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Journal of Clinical Oncology, Vol 25, No 28 (October 1), 2007: pp. 4339-4340 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.12.8892
Adjuvant Management of Rectal Cancer: The More We Learn, the Less We KnowDepartment of Radiation and Cellular Oncology, University of Chicago Medical Center, Chicago, IL Two decades ago, the adjuvant management of rectal cancer was less complex and far less controversial. Patients in the United States underwent surgery, commonly by blunt dissection, and if there was pT3 and/or pN1-2 disease, they received 6 months of postoperative fluouracil (FU)-based chemotherapy with pelvic radiation during months 3 and 4 (combined-modality therapy). Subsequent randomized and nonrandomized trials have taught us many new lessons. Among these are total mesorectal excision as the preferred surgical technique1; at least 12 examined nodes to accurately determine the nodal stage2; the relationship of local failure not only to stage but also to the location of the tumor in the rectum and the presence of a positive circumferential margin3; and the subsets of patients with pT3N0 of pT1-2N1 disease who may not require postoperative radiation.4 Furthermore, for patients with cT3 and or N+ disease, the German trial confirmed that preoperative combined-modality therapy has significantly improved local control, caused less acute short and long-term toxicity, and increased sphincter preservation compared with postoperative combined-modality therapy.5 The paradigm shift from postoperative to preoperative therapy has opened a series of new questions that have practical clinical implications. For example, does combining newer chemotherapeutic agents with radiation improve the pathologic complete response rate?6 Is the response rate a surrogate marker for outcome?7 Are there molecular markers that can help predict the response rate and preoperative nodal stage?7 And do all patients with uT3N0 or pT3N0 disease require adjuvant radiation?8 The European Organisation for Research and Treatment of Cancer (EORTC) 22921 trial (which provides the data for the current subset analysis) is one of the only two prospective randomized trials reported in more than two decades that did not confirm a significant survival benefit for adjuvant FU-based chemotherapy for node-positive colon and rectal cancers.9,10 Since its publication in 2006, it has challenged our thinking, and GI oncologists have struggled with whether to change their standard of care. In the current analysis,11 Collette et al have performed a secondary analysis of the EORTC 22921 trial to determine whether there is a subset of patients who, after preoperative combined-modality therapy and surgery, may benefit from adjuvant postoperative bolus FU/leucovorin chemotherapy. The analysis was limited to 785 (78%) of the 1,011 patients who underwent an R0 resection and had M0 disease at surgery. In this eligible group, 74% of patients who were assigned to receive postoperative chemotherapy received all four cycles of adjuvant chemotherapy. This is similar to the 66% reported in the total group of 1,011 patients described in their initial report.9 In brief, their analysis confirmed the earlier finding that postoperative chemotherapy did not significantly improve disease-free or overall survival for the total group of 785 patients. However, multivariate analysis revealed that chemotherapy did significantly improve overall survival in those patients whose tumors were downstaged to ypT0-2 compared with stages ypT3-4. This new information may help to explain why there was no survival benefit with postoperative adjuvant chemotherapy in their earlier report for the total group of 1,011 patients. In contrast, a preliminary report from Frietkau et al12 questioned the value of postoperative adjuvant chemotherapy for patients whose tumors were downstaged to ypN0 after preoperative combined-modality therapy. It must be emphasized that there is no trial, including EORTC 22921, that has been designed with the necessary stratification to answer this question. The authors appropriately caution that their analysis is "exploratory in nature: Neither the end point nor the hypotheses studied were planned in the study protocol." Are the results explained by the impact of the preoperative treatment, the biology of the tumor, or both? Is the response rate a marker for those who will benefit from postoperative bolus FU/leucovorin chemotherapy, or is it merely a surrogate marker of chemotherapy resistance? In the discussion, the authors do caution us not to confuse causality with association. Valentini et al13 hypothesize that tumors are heterogeneous and that the response to preoperative therapy helps to identify prognostic subsets. This is one of a variety of explanations, and this issue remains an area of substantial controversy.7 The practical dilemma is, given these provocative results, how do we manage the postoperative patient who has received preoperative combined-modality therapy? Although there was no survival benefit to postoperative chemotherapy for those with