Patterns of neurological adverse events among a retrospective cohort of patients receiving immune checkpoint inhibitors.

Aim: Neurological adverse events (NAEs) are infrequent immune checkpoint inhibitor (ICI) outcomes poorly characterized in extant research, complicating their clinical management. Methods: This study characterized the frequency, severity, patterning and timing of NAEs using a large retrospective registry, including all patients who received at least one dose of an ICI from 2/1/2011-4/7/2022 within our health network. Results: Among 3137 patients, there were 54 NAEs (1.72% any grade; 0.8% grade 3-4). Most NAEs were peripheral (57.4%) versus central (42.6%). Melanoma and renal cell carcinoma were significantly associated with NAEs. Conclusion: The incidence of NAEs was rare though higher than many prior case estimates; the timing was consistent with other AEs. NAEs frequently occurred in tumor types known to favor brain metastases.

Immune checkpoint inhibitors are new drugs for cancer. They boost your body's defenses to fight cancer cells. These drugs can be used alone or with other cancer treatments. Most people are okay with these medicines, but some might have problems in different parts of the body. This can be tricky to figure out. Rarely, there can be issues in the brain or nerves. These side effects are rare, happening in about 2 in every 100 people who use the drugs. They are more common in certain cancers like melanoma and kidney cancer. As doctors learn more about these side effects, they can better predict, treat, and prevent them.

Reducing Anxiety and Dyspnea via Device-Guided Breathing (RELAX): A Multi-Site Feasibility Study in Post-Treatment Lung Cancer Survivors at Community Cancer Clinics (WF-01213).

INTRODUCTION: Anxiety and dyspnea are 2 common symptoms for lung cancer survivors. Although research suggests decreasing respiration rate can reduce anxiety in several populations, potential benefits of device-guided breathing have not been studied in lung cancer survivors. This feasibility study (WF-01213) provides estimates of accrual, adherence, retention, and preliminary efficacy of 2 doses of a device-guided breathing intervention versus a usual breathing control group for improving self-reported anxiety and dyspnea in post-treatment lung cancer survivors. METHODS: Stage I-IV lung cancer survivors were recruited through the NCI Community Oncology Research Program (NCORP) and randomized to 12 weeks of a device-guided breathing intervention (high dose vs. low dose) or control device. Self-reported outcomes (anxiety, depression, dyspnea, cancer-related worry, fatigue) were assessed at baseline, mid-intervention (Week-6), and post-intervention (Week-12). RESULTS: Forty-six participants (ages 41-77, median = 65; 78% White) were randomized to the high-dose intervention (n = 14), low-dose intervention (n = 14), or control (n = 18) groups between July 2015 and September 2019. Study accrual rate was 0.92 per month for 50 months (projected accrual was 6.3/month). Fourteen participants (30%) withdrew early from the study, with almost half of those discontinuing at or immediately following baseline assessment. No participants were adherent with the intervention per protocol specifications. The proportion minimally adherent (using device at least 1x/week) was 43% (6/14), 64% (9/14), and 61% (11/18) for high-dose, low-dose, and control groups, respectively. Anxiety significantly decreased from baseline for all groups at Week 12. Adherence to the intervention was low across all treatment groups. CONCLUSIONS: This study did not establish feasibility of a community-based randomized trial of 2 doses of device-guided breathing and a control group using an identical-looking device for lung cancer survivors. In both the high-dose and control groups, there were significant improvements from baseline for anxiety and dyspnea. In the low-dose group, there were significant improvements from baseline for anxiety and depression. Ratings and feedback on the intervention were mixed (although leaned in a positive direction). Participants reported liking the feeling of relaxation/calm, helping others, breathing awareness, and music. Participants reporting liking least finding/making time to use the device, frustration with the device, and completing study forms. TRIAL REGISTRATION: CLINICAL TRIALS ID: NCT02063828, clinicaltrials.gov.

Team-Based Hospice Referrals: A Potential Quality Metric for Lung Cancer in the Immunotherapy Era.

