Subclassification of Recursive Partitioning Analysis Class II Patients With Brain Metastases Treated Radiosurgically

doi:10.1016/j.ijrobp.2011.10.018

International Journal of Radiation OncologyBiologyPhysics

Volume 83, Issue 5, 1 August 2012, Pages 1399-1405

Presented at the 2010 Annual Meeting of the Japanese Society for Therapeutic Radiology and Oncology, Tokyo, Japan, November 2010, and at the 2011 Annual Meeting of the American Association of Neurological Surgeons, Denver, Colorado, April 2011.

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Purpose

Although the recursive partitioning analysis (RPA) class is generally used for predicting survival periods of patients with brain metastases (METs), the majority of such patients are Class II and clinical factors vary quite widely within this category. This prompted us to divide RPA Class II patients into three subclasses.

Methods and Materials

This was a two-institution, institutional review board–approved, retrospective cohort study using two databases: the Mito series (2,000 consecutive patients, comprising 787 women and 1,213 men; mean age, 65 years [range, 19–96 years]) and the Chiba series (1,753 patients, comprising 673 female and 1,080 male patients; mean age, 65 years [range, 7–94 years]). Both patient series underwent Gamma Knife radiosurgery alone, without whole-brain radiotherapy, for brain METs during the same 10-year period, July 1998 through June 2008. The Cox proportional hazard model with a step-wise selection procedure was used for multivariate analysis.

Results

In the Mito series, four factors were identified as favoring longer survival: Karnofsky Performance Status (90% to 100% vs. 70% to 80%), tumor numbers (solitary vs. multiple), primary tumor status (controlled vs. not controlled), and non-brain METs (no vs. yes). This new index is the sum of scores (0 and 1) of these four factors: RPA Class II-a, score of 0 or 1; RPA Class II-b, score of 2; and RPA Class II-c, score of 3 or 4. Next, using the Chiba series, we tested whether our index is valid for a different patient group. This new system showed highly statistically significant differences among subclasses in both the Mito series and the Chiba series (p < 0.001 for all subclasses). In addition, this new index was confirmed to be applicable to Class II patients with four major primary tumor sites, that is, lung, breast, alimentary tract, and urogenital organs.

Conclusions

Our new grading system should be considered when designing future clinical trials involving brain MET patients.

Introduction

Brain metastases (METs), a common neurologic problem, are life-threatening for cancer patients in the absence of effective treatment. Because numerous factors in patients with brain METs impact outcomes, clinicians are often uncertain as to the optimal treatment, that is, whole-brain radiotherapy (WBRT), surgery, stereotactic radiosurgery (SRS) or stereotactic radiotherapy, anticancer agent administration, or combinations of these modalities, the efficacies of which vary among patient subsets. An improved prognostic index might resolve some of the uncertainty in making treatment decisions as well as guiding future research efforts.

Gasper et al. (1) proposed the now well-established recursive partitioning analysis (RPA). This index divides patients as follows: Class I, age younger than 65 years, Karnofsky Performance Status (KPS) (2) of at least 70%, controlled primary tumor, and no extracranial METs; Class III, KPS less than 70%; and Class II, all patients not in Class I or III. The RPA index is very simple and has long been widely used for predicting survival periods of brain MET patients. However, in the two series reported herein, more than 80% of patients were Class II (Table 1). Large patient number discrepancies among the three classes might reflect clinical factors. Survival periods vary markedly within Class II. This prompted us to develop a subclassification of RPA Class II patients, with division into three subclasses.

This study had two parts. First, using clinical factor median survival time (MST) analysis of 2,000 patients who underwent Gamma Knife radiosurgery (GKRS) at the Katsuta Hospital Mito GammaHouse (Mito series), we developed an index based on three subclasses of RPA Class II patients. Subsequently, we tested the validity of this index using another series, comprising 1,753 patients independently undergoing GKRS at the Gamma Knife House, Chiba Cardiovascular Center (Chiba series). In each series one author (M.Y. or T.S.) was responsible for all aspects of patient selection, dose planning, dose selection, performing GKRS, and collecting follow-up data.

