Chemotherapy plus Radiotherapy Compared with Radiotherapy Alone in the Treatment of Locally Advanced, Unresectable, Non-Small-Cell Lung Cancer

Lung cancer is common and difficult to treat. By the end of 1996, approximately 177 000 persons will have received a diagnosis of lung cancer and 159 000 will die of it, making it the leading cause of cancer-related death in the United States [1]. Most persons will have non-small-cell lung cancer, which includes squamous-cell carcinoma, adenocarcinoma, and large-cell carcinoma. Three fourths of these cancers are unresectable at the time of presentation because the disease is metastatic (stage IV) or locally advanced (stage III) [2]. Although thoracic radiotherapy is generally considered standard therapy for stage III disease, it has a limited effect on survival [3]. Most patients develop distant metastatic cancer and eventually die as a result. The addition of chemotherapy to radiotherapy might improve the outcome for these patients [4]. Chemotherapy may reduce local tumor burden, thereby improving local control. More important, chemotherapy may also eliminate or delay the emergence of metastatic disease. In an attempt to verify these hypotheses, several randomized studies of radiotherapy alone compared with chemotherapy and radiotherapy in combination have been done [5-18]. Unfortunately, the results of these studies are conflicting; consequently, it is unknown whether the addition of chemotherapy to radiotherapy improves survival in patients with locally advanced, unresectable, non-small-cell lung cancer. This lack of knowledge concerns not only whether chemotherapy provides additional benefit but also whether any benefit is substantial enough to offset the side effects of therapy. To better estimate the magnitude of the treatment effect, we did a meta-analysis of randomized trials of combination therapy and radiotherapy alone in patients with locally advanced, unresectable, non-small-cell lung cancer. Methods Overview Our primary intent was to ascertain whether the addition of chemotherapy to radiotherapy improved survival in patients with locally advanced, unresectable (stage III), non-small-cell lung cancer. However, because randomized trials in this group of patients have used different drugs in different sequences with radiotherapy, other relevant questions about the value of chemotherapy also emerge. The questions addressed in this analysis are listed in Table 1. Table 1. Questions in the Evaluation of the Efficacy of Radiotherapy Alone or with Chemotherapy in Locally Advanced, Unresectable, Non-Small-Cell Lung Cancer Literature Search Randomized, clinical trials that compared chemotherapy plus radiotherapy with radiotherapy alone for patients with locally advanced, unresectable, non-small-cell lung cancer were identified in a MEDLINE search of English-language articles published between January 1987 and June 1995 and in a manual review of the references of potentially relevant articles. Eligible articles included an actuarial survival curve or a life table and reported survival for at least 2 years. Articles were excluded from analysis if the trials were reported only in abstract form or were preliminary publications for which more mature data were subsequently published. Data Extraction From the reported survival curves in the eligible articles, we took the number of patients randomly assigned to each treatment group and their probability of survival at 6, 12, 18, 24, 30, and 36 months. Explicit information on censoring was obtained if available. If this information was not available, we assumed that no censoring had occurred. This assumption does not introduce substantial bias in the point estimate of the treatment effect if the pattern of censoring was similar in both treatment groups. However, it may result in unduly narrow CIs caused by underestimation of the variance. From the data extracted from eligible articles, we determined the number of deaths and the number of patients at risk at 6-month intervals. Statistical Analysis The goal was to calculate a pooled relative risk for death at 1, 2, and 3 years in the group that received combined therapy compared with the risks in the group that received radiotherapy. We used the two-step method reported by Grilli and colleagues [19]. First, a summary relative risk for death at 1, 2, and 3 years was calculated according to the Mantel-Haenszel technique [20] on the basis of the estimated number of deaths at 6-month intervals and the number of patients at risk during each interval. Thus, the 1-year summary relative risk for death was derived from the number of deaths and patients at risk at 6 and 12 months; the 2-year summary relative risk from the number of deaths and patients at risk at 6, 12, 18, and 24 months; and the 3-year summary relative risk from the number of deaths and patients at risk at 6, 12, 18, 24, 30, and 36 months. The variance of the logarithm of the summary relative risk was estimated by the method of Greenland and Robbins [21], and the 95% CIs shown in Figure 