BACKGROUND: Immune checkpoint inhibitors (ICIs) can lead to durable responses in patients with lung cancer but may delay transitions to hospice at the end of life (EOL). We aimed to test the association of continuity of care with EOL outcomes in the ICI era. METHODS: We collected retrospective data on all patients with lung cancer who started ICI treatment at a single comprehensive cancer center in the United States (1/1/14-5/1/18) and subsequently died. We defined a hospice referral as having continuity of care if placed by a provider from the patient's multidisciplinary cancer team (e.g., a medical oncologist, palliative care specialist, intensivist, and hospitalist). RESULTS: In this cohort of 143 patients, 58% had a team-based hospice referral which was associated with a lower risk of death in the hospital. The most common reason patients declined hospice at EOL was an unwillingness to discontinue cancer-directed therapy. As compared to a similar historical cohort of patients treated with chemotherapy alone (2008-2010), there was a similar rate of hospice referral (68% vs 74%) but higher rates of new systemic therapy initiated within 30 days of death (17% vs 6%, p .001) and last dose within 14 days of death (13% vs 5%, p .005). CONCLUSIONS: Future studies should test the continuity of care at EOL as a new quality metric for advanced NSCLC.

SMARCA4 mutations in KRAS-mutant lung adenocarcinoma: a multi-cohort analysis.

KRAS is a key oncogenic driver in lung adenocarcinoma (LUAD). Chromatin-remodeling gene SMARCA4 is comutated with KRAS in LUAD; however, the impact of SMARCA4 mutations on clinical outcome has not been adequately established. This study sought to shed light on the clinical significance of SMARCA4 mutations in LUAD. The association of SMARCA4 mutations with survival outcomes was interrogated in four independent cohorts totaling 564 patients: KRAS-mutant patients with LUAD who received nonimmunotherapy treatment from (a) The Cancer Genome Atlas (TCGA) and (b) the MSK-IMPACT Clinical Sequencing (MSK-CT) cohorts; and KRAS-mutant patients with LUAD who received immune checkpoint inhibitor-based immunotherapy treatment from (c) the MSK-IMPACT (MSK-IO) and (d) the Wake Forest Baptist Comprehensive Cancer Center (WFBCCC) immunotherapy cohorts. Of the patients receiving nonimmunotherapy treatment, in the TCGA cohort (n = 155), KRAS-mutant patients harboring SMARCA4 mutations (KS) showed poorer clinical outcome [P = 6e-04 for disease-free survival (DFS) and 0.031 for overall survival (OS), respectively], compared to KRAS-TP53 comutant (KP) and KRAS-only mutant (K) patients; in the MSK-CT cohort (n = 314), KS patients also exhibited shorter OS than KP (P = 0.03) or K (P = 0.022) patients. Of patients receiving immunotherapy, KS patients consistently exhibited the shortest progression-free survival (PFS; P = 0.0091) in the MSK-IO (n = 77), and the shortest PFS (P = 0.0026) and OS (P = 0.0014) in the WFBCCC (n = 18) cohorts, respectively. Therefore, mutations of SMARCA4 represent a genetic factor leading to adverse clinical outcome in lung adenocarcinoma treated by either nonimmunotherapy or immunotherapy.

Pleural Effusion Aspirate for use in 3D Lung Cancer Modeling and Chemotherapy Screening.

Lung cancer is the leading cause of cancer-related death worldwide yet in vitro disease models have been limited to traditional 2D culture utilizing cancer cell lines. In contrast, recently developed 3D models (organoids) have been adopted by researchers to improve the physiological relevance of laboratory study. We have hypothesized that 3D hydrogel-based models will allow for improved disease replication and characterization over standard 2D culture using cells taken directly from patients. Here, we have leveraged the use of 3D hydrogel-based models to create lung cancer organoids using a unique cell source, pleural effusion aspirate, from multiple lung cancer patients. With these 3D models, we have characterized the cell populations comprising the pleural effusion aspirate and have tracked phenotypic changes that develop during short-term in vitro culture. We found that isolated, patient cells placed directly into organoids created anatomically relevant structures and exhibited lung cancer specific behaviors. On the other hand, cells first grown in plastic dishes and then cultured in 3D did not create similar structures. Further, we have been able to compare chemotherapeutic response of patient cells between 2D and 3D cell culture systems. Our results show that cells in 2D culture were more sensitive to treatment when compared with 3D organoids. Collectively, we have been able to utilize tumor cells from pleural effusion fluid of lung cancer patients to create organoids that display in vivo like anatomy and drug response and thus could serve as more accurate disease models for study of tumor progression and drug development.

