Daniel Gorovets

Predictors for long-term survival free from whole brain radiation therapy in patients treated with radiosurgery for limited brain metastases

Purpose To identify predictors for prolonged survival free from salvage whole brain radiation therapy (WBRT) in patients with brain metastases treated with stereotactic radiosurgery (SRS) as their initial radiotherapy approach. Materials and methods Patients with brain metastases treated with SRS from 2001 to 2013 at our institution were identified. SRS without WBRT was typically offered to patients with 1–4 brain metastases, Karnofsky performance status ≥70, and life expectancy ≥3 months. Three hundred and eight patients met inclusion criteria for analysis. Medical records were reviewed for patient, disease, and treatment information. Two comparison groups were identified: those with ≥1-year WBRT-free survival (N = 104), and those who died or required salvage WBRT within 3 months of SRS (N = 56). Differences between these groups were assessed by univariate and multivariate analyses. Results Median survival for all patients was 11 months. Among patients with ≥1-year WBRT-free survival, median survival was 33 months (12–107 months) with only 21% requiring salvage WBRT. Factors significantly associated with prolonged WBRT-free survival on univariate analysis (p < 0.05) included younger age, asymptomatic presentation, RTOG RPA class I, fewer brain metastases, surgical resection, breast primary, new or controlled primary, absence of extracranial metastatic disease, and oligometastatic disease burden (≤5 metastatic lesions). After controlling for covariates, asymptomatic presentation, breast primary, single brain metastasis, absence of extracranial metastases, and oligometastatic disease burden remained independent predictors for favorable WBRT-free survival. Conclusion A subset of patients with brain metastases can achieve long-term survival after upfront SRS without the need for salvage WBRT. Predictors identified in this study can help select patients that might benefit most from a treatment strategy of SRS alone.

Stereotactic radiosurgery for large brain metastases

We evaluated patient outcomes following stereotactic radiosurgery (SRS)-treatment of large brain metastasis (⩾3 cm) at our institution. SRS is an established treatment for limited brain metastases. However, large tumors pose a challenge for this approach. For this study, 343 patients with 754 total brain metastases were treated with SRS, of which 93 had large tumors. The tumor size was 3-3.5, 3.5-4, and ⩾4 cm in 29%, 32%, and 39% of these patients. Surgical resection was performed prior to SRS in 68% of patients, and 53% achieved a gross total resection. The local control of large metastases was inferior compared to smaller tumors, with 1 year local control of 68 versus 86%, respectively (p<0.001). Among the patients with large metastases, no correlation between local control and surgical resection (p=0.747), or extent of surgery (gross total versus subtotal resection; p=0.120), was identified. Histology (p=0.939), tumor size (3-4 versus >4 cm; p=0.551), and SRS dose (⩽16 versus >16 Gy; p=0.539) also showed no correlation with local failure. The overall survival at 1, 2, and 5 years was 46%, 29% and 5%, respectively. Prolonged survival was seen in patients with age <65 years (p=0.009), primary treatment compared with salvage (p=0.077), and controlled primary tumors (p=0.022). Radiation necrosis developed in 10 patients (11.8%). For patients with large brain metastases, SRS is well tolerated and can achieve local central nervous system disease control in the majority of patients, and extended survival in some, though the local control rate is suboptimal. Further strategies to improve the outcomes in this subgroup of patients are needed.

Prediction of new brain metastases after radiosurgery: validation and analysis of performance of a multi-institutional nomogram

Stereotactic radiosurgery (SRS) without whole brain radiotherapy (WBRT) for brain metastases can avoid WBRT toxicities, but with risk of subsequent distant brain failure (DBF). Sole use of number of metastases to triage patients may be an unrefined method. Data on 1354 patients treated with SRS monotherapy from 2000 to 2013 for new brain metastases was collected across eight academic centers. The cohort was divided into training and validation datasets and a prognostic model was developed for time to DBF. We then evaluated the discrimination and calibration of the model within the validation dataset, and confirmed its performance with an independent contemporary cohort. Number of metastases (≥8, HR 3.53 p = 0.0001), minimum margin dose (HR 1.07 p = 0.0033), and melanoma histology (HR 1.45, p = 0.0187) were associated with DBF. A prognostic index derived from the training dataset exhibited ability to discriminate patients’ DBF risk within the validation dataset (c-index = 0.631) and Heller’s explained relative risk (HERR) = 0.173 (SE = 0.048). Absolute number of metastases was evaluated for its ability to predict DBF in the derivation and validation datasets, and was inferior to the nomogram. A nomogram high-risk threshold yielding a 2.1-fold increased need for early WBRT was identified. Nomogram values also correlated to number of brain metastases at time of failure (r = 0.38, p < 0.0001). We present a multi-institutionally validated prognostic model and nomogram to predict risk of DBF and guide risk-stratification of patients who are appropriate candidates for radiosurgery versus upfront WBRT.