1 were calculated. Figure 1. Chemotherapy plus radiotherapy compared with radiotherapy alone for the treatment of locally advanced, unresectable, non-small-cell lung cancer. Second, a directly pooled estimate of the effect of chemotherapy at 1, 2, and 3 years was calculated by taking a weighted average of the study-specific summary relative risks. The inverse of the logarithms of the study-specific variances was used as weights [20] so that trials with the most stable estimates of the effect of chemotherapy (generally those with larger sample sizes) were more influential. To construct approximate 95% CIs, an estimate of the variance of the pooled effect was calculated as the similarly weighted average of the study-specific variances [20]. For all comparisons, combined therapy was compared with radiotherapy. Thus, a relative risk less than 1 indicates a beneficial effect of chemotherapy, and a relative risk greater than 1 indicates a harmful effect of chemotherapy. A chi-square test of homogeneity for each pooled effect was calculated as described elsewhere [20]. A summary actuarial curve of survival was calculated by pooling the relative risk for death from every study for each 6-month interval between 0 and 36 months. To accomplish this, we adopted a generalized linear statistical model that was similar to the one used in the meta-analysis of chemotherapy for metastatic lung cancer by Grilli and colleagues [19]. The information taken from the studies can be viewed as discrete survival data with censoring and failures occurring during one of six periods: 0 to 6 months, 7 to 12 months, 13 to 18 months, 19 to 24 months, 25 to 30 months, or 31 to 36 months. This generalized linear model was used to estimate the hazard in each time period and was calculated in STATA (College Station, Texas) using the complementary log-log link and a binomial error distribution with the number of trials equal to the number at risk at the beginning of the interval. The resulting hazard is interpreted as the probability of death at some time in that interval, with the condition of being alive at the start of the interval. The dependent variable was the number of deaths in each period, and the covariates included categorical variables for the time frame, treatment, and study. To test whether the effect of chemotherapy was proportional in each 6-month interval, an interaction term between the time frame and treatment was included in the model. The relative risk for death during treatment in each interval shown in Figure 2 was then approximated by the ratio of the estimated hazards. Finally, the hazards were used to estimate the interval-specific probability of surviving time interval t (pt). The cumulative probability for surviving time interval t (St) was then calculated as the product of the interval-specific survival probabilities: St = ptpt-1p2p1 (Figure 3). Figure 2. Pooled relative risk for death in locally advanced, unresectable, non-small-cell lung cancer and 95% CI for each 6-month period. Figure 3. Cumulative survival probabilities in patients with locally advanced, unresectable, non-small-cell lung cancer treated with chemotherapy plus radiotherapy (solid line) and radiotherapy alone (dashed line). To aid description and interpretation of the overall result, we also estimated a measure of the absolute benefit of the addition of chemotherapy to radiotherapy. First, the mean gain in life expectancy seen with chemotherapy at the end of 3 years was taken as the area between the cumulative survival curves (as calculated above). Second, the weighted average of median survival was calculated by assigning each study a weight equal to its total sample size. Results Literature Search Seventeen randomized trials published between January 1987 and June 1995 that compared radiotherapy alone with combined chemotherapy and radiotherapy in patients with locally advanced, unresectable, non-small-cell lung cancer were identified for possible review. Three were considered ineligible for further review: Two were reported in abstract form only [22, 23], and one included weekly chemotherapy in the group receiving radiotherapy [24]. Fourteen trials [5-18] were thus eligible for this meta-analysis. These 14 trials are listed in Table 2 with treatment specification, trial size, and median length of survival. Chemotherapy was administered concurrently with radiotherapy in 6 trials [7, 9, 10, 13, 15, 17]; all but 1 of these [17] included cisplatin as part of the chemotherapy. In the remaining 8 trials, patients received chemotherapy before [5, 8, 11, 12, 14], after [16], or before and after [6, 18] radiotherapy. Cisplatin was used in 5 of these 8 trials. Table 2. Randomized Trials Comparing Chemotherapy plus Radiotherapy with Radiotherapy Alone in Locally Advanced, Unresectable, Non-Small-Cell Lung Cancer* Comparative Analyses The answers to the question What is the relative efficacy of chemotherapy plus radiotherapy compared with radiotherapy alone? are presented graphically in Figure 1. All 14 trials were eligible fo