolize capecitabine normally and may have severe unexpected toxicity.

b  Patients with dihydropyrimidine dehydrogenase (DPD) deficiency are unable to metabolize fluorouracil normally and may have severe unexpected toxicity.

c  Hydration is required with supplemental electrolyte pre- and post-administration of Cisplatin.

d  For Paclitaxel: premedication for hypersensitivity is required. H2 antagonist – famotidine 20mg IV or orally (or equivalent H2 blockers) 30-60 minutes pre-paclitaxel AND H1 antagonist – diphenhydramine 12.5-50mg IV or orally 30-60 minutes pre-paclitaxel AND dexamethasone (21-day regimen) – 20mg orally approximately 12 and 6 hours pre-paclitaxel OR dexamethasone 20mg orally 30 minutes pre-paclitaxel OR dexamethasone (for weekly regimens) – 10mg IV 30 minutes pre-paclitaxel. In the absence of infusion reactions for Doses 1-3, may consider dexamethasone 4mg IV 30 minutes pre-paclitaxel starting with Dose 4.

e  CSFs (Colony stimulating factor) may be considered for primary prophylaxis based on febrile neutropenia risk of the chemotherapy regimen.

f  Discontinuation of Oxaliplatin should be strongly considered after 3 – 4 months of therapy (or sooner if neurotoxicity grade 2 or greater develops) while maintaining other agents until time of tumor progression. Oxaliplatin may be reintroduced if it was discontinued for neurotoxicity rather than for disease progression.

g  Leucovorin infusion time should match the infusion time of Oxaliplatin when these agents are given concurrently.

h  For Docetaxel: premedication with dexamethasone for fluid retention is required. One recommended dosing strategy is: dexamethasone 8mg orally twice daily for three consecutive days starting day 1 prior to docetaxel administration.

 i  Filgrastim, Pegfilgrastim, or clinically appropriate biosimilar are recommended to start the day following or up to 3-4 days after completion of chemotherapy.

 j  Early and late-onset immune-related adverse events affecting multiple organ systems can occur in patients receiving immune checkpoint inhibitors. Patients with neurologic or life-threatening autoimmune disorders as well as those receiving high levels of immunosuppression for their underlying disease should be approached with caution when considering immunotherapy. All patients will require extensive resources including ongoing intensive monitoring and supportive care.

 1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology^TM. Anal Carcinoma v2.2021. https://www.nccn.org/professionals/ physician_gls/pdf/anal.pdf. Accessed January 15, 2022.

 2. Capecitabine (Xeloda) [package insert]. South San Francisco, CA: Genentech, Inc.; 2021.

 3. Goodman KA, Rothenstein D, Cambridge L, et al. Capecitabine plus mitomycin in patients undergoing definitive chemoradiation for anal squamous cell carcinoma. Int J Radiat Oncol Biol Phys. 2014;90:S32–S33.

 4. Thind G, Johal B, Follwell M, Kennecke HF. Chemoradiation with capecitabine and mitomycin-C for stage I-III anal squamous cell carcinoma. Radiation Oncology. 2014;9:124.

 5. Ajani JA, Winter KA, Gunderson LL, et al. Fluorouracil, mitomycin, and radio­therapy vs fluorouracil, cisplatin, and radiotherapy for carcinoma of the anal canal: a randomized controlled trial. JAMA. 2008;299:1914–1921.

 6. James RD, Glynne-Jones R, Meadows HM, et al. 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;14:516–524.

 7. Gunderson LL, Winter KA, Ajani JA, et al. 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;30:4344-4351.

 8. Eng C, Chang GJ, You YN, et al. The role of systemic chemotherapy and multidisciplinary management in improving the overall survival of patients with metastatic squamous cell carcinoma of the anal canal. Oncotarget. 2014;5:11133-11142.

 9. Kim R, Byer J, Fulp WJ, et al. Carboplatin and paclitaxel treatment is effective in advanced anal cancer. Oncology. 2014;87:125-132.

10. Rao S, Sclafani F, Eng Cathy, et al. International Rare Cancers Initiative multicenter randomized phase II trial of cisplatin and fluorouracil versus carboplatin and paclitaxel in advanced anal cancers with InterAAct. J Clin Oncol. 2020;38(22):2510-2518.

11. Sclafani F, Adams RA, Eng C, 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. J Clin Oncol. 2015;33(3_suppl_abstr TPS792).

12. Mondaca S, Chatila WK, Bates D, et al. FOLFCIS Treatment and genomic correlates of response in advanced anal squamous cell cancer. Clin Colorectal Cancer. 2019;18:e39-e52.

13. Matsunaga M, Miwa K, Oka Y, et al. Successful treatment of metastatic anal canal adenocarcinoma with mFOLFOX + bevacizumab. Case Rep Oncol. 2016;9:249-254.

14. Kim S, François E, André T, et al. 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;19(8):1094- 1106.

15. Nivolumab (Opdivo) [package insert]. Princeton, NJ: Bristol-Myers Squibb, Inc; 2021.

16. Morris VK, Salem ME, Nimeiri H, et al. Nivolumab for previously treated unresectable metastatic anal cancer (NCI9673):a multicenter, single-arm, phase 2 study. Lancet Oncol. 2017;18:446-453.

17. Pembrolizumab (Keytruda) [package insert]. Whitehouse Station, NJ: Merck & Co, Inc.; 2021.

18. Ott PA, Piha-Paul SA, Munster P, et al. Safety and antitumor activity of the anti–PD-1 antibody pembrolizumab in patients with recurrent carcinomma of the anal canal. Ann Oncol. 2017;28:1036-1041.

19. Lala M, Li TR, de Alwis DP, et al. A six-weekly dosing schedule for pembrolizumab in patients with cancer based on evaluation using modelling and simulation. Eur J Cancer. 2020;131:68-75.