Adjuvant Reirradiation With Proton Therapy in Head and Neck Squamous Cell Carcinoma.

Purpose: For patients with head and neck squamous cell carcinoma (HNSCC), locoregional failure and second primary tumors are common indications for adjuvant reirradiation (re-RT). Given an absence of clear consensus on the role of adjuvant re-RT, we sought to assess histopathologic risk factors of patients with HNSCC and their resulting outcomes after adjuvant re-RT with proton therapy. Methods and Materials: We conducted a retrospective analysis of patients with HNSCC who underwent salvage surgery at our institution followed by adjuvant re-RT with proton therapy over 1.5 years. All included patients received prior radiation therapy. The Kaplan-Meier method was used to evaluate locoregional recurrence-free survival and overall survival. Results: The cohort included 22 patients, with disease subsites, including oropharynx, oral cavity, hypopharynx, larynx, and nasopharynx. Depending on adverse pathologic features, adjuvant re-RT to 66 Gy (32% of cohort) or 60 Gy (68%), with (59%) or without (41%) concurrent systemic therapy was administered. The majority (86%) completed re-RT with no reported treatment delay; 3 patients experienced grade ≥3 acute Common Terminology Criteria for Adverse Events toxicity and no patient required enteral feeding tube placement during re-RT. Median follow-up was 21.0 months (IQR, 11.7-25.2 months). Five patients had biopsy-proven disease recurrences a median of 5.9 months (IQR, 3.8-9.7 months) after re-RT. Locoregional recurrence-free survival was 95.2%, 70.2%, 64.8% at 6, 12, and 24 months, respectively. OS was 100%, 79.2%, and 79.2% at 6, 12, and 24 months, respectively. Four patients had osteoradionecrosis on imaging a median of 13.2 months (IQR, 8.7-17.4 months) after re-RT, with 2 requiring surgical intervention. Conclusions: Adjuvant re-RT for patients with HNSCC was well-tolerated and offered reasonable local control in this high-risk cohort but appears to be associated with a risk of osteoradionecrosis. Additional study and longer follow-up could help define optimal patient management in this patient population.

Reirradiation With Proton Therapy for Recurrent Malignancies of the Esophagus and Gastroesophageal Junction: Results of the Proton Collaborative Group Multi-Institutional Prospective Registry Trial.

Purpose: Treatment options for recurrent esophageal cancer (EC) previously treated with radiation therapy (RT) are limited. Reirradiation (reRT) with proton beam therapy (PBT) can offer lower toxicities by limiting doses to surrounding tissues. In this study, we present the first multi-institutional series reporting on toxicities and outcomes after reRT for locoregionally recurrent EC with PBT. Methods and Materials: Analysis of the prospective, multicenter, Proton Collaborative Group registry of patients with recurrent EC who had previously received photon-based RT and underwent PBT reRT was performed. Patient/tumor characteristics, treatment details, outcomes, and toxicities were collected. Local control (LC), distant metastasis-free survival (DMFS), and overall survival (OS) were estimated using the Kaplan-Meier method. Event time was determined from reRT start. Results: Between 2012 and 2020, 31 patients received reRT via uniform scanning/passive scattering (61.3%) or pencil beam scanning (38.7%) PBT at 7 institutions. Median prior RT, PBT reRT, and cumulative doses were 50.4 Gy (range, 37.5-110.4), 48.6 Gy (relative biological effectiveness) (25.2-72.1), and 99.9 Gy (79.1-182.5), respectively. Of these patients, 12.9% had 2 prior RT courses, and 67.7% received PBT with concurrent chemotherapy. Median follow-up was 7.2 months (0.9-64.7). Post-PBT, there were 16.7% locoregional only, 11.1% distant only, and 16.7% locoregional and distant recurrences. Six-month LC, DMFS, and OS were 80.5%, 83.4%, and 69.1%, respectively. One-year LC, DMFS, and OS were 67.1%, 83.4%, and 27%, respectively. Acute grade ≥3 toxicities occurred in 23% of patients, with 1 acute grade 5 toxicity secondary to esophageal hemorrhage, unclear if related to reRT or disease progression. No grade ≥3 late toxicities were reported. Conclusions: In the largest report to date of PBT for reRT in patients with recurrent EC, we observed acceptable acute toxicities and encouraging rates of disease control. However, these findings are limited by the poor prognoses of these patients, who are at high risk of mortality. Further research is needed to better assess the long-term benefits and toxicities of PBT in this specific patient population.

