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This study aimed to assess the prognostic value of baseline disease distribution for patients with the secondary central nervous system (CNS) diffuse large B-cell lymphoma (DLBCL) treated with chemotherapy and radiation (RT). 44 patients with secondary CNS DLBCL were reviewed. Twenty patients had leptomeningeal disease (LMD), and 24 had localized/targetable disease (LTD). Of 8 patients who received stem cell transplantation (SCT) after RT, 6 had LTD with a complete or partial response after RT. Median time to CNS relapse after RT was 10.1 months; 3/24 patients with LTD and 5/15 with LMD had CNS relapse. The median overall survival (OS) was 8 and 20 months for patients with LMD and LTD, respectively (

Background To determine if proton radiotherapy (PT), compared to intensity-modulated radiotherapy (IMRT), delayed time to cognitive failure in patients with newly diagnosed glioblastoma (GBM). Methods Eligible patients were randomized unblinded to PT vs IMRT. The primary endpoint was time to cognitive failure. Secondary endpoints included overall survival (OS), intracranial progression-free survival (PFS), toxicity, and patient-reported outcomes (PROs). Results A total of 90 patients were enrolled and 67 were evaluable with median follow-up of 48.7 months (range 7.1-66.7). There was no significant difference in time to cognitive failure between treatment arms (HR, 0.88; 95% CI, 0.45-1.75; P = .74). PT was associated with a lower rate of fatigue (24% vs 58%, P = .05), but otherwise, there were no significant differences in PROs at 6 months. There was no difference in PFS (HR, 0.74; 95% CI, 0.44-1.23; P = .24) or OS (HR, 0.86; 95% CI, 0.49-1.50; P = .60). However, PT significantly reduced the radiation dose for nearly all structures analyzed. The average number of grade 2 or higher toxicities was significantly higher in patients who received IMRT (mean 1.15, range 0-6) compared to PT (mean 0.35, range 0-3; P = .02). Conclusions In this signal-seeking phase II trial, PT was not associated with a delay in time to cognitive failure but did reduce toxicity and patient-reported fatigue. Larger randomized trials are needed to determine the potential of PT such as dose escalation for GBM and cognitive preservation in patients with lower-grade gliomas with a longer survival time.

A large proportion of patients with cancer are unresponsive to treatment with immune checkpoint blockade and other immunotherapies. Here, we report a mathematical model of the time course of tumour responses to immune checkpoint inhibitors. The model takes into account intrinsic tumour growth rates, the rates of immune activation and of tumour-immune cell interactions, and the efficacy of immune-mediated tumour killing. For 124 patients, four cancer types and two immunotherapy agents, the model reliably described the immune responses and final tumour burden across all different cancers and drug combinations examined. In validation cohorts from four clinical trials of checkpoint inhibitors (with a total of 177 patients), the model accurately stratified the patients according to reduced or increased long-term tumour burden. We also provide model-derived quantitative measures of treatment sensitivity for specific drug-cancer combinations. The model can be used to predict responses to therapy and to quantify specific drug-cancer sensitivities in individual patients.

Background This retrospective study investigated the impact of, in addition to age, the management and outcomes of elderly patients with glioblastoma (GBM). Methods The National Cancer Database was queried between 2004 and 2015 for GBM patients age 60 years and older. Three age groups were created: 60 to 69, 70 to 79, and 80 years and older, and 4 age/KPS groups: “age ≥ 60/ KPS Results A total of 48 540 patients with a median age of 70 years (range, 60-90 years) at diagnosis, and a median follow-up of 6.8 months (range, 0-151 months) were included. Median survival was 5.0, 15.2, 9.6, and 6.8 months in groups 1, 2, 3, and 4, respectively (P Conclusions In elderly patients with newly diagnosed GBM, those with good KPS fared best with combined ChT and RT across all age groups. Performance status is a key prognostic factor that should be considered for management decisions in these patients.

