Isolated progression of metastatic lung cancer: Clinical outcomes associated with definitive radiotherapy.

BACKGROUND: Progressive, metastatic non-small cell lung cancer (NSCLC) often requires the initiation of new systemic therapy. However, in patients with NSCLC that is oligoprogressive (≤3 lesions), local radiotherapy (RT) may allow for the eradication of resistant microclones and, therefore, the continuation of otherwise effective systemic therapy. METHODS: Patients treated from 2008 to 2019 with definitive doses of RT to all sites of intracranial or extracranial oligoprogression without a change in systemic therapy were identified. Radiographic progression-free survival (rPFS) and time to new therapy (TNT) were measured. Associations between baseline clinical and treatment-related variables were correlated with progression-free survival via Cox proportional hazards modeling. RESULTS: Among 198 unique patients, 253 oligoprogressive events were identified. Intracranial progression occurred in 51% of the patients, and extracranial progression occurred in 49%. In the entire cohort, the median rPFS was 7.9 months (95% CI, 6.5-10.0 months), and the median TNT was 8.8 months (95% CI, 7.2-10.9 months). On adjusted modeling, patients with the following disease characteristics were associated with better rPFS: better performance status (P = .003), fewer metastases (P = .03), longer time to oligoprogression (P = .009), and fewer previous systemic therapies (P = .02). Having multiple sites of oligoprogression was associated with worse rPFS (P < .001). CONCLUSIONS: In select patients with oligoprogression, definitive RT is a feasible treatment option to delay the initiation of next-line systemic therapies, which have more limited response rates and efficacy. Further randomized prospective data may help to validate these findings and identify which patients are most likely to benefit.

Neoadjuvant nivolumab or nivolumab plus LAG-3 inhibitor relatlimab in resectable esophageal/gastroesophageal junction cancer: a phase Ib trial and ctDNA analyses.

Gastroesophageal cancer dynamics and drivers of clinical responses with immune checkpoint inhibitors (ICI) remain poorly understood. Potential synergistic activity of dual programmed cell death protein 1 (PD-1) and lymphocyte-activation gene 3 (LAG-3) inhibition may help improve immunotherapy responses for these tumors. We report a phase Ib trial that evaluated neoadjuvant nivolumab (Arm A, n = 16) or nivolumab-relatlimab (Arm B, n = 16) in combination with chemoradiotherapy in 32 patients with resectable stage II/stage III gastroesophageal cancer together with an in-depth evaluation of pathological, molecular and functional immune responses. Primary endpoint was safety; the secondary endpoint was feasibility; exploratory endpoints included pathological complete (pCR) and major pathological response (MPR), recurrence-free survival (RFS) and overall survival (OS). The study met its primary safety endpoint in Arm A, although Arm B required modification to mitigate toxicity. pCR and MPR rates were 40% and 53.5% for Arm A and 21.4% and 57.1% for Arm B. Most common adverse events were fatigue, nausea, thrombocytopenia and dermatitis. Overall, 2-year RFS and OS rates were 72.5% and 82.6%, respectively. Higher baseline programmed cell death ligand 1 (PD-L1) and LAG-3 expression were associated with deeper pathological responses. Exploratory analyses of circulating tumor DNA (ctDNA) showed that patients with undetectable ctDNA post-ICI induction, preoperatively and postoperatively had a significantly longer RFS and OS; ctDNA clearance was reflective of neoantigen-specific T cell responses. Our findings provide insights into the safety profile of combined PD-1 and LAG-3 blockade in gastroesophageal cancer and highlight the potential of ctDNA analysis to dynamically assess systemic tumor burden during neoadjuvant ICI that may open a therapeutic window for future intervention. ClinicalTrials.gov registration: NCT03044613 .

Improving Quality Metrics in Radiation Oncology: Implementation of Pretreatment Peer Review for Stereotactic Body Radiation Therapy in Patients with Thoracic Cancer.

