Current Treatments for Anal Cancer: An Overview
In recent years, there have been improvements in the treatment of anal cancer. Patients armed with knowledge about recent research on anal cancer can better advocate for themselves and get the best care.
Well known anal cancer researcher Cathy Eng has joined with her colleagues to publish an important review of current treatments for anal cancer in the Journal of Clinical Oncology. The review provides extensive and important information about recent developments in treatment for anal cancer patients.
IMRT radiation is preferred.
Image-guided radiation therapy with daily cone beam computed tomography is recommended because it provides more targeted treatment with lower levels of toxicity that improve both short- and long-term side effects from treatment.
Vaginal dilators used during and/or after radiation may reduce long-term vaginal stenosis.
Retrospective studies suggest that for people with tumors smaller then 4cm, lower doses of chemoradiation might be equally effective. There are currently ongoing trials studying this.
One dose of Mitomycin significantly reduces toxicity compared to two doses.
Oral chemotherapy, capecitabine, has been shown to have less toxicity than infusional 5-FU.
Risk of Recurrence
The risk of recurrence is increased by lack of adherence to the treatment protocol such as lowering doses of radiation or chemotherapy in the last week of treatment and/or by delaying the start of treatment by more than 42 days.
Other risk factors for recurrence are a tumor size of 5cm or higher and/or lymph node involvement.
There are numerous current trials of immunotherapies, but the writers emphasize that even more research in this area is needed.
The Anchor Study has shown that screening for and treating precancerous cells reduces the incidence of anal cancer. However, the lack of trained and experienced professionals in anal cytology limits widespread adoption of screening for SCCA.
Surveillance after Treatment
The surgeon’s role is critical in assessing the success of treatment or regression of the disease.
It is recommended that follow up begin 8-12 weeks after completion of treatment, and lesions with evidence of growth at 3 months may be considered for biopsy.
Persistent disease that is stable or regressing at 3 months does not necessarily indicate a lack of response and should be followed monthly.
It is reasonable to wait up to 6 months to achieve a clinical complete response.
Full Explanation of “Anal Cancer: Emerging Standards in a Rare Rare Cancer Disease”
Although open discussion about anal cancer has been hampered by social stigma, awareness is growing because of the rising number of anal cancer patients. The incidence of anal cancer has been rising for three decades. Despite the availability of a vaccine against HPV, the incidence rates of anal cancer in the US are increasing by 2.7% annually, with the greatest increase being in women over 50 (with a median age of 63). The mortality rate from anal cancer is rising by 3.1% annually. In total, an estimated 9090 people in the US and 27,000 people worldwide were diagnosed with anal cancer in 2021. It was estimated that 1430 deaths would occur in 2021.
Although most patients with early-stage disease can be cured with chemoradiation therapy, there is room for improvement in treatments and screenings, and more research is needed to find better treatments for advanced stages of anal cancer.
HIV patients are 19 times more likely than the general population to develop anal cancer. Patients who have had HIV for 12 years or more are 15 times more likely to get anal cancer than patients who have had HIV for 5 years or less. In fact, amongst men who have sex with men, HIV positive men have an 80% chance of getting anal cancer as opposed to a 26.7% chance in men who are not HIV positive. Nevertheless, to date, only New York State Department of Health AIDS Institute recommends screening HIV patients for anal cancer. Anal cancer screening should be considered in all patients with HIV who are 35 and older.
Screening for Anal Cancer
Pivotal results from the phase 3 ANCHOR study demonstrate that treatment of high-grade squamous intraepithelial lesions (HSILs) in patients who are HIV-positive significantly reduces the rates of squamous cell carcinoma of the anus (SSCA) compared to active monitoring. Although anal cytology and digital anorectal examination are available, the lack of trained and experienced professionals in anal cytology limits widespread adoption of screening for SCCA.
Best Tools for Staging Anal Cancer
For T categorization, to find the size of the primary tumor, computer tomography (CT) with soft tissue contrast is required. However, a pelvic Magnetic Resonance Image (MRI) provides better anatomic resolution and delineation of the anal canal. Nodal assessment is improved with positron emission tomography-computed tomography (PET/CT).
Post treatment imaging is not standardized.
Anal Cancer that Is Not Squamous Cell Carcinoma
SCCA represents the majority of anal malignancies. There are, however, rare carcinoma types like anal adenocarcinoma (ACC) arising from the anal glands and neuroendocrine neoplasms. Treatment for ACC should follow current guidelines for treating rectal cancer. SCC of the rectum is extremely rare representing 0.3% of rectal cancers.