Novel Treatment Approaches for Locally Advanced Pancreatic Cancer

Despite decades of research, pancreatic cancer remains essentially incurable for patients with unresectable tumors. In the United States, most patients with locally advanced pancreatic cancer are treated with chemotherapy alone or combined with conventionally fractionated radiotherapy. Regardless of the treatment strategy, average survival for these patients is less than 1 year, indicating that the current approaches are indisputably inadequate. For locally advanced pancreatic cancer patients, effective local-regional control is not only crucial for any hope at long-term survival, but also for symptom management. The aim of this paper is to highlight abstracts from the 2014 ASCO Gastrointestinal Cancers Symposium that demonstrate the use of novel local-regional therapies in locally advanced pancreatic cancer. Abstracts #317, #328, and #361 describe their results with an advanced method of delivering radiation called stereotactic body radiation therapy (SBRT). In these studies, patients treated with combined chemotherapy and SBRT had exceptional local control rates and acceptable toxicity. An innovative alternative to radiation for local-regional treatment is presented in Abstract #270. This study shows encouraging results from a phase I investigation of a regionally delivered siRNA that targets the K-ras(G12D) mutation. Investigation of novel approaches such as those presented here holds the greatest promise for improving treatment of this deadly disease.

Techniques for Reducing Toxicity After SBRT

The goal of any effective radiotherapeutic regimen is to deliver optimal tumoricidal doses with minimal subsequent toxicity. In order to accomplish this goal, careful patient selection, simulation, treatment planning, and radiation delivery are required. This is particularly important when delivering ultra-hypofractionated radiation therapy with SBRT. In this chapter, we review strategies that may be used to reduce toxicity of SBRT for prostate cancer.

Management approach for recurrent brain metastases following upfront radiosurgery may affect risk of subsequent radiation necrosis

Purpose Many patients treated with stereotactic radiosurgery (SRS) alone as initial treatment require 1 or more subsequent salvage therapies. This study aimed to determine if commonly used salvage strategies are associated with differing risks of radiation necrosis (RN). Methods and materials All patients treated with upfront SRS alone for brain metastases at our institution were retrospectively analyzed. Salvage treatment details were obtained for brain failures. Patients who underwent repeat SRS to the same lesion were excluded. RN was determined based on pathological confirmation or advanced brain imaging consistent with RN in a symptomatic patient. Patients were grouped according to salvage treatment and rates of RN were compared via Fishers exact tests. Results Of 284 patients treated with upfront SRS alone, 132 received salvage therapy and 44 received multiple salvage treatments. This included 31 repeat SRS alone, 58 whole brain radiation therapy (WBRT) alone, 28 SRS and WBRT, 7 surgery alone, and 8 surgery with adjuvant radiation. With a median follow-up of 10 months, the rate of RN among all patients was 3.17% (9/284), salvaged patients 4.55% (6/132), and never salvaged patients 1.97% (3/152). Receiving salvage therapy did not significantly increase RN risk (P = .31). Of the patients requiring salvage treatments, the highest RN rate was among patients that had both salvage SRS and WBRT (delivered as separate salvage therapies) (6/28, 21.42%). RN rate in this group was significantly higher than in those treated with repeat SRS alone (0/31), WBRT alone (0/58), surgery alone (0/7), and surgery with adjuvant radiation (0/8). Comparing salvage WBRT doses <30 Gy versus ≥30 Gy revealed no effect of dose on RN rate. Additionally, among patients who received multiple SRS treatments, number of treated lesions was not predictive of RN incidence. Conclusion Our results suggest that initial management approach for recurrent brain metastasis after upfront SRS does not affect the rate of RN. However, the risk of RN significantly increases when patients are treated with both repeat SRS and salvage WBRT. Methods to improve prediction of toxicity and optimize patient selection for salvage treatments are needed.