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Journal of Clinical Oncology, Vol 26, No 3 (January 20), 2008: pp. 350-351 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.14.6365
Rectal Cancer at the Crossroads: The Dilemma of Clinically Staged T3, N0, M0 DiseaseDepartments of Radiation Oncology, Boston University Medical Center and Massachusetts General Hospital, Boston, MA
Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA
Department of Medical Oncology, Massachusetts General Hospital, Boston, MA Imagine that tomorrow you develop some minor rectal bleeding. Your primary care physician refers you to a gastroenterologist who performs a colonoscopy finds a 3-cm moderately differentiated adenocarcinoma beginning at 8 cm from the anal verge. Staging computed tomography scans show no evidence of distant metastases. Pelvic magnetic resonance imaging (MRI) confirms a 3-cm mass, and a small part of the smooth black line of the muscularis propria is violated by the tumor on two contiguous MRI slices. There is no perirectal lymphadenopathy. Is preoperative chemoradiotherapy the right initial treatment for your clinical stage of disease? Our current uncertainty regarding the optimal adjuvant therapy for all clinically staged T3, N0, M0 rectal cancers was not always the case. More than two decades ago, the results of two randomized North American trials (the Gastrointestinal Tumor Study Group Protocol 7175 and the Mayo/North Central Cancer Treatment Group Protocol 79-47-51) demonstrated an increase in local control, disease-free survival, and overall survival when long-course radiation was administered concurrently with fluorouracil (FU) -based chemotherapy after surgical resection for patients with stage II and III rectal cancer.1,2 The National Surgical Adjuvant Breast and Bowel Project R01 trial then established that adjuvant FU chemotherapy after a rectal cancer resection was associated with improved survival compared with surgery alone or surgery with postoperative radiation.3 After the publication of these studies, it became standard of care for all patients with completely resected stage II or III rectal cancer to be treated in the postoperative setting with both FU-based chemoradiotherapy and FU chemotherapy for the best possible chance of achieving local control and overall survival. More recently, before preoperative chemoradiotherapy and total mesorectal excision (TME) emerged as a new standard of care,4 investigators evaluated whether there was a select group of patients in which adjuvant chemoradiotherapy could be safely omitted. Retrospective data from the non-TME era suggest that there may be a favorable subset of patients with pathologic T3, N0 disease (well to moderately differentiated histology, extending 2 mm or less into the perirectal fat, without lymphatic or vascular invasion, upper rectal location, and adequate node dissection) who may not benefit from adjuvant treatment.5-9 Furthermore, subset analyses of the largest postoperative trials evaluating adjuvant chemoradiotherapy demonstrate significantly improved local control and survival outcomes for patients with T3, N0 or T1/2, N1 disease.9,10 It is reasonable to expect even better results in the TME era. The landmark German Rectal Cancer Study, which directly compared preoperative versus postoperative chemoradiotherapy in the setting of modern clinical staging with endorectal ultrasound (ERUS) and modern surgical resection with TME, transformed our postoperative treatment standard and challenged our growing consensus that not all pathologically staged T3, N0 cancers require adjuvant therapy.4 This large randomized trial demonstrated that local control, rate of any grade 3 or 4 acute or late toxicity, and treatment compliance were significantly improved when chemoradiotherapy was administered preoperatively. Although preoperative chemoradiotherapy was the clear winner, new concerns emerged. First, 18% of the patients on the postoperative treatment arm who were clinically staged by ERUS as having T3 or N+ cancer, were found at resection to have T1-2, N0 disease and did not need adjuvant therapy. Second, due to preoperative chemoradiotherapy downstaging, we lost accuracy in predicting which patients may not benefit from adjuvant therapy, such as those with good-risk pathologic T3, N0 tumors. It is important to note that administering chemoradiotherapy and additional chemotherapy comes with a price: increased treatment-related deaths, and enhanced morbidity including radiation enteritis, diarrhea, ileus, bowel obstruction, and hematologic toxicities.1-4,11 In addition, functional anorectal outcome such as number of bowel movements per day, fecal continence, and sexual function have been demonstrated to be worse in patients receiving radiation.12,13 Guillem et al,14 in this issue of the Journal of Clinical Oncology, admirably address the question regarding the necessity of adjuvant therapy for all patients with T3, N0 rectal cancer in this new era of preoperative therapy. Although we are now aware of the potential overstaging risk from the German study, how often do we miss more advanced disease for patients with ERUS- or MRI-staged T3, N0 rectal cancer? In this large multicenter review, 22% of the patients believed to have clinically node-negative T3 disease were identified after chemoradiotherapy at the time of resection to have positive mesorectal lymph nodes. Although this analysis may be criticized for its retrospective nature, heterogeneity in the treatment techniques among institutions, as well as for the lack of central staging and pathology review, it still strongly emphasizes the significant degree of understaging that can occur with modern ERUS and MRI practice at some of the best academic cancer centers. Moreover, because significant downstaging occurs with preoperative chemoradiotherapy, many more patients would be expected to have had node-positive status if they had gone immediately to surgery without preoperative therapy. The authors therefore appropriately conclude that despite the risk of overtreating early-stage disease, preoperative chemoradiotherapy is still