Approach

Chemoradiation (combined-modality treatment [CMT]) is the standard of care for locoregional squamous cell carcinoma of the anus.[4][8][35][36][37][38][39] Although trials have not found an overall significant survival advantage with CMT, it improves local control and colostomy-free survival compared with radiation alone.[40]

Surgery, most commonly an abdominoperineal resection, is reserved for salvage. Although the complete response rates are lower (50% to 75%) in patients with large (>5 cm) primary cancers, most patients can be spared a colostomy and the overall survival is excellent. Some patients with fecal incontinence or a fistula may require a pretreatment diverting colostomy, which would be reversed after successful therapy.

Patients with distant metastatic disease are typically treated with chemotherapy.

Patients should be managed by a multidisciplinary team meeting which specializes in anal tumors.[4][8]

Locoregional disease

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

CMT

CMT is well established and randomized trials have focused on identifying the ideal regimen.[35][36][37][38][39][41] One phase 3 randomized trial compared treatment with fluorouracil plus radiation therapy with treatment with fluorouracil plus mitomycin plus radiation therapy.[41] Patients who received fluorouracil plus mitomycin plus radiation therapy were less likely to need salvage radiation therapy after primary treatment, compared with patients who received fluorouracil plus radiation therapy. After 4 years, patients who were treated with fluorouracil plus mitomycin plus radiation therapy 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 radiation therapy.[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 radiation therapy had significantly fewer hematologic toxicities and fewer treatment interruptions, compared with patients who received fluorouracil plus mitomycin plus radiation therapy.[43] One prospective cohort study reported that capecitabine plus mitomycin plus radiation therapy regimens resulted in similar levels of grade 3-4 toxicity and similar 1-year oncologic outcomes as fluorouracil plus mitomycin plus radiation therapy regimens. Significantly fewer patients in the capecitabine plus mitomycin plus radiation therapy cohort experienced grade 3 hematologic toxicity (4% vs. 27%).[38]

Two randomized trials found that capecitabine plus mitomycin plus radiation therapy results in a significant improvement in disease-free and overall survival compared with fluorouracil/cisplatin-based chemoradiation.[44][45] The ACCORD 3 trial found that induction chemotherapy or a brachytherapy boost to standard chemoradiation showed no advantage in colostomy-free survival.[46]

Pelvic radiation therapy

Intensity-modulated radiation therapy (IMRT) is the standard of care for delivering pelvic radiation therapy because of its lower acute and long-term toxicity.[4][8]​ By identifying the dose-limiting tissues surrounding the primary tumor and pelvic nodes, and using multiple radiation fields to avoid them, IMRT may allow for radiation dose escalation with less toxicity.[47][48]

CMT regimens

Pelvic radiation is delivered 5 days/week for 5 weeks. A trial is in progress to determine the optimal dose.[49] The chemotherapy is given concurrently with weeks 1 and 5 of the radiation: fluorouracil is delivered as a 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 radiation therapy only, for the duration of radiation therapy.[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]

The treatment is delivered on an outpatient basis. However, patients with grade 3+ acute toxicity (neutropenia, thrombocytopenia, skin breakdown, anal/rectal pain) may require a treatment break and/or hospital admission.

Post-treatment assessment and management of incomplete response

At 8-12 weeks after the completion of treatment, patients undergo a physical exam, and the tumor response is assessed by rectal exam and anoscopy.[8]

Complete remission may be confirmed clinically in patients with no evidence of tumor or ulceration on rectal exam.[4] Patients who have progressive disease should have a biopsy and restaging imaging with CT or PET/CT.[8] Patients with persistent disease, but no evidence of progression, may have a further evaluation after 4 weeks to assess whether regression occurs.[8] Provided there is no evidence of progressive disease, patients with persistent anal cancer may be monitored at 3 months and 6 months after completing CMT.[8] Post-hoc analysis of one phase 3 trial indicated that the optimum time to assess clinical response is 26 weeks after the start of CMT. Complete clinical response was achieved in 52% of patients at 11 weeks after starting CMT, in 71% of patients at 18 weeks after starting CMT, and in 78% of patients at 26 weeks after starting CMT.[52]

Abdominoperineal resection and colostomy formation should be considered for patients with biopsy-proven locally progressive disease or if disease stops responding.[4][8] Groin dissection should be performed if there is clinical evidence of inguinal node metastasis.[8]

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]

Distant metastatic disease

Carboplatin plus paclitaxel is the preferred first-line regimen.[4][8]

One multicenter, randomized 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 toward longer survival.[53]

Alternative regimens include: fluorouracil, leucovorin, and cisplatin (FOLFCIS); fluorouracil, leucovorin, 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]

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]​ 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 or CMT will depend on the initial chemotherapy regimen.

Palliative radiation therapy may be delivered with chemotherapy for symptomatic, bulky primary tumors.[8]

Treatment of people living with HIV

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]

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