Local control and overall survival for adjuvant stereotactic radiosurgery in patients with residual or recurrent disease.

Prior studies of post-operative stereotactic radiosurgery (SRS) have not distinguished between Adjuvant SRS (ARS) versus Adjuvant SRS to residual/recurrent disease (ARD). In this study, we defined ARS and ARD and investigated local control (LC), overall survival (OS), distant development of brain metastases (DBF), and leptomeningeal disease (LMD). We retrospectively identified BM patients who received surgical resection and SRS for BM from an IRB approved database between Jan 2009-Aug 2015. Patients were stratified into two groups: ARS and ARD. LC was determined by follow-up MRI studies and OS was measured from the date of surgery. LC and OS were assessed using the Kaplan-Meier method. 70 cavities underwent surgical resection of BM and received SRS to the post-operative bed. 41 cavities were classified as ARS and 29 as ARD. There was no significant difference in 12-month LC between the ARS and ARD group (71.4 vs. 80.8%, respectively; p = 0.135) from the time point of SRS. The overall 1-year survival for ARS and ARD was 79.9 and 86.1%, respectively (p = 0.339). Mean time to progression was 6.45 and 8.0 months and median follow-up was 10 and 15 months for ARS and ARD, respectively. 11.8% of ARS patients and 15.4% of ARD patients developed LMD, p = 0.72. 29.4% of ARS and 48.0% of ARD patients developed DBF, p = 0.145. Our findings suggest that observation after surgical resection, with subsequent treatment with SRS after the development of local failure, may not compromise treatment efficacy. If validated, this would spare patients who do not recur post-surgically from additional treatment.

Breast cancer subtype as a predictor for outcomes and control in the setting of brain metastases treated with stereotactic radiosurgery.

We investigated effects of breast cancer subtype on overall survival (OS), local and distant control, and time from initial diagnosis to brain metastases (BM). We also investigated advances in graded prognostic assessment (GPA) scores. A cohort of 72 patients treated for BM from breast cancer with Gamma Knife stereotactic radiosurgery at our institution from 2000 to 2014 had subtyping available and were used for this study. Median follow up for OS was 12 months and for control was 6 months. OS for luminal, HER2, and triple negative subtypes were 26, 20, and 22 months. OS when stratified by Sperduto et al. (J Clin Oncol 30(4):419-425, 2012) and Subbiah et al. (J Clin Oncol 33(20):2239-2245, 2015) GPAs were similar (p = 0.087 and p = 0.063). KPS and treatment modality were significant for OS (p = 0.002; p = 0.034). On univariate analysis, triple negative subtype and >3 BM were trending and significant for decreased OS (p = 0.084; p = 0.047). On multivariable analysis HER2, triple negative, and >3 BM were significant for OS (p = 0.022; p = 0.040; p = 0.009). Subtype was significant for response on a per lesion basis (p = 0.007). Subtype was trending towards significance when analyzing time from initial diagnosis to BM treatment (p = 0.064). Breast cancer subtype is an important prognostic factor when stratifying breast cancer patients with BM. The addition of number of BM to the GPA is a useful addition and should be further investigated. Subtype has an effect on lesion response, and also on rate of development BM after initial diagnosis.

Randomized Phase II Trial of Erlotinib Beyond Progression in Advanced Erlotinib-Responsive Non-Small Cell Lung Cancer.

