Phase II multicenter trial combining nivolumab and radiosurgery for NSCLC and RCC brain metastases.

Background: Anti-PD-1 has activity in brain metastases (BM). This phase II open labeled non-randomized single arm trial examined the safety and efficacy of combining nivolumab with radiosurgery (SRS) in the treatment of patients with BM from non-small cell lung cancer (NSCLC) and renal cell carcinoma (RCC). Methods: This was a multicenter trial (NCT02978404) in which patients diagnosed with NSCLC or RCC, having ≤ 10 cc of un-irradiated BM and no prior immunotherapy were eligible. Nivolumab (240 mg or 480 mg IV) was administered for up to 2 years until progression. SRS (15-21 Gy) to all un-irradiated BM was delivered within 14 days after the first dose of nivolumab. The primary endpoint was intracranial progression free survival (iPFS). Results: Twenty-six patients (22 NSCLC and 4 RCC) were enrolled between August 2017 and January 2020. A median of 3 (1-9) BM were treated with SRS. Median follow-up was 16.0 months (0.43-25.9 months). Two patients developed nivolumab and SRS related grade 3 fatigue. One-year iPFS and OS were 45.2% (95% CI 29.3-69.6%) and 61.3% (95% CI 45.1-83.3%), respectively. Overall response (partial or complete) of SRS treated BM was attained in 14 out of the 20 patients with ≥1 evaluable follow-up MRI. Mean FACT-Br total scores were 90.2 at baseline and improved to 146.2 within 2-4 months (P = .0007). Conclusions: The adverse event profile and FACT-Br assessments suggested that SRS during nivolumab was well tolerated. Upfront SRS with the initiation of anti-PD-1 prolonged the 1-year iPFS and achieved high intracranial control. This combined approach merits validation randomized studies.

Stereotactic Ablative Radiotherapy for oligo-progressive disease refractory to systemic therapy in Non-Small Cell Lung Cancer: A registry-based phase II randomized trial (SUPPRESS-NSCLC).

BACKGROUND: Management of Non-Small Cell Lung Cancer (NSCLC) patients with oligoprogression remains controversial. There is limited data to support the strategy of Stereotactic Ablative Radiotherapy (SABR) targeting the oligoprogressive disease in combination with ongoing systemic treatment. We aim to assess the benefit of this approach compared to standard of care in the treatment of oligoprogressive NSCLC. METHODS: This phase II study will enroll 68 patients with oligoprogressive NSCLC, defined as 1-5 progressive extracranial lesions ≤5 cm involving ≤3 organs. Patients on active systemic therapy (chemotherapy, immunotherapy, targeted therapy or a combination) will be randomized 1:1 to either continue their current systemic therapy in combination with SABR to all lesions or the standard of care (switch to the next line of treatment, continue same treatment or observation). The co-primary endpoints are progression-free survival (PFS) and overall survival (OS). Secondary endpoints include time to next systemic treatment, patient-reported quality of life, cost effectiveness as well as translational analysis to characterize both adaptive immunity and immunogenic cell death markers in the peripheral blood. DISCUSSION: There is an unmet need to carefully examine the efficacy, safety and quality of life impact of SABR in the context of oligoprogressive disease. The present study will provide higher level randomized evidence on the role of SABR in oligoprogressive NSCLC.

Adult Medulloblastoma Demographic, Tumor and Treatment Impact since 2006: A Canadian University Experience.

Medulloblastoma is an aggressive primary brain tumor that is extremely rare in adults; therefore, prospective studies are limited. We reviewed the information of all MB patients treated at the CHUM between 2006 and 2017. We divided our cohort by age and further divided adult patients (53%) in two groups, those diagnosed between 2006-2012 and 2013-2017. In our adult population, median follow up was 26 months and SHH-activated MB comprised 39% of tumors. Adult 5yOS was 80% and first-line therapy led to a 5yPFS of 77%. The absence of radiosensitizing chemotherapy (100% vs. 50%; p = 0.033) negatively influenced 5yPFS. 96% of adult patients received radiotherapy and 48% of them received concomitant radiosensitizing chemotherapy. Complete surgical resection was performed on 85% of adults, but the extent of resection did not have a discernable impact on survival and did not change with time. Adjuvant chemotherapy did not clearly affect prognosis (5yOS 80% vs. 67%, p = 0.155; 5yPFS 78% vs. 67%, p = 0.114). From 2006-2012, the most common chemotherapy regimen (69%) was Cisplatinum, Lomustine and Vincristine, which was replaced in 2013 by Cisplatinum, Etoposide and Cyclophosphamide (77%) with a trend for worse survival. Nine patients recurred and seven of these (78%) were treated with palliative chemotherapy. In conclusion, we did not identify prognostic demographic or tumor factors in our adult MB population. The presence of radiosensitizing chemotherapy was associated with a more favorable PFS. Cisplatinum, Lomustine and Vincristine regimen might be a better adjuvant chemotherapy regimen.