ypT3-4 disease it should be emphasized that this does not mean that chemotherapy is not necessary but rather, in this single trial, bolus FU/leucovorin chemotherapy was not helpful for those patients who received this regimen preoperatively. In my opinion, 4 months of postoperative adjuvant chemotherapy is still appropriate. However, in those patients with tumors that did not respond to preoperative treatment, I recommend using an alternative chemotherapeutic regimen in the postoperative setting such as FOLFOX (infusional FU, leucovorin, and oxaliplatin). Because the standard of care has evolved from postoperative to preoperative combined-modality therapy, the identification of pathologic and molecular predictive markers needs to be an integral component in the design of our clinical trials. For example, the degree of tumor regression correlates with outcome.14 Molecular markers such as gene expression profiling to predict tumor response15 and thymidylate synthase expression to determine who may benefit from FU-based chemotherapy16 may help us understand the underlying molecular mechanisms and provide a rationale for selection of the appropriate therapies. Just as there is still great art and music to be created, there is no shortage of clinical questions to be answered in the management of rectal cancer. Our national and international cooperative groups are ripe to meet this opportunity. 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: Bruce D. Minsky, Sanofi-Aventis (C), Genentech (C), Bristol Myers Squibb (C) Stock Ownership: None Honoraria: Bruce D. Minsky, Sanofi-Aventis, Genentech, Bristol Myers Squibb Research Funding: Bruce D. Minsky, Genentech, Bristol Myers Squibb Expert Testimony: None Other Remuneration: None REFERENCES
1. Kapiteijn E, Marijnen CAM, Nagtegaal ID, et al: Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med 345: 638-646, 2001 2. Tepper JE, O'Connell MJ, Niedzwiecki D, et al: Impact of number of nodes retrieved on outcome in patients with rectal cancer. J Clin Oncol 19: 157-163, 2001 3. Marijnen CAM, Nagtegaal ID, Kapiteijn E, et al: Radiotherapy does not compensate for positive resection margins in rectal cancer patients: Report of a multicenter randomized trial. Int J Radiat Oncol Biol Phys 55: 1311-1320, 2003[CrossRef][Medline] 4. Gunderson LL, Sargent D, Tepper JE, et al: Impact of T and N stage and treatment on survival and relapse in adjuvant rectal cancer: A pooled analysis. J Clin Oncol 22: 1785-1796, 2004 5. Sauer R, Becker H, Hohenberger P, et al: Preoperative chemoradiotherapy as compared with postoperative chemoradiotherapy for locally advanced rectal cancer. N Engl J Med 351: 1731-1740, 2004 6. Roedel C, Valentini V, Minsky BD: Rectal cancer, in Gunderson LL, Tepper JE (eds): Clinical Radiation Oncology (ed 2). New York, NY, Elsevier, 2007, pp 1113-1143 7. Johnston PG: Prognostic markers of local relapse in rectal cancer: Are we any further forward? J Clin Oncol 24: 4049-4050, 2006 8. Gunderson LL, Callister M, Marschke R, et al: Stratifying risks for patients with localized rectal cancer: Do all stage II patients require adjuvant radiation or chemoradiation? Current Colorectal Cancer Reports 2: 151-159, 2006[CrossRef] 9. Bosset JF, Collette L, Bardet E, et al: Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med 355: 1114-1123, 2006 10. Gérard JP, Conroy T, Bonnetain F, et al: Preoperative radiotherapy with or without concurrent fluorouracil and leucovorin in T3-4 rectal cancers: Results of FFCD 9203. J Clin Oncol 24: 4620-4625, 2006 11. Collette L, Bosset JF, den Dulk M, et al: Patients with curative resection of cT3-4 rectal cancer after preoperative radiotherapy or radiochemotherapy: Does anybody benefit from adjuvant fluorouracil-based chemotherapy? A trial of the European Organisation for Research and Treatment of Cancer Radiation Oncology Group. J Clin Oncol 25: 4379-4386, 2007 12. Fietkau R, Barten M, Klautke G, et al: Postoperative chemotherapy may not be necessary for patients with ypN0-category after neoadjuvant chemoradiotherapy of rectal cancer. Dis Colon Rectum 49: 1284-1292, 2006[CrossRef][Medline] 13. Valentini V, Coco C, Picciocchi A, et al: Does downstaging predict improved outcome after preoperative chemoradiation for extraperitoneal locally advanced rectal cancer? A long-term analysis of 165 patients. Int J Radiat Oncol Biol Phys 53: 664-674, 2002[CrossRef][Medline] 14. Rödel C, Martus P, Papadoupolos T, et al: Prognostic significance of tumor regression after preoperative chemoradiotherapy for rectal cancer. J Clin Oncol 23: 8688-8696, 2005 15. Ghadimi BM, Grade M, Difilppantonio MJ, et al: Effectiveness of gene expression profiling for response prediction of rectal adenocarcinomas to preoperative chemoradiotherapy. J Clin Oncol 23: 1826-1838, 2005 16. Liersch T, Langer C, Ghadimi BM, et al: Lymph node status and TS gene expression are prognostic markers in stage II/III rectal cancer after neoadjuvant fluorouracil-based chemoradiotherapy. J Clin Oncol 24: 4062-4068, 2006
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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