Intensity-Modulated Radiation Therapy for Anal Cancer: Toxicity versus Outcomes

The treatment of cancer of the anal canal has changed significantly over the past several decades. Although the abdominoperineal resection (APR) was the historical standard of care, a therapeutic paradigm shift occurred with the seminal work of Nigro, who reported that anal canal cancer could be treated with definitive chemoradiation, with APR reserved for salvage therapy only. This remains an attractive approach for patients and physicians alike and the standard of care in this disease. Now, nearly four decades later, a similar approach continues to be utilized, albeit with higher radiation doses; however, this strategy remains fraught with considerable treatment-related morbidities. With the advent of intensity-modulated radiation therapy (IMRT), many oncologists are beginning to utilize this technology in the treatment of anal cancer in order to decrease these toxicities while maintaining similar treatment efficacy. This article reviews the relevant literature leading up to the modern treatment of anal canal cancer, and discusses IMRT-related toxicity and disease-related outcomes in the context of outcomes of conventionally treated anal cancer.

Introduction

Cancer of the anal canal is an uncommon malignancy, with an estimated 5,290 cases diagnosed in the United States in 2009; however, its incidence has been increasing over the past several decades (www.cancer.gov). Historically, first-line therapy was an abdominoperineal resection (APR), resulting in a permanent colostomy. Long-term cure rates following resection alone have varied in the literature, but results as high as 71% have been reported. For most patients, however, avoidance of radical resection and permanent colostomy placement are highly desirable.[1]

Nigro and colleagues at Wayne State University pioneered the non-operative treatment paradigm for anal canal cancers.[2,3] Their initial investigation consisted of three patients treated with approximately 30 Gy radiation therapy (RT) with concurrent 5-fluorouracil (5FU) and mitomycin C (MMC). Two patients underwent planned APR with no residual disease demonstrated by pathologic assessment and the third patient declined surgical intervention, with no disease relapse in follow-up. This important preliminary data spawned numerous investigations of non-operative management of anal canal cancer.

Randomized Trials of Chemoradiotherapy

Two simultaneously conducted randomized phase III trials from Europe established the superiority of chemoradiation to radiation therapy alone.[4,5] The larger of these was conducted by the United Kingdom Coordinating Committee on Cancer Research (UKCCCR), and included 585 patients (ACT I trial). This trial randomized patients to treatment with radiotherapy alone versus radiotherapy with concomitant 5FU and MMC. Similar to the UKCCCR trial, the European Organization for Research and Treatment of Cancer (EORTC) trial randomized 110 patients to treatment with radiotherapy alone (45 Gy) versus radiotherapy (45 Gy) with concomitant 5FU and MMC. Both trials mandated a treatment break prior to an additional “boost” dose of radiation (15-20 Gy), based on tumor response. In both cases, an improvement in local control (LC) and colostomy-free survival (CFS) with combined modality therapy was reported, with no significant difference in overall survival (OS), although the risk of death from anal cancer was reduced by 29% (P = .02) in the UKCCCR trial. Locoregional failure (LRF) decreased from 50% to 32% with the addition of chemotherapy to radiation in the EORTC trial.[5]

TABLE 1

Toxicity and treatment efficacy from selected anal canal cancer studies

Recently, the UKCCCR updated their results with a median follow-up of 13 years. The LRF rate was 32% at five years with the use of combined modality therapy versus 57% in patients treated with radiation therapy only.[6] These results highlight that concurrent chemotherapy has an important role in the treatment of anal canal cancer, but that local failure occurs frequently, even with definitive chemoradiotherapy.

Internal server error