BACKGROUND: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy is clearly beneficial in patients with advanced EGFR-mutated non-small cell lung cancer (NSCLC). However, acquired resistance develops uniformly and the benefit of continuation of EGFR TKI therapy beyond progression remains unclear. MATERIALS AND METHODS: This was a randomized phase II study of chemotherapy (arm A: pemetrexed or docetaxel) versus chemotherapy plus erlotinib (ERL) (arm B) in patients with progressive NSCLC following clinical benefit from erlotinib. In arm B, chemotherapy was given with erlotinib at an oral daily dose of 150 mg on days 2-19 of each cycle to minimize negative pharmacodynamic interactions. The primary endpoint was that continuation of erlotinib in this patient population could extend progression-free survival (PFS) by 50%. RESULTS: A total of 46 patients were randomized (arm A: 24; arm B: 22). Patient characteristics were well balanced except there were more female patients in arm A (p = .075). The median PFS of patients in arm A was 5.5 months and for those in arm B, 4.4 months (p = .699). The response rates were 13% and 16% in arms A and B, respectively (p = .79). EGFR status data were available for 39 of the 46 patients and no significant difference in PFS was seen for continuing ERL beyond progression in mutation-positive patients. Substantially more toxicity was seen in arm B than arm A. CONCLUSION: There was added toxicity but no benefit with the continuation of ERL beyond progression along with chemotherapy as compared with chemotherapy alone. IMPLICATIONS FOR PRACTICE: The benefits of continuing erlotinib upon progression alongside conventional chemotherapy are unclear. This randomized phase II study, initiated prior to the establishment of routine epidermal growth factor receptor (EGFR) mutation testing, addressed this clinically relevant issue through randomizing patients with prior clinical benefit from erlotinib (thereby enriching for EGFR-mutated tumors) upon progression in the second- or third-line setting to conventional chemotherapy (single-agent pemetrexed or docetaxel) with or without continued erlotinib. The results showed no benefit to continuing erlotinib beyond progression, while significantly more side effects were noted in the combination arm. Along with other recently presented study findings, these results argue against the routine practice of continuing erlotinib in this setting.

Outcomes of gamma knife radiosurgery, bi-modality & tri-modality treatment regimens for patients with one or multiple brain metastases: the Columbia University Medical Center experience.

Optimal treatment of brain metastases (BMs) is debatable. However, surgery or gamma knife radiosurgery (GKRS) improves survival when combined with whole brain radiotherapy (WBRT) versus WBRT alone. We retrospectively reviewed an institutional database of patients treated with GKRS for BMs from 1998 to 2013 to explore effects of single or multi-modality therapies on survival. There were 528 patients with median age 62 years. Histologies included 257 lung, 102 breast, 62 melanoma, 40 renal cell, 29 gastrointestinal, and 38 other primary cancers. Treatments included: 206 GKRS alone, 111 GKRS plus WBRT, 109 GKRS plus neurosurgical resection (NSG), and 102 all three modalities. Median overall survival (mOS) was 16.6 months. mOS among patients with one versus multiple metastasis was 17.2 versus 16.0 months respectively (p = 0.825). For patients with one BM, mOS following GKRS alone, GKRS plus WBRT, GKRS plus NSG, and all three modalities was 9.0, 19.1, 25.5, and 25.0 months, respectively, and for patients with multiple BMs, mOS was 8.6, 20.4, 20.7, 24.5 months for the respective groups. Among all patients, multivariate analysis confirmed that tri-modality group had the longest survival (HR 0.467; 95 % CI 0.350-0.623; p < 0.001) compared to GKRS alone; however, this was not significantly different than bi-modality approaches. Uncontrolled primary extra-CNS disease, age and KPS were also independent predictors of survival. Patients treated with GKRS plus NSG, GKRS plus WBRT, or all three modalities had improved OS versus GKRS alone. In our analysis, resection and GKRS allowed avoidance of WBRT without shortening survival.

Control of brain metastases from radioresistant tumors treated by stereotactic radiosurgery.