PURPOSE: To ascertain the dose-toxicity relationship for the prevalence of self-reported trismus in long-term survivors after intensity-modulated radiotherapy (IMRT) for oropharyngeal carcinoma (OPC). MATERIALS AND METHODS: Self-reported mouth opening was ascertained prospectively via a cross-sectional survey of OPC survivors using the intraoral finger-test. RT dose-volume histograms (DVHs) were generated for the following masticatory regions of interest: medial pterygoid, lateral pterygoid, and masseter muscles which were designated as ipsilateral or contralateral to the primary tumor. Trismus was defined as self-reported mouth opening of

BACKGROUND We report outcomes for patients with T2N0M0 glottic squamous cell carcinoma (SCC) treated with radiation therapy (RT). METHODS Patients who received definitive RT for T2 glottic SCC from 2000 through 2013 were retrospectively reviewed. RESULTS One hundred and thirteen patients were analyzed (median follow-up time 91 months; 85 patients received three-dimensional conformal radiotherapy [3D-CRT] and 28 received intensity-modulated radiation therapy [IMRT]). Fractionation was conventional (58%) or altered (42%); 20 patients (18%) received concurrent chemotherapy. Five-year local control was 83% for the 3D-CRT vs 81% for the IMRT group (P = .76). The ultimate locoregional control at 5 years was 100% for IMRT vs 91% for 3D-CRT (P = .1). The 5-year overall survival (OS) was 78% for 3D-CRT vs 81% for IMRT (P = .83). On multivariate analysis, younger age was the only independent predictor of improved OS (P = .0002). CONCLUSIONS Oncologic and survival outcomes were excellent for patients with T2N0 glottic cancer. Patients treated with IMRT and 3D-CRT had no statistically significant differences in all investigated endpoints.

Background This secondary image analysis of a randomized trial of proton radiotherapy (PT) vs. photon intensity modulated radiotherapy (IMRT) compares tumor progression based on clinical radiological assessment vs. Response Assessment in Neuro-Oncology (RANO). Methods Eligible patients were enrolled in the randomized trial and had MR imaging at baseline and follow-up beyond 12 weeks from completion of radiotherapy. ‘Clinical progression’ was based on a clinical radiology report of progression and/or change in treatment for progression. Results Of 90 enrolled patients, 66 were evaluable. Median clinical progression-free survival (PFS) was 10.8 (Range: 9.4-14.7) months; 10.8 months IMRT vs. 11.2 months PT (p=0.14). Median RANO PFS was 8.2 (Range: 6.9, 12): 8.9 months IMRT vs. 6.6 months PT (p=0.24). RANO PFS was significantly shorter than clinical PFS overall (p=0.001) and for both the IMRT (p=0.01) and PT (p=0.04) groups. There were 31 (46.3%) discrepant cases of which 17 had RANO progression more than a month prior to clinical progression, and 14 had progression by RANO but not clinical criteria. Conclusion Based on this secondary analysis of a trial of PT vs. IMRT for GBM, while no difference in PFS was noted relative to treatment technique, RANO criteria identified progression more often and earlier than clinical assessment. This highlights the disconnect between measures of tumor response in clinical trials versus clinical practice. With growing efforts to utilize real-world data and personalized treatment with timely adaptation, there is a growing need to improve the consistency of determining tumor progression within clinical trials and clinical practice.

Osteoradionecrosis (ORN) is a major side-effect of radiation therapy in oropharyngeal cancer (OPC) patients. In this study, we demonstrate that early prediction of ORN is possible by analyzing the temporal evolution of mandibular subvolumes receiving radiation. For our analysis, we use computed tomography (CT) scans from 21 OPC patients treated with Intensity Modulated Radiation Therapy (IMRT) with subsequent radiographically-proven ≥ grade II ORN, at three different time points: pre-IMRT, 2-months, and 6-months post-IMRT. For each patient, radiomic features were extracted from a mandibular subvolume that developed ORN and a control subvolume that received the same dose but did not develop ORN. We used a Multivariate Functional Principal Component Analysis (MFPCA) approach to characterize the temporal trajectories of these features. The proposed MFPCA model performs the best at classifying ORN vs. Control subvolumes with an area under curve (AUC) = 0.74 [95% confidence interval (C.I.): 0.61–0.90], significantly outperforming existing approaches such as a pre-IMRT features model or a delta model based on changes at intermediate time points, i.e., at 2- and 6-month follow-up. This suggests that temporal trajectories of radiomics features derived from sequential pre- and post-RT CT scans can provide markers that are correlates of RT-induced mandibular injury, and consequently aid in earlier management of ORN.