warranted for ERUS or MRI staged T3, N0, M0 rectal cancers. Is there a better way? Given the current limitations of pretherapy imaging, perhaps short-course (5 x 5 Gy) preoperative radiation therapy should be given greater consideration in the United States. Although short-course preoperative radiation significantly improves local control in the setting of TME,15 it also allows for a more accurate pathologic node assessment at the time of resection. This is because there is limited tumor downstaging, given that TME typically is performed 1 week after irradiation. As such, recommendations for adjuvant chemotherapy can be appropriately made. One small, randomized trial from Poland suggests that short-course preoperative radiation is equivalent to standard preoperative chemoradiotherapy in terms of local control, sphincter preservation, and survival.16 Despite these results, short-course radiation has not gained acceptance in the United States due to the concern about late morbidity.12,13,17 However, the Polish study failed to demonstrate any significant difference in late effects between short-course and long-course adjuvant therapy. Comparative long-term toxicity data, as well as patient-reported symptom and quality-of-life assessments from large prospective trials using standard preoperative or postoperative chemoradiotherapy regimens, are warranted. Currently, the United States Intergroup is conducting two large, linked, ongoing randomized studies (National Surgical Adjuvant Breast and Bowel Project trial R04 and Eastern Cooperative Oncology Group trial 5204) examining intensified adjuvant treatment for patients with clinical stage II and III rectal cancer.18 Is intensified therapy the appropriate investigative strategy for patients with ERUS or MRI staged T3, N0 disease? Short-course radiation, which does not compromise local control or survival in comparison with standard chemoradiotherapy, should be considered for this subset. By using short-course preoperative radiation, patients found to have positive nodes at the time of surgery may still receive postoperative chemotherapy, as they would for colon cancer. With this strategy, the role of adjuvant systemic therapy for patients with T3, N0 rectal cancer may be assessed adequately, and more importantly, patients found to have T1 or T2, N0 disease would avoid additional overtreatment. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. AUTHOR CONTRIBUTIONS Conception and design: Lisa A. Kachnic, Theodore S. Hong, David P. Ryan Manuscript writing: Lisa A. Kachnic, Theodore S. Hong, David P. Ryan Final approval of manuscript: Lisa A. Kachnic REFERENCES 1. Gastrointestinal Tumor Study Group: Prolongation of the disease-free survival in surgically treated rectal carcinoma. N Engl J Med 312:1465-1472, 1985[Abstract] 2. Krook JE, Moertel CG, Gunderson LL, et al: Effective surgical adjuvant therapy for high-risk rectal carcinoma. N Engl J Med 324:709-715, 1991[Abstract] 3. Fisher B, Wolmark N, Rockette H, et al: Postoperative adjuvant chemotherapy or radiation therapy for rectal cancer: Results from NSABP Protocol R-01. J Natl Cancer Inst 80:21-29, 1988 4. Sauer R, Becker H, Hohenberger W, et al: Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 351:1731-1740, 2004 5. Willett CG, Badizaadegan K, Ancukiewicz M, et al: Prognostic factors in stage T3N0 rectal cancer: Do all patients require postoperative irradiation and chemotherapy? Dis Colon Rectum 42:167-173, 1999[CrossRef][Medline] 6. Merchant NB, Guillem JG, Paty PB, et al: T3N0 rectal cancer: Results following sharp mesorectal excision and no adjuvant therapy. J Gastrointest Surg 3:647-647, 1999 7. Lopez-Kostner F, Lavery IC, Hool GR, et al: Total mesorectal excision is not necessary for cancers of the upper rectum. Surgery 124:612-617, 1998[CrossRef][Medline] 8. Faerden AE, Naimy N, Wilk P, et al: Total mesorectal excision for rectal cancer: Differences in outcome for low and high rectal cancer. Dis Colon Rectum 48:2224-2231, 2005[CrossRef][Medline] 9. Tepper JE, O’Connell MJ, Niedzwiecki DR, et al: Adjuvant therapy in rectal cancer: Analysis of stage, sex, and local control—Final report of Intergroup 0114. J Clin Oncol 20:1744-1750, 2002 10. Gunderson LL, Sargent DJ, 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 11. Cedermark B, Johansson H, Rutqvist LE, et al: The Stockholm I Trial of preoperative short term radiotherapy in operable rectal carcinoma: A prospective randomized trial. Cancer 75:2269-2275, 1995[CrossRef][Medline] 12. Marijnen CA, van de Velde CJ, Putter H, et al: Impact of short-term preoperative radiotherapy on health-related quality of life and sexual functioning in primary rectal cancer: Report of a multicenter randomized trial. J Clin Oncol 23:1847-1858, 2005 13. Peeters KC, van de Velde CJ, Leer JW, et al: Late side effects of short-course preoperative radiotherapy combined with total mesorectal excision for rectal cancer: Increased bowel dysfunction in irradiated patients—A Dutch colorectal cancer group study. J Clin Oncol 23:6199-6206, 2005 14. Guillem JG, Diaz-Gonzalez JA, Minsky BD, et al: CT3N0 rectal cancer: Potential overtreatment with preoperative chemoradiation is warranted. J Clin Oncol 26:368-373, 2008 15. Kapiteijn E, Marijnen CA, Nagtegaal ID, et al: Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med 345:638-646, 2001 16. Bujko K, Nowacki MP, Nasieroswka-Guttmejer A, et al: Long-term results of a randomized trial comparing preoperative short-course radiotherapy with preoperative conventionally fractionated chemoradiation for rectal cancer. Br J Surg 93:1215-1223, 2006[CrossRef][Medline] 17. Birgisson H, Pahlman L, Gunnarsson U, et al: Adverse effects of preoperative radiation therapy for rectal cancer: Long-term follow-up of the Swedish Rectal Cancer Trial. J Clin Oncol 23:8697-8705, 2005 18. O’Connell MJ, Wolmark N, Beart R, et al: Update on the design of the National Surgical Adjuvant Breast and Bowel Project trial R-04. J Clin Oncol 23:933-934, 2005
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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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