Showing papers in "International Journal of Radiation Oncology Biology Physics in 2020"

Design, Implementation, and in Vivo Validation of a Novel Proton FLASH Radiation Therapy System.

Abstract: Purpose Recent studies suggest that ultrahigh-dose-rate, “FLASH,” electron radiation therapy (RT) decreases normal tissue damage while maintaining tumor response compared with conventional dose rate RT. Here, we describe a novel RT apparatus that delivers FLASH proton RT (PRT) using double scattered protons with computed tomography guidance and provide the first report of proton FLASH RT-mediated normal tissue radioprotection. Methods and Materials Absolute dose was measured at multiple depths in solid water and validated against an absolute integral charge measurement using a Faraday cup. Real-time dose rate was obtained using a NaI detector to measure prompt gamma rays. The effect of FLASH versus standard dose rate PRT on tumors and normal tissues was measured using pancreatic flank tumors (MH641905) derived from the KPC autochthonous PanCa model in syngeneic C57BL/6J mice with analysis of fibrosis and stem cell repopulation in small intestine after abdominal irradiation. Results The double scattering and collimation apparatus was dosimetrically validated with dose rates of 78 ± 9 Gy per second and 0.9 ± 0.08 Gy per second for the FLASH and standard PRT. Whole abdominal FLASH PRT at 15 Gy significantly reduced the loss of proliferating cells in intestinal crypts compared with standard PRT. Studies with local intestinal irradiation at 18 Gy revealed a reduction to near baseline levels of intestinal fibrosis for FLASH-PRT compared with standard PRT. Despite this difference, FLASH-PRT did not demonstrate tumor radioprotection in MH641905 pancreatic cancer flank tumors after 12 or 18 Gy irradiation. Conclusions We have designed and dosimetrically validated a FLASH-PRT system with accurate control of beam flux on a millisecond time scale and online monitoring of the integral and dose delivery time structure. Using this system, we found that FLASH-PRT decreases acute cell loss and late fibrosis after whole-abdomen and focal intestinal RT, whereas tumor growth inhibition is preserved between the 2 modalities.

Practice recommendations for risk-adapted head and neck cancer radiotherapy during the COVID-19 pandemic: an ASTRO-ESTRO consensus statement

Abstract: PURPOSE: Because of the unprecedented disruption of health care services caused by the COVID-19 pandemic, the American Society of Radiation Oncology (ASTRO) and the European Society for Radiotherapy and Oncology (ESTRO) identified an urgent need to issue practice recommendations for radiation oncologists treating head and neck cancer (HNC) in a time of limited resources and heightened risk for patients and staff. METHODS AND MATERIALS: A panel of international experts from ASTRO, ESTRO, and select Asia-Pacific countries completed a modified rapid Delphi process. Topics and questions were presented to the group, and subsequent questions were developed from iterative feedback. Each survey was open online for 24 hours, and successive rounds started within 24 hours of the previous round. The chosen cutoffs for strong agreement (≥80%) and agreement (≥66%) were extrapolated from the RAND methodology. Two pandemic scenarios, early (risk mitigation) and late (severely reduced radiation therapy resources), were evaluated. The panel developed treatment recommendations for 5 HNC cases. RESULTS: In total, 29 of 31 of those invited (94%) accepted, and after a replacement 30 of 30 completed all 3 surveys (100% response rate). There was agreement or strong agreement across a number of practice areas, including treatment prioritization, whether to delay initiation or interrupt radiation therapy for intercurrent SARS-CoV-2 infection, approaches to treatment (radiation dose-fractionation schedules and use of chemotherapy in each pandemic scenario), management of surgical cases in event of operating room closures, and recommended adjustments to outpatient clinic appointments and supportive care. CONCLUSIONS: This urgent practice recommendation was issued in the knowledge of the very difficult circumstances in which our patients find themselves at present, navigating strained health care systems functioning with limited resources and at heightened risk to their health during the COVID-19 pandemic. The aim of this consensus statement is to ensure high-quality HNC treatments continue, to save lives and for symptomatic benefit.

A Phase 2 Trial of Alternative Volumes of Oropharyngeal Irradiation for De-intensification (AVOID): Omission of the Resected Primary Tumor Bed After Transoral Robotic Surgery for Human Papilloma Virus-Related Squamous Cell Carcinoma of the Oropharynx.