Renal cell carcinoma, sarcoma, and melanoma are considered to be "radioresistant" tumor histologies. Brain metastases (BM) from these tumors are considered unlikely to be controlled using the relatively low doses used in whole brain radiotherapy (WBRT). Our objective was to analyze the efficacy of stereotactic radiosurgery (SRS) on local control and overall survival of BM from radioresistant primary tumors. We reviewed all patients who received Gamma Knife Radiosurgery (GKRS) for BM at Columbia University Medical Center between January 2009 and April 2014. All patients were treated using the Gamma Knife Perfexion System. Dosimetric data was collected from treatment plans and metastases were categorized as radioresistant or not. Response was assessed by reviewing follow-up brain imaging studies and classified according to RECIST. Local control and median overall survival were calculated using the Kaplan-Meier method. In total, 373 tumors were analyzed from 126 patients. Of these tumors, 49 (13.1 %) originated from radioresistant cancers. The overall local control rate in the radioresistant cohort was 89.8 and 90.1 % in the non-radioresistant cohort. Univariate and multivariate analyses demonstrated that radioresistance status of the primary tumor had no statistically significant effect on local control with hazard ratios of 1.0 (p = 1.0, 95 % CI 0.388-2.576) and 0.954 (p = 0.926, 95 % CI 0.349-2.603) respectively. Median overall survival for both radioresistant and non-radioresistant cohorts was 20.0 months, with a p value of 0.926. There was no significant difference in local control of BM from radioresistant and non-radioresistant primary tumors treated with GKRS. Both cohorts showed excellent response and local control, suggesting that SRS upfront or in addition to WBRT may be an appropriate strategy in the treatment of BM from radioresistant cancers. Median overall survival for both cohorts was equal, suggesting that improved local control may be associated with an improvement in long-term survival.

Comparison of biochemical failure definitions for predicting local cancer recurrence following cryoablation of the prostate.

BACKGROUND: Various definitions of biochemical failure (BF) have been used to predict cancer recurrence following prostate cryoablation. However to date, none of these definitions have been validated for this use. We have reviewed several definitions of BF to determine their accuracy in predicting biopsy-proven local recurrence following prostate cryoablation. METHODS: The Columbia University Urologic Oncology Database was queried for patients who underwent prostate cryoablation between 1994 and 2010, and who subsequently underwent surveillance biopsy due to clinical suspicion of prostate cancer recurrence. Serial postoperative prostate-specific antigen (PSA) results were used to determine BF according to various definitions of BF. Biopsy results were used to determine local recurrence. Sensitivity, specificity, positive and negative predictive value, and receiver operating characteristic (ROC) curve area were calculated for each of the BF definitions. RESULTS: A total of 110 patients met inclusion criteria for the study. These patients were treated with primary full-gland (n = 38), primary focal (n = 24), or salvage cryoablation (n = 48). On surveillance biopsy, 66 patients (60%) were found to have locally recurrent prostate cancer. The most accurate BF definition overall was PSA nadir plus 2 ng/ml (Phoenix definition), with sensitivity, specificity, and ROC curve area of 68%, 59%, and 0.64, respectively. CONCLUSIONS: Overall, the Phoenix definition best predicted local cancer recurrence following prostate cryoablation. These preliminary data may be useful for researchers evaluating the short-term efficacy of cryoablation, and for urologists assessing their patients for potential cancer recurrence.

Timing of Adjuvant Radiotherapy in Glioblastoma Patients: A Single-Institution Experience With More Than 400 Patients.

BACKGROUND: The standard of care for patients with newly diagnosed glioblastoma (GBM) is maximal safe resection followed by adjuvant radiation therapy (RT) and temozolomide (TMZ). OBJECTIVE: To investigate whether the timing of adjuvant RT after surgery affected outcome in patients with GBM. METHODS: We retrospectively reviewed all patients with a diagnosis of GBM at our institution. A total of 447 patients were included in our analysis. Patients were divided into 3 equal groups based on the interval between surgery and RT. The primary outcome was overall survival (OS). RESULTS: Patients who began RT less than 21 days after surgery tended to be older, have a lower a Karnofsky Performance Status score, and higher recursive partitioning analysis class. These patients were more likely to have undergone biopsy only and received 3-dimensional conformal RT or 2-dimensional RT. The median OS for patients who started RT less than 21 days after surgery, between 21 and 32 days after surgery, and more than 32 days after surgery was 374, 465, and 478 days, respectively (P = .004). On multivariate Cox regression analysis, Karnofsky Performance Status score lower than 70, undergoing biopsy only, recursive partitioning analysis classes IV and V/VI, use of less than 36 Gy RT, and lack of TMZ chemotherapy were predictors of worse OS. The interval between surgery and RT was not significantly associated with OS on multivariate analysis. CONCLUSION: Patients who begin RT less than 21 days after surgery tend to have worse prognostic factors than those who begin RT later. When accounting for significant covariates, the effect of timing between surgery and RT is not significant.