Treatment for Squamous Cell Carcinoma of the Anus
SCCA is unique in that chemoradiation alone may preserve the sphincter and be curative.
The original Nigro regimen of 5-FU and Mitomycin used as radiation sensitizers has been validated in subsequent studies. However, phase III trials were not able to establish the superiority of cisplatin over Mitomycin. Retrospective analyses report that capecitabine is a reasonable substitute for 5-FU infusion when appropriate.
Advances in Radiation Therapy
IMRT is now preferred over 3D conformal radiation therapy since it reduces toxicity and is equally effective. In addition, guided radiation therapy with daily cone beam computed tomography is recommend and may allow tighter clinical margin lines. Vaginal dilator use during and/or after radiation may minimize the impact of radiation and reduce vaginal stenosis. Efforts to narrow the therapeutic window continue.
Although improved dosimetry has been shown for proton radiation, particularly pencil beam scanning, data outside of the recurrent disease setting are limited to one multi-institutional pilot study.
Risk Factors for Recurrence
The likelihood of recurrence may be related to adherence to treatment. Omission of the last week of chemotherapy, dose reductions, and/or treatment delays greater than 42 days increased the risk of local recurrence and reduced the likelihood of disease-free survival.
Initial tumor volume greater than 5cm and/or positive lymph nodes are also associated with reduced overall survival, disease free survival, and local recurrence free survival.
There is a high burden of acute toxicity from chemoradiation treatment. Studies have shown
lower levels of toxicity from one dose of Mitomycin as opposed to two and from the use of capecitabine instead of infusional 5-FU. Managing hematologic toxicity is paramount to preventing life-threatening infections and treatment delays.
Other reported side effects from chemoradiation include fecal incontinence for 22% of patients, lifestyle impairment because of bowl function for 29%, erectile dysfunction for 67%, painful sexual intercourse for 24%, and buttock pain for 24% of patients. Regular communication between physicians and patients is important for managing short- and long-term side effects.
The surgeon’s role is critical in the baseline evaluation and determination of response to therapy. As tumors will continue to regress after chemoradiation is complete, the recommendation is that follow up begin 8-12 weeks after completion of treatment. Lesions with clinical evidence of growth at 3 months may be considered for biopsy. Persistent disease that is stable or regressing at 3 months does not necessarily indicate a lack of response and should be followed monthly. It is reasonable to wait up to 6 months to achieve a clinical complete response.
The ACT II trial showed that 21% of tumors still present at 11 weeks had regressed by 26 weeks after starting treatment, and this supports more time for regression before salvage surgery.
Approximately 10-30% of patients will have either persistent or recurrent disease for whom abdominal perineal resection (APR) is recommended. The 5-year overall survival and disease-free survival rates after salvage APR are 39 -51% and 44-47% respectively.
Predictors of worse outcomes include positive lymph nodes and positive margins.
Standard surveillance for patients with no evidence of disease includes physical examination, digital anorectal examination, anoscopy/flexible sigmoidoscopy, and inguinal lymph node examination for the first 5 years, and an annual CT scan is recommended for the first 3 years.
Studies in the US and UK hypothesize that lower chemoradiation doses will be able to effectively treat early-stage SCCA with tumors measuring less than 4 cm while improving patient reported health-related quality of life related to anorectal dysfunction, erectile dysfunction, painful intercourse, and vaginal stenosis. Retrospective studies have reported excellent results with lower dose chemoradiation treatment.
Currently there is no established standard treatment for early-stage SCC T-1-2 N0M0. Across these differing treatment intensities, local control is at around 90%.
Novel treatment options are needed for surgically unresectable or metastatic patients even though therapeutic options have increased in the past 5 years. Given the clinical activity observed with checkpoint inhibitor therapy in advanced anal cancer, several studies are evaluating its role in locally advanced anal cancer. Immunotherapy remains a well-tolerated and effective recent advance in the management of metastatic anal cancer, and there are a number of important ongoing trials in this area. Consideration of more clinical trials with novel combinations may help to identify improved immune-based approaches in the future.
Investigational advances in anal cancer also help advanced research options in other HPV-related malignancies like cervical cancer, head and neck cancer, and penile, vaginal, and vulvar cancer.