Osteoradionecrosis (ORN) is a major side-effect of radiation therapy in oropharyngeal cancer (OPC) patients. In this study, we demonstrate that early prediction of ORN is possible by analyzing the temporal evolution of mandibular subvolumes receiving radiation. For our analysis, we use computed tomography (CT) scans from 21 OPC patients treated with Intensity Modulated Radiation Therapy (IMRT) with subsequent radiographically-proven ≥ grade II ORN, at three different time points: pre-IMRT, 2-months, and 6-months post-IMRT. For each patient, radiomic features were extracted from a mandibular subvolume that developed ORN and a control subvolume that received the same dose but did not develop ORN. We used a Multivariate Functional Principal Component Analysis (MFPCA) approach to characterize the temporal trajectories of these features. The proposed MFPCA model performs the best at classifying ORN vs Control subvolumes with an area under curve (AUC) = 0.74 (95% confidence interval (C.I.): 0.61-0.90), significantly outperforming existing approaches such as a pre-IMRT features model or a delta model based on changes at intermediate time points, i.e. at 2- and 6-month follow-up. This suggests that temporal trajectories of radiomics features derived from sequential pre- and post-RT CT scans can provide markers that are correlates of RT-induced mandibular injury, and consequently aid in earlier management of ORN.

Objectives Stereotactic radiosurgery is a common treatment for brain metastases and is typically planned on magnetic resonance imaging (MRI). However, the MR acquisition parameters used for patient selection and treatment planning for stereotactic radiosurgery can vary within and across institutions. In this work, we investigate the effect of MRI slice thickness on the detection and contoured volume of metastatic lesions in the brain. Methods and Materials A retrospective cohort of 28 images acquired with a slice thickness of 1 mm were resampled to simulate acquisitions at 2- and 3-mm slice thickness. A total of 102 metastases ranging from 0.0030 cc to 5.08 cc (75-percentile 0.36 cc) were contoured on the original images. All 3 sets of images were recontoured by experienced physicians. Results Of all the images detected and contoured on the 1 mm images, 3% of lesions were missed on the 2 mm images, and 13% were missed on the 3 mm images. One lesion that was identified on both the 2 mm and 3 mm images was determined to be a blood vessel on the 1 mm images. Additionally, the lesions were contoured 11% larger on the 2 mm and 43% larger on the 3 mm images. Conclusions Using images with a slice thickness >1 mm effects detection and segmentation of brain lesions, which can have an important effect on patient management and treatment outcomes.

Treatment for glioblastoma (GBM) includes surgical resection and adjuvant radiotherapy (RT) and chemotherapy. The optimal time interval between surgery and RT remains unclear. The National Cancer Database (NCDB) was queried for patients with GBM. Overall survival (OS) was estimated using Kaplan-Meier and log-rank tests. Univariate (UVA) and multivariable Cox regression (MVA) modeling was used to determine predictors of OS. A total of 45,942 patients were included. On MVA: younger age, female gender, black ethnicity, higher KPS, obtaining a gross total resection (GTR), MGMT promoter-methylated gene status, unifocal disease, higher RT dose, and RT delay of 4–8 weeks had improved OS. Patients who underwent a subtotal resection (STR) had worsened survival with RT delay ≤4 weeks and patients with GTR had worsened survival when RT was delayed >8 weeks. This analysis suggests that an interval of 4–8 weeks between resection and RT results in better survival. Delays >8 weeks in patients with a GTR and delays