Abstract: Purpose This trial tested the safety and efficacy of a novel, deintensified radiation therapy (RT) approach after initial surgical resection for patients with human papilloma virus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC). Methods and Materials This single-arm phase 2 prospective clinical trial enrolled 60 patients with stage pT1-pT2 N1-3 HPV-associated OPSCC treated with transoral robotic surgery (TORS) and selective neck dissection at a single institution between May 2014 and September 2017. Patients had favorable features at the primary site (negative surgical margins ≥2 mm, no perineural invasion, and no lymphovascular invasion) but required adjuvant therapy based on lymph node involvement. Surgeries were all performed at a high-volume head and neck cancer center with expertise in TORS. Patients received postoperative RT to at-risk areas in the involved neck (60-66 Gy) and uninvolved neck (54 Gy). The resected primary site was treated as an active avoidance structure in the treatment planning of postoperative RT. Concurrent chemotherapy was administered for patients with extranodal extension. Results Median follow-up of the 60 patients enrolled was 2.4 years (range, 8.5-53.8 months). A single patient recurred at the primary site, for 2-year local control of 98.3%. One patient (1.7%) developed a regional neck recurrence, and 2 patients (3.3%) developed distant metastases. Measured 2-year local recurrence–free survival was 97.9% (95% confidence interval, 86.1%-99.7%). Overall survival was 100% at the time of analysis. The mean radiation dose to the primary site was 36.9 Gy (standard deviation, 10.3 Gy). Two patients (3.3%) experienced late soft tissue necrosis in the primary site surgical bed that resolved within 2 months. Feeding tube dependence rates were 0% during RT, 3.3% temporarily during follow-up, and 0% at last follow-up. Conclusions Deintensified postoperative RT that avoids the resected primary tumor site and targets only the at-risk neck after TORS for selected patients with HPV-associated OPSCC may be safe and is worthy of further study.

The Promise of Combining Radiation Therapy With Immunotherapy.

Abstract: The development of immunotherapy in oncology builds upon many years of scientific investigation into the cellular mechanics underlying interactions between tumor cells and immune cell populations. The past decade has brought an accelerating pace to the clinical investigation of new immunotherapy agents, particularly in the setting of metastatic disease. The integration of immunotherapy into phase 3 clinical trial design has lagged in settings of advanced locoregional disease, where combination with radiation therapy may be critical. Yet, such may be the settings where immunotherapies have their greatest potential to affect patient survival and achieve curative outcomes. In this review, we discuss the interaction of radiation with the immune system and the potential to augment antitumor immunity through combined-modality approaches that integrate radiation and immunotherapies. The dynamics of cellular and tumor response to radiation offer unique opportunities for beneficial interplay with immunotherapy that may go unrecognized with conventional screening and monotherapy clinical testing of novel pharmaceutical agents. Using immune checkpoint blockade as a primary example, we discuss recent preclinical and clinical studies that illustrate the potential synergy of such therapies in combination with radiation, and we highlight the potential clinical value of such interactions. For various immunotherapy agents, their greatest clinical effect may rest in combination with radiation, and efforts to facilitate systematic investigation of this approach are highly warranted.

A Quantitative Analysis of the Role of Oxygen Tension in FLASH Radiation Therapy

Abstract: Purpose Recent demonstrations of normal tissue sparing by high-dose, high-dose-rate FLASH radiation therapy have driven considerable interest in its application to improve clinical outcomes. However, significant uncertainty remains about the underlying mechanisms of FLASH sparing and how deliveries can be optimized to maximize benefit from this effect. Rapid oxygen depletion has been suggested as a potential mechanism by which these effects occur, but this has yet to be quantitatively tested against experimental data. Methods and Materials Models of oxygen kinetics during irradiation were used to develop a time-dependent model of the oxygen enhancement ratio in mammalian cells that incorporates oxygen depletion. The characteristics of this model were then explored in terms of the dose and dose-rate dependence of the oxygen enhancement ratio. This model was also fit to experimental data from both in vitro and in vivo data sets. Results In cases of FLASH radiation therapy, this model suggests that oxygen levels can be depleted by amounts that are sufficient to affect radiosensitivity only in conditions of intermediate oxygen tension, with no effect seen at high or very low initial oxygen levels. The model also effectively reproduced the dose, dose rate, and oxygen tension dependence of responses to FLASH radiation therapy in a range of systems, with model parameters compatible with published data. Conclusions Oxygen depletion provides a credible quantitative model to understand the biological effects of FLASH radiation therapy and is compatible with a range of experimental observations of FLASH sparing. These results highlight the need for more detailed quantification of oxygen depletion under high-dose-rate radiation exposures in relevant systems and the importance of oxygen tension in target tissues for FLASH sparing to be observed.