Survival in Patients With Brain Metastases: Summary Report on the Updated Diagnosis-Specific Graded Prognostic Assessment and Definition of the Eligibility Quotient.

PURPOSE: Conventional wisdom has rendered patients with brain metastases ineligible for clinical trials for fear that poor survival could mask the benefit of otherwise promising treatments. Our group previously published the diagnosis-specific Graded Prognostic Assessment (GPA). Updates with larger contemporary cohorts using molecular markers and newly identified prognostic factors have been published. The purposes of this work are to present all the updated indices in a single report to guide treatment choice, stratify research, and define an eligibility quotient to expand eligibility. METHODS: A multi-institutional database of 6,984 patients with newly diagnosed brain metastases underwent multivariable analyses of prognostic factors and treatments associated with survival for each primary site. Significant factors were used to define the updated GPA. GPAs of 4.0 and 0.0 correlate with the best and worst prognoses, respectively. RESULTS: Significant prognostic factors varied by diagnosis and new prognostic factors were identified. Those factors were incorporated into the updated GPA with robust separation (P < .01) between subgroups. Survival has improved, but varies widely by GPA for patients with non-small-cell lung, breast, melanoma, GI, and renal cancer with brain metastases from 7-47 months, 3-36 months, 5-34 months, 3-17 months, and 4-35 months, respectively. CONCLUSION: Median survival varies widely and our ability to estimate survival for patients with brain metastases has improved. The updated GPA (available free at brainmetgpa.com) provides an accurate tool with which to estimate survival, individualize treatment, and stratify clinical trials. Instead of excluding patients with brain metastases, enrollment should be encouraged and those trials should be stratified by the GPA to ensure those trials make appropriate comparisons. Furthermore, we recommend the expansion of eligibility to allow for the enrollment of patients with previously treated brain metastases who have a 50% or greater probability of an additional year of survival (eligibility quotient > 0.50).

Do Women Have Equal Chances for an Academic Career in Radiation Oncology in Canada? A Comparison With Related Specialties.

PURPOSE: The progress of women in academic medicine appears to be curtailed. We evaluated gender differences in academia for residents in radiation oncology compared with 2 of its related specialties, radiology and medical oncology, across Canada. METHODS AND MATERIALS: We analyzed abstracts presented between 2013 and 2016 at the annual meetings of the Canadian Association of Radiation Oncologists and compared it to the corresponding data for the meetings of the Canadian Association of Radiologists and Canadian Association of Medical Oncology. We further evaluated gender composition of abstracts, presentations, and publications available on PubMed. Conversion rates according to gender and to medical specialties were assessed. Proportions were compared using Fisher exact test or the chi-squared test. RESULTS: Among the 198 presented abstracts, 103 (52%) were published. Radiation oncology had the highest publishing rate with 90% (oncology 56%, radiology 40%). The publication rate between the medical specialties was significantly different (P < .001).Fifty-seven percent of abstracts presented by women were published versus 48% of abstracts presented by men. Overall, there was no significant difference between genders in terms of subsequent conversions into a scientific publication within each specialty (P = .25-1.0).In radiation oncology, women presented 67% of abstracts and published 95% of their presented abstracts, and in medical oncology, 66% of abstracts were from women and 57% of the presented abstracts were published. Among the published abstracts, 83% had the same first author in the abstract and the publication. Among those who lost their first-authorship status, 59% were women. However, there was no statistically significant difference between specialties for loss of first-author status. CONCLUSIONS: We observed that from 2013 to 2016, women had the highest presentation and publication rate in radiation oncology. More prospective data are needed to monitor the progress of women in all specialties and their specific needs.

Beyond an Updated Graded Prognostic Assessment (Breast GPA): A Prognostic Index and Trends in Treatment and Survival in Breast Cancer Brain Metastases From 1985 to Today.

