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Journal of Clinical Oncology, Vol 24, No 8 (March 10), 2006: pp. 1320-1321 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.05.1557
In Reply:From the Department of Radiation Therapy, University of Erlangen, Erlangen, Germany In Reply: Given that preoperative therapy has now become the standard of care in rectal cancer patients,1 the question raised by Machiels et al in their discussion of our article2 "Prognostic Significance of Tumor Regression After Preoperative Chemoradiotherapy for Rectal Cancer" is of utmost importance: What is the best to predict disease-free survival (DFS) in the setting of preoperative CRT? To address this question of end points, at least three time points need to be considered: First, are there clinicopathologic or molecular factors before neoadjuvant treatment that may reliably predict tumor response and long-term outcome? Second, what is the prognostic impact of monitoring tumor response during (or shortly after) CRT? Third, what is the role of parameters as assessed in the resected specimens after preoperative CRT? The scenario becomes even more complex, when determining how these end points are interrelated and, more importantly, which clinical consequences should be drawn from this information. In rectal cancer, patients are eligible for preoperative CRT if clinical staging (by digital rectal examination, endorectal ultrasound, and computed tomography or magnetic resonance imaging scans) reveals locally advanced disease, variously defined as tethered or fixed tumor, endosonographically staged (u-) T3-4 and/or uN+, or tumors close to the mesorectal resection margin. In our CAO/ARO/AIO-94 trial (Working Group of Surgical Oncology [CAO]/Working Group of Radiation Oncology [ARO]/Working Group of Medical Oncology [AIO] of the German Cancer Society), which included uT3-4 or uN+ patients, none of the pretreatment clinical factors, including the T and N stage, revealed a statistically significant prognostic value for DFS after curative surgery (manuscript in preparation). This may be due to the high interobserver variability and low overall accuracy of all clinical staging methods, especially with respect to the detection of lymph-node involvement, but also to downstaging effects caused by preoperative CRT. With these results, it is indeed questionable whether we should continue to apply postoperative adjuvant chemotherapy solely based on pretreatment clinical findings (as was done in the our trial that scheduled the same regimen of four cycles of postoperative fluorouracil to all patients after preoperative CRT regardless of postoperative TNM stage). Interestingly, recent investigations of sequential preoperative [18F]fluorodeoxyglucose positron emission tomography assessment of rectal cancer response to CRT have demonstrated the predictive value of this technique for pathologic response and long-term outcome.3 This information may be helpful in identifying patients who might benefit from novel chemotherapeutic regimens. Ideally, the identification of pretreatment features, such as tumor microcirculation by dynamic magnetic resonance imaging or molecular markers that may predict response, could be used to direct specific pre- and postoperative treatment to patients most likely to benefit.4-6 However, at present, none of these techniques and markers are sufficiently validated to be implemented in daily practice. In contrast, it has been shown consistently in our trial, the data by Machiels et al, and other investigators, that postoperative TNM staging and factors like mesorectal resection margin invasion, or the assessment of the completeness of total mesorectal excision, are important prognostic factors for DFS both in univariate and multivariate analysis.7,8 In our study, the 5-year DFS after curative (R0) resection was 85% for patients with ypN0 nodal status, but decreased to only 18% for patients with metastasis in three or more lymph nodes. Thus, an imminent issue both for daily practice and the design of future clinical trials is the question of treatment stratification according to risk factors, such as the ypN stage or mesorectal resection margin involvement. It is our opinion that addressing these questions is clinically and scientifically at least equally important as incorporating ever more intense chemotherapy into combined modality approaches for rectal cancer regardless of risk factors and treatment response. 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)
Acknowledgment Supported by Grant No. 70-578 from Deutsche Krebshilfe. REFERENCES
1. Sauer R, Becker H, Hohenberger W, et al: Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 351:1731-1740, 2004 2. 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 3. Guillem JG, Moore HG, Akhurst T, et al: Sequential preoperative fluorodeoxyglucose-positron emission tomography assessment of response to preoperative chemoradiation: A means for determining longterm outcomes of rectal cancer. J Am Coll Surg 199:1-7, 2004[Medline] 4. Devries AF, Griebel J, Kremser C, et al: Tumor microcirculation evaluated by dynamic magnetic resonance imaging predicts therapy outcome for primary rectal carcinoma. Cancer Res 61:2513-2516, 2001 5. Rodel F, Hoffmann J, Grabenbauer GG, et al: High surviving expression is associated with reduced apoptosis in rectal cancer and may predict disease-free survival after preoperative radiochemotherapy and surgical resection. Strahlenther Onkol 178:426-435, 2002[CrossRef][Medline] 6. Ghadimi BM, Grade M, Difilippantonio MJ, et al: Effectiveness of gene expression profiling for response prediction of rectal adenocarcinomas to preoperative chemoradiotherapy. J Clin Oncol 23:1826-1838, 2005 7. Chapet O, Romestaing P, Mornex F, et al: Preoperative radiotherapy for rectal adenocarcinoma: Which are strong prognostic factors? Int J Radiat Oncol Biol Phys 61:1371-1377, 2005[Medline] 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]
Related Correspondence
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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