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

Abstract: Purpose Brain metastases are a common sequelae of breast cancer. Survival varies widely based on diagnosis-specific prognostic factors (PF). We previously published a prognostic index (Graded Prognostic Assessment [GPA]) for patients with breast cancer with brain metastases (BCBM), based on cohort A (1985-2007, n = 642), then updated it, reporting the effect of tumor subtype in cohort B (1993-2010, n = 400). The purpose of this study is to update the Breast GPA with a larger contemporary cohort (C) and compare treatment and survival across the 3 cohorts. Methods and Materials A multi-institutional (19), multinational (3), retrospective database of 2473 patients with breast cancer with newly diagnosed brain metastases (BCBM) diagnosed from January 1, 2006, to December 31, 2017, was created and compared with prior cohorts. Associations of PF and treatment with survival were analyzed. Kaplan-Meier survival estimates were compared with log-rank tests. PF were weighted and the Breast GPA was updated such that a GPA of 0 and 4.0 correlate with the worst and best prognoses, respectively. Results Median survival (MS) for cohorts A, B, and C improved over time (from 11, to 14 to 16 months, respectively; P Conclusions MS has improved modestly but varies widely by diagnosis-specific PF. New PF are identified and incorporated into an updated Breast GPA (free online calculator available at brainmetgpa.com ). The Breast GPA facilitates clinical decision-making and will be useful for stratification of future clinical trials. Furthermore, these data suggest human epidermal receptor 2-targeted therapies improve clinical outcomes in some patients with BCBM.

Bringing FLASH to the Clinic: Treatment Planning Considerations for Ultrahigh Dose-Rate Proton Beams.

Abstract: Purpose Preclinical research into ultrahigh dose rate (eg, ≥40 Gy/s) “FLASH”-radiation therapy suggests a decrease in side effects compared with conventional irradiation while maintaining tumor control. When FLASH is delivered using a scanning proton beam, tissue becomes subject to a spatially dependent range of dose rates. This study systematically investigates dose rate distributions and delivery times for proton FLASH plans using stereotactic lung irradiation as the paradigm. Methods and Materials Stereotactic lung radiation therapy FLASH-plans, using 244 MeV scanning proton transmission beams, with the Bragg peak behind the body, were made for 7 patients. Evaluated parameters were dose rate distribution within a beam, overall irradiation time, number of times tissue is irradiated, and quality of the FLASH-plans compared with the clinical volumetric-modulated arc therapy (VMAT) plans. Results Sparing of lungs, thoracic wall, and heart in the FLASH-plans was equal to or better than that in the VMAT-plans. For a spot peak dose rate (SPDR, the dose rate in the middle of the spot) of 100 Gy/s, ∼40% of dose is delivered at FLASH dose rates, and for SPDR = 360 Gy/s this increased to ∼75%. One-hundred percent FLASH dose rate cannot be achieved owing to small contributions from distant spots with lower dose rates. The total irradiation time varied between 300 to 730 ms, and around 85% of the dose-receiving body volume was irradiated by either 1 or 2 beams. Conclusions Clinical implementation of FLASH using scanning proton beams requires multiple treatment planning considerations: dosimetric, temporal, and spatial parameters all seem important. The FLASH efficiency of a scanning proton beam increases with SPDR. The methodology proposed in this proof-of-principle study provides a framework for evaluating the FLASH characteristics of scanning proton beam plans and can be adapted as FLASH parameters are better defined. It currently seems logical to optimize plans for the shortest delivery time, maximum amount of high dose rate coverage, and maximum amount of single beam and continuous irradiation.

NRG Oncology Updated International Consensus Atlas on Pelvic Lymph Node Volumes for Intact and Postoperative Prostate Cancer.

