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Journal of Clinical Oncology, Vol 24, No 28 (October 1), 2006: pp. 4664-4665 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.07.9491
Role of Neoadjuvant Chemotherapy in Rectal Cancer: Interpretation of the EXPERT StudyMount Vernon Centre for Cancer Treatment, Northwood, Middlesex, United Kingdom
Leeds Cancer Centre, Cookridge Hospital, Leeds, West Yorkshire, United Kingdom To the Editor: The recent article in the Journal of Clinical Oncology concerning locally advanced rectal cancer by Chau et al1 is interesting in that it advocates the addition of a long (12-week) induction phase of two cytotoxic chemotherapy agents (capecitabine and oxaliplatin) before single-agent preoperative chemoradiotherapy (total dose 54 Gy) with capecitabine alone in locally advanced rectal cancer. This thought-provoking phase II study uses magnetic resonance imaging-defined entry criteria, and detailed histopathologic information on the circumferential resection margin. In addition, patients underwent total mesorectal excision after a defined interval. The early results of this study appear impressive, and the authors imply this outcome to the addition of the induction neoadjuvant chemotherapy. However, it is not possible to determine the relative contributions of the neoadjuvant chemotherapy and the concurrent chemoradiotherapy schedule. These results might simply reflect a high-dose of pelvic radiotherapy (54 Gy) with all the attendant expected increase in pelvic morbidity from such a high dose. Similar results have been achieved with a 20% reduction in the dose of radiotherapy (45 to 50.4 Gy) and much shorter synchronous chemoradiotherapy regimens utilizing capecitabine and either oxaliplatin or irinotecan.2-5 We are not aware of any data in other tumor models, which convincingly endorse this strategy of induction platinum-based chemotherapy followed by chemoradiotherapy. In fact, induction chemotherapy is being increasingly questioned, as it may inhibit the effectiveness of subsequent radiotherapy,6 and the available data show that the most effective combination of drugs has usually been seen with early synchronous chemoradiotherapy. Albeit in a different model, the recent data in anal cancer has also failed to show any benefit from the addition of a platinum based-induction chemotherapy regimen.7 The authors are to be congratulated for showing the true denominator for pathologic complete response for such a study, which must include patients who died, refused surgery, remained unresectable, or who never achieved a resection. Few studies document this denominator. The authors also make a salient point that 5% of patients died during this neoadjuvant phase of this study. The authors report the pathological complete response rate (the primary end point of the study) both as an intention-to-treat (21%) and a rate restricted to those who underwent potentially curative surgery (24%). Similar information is not reported for the achievement of a negative circumferential margin. The text states that "of the 67 patients who underwent TME, R0 resections were achieved in all but one patient (99%)." However, while factually correct, the information is misleading. By restricting the denominator to resected patients, this information excludes those who experienced a toxic death (n = 4), and those who remained unresectable at laparotomy (n = 3), refused surgery (n = 2), or were unfit for surgery (n = 1). This figure should therefore be considered in the context of the overall denominator (ie, the intention-to-treat denominator which is 67 of 78; 86%.) This information allows the study to be compared with other studies with similar entry criteria.8,9 We believe that the intention-to-treat proportion of patients achieving an uninvolved circumferential resection could potentially provide an early efficacy end point comparison. The study by Chau et al, raises several issues regarding the role of adjuvant chemotherapy in rectal cancer. First, a toxic death rate of 5% is not acceptable. Second, is chemotherapy most effective as a part of an induction or a synchronous chemoradiotherapy schedule preoperatively? Third, should chemoradiotherapy schedules include a single drug (as in the current study) or two cytotoxic drugs if we are to influence both local control and overall survival? Finally, is the use of neoadjuvant chemotherapy an advantage over postoperative chemotherapy? Multiple trials in head and neck cancer, nasopharyngeal cancer, non–small-cell lung cancer, small-cell lung cancer, bladder cancer, cervical cancer, and anal cancer do not support the routine use of neoadjuvant chemotherapy either as an alternative or as additional benefit to chemoradiotherapy. There is a paucity of data to suggest any benefit in local control with neoadjuvant chemotherapy over that achieved with concurrent chemoradiotherapy. Concurrent chemoradiotherapy with early positioning of radiotherapy appears the most effective option. There is a clear need to compare these strategies (neoadjuvant chemotherapy, neoadjuvant chemoradiotherapy, and postoperative adjuvant chemotherapy) in properly controlled randomized studies. In our opinion, neoadjuvant chemotherapy before chemoradiotherapy in rectal cancer should be used with caution, and only in the context of randomized trials. Authors' Disclosures of Potential Conflicts of Interest
Although all authors completed the disclosure declaration, the following author or immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. 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.
Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C)
REFERENCES
1. Chau I, Brown G, Cunningham D, et al: Neoadjuvant capecitabine and oxaliplatin followed by synchronous chemoradiation and total mesorectal excision in magnetic resonance imaging–defined poor-risk rectal cancer. J Clin Oncol 24:668-674, 2006 2. Rödel C, Grabenbauer GG, Papadopoulos T, et al: Phase I/II trial of capecitabine, oxaliplatin, and radiation for rectal cancer. J Clin Oncol 21:3098-3104, 2003 3. Hofheinz RD, von Gerstenberg-Helldorf B, Wenz F, et al: Phase I trial of capecitabine and weekly irinotecan in combination with radiotherapy for neoadjuvant therapy of rectal cancer. J Clin Oncol 23:1350-1357, 2005 4. Glynne-Jones R, Sebag-Montefiore D, Samuel L, et al: Socrates phase II study results: Capecitabine (CAP) combined with oxaliplatin (OX) and preoperative radiation (RT) in patients (pts) with locally advanced rectal cancer (LARC). J Clin Oncol 23:252s, 2005 (abstr 3527) 5. Sebag-Montefiore D, Brown G, Rutten H, et al: An international phase II study of capecitabine, oxaliplatin, radiotherapy and excision (CORE) in patients with MRI-defined locally advanced rectal adenocarcinoma: Interim results. Eur J Cancer 3: 170, 2005 (abstr 608) 6. Brada AM, Tannock IF: Scheduling of radiation and chemotherapy for limited stage small cell lung cancer: Repopulation as a cause of treatment failure. J Clin Oncol 24:1020-1022, 2006 7. Ajani JA, Winter KA, Gunderson LL, et al: Intergroup RTOG 98-11: A phase III randomized study of (5FU), mitomycin, and radiotherapy versus 5-fluorouracil, cisplatin and radiotherapy in carcinoma of the anal canal. J Clin Oncol 24:180s, 2006 (abstr 4009) 8. Mawdsley S, Glynne-Jones R, Grainger J, et al: Can histopathologic assessment of circumferential margin after preoperative pelvic chemoradiotherapy for T3–T4 rectal cancer predict for 3-year disease-free survival? Int J Radiat Oncol Biol Phys 63:745-752, 2005[CrossRef][Medline] 9. Sebag-Montefiore D, Hingorani M, Cooper R, et al: Circumferential resection margin status predicts outcome after pre-operative chemoradiation for locally advanced rectal cancer. Proceedings of J Clin Oncol GI Symposium 2005 (abstr 193)
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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$100,000 (N/R) Not Required
