Correspondence
Adjuvant Chemotherapy for Completely Resected Non–Small-Cell Lung Cancer
N Engl J Med 2001; 344:689-690March 1, 2001
- Article
To the Editor:
In a randomized trial, three quantities related to sample size must be defined so as to ensure small enough error rates to make the conclusions credible: the significance level (α), the power of a test for a particular alternative hypothesis (1–β), and the difference one wishes to detect (δ). Since only the P value (α) is specified in the study by Keller et al. on adjuvant chemotherapy for completely resected non–small-cell lung cancer (Oct. 26 issue),1 the negative results could be due to the use of a sample that was insufficiently large to show benefit.
Keller et al. state that newer agents with substantial activity against non–small-cell lung cancer appear to offer no survival advantage, but we disagree. There is evidence of improved survival or increased time to progression among patients with advanced non–small-cell lung cancer who are treated with a combination of paclitaxel and cisplatin,2 a combination of cisplatin and gemcitabine,3 or with a regimen of three drugs (cisplatin and mitomycin with either vindesine or ifosfamide),4 as compared with those treated with the older regimen of cisplatin and etoposide. Furthermore, the conference abstract5 cited by Keller et al. does not show a comparison of survival according to study group and has not yet been published in a peer-reviewed medical journal.
5 ReferencesJavier Cortes, M.D.
Javier Rodriguez, M.D.
Emiliano Calvo, M.D.
Clínica Universitaria de Navarra, 31008 Pamplona, Spain1
Keller SM ,Adak S ,Wagner H , et al. A randomized trial of postoperative adjuvant therapy in patients with completely resected stage II or IIIa non-small-cell lung cancer. N Engl J Med 2000;343:1217-1222
Full Text | Web of Science | Medline2
Bonomi P ,Kim K ,Fairclough D , et al. Comparison of survival and quality of life in advanced non-small-cell lung cancer patients treated with two dose levels of paclitaxel combined with cisplatin versus etoposide with cisplatin: results of an Eastern Cooperative Oncology Group trial. J Clin Oncol 2000;18:623-631
Web of Science | Medline3
Cardenal F ,Lopez-Cabrerizo MP ,Anton A , et al. Randomized phase III study of gemcitabine-cisplatin versus etoposide-cisplatin in the treatment of locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol 1999;17:12-18
Web of Science | Medline4
Crino L ,Clerici M ,Figoli F , et al. Chemotherapy of advanced non-small-cell lung cancer: a comparison of three active regimens. Ann Oncol 1995;6:347-353
Web of Science | Medline5
Belani CP ,Natale RB ,Lee JS , et al. Randomized phase III trial comparing cisplatin/etoposide versus carboplatin/paclitaxel in advanced and metastatic non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 1998;17:455a-455a abstract.
To the Editor:
Keller et al. were unable to identify any survival advantage associated with postoperative chemotherapy in patients with completely resected stage II or III non–small-cell lung cancer. Although this was a well-designed phase 3 trial, the fact that a number of patients in the experimental group (those given chemotherapy and radiotherapy) did not receive adequate chemotherapy is an important limitation. Fourteen patients received no chemotherapy at all, and 160 patients “received all or part of the four cycles of chemotherapy.” How many received only part, and how much of each cycle did they receive? We need to know more precisely the amount of chemotherapy delivered to the 246 patients assigned to chemotherapy plus radiotherapy, including the percentage of the doses planned that were actually delivered to the patients who received “part” of one, two, three, or four cycles.
F. Anthony Greco, M.D.
Sarah Cannon Cancer Center, Nashville, TN 37203To the Editor:
Keller et al. provide no information about how they established recurrence of disease, an important outcome of interest in this prospective investigation. Were participants screened for recurrence of disease in a systematic manner, or were evaluations symptom-driven and carried out at the discretion of the treating clinicians? Was a new radiographic abnormality sufficient to establish a diagnosis of recurrent disease, or was histopathological proof required?
The investigators' data show a trend toward a lower incidence of distant recurrence of disease, excluding the central nervous system, among participants treated with a combination of chemotherapy and radiotherapy (19 percent), as compared with participants treated with radiotherapy alone (23 percent) (P=0.09). Systematic prospective surveillance for distant recurrence of disease might have reduced noise in the measurement of this outcome and might have yielded a more accurate assessment of potential differences in the efficacy of the treatments. A rigorously defined strategy for detecting recurrence of disease, which is typically used in prospective trials of cancer treatments,1-3 should have been delineated by the investigators.
3 ReferencesHidenobu Shigemitsu, M.D.
Ware G. Kuschner, M.D.
Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 943041
Mayer R ,Smolle-Juettner FM ,Szolar D , et al. Postoperative radiotherapy in radically resected non-small cell lung cancer. Chest 1997;112:954-959[Erratum, Chest 1998;113:564.]
