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Journal of Clinical Oncology, Vol 25, No 4 (February 1), 2007: pp. 460-461 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.09.4771
In ReplyWake Forest University, School of Medicine, Winston-Salem, NC
Yale University, New Haven, CT
Yale University School of Medicine, New Haven, CT
Robert Wood Johnson Medical School, Piscataway, NJ
Yale University School of Medicine, New Haven, CT
Yale University School of Medicine, New Haven, CT We read with great interest the letter from Drs Turrisi and Keller. We do agree with their conclusion, that a prospective randomized postoperative radiotherapy (PORT) trial for patients with non–small-cell lung cancer (NSCLC) needs to be performed and such will likely require an international effort. We appreciate that they provided the design of such a trial. While the prognostic capability of ERCC1 (Excision Repair Cross-Complementation Group 1) is both interesting and promising it still needs to be validated in a prospective manner, similar to a validation for PORT which Drs Turrisi and Keller propose. The retrospective evaluation of ERCC1 positivity in the International Adjuvant Lung Cancer Trial1 (IALT) was based on an arbitrary threshold. Results of other biologic markers have proven to be difficult due to conflicting data—stemming in part from variations in the assays used as well as the definitions of positive or negative results. The IALT2 was a large prospective trial examining the impact of adjuvant cisplatin-based chemotherapy for patients with stage I-III NSCLC. The results of the trial showed an approximately 5% survival benefit at 5 years with the use of adjuvant chemotherapy. On subgroup analysis, it does appear that this benefit was seen predominately in the N2 population. Furthermore, the survival benefit from cisplatin was seen only in ERCC1-negative tumors in a recent analysis1 involving 83% of the patients who participated in IALT. This is plausible because ERCC1 is involved in nucleotide excision repair and high ERCC1 levels have been associated with resistance to cisplatin. However, many factors may confound these results. In the IALT, the results presented also suggest that the survival benefit seen originated within the patients who presented with more advanced disease. In the IALT trial, PORT was planned for 30.6% of patients (1.9% with pathologic stage N0 disease; 33.7% with pathologic stage N1; and 64.3% with pathologic stage N2). A descriptive analysis of the radiotherapy results has not been presented; thus the impact of PORT on the results cannot be evaluated. Still, it is plausible that low levels of ERCC1 (with its involvement in DNA repair) may also be a marker for radiosensitivity; although we acknowledge that this is very speculative given that mutated nucleotide excision repair genes do not confer radiation hypersensitivity. The Adjuvant Navelbine International Trialist Association trial3 was another large trial designed similarly to IALT. A descriptive analysis of the radiation therapy (predetermined by treatment center) was presented at the 2006 American Society of Therapeutic Radiology and Oncology meeting (Philadelphia, PA; November 5-9, 2006). For patients with N2 involvement, chemoradiotherapy was superior to chemotherapy alone. For patients with N1 involvement, the opposite was true. The results were similar to those in our analysis,4 and suggest that PORT may have a significant effect on outcomes in N2 patients. This provides an impetus to develop a phase III trial to evaluate PORT. An expert opinion in thoracic radiotherapy has recently stated that an adequately powered prospective clinical trial investigating PORT would require a sample size on the order of 1,500 patients.5 Radiotherapy dose and treatment planning must be standardized with proper centralized quality assurance of the radiation technique utilized. Serial pulmonary function testing and cardiac evaluation would be needed to ensure that PORT is not increasing toxicity. In short, performing such a PORT trial for N2 patients is no easy task. Such may be beyond the capabilities of the United States cooperative groups and, as Drs Turrisi and Keller wisely point out, require an international effort. A European Intergroup trial, the Lung Adjuvant Radiotherapy Trial (Lung ART), is about to be launched; patients with N2 nodal involvement will be randomly assigned to PORT or no PORT after resection. This trial is not powered to detect an overall survival benefit, but instead, a disease-free survival benefit; thus the accrual goal is only 700 patients. In personal communications with the principal investigator of Lung ART (personal communication, C. Le Pechoux, October 2006), it is hoped that a similar trial will take place in the United States and a joint European-United States analysis will be possible. When the two trials are combined, an overall survival end point could be analyzed. We think it is premature to use ERCC1 analysis to select for patients to participate in a PORT trial. This is because the data for ERCC1 is only retrospective, there are potential confounding factors, and potential difficulties in developing a reproducible assay. This does emphasize that any future prospective PORT trial, which fails to include preplanned correlative studies is flawed. The Cancer and Leukemia Group B (CALGB) initiated a prospective registry to evaluate ERCC1 at both protein and genomic levels along with other promising NSCLC prognostic factors. Until the results are available, an acceptable alternative might be to stratify by ERCC1 status. The option also exists of offering ERCC1-positive tumors noncisplatin-based chemotherapy. In conclusion, we agree with Drs Turrisi and Keller that a prospective adjuvant chemoradiation therapy trial is needed. This trial needs to be properly designed with acceptable end points and adequate power. Radiotherapy dose and treatment planning must be standardized with proper centralized quality assurance of radiation technique. Preplanned prospective correlative studies are also essential. Failure to do such will not only result in more controversy, but also fail to improve the standard of care for patients with lung cancer after surgery. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The authors indicated no potential conflicts of interest. REFERENCES
1. Olaussen KA, Dunant A, Fouret P, et al: DNA repair by ERCC1 in non-small-cell lung cancer and cisplatin-based adjuvant chemotherapy. N Engl J Med 355:983-991, 2006 2. Arriagada R, Bergman B, Dunant A, et al: Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med 350:351-360, 2004 3. Douillard JY, Rosell R, De LM, et al: Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): A randomised controlled trial. Lancet Oncol 7:719-727, 2006[CrossRef][Medline] 4. Lally BE, Zelterman D, Colasanto JM, et al: Postoperative radiotherapy for stage II or III non-small-cell lung cancer using the Surveillance, Epidemiology, and End Results database. J Clin Oncol 24:2998-3006, 2006 5. Wagner H Jr: Thoracic irradiation for patients with resected non-small cell lung cancer: Adjuvant or salvage? Cancer J 12:253-256, 2006[Medline]
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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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