Immunotherapy is associated with improved survival and decreased neurologic death after SRS for brain metastases from lung and melanoma primaries.

BACKGROUND: The effect of immunotherapy on brain metastasis patients remains incompletely understood. Our goal was to evaluate its effect on survival, neurologic death, and patterns of failure after stereotactic radiosurgery (SRS) without prior whole-brain radiation therapy (WBRT) in patients with lung and melanoma primaries metastatic to the brain. METHODS: We performed a retrospective analysis of 271 consecutive lung or melanoma patients treated with upfront SRS for brain metastases between 2013 and 2018. Of these patients, 101 (37%) received immunotherapy and 170 (63%) did not. Forty-three percent were treated with nivolumab. Thirty-seven percent were treated with pembrolizumab. Fifteen percent were treated with ipilimumab. One percent were treated with a combination of nivolumab and ipilimumab. One percent were treated with atezolizumab. Three percent were treated with another immunotherapy regimen. Survival was estimated by the Kaplan-Meier method and cumulative incidences of neurologic death, and local and distant brain failure were estimated using death as a competing risk. RESULTS: The median overall survival (OS) of patients treated with immunotherapy vs without was 15.9 (95% CI: 13.3 to 24.8) vs 6.1 (95% CI: 5.1 to 8.8) months (P < .01). The 1-year cumulative incidence of neurologic death was 9% in patients treated with immunotherapy vs 23% in those treated without (P = .01), while nonneurologic death was not significantly different (29% vs 41%, P = .51). Median brain metastasis velocity (BMV) did not differ between groups, and rates of salvage SRS and WBRT were similar. CONCLUSIONS: The use of immunotherapy in patients with lung cancer or melanoma metastatic to the brain treated with SRS is associated with improved OS and decreased incidence of neurologic death.

Circulating immune biomarkers as predictors of the response to pembrolizumab and weekly low dose carboplatin and paclitaxel in NSCLC and poor PS: An interim analysis.

The combination of standard-dose chemotherapy and immunotherapy has been shown to be beneficial for patients with non-small cell lung cancer (NSCLC) with good performance status (PS). However, treatment options for patients with poor PS are limited. In the present study, the feasibility and immunological effects of low-dose chemotherapy with carboplatin and paclitaxel combined with immunotherapy with pembrolizumab were examined in patients with metastatic NSCLC and a poor PS. Patients with advanced NSCLC and a PS of 2 were randomized to single-agent pembrolizumab at 200 mg every 3 weeks or pembrolizumab combined with weekly carboplatin area under the curve 1 and paclitaxel 25 mg/m2. Blood for circulating immune cell phenotyping, soluble program death ligand 1 (sPD-L1) and immune-modulatory microRNAs (miRNAs) was collected prior to treatment and at weeks 4 and 7. Ten patients were randomized to the combination arm and 10 to the single-agent arm. Therapy was well tolerated. Four patients discontinued carboplatin due to hypersensitivity reactions but continued pembrolizumab and paclitaxel treatments. Increases in activated CD4+ T cells and in immune-regulatory miRNA, and decreases in myeloid derived suppressor cells were observed in the blood of patients in the combination arm and not in the single-agent arm. Changes in circulating regulatory T cells and sPD-L1 were not observed. Seven patients in the combination arm manifested a partial response compared with only two in the single-agent arm. Weekly low-dose chemotherapy carboplatin and paclitaxel was well tolerated and immunologically active when combined with pembrolizumab in patients with advanced NSCLC and a PS of 2. This combination merits further study in this patient population.