PURPOSE: Brain metastases are a common sequelae of breast cancer. Survival varies widely based on diagnosis-specific prognostic factors (PF). We previously published a prognostic index (Graded Prognostic Assessment [GPA]) for patients with breast cancer with brain metastases (BCBM), based on cohort A (1985-2007, n = 642), then updated it, reporting the effect of tumor subtype in cohort B (1993-2010, n = 400). The purpose of this study is to update the Breast GPA with a larger contemporary cohort (C) and compare treatment and survival across the 3 cohorts. METHODS AND MATERIALS: A multi-institutional (19), multinational (3), retrospective database of 2473 patients with breast cancer with newly diagnosed brain metastases (BCBM) diagnosed from January 1, 2006, to December 31, 2017, was created and compared with prior cohorts. Associations of PF and treatment with survival were analyzed. Kaplan-Meier survival estimates were compared with log-rank tests. PF were weighted and the Breast GPA was updated such that a GPA of 0 and 4.0 correlate with the worst and best prognoses, respectively. RESULTS: Median survival (MS) for cohorts A, B, and C improved over time (from 11, to 14 to 16 months, respectively; P < .01), despite the subtype distribution becoming less favorable. PF significant for survival were tumor subtype, Karnofsky Performance Status, age, number of BCBMs, and extracranial metastases (all P < .01). MS for GPA 0 to 1.0, 1.5-2.0, 2.5-3.0, and 3.5-4.0 was 6, 13, 24, and 36 months, respectively. Between cohorts B and C, the proportion of human epidermal receptor 2 + subtype decreased from 31% to 18% (P < .01) and MS in this subtype increased from 18 to 25 months (P < .01). CONCLUSIONS: MS has improved modestly but varies widely by diagnosis-specific PF. New PF are identified and incorporated into an updated Breast GPA (free online calculator available at brainmetgpa.com). The Breast GPA facilitates clinical decision-making and will be useful for stratification of future clinical trials. Furthermore, these data suggest human epidermal receptor 2-targeted therapies improve clinical outcomes in some patients with BCBM.

Estrogen/progesterone receptor and HER2 discordance between primary tumor and brain metastases in breast cancer and its effect on treatment and survival.

BACKGROUND: Breast cancer treatment is based on estrogen receptors (ERs), progesterone receptors (PRs), and human epidermal growth factor receptor 2 (HER2). At the time of metastasis, receptor status can be discordant from that at initial diagnosis. The purpose of this study was to determine the incidence of discordance and its effect on survival and subsequent treatment in patients with breast cancer brain metastases (BCBM). METHODS: A retrospective database of 316 patients who underwent craniotomy for BCBM between 2006 and 2017 was created. Discordance was considered present if the ER, PR, or HER2 status differed between the primary tumor and the BCBM. RESULTS: The overall receptor discordance rate was 132/316 (42%), and the subtype discordance rate was 100/316 (32%). Hormone receptors (HR, either ER or PR) were gained in 40/160 (25%) patients with HR-negative primary tumors. HER2 was gained in 22/173 (13%) patients with HER2-negative primary tumors. Subsequent treatment was not adjusted for most patients who gained receptors-nonetheless, median survival (MS) improved but did not reach statistical significance (HR, 17-28 mo, P = 0.12; HER2, 15-19 mo, P = 0.39). MS for patients who lost receptors was worse (HR, 27-18 mo, P = 0.02; HER2, 30-18 mo, P = 0.08). CONCLUSIONS: Receptor discordance between primary tumor and BCBM is common, adversely affects survival if receptors are lost, and represents a missed opportunity for use of effective treatments if receptors are gained. Receptor analysis of BCBM is indicated when clinically appropriate. Treatment should be adjusted accordingly. KEY POINTS: 1. Receptor discordance alters subtype in 32% of BCBM patients.2. The frequency of receptor gain for HR and HER2 was 25% and 13%, respectively.3. If receptors are lost, survival suffers. If receptors are gained, consider targeted treatment.

Estimating survival in patients with gastrointestinal cancers and brain metastases: An update of the graded prognostic assessment for gastrointestinal cancers (GI-GPA).