Abstract: Purpose In 2009, the Radiation Therapy Oncology Group (RTOG) genitourinary members published a consensus atlas for contouring prostate pelvic nodal clinical target volumes (CTVs). Data have emerged further informing nodal recurrence patterns. The objective of this study is to provide an updated prostate pelvic nodal consensus atlas. Methods and Materials A literature review was performed abstracting data on nodal recurrence patterns. Data were presented to a panel of international experts, including radiation oncologists, radiologists, and urologists. After data review, participants contoured nodal CTVs on 3 cases: postoperative, intact node positive, and intact node negative. Radiation oncologist contours were analyzed qualitatively using count maps, which provided a visual assessment of controversial regions, and quantitatively analyzed using Sorensen-Dice similarity coefficients and Hausdorff distances compared with the 2009 RTOG atlas. Diagnostic radiologists generated a reference table outlining considerations for determining clinical node positivity. Results Eighteen radiation oncologists’ contours (54 CTVs) were included. Two urologists’ volumes were examined in a separate analysis. The mean CTV for the postoperative case was 302 cm3, intact node positive case was 409 cm3, and intact node negative case was 342 cm3. Compared with the original RTOG consensus, the mean Sorensen-Dice similarity coefficient for the postoperative case was 0.63 (standard deviation [SD] 0.13), the intact node positive case was 0.68 (SD 0.13), and the intact node negative case was 0.66 (SD 0.18). The mean Hausdorff distance (in cm) for the postoperative case was 0.24 (SD 0.13), the intact node positive case was 0.23 (SD 0.09), and intact node negative case was 0.33 (SD 0.24). Four regions of CTV controversy were identified, and consensus for each of these areas was reached. Conclusions Discordance with the 2009 RTOG consensus atlas was seen in a group of experienced NRG Oncology and international genitourinary radiation oncologists. To address areas of variability and account for new data, an updated NRG Oncology consensus contour atlas was developed.

Absolute Lymphocyte Count Predicts Abscopal Responses and Outcomes in Patients Receiving Combined Immunotherapy and Radiation Therapy: Analysis of 3 Phase 1/2 Trials.

Abstract: Purpose Research to elucidate predictive factors of the abscopal effect is an essential first step toward potentially modifying these factors to increase the incidence of systemic antitumor effects. This study, using data from 3 institutional phase 1/2 trials, examined the predictive capacity of recorded parameters in patients undergoing combined radiation therapy (RT) and immunotherapy and explored outcomes based on those predictive factors. Methods and Materials All patients underwent combined immunotherapy and RT and had at least 1 nonirradiated noncontiguous lesion to evaluate out-of-field (abscopal) responses, defined as the best Response Evaluation Criteria in Solid Tumors response. Results Altogether, 153 patients met study criteria, and the median follow-up was 21.1 months. The most common cancer types were non-small cell lung carcinoma (n = 62), small cell lung carcinoma (n = 25), head and neck cancers (n = 16), and renal cell carcinoma (n = 13). Immunotherapies included ipilimumab (n = 98) and pembrolizumab (n = 55). Multivariable linear regression indicated that post-RT absolute lymphocyte count (ALC), when analyzed as a continuous variable, correlated with abscopal responses (P Conclusions Lymphopenia, measured as the continuous variable of post-RT ALC, may affect the occurrence of abscopal responses and thus influence prognosis in patients treated with RT and immunotherapy. Although this hypothesis-generating finding requires corroboration by additional data, it suggests the importance of ALC monitoring and the potential of therapeutic manipulation of this parameter to induce abscopal effects.

Understanding High-Dose, Ultra-High Dose Rate, and Spatially Fractionated Radiation Therapy.

Abstract: The National Cancer Institute's Radiation Research Program, in collaboration with the Radiosurgery Society, hosted a workshop called Understanding High-Dose, Ultra-High Dose Rate and Spatially Fractionated Radiotherapy on August 20 and 21, 2018 to bring together experts in experimental and clinical experience in these and related fields. Critically, the overall aims were to understand the biological underpinning of these emerging techniques and the technical/physical parameters that must be further defined to drive clinical practice through innovative biologically based clinical trials.

Late Contrast Enhancing Brain Lesions in Proton-Treated Patients With Low-Grade Glioma: Clinical Evidence for Increased Periventricular Sensitivity and Variable RBE.

Abstract: Purpose Late radiation-induced contrast-enhancing brain lesions (CEBLs) on magnetic resonance imaging (MRI) after proton therapy of brain tumors have been observed to occur frequently in regions of high linear energy transfer (LET) and in proximity to the ventricular system. We analyzed 110 patients with low-grade glioma treated with proton therapy to determine whether the risk for CEBLs is increased in proximity to the ventricular system and if there is a relationship between relative biological effectiveness (RBE) and LET. Methods and Materials We contoured CEBLs identified on follow-up T1-MRI scans and computed dose and dose-averaged LET (LETd) distributions for all patients using the Monte Carlo method. We then performed cross-validated voxel-level logistic regression to predict local risks for image change and to extract model parameters, such as the RBE. From the voxel-level model, we derived a model for patient-level risk prediction based on the treatment plan. Results Of 110 patients, 23 exhibited 1 or several CEBLs on follow-up MRI scans. The voxel-level logistic model has an accuracy as follows: area under the curve of 0.94 and Brier score of 2.6 × 10-5. Model predictions are a 3-fold increased risk in the 4 mm region around the ventricular system and an LETd-dependent RBE of, for example, 1.20 for LETd = 2 keV/μm and 1.50 for LETd = 5 keV/μm. The patient-level risk model has an accuracy as follows: area under the curve of 0.78 and Brier score of 0.13. Conclusions Our findings present clinical evidence for an increased risk in ventricular proximity and for a proton RBE that increases significantly with increasing LET. We present a voxel-level model that accurately predicts the localization of late MRI contrast change and extrapolate a patient-level model that allows treatment plan–based risk prediction.