Purpose: Traditional peer reviews occur weekly, and can take place up to 1 week after the start of treatment. The American Society for Radiation Oncology peer-review white paper identified stereotactic body radiation therapy (SBRT) as a high priority for contour/plan review before the start of treatment, considering both the rapid-dose falloff and short treatment course. Yet, peer-review goals for SBRT must also balance physician time demands and the desire to avoid routine treatment delays that would occur in the setting of a 100% pretreatment (pre-Tx) review compliance requirement or prolonging the standard treatment planning timeline. Herein, we report on our pilot experience of a pre-Tx peer review of thoracic SBRT cases. Methods and Materials: From March 2020 to August 2021, patients undergoing thoracic SBRT were identified for pre-Tx review, and placed on a quality checklist. We implemented twice-weekly meetings for detailed pre-Tx review of organ-at-risk/target contours and dose constraints in the treatment planning system for SBRT cases. Our quality metric goal was to peer review ≥90% of SBRT cases before exceeding 25% of the dose delivered. We used a statistical process control chart with sigma limits (ie, standard deviations [SDs]) to access compliance rates with pre-Tx review implementation. Results: We identified 252 patients treated with SBRT to 294 lung nodules. When comparing pre-Tx review completion from initial rollout to full implementation, our rates improved from 19% to 79% (ie, from 1 sigma limit [SDs]) below to >2 sigma limits (SDs) above. Additionally, early completion of any form of contour/plan review (defined as any pre-Tx or standard review completed before exceeding 25% of the dose delivered) increased from 67% to 85% (March 2020-November 2020) to 76% to 94% (December 2020-August 2021). Conclusions: We successfully implemented a sustainable workflow for detailed pre-Tx contour/plan review for thoracic SBRT cases in the context of twice-weekly disease site-specific peer-review meetings. We reached our quality improvement objective to peer review ≥90% of SBRT cases before exceeding 25% of the dose delivered. This process was feasible to conduct in an integrated network of sites across our system.

Definitive Chemoradiation and Durvalumab Consolidation for Locally Advanced, Unresectable KRAS-mutated Non-Small Cell Lung Cancer.

BACKGROUND: Consolidation durvalumab immunotherapy following definitive chemoradiation (CRT) for unresectable stage III non-small cell lung cancer (NSCLC) improves overall survival. As therapeutic options for patients with KRAS-driven disease evolve, more understanding regarding genomic determinants of response and patterns of progression for durvalumab consolidation is needed to optimize outcomes. METHODS: We conducted a single-institutional retrospective analysis of real-world patients with locally advanced, unresectable NSCLC who completed CRT and received durvalumab consolidation. Kaplan-Meier analyses compared progression-free survival (PFS) and overall survival (OS) from start of durvalumab consolidation between patients with KRAS-mutated and non-mutated tumors. Fisher's exact test was used to compare rates of intrathoracic or extrathoracic progression. RESULTS: Of 74 response-evaluable patients, 39 had clinical genomic profiling performed. 18 patients had tumors with KRAS mutations, 7 patients had tumors with non-KRAS actionable alterations (EGFR, ALK, ERBB2, BRAF, MET, RET, or ROS1), and 14 patients had tumors without actionable alterations. Median PFS for the overall cohort was 16.1 months. PFS for patients with KRAS-mutated NSCLC was 12.6 months versus 12.7 months for patients with non-actionable tumors (P= 0.77, log-rank). Fisher's exact test revealed a statistically significantly higher rate of extrathoracic progression versus intrathoracic-only progression for patients with KRAS-driven disease compared to patients with non-actionable tumors (P= 0.015). CONCLUSION: Patients with KRAS-mutated NSCLC derived similar benefit from durvalumab as patients with non-actionable tumors. A higher rate of extrathoracic progression was also observed among the patients with KRAS-mutated NSCLC compared to patients with non-actionable tumors. This highlights the potential unmet needs for novel systemic therapies and surveillance methods for KRAS-mutated stage III NSCLC.

Evaluation of the Clinical Utility of the Bone Metastases Ensemble Trees for Survival Decision Support Platform (BMETS-DSP): A Case-Based Pilot Assessment.

PURPOSE: The Bone Metastases Ensemble Trees for Survival Decision Support Platform (BMETS-DSP) provides patient-specific survival predictions and evidence-based recommendations to guide multidisciplinary management for symptomatic bone metastases. We assessed the clinical utility of the BMETS-DSP through a pilot prepost design in a simulated clinical environment. METHODS: Ten Radiation Oncology physicians reviewed 55 patient cases at two time points: without and then with the use of BMETS-DSP. Assessment included 12-month survival estimate, confidence in and likelihood of sharing estimates with patients, and recommendations for open surgery, systemic therapy, hospice referral, and radiotherapy (RT) regimen. Paired statistics compared pre- versus post-DSP outcomes. Reported statistical significance is P < .05. RESULTS: Pre- versus post-DSP, overestimation of true minus estimated survival time was significantly reduced (mean difference -2.1 [standard deviation 4.1] v -1 month [standard deviation 3.5]). Prediction accuracy was significantly improved at cut points of < 3 (72 v 79%), ≤ 6 (64 v 71%), and ≥ 12 months (70 v 81%). Median ratings of confidence in and likelihood of sharing prognosis significantly increased. Significantly greater concordance was seen in matching use of 1-fraction RT with the true survival < 3 months (70 v 76%) and < 10-fraction RT with the true survival < 12 months (55 v 62%) and appropriate use of open surgery (47% v 53%), without significant changes in selection of hospice referral or systemic therapy. CONCLUSION: This pilot study demonstrates that BMETS-DSP significantly improved physician survival estimation accuracy, prognostic confidence, likelihood of sharing prognosis, and use of prognosis-appropriate RT regimens in the care of symptomatic bone metastases, supporting future multi-institutional validation of the platform.