BACKGROUND: Patients with gastrointestinal cancers and brain metastases (BM) represent a unique and heterogeneous population. Our group previously published the Diagnosis-Specific Graded Prognostic Assessment (DS-GPA) for patients with GI cancers (GI-GPA) (1985-2007, n = 209). The purpose of this study is to update the GI-GPA based on a larger contemporary database. METHODS: An IRB-approved consortium database analysis was performed using a multi-institutional (18), multi-national (3) cohort of 792 patients with gastrointestinal (GI) cancers, with newly-diagnosed BM diagnosed between 1/1/2006 and 12/31/2017. Survival was measured from date of first treatment for BM. Multiple Cox regression was used to select and weight prognostic factors in proportion to their hazard ratios. These factors were incorporated into the updated GI-GPA. RESULTS: Median survival (MS) varied widely by primary site and other prognostic factors. Four significant factors (KPS, age, extracranial metastases and number of BM) were used to formulate the updated GI-GPA. Overall MS for this cohort remains poor; 8 months. MS by GPA was 3, 7, 11 and 17 months for GPA 0-1, 1.5-2, 2.5-3.0 and 3.5-4.0, respectively. >30% present in the worst prognostic group (GI-GPA of ≤1.0). CONCLUSIONS: Brain metastases are not uncommon in GI cancer patients and MS varies widely among them. This updated GI-GPA index improves our ability to estimate survival for these patients and will be useful for therapy selection, end-of-life decision-making and stratification for future clinical trials. A user-friendly, free, on-line app to calculate the GPA score and estimate survival for an individual patient is available at brainmetgpa.com.

Diagnostic Reliability of Leptomeningeal Disease Using Magnetic Resonance Imaging.

Brain metastases are seen in 20%-50% of patients with metastatic solid tumors. On the other hand, leptomeningeal disease (LMD) occurs more rarely. The gold standard for the diagnosis of LMD is serial cerebrospinal fluid (CSF) analyses, although in daily practice, the diagnosis of LMD is often made by neuroimaging. Leptomeningeal metastases (LM) have been a relative contra-indication to radiosurgery. It can be noted that focal LMD can be difficult to distinguish from a superficially located/cortical-based brain metastasis which is not a contra-indication for radiosurgery. Hence, justifying the need of a reliable diagnosis method. The goal of this study was to determine the inter-observer reliability of contrast-enhanced magnetic resonance imaging (gdMRI) in the differentiation of focal cortical-based metastases from leptomeningeal spread. This is a retrospective review of a prospectively collected database of patients with brain metastases. A total of 42 cases with superficial lesions were selected for review. Additionally, eight control cases demonstrating deep and/or white-matter based lesions were included in the study. Three neuroradiologists and three radiation oncologists were asked to review each study and score the presence of LM. Inter-observer agreement was calculated using group-derived agreement coefficients (Gwet's AC1 and Gwet's AC2). Pair-wise inter-observer agreement coefficients never reached substantial values for trichotomized outcomes (LMD, non-LMD or indeterminate) but did reach a substantial value in a minority of cases for dichotomised outcomes (LMD or non-LMD). The control subgroup analysis revealed substantial agreement between most pairs for both trichotomized and dichotomised outcomes. We observed low inter-observer agreement amongst specialists for the diagnosis of focal LMD by gdMRI. Neuroimaging should not be relied upon to make treatment decisions, notably to deny patients radiosurgery.

Survival and prognostic factors in patients with gastrointestinal cancers and brain metastases: have we made progress?

The literature describing the prognosis of patients with gastrointestinal (GI) cancers and brain metastases (BM) is sparse. Our group previously published a prognostic index, the Graded Prognostic Assessment (GPA) for GI cancer patients with BM, based on 209 patients diagnosed from 1985-2005. The purpose of this analysis is to identify prognostic factors for GI cancer patients with newly diagnosed BM in a larger contemporary cohort. A multi-institutional retrospective IRB-approved database of 792 GI cancer patients with new BM diagnosed from 1/1/2006 to 12/31/2016 was created. Demographic data, clinical parameters, and treatment were correlated with survival and time from primary diagnosis to BM (TPDBM). Kaplan-Meier median survival (MS) estimates were calculated and compared with log-rank tests. The MS from time of first treatment for BM for the prior and current cohorts were 5 and 8 months, respectively (P < 0.001). Eight prognostic factors (age, stage, primary site, resection of primary tumor, Karnofsky Performance Status (KPS), extracranial metastases, number of BM and Hgb were found to be significant for survival, in contrast to only one (KPS) in the prior cohort. In this cohort, the most common primary sites were rectum (24%) and esophagus (23%). Median TPDBM was 22 months. Notably, 37% (267/716) presented with poor prognosis (GPA 0-1.0). Although little improvement in overall survival in this cohort has been achieved in recent decades, survival varies widely and multiple new prognostic factors were identified. Future work will translate these factors into a prognostic index to facilitate clinical decision-making and stratification of future clinical trials.