Hypofractionated radiation therapy versus standard fractionated radiation therapy with concurrent temozolomide in elderly patients with newly diagnosed glioblastoma.

PURPOSE: Adjuvant hypofractionated radiation therapy (HRT) for elderly patients with newly diagnosed glioblastoma (GBM) is a reasonable option compared with standard fractionation radiation therapy (SFRT). Outcomes in patients receiving HRT in the presence of temozolomide (TMZ) compared with SFRT with TMZ are unclear. We examined HRT for GBM with TMZ in comparison to SFRT with TMZ. METHODS AND MATERIALS: We conducted a retrospective analysis of patients ≥60 years of age with newly diagnosed GBM who received SFRT or HRT from 1994 to 2014 in the postoperative setting. Inclusion criteria included SFRT (60 Gy/30 fractions or 59.4 Gy/33 fractions) versus HRT (40 Gy/15 fractions). RESULTS: In this cohort, 158 patients were treated with SFRT versus 26 with HRT. Median survival in patients receiving SFRT compared with HRT was 430 and 475 days (P = .550), respectively. Ninety-five percent of the SFRT patients received TMZ versus 100% of those treated with HRT. Patients receiving HRT were older (median, 72 vs 66 years). All HRT patients were treated with the intensity modulated radiation therapy (IMRT) technique versus SFRT, in which 57% had IMRT. Multivariate Cox regression showed decreased overall survival (OS) associated with patient age >70 (hazard ratio [HR], 1.84), lower Karnofsky performance status (HR, 5.25), biopsy versus surgical resection (HR, 4.18), radiation therapy planning technique 3- or 2-dimensional planning versus IMRT (HR, 1.91; HR, 3.40, respectively). Analysis restricted to patients receiving IMRT-based planning showed no difference in OS between HRT and SFRT. For patients receiving TMZ, there was no survival difference between those treated with HRT and those treated with SFRT. CONCLUSIONS: Elderly GBM patients receiving HRT and those receiving SFRT had similar OS. Subset analysis patients receiving concurrent TMZ showed no difference in OS between the HRT and SFRT groups.

A Modern Radiotherapy Series of Survival in Hispanic Patients with Glioblastoma.

BACKGROUND: Studies have shown racial differences in cancer outcomes. We investigate whether survival differences existed in Hispanic patients with glioblastoma (GBM) compared with other ethnicities from our modern radiotherapy series, because no study to date has focused on outcomes in this group after radiation therapy. METHODS: We retrospectively evaluated 428 patients diagnosed with GBM from 1996 to 2014 at our institution, divided into 4 groups based on self-report: white, black, Hispanic, and Asian/Indian. The primary outcome was overall survival. We analyzed differences in prognostic factors among the whole cohort compared with the Hispanic cohort alone. RESULTS: Baseline characteristics of the 4 racial groups were comparable. With a median follow-up of 387 days, no survival differences were seen by Kaplan-Meier analysis. Median overall survival for Hispanic patients was 355 days versus 450 days for the entire cohort. Factors significant for patient outcomes in the entire cohort differed slightly from those specific to Hispanic patients. Low Karnofsky Performance Status was significant on multivariate analysis in the whole population, but not in Hispanic patients. Extent of resection, recursive partitioning analysis class, and radiation therapy total dose were significant on multivariate analysis in both the whole population and Hispanic patients. CONCLUSIONS: We found that Hispanic patients with GBM had no difference in survival compared with other ethnicities in our cohort. Differences exist in factors associated with outcomes on single and multivariate analysis for Hispanic patients with GBM compared with the entire cohort. Additional studies focusing on Hispanic patients will aid in more personalized treatment approaches in this group.