Bone density and fracture risk following SBRT for non-spine bone metastases.

PURPOSE/METHODS: This retrospective study evaluated local recurrence (LR) and fracture risk in non-spine bone metastases treated with SBRT. RESULTS: 181 lesions in 116 patients are reported. The median dose was 27 Gy (range 15-40) in 3 fractions (range 1-6). The cumulative incidence of LR was 2.8%, 7.2% and 12.5% at 6 mo, 1 yr and 2 yrs. Fractures occurred in 11 lesions (6%). Radioresistant histology and increasing PTV predicted for LR on univariate analysis, while rib location was associated with control. Increasing PTV remained a significant predictor for LR on multivariate analysis. Univariate predictors of fracture risk included female gender, lytic lesions and poorer KPS. Average CT-approximated L1 trabecular attenuation in patients with fracture was significantly lower than in patients without fracture (112.2 vs. 142.6 Hounsfield units). CONCLUSION: In the largest series to date, we report excellent local control for SBRT to non-spine bone metastases and a novel relationship between CT-based bone quality assessment and fracture risk.

Trimodality therapy for esophageal cancer: The role of surgical and radiation treatment parameters in the development of anastomotic complications.

BACKGROUND: Here, we investigated the relationship between clinical parameters, including the site of surgical anastomosis and radiation dose to the anastomotic region, and anastomotic complications in esophageal cancer patients treated with trimodality therapy. METHODS: Between 2007 and 2016, esophageal cancer patients treated with trimodality therapy at a tertiary academic cancer center were identified. Patient, treatment, and outcome parameters were collected. Radiation dose to the gastric regions were extracted. Anastomotic complication was defined as leak and/or stricture. We used Fisher's exact and Wilcoxon rank-sum tests to compare the association between clinical parameters and anastomotic complications. RESULTS: Of 89 patients identified, the median age was 63 years, 82% (n = 73) were male, and 82% had distal (n = 47) or gastroesophageal junction (n = 26) tumors. Median follow-up was 25.8 months. Esophagectomies were performed with cervical (65%, n = 58) or thoracic anastomoses (35%, n = 31). Anastomotic complications developed in 60% (n = 53). Cervical anastomosis was associated with anastomotic complications (83%, n = 44/53, p < 0.01). Radiation to any gastric substructure was not associated with anastomotic complications (p > 0.05). In the subset of patients with distal/gastroesophageal junction tumors undergoing esophagectomy with cervical anastomosis where radiation was delivered to the future neoesophagus, 80% (n = 35/44) developed anastomotic complications. In this high-risk subgroup, radiation was not associated with anastomotic complications (p > 0.05). CONCLUSIONS: Our analysis did not demonstrate an association between radiation dose to gastric substructures and anastomotic complications. However, it showed an association between esophagectomy with cervical anastomosis and anastomotic complications. Patients with distal/gastroesophageal junction tumors who undergo esophagectomy with cervical anastomosis have higher rates of anastomotic complications unrelated to radiation to gastric substructures.

Improving Early Identification of Significant Weight Loss Using Clinical Decision Support System in Lung Cancer Radiation Therapy.

PURPOSE: Early identification of patients who may be at high risk of significant weight loss (SWL) is important for timely clinical intervention in lung cancer radiotherapy (RT). A clinical decision support system (CDSS) for SWL prediction was implemented within the routine clinical workflow and assessed on a prospective cohort of patients. MATERIALS AND METHODS: CDSS incorporated a machine learning prediction model on the basis of radiomics and dosiomics image features and was connected to a web-based dashboard for streamlined patient enrollment, feature extraction, SWL prediction, and physicians' evaluation processes. Patients with lung cancer (N = 37) treated with definitive RT without prior RT were prospectively enrolled in the study. Radiomics and dosiomics features were extracted from CT and 3D dose volume, and SWL probability (≥ 0.5 considered as SWL) was predicted. Two physicians predicted whether the patient would have SWL before and after reviewing the CDSS prediction. The physician's prediction performance without and with CDSS and prediction changes before and after using CDSS were compared. RESULTS: CDSS showed significantly better prediction accuracy than physicians (0.73 v 0.54) with higher specificity (0.81 v 0.50) but with lower sensitivity (0.55 v 0.64). Physicians changed their original prediction after reviewing CDSS prediction for four cases (three correctly and one incorrectly), for all of which CDSS prediction was correct. Physicians' prediction was improved with CDSS in accuracy (0.54-0.59), sensitivity (0.64-0.73), specificity (0.50-0.54), positive predictive value (0.35-0.40), and negative predictive value (0.76-0.82). CONCLUSION: Machine learning-based CDSS showed the potential to improve SWL prediction in lung cancer RT. More investigation on a larger patient cohort is needed to properly interpret CDSS prediction performance and its benefit in clinical decision making.

