Survival after Stereotactic Radiosurgery in the Era of Targeted Therapy: Number of Metastases No Longer Matters.

Randomised control trial data support the use of stereotactic radiosurgery (SRS) in up to 4 brain metastases (BMs), with non-randomised prospective data complementing this for up to 10 BMs. There is debate in the neuro-oncology community as to the appropriateness of SRS in patients with >10 BMs. We present data from a large single-centre cohort, reporting survival in those with >10 BMs and in a >20 BMs subgroup. A total of 1181 patients receiving SRS for BMs were included. Data were collected prospectively from the time of SRS referral. Kaplan-Meier graphs and logrank tests were used to compare survival between groups. Multivariate analysis was performed using the Cox proportional hazards model to account for differences in group characteristics. Median survival with 1 BM (n = 379), 2-4 BMs (n = 438), 5-10 BMs (n = 236), and >10 BMs (n = 128) was 12.49, 10.22, 10.68, and 10.09 months, respectively. Using 2-4 BMs as the reference group, survival was not significantly different in those with >10 BMs in either our univariable (p = 0.6882) or multivariable analysis (p = 0.0564). In our subgroup analyses, median survival for those with >20 BMs was comparable to those with 2-4 BMs (10.09 vs. 10.22 months, p = 0.3558). This study contributes a large dataset to the existing literature on SRS for those with multi-metastases and supports growing evidence that those with >10 BMs should be considered for SRS.

DNA fusion-gene vaccination in patients with prostate cancer induces high-frequency CD8(+) T-cell responses and increases PSA doubling time.

We report on the immunogenicity and clinical effects in a phase I/II dose escalation trial of a DNA fusion vaccine in patients with prostate cancer. The vaccine encodes a domain (DOM) from fragment C of tetanus toxin linked to an HLA-A2-binding epitope from prostate-specific membrane antigen (PSMA), PSMA(27-35). We evaluated the effect of intramuscular vaccination without or with electroporation (EP) on vaccine potency. Thirty-two HLA-A2(+) patients were vaccinated and monitored for immune and clinical responses for a follow-up period of 72 weeks. At week 24, cross-over to the immunologically more effective delivery modality was permitted; this was shown to be with EP based on early antibody data, and subsequently, 13/15 patients crossed to the +EP arm. Thirty-two HLA-A2(-) control patients were assessed for time to next treatment and overall survival. Vaccination was safe and well tolerated. The vaccine induced DOM-specific CD4(+) and PSMA(27)-specific CD8(+) T cells, which were detectable at significant levels above baseline at the end of the study (p = 0.0223 and p = 0.00248, respectively). Of 30 patients, 29 had a measurable CD4(+) T-cell response and PSMA(27)-specific CD8(+) T cells were detected in 16/30 patients, with or without EP. At week 24, before cross-over, both delivery methods led to increased CD4(+) and CD8(+) vaccine-specific T cells with a trend to a greater effect with EP. PSA doubling time increased significantly from 11.97 months pre-treatment to 16.82 months over the 72-week follow-up (p = 0.0417), with no clear differential effect of EP. The high frequency of immunological responses to DOM-PSMA(27) vaccination and the clinical effects are sufficiently promising to warrant further, randomized testing.

Hypofractionated stereotactic radiotherapy in the management of recurrent or residual medulloblastoma/PNET.

PURPOSE: To evaluate the efficacy and toxicity of hypofractionated stereotactic radiotherapy in the management of locally recurrent or residual central nervous system (CNS) primitive neuroectodermal tumors (PNETs). PATIENTS AND METHODS: Between 1991 and 2005, 12 patients with locally recurrent medulloblastoma and two patients with residual supratentorial PNET were treated with hypofractionated stereotactic conformal radiotherapy (SCRT). Nine patients were treated for first recurrence, two patients after the 2nd, and one patient after 3rd recurrence. Median age at diagnosis was 20 years (range: 4-35 years) and median age at SCRT 25 years (range: 7-41 years). Nine of 12 patients underwent resection at recurrence and 13 patients received at least one cycle of chemotherapy prior to SCRT. All received focal SCRT (30-40 Gy/6-8 #) using non-coplanar arcs (n = 6) or fixed conformal non-coplanar fields (n = 8). RESULTS: Median overall survival was 29 months (95% CI: 6-51 months) and median progression-free survival was 12 months (95% CI: 5-19 months). Local progression-free survival at 1 and 3 years was 80% (95% CI: 55-100%) and 48% (95% CI: 11-85%). Causes of death were recurrent CNS disease (n = 7), herpes encephalitis (n = 1), and metastatic PNET outside the CNS (n = 1). CONCLUSION: Hypofractionated SCRT provides effective local control with acceptable toxicity for patients with recurrent localized PNET. However, overall long-term disease control is rare and limited by the occurrence of CSF mediated relapses, which thus could benefit from intensive systemic chemotherapy as part of the primary relapse strategy even in local recurrences. Larger multi-national studies will be necessary to assess the value of such combined treatment approaches.