Anal Cancer Treatment Protocols

Anal cancer treatment protocols are provided below, including those for limited localized disease, metastatic disease, salvage therapy, and additional special considerations.

Limited localized disease

Stage I-III (any T, any N, M0):

Current primary recommendations for non-metastatic anal cancer include concurrent chemotherapy and radiation therapy.[1] Common drugs include 5-fluorouracil (5-FU) and mitomycin; capecitabine may be substituted for 5-FU. There is some controversy regarding substituting cisplatin for mitomycin in limited-stage disease (conflicting clinical trial results); the National Comprehensive Cancer Network (NCCN) lists 5FU plus cisplatin and radiation therapy as a category 2B rcommendation.[2]

Mitomycin + 5-FU + radiotherapy[2, 3]

• 5-FU 1000 mg/m ²/day IV continuous infusion on days 1-4 and 29-32 (maximum daily dose of 5-FU of 2000 mg/day) plus  mitomycin 10 mg/m ² IV bolus on days 1 and 29 (maximum 20 mg per dose)

• Radiotherapy (RT) should be included with all stages of disease; minimum of 45 Gy given over 5wk

• Additional RT of 9-14 Gy may be considered for patients with T3, T4, or node-positive disease or in those with residual disease after an initial 45 Gy

• Substitution of cisplatin for 5-FU can be considered; it provides comparable rates of complete remission (CR) and colostomy​ ^[4]

Mitomycin + capecitabine + RT[2]

• Capecitabine 825 mg/m ² PO BID, Monday–Friday, on each day that RT is given, throughout the duration of RT (typically 28 treatment days)  plus  mitomycin 10 mg/m ² days 1 and 29 plus  concurrent RT  or
• Capecitabine 825 mg/m ² PO BID days 1–5 weekly x 6 weeks plus  mitomycin 12 mg/m ² IV bolus day 1 plus concurrent RT

Metastatic disease

Stage IV (any T, any N, M1):

Metastatic disease is commonly treated with platinum-based chemotherapy. Regimens may include 5-FU or other agents.[2, 5]

Cisplatin + 5-FU(FOLFCIS):

• Cisplatin 60 mg/m ² day 1 plus  5-FU 1000 mg/m ²/d IV continuous infusion on days 1–4; repeat every 3 weeks  or
• Cisplatin 75 mg/m ² day 1  plus  5-FU 750 mg/m ²/d IV continuous infusion on days 1–4; repeat every 4 weeks 

mFOLFOX: 

• Oxaliplatin 85 mg/m ² IV day 1 plus
• Leucovorin 400 mg/m ² IV day 1 plus
• 5-FU 400 mg/m ² IV bolus on day 1, then 1200 mg/m ²/d x 2 days (total 2400 mg/m ² over 46–48 hours) IV continuous infusion
• Repeat every 2 weeks 

Carboplatin + paclitaxel

• Carboplatin area under the curve (AUC) 5 (see Carboplatin AUC Dose Calculation [Calvert formula]) IV day 1 plus
• Paclitaxel 175 mg/m ² IV day 1
• Repeat every 21 days

Subsequent therapy after failure of more standard treatments may include the following[2] :

• Nivolumab 240 mg IV q2wk or 480 mg q4wk over 30 min until disease progression or unacceptable toxicity or
• Pembrolizumab 200 IV q3wk or 400 mg IV q6wk until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression 

Salvage therapy

See the list below:

• Salvage therapy may be needed for recurrent or persistent disease after the use of chemoradiotherapy.

• Local recurrences may be successfully salvaged with surgery; however, locally recurrent anal squamous cell carcinoma poses a greater problem and higher rate of morbidity.

• In a 1999 analysis of 185 patients who received either radiotherapy or chemoradiotherapy between 1976 and 1996, a total of 42 went on to develop local failure; 26 of these patients had salvage therapy consisting of abdominoperineal resection, and of these patients, 43% had long-term 5-y survival and control of their disease.[5]

• Additionally, in the trial by Flam et al, 25 patients with positive post-treatment biopsies went on to receive salvage chemotherapy with cisplatin and 5-FU; 22 had subsequent biopsies, and 12 (55%) of the post-treatment biopsies in this setting were negative; 4 of 12 remained disease free at 4y.[3] Either cisplatin or 5-FU is an acceptable option; the choice depends on patient performance status and degree of local failure.

Surgical Management

Superficially invasive cancer:

• Surgical excision is appropriate in very limited circumstances (maximum invasion 3 mm to basement membrane and less than 7 mm horizontal spread) 
• Negative margins should be ≥2 mm for anal canal and ≥1 cm for perianal; consider adjunctive radiation therapy if positive margins
• May have been completely excised during intial biopsy

Locally progressive during chemoradiation or recurrent:

• Radical surgery such as abdominoperineal resection (APR)
• Consideration of lymph node dissection should be made, based on the clinical scenario 

Special considerations

See the list below:

• Consider HIV testing and CD4 count analysis in patients with clinical risk factors.

• No changes to therapy are indicated in HIV-infected patients; however, consider dose reduction of mitomycin in patients with low CD4 counts and a history of complications such as opportunistic infections or other malignancies.[6]

• Mitomycin + 5-FU: If nadir WBC count is less than 2400 but more than 1000/μL or if nadir platelet count is more than 50,000 but less than 85,000/μL, the second dose of mitomycin is reduced to 7.5 mg/m2 from 10 mg/m2

• If nadir WBC count is less than 1000/μL or if platelet count is less than 50,000/μL, the second dose of mitomycin is reduced to 5 mg/m2 from 10 mg/m2

• If on day 28 the WBC count is less than 2400/μL or if the platelet count is less than 85,000/μL, delay chemotherapy 1wk[3]