Propensity score adjusted analysis of patients with isolated locoregional recurrence versus de novo locally advanced NSCLC treated with definitive therapy.

OBJECTIVES: Definitive intent treatment of isolated locoregional recurrence (iLR) for non-small cell lung cancer (NSCLC) is becoming more common. This study explores outcomes associated with the definitive local treatment of iLR and compares these outcomes to newly diagnosed locally advanced NSCLC (LA-NSCLC) patients. MATERIALS AND METHODS: Patients with NSCLC treated with curative therapy between 2008 and 2019 at a tertiary academic institution were screened for iLR treated with subsequent definitive salvage therapy. Progression free survival (PFS), time to distant metastasis (TTDM), and overall survival (OS) were calculated via Kaplan-Meier methodology. Clinical outcomes were compared to a separate group of patients with de novo LA-NSCLC after adjusting for propensity score (PS). RESULTS: Sixty five cases of definitively salvaged iLR were compared to 302 patients with de novo LA-NSCLC. Most patients were treated with chemoradiotherapy (83.1% in iLR, 74.5% in LA-NSCLC). The median PFS, TTDM, and OS for the iLR cohort was 16.7 months (95% CI: 9.6-24.7), 35.8 months (95% CI: 17.1-NR), and 49.5 months (95% CI: 30.1-NR), respectively. After adjusting for PS, the iLR group was no different from the LA-NSCLC group in risk for progression (HR 0.78, 95% CI: 0.53-1.16, p = 0.22), distant metastasis (HR 0.81, 95% CI: 0.52-1.27, p = 0.36), or death (HR 0.90, 95% CI: 0.47-1.73, p = 0.75). Patterns of failure did not different significantly between groups. In the iLR cohort, patients with older age (HR 1.06, 95 CI: 1.01-1.10, p = 0.01) had a higher risk of death on multivariate analysis. CONCLUSION: To our knowledge, this is the first report that compares the definitive treatment of iLR to de novo LA-NSCLC. When treated with definitive local therapy, patients with iLR had no difference in clinical outcomes from de novo LA-NSCLC. The use of curative local therapy according to a LA-NSCLC paradigm is advisable in patients with iLR of NSCLC for whom definitive therapy is feasible.

Multi-view radiomics and dosiomics analysis with machine learning for predicting acute-phase weight loss in lung cancer patients treated with radiotherapy.

We propose a multi-view data analysis approach using radiomics and dosiomics (R&D) texture features for predicting acute-phase weight loss (WL) in lung cancer radiotherapy. Baseline weight of 388 patients who underwent intensity modulated radiation therapy (IMRT) was measured between one month prior to and one week after the start of IMRT. Weight change between one week and two months after the commencement of IMRT was analyzed, and dichotomized at 5% WL. Each patient had a planning CT and contours of gross tumor volume (GTV) and esophagus (ESO). A total of 355 features including clinical parameter (CP), GTV and ESO (GTV&ESO) dose-volume histogram (DVH), GTV radiomics, and GTV&ESO dosiomics features were extracted. R&D features were categorized as first- (L1), second- (L2), higher-order (L3) statistics, and three combined groups, L1 + L2, L2 + L3 and L1 + L2 + L3. Multi-view texture analysis was performed to identify optimal R&D input features. In the training set (194 earlier patients), feature selection was performed using Boruta algorithm followed by collinearity removal based on variance inflation factor. Machine-learning models were developed using Laplacian kernel support vector machine (lpSVM), deep neural network (DNN) and their averaged ensemble classifiers. Prediction performance was tested on an independent test set (194 more recent patients), and compared among seven different input conditions: CP-only, DVH-only, R&D-only, DVH + CP, R&D + CP, R&D + DVH and R&D + DVH + CP. Combined GTV L1 + L2 + L3 radiomics and GTV&ESO L3 dosiomics were identified as optimal input features, which achieved the best performance with an ensemble classifier (AUC = 0.710), having statistically significantly higher predictability compared with DVH and/or CP features (p < 0.05). When this performance was compared to that with full R&D-only features which reflect traditional single-view data, there was a statistically significant difference (p < 0.05). Using optimized multi-view R&D input features is beneficial for predicting early WL in lung cancer radiotherapy, leading to improved performance compared to using conventional DVH and/or CP features.

Exploring the Relationship of Radiation Dose Exposed to the Length of Esophagus and Weight Loss in Patients with Lung Cancer.