Low-Dose Whole-Lung Irradiation for COVID-19 Pneumonia: Short Course Results.

Abstract: Purpose The COVID-19 outbreak is affecting people worldwide. Many of the infected patients suffer from respiratory involvement that may progress to acute respiratory distress syndrome. This pilot study aimed to evaluate the clinical efficacy of low-dose whole-lung radiotherapy in patients with COVID-19 pneumonia. Methods and Materials In this clinical trial, conducted in ***, we enrolled patients with COVID-19 who were older than 60 years and hospitalized to receive supplementary oxygen for their documented pneumonia. Participants were treated with whole-lung irradiation in a single fraction of 0.5 Gy plus the national protocol for the management of COVID-19. Vital signs (including blood oxygenation and body temperature) and laboratory findings (IL-6 and CRP) were recorded before and after irradiation. Results Between 21 May 2020 and 24 June 2020, five patients received whole-lung irradiation. They were followed for 5-7 days to evaluate the response to treatment and toxicities. The clinical and paraclinical findings of four of the five patients (patient #4 became worse and died on day 3) improved on the first day of irradiation. Patient #3 opted-out of the trial on the third day after irradiation. The mean time to discharge was 6 days for the other three patients. No acute radiation-induced toxicity was recorded. Conclusions With a response rate of 80%, whole-lung irradiation in a single fraction of 0.5 Gy had encouraging results in oxygen-dependent patients with COVID-19 pneumonia.

Clinical Outcomes of Stereotactic MR-Guided Adaptive Radiation Therapy for High-Risk Lung Tumors

Abstract: Purpose Magnetic resonance (MR)-guided SABR was performed for patients with lung tumors in whom treatment delivery was challenging owing to tumor location, motion, or pulmonary comorbidity. Because stereotactic MR-guided adaptive radiation therapy (SMART) is a novel approach, we studied clinical outcomes in these high-risk lung tumors. Methods and Materials Fifty consecutive patients (54 lung tumors) underwent SMART between 2016 and 2018 for either a primary lung cancer (29 patients) or for lung metastases (21 patients). Eligible patients had risk factors that could predispose them to toxicity, including a central tumor location (n = 30), previous thoracic radiation therapy (n = 17), and interstitial lung disease (n = 7). A daily 17-second breath-hold MR scan was acquired in treatment position, and on-table plan adaptation was performed using the anatomy of the day. Gated SABR was delivered during repeated breath-holds under continuous MR guidance. Results All but 1 patient completed the planned SMART schedule. With daily plan adaptation, a biologically effective dose ≥100 Gy to 95% of the planning target volume was delivered in 50 tumors (93%). Median follow-up was 21.7 months (95% confidence interval, 19.9-28.1). Local control and overall and disease-free survival rates at 12 months were 95.6%, 88.0%, and 63.6%, respectively. Local failures developed in 4 patients: in 2 after reirradiation for a recurrent lung cancer and in 2 patients with a colorectal metastasis. Overall rates of any grade ≥2 and ≥3 toxicity were 30% and 8%, respectively. Commonest toxicities were grade ≥2 radiation pneumonitis (12%) and chest wall pain (8%). No grade 4 or 5 toxicities were observed. Conclusions Use of MR-guided SABR resulted in low rates of high-grade toxicity and encouraging early local control in a cohort of high-risk lung tumors. Additional studies are needed to identify patients who are most likely to benefit from the SMART approach.