CrossRef | Web of Science | Medline2
Ohta M ,Tsuchiya R ,Shimoyama M , et al. Adjuvant chemotherapy for completely resected stage III non-small-cell lung cancer: results of a randomized prospective study. J Thorac Cardiovasc Surg 1993;106:703-708
Web of Science | Medline3
Dautzenberg B ,Chastang C ,Arriagada R , et al. Adjuvant radiotherapy versus combined sequential chemotherapy followed by radiotherapy in the treatment of resected nonsmall cell lung carcinoma: a randomized trial of 267 patients. Cancer 1995;76:779-786
CrossRef | Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: Cortes et al. inquire about the trial's statistical power. The trial was designed to have 85 percent power to detect a 40 percent improvement in median survival with the use of a one-sided hypothesis test with a type I error of 5 percent. At a November 1998 meeting of the data-monitoring committee, when 71 percent of the information was available, the 90 percent repeated confidence interval for the hazard ratio, determined according to the method of Jennison and Turnbull,1 was 0.76 to 1.29, which did not include the target alternative of 1.4. A 90 percent confidence interval was used because of the one-sided type I error of 5 percent in the design. Although early stopping in favor of the null hypothesis was not part of the original design of the trial, the data monitoring committee elected to release the results because there was strong evidence that any improvement in median survival due to adjuvant chemotherapy would be less than 40 percent. Cortes et al. also suggest that the results might have been different if a different drug regimen had been used, and they cite studies that demonstrate a survival advantage with newer drug regimens in advanced disease. However, substantial improvements in the survival of patients with completely resected stage II or IIIa non–small-cell lung cancer are not consistently achieved with newer regimens.2,3 Furthermore, the limited prolongation of survival in patients with advanced disease may not apply to patients receiving adjuvant chemotherapy.4,5 A randomized trial is required to demonstrate such a survival benefit.
Greco raises an important point pertaining to the adequacy of chemotherapy. Of the 246 patients assigned to receive chemotherapy, 69 percent received all four planned cycles. Common reasons for receiving less than the planned treatment included refusal by the patient (16 percent), toxic effects (8 percent), and progression of disease (3 percent). These figures are consistent with those in similarly designed trials. Survival advantages have been reported in randomized trials using fewer cycles of chemotherapy only when treatment was given before surgery.6 This suggests that differences in the effectiveness of treatment depend on the timing of the administration of chemotherapy relative to surgical intervention, rather than on the number of cycles delivered.
Shigemitsu and Kuschner inquire about follow-up procedures. All patients were followed systematically with physical examinations, screening chemistry, chest radiography, and computed tomographic scanning (including the upper abdomen) every three months for two years. Patients then had follow-up visits every six months for two to five years and annually thereafter. Between scheduled visits, patients returned as needed if they had symptoms, and the assessment was performed by the treating physician. Histologic proof of recurrence was requested whenever it was feasible and safe. In other cases, the treating physician used clinical judgment.
6 ReferencesSteven M. Keller, M.D.
Montefiore Medical Center, Bronx, NY 10467David H. Johnson, M.D.
Vanderbilt–Ingram Cancer Center, Nashville, TN 372321
Jennison C ,Turnbull BW . Interim analyses: the repeated confidence interval approach. J R Stat Soc [B] 1989;51:305-3612
Giaccone G ,Splinter TA ,Debruyne C , et al. Randomized study of paclitaxel-cisplatin versus cisplatin-teniposide in patients with advanced non-small-cell lung cancer. J Clin Oncol 1998;16:2133-2141
Web of Science | Medline3
Gatzemeier U ,von Pawel J ,Gottfried M , et al. Phase III comparative study of high-dose cisplatin versus a combination of paclitaxel and cisplatin in patients with advanced non-small-cell lung cancer. J Clin Oncol 2000;18:3390-3399
Web of Science | Medline4
Rapp E ,Pater JL ,Willen A , et al. Chemotherapy can prolong survival in patients with advanced non-small-cell lung cancer: report of a Canadian multicenter randomized trial. J Clin Oncol 1988;6:633-641
Web of Science | Medline5
Ohta M ,Tsuchiya R ,Shimoyama M , et al. Adjuvant chemotherapy for completely resected stage III non-small-cell lung cancer: results of a randomized prospective study. J Thorac Cardiovasc Surg 1993;106:703-708
Web of Science | Medline6
Rosell R ,Gomez-Codina J ,Camps C , et al. A randomized trial comparing preoperative chemotherapy plus surgery with surgery alone in patients with non-small-cell lung cancer. N Engl J Med 1994;330:153-158
Full Text | Web of Science | Medline
