Treatment algorithm

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

ACUTE

locoregional disease

1st line – combined-modality treatment (CMT)

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ACUTE
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locoregional disease
1st line – 

combined-modality treatment (CMT)

Combined-modality treatment (CMT) with chemoradiation is the standard of care for locoregional squamous cell carcinoma of the anus.[4][8][35][36][37][38][39][41]

Preferred CMT regimens are fluorouracil plus mitomycin plus radiotherapy, or capecitabine plus mitomycin plus radiotherapy.[4][8]​ Fluorouracil plus cisplatin plus radiotherapy is an alternative regimen.[8]

One phase 3 randomised trial compared treatment with fluorouracil plus radiotherapy with treatment with fluorouracil plus mitomycin plus radiotherapy.[41] Patients who received fluorouracil plus mitomycin plus radiotherapy were less likely to need salvage radiotherapy after primary treatment, compared with patients who received fluorouracil plus radiotherapy. After 4 years, patients who were treated with fluorouracil plus mitomycin plus radiotherapy had lower colostomy rates (9% vs. 22%), higher colostomy-free survival (71% vs. 59%), and higher disease-free survival (73% vs. 51%), compared with patients who received fluorouracil plus radiotherapy.[41]

Capecitabine has been investigated as an alternative to fluorouracil because it can be administered orally and may be better tolerated.[39][42]​ One retrospective study reported that patients who received capecitabine plus mitomycin plus radiotherapy had significantly fewer haematological toxicities and fewer treatment interruptions, compared with patients who received fluorouracil plus mitomycin plus radiotherapy.[43] One prospective cohort study reported that capecitabine plus mitomycin plus radiotherapy regimens resulted in similar levels of grade 3-4 toxicity and similar 1-year oncological outcomes as fluorouracil plus mitomycin plus radiotherapy regimens. Significantly fewer patients in the capecitabine plus mitomycin plus radiotherapy cohort experienced grade 3 haematological toxicity (4% vs. 27%).[38]

Two randomised trials found that capecitabine plus mitomycin plus radiotherapy results in a significant improvement in disease-free and overall survival compared with fluorouracil/cisplatin-based chemoradiation.[44][45]

Intensity-modulated radiotherapy (IMRT) is the standard of care for delivering pelvic radiotherapy because of its lower acute and long-term toxicity.[4][8]​ 

Pelvic radiation is delivered 5 days/week for 5 weeks. A trial is in progress to determine the optimal dose.[49] Chemotherapy is given concurrently with weeks 1 and 5 of the radiation. Fluorouracil is delivered as a 96-hour continuous infusion (on days 1 to 4 and days 29 to 32) and mitomycin is delivered as a single bolus on day 1 or days 1 and 29.[8] Capecitabine is given 5 days per week, on days of radiotherapy only, for the duration of radiotherapy.[8]

For patients with T3 or T4 and/or N1 disease, the total radiation dose is increased.[50][51]​ One small retrospective study reported increased 5-year colostomy-free survival in patients with T4 anal carcinoma who received induction chemotherapy.[51]

Modifications to CMT are not recommended on the basis of HIV status.[8][57]​ People living with HIV have equivalent anal cancer survival rates, compared to people without HIV.[58] CMT appears to be safe and effective in immunodeficient people.[59] Patients should be jointly managed by an oncologist and an HIV specialist.[57] Antiretroviral therapy should be initiated or continued during cancer treatment and may improve poor performance status related to HIV.[8][57]

See local specialist protocol for dosing guidelines.

Primary options

fluorouracil

and

mitomycin

OR

capecitabine

and

mitomycin

Secondary options

fluorouracil

and

cisplatin

2nd line – abdominoperineal resection

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ACUTE
|
locoregional disease
2nd line – 

abdominoperineal resection

Abdominoperineal resection and colostomy formation should be considered for patients with biopsy-proven locally progressive disease after combined modality treatment or if disease stops responding.[4][8]​ Groin dissection should be performed if there is clinical evidence of inguinal node metastasis.[8] Clinical response may take up to 6 months after initial chemoradiation.