Involved Site Radiation Therapy in Adult Lymphomas: An Overview of International Lymphoma Radiation Oncology Group Guidelines

Abstract: Involved node radiation therapy for lymphoma was introduced with the aim of using the smallest effective treatment volume, individualized to the patient's disease distribution, to avoid the potentially unnecessary normal tissue exposure and toxicity risks associated with traditional involved field radiation therapy. The successful implementation of involved node radiation therapy requires optimal imaging and precise coregistration of baseline imaging with the radiation therapy planning computed tomography scan. Limitations of baseline imaging, changes in patient position, and anatomic changes after chemotherapy may make this difficult in routine practice. Involved site radiation therapy (ISRT) was introduced by the International Lymphoma Radiation Oncology Group as a slightly larger treated volume, intended to allow for commonly encountered uncertainties. In addition to imaging considerations, the optimal ISRT treatment volume also depends on disease histology, stage, nodal or extranodal location, and the type and efficacy of systemic therapy, which in turn influence the distribution of macroscopic and potential subclinical disease. This article presents a systematic overview of ISRT, updating key evidence and highlighting differences in the application of ISRT across the lymphoma clinical spectrum.

A Phase II Trial of Stereotactic Ablative Radiation Therapy as a Boost for Locally Advanced Cervical Cancer.

Abstract: Purpose Our purpose was to assess the feasibility, safety, and efficacy of stereotactic ablative radiation therapy (SAbR) as an alternative for intracavitary/interstitial brachytherapy boost for locally advanced cervical cancer (LACC) after initial chemoradiation. Methods and Materials A single arm institutional phase II study of SAbR as a boost for LACC was conducted. Eligible patients had LACC FIGO 2009 stage IB2-IVB, performance status 0 to 3, and one of the following: medically unfit or refused intracavitary or tumor extent required interstitial brachytherapy for coverage. The cervix planning target volume boost (PTVboost) received 28 Gy in 4 fractions. Results The study was closed with 15 of 21 patients completed owing to concern for toxicity. Median follow-up for this cohort was 19 months. Patients had predominantly advanced stage (III-IV, 53%) with median Charlson comorbidity score of 4. Most tumors were large with a median SAbR boost PTV size of 139 cc (range, 51-268 cc). Tumor size and patient comorbidities probably contributed to the lower-than-expected 2-year local control, progression free, and overall survival of 70.1%, 46.7%, and 53.3%, respectively. The SAbR boost 2 year cumulative grade ≥ 3 toxicity of 26.7% was predominantly rectal (ulcer/fistula).The median SAbR PTV volume was 225 cc versus 95 cc for patients with and without grade ≥ 3 toxicity. On dosimetric analysis, only the percentage of rectal circumference receiving 15 Gy (PRC15) for the SAbR boost was associated with development of grade 3 ulcer or rectovaginal fistula (P = .04), with PRC15 > 62.7% being the strongest predictor of toxicity (AUC, 0.93; sensitivity, 100%; specificity, 90%). Conclusions In this SAbR boost series suboptimal outcomes were probably related to patient selection and very large tumor volume. This approach may still be considered in patients with smaller tumors unable to undergo standard brachytherapy for cervix cancer.

Single Stage Direct-to-Implant Breast Reconstruction Has Lower Complication Rates Than Tissue Expander and Implant and Comparable Rates to Autologous Reconstruction in Patients Receiving Postmastectomy Radiation

Abstract: Purpose To compare single-stage direct-to-implant (DTI) immediate reconstruction to the commonly used 2-stages expander and implant (TE/I) or autologous reconstruction with focus on postmastectomy radiation therapy (PMRT) setting. Methods and Materials We reviewed the charts of 1,286 patients who underwent 1,814 breast reconstructions at our institution with and without PMRT from 1997 to 2017. Patients were divided into 6 groups according to type of reconstruction and PMRT status. Primary objective was reconstruction complications defined solely on surgical reintervention operative notes such as infection, skin necrosis, and fat necrosis across all groups. Implant-related complications such as capsular contracture, implant rupture or exposure, or implant failure were compared between TE/I and DTI. Kaplan–Meier estimates were used to calculate 5-year cumulative incidence of complications. The secondary objective was to compare the 3 reconstruction types in settings of immediate reconstruction followed by PMRT on multivariable analysis. Results Median follow-up was 5.8 years. Among 1286 patients, 41.1% (N = 529/1286) received PMRT. Among 1814 reconstructed breasts, autologous, single-stage, and TE/I represented 18.7%, 34.8%, and 46.2%, respectively. With no PMRT, the 5-year cumulative incidence of any reconstruction complication was 11.1%, 12.6%, and 19.5% for autologous, DTI, and TE/I reconstructions, respectively. The addition of PMRT resulted in 5-year cumulative incidence of 15.1%, 18.2%, and 36.8%, respectively. The multivariable analysis showed that DTI was associated with lesser complications compared with TE/I, whereas no significant difference was noted between DTI and autologous. Conclusions Single-stage DTI reconstruction had significantly lower complication rates than TE/I with and without PMRT. Single-stage complication rates were not significantly different from autologous complication rates in PMRT settings. Single-stage reconstruction may offer a valuable option for patients receiving PMRT.