Glioblastoma is an aggressive brain tumor with a propensity for intracranial recurrence. We hypothesized that tumors can be visualized with diffusion tensor imaging (DTI) before they are detected on anatomical magnetic resonance (MR) images. We retrospectively analyzed serial MR images from 30 patients, including the DTI and T1-weighted images at recurrence, at 2 months and 4 months before recurrence, and at 1 month after radiation therapy. The diffusion maps and T1 images were deformably registered longitudinally. The recurrent tumor was manually segmented on the T1-weighted image and then applied to the diffusion maps at each time point to collect mean FA, diffusivities, and neurite density index (NDI) values, respectively. Group analysis of variance showed significant changes in FA (p = 0.01) and NDI (p = 0.0015) over time. Pairwise t tests also revealed that FA and NDI at 2 months before recurrence were 11.2% and 6.4% lower than those at 1 month after radiation therapy (p &lt, 0.05), respectively. Changes in FA and NDI were observed 2 months before recurrence, suggesting that progressive microstructural changes and neurite density loss may be detectable before tumor detection in anatomical MR images. FA and NDI may serve as non-contrast MR-based biomarkers for detecting subclinical tumors.

Brain metastases are the most common intracranial tumors, occurring in more than 15% of cancer patients. The treatment of brain metastases involves a multidisciplinary approach that may consist of surgery, radiation therapy (stereotactic radiosurgery or whole-brain radiation therapy), and/or systemic therapy. Unfortunately, all these treatment strategies, as well as the disease process itself, can be associated with debilitating and life-altering neurocognitive adverse effects. Balancing the benefits and toxicities of brain metastasis treatment is a challenging task that medical, radiation, and surgical oncologists face daily. Strategies have been developed to try mitigating these toxicities, such as stereotactic radiosurgery, hippocampal avoidance whole-brain radiation therapy, and “neuroprotective” drugs. Efforts have also been deployed in developing formal instruments/battery of tests to capture neurocognitive changes consistently in patients with brain metastases.

Brain metastases are the most common intracranial tumors, with an incidence rate ranging from 7 to 14 per 100,000. Both the disease process itself and its treatments can be associated with debilitating and life-altering neurocognitive adverse effects. The treatment of brain metastases involves a multidisciplinary team that aims to maximize the benefits and minimize the toxicities of treatment, which may include surgical resection, radiation therapy (stereotactic radiosurgery or whole-brain radiation therapy), and/or systemic therapy. Additionally, strategies have been investigated to prevent and treat these toxicities, such as stereotactic radiosurgery, hippocampal avoidance whole-brain radiation therapy, and “neuroprotective” drugs, respectively. In order to better detect and measure treatment toxicity, efforts have also been deployed in tracking neurocognitive changes consistently in patients with brain metastases.

Introduction: Metformin, the most widely used treatment for diabetes, is lethal to cancer cells and increases in toxicity when used in combination with radiation. In addition to various molecular and metabolic mechanisms that have been previously proposed, the studies presented provide evidence of an additional, novel mechanism of sensitization following high dose radiotherapy; the magnitude of sensitization depends on the microenvironmental levels of glucose and oxygen which are in turn affected by high dose radiation. Methods: Cancer cells (A549 and MCF7) were studied in vitro under various controlled conditions. Endpoints included clonogenic cell survival and ROS expression measured by DHE and DCFDA. CD1 nu/nu athymic mice implanted with A549 cells received metformin alone (200 mg/kg, i.p.), radiation alone (15 Gy) or a combination of metformin and radiation; the effect of treatment sequence on efficacy was assessed by tumor growth delay and histology. In a separate set of experiments, tumor blood flow was measured using a tracer clearance technique using SPECT after the administration of metformin alone, radiation alone and the combined treatment. Results: In vivo, metformin provided equally effective tumor growth delay when given 24 hours after radiation as when given 1hour or 4 hours before radiation, an observation not previously reported and, in fact, unexpected based on published scientific literature. When drug followed radiation, the tumors were histologically characterized by massive cellular necrosis. In vitro, cancer cells when glucose depleted and/or hypoxic were preferentially killed by metformin, in a drug dose dependent manner. A549 cells exposed to 5.0 mM of metformin was reduced seven fold in survival when in a glucose deprived as compared to a low-glucose medium (0 vs 1.0 g/L). Finally, using a SPECT detector to follow the washout of a radioactive tracer, it was shown that a high single dose of radiosurgery (15 Gy) could dramatically inhibit blood flow and presumably diminish glucose and oxygen. Discussion: Insight into the best timing of drug and radiation administration is gained through an understanding of the mechanisms of interaction. A new mechanism of metformin sensitization by high dose radiation is proposed based on the blood flow, glucose and oxygen.