2nd line – immunotherapy

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ACUTE
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locoregional disease
2nd line – 

immunotherapy

In some patients, immunotherapy with nivolumab, pembrolizumab, retifanlimab, cemiplimab, dostarlimab, tislelizumab, or toripalimab may be considered before proceeding to abdominoperineal resection in order to avoid surgery, as some patients may have a good response. However, this strategy is based on institutional experience only, and there is no evidence to support its use in this setting.[8]

See local specialist protocol for dosing guidelines.

Primary options

nivolumab

OR

pembrolizumab

OR

retifanlimab

OR

cemiplimab

OR

dostarlimab

OR

tislelizumab

OR

toripalimab

distant metastatic disease

1st line – chemotherapy

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ACUTE
|
distant metastatic disease
1st line – 

chemotherapy

Carboplatin plus paclitaxel is the preferred first-line regimen.[4][8]​ One multicentre, randomised phase 2 study compared carboplatin plus paclitaxel with fluorouracil plus cisplatin for the treatment of chemotherapy-naive patients with advanced rectal cancer. Overall response rates were equivalent for the two regimens; carboplatin plus paclitaxel was associated with significantly fewer adverse events and a trend towards longer survival.[53]

Alternative regimens include: fluorouracil, folinic acid, and cisplatin (FOLFCIS); fluorouracil, folinic acid, and oxaliplatin (FOLFOX); fluorouracil plus cisplatin; modified docetaxel, cisplatin, and fluorouracil (DCF); carboplatin plus paclitaxel plus retifanlimab.[8][54][55]​​ There is limited experience with newer agents such as irinotecan and cetuximab.[56]

See local specialist protocol for dosing guidelines.

Primary options

carboplatin

and

paclitaxel

Secondary options

fluorouracil

and

folinic acid

and

cisplatin

OR

fluorouracil

and

folinic acid

and

oxaliplatin

OR

fluorouracil

and

cisplatin

OR

docetaxel

and

fluorouracil

and

cisplatin

OR

carboplatin

and

paclitaxel

and

retifanlimab

Consider – radiotherapy

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ACUTE
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distant metastatic disease
Consider – 

radiotherapy

Additional treatment recommended for SOME patients in selected patient group

Palliative radiotherapy may be delivered with chemotherapy for symptomatic, bulky primary tumours.[8]

2nd line – combined-modality treatment (CMT)

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ACUTE
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distant metastatic disease
2nd line – 

combined-modality treatment (CMT)

If patients progress on first-line chemotherapy, treatment should be re-evaluated. Chemoradiation to the primary site should be considered with fluorouracil or capecitabine for local control.[8]​ The decision to treat with CMT will depend on the initial chemotherapy regimen.

See local specialist protocol for dosing guidelines.

Primary options

fluorouracil

OR

capecitabine

2nd line – immunotherapy

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ACUTE
|
distant metastatic disease
2nd line – 

immunotherapy

Nivolumab, pembrolizumab, retifanlimab, cemiplimab, dostarlimab, tislelizumab, or toripalimab are the preferred second-line treatment options for patients who progress on first-line chemotherapy and have not received prior immunotherapy.[4][8]​​​ The decision to treat with immunotherapy will depend on the initial chemotherapy regimen.

See local specialist protocol for dosing guidelines.

Primary options

nivolumab

OR

pembrolizumab

OR

retifanlimab

OR

cemiplimab

OR

dostarlimab

OR

tislelizumab

OR

toripalimab

Consider – radiotherapy

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ACUTE
|
distant metastatic disease
Consider – 

radiotherapy

Additional treatment recommended for SOME patients in selected patient group

Palliative radiotherapy may be delivered with chemotherapy for symptomatic, bulky primary tumours.[8]

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Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups. See disclaimer

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