Frailty assessment predicts toxicity during first cycle chemotherapy for advanced lung cancer regardless of chronologic age.

BACKGROUND: Improved assessment strategies are needed to individualize treatment for adults of all ages receiving palliative chemotherapy for non-small cell lung cancer (NSCLC). Our aim was to evaluate the utility of the Fried Frailty Index (FFI) and a cancer-specific geriatric assessment (GA) to predict chemotherapy toxicity and overall survival (OS). METHODS: We conducted a multi-site pilot study of 50 patients with newly diagnosed advanced NSCLC, age ≥ 18 years. All participants received carboplatin AUC 6, paclitaxel 200 mg/m2 every 3 weeks. FFI and the GA were administered prior to chemotherapy. A GA toxicity risk score was calculated. Grade 3-5 toxicity was assessed during 1st two cycles of chemotherapy. OS was measured from chemotherapy initiation. Logistic regression and Cox proportional hazards models were fit to estimate the association between baseline characteristics and toxicity and OS respectively. RESULTS: Among 50 participants, 48 received chemotherapy and were evaluable. The mean age was 68.5 y (range 42-86), 79% male, 85% KPS ≥80. The median OS was 8 months. Many (27%) met FFI criteria for frailty with ≥3 impairments. Impairments detected by the GA were common. In multivariable analyses both FFI ≥ 3 and GA toxicity risk score > 7 were independently associated with higher odds of toxicity (Odds ratio [OR] 7.0; 95% confidence interval [CI] 1.1-44.6 and OR 4.3; 95% CI 1.0-17.7, respectively) in first cycle chemotherapy. Neither score was associated with OS. CONCLUSIONS: Frailty predicts chemotherapy toxicity during first cycle. Frailty assessment may inform toxicity risk regardless of chronologic age.

Severe neurologic complications of immune checkpoint inhibitors: a single-center review.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are a promising class of anticancer drugs associated with immune-related adverse events (IRAEs). In registration studies of selected cancer populations, neurologic IRAEs were rare. Post-marketing experience describing their prevalence in clinical practice continues to be reported. METHODS: A retrospective cohort of patients treated at our institution with ICIs from 2005 to 2017 was identified. Patients with new neurologic ICD codes documented during or after ICI treatment were enrolled. Comprehensive medical record review identified patients with neurologic IRAEs causally linked to ICIs. This study focused on CTCAE grade 2-4 IRAEs. RESULTS: 526 patients were screened; 55 candidate patients were identified; 5 cases met criteria for neurologic IRAEs, an incidence of 0.95% (n = 5/526). IRAEs identified were transverse myelopathy, demyelinating sensorimotor polyneuropathy, oculomotor nerve palsy, sensory neuropathy, and posterior reversible encephalopathy syndrome. ICIs were held in three patients, rechallenged in one, and dose-reduced in one. Corticosteroids were given in three patients, and response varied from complete symptom resolution to minimal response and ultimately death. Other treatments were based on IRAE presentation, including gabapentin, antihypertensives, and IV immunoglobulin. Patients with combination therapy appeared to suffer more severe IRAEs producing more substantial long-term morbidity and mortality. CONCLUSION: In this clinical practice study, the incidence of neurologic IRAEs from ICIs was 0.95%. Although rare, neurologic IRAEs can be highly variable and severe, and patients with combination immunotherapy appeared to suffer more severe IRAEs. Neurologists play an important role in the early identification and management of IRAEs to reduce long-term morbidity and mortality.

Cure of Oligometastatic Classic Biphasic Pulmonary Blastoma Using Aggressive Tri-modality Treatment: Case Series and Review of the Literature.