OBJECTIVES: This retrospective study evaluates the impact of Karnofsky performance status (KPS) in addition to age on the management and outcomes of elderly patients with glioblastoma (GBM). METHODS: The National Cancer Database (NCDB) was queried between 2004–2015 for GBM patients with age 60 and reported KPS. Four groups were created: Age 60/ KPS

Background Linear accelerator–based stereotactic radiosurgery delivered to cardiac arrhythmogenic foci could be a promising catheter‐free ablation modality. We tested the feasibility of in vivo atrioventricular ( AV ) node ablation in swine using stereotactic radiosurgery. Methods and Results Five Large White breed swine (weight 40–75 kg; 4 females) were studied. Single‐chamber St Jude pacemakers were implanted in each pig. The pigs were placed under general anesthesia, and coronary/cardiac computed tomography simulation scans were performed to localize the AV node. Cone beam computed tomography was used for target positioning. Stereotactic radiosurgery doses ranging from 35 to 40 Gy were delivered by a linear accelerator to the AV node, and the pigs were followed up with weekly pacemaker interrogations to observe for potential electrocardiographic changes. Once changes were observed, the pigs were euthanized, and pathology specimens of various tissues, including the AV node and tissues surrounding the AV node, were taken to study the effects of radiation. All 5 pigs had disturbances of AV conduction with progressive transition into complete heart block. Macroscopic inspection did not reveal damage to the myocardium, and pigs had preserved systolic function on echocardiography. Immunostaining revealed fibrosis in the target region of the AV node, whereas no fibrosis was detected in the nontargeted regions. Conclusions Catheter‐free radioablation using linear accelerator–based stereotactic radiosurgery is feasible in an intact swine model.

Every year, almost 62,000 are diagnosed with a head and neck cancer (HNC) and 13,000 will succumb to their disease. In the primary setting, intraoperative radiation therapy (IORT) can be used as a boost in select patients in order to optimize local control. Addition of external beam radiation to limited volumes results in improved disease control over surgery and IORT alone. In the recurrent setting, IORT can improve outcomes from salvage surgery especially in patients previously treated with external beam radiation. The use of IORT remains limited to select institutions with various modalities being currently employed including orthovoltage, electrons, and high-dose rate brachytherapy. Practically, execution of IORT requires a coordinated effort and careful planning by a multidisciplinary team involving the head and neck surgeon, radiation oncologist, and physicist. The current review summarizes common uses, outcomes, toxicities, and technical aspects of IORT in HNC patients.

Basaloid squamous cell carcinoma (BSCC) is a rare variant of squamous cell carcinoma (SCC), which is highly aggressive, with a tendency for multifocality, local invasion, and with a high metastatic potential. Less than forty cases of BSCC of the sinonasal tract have been reported in the literature, and no reports were found on sinonasal BSCC arising from the ethmoid sinus. We report the case of a 78-year-old man who presented with BSCC arising from the ethmoid sinus with extensive bone destruction and intracranial extension. He was treated with craniofacial resection followed by adjuvant intensity-modulated radiation therapy to the tumor bed (60 Gy in 30 fractions), and the upper neck lymph nodes (50 Gy in 25 fractions). At the patient’s last follow-up, four months after diagnosis, there was no evidence of disease. Aggressive management using craniofacial resection followed by adjuvant radiation therapy with or without radiosensitizing chemotherapy seems to be a reasonable approach to this challenging disease.