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Originally published as JCO Early Release 10.1200/JCO.2008.18.1651 on June 2 2008 © 2008 American Society of Clinical Oncology.
Anal Cancer: The End of the Road for Neoadjuvant Chemoradiotherapy?
Mount Vernon Cancer Centre, Northwood, Middlesex, United Kingdom 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.1 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.2,3 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, disease-free 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 3- and 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 3- and 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.4,5 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.6 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 sphincter-preserving, nonsurgical treatment using combined-modality chemotherapy and radiation.7-10 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). Interest in NACT initially arose after the observation that patients with local failure also experience recurrence with distant disease. High rates of response can be achieved with cisplatin in untreated chemotherapy-naïve tumors—hence the belief that systemic chemotherapy could decrease the risk of distant metastases. But is this strategy convincing? Anal cancer is predominantly a locoregional disease. In the United Kingdom Coordinating Committee for Cancer Research ACT I trial, only 21 (7%) of 285 patients treated with CRT developed metastatic disease outside the pelvis in the absence of evidence of pelvic recurrence.8 However, we should not abandon investigating the role of NACT. It may be more appropriate to consider using a non–cross-resistant chemotherapy combination such as a taxane in the neoadjuvant setting, rather than a platinum-based drug in both schedules. Recent randomized trials in head and neck cancer demonstrate that the addition of a taxane to FU/cisplatin induction chemotherapy before concurrent CRT significantly improves response rates, time to progression, and survival compared with FU/cisplatin induction chemotherapy.11,12 Previous attempts at dose intensification have not always been successful, particularly when a gap in treatment has been introduced.13 With current planning techniques, dose escalation may not be the most appropriate strategy to improve local control, because the risk of late effects is related to the total radiotherapy dose and late morbidity becomes a significant issue for patients. Intensity-modulated radiotherapy is a novel technology, which may allow the delivery of high doses of radiotherapy to the tumor while sparing normal surrounding structures to a greater degree than conventional two-dimensional or three-dimensional planning. Reduced clinical complication rates and improved clinical outcomes have been shown in a number of sites, leading the RTOG to pilot a study that integrated intensity-modulated radiotherapy with FU/mitomycin, such as RTOG 0529, which closed to accrual in March 2008. The central role of mitomycin in anal cancer therapy had been demonstrated previously by the RTOG.9 Using an alternative strategy, the European Organisation for Research and Treatment of Cancer piloted a randomized phase II study of 80 patients comparing FU/mitomycin versus cisplatin/mitomycin, which demonstrated that this combination is feasible.14 The Intergroup/ACCORD 03 randomized study compared in a 2 x 2 factorial manner moderate-dose with high-dose RT, and induction chemotherapy with FU/cisplatin before CRT or not, and showed that neoadjuvant FU cisplatin followed by CRT with concurrent FU and mitomycin could be delivered with acceptable toxicity.15 However, an interim analysis suggested this study might be underpowered to show a significant difference for NACT. The current United Kingdom national ACT II trial also uses a 2 x 2 factorial design and randomly assigns patients between FU/mitomycin and FU/cisplatin administered concurrently with radiotherapy.4 The second randomization is between two courses of FU/cisplatin consolidation chemotherapy or no further treatment. To date, 850 patients have been randomly assigned, and accrual will be completed by the end of August 2008. Regular updates from the data monitoring committee have not caused concern about excess toxicity or suggested that an arm is inferior. Randomized trials to date have failed to demonstrate any additional benefits from the addition of cisplatin either in the neoadjuvant setting or combined with radiotherapy in the treatment of anal cancer, despite a number of phase II trials suggesting potentially superior efficacy.3,16 Alternative approaches with cytotoxic agents are also being explored, including a phase II trial at the M.D. Anderson Cancer Center (Houston, TX) of capecitabine and oxaliplatin with concomitant radiotherapy. However, the gold standard nonsurgical treatment remains a combination of FU and mitomycin, with doses of radiotherapy in the range of 45 to 59.4 Gy. This schedule achieves long-term control for the majority of patients, but local failure remains unacceptably high for more advanced tumors. It remains unclear why different cytotoxic drug schedules are more or less successful in squamous cell carcinoma models of the head and neck, lung, cervix, and anal cancer. The combination of FU and mitomycin has not been bettered in anal cancer, whereas cisplatin is the standard companion to radiotherapy in esophageal and cervical cancer. Do these different approaches really reflect a distinct biology, or have we just not designed the right