Ashley W. Jensen

Summary Report on the Graded Prognostic Assessment: An Accurate and Facile Diagnosis-Specific Tool to Estimate Survival for Patients With Brain Metastases

PURPOSE Our group has previously published the Graded Prognostic Assessment (GPA), a prognostic index for patients with brain metastases. Updates have been published with refinements to create diagnosis-specific Graded Prognostic Assessment indices. The purpose of this report is to present the updated diagnosis-specific GPA indices in a single, unified, user-friendly report to allow ease of access and use by treating physicians. METHODS A multi-institutional retrospective (1985 to 2007) database of 3,940 patients with newly diagnosed brain metastases underwent univariate and multivariate analyses of prognostic factors associated with outcomes by primary site and treatment. Significant prognostic factors were used to define the diagnosis-specific GPA prognostic indices. A GPA of 4.0 correlates with the best prognosis, whereas a GPA of 0.0 corresponds with the worst prognosis. RESULTS Significant prognostic factors varied by diagnosis. For lung cancer, prognostic factors were Karnofsky performance score, age, presence of extracranial metastases, and number of brain metastases, confirming the original Lung-GPA. For melanoma and renal cell cancer, prognostic factors were Karnofsky performance score and the number of brain metastases. For breast cancer, prognostic factors were tumor subtype, Karnofsky performance score, and age. For GI cancer, the only prognostic factor was the Karnofsky performance score. The median survival times by GPA score and diagnosis were determined. CONCLUSION Prognostic factors for patients with brain metastases vary by diagnosis, and for each diagnosis, a robust separation into different GPA scores was discerned, implying considerable heterogeneity in outcome, even within a single tumor type. In summary, these indices and related worksheet provide an accurate and facile diagnosis-specific tool to estimate survival, potentially select appropriate treatment, and stratify clinical trials for patients with brain metastases.

Diagnosis-specific prognostic factors, indexes, and treatment outcomes for patients with newly diagnosed brain metastases: a multi-institutional analysis of 4,259 patients.

PURPOSE Controversy endures regarding the optimal treatment of patients with brain metastases (BMs). Debate persists, despite many randomized trials, perhaps because BM patients are a heterogeneous population. The purpose of the present study was to identify significant diagnosis-specific prognostic factors and indexes (Diagnosis-Specific Graded Prognostic Assessment [DS-GPA]). METHODS AND MATERIALS A retrospective database of 5,067 patients treated for BMs between 1985 and 2007 was generated from 11 institutions. After exclusion of the patients with recurrent BMs or incomplete data, 4,259 patients with newly diagnosed BMs remained eligible for analysis. Univariate and multivariate analyses of the prognostic factors and outcomes by primary site and treatment were performed. The significant prognostic factors were determined and used to define the DS-GPA prognostic indexes. The DS-GPA scores were calculated and correlated with the outcomes, stratified by diagnosis and treatment. RESULTS The significant prognostic factors varied by diagnosis. For non-small-cell lung cancer and small-cell lung cancer, the significant prognostic factors were Karnofsky performance status, age, presence of extracranial metastases, and number of BMs, confirming the original GPA for these diagnoses. For melanoma and renal cell cancer, the significant prognostic factors were Karnofsky performance status and the number of BMs. For breast and gastrointestinal cancer, the only significant prognostic factor was the Karnofsky performance status. Two new DS-GPA indexes were thus designed for breast/gastrointestinal cancer and melanoma/renal cell carcinoma. The median survival by GPA score, diagnosis, and treatment were determined. CONCLUSION The prognostic factors for BM patients varied by diagnosis. The original GPA was confirmed for non-small-cell lung cancer and small-cell lung cancer. New DS-GPA indexes were determined for other histologic types and correlated with the outcome, and statistical separation between the groups was confirmed. These data should be considered in the design of future randomized trials and in clinical decision-making.

Effect of Tumor Subtype on Survival and the Graded Prognostic Assessment for Patients With Breast Cancer and Brain Metastases

PURPOSE The diagnosis-specific Graded Prognostic Assessment (GPA) was published to clarify prognosis for patients with brain metastases. This study refines the existing Breast-GPA by analyzing a larger cohort and tumor subtype. METHODS AND MATERIALS A multi-institutional retrospective database of 400 breast cancer patients treated for newly diagnosed brain metastases was generated. Prognostic factors significant for survival were analyzed by multivariate Cox regression and recursive partitioning analysis (RPA). Factors were weighted by the magnitude of their regression coefficients to define the GPA index. RESULTS Significant prognostic factors by multivariate Cox regression and RPA were Karnofsky performance status (KPS), HER2, ER/PR status, and the interaction between ER/PR and HER2. RPA showed age was significant for patients with KPS 60 to 80. The median survival time (MST) overall was 13.8 months, and for GPA scores of 0 to 1.0, 1.5 to 2.0, 2.5 to 3.0, and 3.5 to 4.0 were 3.4 (n = 23), 7.7 (n = 104), 15.1 (n = 140), and 25.3 (n = 133) months, respectively (p < 0.0001). Among HER2-negative patients, being ER/PR positive improved MST from 6.4 to 9.7 months, whereas in HER2-positive patients, being ER/PR positive improved MST from 17.9 to 20.7 months. The log-rank statistic (predictive power) was 110 for the Breast-GPA vs. 55 for tumor subtype. CONCLUSIONS The Breast-GPA documents wide variation in prognosis and shows clear separation between subgroups of patients with breast cancer and brain metastases. This tool will aid clinical decision making and stratification in clinical trials. These data confirm the effect of tumor subtype on survival and show the Breast-GPA offers significantly more predictive power than the tumor subtype alone.