PURPOSE: We investigate whether esophageal dose-length parameters (Ldose) can robustly predict significant weight loss-≥5% weight loss during radiation therapy (RT) compared with the weight before RT-in patients with lung cancer treated with definitive intent. METHODS AND MATERIALS: Patients with lung cancer treated with conventionally fractionated RT between 2010 and 2018 were retrospectively identified. LFdose and LPdose, the length of full- and partial-circumferential esophagus receiving greater than a threshold dose in Gy, respectively, were created. Multivariate logistic regression examined the associations between individual Ldose and weight loss after adjusting for clinical parameters and correcting for multiple comparisons. Ridge logistic regression examined the relative importance of Ldose compared with dose-volume (Vdose), mean dose (Dmean), and clinical parameters in determining weight loss. Univariate logistic regression examined the unadjusted probability of weight loss for important Ldose parameters. RESULTS: Among the 214 patients identified, median age was 66.9 years (range, 31.5-88.9 years), 50.5% (n = 108) were male, 68.2% (n = 146) had stage III lung cancer, median RT dose was 63 Gy (range, 60-66 Gy), and 88.3% (n = 189) received concurrent chemotherapy. Esophagus lengths receiving high full-circumferential (LF50-LF60) and high partial-circumferential doses (LP60) were associated with significant weight loss (P ≤ .05). LF65 and LP65 reached near significance (P = .06 and .053, respectively). LF65 > LF60 > LP65 were the most important dose parameters in determining weight loss compared with other Ldose, Vdose, and Dmean parameters. CONCLUSIONS: Esophageal Ldose parameters are an efficient way of interpreting complex dose parameters in relation to weight loss toxicity among patients with lung cancer receiving definitive RT.

Chronic immune checkpoint inhibitor pneumonitis.

BACKGROUND: Pneumonitis from immune checkpoint inhibitors (ICI) is a potentially fatal immune-related adverse event (irAE) from antiprogrammed death 1/programmed death ligand 1 immunotherapy. Most cases of ICI pneumonitis improve or resolve with 4-6 weeks of corticosteroid therapy. Herein, we report the incidence, clinicopathological features and management of patients with non-small cell lung cancer (NSCLC) and melanoma who developed chronic ICI pneumonitis that warrants ≥12 weeks of immunosuppression. METHODS: Patients with ICI pneumonitis were identified from institutional databases of ICI-treated patients with advanced melanoma and NSCLC between January 2011 and July 2018. ICI pneumonitis was defined as clinical/radiographic evidence of lung inflammation without alternative diagnoses, adjudicated by a multidisciplinary team. Chronic ICI pneumonitis was defined as pneumonitis that persists or worsens with steroid tapering, and necessitates ≥12 weeks of immunosuppression, after ICI discontinuation. Serial chest CT was used to assess radiological features, and tumor response by Response EvaluationCriteria for Solid Tumors V.1.1. Bronchoalveolar lavage fluid (BALF) samples were assessed by cell differential. Lung biopsy samples were evaluated by H&E staining and multiplex immunofluorescence (mIF), where available. RESULTS: Among 299 patients, 44 developed ICI pneumonitis (NSCLC: 5/205; melanoma: 1/94), and of these, 6 experienced chronic ICI pneumonitis. The overall incidence of chronic ICI pneumonitis was thus 2%. Of those who developed chronic ICI pneumonitis: the majority had NSCLC (5/6), all sustained disease control from ICIs, and none had other concurrent irAEs. Timing of chronic ICI pneumonitis development was variable (range: 0-50 months), and occurred at a median of 12 months post ICI start. Recrudescence of ICI pneumonitis occurred at a median of 6 weeks after initial steroid start (range: 3-12 weeks), with all patients requiring steroid reintroduction when tapered to ≤10 mg prednisone/equivalent. The median total duration of steroids was 37 weeks (range: 16-43+weeks). Re-emergence of radiographic ICI pneumonitis occurred in the same locations on chest CT, in most cases (5/6). All patients who developed chronic ICI pneumonitis had BALF lymphocytosis on cell differential and organising pneumonia on lung biopsy at initial ICI pneumonitis presentation, with persistent BALF lymphocytosis and brisk CD8+ infiltration on mIF at pneumonitis re-emergence during steroid taper. CONCLUSIONS: A subset of patients who develop pneumonitis from ICIs will develop chronic ICI pneumonitis, that warrants long-term immunosuppression of ≥12 weeks, and has distinct clinicopathological features.

Regulation of histone deacetylase 4 expression by the SP family of transcription factors.