The effects of radiation therapy on the heart: implications for management.

Chemotherapy, radiotherapy, and surgery constitute the three primary modalities employed in the treatment of patients with cancer. Radiotherapy, in particular, is a mainstay of treatment for patients with cancers of the breast, esophagus, lung, and lymph nodes. Prior studies have shown, however, that radiotherapy can impact the heart. Radiation exposure, in fact, can lead to pathophysiological changes that may result in short- and long-term radiation-induced cardiac toxicities. Such toxicities can cause substantial morbidity and may manifest clinically in the weeks to years after the completion of treatment. As a result, in both modern clinical practice and clinical trials, the heart has been recognized as an organ-at-risk, and radiotherapy treatment plans seek to minimize the dose that it receives. In this review, we focus on the impacts of radiotherapy on underlying cardiac risk factors, the pathophysiology of radiotherapy-induced cardiac changes, and the clinical impacts of radiotherapy on the heart. Due to the location of the heart, we focus primarily on patients who have received radiotherapy for cancers of the breast, esophagus, lung, and lymph nodes, and those who have received cardiac-directed therapy. We then elaborate on the ongoing attempts to further lower the doses delivered to the heart during therapeutic courses of radiation.

The incorporation of cognitive-sparing techniques into prophylactic cranial irradiation in the management of small cell lung cancer.

The use of prophylactic cranial irradiation (PCI) remains an important component in the management of small cell lung cancer (SCLC). This is due to the high rates of subclinical brain metastases at the time of diagnosis. Following a response to initial treatment, PCI historically has been associated with improvements in overall survival and decreased development of brain metastases in patients with limited stage (LS-SCLC) and extensive stage (ES-SCLC) SCLC. However, PCI is commonly withheld in these settings in favor of observation, largely due to its association with cognitive sequelae following treatment. While randomized data has demonstrated that in patients with ES-SCLC, PCI may be withheld in favor of close MRI surveillance without a detriment in overall survival or cognitive functioning, these patients did not undergo formal neuropsychological assessments. In recent years, cognitive sparing techniques incorporated into whole brain radiation therapy and PCI, such as the addition of memantine and hippocampal avoidance, have demonstrated significant improvements in cognitive outcomes. As the overall survival in patients with SCLC continues to improve due to the incorporation of novel systemic therapies (e.g., immune checkpoint inhibitors), the role of PCI and maximizing quality of life remains a highly relevant topic. This article reviews the role of PCI and cognitive-sparing techniques in the management of SCLC.

The Impact of Medicaid Expansion on Patients with Cancer in the United States: A Review.

Since 2014, American states have had the option to expand their Medicaid programs as part of the Affordable Care Act (ACA), which was signed into law by former President Barack H. Obama in 2010. Emerging research has found that Medicaid expansion has had a significant impact on patients with cancer, who often face significant financial barriers to receiving the care they need. In this review, we aim to provide a comprehensive examination of the research conducted thus far on the impact of Medicaid expansion on patients with cancer. We begin with a discussion of the history of Medicaid expansion and the key features of the ACA that facilitated it. We then review the literature, analyzing studies that have investigated the impact of Medicaid expansion on cancer patients in terms of access to care, quality of care, and health outcomes. Our findings suggest that Medicaid expansion has had a positive impact on patients with cancer in a number of ways. Patients in expansion states are more likely to receive timely cancer screening and diagnoses, and are more likely to receive appropriate cancer-directed treatment. Additionally, Medicaid expansion has been associated with improvements in cancer-related health outcomes, including improved survival rates. However, limitations and gaps in the current research on the impact of Medicaid expansion on patients with cancer exist, including a lack of long-term data on health outcomes. Additionally, further research is needed to better understand the mechanisms through which Medicaid expansion impacts cancer care.