Estimating survival for renal cell carcinoma patients with brain metastases: an update of the Renal Graded Prognostic Assessment tool.

Background: Brain metastases are a common complication of renal cell carcinoma (RCC). Our group previously published the Renal Graded Prognostic Assessment (GPA) tool. In our prior RCC study (n = 286, 1985-2005), we found marked heterogeneity and variation in outcomes. In our recent update in a larger, more contemporary cohort, we identified additional significant prognostic factors. The purpose of this study is to update the original Renal-GPA based on the newly identified prognostic factors. Methods: A multi-institutional retrospective institutional review board-approved database of 711 RCC patients with new brain metastases diagnosed from January 1, 2006 to December 31, 2015 was created. Clinical parameters and treatment were correlated with survival. A revised Renal GPA index was designed by weighting the most significant factors in proportion to their hazard ratios and assigning scores such that the patients with the best and worst prognoses would have a GPA of 4.0 and 0.0, respectively. Results: The 4 most significant factors were Karnofsky performance status, number of brain metastases, extracranial metastases, and hemoglobin. The overall median survival was 12 months. Median survival for GPA groups 0-1.0, 1.5-2.0, 2.5-3, and 3.5-4.0 (% n = 25, 27, 30 and 17) was 4, 12, 17, and 35 months, respectively. Conclusion: The updated Renal GPA is a user-friendly tool that will help clinicians and patients better understand prognosis, individualize clinical decision making and treatment selection, provide a means to compare retrospective literature, and provide more robust stratification of future clinical trials in this heterogeneous population. To simplify use of this tool in daily practice, a free online application is available at brainmetgpa.com.

Anterolateral Cervical Kyphoplasty for Metastatic Cervical Spine Lesions.

STUDY DESIGN: Retrospective case series. PURPOSE: To evaluate the clinical and radiological efficacy of anterolateral kyphoplasty for cervical spinal metastasis. OVERVIEW OF LITERATURE: Although the spine is the third most common site of tumor metastasis, the cervical spine is the least commonly affected (incidence, 10%-15%). Surgical decompression is highly challenging because of the proximity of neural and vascular elements. Kyphoplasty for cervical spine metastasis has been described in small case reports with promising results. METHODS: Retrospective analysis of a prospective collected single-center spine metastasis database was done for cervical kyphoplasty cases. Data pertaining to age, sex, primary tumor diagnosis, modified Tokuhashi score, Spinal Instability Neoplastic Score (SINS), preoperative Visual Analog Scale (VAS) score, and analgesic medication were extracted. Postoperative data included VAS score at postoperative day 1, duration of hospitalization, self-reported functional outcome, and VAS score at the last follow-up. RESULTS: Eleven patients (mean age, 62.5 years) with cervical spine metastases were treated with 15-level kyphoplasty. Mean Tokuhashi score was 8.1, and mean SINS was 7.85. Mean preoperative pain score was 7.1, and 82% of patients used opioid analgesics. Mean total bleeding volume was 100 mL. Mean complication-free length of stay was 2.6 days with a decrease in postoperative pain (VAS score=2.8, p <0.05). There was a 56% decrease in opioid dosage and the number of consumed analgesics (1.09, p =0.004). Eightytwo percent of the patients reported excellent improvement at the last follow-up self-assessment. CONCLUSIONS: To our knowledge, this case series represents the largest series of vertebral augmentation using balloon kyphoplasty for cervical spinal metastasis. This technique is associated with low postoperative complications as well as significant decrease in pain, use of opioids, and length of hospital stay. The main indications for vertebral kyphoplasty are lytic lesions of the cervical spine, painful lesions refractory to medical treatment, SINS score of 6-10, and absence of posterior wall defect.

Effect of Targeted Therapies on Prognostic Factors, Patterns of Care, and Survival in Patients With Renal Cell Carcinoma and Brain Metastases.