Histone deacetylases mediate critical cellular functions but relatively little is known about mechanisms controlling their expression, including expression of HDAC4, a class II HDAC implicated in the modulation of cellular differentiation and viability. Endogenous HDAC4 mRNA, protein levels and promoter activity were all readily repressed by mithramycin, suggesting regulation by GC-rich DNA sequences. We validated consensus binding sites for Sp1/Sp3 transcription factors in the HDAC4 promoter through truncation studies and targeted mutagenesis. Specific and functional binding by Sp1/Sp3 at these sites was confirmed with chromatin immunoprecipitation (ChIP) and electromobility shift assays (EMSA). Cotransfection of either Sp1 or Sp3 with a reporter driven by the HDAC4 promoter led to high activities in SL2 insect cells (which lack endogenous Sp1/Sp3). In human cells, restored expression of Sp1 and Sp3 up-regulated HDAC4 protein levels, whereas levels were decreased by RNA-interference-mediated knockdown of either protein. Finally, variable levels of Sp1 were in concordance with that of HDAC4 in a number of human tissues and cancer cell lines. These studies together characterize for the first time the activity of the HDAC4 promoter, through which Sp1 and Sp3 modulates expression of HDAC4 and which may contribute to tissue or cell-line-specific expression of HDAC4.

Preoperative contralateral lung radiation dose is associated with postoperative pulmonary toxicity in patients with locally advanced non-small cell lung cancer treated with trimodality therapy.

PURPOSE: In patients with non-small cell lung cancer (NSCLC) who undergo trimodality therapy (chemoradiation followed by surgical resection), it is unknown whether limiting preoperative radiation dose to the uninvolved lung reduces postsurgical morbidity. This study evaluated whether radiation fall-off dose parameters to the contralateral lung that is unaffected by NSCLC are associated with postoperative complications in NSCLC patients treated with trimodality therapy. METHODS AND MATERIALS: We retrospectively reviewed NSCLC patients who underwent trimodality therapy between March 2008 and October 2016, with available restored digital radiation plans. Fischer's exact test was used to assess associations between patient and treatment characteristics and the development of treatment-related toxicity. Spearman rank correlation was used to measure the strength of association between dosimetric parameters. RESULTS: Forty-six patients were identified who received trimodality therapy with intensity modulated radiation (median, 59.4 Gy; range, 45-70) and concurrent platinum doublet chemotherapy, followed by surgical resection. The median age was 64.9 years (range, 45.6-81.6). The median follow-up time was 1.9 years (range, 0.3-8.4). Twenty-four (52.2%) patients developed any-grade pulmonary toxicity and 14 (30.4%) patients developed grade 2+ pulmonary toxicity. There was an increased incidence of any-grade pulmonary toxicity in patients with contralateral lung volume receiving at least 20 Gy (V20) ≥7% compared with <7% (90%, n = 9 vs 41.7%, n = 15; P = .01). Similarly, contralateral lung V10 ≥20% was associated with an increased rate of any-grade pulmonary toxicity compared with V10 <20% (80%, n = 12 vs 38.7%, n = 12; P = .01). Pneumonectomy/bilobectomy was associated with grade 2+ pulmonary toxicity (P = .04). CONCLUSIONS: Patients who received a higher radiation fall-off dose volume parameter (V20 ≥7% and V10 ≥20%) to the contralateral uninvolved lung had a higher incidence of any-grade postoperative pulmonary toxicity. Limiting radiation fall-off dose to the uninvolved lung may be an important modifiable radiation parameter in limiting postoperative toxicity in trimodality patients.

Randomized Trial of Hypofractionated, Dose-Escalated, Intensity-Modulated Radiation Therapy (IMRT) Versus Conventionally Fractionated IMRT for Localized Prostate Cancer.

PURPOSE: Hypofractionated radiotherapy delivers larger daily doses of radiation and may increase the biologically effective dose delivered to the prostate. We conducted a randomized trial testing the hypothesis that dose-escalated, moderately hypofractionated intensity-modulated radiation therapy (HIMRT) improves prostate cancer control compared with conventionally fractionated IMRT (CIMRT) for men with localized prostate cancer. PATIENTS AND METHODS: Men were randomly assigned to 75.6 Gy in 1.8-Gy fractions delivered over 8.4 weeks (CIMRT) or 72 Gy in 2.4 Gy fractions delivered over 6 weeks (HIMRT, biologically equivalent to 85 Gy in 1.8-Gy fractions assuming prostate cancer α-to-ß ratio of 1.5). Failure was defined as prostate-specific antigen (PSA) failure (nadir plus 2 ng/mL) or initiation of salvage therapy. Modified Radiation Therapy Oncology Group criteria were used to grade late (≥ 90 days after completion of radiotherapy) GI and genitourinary toxicity. RESULTS: Most of the 206 men (72%) had cT1, Gleason score 6 or 7 (99%), and PSA level ≤ 10 ng/mL (90%) disease. Androgen deprivation therapy was received by 24%. With a median follow-up of 8.5 years, men treated with HIMRT experienced fewer treatment failures (n = 10) than men treated with CIMRT (n = 21; P = .036). The 8-year failure rate was 10.7% (95% CI, 5.8% to 19.1%) with HIMRT and 15.4% (95% CI, 9.1% to 25.4%) with CIMRT. There was no difference in overall survival ( P = .39). There was a nonsignificant increase in late grade 2 or 3 GI toxicity with HIMRT (8-year 5.0% v 12.6%; P = .08). However, GI toxicity was only 8.6% when rectal volume receiving 65 Gy of HIMRT was ≤ 15%. Late genitourinary toxicity was similar ( P = .84). There was no grade 4 toxicity. CONCLUSION: The results of this randomized trial demonstrate superior cancer control for men with localized prostate cancer who receive dose-escalated moderately hypofractionation radiotherapy while shortening treatment duration.

