Treatment for anal cancer
Anal cancers are mostly of squamous cell histology. They are separated into anal canal cancers and peri-anal cancers based on the location of the primary tumor. The location of the tumor in the anal region also affects the lymphatic drainage, with peri-anal and distal anal canal cancers draining mainly to the inguinal nodes, and anal canal cancers draining mainly to the anorectal, perirectal and nodes in the internal iliac system. The prognosis of anal cancer is related to the size of the primary tumor and presence of lymph node metastases.1 If there are hypermetabolic or clinically/radiographically-enlarged lymph nodes, fine needle aspiration or excisional biopsy are recommended to confirm metastatic disease.
Surgical excision can be used to treat peri-anal cancers that are less than 2 centimeters and do not involve the anal sphincter. More advanced peri-anal cancers will need to be treated with concurrent chemoradiotherapy (CRT). Surgical excision can also be used to treat superficially invasive anal cancer (SISCCA), which is defined as anal cancer that is completely excised with at least 1mm margin clear of cancer, 3 mm or less depth of invasion, and horizontal spread of 7 mm or less.2 To adequately treat SISCCA or stage 1 peri-anal cancer with surgery, surgeons need to have access to high-resolution anoscopy and the ability to treat high-grade squamous intraepithelial lesions (HSIL). SISCCA may be hard to diagnose without high resolution anoscopy and the surgical management of early anal cancer may be less definitive than chemoradiation and therefore have higher risk of recurrence. It would therefore be imperative to detect local recurrence of early anal cancer so patients can be referred for CRT or repeat surgery in a timely manner.
For non-metastatic anal cancers that are not resectable, CRT with 5-fluorouracil (5-FU) infusion and mitomycin (or cisplatin) has been established as the standard-of-care regimen.3,4 Mitomycin or cisplatin with capecitabine is an acceptable alternative. Most studies have delivered 5-FU as a 96-hour infusion during the first and fifth week of radiotherapy, and bolus injection of mitomycin is typically given on the first day of the 5-FU infusion. Capecitabine is given orally (Monday to Friday) for 4 or 6 weeks, with bolus injection of mitomycin and concurrent radiotherapy. CRT can provide 5-year overall survival of 60-70% for most patients. A compilation of the regimens, patient outcomes, and toxicities can be seen in Table 1.
People living with HIV (PLWH) are at increased risk for developing anal cancer but most anal cancer clinical trials have excluded PLWH. Most evidence regarding anal cancer outcomes in PLWH are retrospective. Older case series have shown poor outcomes in terms of higher relapse rates and higher rates of treatment toxicities. However, more modern case series including PLWH with better CD4 and virologic control have demonstrated similar outcomes for PLWH with anal cancer that are comparable with their HIV-negative counterparts. Therefore, the most up-to-date national guidelines recommend that PLWH receive the same treatment for anal cancer as the general population.
Following the completion of CRT, digital rectal examination should be performed 8-12 weeks later to evaluate for presence of residual disease. Some experts also perform high resolution anoscopy to look for residual disease and high-grade squamous intraepithelial lesions. It is appropriate to wait up to 6 months post-CRT to determine if further treatment is needed because frequently residual anal cancer can resolve (as long as there is no evidence of progressive disease). If persistent residual cancer or recurrent cancer is diagnosed in the anal region, abdominoperineal resection will be needed. This surgery can be quite morbid, as anal cancer patients are prone to poor wound healing due to radiation exposure to the perineum, and a permanent colostomy is required.
If distant metastases are found, systemic chemotherapy with 5-FU/cisplatin or carboplatin/paclitaxel are usually used. These 2 regimens have similar response rates of about 60%, but carboplatin/paclitaxel may have lower rates of toxicities and higher relapse-free survival and overall survival.5 For patients who do not respond to chemotherapy, immunotherapy with nivolumab or pembrolizumab are recommended.
DISCLOSURE The author declares nothing to disclose.
References
1. Ryan DP, Compton CC and Mayer RJ. Carcinoma of the anal canal. N Engl J Med 2000;342(11):792-800. Available at: https://pubmed.ncbi.nlm.nih.gov/10717015/
2. Darragh TM, Colgan TJ, Thomas Cox J et al. The Lower Anogenital Squamous Terminology Standardization Project for HPV-Associated Lesions: background and consensus recommendations from the College of American Pathologists and the American Society for Colposcopy and Cervical Pathology. J Low Genit Tract Dis 2012;16(3):205-42. Available at: https://pubmed.ncbi.nlm.nih.gov/23202792/
3. Gunderson LL, Moughan J, Ajani JA et al. Anal carcinoma: impact of TN category of disease on survival, disease relapse, and colostomy failure in US Gastrointestinal Intergroup RTOG 98-11 phase 3 trial. Int J Radiat Oncol Biol Phys 2013;87(4):638-45. Available at: https://pubmed.ncbi.nlm.nih.gov/24035327/
4. 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 x 2 factorial trial. Lancet Oncol 2013;14(6):516-24. Available at: https://pubmed.ncbi.nlm.nih.gov/23578724/
5. Rao S, Sclafani F, Eng C et al. InterAACT: A multicentre open label randomised phase II advanced anal cancer trial of cisplatin (CDDP) plus 5-fluorouracil (5-FU) vs carboplatin (C) plus weekly paclitaxel (P) in patients (pts) with inoperable locally recurrent (ILR) or metastatic treatment naïve disease - An International Rare Cancers Initiative (IRCI) trial, in 43rd ESMO Congress, Oct. 18-23, 2018. 2018: Munich, Germany. Available at: https://www.esmo.org/oncology-news/InterAACT-inoperable-locally-recurrent-metastatic-anal-cancer-Rao (Last accessed October 15th 2020).
6. 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;348(9034):1049-54. Available at: https://pubmed.ncbi.nlm.nih.gov/8874455/
7. Bartelink H, Roelofsen F, Eschwege F et al. 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;15(5):2040-9. Available at: https://pubmed.ncbi.nlm.nih.gov/9164216/
8. Flam M, John M, Pajak TF et al. 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;14(9):2527-39. Available at: https://pubmed.ncbi.nlm.nih.gov/8823332/
9. 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(16):1914-21. Available at: https://pubmed.ncbi.nlm.nih.gov/18430910/
OTHER ARTICLES INCLUDED IN THE HPW SPECIAL ISSUE ON ANAL CANCER
J Palefsky. Screening for anal high-grade squamous intraepithelial lesions and anal cancer- has its time come?
EA Stier. Anal HPV infection: risk groups and natural history
JP Terlizzi, SE Goldstone. Treatment for anal high grade squamous intraepithelial lesions
J Kauffmann. The modern anal neoplasia clinic
C Brickman. Cytology and HPV testing for anal HSIL screening
GB Ellsworth, TJ Wilkin. Early HPV vaccination could reduce anal cancer incidence
TM Darragh. Pathology of anal squamous intraepithelial lesions and cancer: similarities and differences from cervical pathology
JM Berry-Lawhorn. Groups at high risk of anal cancer
RJ Hillman. Digital anal rectal examination (DARE) for anal cancer prevention
A Curran. Current guidelines recommendations for anal HPV-related disease screening
N Jay. Practising and training for high resolution anoscopy
IM Poynten, F Jin, AE Grulich. Anal squamous intraepithelial lesions: risk groups and natural history