Neurocognitive Deficits After Radiation Therapy for Brain Malignancies.

Radiotherapy (RT) has proven to be an effective therapeutic tool in treatment of a wide variety of brain tumors; however, it has a negative impact on quality of life and neurocognitive function. Cognitive dysfunction associated with both the disease and adverse effects of RT is one of the most concerning complication among long-term survivors. The effects of RT to brain can be divided into acute, early delayed, and late delayed. It is, however, the late delayed effects of RT that lead to severe neurological consequences such as minor-to-severe cognitive deficits due to irreversible focal or diffuse necrosis of brain parenchyma. In this review, we discuss current and emerging data regarding the relationship between RT and neurocognitive outcomes, and therapeutic strategies to prevent/treat postradiation neurocognitive deficits.

Increasing volume of non-neoplastic parenchyma in partial nephrectomy specimens is associated with chronic kidney disease upstaging.

INTRODUCTION: We examined the effect of non-neoplastic parenchymal volumes (NNPVs) in partial nephrectomy (PN) surgical specimens on long-term postoperative renal function. PN for renal cortical neoplasms has demonstrated superior long-term renal function outcomes compared with radical nephrectomy. Minimizing the distance between the surgical margin and tumor will reduce the NNPV removed. The role of NNPV on postoperative outcomes has been preliminarily investigated, with varying results. Thus, we sought to determine the association between the NNPV removed and postoperative chronic kidney disease (CKD) staging. MATERIALS AND METHODS: Our institutional database was queried for patients who had undergone PN from 1990 to 2012. The demographic and pathologic data were collected. The ellipsoid formula was used to calculate the surgical specimen and tumor volumes, which were then subtracted from each other to determine the NNPV. The estimated glomerular filtration rate (eGFR) was calculated using the Modification of Diet in Renal Disease formula. Binary logistic regression analysis was used to determine the predictors of postoperative CKD upstaging according to the eGFR. RESULTS: A total of 584 patients meeting the inclusion criteria had undergone PN. On binary logistic regression analysis, controlling for age, tumor volume, surgical modality, and preoperative CKD stage, an increasing NNPV in the surgical specimen was independently associated with postoperative CKD upstaging (odds ratio, 1.004; P = .007). CONCLUSION: An increasing NNPV removed during PN correlated with CKD upstaging using the eGFR; therefore, additional emphasis should be placed on healthy parenchymal preservation, with long-term follow-up to ensure adequate oncologic outcomes.

The Energy Index Does Not Affect Local Control of Brain Metastases Treated by Gamma Knife Stereotactic Radiosurgery.

BACKGROUND: The energy index (EI) is a measure of dose homogeneity within a target volume calculated by the integral dose divided by the product of prescription dose and tumor volume. OBJECTIVE: To assess whether a higher EI is associated with greater local control for brain metastases (BMs) treated by Gamma Knife radiosurgery (GKRS). METHODS: We reviewed all patients treated with GKRS for BM at our institution between January 2009 and February 2014. Data on the prescription dose, prescription isodose line, minimum dose, mean dose, integral dose, tumor volume, and EI were collected. Tumor response was assessed by reviewing follow-up brain imaging studies and classified according to the Response Evaluation Criteria in Solid Tumors. Local control per lesion and dosimetric prognostic factors for local control were assessed by univariate and multivariate Cox proportional hazards regression analyses. RESULTS: Of 213 patients treated, 126 had follow-up imaging available with a median follow-up of 6 months. Three hundred seventy-three individual tumors were analyzed. Of these, 133 showed a complete response, 157 showed a partial response, 46 remained stable, and 37 developed local failure. Tumors with EI ≥1.6 mJ·mL(-1)·Gy(-1) showed a higher rate of complete response. Local control rates at 6, 11, and 17 months were 95.4%, 86.5%, and 81.5%, respectively. On univariate analysis, the following factors were associated with higher rates of local failure: prescription doses of 16 and 18 Gy compared with a prescription dose of 20 Gy. The following factors were associated with a greater rate of local control: maximum dose and mean dose. On multivariate analysis, the only statistically significant factor associated with a greater rate of local failure was prescription dose of 16 Gy compared with 20 Gy. CONCLUSION: GKRS for BM results in a high rate of local control with an 11-month rate of 86.5%. A higher EI was not significantly associated with a higher rate of local control on multivariate analysis. Prescription dose was found to be the only significant predictor of local control on multivariate analysis.

