The baseline characteristics of the patient groups are provided in . P-values are provided to indicate where patient characteristics may differ between treatment groups. It was anticipated that there would be some differences between the patients enrolled in brachytherapy protocols and patients enrolled in nonbrachytherapy protocols, and this was confirmed. KPS tended to be higher, the extent of resection tended to be greater, and fewer patients had a frontal tumor site in the brachytherapy studies. Among those in nonbrachytherapy trials, patients in chemotherapy trials tended to be younger and to have more extensive resections, and fewer had frontal lobe–only tumors than for the protocols with no chemotherapy. In interpreting the results, it must be kept in mind that because the number of patients in the brachytherapy trials was smaller, the P-values would be higher than for the nonbrachytherapy comparisons, even if the difference between chemotherapy and nonchemotherapy studies was the same. While the differences between chemotherapy and nonchemotherapy trials in terms of age and tumor site were statistically significant for the nonbrachytherapy studies and not significant for the brachytherapy studies, the pattern of the differences seems to be the same. For example, in both cases, nonchemotherapy trials tended to include proportionately more patients over the age of 65. On the other hand, the patients in the nonchemotherapy trials that included brachytherapy were more likely to have had extensive resections, the opposite from the non-brachytherapy trials. All variables presented in were considered potential predictors of survival. Age at diagnosis was initially considered as a continuous variable and then categorized for the purposes of the RPAs as described below.
Baseline characteristics of patient groups
Predictors of Survival (Overall Analysis)
Cox proportional hazards results are presented in . Only variables statistically significant at P < 0.01 are presented. Younger age at diagnosis, higher KPS, adjuvant chemotherapy, use of brachytherapy, and greater extent of resection all predicted for improved survival. Because of missing data on one or more of the predictors, only 776 patients were included in this analysis.
Multivariate Cox proportional hazards results. All protocols (776 patients)
The results of the RPA are presented in . Eight hundred thirty-two patients were included in this analysis. Initially, when we used age at diagnosis as a continuous variable, the patients were split by a diagnosis age of 41.6 and then divided on the basis of the ages of 65.9 and 29.6. Based on these splits, we created an ordered age category that was age <30, age 30 to 40 inclusive, age 40 to 50, age 50 to 60, age 60 to 65, and age ≥65, adding extra categories to more evenly balance the number of patients per category. With these categories, both the ≤40 and ≥65 age categories were retained. The under 30 category was no longer selected. One reason may have been that there were only 31 patients in this category. Since it was felt that the use of the categories was more logical, and the results were similar, all RPAs presented are based on this age categorization.
Fig. 1 Recursive partitioning analysis for all patients (N = 832). For terminal nodes (□), median survival and the 95% confidence interval for the median are given. N = number of patients. Estimates with an asterisk (*) exclude 40 patients missing KPS (more ...)
As would have been predicted from the proportional hazards model, age at diagnosis, KPS, and extent of surgery were among the factors selected to divide the patient population. The group of youngest patients (age ≤40) had the best outcome. Interestingly, within this relatively small group, a further split occurred into those who had frontal-only tumors versus all others. Five hundred forty patients were between the ages of 40 and 65. For the patients in this group, KPS of ≤70 indicated a poorer prognosis, and among those with KPS >70, biopsy-only indicated a poorer prognosis. The outcomes for these 2 groups were similar to those for the group of patients who were ≥65 years old. Thus 4 groups were ultimately defined, and the Kaplan-Meier curves for these 4 groups are provided in . The median survival and 95% CI were 132 weeks (110–226), 71 weeks (60–97), 63 weeks (58–69), and 37 weeks (32–42) for the low-risk, low-moderate-risk, moderate-high-risk, and high-risk groups, respectively. The estimated 2-year survival rates were 65%, 35%, 17%, and 4%, respectively. These results are summarized in .
Fig. 2 Survival for all patients, by risk group. Fourteen patients in group 1, 12 patients in group 2, and 9 patients in group 3 lived beyond 5 years (260 weeks). Individual survival times (including those for patients who are censored) are indicated by a solid (more ...)
Risk-group splits, results of RPA analysis including all protocols
Impact of Postoperative Therapy
It is of note that the nature of the planned postoperative treatment did not appear in the RPA, even though both chemotherapy and brachytherapy were highly statistically significant in the Cox proportional hazards model where adjustments were made for patient characteristics. We therefore divided the patients on the basis of the protocols to see if we could more fully understand the impact of the planned treatment regimens.
Initially we considered the 660 patients who were on nonbrachytherapy trials. The proportional hazards results are presented in . Age at diagnosis, chemotherapy, extent of resection, and KPS continued to be highly statistically significant. The hazard ratio estimates were similar to those for the overall analysis, which is not surprising given that this group constitutes the majority of the cases.
Multivariate Cox proportional hazards results. Nonbrachytherapy protocols (618 patients)
The RPA analysis was also similar (). Comparison of and reveals that the only difference is the split criterion for good-KPS patients between ages 40 and 65. Whereas previously the split for this group was based on extent of resection, in this analysis it was based on whether or not the protocol included chemotherapy. On review of the overall RPA analysis, we found that if one more split had been included, it would have been for this group (middle age, good KPS), excluding the biopsy-only patients, and would have been based on whether or not the patients received chemotherapy. Therefore, the results of the 2 analyses are not inconsistent.