Detrimental Effects of Tumor Progression on Cognitive Function of Patients With High-Grade Glioma

PURPOSE There is growing recognition that the primary cause of cognitive deficits in adult patients with primary brain tumors is the tumor itself and more significantly, tumor progression. To assess the cognitive performance of high-grade glioma patients, prospectively collected cognitive performance data were analyzed. PATIENTS AND METHODS We studied 1,244 high-grade brain tumor patients entered onto eight consecutive North Central Cancer Treatment Group treatment trials that used radiation and nitrosourea-based chemotherapy. Imaging studies and Folstein Mini-Mental State Examination (MMSE) scores recorded at baseline, 6, 12, 18, and 24 months were analyzed to assess tumor status and cognitive function over time. RESULTS The proportion of patients without tumor progression who experienced clinically significant cognitive deterioration compared with baseline was stable at 6, 12, 18, and 24 months (18%, 16%, 14%, and 13%, respectively). In patients without radiographic evidence of progression, clinically significant deterioration in MMSE scores was a strong predictor of a more rapid time to tumor progression and death. At evaluations preceding interval radiographic evidence of progression, there was significant deterioration in MMSE scores for patients who were to experience progression, whereas the scores remained stable for the patients who did not have tumor progression. CONCLUSION The proportion of high-grade glioma patients with cognitive deterioration over time is stable, most consistent with the constant pressure of tumor progression over time. Although other factors may contribute to cognitive decline, the predominant cause of cognitive decline seems to be subclinical tumor progression that precedes radiographic changes.

Long-Term Follow-Up of Dose-Adapted and Reduced-Field Radiotherapy With or Without Chemotherapy for Central Nervous System Germinoma

PURPOSE To update our institutional experience with neoadjuvant chemotherapy and minimized radiotherapy vs. radiation monotherapy for intracranial germinoma. METHODS AND MATERIALS We retrospectively reviewed records of 59 patients with diagnosis of primary intracranial germinoma between 1977 and 2007. Treatment was irradiation alone or neoadjuvant platinum-based chemotherapy and local irradiation (initial tumor plus margin) for patients with localized complete response and reduced-dose craniospinal irradiation for others. RESULTS For the chemoradiotherapy group (n = 28), median follow-up was 7 years. No patient died. The freedom from progression (FFP) rate was 88% at 5 years and 80% at 10 years. In 4 patients, disease recurred 1.1 to 6.8 years after diagnosis. All were young male patients who received 30.6 Gy to local fields after complete response to chemotherapy. The FFP rate was 88% for local irradiation vs. 100% for more extensive fields (p = .06). For the radiotherapy-alone group (n = 31), median follow-up was 15 years. Overall and disease-free survival rates were 93% and 93% at 5 years and 90% and 87% at 15 years. In 5 patients, disease recurred 1.1 to 4.9 years after diagnosis. Most patients in this group were young men 18 to 23 years of age with suprasellar primary disease treated with about 50 Gy to local fields. The FFP rate was 44% for local irradiation vs. 100% for more extensive fields (p < .01). CONCLUSIONS The addition of neoadjuvant chemotherapy to local-field radiotherapy reduced central nervous system cancer recurrence when high-risk patients were excluded by thorough pretreatment staging. There was trend toward improved central nervous system tumor control when larger fields (whole brain, whole ventricle, or craniospinal axis) were used.

Long-term results of radiation prophylaxis for heterotopic ossification in the temporomandibular joint.

PURPOSE To assess the long-term efficacy and toxicity of radiation therapy (RT) for postoperative prophylaxis of recurrent heterotopic ossification (HO) in the temporomandibular joint (TMJ). PATIENTS AND METHODS Twelve patients (18 joints) with bony ankylosis of the TMJ from HO were referred to undergo RT after arthrotomy with osseous recontouring, gap arthroplasty, or costochondral grafting. Treatment consisted of 10 Gy in 5 daily fractions to a field encompassing the TMJ with an adequate margin. RT was initiated 1 to 3 days postoperatively. Response to therapy was assessed by routine x-ray films obtained preoperatively, immediately postoperatively, and at follow-up by use of the Turlington-Durr grading system. Treatment efficacy was defined as freedom from HO re-formation requiring further surgical intervention. Efficacy and toxicity data were obtained from review of the medical records and were augmented by telephone interview of patients when possible (6 patients, all with follow-up >16 years). Efficacy rates by patient were estimated by the Kaplan-Meier method. RESULTS The median follow-up after RT was 16.4 years (range, 2.5-19.2 years). Symptomatic re-formation of HO requiring further surgery occurred in 5 patients (7 joints). Treatment efficacy rates were 71% (95% confidence interval [CI], 44-99) at 5 years and 48% (95% CI, 15-80) at 10 years. Of the 6 patients contacted regarding late toxicity, 2 had clinical xerostomia (grade 1, CTCAE v3.0) attributable to RT; no other late RT-related toxicities were noted. None of the 12 patients had malignancy attributable to RT. CONCLUSIONS Postoperative RT prevented re-formation of TMJ HO in 50% of treated patients long term. Late toxicities from RT were mild and infrequent.

