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Abstract & Commentary
Synopsis: During the past several decades, the Radiation Therapy Oncology Group (RTOG) has sponsored trials aimed at finding radiotherapy dose and fractionation schedules that improved median survival in brain metastases patients. Unfortunately, little progress was made. This study evaluated retrospective, pooled data from 10 institutions comparing overall survival in patients that received a stereotactic radiosurgery (SRS) boost to RTOG historical controls treated with whole brain radiotherapy (WBRT) alone. They concluded that a SRS boost confers a statistically significant improvement in OS across all 3 stratified groups tested.
Source: Sanghavi SN, et al. Int J Radiat Oncol Biol Phys. 2001;51:426-434.
There is a dearth of randomized data relat-ing to the effect of SRS on overall survival in patients with brain metastases. Although retrospective data do suggest a survival advantage, selection bias may be a confounding factor. While previous work, like the Patchell randomized study,1 has shown us that local resection of solitary metastases can improve survival when combined with WBRT, it is unclear whether SRS can offer an analogous benefit through a minimally invasive technique. Sanghavi and colleagues from 10 institutions set out to analyze their data on 973 SRS patients in order to determine whether median survival in SRS patients is extended beyond what is typically seen after palliative WBRT. After eliminating those patients who did not receive WBRT prior to SRS, did not receive a SRS boost to all visible residual lesions, did not have complete follow-up data, underwent resection of metastases, or were treated for salvage of recurrences in the brain, there were 502 evaluable patients.
In order to overcome problems analyzing their patient population with its diverse prognostic characteristics, Sanghavi et al borrowed the 3-tiered classification schema for patients with brain metastases previously published by Gaspar,2 and assigned all of their patients to the corresponding groups. This schema was derived using recursive partitioning. Class I patients were those with a Karnofsky Performance Score (KPS) > 70, < 65 years of age, with no active disease at the primary tumor site and no evidence of systemic metastases. Class III patients had a KPS < 70, and Class II patients represented everyone else. Then Sanghavi et al used the patients from the 3 previously published RTOG whole brain radiotherapy trials analyzed and sorted by Gaspar for comparison purposes. Those trials were conducted between 1976 and 1993.
The pooled SRS study patients could have any KPS, primary tumor histology, number of brain metastases, size of brain metastases, age, comorbidities, history of chemotherapy, and dose of WBRT and SRS. Both methods of SRS boosting, either with a gamma knife or linear accelerator, were acceptable. Median age for the entire group was 59 years (r = 26-83), and 52% were male. Median KPS was 80, and only 7% (n = 34) had a KPS < 70 (Class III). Fifty-six percent (n = 279) of patients had lung cancer metastatic to brain, 21% had malignant melanoma, 12% had breast cancer, and the remainder were unspecified. Sixty-four percent (n = 320) of patients had their primary tumors controlled, and 57% (n = 285) had systemic metastases. There were 112 patients in Class I (22%), 356 in Class II (71%), and 34 in Class III (7%). The median number of patients contributed per institution was 46 (r = 11-99). Three institutions administered SRS boosts with a gamma knife, 6 with a linear accelerator, and 1 with both. One hundred and seventy-seven patients were treated on a gamma knife, and 325 on a linear accelerator. Median follow-up for alive patients was 37 months (r = 2-133). The demographics between the SRS study group and the RTOG historical controls were similar, except for a higher median KPS in the current study.
Survival was measured from the first treatment day. Median overall survival (OS) for the entire group was 10.7 months. Median OS for Class I was 16.1 months, Class II = 10.3 months, and Class III = 8.7 months. Survival comparisons with the RTOG database were carried out for each prognostic class using variance estimates. Univariate and multivariate analyses yielded the same statistically significant independent prognostic factors: KPS, primary tumors that were controlled, and absence of systemic metastases (P < .002). After adjusting for prognostic class, no significant differences were found by treating institution, and no differences were found by method of SRS boost. For all 3 classes, SRS prolonged median survival compared with the RTOG controls, who received WBRT alone. The RTOG patients survived a median of 7.1 months for Class I, 4.2 months for Class II, and 2.3 months for Class III (P < .05).
Sanghavi et al concluded that their study showed promising findings that should be evaluated in a randomized trial. While there was a significant benefit seen in all 3 prognostic categories, the patients in the lowest category, KPS < 70, showed the most marked increase in OS. Given these results, and notwithstanding the lack of randomized data, Sanghavi et al recommended SRS as an excellent, relatively noninvasive, alternative for brain metastases patients who are not surgical candidates.
Comment by Edward J. Kaplan, MD
This study is especially interesting, not only because it reports the largest published experience on the use of SRS in patients with brain metastases, but because Sanghavi et al stratified their patients using previously published criteria based on recursive partitioning. Recursive partitioning analysis (RPA) is founded on statistical clustering, and its goal is to identify groups or classes that are homogeneous in terms of survival. This appears to be a logical tool to use when dealing with the hodgepodge of patients that present with brain metastases. Sanghavi et al point out that 1 potential pitfall of this model as adapted from Gaspar was that it does not take into account the number of brain metastases per patient. Sanghavi et al feel that this is problematic, and is as yet an unresolved issue. Another questionable aspect of the study was the use of the RTOG patients as historical controls. Shanghavi et al cite "time-shifting" as a possible source of bias, whereby differences in diagnostic and therapeutic resources available during the respective study periods may have skewed the outcome in favor of the more modern study population. This seems to be a real possibility.
Sanghavi et al report that preliminary data from a recent RTOG randomized trial comparing WBRT to WBRT + SRS boost show an improvement in local control, but no difference in OS for patients with 2-3 lesions. Data on patients with solitary brain metastases have not yet been reported. Unfortunately, there were relatively low numbers of patients in each arm and high numbers of protocol violations, so the results may not be conclusive.
For the many brain metastases patients who are not surgical candidates, SRS boosting with either a linear accelerator or gamma knife helps establish improved local control, and may confer a survival benefit. Confirmatory studies are needed to verify the results of this pooled data analysis.
1. Patchell R, et al. N Engl J Med. 1990;332:494-500.
2. Gaspar L, et al. Int J Radiat Oncol Biol Phys. 1997;37: 745-751.