Effect of Low-Dose Radiation Therapy on Abscopal Responses to Hypofractionated Radiation Therapy and Anti-PD1 in Mice and Patients With Non-Small Cell Lung Cancer.

Abstract: Purpose Hypofractionated radiation therapy (HFRT) can induce antitumor T cell responses, particularly in combination with immune checkpoint inhibitors (ICI), but abscopal effects are often precluded by insufficient T cell infiltration of distant, nonirradiated tumors. Additional noncytotoxic, low-dose radiation therapy (LDRT) of distant tumors may enhance the abscopal response, but clinical evidence and preclinical studies for this scenario are lacking. Methods and Materials We investigated whether triple treatment consisting of HFRT, ICI, and LDRT could achieve better systemic antitumor response in bilateral mouse tumor models and in patients with stage IV non-small cell lung cancer. Results Our analyses of bilateral mouse tumor models show that HFRT treatment of the primary tumor combined with LDRT treatment of the abscopal tumor and anti-PD1 therapy enhances the abscopal response compared with HFRT/anti-PD1, HFRT/LDRT, or LDRT/anti-PD1 double treatments; complete cure was observed in more than half of the mice treated with triple therapy. The enhanced abscopal effect was associated with increased infiltration of CD8+ effector T cells and upregulated expression of T cell–attracting chemokines. Of 9 patients with metastatic non-small cell lung cancer who were treated with this triple therapy, 3 and 2 patients showed partial responses and stable disease, respectively. Among 9 relatively large (175.7 ± 42.3 cm3) LDRT lesions, 6 lesions decreased by 28% in size, on average. Conclusions Our study demonstrates preclinically that LDRT of established metastases significantly enhances the abscopal response to HFRT plus ICI. It also shows that additional LDRT was well tolerated by patients and that this treatment profile is effective and worth further study.

A Dose of Reality: How 20 Years of Incomplete Physics and Dosimetry Reporting in Radiobiology Studies May Have Contributed to the Reproducibility Crisis.

Abstract: Purpose A large proportion of preclinical or translational studies using radiation have poor replicability. For a study involving radiation exposure to be replicable, interpretable, and comparable, its experimental methodology must be well reported, particularly in terms of irradiation protocol, including the amount, rate, quality, and geometry of radiation delivery. Here we perform the first large-scale literature review of the current state of reporting of essential experimental physics and dosimetry details in the scientific literature. Methods and Materials For 1758 peer-reviewed articles from 469 journals, we evaluated the reporting of basic experimental physics and dosimetry details recommended by the authoritative National Institute of Standards and Technology symposium. Results We demonstrate that although some physics and dosimetry parameters, such as dose, source type, and energy, are well reported, the majority are not. Furthermore, highly cited journals and articles are systematically more likely to be lacking experimental details related to the irradiation protocol. Conclusions These findings show a crucial deficiency in the reporting of basic experimental details and severely affect the reproducibility and translatability of a large proportion of radiation biology studies.

Curative Irradiation Treatment of Hepatocellular Carcinoma: A Multicenter Phase 2 Trial.

Abstract: Purpose Liver transplantation is the standard definitive treatment for nonmetastatic hepatocellular carcinoma (HCC). However, less than 5% of patients are ultimately candidates as a result of frequent comorbidities and graft shortage. The aim of this study was to evaluate stereotactic body radiation therapy (SBRT) as an ablative treatment for inoperable HCC. Methods and Materials A prospective phase 2 trial included newly diagnosed single HCC lesions that were without extrahepatic extension and that were deemed unsuitable for standard locoregional therapies, with a tumor size ranging from 1 to 6 cm. The SBRT dose was 45 Gy in 3 fractions. Primary endpoint was the local control of irradiated HCC at 18 months, defined by Response Evaluation Criteria in Solid Tumors. Results Forty-three patients were treated and evaluable. Median follow-up was 4.0 years (range, 1.2-4.6 years). All 43 patients had cirrhosis; 37 (88%) were Child–Pugh grade A and 5 (12%) grade B (1 missing data). No patients had received prior local treatment. Thirteen patients (31%) presented grade ≥3 acute adverse events, including 8 patients with an abnormality of the liver function tests (19%). Three patients (10%) experienced a decline in Child–Pugh at 3 months post-SBRT. The 18-month local control rate was 98% (95% confidence interval, 85%-99%). The 18-month overall survival rate was 72% (range, 56%-83%). Median overall survival was 3.5 years. Conclusions Local control and overall survival after SBRT for untreated solitary HCC were excellent despite candidates being unfit for transplantation, resection, ablation, or embolization treatments. SBRT should be considered as a bridge to transplant or as definitive therapy for those ineligible for transplant.

