Squamous cell carcinoma in the anal region: prevention and therapy

Anal carcinoma is closely associated with infection by human papillomaviruses. An HPV vaccination, therefore, offers a good possibility for prevention.

High hopes for radiochemotherapy and immunotherapeutics

Anal carcinoma is closely associated with infection by human papillomaviruses. An HPV vaccination, therefore, offers a good possibility for prevention.

Anal carcinoma is closely associated with infection by human papillomaviruses. An HPV vaccination, therefore, offers a good possibility for prevention. Additional risk groups and treatment options for this rare cancer were presented at a symposium during the 2019 Annual Meeting of the American Society of Clinical Oncology (ASCO) in early June.

Squamous cell carcinoma of the anal region (anal carcinoma) is a rare cancer with an annual incidence of about 1-2 per 100,000. However, the incidence is rising by 2.2% per year in western countries. Worldwide, around 48,000 cases were expected to occur in 2018. LSIL (low-grade squamous intraepithelial lesion) and HSIL (high-grade squamous intraepithelial lesion) are considered precursors of anal carcinoma.

Risk factors for anal carcinoma

Known risk factors, according to Joel Palefsky, University of California, San Francisco, USA, are infections with human papillomavirus (HPV), immunosuppression, sexually transmitted diseases in anamnesis, and tobacco abuse. HPV are small double-stranded DNA viruses that infect epithelial cells of the skin and mucous membrane and can trigger uncontrolled cell growth. Of the more than 200 known HPV types, about 15 subtypes are considered oncogenic, with 90 to 95% of anal carcinomas associated with HPV 16 and HPV 18.

Due to immunosuppression, the risk of anal carcinoma is greatly increased in HIV-infected persons. For example, the incidence of HIV-infected gay men is 131/100,000, HIV-infected men 46/100,000 and HIV-infected women 30/100,000. Despite the availability of effective therapy against HIV infection, the risk of anal carcinoma is high because HIV patients very often suffer from latent HPV infection.

Primary prevention

Primary prevention aims to prevent both initial HPV infection and long-term persistence of the virus with oncogenetic effects. HPV vaccination programs can reduce the incidence of anal, cervical, vaginal and vulvar cancer and penile cancer. A quadrivalent vaccine with efficacy against HPV 6/11/16 and 18 reduced the incidence of grade 2 and grade 3 anal intraepithelial neoplasia in men having sex with men (MSM) by 54.2% in the intention-to-treat group and by 74.9% in the per-protocol group compared to placebo.

The Advisory Committee on Immunization Practices (ACIP) of the American Center for Disease Control and Prevention (CDC) recommends that boys and girls up to the age of 14 receive two vaccinations every 6 months. Three injections are to be given in months 0, 1-2 and 6 from the age of 15 and for HIV-positive and other immunosuppressed persons. The effect lasts at least 10 years.

Secondary prevention

Secondary prevention is based on screening in order to find precancerous lesions at an early stage. Screening is recommended for the following persons:

The treatment of anal HSIL is a challenge, often requiring multiple ablative procedures. There is still considerable need for optimization here.

First-line therapy of anal carcinoma

Therapy standard is radiochemotherapy with fluorouracil and mitomycin, according to Rob Glynne-Jones, Mount Vernon Cancer Centre, Northwood, Middlesex, UK. Depending on the stage of the disease, 70 to 90% of patients benefit from radiochemotherapy. 10 to 20% of patients are not sensitive to treatment or suffer an early relapse. After a relapse, 30 to 40% of patients can be successfully resected abdominoperineally.

Glynne-Jones sees a high need for better initial treatment procedures. Additional induction therapy with fluorouracil and cisplatin before and consolidation after chemoradiation had no positive effect in studies.

Current studies are investigating immunotherapeutics such as pembrolizumab and nivolumab.

Treatment of relapsed/metastatic anal carcinoma

The majority of patients with anal carcinoma suffer from locally advanced disease and can be treated with radiochemotherapy as a curative approach. According to Cathy Eng, Vanderbilt, University Medical Center, Nashville, Texas, USA, less than 20% of patients develop metastases. Then five-year survival's 30%. The 2018 NCCN Guidelines recommend fluorouracil/cisplatin for the treatment of metastatic disease.

In the InterAACT study, patients with relapsed or metastatic therapeutic anal carcinoma were randomly treated with cisplatin/fluorouracil (n = 39) or carboplatin plus weekly paclitaxel (n = 35). Response rates were similar in both groups, 57%, and 59% respectively. However, patients in the carboplatin/ paclitaxel arm lived in the median 20 months longer than those in the cisplatin/fluorouracil arm 12.3 months (p= 0.014). Progression-free survival was also longer with 8.1 vs. 5.7 months (p = 0.375). Severe adverse effects were less frequent in the carboplatin/ paclitaxel arm with 36% than in the comparison arm with 62%.

Since the majority of anal carcinomas are associated with HPV infection, immunotherapeutics such as nivolumab or pembrolizumab are expected to have beneficial effects. The effect of nivolumab was evaluated in the single-arm NCI9673 study in 37 pretreated patients with metastatic anal carcinoma. 9/37 patients (24%) responded to nivolumab, 2 complete and 7 partial.

The current NCCN 2019 guidelines now include cisplatin/fluorouracil and preferred carboplatin/ paclitaxel, and later nivolumab or pembrolizumab.

Eng called for patients to be motivated to be treated in clinical trials.

The management and prevention of anal squamous cell carcinoma. Educational Symposium, 2019 ASCO Annual Meeting, Chicago, May 31 to June 4, 2019.