Fig. 3 Recursive partitioning analysis for all patients on non-brachytherapy protocols (n = 660). For terminal nodes (□), median survival and the 95% confidence interval for the median are given. N = number of patients. *Twenty-eight patients without (more ...)
It seemed unlikely that the inclusion of adjuvant chemotherapy would impact the outcome for patients between the ages of 40 and 65 and not be of benefit for those younger than 40. On further exploration of the regression tree algorithm, it was found that chemotherapy was a very close competitor for anatomic site as a split for the younger patients within the group of patients on nonbrachytherapy trials. In fact, if the 111 patients under 40 were split according to chemotherapy protocol (Y/N), median survival was 60 weeks (CI, 37–76) and 110 weeks (CI, 86–141) for nonchemotherapy protocols and chemotherapy protocols, respectively. This is in contrast to the patients over 65, where the median survival was 32 weeks for both chemotherapy protocols and nonchemotherapy protocols.
One major purpose of this analysis was to identify stratification variables for planning future studies. For this purpose, it was useful to consider only patients on trials including adjuvant chemotherapy. This also provided a group of patients who could be considered to have been on equivalent postoperative therapy. is the result of this analysis of 437 patients on non-brachytherapy trials who received adjuvant chemotherapy. The resulting tree cut points are similar to the overall tree, although the estimated median survival is slightly better for those groups that previously included some patients who were not on adjuvant chemotherapy protocols. With the smaller number of patients, the split on anatomical site in the younger patient group no longer met the criterion of P < 0.01 based on the log-rank test. However, it did meet the other RPA criteria and is included in the figures for comparison purposes. The resulting survival curves with this split are presented in , and the summary survival estimates are provided in .
Fig. 4 Recursive partitioning analysis for all patients on non-brachytherapy protocols that included adjuvant chemotherapy (n = 437). For terminal nodes (□), median survival and the 95% confidence interval for the median are given. N = number of patients. (more ...)
Fig. 5 Survival for patients on nonbrachytherapy protocols that included adjuvant chemotherapy. Nine patients in group 1, 6 patients in group 2, and 7 patients in group 3 survived beyond 5 years (260 weeks). Individual survival times (including those for patients (more ...)
Risk-group splits, results of RPA analysis including nonbrachytherapy protocols with adjuvant chemotherapy
Initially, we analyzed the data using the Cox proportional hazards model with the variables identified in the overall Cox proportional hazards model (). Again, KPS and age at diagnosis were clearly important. The importance of chemotherapy and extent of surgery was less clear. While some increase in P-value would be expected because of the smaller sample size, the hazard ratio estimates give no indication of benefit from increased resection or addition of adjuvant chemotherapy in the setting of brachytherapy.
Multivariate Cox proportional hazards model. Brachytherapy protocols (158 patients)
The number of patients on brachytherapy trials was too small to complete an independent RPA. However, we did assign patients from these protocols to groups based on the risk assignments from the overall RPA analysis to confirm that the results were consistent. provides the Kaplan-Meier curves that resulted for all patients on these trials, and includes only those on chemotherapy trials. On the basis of , it would appear that the strata selected provide a meaningful grouping of patients in this new data set, although the number in the lowest risk group is small. The similarity in the curves comparing outcome in all patients and in the chemotherapy-only group is consistent with the assessment that chemotherapy has a smaller role to play when brachytherapy is given.
Fig. 6 Survival for all patients on brachytherapy protocols (n = 160). Risk groups are as defined in for all patients. Three patients in group 1 and 5 patients in group 2 lived beyond 5 years (260 weeks). Individual survival times (including those for (more ...)
Fig. 7 Survival for patients on brachytherapy protocols that included adjuvant chemotherapy (n = 49). Risk groups are as defined for all patients in . Two patients in group 1 and 2 patients in group 2 lived beyond 5 years (260 weeks). Individual survival (more ...)
Anatomic Site as a Predictor in Younger Patients
The finding that age, KPS, and adjuvant chemotherapy predicted survival was expected. The finding of the anatomic site of tumor as a predictor was not. We therefore evaluated this further using Cox proportional hazards models. When analyses included all ages, there was some trend toward improved survival among those with frontal-only tumors, but the results were never statistically significant at the 0.05 level. However, when the patient group was limited to those ≤40 years old at the time of diagnosis, the results were statistically significant. The results of this analysis for all patients ≤40 are provided in . Initially, we hypothesized that tumor site might be a surrogate for extent of resection. However, the Cox proportional hazards model indicates that the association with location is much stronger than any association with extent of resection. On review of the data, few of these younger patients had biopsy only (11% of cases), and 73% of those with frontal tumors had a subtotal resection compared to between 68% and 73% in the remaining three groups. Thus, the lack of association with extent of resection is likely due to the high proportion of patients with subtotal resections, limiting the ability to detect impact of resection, and the association of frontal-only tumors compared with other locations remains to be confirmed and explained with further studies.
Multivariate Cox proportional hazards model including anatomic site and other variables as predictors. Patient age ≤ 40 (124 patients)