Anal cancer: the end of the road for neoadjuvant chemoradiotherapy?

The publication of the Radiation Therapy Oncology Group (RTOG) 98-11 Intergroup study in late April 2008, which randomly assigned patients to receive neoadjuvant fluorouracil (FU)/cisplatin followed by chemoradiotherapy (CRT) or to receive standard concomitant FU and mitomycin, provides an opportunity to examine the role of neoadjuvant chemotherapy (NACT) in the management of anal cancer. In this trial, no benefit was seen for the neoadjuvant approach, despite the obvious attraction and rationale for using cisplatin in this setting. Notably, although neoadjuvant FU/cisplatin chemotherapy was piloted before this study, the studies justifying the neoadjuvant approach in RTOG 98-11—one using FU and mitomycin as the CRT component—were not reported until 2001 and 2005, well into the accrual for this trial. This important study accrued a total of 682 patients between 1998 and 2005. Patients were randomly assigned between the standard arm of concurrent CRT with FU and mitomycin (341 patients), and the novel arm of neoadjuvant FU and cisplatin for two cycles before CRT with concurrent FU and cisplatin (341 patients). The majority of patients had T2 tumors, but 35% had stage T3/T4, and 26% had clinically involved lymph nodes. Of these 682 patients, 644 were deemed eligible for the trial. The results demonstrated that NACT with cisplatin/FU followed by FU/cisplatin–based CRT failed to improve overall survival, diseasefree survival (DFS), loco-regional control and distant relapse when compared to the standard treatment arm of FU/mitomycin C CRT. In fact, trends favored the FU/mitomycin C CRT arm. With a median follow-up of 2.51 years, the 3and 5-year DFS rates were 67% (95% CI, 62% to 72%) and 61% (95% CI, 53% to 67%), respectively, in the mitomycin arm compared with 61% (95% CI, 55% to 66%) and 54% (95% CI, 46% to 60%) for the cisplatin arm. The DFS curves separate at approximately 1 year and continue to widen throughout the duration of follow-up. The 3and 5-year overall survival rates at 84% and 75% for the mitomycin arm compared with 76% and 70%, respectively, for the cisplatin arm were not significantly different (P .1). The incidence of treatment failure was 32% (105 of 324) for mitomycin and 40% (127 of 320) for cisplatin, respectively. The cumulative rate for colostomy requirement was significantly higher for the cisplatin arm compared with the standard of mitomycin (19% v 10%; P .02), and the lack of any major compliance differences between the two treatment arms suggests that this difference does not relate to inadequate treatment delivery. We believe the conclusion in the abstract, “These findings do not support the use of cisplatin in place of mitomycin in combination with fluorouracil and radiotherapy in the treatment of anal canal carcinoma” could be construed as misleading. The two different CRT schedules of concurrent FU/cisplatin and concurrent FU/mitomycin CRT had not been directly compared due to the additional confounding factor of NACT in one arm. The results of RTOG 98-11 could suggest that it is the strategy of NACT that should not be supported, rather than the integration of cisplatin into the CRT. The ongoing Cancer Research United Kingdom Anal Cancer Trial (ACT II) also compares FU/cisplatin and FU/mitomycin CRT directly as primary treatment, but this comparison may also be blurred by the confounding factor of a second randomization to an additional two courses of consolidation chemotherapy 6 to 8 weeks after the completion of the CRT. Several hypotheses can be generated to account for a detrimental outcome from NACT, some of which were raised in a general review of NACT in solid tumors by one of us (R.G.-J.) in this Journal. The prolongation of overall radiotherapy treatment time has a significant adverse effect on survival in anal cancer, and given that the use of NACT extends the overall treatment time, this could have a deleterious effect, especially in tumors with accelerated repopulation. Tumors that initially respond and shrink with NACT may then subsequently proliferate and regrow at an even faster rate, potentially compromising the efficacy of CRT—the most important component of treatment. The majority of patients with squamous cell cancer of the anus, treated within clinical trials, have been cured with sphincterpreserving, nonsurgical treatment using combined-modality chemotherapy and radiation. However, patients with larger tumors (T3 and T4) and macroscopic lymph node involvement consistently have had a worse prognosis, with local control rates of only 50% to 60%. A more aggressive strategy is clearly needed for these more advanced patients. Hence, recent efforts to improve outcome have centered on attempts to integrate cisplatin at systemic doses into both the neoadjuvant and CRT component of treatment. Thus, if cisplatin-based therapy (NACT) as administered in RTOG 98-11 has proved to be a “dead end,” where do we go from here? There are several possible alternative strategies for improving both locoregional and distant control, particularly in T3/T4 patients: radiotherapy dose escalation, integration of different cytotoxic chemotherapy agents into CRT schedules, consolidation chemotherapy after CRT, and integration of biologic agents targeted to the epidermal growth factor receptor (EGFR). JOURNAL OF CLINICAL ONCOLOGY COMMENTS AND CONTROVERSIES VOLUME 26 NUMBER 22 AUGUST 1 2008