Management of Older Adults with Locally Advanced Head and Neck Cancer.

Thirty percent of patients with head and neck squamous cell carcinoma (HNSCC) are at least 70 years of age. This number continues to rise as life expectancy continues to increase. Still, older adults with HNSCC remain underrepresented in clinical trials, resulting in ambiguity on optimal management. Older adults are a complex patient population, often requiring increased support due to issues relating to functional and performance status, medical comorbidities, and medication management. Furthermore, in older adults with HNSCC, many of these conditions are independently associated with increased toxicity and worse outcomes. Toxicity in the older adult remains difficult to predict and to understand, and as treatment decisions are based on treatment tolerability, it is essential to understand the toxicities and how to minimize them. Novel predictive scores are being developed specifically for older adults with HNSCC to understand toxicity and to assist in personalized treatment decisions. There are clinical trials presently underway that are investigating shortened radiation courses and novel, less toxic systemic treatments in this population. In the forthcoming sections, we provide a detailed overview of the clinical data, treatment paradigms, and considerations in this population. This review provides a comprehensive overview of existing clinical data and clinical considerations in the older adult head and neck cancer population. Additionally, we provide a detailed overview of pertinent current and ongoing clinical trials, as well as future areas for investigation.

The Multimodal Management of Locally Advanced Rectal Cancer: Making Sense of the New Data.

In the past 40 years, the treatment of locally advanced rectal cancer has evolved with the addition of radiotherapy or chemoradiotherapy and providing (neo)adjuvant systemic chemotherapy to major surgery. However, recent trends have focused on improving our ability to risk-stratify patients and tailoring treatment to achieve the best oncologic outcome while limiting the impact on long-term quality of life. Therefore, there has been increasing interest in pursuing a watch-and-wait approach to achieve organ preservation. Several retro- and prospective studies suggest safety of the watch-and-wait approach, though it is still considered controversial due to limited clinical evidence, concerns about tumor regrowth, and subsequent distant progression. To further reduce treatment, MRI risk stratification, together with patient characteristics and patient preferences, can guide personalized treatment and reserve radiation and chemotherapy for a select patient population. Ultimately, improved options for reassessment during neoadjuvant treatment may allow for more adaptive therapy options based on treatment response. This article provides an overview of some major developments in the multimodal treatment of locally advanced rectal cancer. It reviews some relevant, controversial issues of the watch-and-wait approach and opportunities to personally tailor and reduce treatment. It also reviews the overall neoadjuvant treatment, including total neoadjuvant therapy trials, and how to best optimize for a potential complete response. Finally, it provides an algorithm as an example of how such a personalized, tailored, adaptive, and reduced treatment could look like in the future.

Cardio-pulmonary substructure segmentation of radiotherapy computed tomography images using convolutional neural networks for clinical outcomes analysis.