trials? Hence, another attractive approach for future studies is the use of biologic targeted agents. Overexpression of the EGFR has been linked to resistance to radiotherapy. An obvious agent in this context would be either an EGFR monoclonal antibody or one of the oral tyrosine kinase inhibitors, which exploit this pathway. This approach is currently being explored in a US cooperative group phase II study (E3205), in which cetuximab in given with FU/cisplatin and radiation. The current challenge in managing anal cancer is to cure the majority of patients without severely compromising ano-rectal function. The real disappointment from the results of the RTOG 98-11 study lies in our fixation with the paradigm of cisplatin-based NACT and our inability to move on from previous successes in anal cancer. Hence, despite the results of four randomized trials in anal cancer, and a much clearer concept of toxicity, avoidance of gaps in treatment, and individual prognostic factors, the optimal chemotherapy regimen in combination with radiotherapy remains the schedule of CRT using mitomycin, infusional FU, and radiotherapy. Quite simply, the paradigm developed by Nigro more than 30 years ago remains the standard of care. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: Rob Glynne-Jones, Roche (C), Sanofi-aventis (C), Merck Serono (C) Stock Ownership: None Honoraria: Rob Glynne-Jones, Roche, Sanofi-aventis, Merck Serono Research Funding: Rob Glynne-Jones, Roche Expert Testimony: None Other Remuneration: None AUTHOR CONTRIBUTIONS Conception and design: Rob Glynne-Jones, Suzy Mawdsley Manuscript writing: Rob Glynne-Jones, Suzy Mawdsley Final approval of manuscript: Rob Glynne-Jones, Suzy Mawdsley NOTES published online ahead of print at www.jco.org on June 2, 2008. REFERENCES
1. Ajani JA, Winter KA, Gunderson LL, et al: Fluorouracil, mitomycin and radiotherapy vs fluorouracil, cisplatin and radiotherapy for carcinoma of the anal canal: A randomised controlled trial. JAMA 299:1914-1921, 2008 2. Peiffert D, Giovannini M, Ducreux M, et al: High-dose radiation therapy and neoadjuvant plus concomitant chemotherapy with 5-fluorouracil and cisplatin in patients with locally advanced squamous-cell anal carcinoma: Final results of a phase II study. Ann Oncol 12:397-404, 2001 3. Meropol NJ, Niedzwiecki D, Shank B, et al: Combined-modality therapy of poor prognosis anal canal carcinoma: A phase II study of Cancer and Leukemia Group B (CALGB). Proceedings of the ASCO Gastrointestinal Symposium, American Society of Clinical Oncology, Alexandria, VA, 2005 (abstr 238) 4. James R, Meadows H, Wan S: ACT II: The second UK phase III anal cancer trial. Clin Oncol (R Coll Radiol) 17:364-366, 2005[Medline] 5. James R, Meadows HM: The second UK phase III anal cancer trial of chemoradiation and maintenance therapy (ACT II): Preliminary results on toxicity and outcome. Proc Am Soc Clin Oncol 22:287, 2003 (abstr 1151) 6. Glynne-Jones R, Hoskin P: Neoadjuvant cisplatin chemotherapy before chemoradiation: A flawed paradigm? J Clin Oncol 25:5281-5286, 2007 7. Bartelink H, Roelofsen F, Eschwege F, et al: Concomitant radiotherapy and chemotherapy is superior to radiotherapy alone in the treatment of locally advanced anal cancer: Results of a phase III randomized trial of the European Organization for Research and Treatment of Cancer Radiotherapy and Gastrointestinal Cooperative Groups. J Clin Oncol 15:2040-2049, 1997 8. UKCCCR Anal Cancer Working Party: Epidermoid anal cancer: Results from the UKCCCR randomised trial of radiotherapy alone versus radiotherapy, 5-fluorouracil and mitomycin c. Lancet 348:1049-1054, 1996[CrossRef][Medline] 9. Flam M, John M, Pajak TF, et al: Role of mitomycin in combination with fluorouracil and radiotherapy, and of salvage chemoradiation in the definitive nonsurgical treatment of epidermoid carcinoma of the anal canal: Results of a phase III randomized Intergroup study. J Clin Oncol 14:2527-2539, 1996[Abstract] 10. John M, Flam M, Berkley B, et al: Five year results and analyses of a phase III randomised RTOG/ECOG chemoradiation protocol for anal cancer. Proc Am Soc Clin Oncol 17, 1998 (abstr 989) 11. Vermorken JB, Remenar E, van Heren C, et al: Cisplatin, fluorouracil and docetaxel in unresectable head and neck cancer. N Engl J Med 357:1695-1704, 2007 12. Posner MR, Hershock DM, Blajman CR, et al: Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer. N Engl J Med 357:1705-1715, 2007 13. John M, Pajak I, Flam M, et al: Dose escalation in chemoradiation for anal cancer: Preliminary results of RTOG 9208. Cancer J Sci Am 2:2205-2211, 1996 14. Crehange G, Bosset M, Lorchel F, et al: Combining cisplatin and mitomycin with radiotherapy in anal carcinoma. Dis Colon Rectum 50:43-49, 2007[CrossRef][Medline] 15. Peiffert D, Gerard JP, Ducreux M, et al: Induction chemotherapy (ICT) and dose intensification of the radiation boost in locally advanced anal cancer (LAACC): Interim analysis of the 101 first randomised patients (pts) in the Intergroup ACCORD 03 trial (Federation Nacionale des Centres de Lutte Contre le Cancer–Fondation Francaise de Cancerologie Digestive). Eur J Cancer 2:172, 2005 (suppl 3; abstr 614) 16. Martenson S, Lipsitz H, Wagner et al: Initial results of a phase II trial of high dose radiation therapy, 5-fluorouracil, and cisplatin for patients with anal cancer (E4292): An Eastern Cooperative Oncology Group study. Int J Radiat Oncol Biol Phys 35:745-749, 1996[CrossRef][Medline]
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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