Pulmonary blastoma is a rare lung cancer classified into three subtypes: classic biphasic pulmonary blastoma (CBPB), well-differentiated fetal adenocarcinoma (WDFA), and pleuropulmonary blastoma (PPB) of childhood. Compared to the other subtypes, CPPB is an aggressive tumor with an overall five-year survival of 16% across all stages. We present two cases of biopsy-proven metastatic CBPB, who have been disease-free for over 10 years since treatment completion. Both patients were treated with surgery to the primary tumor followed by an adjuvant cisplatin-based chemotherapy for four cycles and thoracic radiation. One patient relapsed shortly after the completion of thoracic radiation with brain metastases and underwent craniotomy, gamma knife radiosurgery (GKRS), and whole brain radiation therapy. The other patient presented with synchronous pelvic metastases and underwent metastasectomy after the completion of chemotherapy but before the initiation of thoracic radiation. We review the literature regarding surgical, chemotherapeutic, and radiation treatment for patients with metastatic pulmonary blastoma. Based on our experience and review of the existing case reports, aggressive tri-modality treatment including surgery, chemotherapy with a cisplatin backbone, and a definitive treatment of oligometastatic lesions amenable to local therapy including resection or radiosurgery is reasonable to consider for medically fit patients with CBPB.

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.

The Impact of Hospice Services in the Care of Patients with Advanced Stage Nonsmall Cell Lung Cancer.

INTRODUCTION: Prior research has shown that advanced stage nonsmall cell lung cancer (NSCLC) patients enrolled in hospice care receive less aggressive treatment at the end of life (EOL) without compromising survival. Our purpose was to profile the continuum of care of these patients, exploring the connection between hospice enrollment and quality indicators for excellence in EOL cancer care. METHODS: One hundred ninety-seven deceased stage IV NSCLC patients diagnosed between 2008 and 2010 at two separate tertiary care centers within the same county were identified. A retrospective review was conducted, collecting data from electronic medical records regarding antitumor treatment, postdiagnosis hospital visits and admissions, hospice referrals and enrollments, and circumstances surrounding the patient's death. Patients were grouped by their status of hospice enrollment, and the remainder of the measures compared accordingly. RESULTS: There was no significant difference found in total number of postdiagnosis hospital admissions between the patients who were enrolled in hospice and those who were not. However, the group who received hospice services had a significantly lower number of hospitalizations (p < 0.001), emergency department visits (p < 0.01), and intensive care unit admissions in the last 30 days of life (p < 0.001). The number of lines of chemotherapy received did not differ significantly between the groups. Median survival, measured by the length of time between diagnosis and death, was significantly longer for hospice patients (p = 0.02). CONCLUSIONS: This study demonstrates that, among patients with metastatic NSCLC, hospice enrollment was associated with optimized EOL oncological care and a significantly longer median survival.

A Phase II Clinical Trial of CPI-613 in Patients with Relapsed or Refractory Small Cell Lung Carcinoma.

BACKGROUND: Small cell lung cancer (SCLC) is a common lung cancer which presents with extensive stage disease at time of diagnosis in two-thirds of patients. For treatment of advanced disease, traditional platinum doublet chemotherapy induces response rates up to 80% but with few durable responses. CPI-613 is a novel anti-cancer agent that selectively inhibits the altered form of mitochondrial energy metabolism in tumor cells. METHODS: We evaluated CPI-613 with a single-arm, open-label phase II study in patients with relapsed or refractory SCLC. CPI-613 was given at a dose of 3,000 mg/m2 on days 1 and 4 of weeks 1-3 of 4 week cycle. The primary outcome was response rate as assessed by CT imaging using RECIST v1.1 criteria. Secondary outcomes were progression-free survival (PFS), overall survival (OS), and toxicity. Twelve patients were accrued (median age 57yo) who had previously received between 1 and 4 lines of chemotherapy (median 1) for SCLC with a treatment-free interval of less than 60 days in 9 of the 12 patients. RESULTS: No complete or partial responses were seen. Ten patients (83%) progressed as best response and 2 (17%) were not evaluable for response. Median time to progression was 1.7 months (range 0.7 to 1.8 months). Eleven patients (92%) died with median overall survival of 4.3 months (range 1.2 to 18.2 months). The study was closed early due to lack of efficacy. Of note, three out of three patients who progressed after CPI-613 and were subsequently treated with standard topotecan then demonstrated treatment response with survival for 18.2, 7.4, and 5.1 months. We conducted laboratory studies which found synergy in-vitro for CPI-613 with topotecan. CONCLUSIONS: Single agent CPI-613 had no efficacy in this study. Further study of CPI 613 in combination with a topoisomerase inhibitor is warranted.