Section snippets

Patient population

This was a two-institution, institutional review board (IRB)–approved, retrospective cohort study using two databases: the Mito series (2,000 consecutive patients) (Tokyo Women’s Medical University IRB No. 1981) and the Chiba series (1,753 patients) (Chiba Cardiovascular Center IRB No. SE363). At both institutes, all patients had been referred for GKRS by their primary physicians. Therefore patient selections had mostly been made outside of our facilities. Nevertheless, we did not perform GKRS

Results

In the Mito series, 4 patients (0.2%) were lost to follow-up. At the end of March 2010, 106 (5.3%) of the 2,000 patients were still alive and the remaining 1,890 (94.5%) were confirmed to have died. The overall MST after GKRS was 7.3 months. Overall post-treatment survival rates were 56.7% at 6 months after GKRS, 33.2% at 12 months, 20.8% at 18 months, 14.9% at 24 months, 8.1% at 36 months, and 4.1% at 60 months. Causes of death could not be determined in 83 patients but were confirmed in the

Discussion

After publication of the index based on RPA by Gasper et al. (1), three other indexes were proposed 7, 8, 9: (1) Score Index for Radiosurgery (SIR), the sum of scores (0, 1, and 2) for each of five prognostic factors (age, KPS, systemic disease status, number of lesions, and volume of largest lesion) (7); (2) Basic Score for Brain Metastases (BSBM), the sum of scores (0 and 1) for three prognostic factors (KPS, controlled primary tumor, and extracranial METs) (8); and (3) Graded Prognostic

Conclusions

According to our new system, RPA Class II-a and II-b patients are good candidates for aggressive treatment of brain METs whereas treatment decisions remain difficult in RPA Class II-c patients because of their poorer outcomes. In addition, this new index was confirmed to be applicable to Class II patients with four primary tumor categories: lung, breast, alimentary tract, and urogenital organ cancers. This index should be considered when designing future clinical trials involving brain MET

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Using the test series, with the Renal-GPA, 95% confidence intervals (CIs) of the post-SRS median survival times (MSTs) overlapped between pairs of neighboring subgroups. Among various pre-SRS clinical factors of the test series, six were highly associated with overall survival. Therefore, we assigned scores for six factors, i.e., “KPS ≥ 80%/<80% (0/3)”, “tumor numbers 1–4/≥5 (score; 0/2)”, “controlled primary cancer/not (0/2)”, “existing extra-cerebral metastases/not (0/3)”, “blood hemoglobin ≥ 11.0/<11.0 g/dl (0/1)” and “interval from primary cancer to SRS ≥ 5/<5 years (0/1)”. Patients were categorized into three subgroups according to the sum of scores, i.e., 0–4, 5–8 and 9–12. In the test and verification series, post-SRS MSTs differed significantly (p < 0.0001) with no overlaps of 95% CIs among the three subgroups.
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Citation Excerpt :
This system divides patients into 3 subclasses based on age, Karnofsky performance status (KPS), primary tumor status, and extracranial metastases.6 The RPA index was found to be applicable to patients with BM undergoing SRS alone, as described in our earlier report.7 However, in our patients with BM who underwent SRS alone, there were large discrepancies in patient numbers among subgroups, with 85.3% of all patients being class II and only 6.2% being class III, yielding rates of 13.7 and 1.0, respectively.
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This was an institutional review board approved retrospective cohort study 2 database comprising 802 patients with GI cancer treated with gamma-knife SRS by 2 experienced neurosurgeons during the 1998 to 2018 period. The Kaplan-Meier method was applied to determine post-SRS survival times, and competing risk analyses were used to estimate cumulative incidences of the secondary endpoints.
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First, using clinical factor-survival time analysis of 3237 patients in whom gamma knife (GK) SRS was performed by the second author (test cohort), we developed the GPM ≥ 3Ys based on survival ≥3 years as the objective variable. The validity of this model was then tested using another series of 3317 patients independently undergoing GK SRS performed by the third author (verification cohort). Number of patients surviving 3 years or more were 289 (8.9%) and 348 (10.5%), respectively.
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Clinical InvestigationSubclassification of Recursive Partitioning Analysis Class II Patients With Brain Metastases Treated Radiosurgically

Purpose

Methods and Materials

Results

Conclusions

Introduction

Section snippets

Patient population

Results

Discussion

Conclusions

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Recursive partitioning analysis (RPA) of prognostic factors in three Radiation Therapy Oncology Group (RTOG) brain metastases trials

Int J Radiat Oncol Biol Phys

The clinical evaluation of chemotherapeutic agents in cancer

Nonparametric estimation from incomplete observations

J Am Stat Assoc

Regression models and life tables

J R Stat Soc Series B

Clinical Investigation
Subclassification of Recursive Partitioning Analysis Class II Patients With Brain Metastases Treated Radiosurgically