BACKGROUND AND PURPOSE: Radiation dose to the cardio-pulmonary system is critical for radiotherapy-induced mortality in non-small cell lung cancer. Our goal was to automatically segment substructures of the cardio-pulmonary system for use in outcomes analyses for thoracic cancers. We built and validated a multi-label Deep Learning Segmentation (DLS) model for accurate auto-segmentation of twelve cardio-pulmonary substructures. MATERIALS AND METHODS: The DLS model utilized a convolutional neural network for segmenting substructures from 217 thoracic radiotherapy Computed Tomography (CT) scans. The model was built in the presence of variable image characteristics such as the absence/presence of contrast. We quantitatively evaluated the final model against expert contours for a hold-out dataset of 24 CT scans using Dice Similarity Coefficient (DSC), 95th Percentile of Hausdorff Distance and Dose-volume Histograms (DVH). DLS contours of an additional 25 scans were qualitatively evaluated by a radiation oncologist to determine their clinical acceptability. RESULTS: The DLS model reduced segmentation time per patient from about one hour to 10 s. Quantitatively, the highest accuracy was observed for the Heart (median DSC = (0.96 (0.95-0.97)). The median DSC for the remaining structures was between 0.81 and 0.93. No statistically significant difference was found between DVH metrics of the auto-generated and manual contours (p-value ⩾ 0.69). The expert judged that, on average, 85% of contours were qualitatively equivalent to state-of-the-art manual contouring. CONCLUSION: The cardio-pulmonary DLS model performed well both quantitatively and qualitatively for all structures. This model has been incorporated into an open-source tool for the community to use for treatment planning and clinical outcomes analysis.

Are unsatisfactory outcomes after concurrent chemoradiotherapy for locally advanced non-small cell lung cancer due to treatment-related immunosuppression?

BACKGROUND AND PURPOSE: We test the hypothesis that unsatisfactory outcomes after concurrent chemoradiotherapy (RT) for locally advanced non-small cell lung cancer (LA-NSCLC) are due to treatment-related immunosuppression. MATERIALS AND METHODS: White blood cells (WBCs) data were retrospectively collected for all stage IIIA/B LA-NSCLC patients before and after (after RT: two weeks, two months, four months) concurrent chemotherapy and intensity-modulated RT in which patients were treated to a median of 63 Gy (1.8-2.0 Gy/fractions) in 2004-2014 (N = 155). Nine WBC variables were generated from pre-RT normalized absolute number of lymphocytes and neutrophils (L, N) and the N/L thereof. A WBC variable was considered a predictor for overall survival and recurrence (distant/local/nodal/regional) if p ≤ 0.006 (corrected for 9 variables) from Cox regression and competing risk analyses, respectively; both conducted using bootstrap resampling. Finally, a WBC variable predicting any of the outcomes was linearly associated with each of eleven disease/patient/treatment characteristics (p ≤ 0.005; corrected for 11 characteristics). RESULTS: At the three post-RT time points both L and N significantly decreased (p < 0.0003). Overall survival was associated with N and N/L four months post-RT (p = 0.00001, 0.0003); regional recurrence was associated with L two months post-RT (p < 0.0001). None of the disease/patient/treatment characteristics was significantly associated with any of the three WBC variables that predicted OS or recurrence (lowest p-value: p = 0.006 for tumour stage,). CONCLUSION: Significantly lower WBC levels after concurrent chemo-RT for LA-NSCLC are associated with worse long-term outcomes. The mechanism behind this treatment-related immunosuppression requires further analysis likely including other characteristics as no statistically significant association was established between any WBC variable and the disease/patient/treatment characteristics.

Dose to the cardio-pulmonary system and treatment-induced electrocardiogram abnormalities in locally advanced non-small cell lung cancer.