Acute and late toxicities of radiotherapy for patients with discoid lupus erythematosus: a retrospective case-control study.

BackgroundThe purpose of this study was to evaluate acute and late toxicities of radiotherapy for patients with discoid lupus erythematosus (DLE).MethodsA retrospective review was performed of patients with DLE who received radiotherapy at our institution between 1980 and 2005. Patients with other connective tissue disorders were excluded. Control patients were matched 2:1 with the DLE treatment courses based on age, cancer diagnosis, year of treatment, radiotherapy dose, and sex. Acute (within 30 days from the completion of radiotherapy) and late toxicities were evaluated for each treatment course using the Common Terminology Criteria for Adverse Events Version 3.0.ResultsTwelve patients with DLE received a total of 15 radiotherapy courses. The median follow-up time was 2.6 years (range, 0.0-15.2 years). Acute toxicity of any organ was observed in 10 (67%) treatment courses, of which 2 (13%) were Grade 3 or higher. Acute Grade 1 or 2 dermatologic toxicity was observed in 8 courses (53%). Late toxicity of any organ was observed in 7 of 12 (58%) evaluable treatment courses, of which 3 (23%) were grade 3 or higher. Late grade 1 or 2 dermatologic toxicity was observed in 5 (42%) courses. No patient experienced acute or late Grade 3 or higher dermatologic toxicity. The rates of any organ or dermatologic acute and late toxicity were not significantly different between DLE and control treatment courses.ConclusionsOur findings do not suggest an increased risk of toxicity to the skin or other organs in patients with DLE receiving radiotherapy.

In Regard to Yamamoto et al

To the Editor: We commend Dr Yamamoto and colleagues for their work on a modified Recursive Partitioning Analysis (RPA) classification for patients with brain metastases (1). Several important points warrant discussion. The authors acknowledge 2 weaknesses of their study: the heterogeneity of the patient populations, and the high number of patients with 5 or more metastases treated with stereotactic radiosurgery (SRS) alone. The first is not a weakness. Heterogeneity is a well-known characteristic of this patient population. The weakness is that the authors fail to account for this heterogeneity in their methodology. The Diagnosis-Specific Graded Prognostic Assessment (DS-GPA) has shown, in a larger database, that prognosis for patients with newly diagnosed brain metastases varies by diagnosis (and by tumor subtype in breast cancer), and that the factors that influence prognosis differ by diagnosis (2-4). The second weakness is important in the context of patient selection for SRS. The authors acknowledge that SRS alone for patients with more than 4 metastases is not the standard of care in Japan or in Western countries. Their study included 1463 patients (39%) with 5 or more brain metastases and 775 patients (21%) with 10 or more brain metastases. Beyond these 2 issues, there are additional points to consider. First, 239 patients (6%) had prior radiation (Table 1) and thus had recurrent, not newly diagnosed, brain metastases and should be excluded from a series of patients with newly diagnosed disease. Second, their system requires assessment of primary tumor control, which is dependent on the type and timing of imaging studies. These were not detailed in their article. This was one of many reasons the DS-GPA, which does not use control of primary as a factor, is considered preferable to the RPA. Third, to their credit, the authors compare their modified RPA to other prognostic indices, including the Score Index for Radiosurgery (SIR), Basic Score for Brain Metastases (BSBM), and the original GPA. The authors reference the DS-GPA, but curiously do not compare their results to it. A user-friendly worksheet for calculation of the DS-GPA has now been published (2). The DS-GPA has also been adopted for purposes of stratification in 2 Radiation Therapy Oncology Group (RTOG) randomized trials. Finally, we again commend the authors for their work, and encourage them to apply the DS-GPA to their data to determine whether the DS-GPA would retain its prognostic validity in patients managed with SRS alone.

Cerebral venous sinus thrombosis associated with essential thrombocytosis in a pediatric patient.

Essential thrombocytosis (ET) is an uncommon pediatric hematologic disorder that can result in thrombotic complications, including cerebral venous sinus thrombosis (CVST). Although CVST associated with ET is exceedingly rare, it can be devastating to the patient. We here report a pediatric case of CVST associated with ET. The patient was treated with hydroxyurea and warfarin, which was later replaced by low-dose aspirin. Platelet counts were well controlled after 16 months of follow-up, and no further thrombotic events occurred. Mucositis was the main adverse effect of treatment.