Is a Clinical Target Volume (CTV) Necessary in the Treatment of Lung Cancer in the Modern Era Combining 4-D Imaging and Image-guided Radiotherapy (IGRT)?

OBJECTIVE: We hypothesized that omission of clinical target volumes (CTV) in lung cancer radiotherapy would not compromise control by determining retrospectively if the addition of a CTV would encompass the site of failure. METHODS: Stage II-III patients were treated from 2009-2012 with daily cone-beam imaging and a 5 mm planning target volume (PTV) without a CTV. PTVs were expanded 1 cm and termed CTVretro. Recurrences were scored as 1) within the PTV, 2) within CTVretro, or 3) outside the PTV. Locoregional control (LRC), distant control (DC), progression-free survival (PFS), and overall survival (OS) were estimated. RESULT: Among 110 patients, Stage IIIA 57%, IIIB 32%, IIA 4%, and IIB 7%. Eighty-six percent of Stage III patients received chemotherapy. Median dose was 70 Gy (45-74 Gy) and fraction size ranged from 1.5-2.7 Gy. Median follow-up was 12 months, median OS was 22 months (95% CI 19-30 months), and LRC at two years was 69%. Fourteen local and eight regional events were scored with two CTVretro failures equating to a two-year CTV failure-free survival of 98%. CONCLUSION: Omission of a 1 cm CTV expansion appears feasible based on only two events among 110 patients and should be considered in radiation planning.

Image guided radiation therapy may result in improved local control in locally advanced lung cancer patients.

PURPOSE: Image guided radiation therapy (IGRT) is designed to ensure accurate and precise targeting, but whether improved clinical outcomes result is unknown. METHODS AND MATERIALS: A retrospective comparison of locally advanced lung cancer patients treated with and without IGRT from 2001 to 2012 was conducted. Median local failure-free survival (LFFS), regional, locoregional failure-free survival (LRFFS), distant failure-free survival, progression-free survival, and overall survival (OS) were estimated. Univariate and multivariate models assessed the association between patient- and treatment-related covariates and local failure. RESULTS: A total of 169 patients were treated with definitive radiation therapy and concurrent chemotherapy with a median follow-up of 48 months in the IGRT cohort and 96 months in the non-IGRT cohort. IGRT was used in 36% (62 patients) of patients. OS was similar between cohorts (2-year OS, 47% vs 49%, P = .63). The IGRT cohort had improved 2-year LFFS (80% vs 64%, P = .013) and LRFFS (75% and 62%, P = .04). Univariate analysis revealed IGRT and treatment year improved LFFS, whereas group stage, dose, and positron emission tomography/computed tomography planning had no impact. IGRT remained significant in the multivariate model with an adjusted hazard ratio of 0.40 (P = .01). Distant failure-free survival (58% vs 59%, P = .67) did not differ significantly. CONCLUSION: IGRT with daily cone beam computed tomography confers an improvement in the therapeutic ratio relative to patients treated without this technology.

Hemolytic anemia in two patients with glioblastoma multiforme: A possible interaction between vorinostat and dapsone.