Does lung cancer mutation status and targeted therapy predict for outcomes and local control in the setting of brain metastases treated with radiation?

BACKGROUND: We investigated effects of genetic alterations in epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), and Kirsten rat sarcoma viral oncogene homolog (KRAS) on overall survival (OS) and local control after stereotactic radiosurgery for brain metastases in non-small cell lung cancer (NSCLC). METHODS: A cohort of 89 out of 262 NSCLC patients (2003-2013) treated with gamma knife radiosurgery for brain metastases had genotyping available and were selected as our study population. RESULTS: Median follow-up was 12 months. Median OS rates for the EGFR, KRAS, echinoderm microtubule-associated protein-like 4 (EML4)-ALK mutated, and wild-type cohorts were 17, 7, 27, and 12 months, respectively (P = .019), and for targeted versus nontargeted therapy 21 and 11 months, respectively (P = .071). Targeted therapy was a strong predictor of increased OS on univariate (P = .037) and multivariate (P = .022) analysis. Gender, primary tumor controlled status, recursive partitioning analysis class, and graded prognostic assessment score were associated with OS (P < .05). On multivariate analysis, positive EGFR mutational status was a highly significant predictor for decreased survival (hazard ratio: 8.2; 95% CI: 2.0-33.7; P = .003). However, when we recategorized EGFR-mutant cases based on whether they received tyrosine kinase inhibitor, OS was no longer significantly shorter (hazard ratio: 1.5; P = .471). Median OS for patients with and without local failure was 17 and 12 months, respectively (P = .577). Local failure rates for EGFR, KRAS, EML4-ALK mutated, and wild-type cohorts by lesion were 8.7%, 5.4%, 4.3%, and 5.1%, respectively. CONCLUSIONS: This study suggests that EGFR tyrosine kinase mutation and ALK translocation results in improved survival to targeted therapies and that mutation status itself does not predict survival and local control in patients with brain metastases from NSCLC.

Successful treatment of a patient with Li-Fraumeni syndrome and metastatic lung adenocarcinoma harboring synchronous EGFR L858R and ERBB2 extracellular domain S310F mutations with the pan-HER inhibitor afatinib.

We report the case of a young, never-smoker woman with Li-Fraumeni syndrome and advanced lung adenocarcinoma refractory to multiple lines of conventional chemotherapy and negative for actionable alterations by routine testing. Comprehensive genomic profiling by clinical-grade next generation sequencing was performed on 3320 exons of 184 cancer-related genes and 37 introns of 14 genes frequently rearranged in cancer. The tumor was found to harbor both EGFR L858R and ERBB2 S310F alterations and also tested positive for a known TP53 germline mutation. The presence of the EGFR mutation was further validated by direct sequencing. Based on these results, a dual EGFR/ERBB2 inhibitor, afatinib, was chosen for treatment. The patient achieved a rapid, complete, and durable response to afatinib monotherapy, both clinically and radiographically. The treatment was very well tolerated. This unique case raises practical questions as to the challenges of molecular testing and highlights the potential association of p53 mutations with concurrent EGFR and ERBB2 aberrations. As this case powerfully illustrates, the combination of broad genomic profiling and targeted therapy guided by mutational analysis offers the possibility of precision management of refractory advanced adenocarcinoma in the background of neoplastic syndromes.