PURPOSE: To identify prognostic factors, define evolving patterns of care, and the effect of targeted therapies in a larger contemporary cohort of renal cell carcinoma (RCC) patients with new brain metastases (BM). METHODS AND MATERIALS: A multi-institutional retrospective institutional review board-approved database of 711 RCC patients with new BM diagnosed from January 1, 2006, to December 31, 2015, was created. Clinical parameters and treatment were correlated with median survival and time from primary diagnosis to BM. Multivariable analyses were performed. RESULTS: The median survival for the prior/present cohorts was 9.6/12 months, respectively (P < .01). Four prognostic factors (Karnofsky performance status, extracranial metastases, number of BM, and hemoglobin b) were significant for survival after the diagnosis of BM. Of the 6 drug types studied, only cytokine use after BM was associated with improved survival. The use of whole-brain radiation therapy declined from 50% to 22%, and the use of stereotactic radiosurgery alone increased from 46% to 58%. Nonneurologic causes of death were twice as common as neurologic causes. CONCLUSIONS: Additional prognostic factors refine prognostication in this larger contemporary cohort. Patterns of care have changed, and survival of RCC patients with BM has improved over time. The reasons for this improvement in survival remain unknown but may relate to more aggressive use of local brain metastasis therapy and a wider array of systemic treatment options for those patients with progressive extracranial tumor.

Estimating Survival in Melanoma Patients With Brain Metastases: An Update of the Graded Prognostic Assessment for Melanoma Using Molecular Markers (Melanoma-molGPA).

PURPOSE: To update the Diagnosis-Specific Graded Prognostic Assessment (DS-GPA) for a markedly heterogeneous patient population, patients with melanoma and brain metastases, using a larger, more current cohort, including molecular markers. METHODS: The original Melanoma-GPA is based on data from 483 patients whose conditions were diagnosed between 1985 and 2005. This is a multi-institutional retrospective database analysis of 823 melanoma patients with newly diagnosed brain metastases from January 1, 2006, to December 31, 2015. Multivariable analyses identified significant prognostic factors, which were weighted and included in the updated index (Melanoma-molGPA). Multiple Cox regression was used to select and weight prognostic factors in proportion to their hazard ratios to design the updated Melanoma-molGPA in which scores of 4.0 and 0.0 are associated with the best and worst prognoses, as with all of the diagnosis-specific GPA indices. Log-rank tests were used to compare adjacent classes. RESULTS: There were 5 significant prognostic factors for survival (age, Karnofsky performance status [KPS], extracranial metastases [ECM], number of brain metastases, and BRAF status), whereas only KPS and the number of brain metastases were significant in the original Melanoma-GPA. Median survival improved from 6.7 to 9.8 months between the 2 treatment eras, and the median survival times for patients with Melanoma-molGPA of 0 to 1.0, 1.5 to 2.0, 2.5 to 3.0, and 3.5 to 4.0 were 4.9, 8.3, 15.8, and 34.1 months (P<.0001 between each adjacent group). CONCLUSIONS: Survival and our ability to estimate survival in melanoma patients with brain metastases has improved significantly. The updated Melanoma-molGPA, a user-friendly tool to estimate survival, will facilitate clinical decision making regarding whether and which treatment is appropriate and will also be useful for stratification of future clinical trials. To further simplify use, a free online/smart phone app is available at brainmetgpa.com.

The Prognostic Value of BRAF, C-KIT, and NRAS Mutations in Melanoma Patients With Brain Metastases.

PURPOSE: Brain metastases are a common problem in patients with melanoma, but little is known about the effect of gene mutations on survival in these patients. METHODS AND MATERIALS: We created a retrospective multi-institutional database of 823 patients with melanoma and brain metastases diagnosed between 2006 and 2015. Clinical parameters, gene mutation status (BRAF, C-KIT, NRAS), and treatment were correlated with survival. Treatment patterns and outcomes were compared with a prior era (1985-2005). RESULTS: BRAF status was known in 584 of 823 patients (71%). BRAF, NRAS, and C-KIT mutations were present in 51%, 22%, and 11% of tested patients, respectively. The median time from primary diagnosis to brain metastasis was 32 months, and overall median survival (MS) from the time of initial treatment of brain metastases was 10 months. MS for BRAF-positive and BRAF-negative patients was 13 months and 9 months, respectively (P=.02). There was no significant difference in MS in patients with or without NRAS or C-KIT mutations. The time from primary diagnosis to brain metastasis did not vary by mutation and was not associated with survival after the diagnosis of brain metastases. MS for the 1985 to 2005 and 2006 to 2015 cohorts was 6.7 months and 10.0 months, respectively (P<.01). Reflecting treatment-trend changes, use of whole-brain radiation therapy decreased from 48% to 26% during this period. Among BRAF-positive patients, 71% received targeted BRAF and/or MEK inhibitors and 57% received some combination of targeted therapy, chemotherapy, and/or immunotherapy. CONCLUSIONS: For melanoma patients with brain metastases, BRAF-positive patients survive longer than BRAF-negative patients and overall survival has improved from 1985-2005 to 2006-2015.

