Docetaxel as Second-Line Chemotherapy for Non–Small-Cell Lung Cancer
Authors: Fausto Roila, Albano Del Favero, Enzo Ballatori, Frances A. Shepherd, Luz Hammershaimb, Yong S. Kim
Journal: Journal of Clinical Oncology (2000)

Article Tools SPECIAL DEPARTMENTS Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.2000.18.21.3738 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 11054450 Docetaxel as Second-Line Chemotherapy for Non–Small-Cell Lung Cancer Fausto RoilaxFausto RoilaSearch for articles by this author , Albano Del FaveroxAlbano Del FaveroSearch for articles by this author , Enzo BallatorixEnzo BallatoriSearch for articles by this author Frances A. ShepherdxFrances A. ShepherdSearch for articles by this author , Luz HammershaimbxLuz HammershaimbSearch for articles by this author , Yong S. KimxYong S. KimSearch for articles by this author Show More Policlinico Hospital Perugia, ItalyInstitute of Internal Medicine and Oncological Sciences, University Perugia, ItalyUniversity of L’Aquila L’Aquila, ItalyUniversity of Toronto Toronto, Ontario, CanadaAventis Pharmaceuticals Inc Collegeville, PAAventis Pharmaceuticals Inc Bridgewater, NJ https://doi.org/10.1200/JCO.2000.18.21.3738 First Page Full Text PDF Figures and Tables © 2000 by American Society of Clinical OncologyjcoJ Clin OncolJournal of Clinical OncologyJCO0732-183X1527-7755American Society of Clinical OncologyResponse01112000In Reply:Drs Roila, Del Favero, and Ballatori have raised several questions concerning the results of the TAX 317 trial of docetaxel versus best supportive care for the treatment of patients with non–small-cell lung cancer (NSCLC) previously treated with cisplatin-based chemotherapy.1 They first questioned whether there might have been patient selection bias in the participating centers because 35 centers were required to accrue 204 patients over a 4-year period. I think that the difficulty with accrual was largely due to the design of the study, which included a best supportive care (BSC) arm in the trial, rather than selection bias. In the United States, where the trial opened initially, neither patients nor physicians were willing to participate in a study in which there was a 50% chance of not receiving chemotherapy. This resulted in very slow accrual and the need to expand the trial to Canadian and European centers. This explanation is supported by the observation that the TAX 320 trial,2 in which docetaxel at doses of 75 mg/m2 and 100 mg/m2 was compared with vinorelbine or ifosfamide without a BSC arm, opened after the TAX 317 study yet completed its accrual of over 360 patients more than a year before TAX 317 finished. Second, patients who had received paclitaxel treatment were excluded from our study, which further hampered accrual in the United States, where first-line paclitaxel and carboplatin therapy is the most frequently used regimen for NSCLC. This problem was circumvented once again by the addition of Canadian and European centers to the trial. Finally, it should be noted that 30% of the patients on the study came from the center of the principal investigator. In that center, all patients who met the eligibility criteria were approached to participate in the trial without any selection bias. The only patients who were not enrolled were those who refused to participate, and for the most part, those patients did not wish to have further chemotherapy.The sample size of 100 patients per group was estimated on the basis of a projected median survival of 4 months for BSC patients and 7 months for docetaxel-treated patients on the basis of the log-rank test with an alpha level of 5% (two-sided) and a power of 90% to compare the groups. In fact, at the time of the updated survival analysis, which was undertaken in October 1999, the survival of the 104 docetaxel-treated patients was exactly as projected (7 months), as was that of the BSC patients (4.6 months), and these differences were statistically significant (log-rank, P = .047). This was the primary analysis planned at the initiation of the trial. Because of the toxicity seen at the 100-mg docetaxel dose in the TAX 317 trial, it was thought that 75 mg/m2 would be a more appropriate dose in the setting of second-line treatment for NSCLC. For this reason, the study protocol was amended to reduce the dose of docetaxel from 100 to 75 mg/m2 at the midpoint of patient enrollment. Thus, two further unplanned analyses of the data were undertaken. First the survival of patients treated with docetaxel 75 mg/m2 was compared with that of the corresponding BSC patients from the second half of the trial, and a