INTRODUCTION: High dose radiotherapy (RT) has been associated with unexpectedly short survival times for locally advanced Non-Small Cell Lung Cancer (LA-NSCLC) patients. Here we tested the hypothesis that cardiac substructure dose is associated with electrocardiography (ECG) assessed abnormalities after RT for LA-NSCLC. MATERIALS AND METHODS: Pre- and post-RT ECGs were analyzed for 155 LA-NSCLC patients treated to a median of 64 Gy in 1.8-2.0 Gy fractions using intensity-modulated RT plus chemotherapy (concurrent/sequential: 64%/36%) between 2004 and 2014. ECG abnormalities were classified as new Arrhythmic, Ischemic/Pericardial, or Non-specific (AΔECG, I/PΔECG, or NSΔECG ) events. Abnormalities were modeled as time to ECG events considering death a competing risk, and the variables considered for analysis were fractionation-corrected dose-volume metrics (α/ß = 3 Gy) of ten cardio-pulmonary structures (aorta, heart, heart chambers, inferior and superior vena cava, lung, pulmonary artery) and 15 disease, patient and treatment characteristics. Each abnormality was modelled using bootstrapping and a candidate predictor was suggested by a median multiple testing-adjusted p-value ≤0.05 across the 1000 generated samples. Forward-stepwise multivariate analysis was conducted in case of more than one candidate. RESULTS: At a median of eight months post-RT, the rate of AΔECG, I/PΔECG, and NSΔECG was 66%, 35%, and 67%. Both AΔECG and I/PΔECG were associated with worse performance status (p = 0.007, 0.03), while a higher superior vena cava minimum dose was associated with NSΔECG (p = 0.002). CONCLUSION: This study suggests that higher radiation doses to the cardio-pulmonary system lead to non-specific ECG abnormalities. Reducing dose to this system, along with effective tumor control, is likely to decrease radiation-induced cardiac toxicity.

A Novel MRI Tool for Evaluating Cortical Bone Thickness of the Proximal Femur.

BACKGROUND: Osteoporotic hip fractures heavily cost the health care system. Clinicians and patients can benefit from improved tools to assess bone health. Herein, we aim to develop a three-dimensional magnetic resonance imaging (MRI) method to assess cortical bone thickness and assess the ability of the method to detect regional changes in the proximal femur. METHODS: Eighty-nine patients underwent hip magnetic resonance imaging. FireVoxel and 3DSlicer were used to generate three-dimensional proximal femur models. ParaView was used to define five regions: head, neck, greater trochanter, intertrochanteric region, and subtrochanteric region. Custom software was used to calculate the cortical bone thickness and generate a color map of the proximal femur. Mean cortical thickness values for each region were calculated. Statistical t-tests were performed to evaluate differences in cortical thickness based on proximal femur region. Measurement reliability was evaluated using coefficient of variation, intraclass correlation coefficients, and overlap metrics. RESULTS: Three-dimensional regional cortical thickness maps for all subjects were generated. The subtrochanteric region was found to have the thickest cortical bone and the femoral head had the thinnest cortical bone. There were statistically significant differences between regions (p < 0.01) for all possible comparisons. CONCLUSIONS: Cortical bone is an important contributor to bone strength, and its thinning results in increased hip fracture risk. We describe the development and measurement reproducibility of an MRI tool permitting assessment of proximal femur cortical thickness. This study represents an important step toward longitudinal clinical trials interested in monitoring the effectiveness of drug therapy on proximal femur cortical thickness.

Patient-specific Hip Fracture Strength Assessment with Microstructural MR Imaging-based Finite Element Modeling.

Purpose To describe a nonlinear finite element analysis method by using magnetic resonance (MR) images for the assessment of the mechanical competence of the hip and to demonstrate the reproducibility of the tool. Materials and Methods This prospective study received institutional review board approval and fully complied with HIPAA regulations for patient data. Written informed consent was obtained from all subjects. A nonlinear finite element analysis method was developed to estimate mechanical parameters that relate to hip fracture resistance by using MR images. Twenty-three women (mean age ± standard deviation, 61.7 years ± 13.8) were recruited from a single osteoporosis center. To thoroughly assess the reproducibility of the finite element method, three separate analyses were performed: a test-retest reproducibility analysis, where each of the first 13 subjects underwent MR imaging on three separate occasions to determine longitudinal variability, and an intra- and interoperator reproducibility analysis, where a single examination was performed in each of the next 10 subjects and four operators independently performed the analysis two times in each of the subjects. Reproducibility of parameters that reflect fracture resistance was assessed by using the intraclass correlation coefficient and the coefficient of variation. Results For test-retest reproducibility analysis and inter- and intraoperator analyses for proximal femur stiffness, yield strain, yield load, ultimate strain, ultimate load, resilience, and toughness in both stance and sideways-fall loading configurations each had an individual median coefficient of variation of less than 10%. Additionally, all measures had an intraclass correlation coefficient higher than 0.99. Conclusion This experiment demonstrates that the finite element analysis model can consistently and reliably provide fracture risk information on correctly segmented bone images. © RSNA, 2016 Online supplemental material is available for this article.