Chemoradiation for High-grade Neuroendocrine Carcinoma of the Rectum and Anal Canal.

OBJECTIVES: We evaluated outcomes in patients with high-grade neuroendocrine (HGNE) carcinoma of the anorectum treated with pelvic chemoradiation. MATERIALS AND METHODS: Between January 1, 2000 and February 17, 2013, 10 patients were confirmed to have HGNE carcinoma of the rectum or anal canal and treated with pelvic chemoradiation (radiation dose ≥45 Gy). Overall survival (OS), locoregional control (LRC), progression-free survival (PFS), and patterns of failure were evaluated. RESULTS: Eight had pure HGNE carcinoma and 2 had HGNE carcinoma with minor component of adenocarcinoma. Median age was 62 years. Median follow-up was 15 months (range, 3 to 128 mo). Tumor stages included TxN0M0 (1), II (1), III (4), and IV (4) including 2 with only inguinal involvement. Median tumor size was 5.5 cm (range, 3 to 7 cm). Patients received postoperative chemoradiation (1), preoperative chemoradiation (2), and chemoradiation without surgery (7). Median dose was 50.4 Gy (range, 45 to 60 Gy). All patients received chemotherapy before or after chemoradiation. Seven had pelvic LRC; 2 had possible and 1 had confirmed local progression. Both patients who had preoperative chemoradiation only had microscopic focus of residual carcinoma at surgery. Seven had disease progression; of which all developed distant progression, with distant progression occurring as the first event in 6 (liver, lung, bone, and abdominal nodes). Actuarial 2-year PFS and OS were 30% and 46%, respectively. One patient received prophylactic cranial irradiation; only one of the other 9 patient developed brain metastasis. CONCLUSIONS: Pelvic chemoradiation provided LRC for the majority of the patients' lifetime. Most patients had distant failure, but patterns of distant failure do not support routine prophylactic cranial irradiation.

Long-term economic value of hypofractionated prostate radiation: Secondary analysis of a randomized trial.

PURPOSE: Moderately hypofractionated intensity modulated radiation therapy (HIMRT) for prostate cancer shortens the treatment course while providing outcomes comparable with those of conventional intensity modulated radiation therapy (CIMRT). To determine the long-term economic value of HIMRT, including the costs of managing long-term radiation toxicities, a cost minimization analysis compared CIMRT with dose-escalated HIMRT using patient-level data from a randomized trial. METHODS AND MATERIALS: Men with localized prostate cancer were randomized to CIMRT (75.6 Gy in 42 fractions over 8.4 weeks) or HIMRT (72 Gy in 30 fractions over 6 weeks). A decision tree modeled trial probabilities of maximum late bowel and urinary toxicities using patient-level data with a median follow-up of 6 years. Costs were estimated from the healthcare perspective using the 2014 national reimbursement rates for services received. Patient-level institutional costs, adjusted to 2014 dollars, verified reimbursements. A sensitivity analysis assessed model uncertainty. RESULTS: The cost for HIMRT and toxicity management was $22,957, saving $7,000 compared with CIMRT ($30,241). CIMRT was the common factor among the 5 most influential scenarios that contributed to total costs. Toxicity represented a small part (<10%) of the average total cost for patients with either grade 2-3 bowel toxicity or grade 2-3 urinary toxicity. However, toxicity management reached up to 26% of the total cost for patients with both high-grade bowel and urinary toxicities. There was no threshold at which CIMRT became the less costly regimen. Institutional costs confirmed the economic value of HIMRT ($6,000 in savings). CONCLUSIONS: HIMRT is more cost-efficient than CIMRT for treating prostate cancer, even when taking into account the costs related to late radiation toxicities. HIMRT enhances the value of prostate radiation when compared with CIMRT.

Radiosensitizing effects of the prenyltransferase inhibitor AZD3409 against RAS mutated cell lines.

