ABSTRACT: 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.
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.
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(Drug information on 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.
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. 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.
Acute and significant toxicities were reported in both trials (Table 1). Although no differences in acute gastrointestinal (GI) or dermatologic side effects were reported between the two treatment groups in the EORTC trial, higher rates of late anal ulceration were observed in the combined modality group. There were two grade 4-5 hematologic toxicities reported with the addition of chemotherapy. In contrast, the UKCCCR reported significantly more acute hematologic, GI, dermatologic, and genitourinary (GU) toxicities with addition of 5FU/MMC, but no increase in late morbidity.
Different Chemotherapy Regimens
MMC contributes significantly to the acute toxicity profile of combined-modality therapy in anal cancer, and studies have been undertaken to examine its potential role in this treatment program.[7-9] A trial by the Radiation Therapy Oncology Group (RTOG) randomized patients to receive radiotherapy and 5FU, with or without MMC (RTOG 87-04). Even though OS was similar in both groups, disease-free and colostomy-free survivals were inferior in patients treated with radiation therapy and 5FU without MMC versus patients treated with radiation therapy, 5FU and MMC. These results justified the use of MMC as an important therapeutic element. While there was no reported difference in acute non-hematologic toxicities between the two groups, 26% of patients receiving MMC (versus 8% who received 5FU alone) experienced grade 4-5 hematologic toxicity.
The RTOG conducted another study (RTOG 98-11), which randomized patients to both induction/concurrent CDDP and 5FU with radiation versus concurrent chemoradiation (45 Gy plus a 10-14 Gy boost) using 5FU and MMC (without induction chemotherapy). It is important to note that this trial was not a direct comparison of 5FU and MMC vs 5FU and cisplatin(Drug information on cisplatin) (CDDP). Complicating the analysis of the trial were the following considerations in the CDDP arm of the trial: (1) the added total length of time of therapy; (2) the initiation of chemotherapy alone followed by chemoradiation; and (3) the toxicity of chemoradiation. Importantly, it was unknown at the time of the design of the trial whether induction chemotherapy was even beneficial, or whether chemoradiation followed by adjuvant chemotherapy was a more effective strategy. Five-year OS rates were not significantly different between the two treatment arms—at 70% in the CDDP-based arm and at 75% in the MMC-based arm, with locoregional recurrence rates of 33% in the CDDP-based arm and 25% in the MMC-based arm, respectively
(P = NS). However, patients receiving CDDP/5FU experienced a statistically higher colostomy rate of 19%, versus 10% (P = .02) in patients randomized to 5FU and MMC. Still, it is unknown whether the increased colostomy rate was instead influenced either by time under therapy or the delay in chemoradiation due to the use of induction chemotherapy. This is especially unclear given the influence of time under therapy in previous trials and the unproved efficacy of induction chemotherapy in anal cancer. Toxicity was substantial, with 74% of both groups experiencing acute grade 3-4 non-hematologic toxicity. Significantly, acute grade 3-4 hematologic toxicity occurred in 61% percent of the patients receiving MMC, versus 42% of those receiving CDDP, despite the more prolonged course of chemotherapy in the CDDP arm (P < .001). However, this did not translate into differences in the rate of long-term toxicities (11% versus 10%).
A phase III trial of 950 anal canal patients by the UKCCCR (ACT II) was recently reported in abstract form. In this trial, patients were randomized to the same radiotherapy regimen (50.4 Gy, in 1.8-Gy fractions) with either concurrent 5FU and CDDP versus 5FU and MMC—followed by a second randomization to receive two cycles of 5FU/CDDP—or no further therapy following the completion of chemoradiation. With a median follow-up of three years, there were no differences in the rates of complete response, recurrence-free survival, OS, or colostomy requirements. Acute grade 3-4 hematologic toxicity rates were higher in patients receiving MMC (25%) versus CDDP (13%) (P = <.001). Preliminary results demonstrate no significant differences in recurrence-free or OS for patients who received adjuvant chemotherapy versus those who did not. Although no statistical difference was seen in rates of high-grade, acute non-hematologic toxicities between treatment arms (61% versus 65%), these figures remained high.