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Annals of Oncology 24: 2844–2849, 2013 doi:10.1093/annonc/mdt339 Published online 23 August 2013
A phase II randomized trial of induction chemotherapy versus no induction chemotherapy followed by preoperative chemoradiation in patients with esophageal cancer J. A. Ajani1, L. Xiao2, J. A. Roth3, W. L. Hofstetter3, G. Walsh3, R. Komaki4, Z. Liao4, D. C. Rice3, A. A. Vaporciyan3, D. M. Maru5, J. H. Lee6, M. S. Bhutani6, A. Eid1, J. C. Yao1, A. P. Phan1, A. Halpin1, A. Suzuki1, T. Taketa1, P. F. Thall2 & S. G. Swisher3 Departments of 1Gastrointestinal Medical Oncology; 2Biostatistics; 3Thoracic and Cardiovascular Surgery; 4Radiation Oncology; 5Pathology; 6Gastroenterology, Hepatology and Nutrition, University of Texas M. D. Anderson Cancer Center, Houston, USA
Received 13 March 2013; revised 10 May 2013 & 17 June 2013; accepted 9 July 2013
Background: The contribution of induction chemotherapy (IC) before preoperative chemoradiation for esophageal cancer (EC) is not known. We hypothesized that IC would increase the rate of pathologic complete response ( pathCR). Methods: Trimodality-eligibile patients were randomized to receive no IC (Arm A) or IC (oxaliplatin/FU; Arm B) before oxaliplatin/FU/radiation. Surgery was attempted ∼5–6 weeks after chemoradiation. The pathCR rate, post-surgery 30-day mortality, overall survival (OS), and toxic effects were assessed. Bayesian methods and Fisher’s exact test were used. Results: One hundred twenty-six patients were randomized dynamically to balance the two arms for histology, baseline stage, gender, race, and age. Fifty-five patients in Arm A and 54 in Arm B underwent surgery. The median actuarial OS *Correspondence to: Dr Jaffer A. Ajani, Department of GI Medical Oncology, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030 USA. Tel: +1-713-792-2828; Fax: +1-713-745-1163; E-mail:
[email protected]
© The Author 2013. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email:
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original articles
Annals of Oncology
for all patients (54 deaths) was 45.62 months [95% confidence interval (CI), 27.63–NA], with median OS 45.62 months (95% CI 25.56–NA) in Arm A and 43.68 months (95% CI 27.63–NA) in Arm B (P = 0.69). The pathCR rate in Arm A was 13% (7 of 55) and 26% (14 of 54) in Arm B (two-sided Fisher’s exact test, P = 0.094). Safety was similar in both arms. Conclusions: These data suggest that IC produces non-significant increase in the pathCR rate and does not prolong OS. Further development of IC before chemoradiation may not be beneficial. Clinical trial no.: NCT 00525915 (www.clinicaltrials.gov). Key words: esophageal carcinoma, induction chemotherapy, chemoradiation, randomized trial, pathologic complete response, esophageal preservation
introduction
patient population
Esophageal cancer is a local-regional disease in ∼50% of newly diagnosed patients in the United States. If a patient can withstand surgery, then localized esophageal cancer (LEC) in North America is most frequently treated with chemoradiation followed by surgery [1, 2]. However, even after trimodality therapy, patient outcomes remain poor. It is known that ∼20% of patients’ tumors are highly sensitive to chemoradiation and, in these patients; no residual cancer cells can be identified in the surgical specimen ( pathologic complete response, pathCR) [3–6]. Some reports also suggest that the achievement of pathCR can be associated with better survival outcome [3–6]. Therefore, achievement of pathCR may be desirable. Moreover, if one could increase the rate of pathCR, it could spur esophageal preservation strategies. We hypothesized that induction chemotherapy before chemoradiation would increase the pathCR rate, and in turn this might yield a survival benefit. The efficacy of systemic therapy in patients with LEC has been debated. Two major randomized trials investigating systemic therapy before surgery have produced opposite results and recommendations, [7, 8] but the contribution of preoperative chemotherapy to LEC patients’ outcomes has been modest at best. In one trial of patients with LEC, preoperative chemotherapy was compared with preoperative chemoradiation in a randomized fashion and, although the trial was terminated prematurely, chemoradiation appeared to have a nonsignificantly higher efficacy than chemotherapy [9]. Our group developed the strategy of induction chemotherapy before chemoradiation [10] and the current trial represents further development of this strategy. The addition of induction chemotherapy to preoperative chemoradiation in a randomized trial has not been reported. Here, we report a randomized phase II trial to compare induction chemotherapy followed by preoperative chemoradiation versus preoperative chemoradiation in trimodality-eligible patients with LEC. The primary end point was pathCR. The chemotherapy regimen used was specifically developed because of considerable interest in oxaliplatin at the time of conception.
The study was conducted at the University of Texas M. D. Anderson Cancer Center between 2005 and 2011. Patients with local-regional thoracic esophageal or gastroesophageal junction carcinoma (histologic documentation of adenocarcinoma or squamous cell carcinoma) who could physiologically withstand surgery were eligible for the trial. Patients had to have adequate organ function, performance status of 0–1, chronological age