In vivo measurement reproducibility of femoral neck microarchitectural parameters derived from 3T MR images.

PURPOSE: To evaluate the within-day and between-day measurement reproducibility of in vivo 3D MRI assessment of trabecular bone microarchitecture of the proximal femur. MATERIALS AND METHODS: This Health Insurance Portability and Accountability Act (HIPPA)-compliant, Institutional Review Board (IRB)-approved study was conducted on 11 healthy subjects (mean age = 57.4 ± 14.1 years) with written informed consent. All subjects underwent a 3T MRI hip scan in vivo (0.234 × 0.234 × 1.5 mm) at three timepoints: baseline, second scan same day (intrascan), and third scan 1 week later (interscan). We applied digital topological analysis and volumetric topological analysis to compute the following microarchitectural parameters within the femoral neck: total bone volume, bone volume fraction, markers of trabecular number (skeleton density), connectivity (junctions), plate-like structure (surfaces), plate width, and trabecular thickness. Reproducibility was assessed using root-mean-square coefficient of variation (RMS-CV) and intraclass correlation coefficient (ICC). RESULTS: The within-day RMS-CVs ranged from 2.3% to 7.8%, and the between-day RMS-CVs ranged from 4.0% to 7.3% across all parameters. The within-day ICCs ranged from 0.931 to 0.989, and the between-day ICCs ranged from 0.934 to 0.971 across all parameters. CONCLUSION: These results demonstrate high reproducibility for trabecular bone microarchitecture measures derived from 3T MR images of the proximal femur. The measurement reproducibility is within a range suitable for clinical cross-sectional and longitudinal studies in osteoporosis.

Precision of volumetric assessment of proximal femur microarchitecture from high-resolution 3T MRI.

PURPOSE: To evaluate the precision of measures of bone volume and bone volume fraction derived from high-resolution 3T MRI of proximal femur bone microarchitecture using non-uniformity correction. METHODS: This HIPAA compliant, institutional review board approved study was conducted on six volunteers (mean age 56 ± 13 years), and written informed consent was obtained. All volunteers underwent a 3T FLASH MRI hip scan at three time points: baseline, second scan same day (intra-scans), and third scan one week later (inter-scans). Segmentation of femur images and values for total proximal femur volume (T), bone volume (B), and bone volume fraction (BVF) were calculated using in-house developed software, FireVoxel. Two types of non-uniformity corrections were applied to images (N3 and BiCal). Precision values were calculated using absolute percent error (APE). Statistical analysis was carried out using one-sample one-sided t test to observe the consistency of the precision and paired t test to compare between the various methods and scans. RESULTS: No significant differences in bone volume measurements were observed for intra- and inter-scans. When using non-uniformity correction and assessing all subjects uniformly at the level of the lesser trochanter, precision values overall improved, especially significantly (p < 0.05) when measuring bone volume, B . B values using the combination of N3 or BiCal with CLT had a significant consistent APE values of less than 2.5 %, while BVF values were all consistently and significantly lower than 2.5 % APE. CONCLUSION: Our results demonstrate the precision of high-resolution 3D MRI measures were comparable to that of dual-energy X-ray absorptiometry. Additional corrections to the analysis technique by cropping at the lesser trochanter or using non-uniformity corrections helped to improve precision. The high precision values from these MRI scans provide evidence for MRI of the proximal femur as a promising tool for osteoporosis diagnosis and treatment.