Limitations of Personalized Medicine and Gene Assays for Breast Cancer.

Adjuvant systemic treatments reduce the risk of breast cancer recurrence following the local treatment of primary stage I-III breast cancers. For patients with hormone-positive breast cancers receiving hormonal therapy, the risk of distant recurrence is under 20% and therefore, many patients may potentially be spared of chemotherapy. Consequently, several molecular signatures based on gene expression were developed to better determine which breast cancer patients would benefit from chemotherapy. We present the case of a 62-year-old woman diagnosed with an early stage hormone receptor-positive breast cancer that was treated with a partial mastectomy. Oncotype DX (Genomic Health, Redwood City, CA) molecular testing was performed on the surgical specimen, which reported a recurrence score of 0. The patient commenced adjuvant radiotherapy during which she developed symptoms suggestive of bone metastasis and was subsequently diagnosed with a spinal cord compression that required neurosurgery and radiotherapy. Pathology review of the specimen from the spine surgery revealed a metastatic breast carcinoma with neuroendocrine differentiation. Molecular assays such as Oncotype DX are increasingly used to prognosticate patient outcomes and help determine who may avoid chemotherapy. This case report seeks to illustrate that such assays should not be used in the presence of rare histological subtypes like neuroendocrine breast cancers, which are often under-reported. The current status of personalized medicine and gene assays in breast cancer is reviewed and potential strategies are suggested to identify these rare cases to better orient diagnostic and treatment decisions.

Efficiency of Crizotinib on an ALK-Positive Inflammatory Myofibroblastic Tumor of the Central Nervous System: A Case Report.

Inflammatory myofibroblastic tumors (IMT) of the central nervous system (CNS) are rare entities that have a predilection for local recurrences. Approximately half of the inflammatory myofibroblastic tumors contain translocations that result in the over-expression of the anaplastic lymphoma kinase (ALK) gene. We hereby present the case of a patient diagnosed with a left parieto-occipital IMT that recurred after multiple surgeries and radiotherapy. Immuno-histochemical examination of the tumor demonstrated ALK overexpression and the presence of an ALK rearrangement observed in lung cancers. The patient was subsequently started on an ALK inhibitor. A response evaluation criteria in solid tumors (RECIST) partial response was observed by the seventh month of ALK inhibition and the tumor remained in control for 14 months. The current case reiterates the activity of ALK inhibitors within the CNS and suggests that radiotherapy may potentiate the permeability of ALK inhibitors in CNS tumors addicted to ALK signalling.

The impacts of mid-treatment CBCT-guided patient repositioning on target coverage during lung VMAT.

INTRODUCTION: The purpose of this study is quantify intrafraction motion (IFM) during lung volumetric-modulated arc therapy (VMAT) and evaluate the impact of mid-treatment cone beam computed tomography (CBCT)-guided patient repositioning on target coverage. METHOD: This analysis included lung tumours treated with VMAT to 50-60 Gy in 3-5 fractions. Treatment planning was based on four-dimensional CT scans from which internal tumour volumes (ITV) were derived. An isotropic 5 mm margin was added to obtain the final planning target volume (PTV). Patients were treated supine with a customized dual vacuum immobilization device (BodyFIX, Elekta, Sweden). All patients underwent pre and mid-treatment CBCTs. Following each CBCT, a rigid registration was performed by a radiation oncologist. IFM was defined as the target displacement from pre to mid-treatment CBCT. For patients with an IFM vector ≥5 mm, a post hoc dose calculation analysis was performed to assess the dosimetric impact of CBCT-guided repositioning. RESULTS: Ninety-seven patients (367 fractions) were included. Mean (±SD) overall treatment time was 53:02 ± 13:08 min. Mean time for mid-treatment CBCT scan acquisition and patient repositioning was 15:49 ± 4:14 min. Mean IFM vector was 1.5 ± 1.4 mm (max = 8.1 mm) and was <5 mm in 354/367 (96%) of fractions. For all 13 fractions with an IFM vector ≥5 mm, dose calculation analysis of worst-case scenario indicates that ITV coverage would have remained ≥95% without mid-treatment repositioning. CONCLUSION: For 96% of fractions, the IFM vector was within the 5 mm PTV margin. Mid-treatment CBCT-guided couch repositioning did not significantly impact ITV coverage and prolonged treatment duration.

