Toxicity, Tolerability, and Compliance of Concurrent Capecitabine or 5-Fluorouracil in Radical Management of Anal Cancer With Single-dose Mitomycin-C and Intensity Modulated Radiation Therapy: Evaluation of a National Cohort

Purpose

Chemoradiation therapy (CRT) with mitomycin C (MMC) and 5-fluorouracil (5-FU) is established as the standard of care for the radical treatment of patients with anal squamous cell carcinoma (ASCC). The use of the oral fluoropyrimidine-derivative capecitabine is emerging as an alternative to 5-FU despite limited evidence of its tolerability and toxicity.

Methods and Materials

A national cohort evaluation of ASCC management within the United Kingdom National Health Service was undertaken from February to July 2015. The toxicity rates were prospectively recorded. For the present analysis, we report data from ASCC patients who underwent intensity modulated RT and a single dose of MMC with either 5-FU (5-FU/MMC) or capecitabine (capecitabine/MMC). All were treated with radical intent and intensity modulated radiation therapy (IMRT) was delivered in accordance with UK guidance.

Results

Of the 242 patients received from 40 centers across the United Kingdom, 147 met the inclusion criteria; 52 of whom were treated with capecitabine/MMC and 95 with 5-FU/MMC. No treatment-related deaths and no overall difference were found in the proportion of patients experiencing any grade ≥3 toxicity between the capecitabine and 5-FU groups (45% vs 55%; P = .35). However, significantly fewer patients in the capecitabine/MMC group experienced grade 3 hematologic toxicity (4% vs 27%; P = .001). A lower proportion of patients completed their planned chemotherapy course in the capecitabine cohort, although this did not reach statistical significance (81% vs 90%; P = .21). The median RT duration was 38 days (interquartile range 38-39) for both groups. No difference was found in the 1-year oncologic outcomes.

Conclusions

Capecitabine/MMC resulted in similar levels of grade 3/4 toxicity overall compared with 5-FU/MMC as CRT for ASCC, although differences were found in the patterns of observed toxicities, with less hematologic toxicity with capecitabine. Further studies of capecitabine/MMC are required to understand the acute toxicity profile and long-term oncologic outcomes of this combination with intensity modulated RT for ASCC.

Introduction

Carcinoma of the anus is a rare cancer, accounting for 2.5% of all digestive malignancies 1, 2. It is increasing in frequency across the developed world and is strongly associated with oncogenic subtypes of human papillomavirus 2, 3. The vast majority of cases are anal squamous cell carcinoma (ASCC), and most patients present with a localized stage, with or without regional lymph node involvement. Treatment is directed toward achieving cure and effective local control and avoiding the requirement for a colostomy (4). Chemoradiation therapy (CRT) forms the international standard of care, achieving a 3-year local control rate of 65% to 74% (5).

Concurrent CRT with mitomycin-C (MMC) and 5-fluorouracil (5-FU) is well established as superior to radiation therapy (RT) alone or RT combined with 5-FU for ASCC 6, 7, 8. Efforts to improve outcomes, including the substitution of MMC with cisplatin and the introduction of neoadjuvant or adjuvant chemotherapy regimens, have not changed this standard of care 9, 10, 11, 12. However, no international consensus has been reached on the optimal dosing of MMC, with 2 doses administered to patients in both RTOG (Radiation Therapy Oncology Group) 8704 and RTOG 9811, in contrast to a single dose used in the ACT (anal cancer trial) I, ACT II, and EORTC (European Organization for Research and Treatment of Cancer) trials (Table E1; available online at www.redjournal.org).

Capecitabine is a tumor-activated fluoropyrimidine derivative, administered orally as a twice-daily tablet. It provides a convenient alternative to 5-FU, which requires continuous infusion and central venous access. In colorectal cancer, capecitabine is noninferior with respect to efficacy and has a comparable toxicity profile to 5-FU in both the adjuvant setting and as part of concurrent CRT 13, 14, 15, 16. With respect to anal cancer, the National Comprehensive Cancer Network, European Society for Medical Oncology, European Society of Surgical Oncology, European Society for Radiotherapy and Oncology, French Intergroup, and recent UK intensity modulated radiation therapy (IMRT) guidelines support the use of capecitabine as an alternative option to 5-FU in radical CRT 17, 18, 19, 20. However, the current evidence for capecitabine to treat ASCC has been derived from single-center studies and a number of relatively small phase II trials 21, 22, 23. Treatment parameters also varied widely across these studies, with significant variation in the use of 3-dimensional (3D)-RT or IMRT, the radiation dose, and the target volume 24, 25, 26, 27.

Within the United Kingdom, national guidance provides a framework for the standardization of IMRT delivery in the treatment of anal cancer (28). A nationwide audit was undertaken to assess the implementation of IMRT for ASCC within the UK National Health Service, including the prospective collection of toxicity and outcomes (29). We present the comparative toxicity and early outcomes data for patients treated with standardized IMRT and either capecitabine/MMC or 5-FU/MMC.