significant survival advantage was seen for the docetaxel-treated patients, despite the small number of patients in this analysis (log-rank, P = .010). Second, the impact of docetaxel 75 mg/m2 treatment was assessed along with other important prognostic variables using Cox modeling, and once again, treatment with docetaxel 75 mg/m2 was found to have a significant impact on survival (hazards ratio, 0.484; P = .004). We agree that a sample size of 104 patients would ordinarily be inadequate to determine that docetaxel is superior to BSC in this patient population. However, the power of the test becomes irrelevant once a significant difference is observed: The observed median survivals of 9 months and 4.6 months for docetaxel and BSC, respectively, are greater than the initially predicted 7 months and 4 months, on which the initial sample size estimation was based. Furthermore, the findings of TAX 317 are confirmed by similar results in the TAX 320 trial. In that study, patients treated with docetaxel 75 mg/m2 had a 1-year survival rate (32%) that was similar to that of the TAX 317 trial and significantly better than that for treatment with either vinorelbine or ifosfamide (χ2, P = .025). Given the data from the two trials, we believe that our conclusion that docetaxel 75 mg/m2 is safe and effective second-line treatment for NSCLC is indeed valid.The reviewers have suggested that BSC should have been standardized, but they do not state how this might be done. We believe that it would be absolutely impossible to do this in view of the variability of symptoms that might develop in patients with progressive NSCLC. Radiation would be offered for painful bone metastases or brain metastases, whereas pleural drainage with possible sclerosing procedures would be offered to patients with increasing effusion. These are a few examples of the protean nature of this malignancy, and they serve to point out the difficulties that would be encountered if one tried to standardize BSC in a protocol. Furthermore, we do not even believe that it would be ethical to prohibit third-line chemotherapy. We would like to emphasize, however, that only nine of the 104 patients in the second half of the TAX 317 trial received off-protocol chemotherapy at the time of disease progression. The difference in survival remained significant even when these patients were included in the survival analysis (log-rank, P = .037).The reviewers also suggest that the benefits seen in quality of life may have been due to corticosteroid therapy. Patients in the docetaxel arm received dexamethasone for only 2.5 days of the 21-day cycle, and most of the quality-of-life assessments were completed after two oral doses at most of the total five (or eight before the amendment) dexamethasone doses. We believe that it is unlikely that this brief time on corticosteroids would have had a significant or lasting effect on global quality of life. Similarly, we do not think that it could affect the total need for pain medications throughout the entire cycle or reduce the need for palliative radiotherapy. We would like to point out that all dimensions of quality of life were not better in the chemotherapy group, as many remained the same or were equal on both arms of the study. A full report of quality-of-life assessment in the two second-line trials is planned.The reviewers recommend another trial of second-line therapy with standardization of a BSC arm. We doubt that it will be possible to mount such a trial. We have discussed the difficulties of recruiting to our trial and of defining BSC above. However, the main reason that another BSC trial is unlikely to be conducted lies in the extreme difficulty of performing such a study. We believe that the time for BSC trials has now passed and that in view of the positive results of the TAX 317 and 320 trials, investigators would question the ethics of a no-chemotherapy arm for patients with a good performance status. Docetaxel 75 mg/m2 should now be considered the gold standard for the second-line treatment of NSCLC, and new treatments or treatment strategies should be compared with this standard.1. Shepherd FA, Dancey J, Ramlau R, et al: Prospective randomized trial of docetaxel versus best supportive care in patients with non–small-cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol 18:: 2095,2000-2013, Link, Google Scholar2. Fossella FV, DeVore R, Kerr RN, et al: Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non–small-cell lung cancer previously treated with platinum-containing chemotherapy regimens. J Clin Oncol 18:: 2354,2000-2362, Link, Google Scholar