A Study of Pseudoprogression After Spine Stereotactic Body Radiation Therapy.

PURPOSE: To determine the incidence of pseudoprogression (PP) after spine stereotactic body radiation therapy based on a detailed and quantitative assessment of magnetic resonance imaging (MRI) morphologic tumor alterations, and to identify predictive factors distinguishing PP from local recurrence (LR). METHODS AND MATERIALS: A retrospective analysis of 35 patients with 49 spinal segments treated with spine stereotactic body radiation therapy, from 2009 to 2014, was conducted. The median number of follow-up MRI studies was 4 (range, 2-7). The gross tumor volumes (GTVs) within each of the 49 spinal segments were contoured on the pretreatment and each subsequent follow-up T1- and T2-weighted MRI sagittal sequence. T2 signal intensity was reported as the mean intensity of voxels constituting each volume. LR was defined as persistent GTV enlargement on ≥2 serial MRI studies for ≥6 months or on pathologic confirmation. PP was defined as a GTV enlargement followed by stability or regression on subsequent imaging within 6 months. Kaplan-Meier analysis was used for estimation of actuarial local control, disease-free survival, and overall survival. RESULTS: The median follow-up was 23 months (range, 1-39 months). PP was identified in 18% of treated segments (9 of 49) and LR in 29% (14 of 49). Earlier volume enlargement (5 months for PP vs 15 months for LR, P=.005), greater GTV to reference nonirradiated vertebral body T2 intensity ratio (+30% for PP vs -10% for LR, P=.005), and growth confined to 80% of the prescription isodose line (80% IDL) (8 of 9 PP cases vs 1 of 14 LR cases, P=.002) were associated with PP on univariate analysis. Multivariate analysis confirmed an earlier time to volume enlargement and growth within the 80% IDL as significant predictors of PP. LR involved the epidural space in all but 1 lesion, whereas PP was confined to the vertebral body in 7 of 9 cases. CONCLUSIONS: PP was observed in 18% of treated spinal segments. Tumor growth confined to the 80% IDL and earlier time to tumor enlargement were predictive for PP.

Assessment of function and quality of life in a phase II multi-institutional clinical trial of fractionated simultaneous in-field boost radiotherapy for patients with 1-3 metastases.

We examined functional outcomes and quality of life of whole brain radiotherapy (WBRT) with integrated fractionated stereotactic radiotherapy boost (FSRT) for brain metastases treatment. Eighty seven people with 1-3 brain metastases (54/87 lung primary, 42/87 single brain metastases) were enrolled on this Phase II trial of WBRT (30 Gy/10) + simultaneous FSRT, (60 Gy/10). Median overall follow-up and survival was 5.4 months, 6 month actuarial intra-lesional control was 78 %; only 1 patient exhibited grade 4 toxicity (worsened seizures); most treatment related toxicity was grade 1 or 2; 2/87 patients demonstrated asymptomatic radiation necrosis on follow-up imaging. Mean (Min-Max) baseline KPS, Mini Mental Status Exam (MMSE) and FACT-BR quality of life were 83 (70-100), 28 (21-30) and 143 (98-153). Lower baseline MMSE (but not KPS or FACT-Br) was associated with worse survival after adjusting for age, number of metastases, primary and extra-cranial disease status. Crude rates of deterioration (>10 points decrease from baseline for KPS and FACT-Br, MMSE fall to <27) ranged from 26 to 38 % for KPS, 32-59 % for FACT-Br and 0-16 % for MMSE depending on the time-point assessed with higher rates generally noted at earlier time points (≤6 months post-treatment). Using a linear mixed models analysis, significant declines from baseline were noted for KPS and FACT-Br (largest effects at 6 weeks to 3 months) with no significant change in MMSE. The effects on function and quality of life of this integrated treatment of WBRT + simultaneous FSRT were similar to other published series combining WBRT + radiosurgery.