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Journal of Clinical Oncology, Vol 23, No 16 (June 1), 2005: pp. 3870-3871 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.05.291
In Reply:Department of Gastrointestinal Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX Do we alter the biology of localized upper GI cancer with therapy or just uncover it? Upper GI (UGI) cancers are clinically and molecularly heterogeneous. At present, however, we lack the tools to take advantage of these differences. Thus, our therapies are likely to remain homogenous and empiric until we get smarter. When preoperative chemoradiotherapy is given to patients with localized UGI cancers, we observe three types of pathologic response: no residual cancer (pathologic complete response, in 20% to 30%), some evidence of response (in 30% to 40%), and no response (in 30% to 40%). The overall survival and disease-free survival are directly correlated with the type of pathologic response.1 Dr Allal asks whether we are simply identifying these biologic subgroups by going through the motions of administering preoperative therapy or the therapy has actually influenced patient outcome. I suspect that he is also asking why, since we are not changing the biology (or outcome), we are putting our patients through these complex and morbid therapies. The questions are valid, but is he arguing against combined modality preoperative therapy research? I am not sure. There are no clear answers at hand without well-designed randomized trials. This is what we proposed in our report.2 The trial by Lee et al3 of 101 patients, which was cited by Dr Allal, is hardly sufficient to argue for or against this notion. I believe we are altering the natural history of localized UGI cancers with the addition of chemoradiotherapy (and more effective systemic agents) to the preoperative strategy, since we now witness lower local relapse rates and longer overall survival and disease-free survival than we do when chemoradiotherapy is not given preoperatively. More patients are manifesting brain metastases, an alarming phenomenon that was witnessed in breast cancer patients when more effective therapies became available. In our recent analysis, involving more than 200 patients who received preoperative chemoradiotherapy, we found that the rate of metastases and the metastases-free survival significantly correlated with the degree of pathologic response.4 This implies that locally resistant cancers are also more metastatic. How can we improve the outcome then? We must develop more effective local and systemic therapies. Dr Allal argues against systemic therapy. In our clinical trials, induction chemotherapy has been a strategic addition to preoperative chemoradiotherapy.5 Our hypothesis is that if the bulk of the primary cancer can be reduced (downsized or downstaged while the metastatic cancer is also being treated), then the ensuing chemoradiotherapy will be more effective. Allum et al6 have reported significant prolongation of progression-free survival by the use of preoperative systemic chemotherapy in patients with localized gastric cancers. I would argue that we need more effective (and specific) systemic therapies. We know that patients with resistant cancers still cannot be identified before therapy. But what if we could identify such patients? More effective systemic therapies would then be required to improve their outcome. Until specific therapies are developed, I agree that an agent from an effective class, such as taxanes, should be incorporated with preoperative radiotherapy. In our recent report on localized gastric cancer patients who received taxane-based preoperative chemoradiotherapy, intriguingly, the median survival time has not been reached at a median follow-up time of more than 36 months (68% of patients remain alive).7 The Radiation Therapy Oncology Group (RTOG) has completed a 49-patient study (RTOG 9904) of preoperative taxane-based chemoradiotherapy in the same group of patients, and the results are forthcoming. We alluded to a clear distinction between the patients who were enrolled in the postoperative chemoradiotherapy Intergroup 0116 trial8 and those who were enrolled on our multi-institutional trial.2 These two populations are not comparable. The patients who were enrolled in the Intergroup 0116 trial were the best group among those with localized gastric cancers (they all survived surgery, they all had a curative resection, and they were selected out for the trial), while the patients who were enrolled in our preoperative chemoradiotherapy study were only clinically staged (and, of course, selected for the study). Thus the similar median survival times for the Intergroup trial and our trial (34 and 35 months, respectively) must be viewed positively, in favor of our preoperative trial, and not negatively, as implied. Despite the limitations of indulging in these types of comparisons, this does make a strong case for further study of the preoperative approach. A phase I publication describing a radiation dose-finding study,9 which was coauthored by Dr Allal but not cited in our report, contradicts his current assertions since the publication emphasizes the need for better systemic therapy, and the tone clearly encourages obtaining pathologic responses and their value to the patients. I thank Dr Allal for raising important issues regarding the biology and preoperative treatment of UGI cancers. One can often get caught in the alphabet soup of combinations (of drugs and modalities) without thinking about the very basics of cancer biology and the built-in genotypic/phenotypic differences among patients. Author's Disclosures of Potential Conflicts of Interest The author indicated no potential conflicts of interest. REFERENCES 1. Chireac LR, Swisher SG, Ajani JA, et al: Posttherapy pathologic stage predicts survival in patients with esophageal carcinoma receiving preoperative chemoradiation. Cancer 103:1347-1355, 2005[CrossRef][Medline]
2. Ajani JA, Mansfield PF, Janjan N, et al: Multi-institutional trial of preoperative chemoradiotherapy in patients with potentially resectable gastric carcinoma. J Clin Oncol 22:2774-2780, 2004
3. Lee JL, Park SI, Kim SB, et al: A single institutional phase III trial of preoperative chemotherapy with hyperfractionation radiotherapy plus surgery-versus surgery alone for resectable esophageal squamous cell carcinoma. Ann Oncol 15:947-954, 2004 4. Rohatgi P, Swisher SG, Correa AM, et al: Failure patterns correlate with the proportion of residual carcinoma after pre-operative chemoradiotherapy for carcinoma for the esophagus. Cancer (in press) 5. Ajani JA, Komaki R, Putnam JB, et al: A three-step strategy of induction chemotherapy then chemoradiation followed by surgery in patients with potentially resectable carcinoma of the esophagus of gastroesophageal junction. Cancer 92:279-286, 2001[CrossRef][Medline] 6. Allum W, Cunningham D, Weeden S, et al: Perioperative chemotherapy in operable gastric and lower esophageal cancer: A randomized controlled trial (the MAGIC trial, ISRCTN 93793971). Proc Am Soc Clin Oncol 22:249, 2003 (abstr 998) 7. Ajani JA, Mansfield PF, Crane CH, et al: Paclitaxel-based chemoradiotherapy in localized gastric carcinoma: Degree of pathologic response and not clinical parameters dictated patient outcome. J Clin Oncol 23:1237-1244, 2003
8. Macdonald JS, Smalley SR, Benedetti J, et al: Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med 345:725-730, 2001
9. Roth AD, Allal AS, Brundler MA, et al: Neoadjuvant radiochemotherapy for locally advanced gastric cancer: A phase I-II study. Ann Oncol 14:110-115, 2003
Related Correspondence
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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