Mutations at the H-, N- and K-ras loci are among the most frequent genetic alterations in human cancers. In this study, we have investigated the effect of AZD3409, a novel, peptidomimetic prenyltransferase inhibitor (PTI), on the radiosensitivity of cells with mutated ras alleles. AZD3409, developed by AstraZeneca, inhibits both farnesyl- and geranylgeranyl transferase in cell free systems. AZD3409 inhibits the growth of a variety of human cancer cell lines, including cells that express mutant alleles of either K- or H- ras and was well tolerated when administered orally to healthy volunteers in a phase I clinical trial. We have previously shown that PTI can radiosensitize human and rodent cancer cell lines that express activated RAS. Here we assessed the ability of AZD3409 to radiosensitize human cancer cell lines in vivo and in vitro and the activation state of RAS proteins in treated cells. Once daily oral administration of AZD3409 to nude mice bearing PSN-1 and MiaPaCa-2 human pancreatic cancer xenografts expressing mutant K-ras was well tolerated and resulted in a supra-additive reduction in clonogenic cell survival after irradiation. Similarly, AZD3409 reduced clonogenic survival in cells that express either mutant K- or H- ras in vitro. We next examined the effect of AZD3409 on the processing and activation of K- and H-RAS. AZD3409-mediated radiosensitization, both in vivo and in vitro, correlates with a decrease in H-RAS processing without detectable effect on K-RAS processing. RAS activation assays show that the decreased H-RAS processing is accompanied by decreased H-RAS activation in cell lines with mutations in either K- or H-ras. However, no decrease in K-RAS activation was detected. Thus, radiosensitization of human cancer cells that express mutated K-RAS occurred under conditions where AZD3409 inihibits the activation of farneyslated H-RAS, but did not inhibit K-RAS activation.

Mitotic spindle checkpoint inactivation by trichostatin a defines a mechanism for increasing cancer cell killing by microtubule-disrupting agents.

Microtubule-disrupting agents such as the taxanes comprise some of the most clinically useful chemotherapeutic agents and invoke the spindle checkpoint in proliferating cells. A robust spindle checkpoint in turn may forestall mitotic catastrophe, potentially providing a mechanism that permits cancer cells to survive transient exposure to these drugs. Previous reports on G2-M cell cycle progression by histone deacetylase inhibitors suggested a potential role in modulating the therapeutic efficacy of microtubule-disrupting agents. As both classes of agents are generally administered in clinical trials as pulse treatments, we investigated in human cancer cells the effects of brief treatments with the histone deacetylase inhibitor trichostatin A (TSA) alone or with nocodazole or paclitaxel (Taxol) on cell cycle progression and the spindle checkpoint. Treatment of synchronized cells with 200 ng/ml of TSA alone for eight hours to completely block class I and II HDACs did not interfere with progression into mitosis with chromosomal condensation as confirmed by MPM-2 expression. TSA treatment at this concentration surprisingly did not interfere with formation of the mitotic spindle or centrosomal separation, but instead led to missegregation of chromosomes, suggesting effects on the spindle checkpoint. Consistent with this hypothesis, TSA abrogated the phosphorylation and kinetochore localization of the mitotic checkpoint protein BubR1 and the phosphorylation of histone H3 after paclitaxel and nocodazole treatment. These effects in turn led to rapid cell death and considerably reduced clonogenic survival. These results together suggest that by inactivating the spindle checkpoint, TSA can potentiate the lethal effects of microtubule-disrupting drugs, a strategy that might be usefully exploited for optimizing anticancer therapy.

A choice of radionuclide: Comparative outcomes and toxicity of ruthenium-106 and iodine-125 in the definitive treatment of uveal melanoma.

PURPOSE: Both iodine-125 ((125)I) Collaborative Ocular Melanoma Study and ruthenium-106 ((106)Ru) eye plaques can achieve excellent tumor control in patients diagnosed with uveal melanoma. We analyzed our single institutional experience in the management of ocular melanoma treated with either (125)I or (106)Ru plaque brachytherapy. METHODS AND MATERIALS: The records of 107 patients with uveal melanoma treated with either (106)Ru (n = 40) or (125)I (n = 67) plaque brachytherapy between 2000 and 2008 were retrospectively reviewed. Tumor control parameters and toxicity were assessed. RESULTS: Actuarial 5-year rates of local control, progression-free survival, and overall survival with (106)Ru were 97%, 94%, and 92%, respectively. For (125)I, these values were 83%, 65%, and 80%. In the subset of patients with tumor apex height ≤5 mm (36 (125)I and 40 (106)Ru), there was no difference in overall survival; however, progression-free survival was significantly improved with (106)Ru (P = .02). Enucleation-free survival was significantly different between the 2 subsets, with no enucleations in the (106)Ru cohort (P = .02). Patients treated with (106)Ru experienced reduced retinopathy (P = .03) and cataracts (P < .01). CONCLUSIONS: Both (125)I and (106)Ru eye plaque brachytherapy treatment result in encouraging tumor control for patients with uveal melanoma. We demonstrate that (106)Ru offers these benefits with reduced toxicity in patients treated for uveal melanomas ≤5 mm in apical height.