Analysis of the drivers of cost of management when patients with brain metastases are treated with upfront radiosurgery.

OBJECTIVES: We aimed to assess the driving factors for increased cost of brain metastasis management when using upfront stereotactic radiosurgery (SRS). PATIENT AND METHODS: 737 patients treated with upfront SRS without whole brain radiotherapy (WBRT). Patients were evaluated for use of craniotomy, length of hospital stay, need for rehabilitation or facility placement, and use of salvage SRS or salvage WBRT. Costs of care of these interventions were estimated based on 2013 Medicare reimbursements. Multiple linear regression was performed to determine factors that predicted for higher cost of treatment per month of life, as well as highest cumulative cost of care for brain metastasis. RESULTS: Mean cost of brain metastasis management per patient was $42,658, and $4673 per month of life. Upfront SRS represented the greatest contributor of total cost of brain metastasis management over a lifetime (49%), followed by use of any salvage SRS (21%), use of initial surgery (14%), use of salvage surgery (10%), hospitalization (3%) and cost of salvage WBRT (3%). Multiple linear regression identified brain metastasis velocity (BMV) (p < 0.001), use of cavity-directed SRS (<0.001), and CNS symptoms at time of presentation (p = 0.005) as factors that increased costs of care per month of survival. Use of salvage WBRT decreased per month cost of care in patients requiring salvage (p < 0.001). CONCLUSION: The cost of upfront SRS is the greatest contributor to cost of brain metastasis management when using upfront SRS. Higher BMV, progressive systemic disease and presence of symptoms are associated with increased cost of care.

Safety of pioglitazone during and after radiation therapy in patients with brain tumors: a phase I clinical trial.

INTRODUCTION: Radiation-induced cognitive decline (RICD) is a late effect of radiotherapy (RT) occurring in 30-50% of irradiated brain tumor survivors. In preclinical models, pioglitazone prevents RICD but there are little safety data on its use in non-diabetic patients. We conducted a dose-escalation trial to determine the safety of pioglitazone taken during and after brain irradiation. METHODS: We enrolled patients > 18 years old with primary or metastatic brain tumors slated to receive at least 10 treatments of RT (≤ 3 Gy per fraction). We evaluated the safety of pioglitazone at 22.5 mg and 45 mg with a dose-escalation phase and dose-expansion phase. Pioglitazone was taken daily during RT and for 6 months after. RESULTS: 18 patients with a mean age of 54 were enrolled between 2010 and 2014. 14 patients had metastatic brain tumors and were treated with whole brain RT. Four patients had primary brain tumors and received partial brain RT and concurrent chemotherapy. No DLTs were identified. In the dose-escalation phase, there were only three instances of grade ≥ 3 toxicity: one instance of neuropathy in a patient receiving 22.5 mg, one instance of fatigue in a patient receiving 22.5 mg and one instance of dizziness in a patient receiving 45 mg. The attribution in each of these cases was considered "possible." In the dose-expansion phase, nine patients received 45 mg and there was only one grade 3 toxicity (fatigue) possibly attributable to pioglitazone. CONCLUSION: Pioglitazone was well tolerated by brain tumor patients undergoing RT. 45 mg is a safe dose to use in future efficacy trials.

Sociodemographic predictors of patients with brain metastases treated with stereotactic radiosurgery.

BACKGROUND: Patient sociodemographic factors such income, race, health insurance coverage, and rural residence impact a variety of outcomes in patients with cancer. The role of brain metastasis at presentation and its subsequent outcomes have not been well characterized in this patient population. RESULTS: Multivariate analysis revealed that median income lower than $50,000 was associated with higher presenting symptom grade for brain metastasis (mean RTOG grade 1.2 vs 1.0, SE = 0.1, p = 0.04) and higher chronic symptom grade (mean RTOG grade 1.3 vs 0.9, SE = 0.1, p = 0.002). Higher area-level median income was associated with a lower symptom grade at diagnosis of brain metastasis (p = 0.0008) and likelihood of hospitalization (p = 0.004). Other sociodemographic factors were not significantly associated with survival, neurologic death, or patterns of failure after stereotactic radiosurgery for brain metastases. CONCLUSIONS: Lower median income was associated with a greater symptom burden at the time of diagnosis and need for hospitalization for patients with brain metastases, suggesting a delayed time to presentation. These differences in symptom burden persisted during treatment. METHODS: Between January 2000 and December 2013, we identified 737 patients treated with stereotactic radiosurgery for brain metastases. They were characterized by 4 sociodemographic factors: median income, race, rural-urban residence, and health insurance status. Clinical outcomes included stage at diagnosis, symptom grade at presentation, likelihood of hospitalization from brain metastasis, overall survival, local failure, distant brain failure, and neurologic death. Multivariate cox proportional hazards model for each outcome was performed controlling for age, sex, number of brain metastases, and dose to brain metastases.

