Although anal squamous cell carcinoma (ASCC) is a rare disease, incidence of this malignancy is gradually increasing in association with human papillomavirus (HPV) infection. While patients with early stage disease can be treated with surgery, chemotherapy, and radiation, about 35% are diagnosed at a metastatic stage or with recurrent disease after initial chemoradiotherapy. Current treatment for patients with metastatic or unresectable recurrent disease includes chemotherapy with cisplatin and fluorouracil (CF) or carboplatin-paclitaxel combinations. In a retrospective study of 8 consecutive patients with advanced ASCC, addition of docetaxel to cisplatin and fluorouracil (DCF) resulted in complete and long-lasting responses in half of the patients.
The multicenter, single-arm, phase II Epitopes-HPV02 trial further evaluated the safety and efficacy of DCF regimen in 66 chemotherapy-naïve patients with metastatic or unresectable locally recurrent ASCC. Depending on age and performance status, patients received either six cycles of standard DCF (75 mg/m2 docetaxel and 75 mg/m2 cisplatin on day 1 and 750 mg/m2 fluorouracil for 5 days every 3 weeks) or eight cycles of a modified DCF regimen (40 mg/m2 docetaxel and 40 mg/m2 cisplatin on day 1 and 1200 mg/m2 fluorouracil for 2 days every 2 weeks). All patients received granulocyte colony-stimulating factor (G-CSF) as primary prophylaxis of febrile neutropenia and to maintain the planned dose intensity. The primary endpoint was progression-free survival (PFS).
At 12 months, the rate of PFS was 47%, surpassing the prespecified threshold of 17%. The median PFS was 11 months. The objective response rate (ORR) was 89%, including complete response in 45% of patients. The estimated 12-month overall survival (OS) was 83.1%, and the median OS had not yet been reached. Modification of DCF regimen did not impact outcome, as patients achieved similar rates of PFS, OS, ORR, and complete response regardless of which DCF regimen they received. Of the two HIV-positive patients included in this trial, one achieved stable disease and progressed 11.5 months after first chemotherapy, and the other achieved complete response and remains disease-free at 24 months follow-up. The monitoring of antigen-specific T lymphocytes during therapy indicated that DCF chemotherapy is immunogenic in ASCC.
Grade 3/4 adverse events (AEs) occurred in 70% of patients, with a greater number of AEs occurring in patients receiving standard DCF, compared to modified DCF (83% vs 53%). The most common grade 3/4 AEs (standard vs modified) were neutropenia (22% vs 23%), diarrhea (25% vs 10%), asthenia (22% vs 7%), anemia (17% vs 13%), lymphopenia (8% vs 17%), mucositis (19% vs 0%), and vomiting (14% vs 7%). Febrile neutropenia occurred in 14% of patients receiving standard DCF and no patients receiving modified DCF. There were no treatment related deaths.
The investigators concluded that the modified DCF regimen is safe and effective in patients with advanced ASCC and should be considered a new standard of care for untreated patients with a performance status of 0 or 1, but that the standard DCF regimen should not be used due to high rates of grade 3/4 AEs and risk of febrile neutropenia, despite G-CSF prophylaxis. The global HRQOL data also favor modified over standard DCF, although the difference was not significant.
In an accompanying commentary, Francesco Sclafani, MD (Royal Marsden NHS Foundation Trust, Sutton, United Kingdom), applauded the investigators for the success of this trial, particularly given the difficulty in conducting clinical trials in rare diseases. Dr Sclafani highlighted the importance of continued investigation in ASCC given the increasing incidence of this disease and indicated the need for robust evidence-based treatment recommendations.