Patients undergoing treatment for glioblastoma multiforme are routinely placed on prophylactic treatment for Pneumocystis jirovecii pneumonia because of significant therapy-induced lymphopenia. In patients with sulfa allergies, dapsone prophylaxis is often used due to its efficacy, long half-life, cost effectiveness, and general safety at low doses. However, dapsone may uncommonly induce a hemolytic anemia, particularly in patients deficient of glucose-6-phosphate dehydrogenase. This hemolysis is thought to be a result of oxidative stress on red blood cells induced by dapsone metabolites which produce reactive oxygen species that disrupt the red blood cell membrane and promote splenic sequestration. A single case report of dapsone-induced hemolytic anemia in a patient with glioblastoma multiforme has been reported. We present two patients with glioblastoma multiforme who developed severe hemolytic anemia shortly after initiating therapy with vorinostat, a pan-active histone deacetylase inhibitor, while on prophylactic dapsone. There are several potential mechanisms by which histone deacetylase inhibition may alter dapsone metabolism including changes in hepatic acetylation or N-glucuronidation leading to an increase in the bioavailability of dapsone's hematotoxic metabolites. In addition, vorinostat may lead to increased hemolysis through inhibition of heat shock protein-90, a chaperone protein that maintains the integrity of the red blood cell membrane cytoskeleton. The potential interaction between dapsone and vorinostat may have important clinical implications as more than 10 clinical trials evaluating drug combinations with vorinostat in patients with malignant glioma are either ongoing or planned in North America.

Management of mediastinal relapse after treatment with stereotactic body radiotherapy or accelerated hypofractionated radiotherapy for stage I/II non-small-cell lung cancer.

PURPOSE/OBJECTIVE(S): Regional failures occur in up to 15% of patients treated with stereotactic body radiotherapy (SBRT) for stage I/II lung cancer. This report focuses on the management of the unique scenario of isolated regional failures. METHODS: Patients treated initially with SBRT or accelerated hypofractionated radiotherapy were screened for curative intent treatment of isolated mediastinal failures (IMFs). Local control, regional control, progression-free survival, and distant control were estimated from the date of salvage treatment using the Kaplan-Meier method. RESULTS: Among 160 patients treated from 2002 to 2012, 12 suffered IMF and were amenable to salvage treatment. The median interval between treatments was 16 months (2-57 mo). Median salvage dose was 66 Gy (60-70 Gy). With a median follow-up of 10 months, the median overall survival was 15 months (95% confidence interval, 5.8-37 mo). When estimated from original treatment, the median overall survival was 38 months (95% confidence interval, 17-71 mo). No subsequent regional failures occurred. Distant failure was the predominant mode of relapse following salvage for IMF with a 2-year distant control rate of 38%. At the time of this analysis, three patients have died without recurrence while four are alive and no evidence of disease. High-grade toxicity was uncommon. CONCLUSIONS: To our knowledge, this is first analysis of salvage mediastinal radiation after SBRT or accelerated hypofractionated radiotherapy in lung cancer. Outcomes appear similar to stage III disease at presentation. Distant failures were common, suggesting a role for concurrent or sequential chemotherapy. A standard full course of external beam radiotherapy is advisable in this unique clinical scenario.

Thoracic re-irradiation using stereotactic body radiotherapy (SBRT) techniques as first or second course of treatment.

BACKGROUND AND PURPOSE: Management for in-field failures after thoracic radiation is poorly defined. We evaluated SBRT as an initial or second course of treatment re-irradiating in a prior high dose region. MATERIALS AND METHODS: Thirty-three patients were treated with re-irradiation defined by the prior 30 Gy isodose line. Kaplan-Meier estimates were performed for local (LC), regional (RC), distant control (DC), and overall survival (OS). The plans when available were summed to evaluate doses to critical structures. Patient and treatment variables were analyzed on UVA for the impact on control and survival measures. RESULTS: Median follow-up was 17 months. Treatment for sequential courses was as follows: (course1:course2) EBRT:SBRT (24 patients), SBRT:SBRT (7 patients), and SBRT:EBRT (3 patients). Median re-irradiation dose and fractionation was 50 Gy and 10 fractions (fx), with a median of 18 months (6-61) between treatments. Median OS was 21 months and 2 year LC 67%, yet LC for >1 fraction was 88% (p=0.006 for single vs. multiple). 10 patients suffered chronic grade 2-3 toxicity (6 chest wall pain, 3 dyspnea, 1 esophagitis) and 1 grade 5 toxicity with aorta-esophageal fistula after 54 Gy in 3 fx for a central tumor with an estimated EQD2 to the aorta of 200 Gy. CONCLUSION: Tumor control can be established with re-irradiation using SBRT techniques for in-field thoracic failures at the cost of manageable toxicity.