The Effects of smoking status and smoking history on patients with brain metastases from lung cancer.

There is limited data on the effects of smoking on lung cancer patients with brain metastases. This single institution retrospective study of patients with brain metastases from lung cancer who received stereotactic radiosurgery assessed whether smoking history is associated with overall survival, local control, rate of new brain metastases (brain metastasis velocity), and likelihood of neurologic death after brain metastases. Patients were stratified by adenocarcinoma versus nonadenocarcinoma histologies. Kaplan-Meier analysis was performed for survival endpoints. Competing risk analysis was performed for neurologic death analysis to account for risk of nonneurologic death. Separate linear regression and multivariate analyses were performed to estimate the brain metastasis velocity. Of 366 patients included in the analysis, the median age was 63, 54% were male and, 60% were diagnosed with adenocarcinoma. Current smoking was reported by 37% and 91% had a smoking history. Current smoking status and pack-year history of smoking had no effect on overall survival. There was a trend for an increased risk of neurologic death in nonadenocarcinoma patients who continued to smoke (14%, 35%, and 46% at 6/12/24 months) compared with patients who did not smoke (12%, 23%, and 30%, P = 0.053). Cumulative pack years smoking was associated with an increase in neurologic death for nonadenocarcinoma patients (HR = 1.01, CI: 1.00-1.02, P = 0.046). Increased pack-year history increased brain metastasis velocity in multivariate analysis for overall patients (P = 0.026). Current smokers with nonadenocarcinoma lung cancers had a trend toward greater neurologic death than nonsmokers. Cumulative pack years smoking is associated with a greater brain metastasis velocity.

Repeat stereotactic radiosurgery as salvage therapy for locally recurrent brain metastases previously treated with radiosurgery.

OBJECTIVE There are a variety of salvage options available for patients with brain metastases who experience local failure after stereotactic radiosurgery (SRS). These options include resection, whole-brain radiation therapy, laser thermoablation, and repeat SRS. There is little data on the safety and efficacy of repeat SRS following local failure of a prior radiosurgical procedure. This study evaluates the clinical outcomes and dosimetric characteristics of patients who experienced tumor recurrence and were subsequently treated with repeat SRS. METHODS Between 2002 and 2015, 32 patients were treated with repeat SRS for local recurrence of ≥ 1 brain metastasis following initial SRS treatment. The Kaplan-Meier method was used to estimate time-to-event outcomes including overall survival (OS), local failure, and radiation necrosis. Cox proportional hazards analysis was performed for predictor variables of interest for each outcome. Composite dose-volume histograms were constructed for each reirradiated lesion, and these were then used to develop a predictive dosimetric model for radiation necrosis. RESULTS Forty-six lesions in 32 patients were re-treated with a second course of SRS after local failure. A median dose of 20 Gy (range 14-22 Gy) was delivered to the tumor margin at the time of repeat SRS. Local control at 1 year was 79% (95% CI 67%-94%). Estimated 1-year OS was 70% (95% CI 55%-88%). Twelve patients had died at the most recent follow-up, with 8/12 patients experiencing neurological death (as described in Patchell et al.). Eleven of 46 (24%) lesions in 11 separate patients treated with repeat SRS were associated with symptomatic radiation necrosis. Freedom from radiation necrosis at 1 year was 71% (95% CI 57%-88%). Analysis of dosimetric data revealed that the volume of a lesion receiving 40 Gy (V40Gy) was the most predictive factor for the development of radiation necrosis (p = 0.003). The following V40Gy thresholds were associated with 10%, 20%, and 50% probabilities of radiation necrosis, respectively: 0.28 cm3 (95% CI 3%-28%), 0.76 cm3 (95% CI 9%-39%), 1.60 cm3 (95% CI 26%-74%). CONCLUSIONS Repeat SRS appears to be an effective salvage option for patients with brain metastases experiencing local failure following initial SRS treatment. This series demonstrates durable local control and, although rates of radiation necrosis are significant, repeat SRS may be indicated for select cases of local disease recurrence. Because the V40Gy is predictive of radiation necrosis, limiting this value during treatment planning may allow for a reduction in radiation necrosis rates.