Ring Versus Ovoids and Intracavitary Versus Intracavitary-Interstitial Applicators in Cervical Cancer Brachytherapy: Results From the EMBRACE I Study.

Abstract: Purpose The aim of this study was to investigate the influence of brachytherapy technique and applicator type on target dose, isodose surface volumes, and organ-at-risk (OAR) dose. Methods and Materials Nine hundred two patients treated with tandem/ovoids (TO reduced bladder and rectum D2cm3 and bladder ICRU-point by 3.5 to 5.0 Gy for ovoids centers; and similar OAR doses for ring centers. CTVHR D90% was 2.8 Gy higher, bladder D2cm3 4.3 Gy lower, rectovaginal ICRU-point 4.8 Gy lower, and vagina 5-mm lateral-point 22.4 Gy higher for ring-IC/IS versus ovoids-IC/IS centers. The P values were Conclusions T&R-IC applicators have better target dose and dose conformity than T&O-IC in this representative patient cohort. IC applicators fail to cover large target volumes, whereas routine application of IC/IS improves target and OAR dose considerably. Patients treated with T&R show a more favorable therapeutic ratio when evaluating target, bladder/rectum doses, and V85Gy. A comprehensive view on technique/applicators should furthermore include practical considerations and clinical outcome.

Novel Methodology to Investigate the Effect of Radiation Dose to Heart Substructures on Overall Survival.

Abstract: Purpose For patients with lung cancer treated with radiation therapy, a dose to the heart is associated with excess mortality; however, it is often not feasible to spare the whole heart. Our aim is to define cardiac substructures and dose thresholds that optimally reduce early mortality. Methods and Materials Fourteen cardiac substructures were delineated on 5 template patients with representative anatomies. One thousand one hundred sixty-one patients with non-small cell lung cancer were registered nonrigidly to these 5 template anatomies, and their radiation therapy doses were mapped. Mean and maximum dose to each substructure were extracted, and the means were evaluated as input to prediction models. The cohort was bootstrapped into 2 variable reduction techniques: elastic net least absolute shrinkage and selection operator and the random survival forest model. Each method was optimized to extract variables contributing most to overall survival, and model coefficients were evaluated to select these substructures. The most important variables common to both models were selected and evaluated in multivariable Cox-proportional hazard models. A threshold dose was defined, and Kaplan-Meier survival curves plotted. Results Nine hundred seventy-eight patients remained after visual quality assurance of the registration. Ranking the model coefficients across the bootstraps selected the maximum dose to the right atrium, right coronary artery, and ascending aorta as the most important factors associated with survival. The maximum dose to the combined cardiac region showed significance in the multivariable model, a hazard ratio of 1.01/Gy, and P = .03 after accounting for tumor volume (P Conclusions The maximum dose to the combined cardiac region encompassing the right atrium, right coronary artery, and ascending aorta was found to have the greatest effect on patient survival. A maximum equivalent dose in 2-Gy fractions of 23 Gy was identified for consideration as a dose limit in future studies.

Pelvic Insufficiency Fractures After External Beam Radiation Therapy for Gynecologic Cancers: A Meta-analysis and Meta-regression of 3929 Patients.

Abstract: Purpose To estimate the overall rate, symptomatic proportion, and most common sites of pelvic insufficiency fracture (PIF) after external beam radiation therapy for gynecologic cancers based on posttreatment computed tomography, magnetic resonance imaging, positron emission tomography, or bone scintigraphy. Methods and Materials A systematic search of databases (PubMed and EMBASE) was performed (CRD42019125679). The pooled summary of overall PIF and the proportion of symptomatic cases were calculated using the random-effects model weighted by the inverse variance. A multivariate meta-regression was performed to evaluate potential sources of heterogeneity regarding PIF fractures. Results Twenty-one studies met the inclusion criteria (total 3929 patients). Five hundred four patients developed PIF, translating to an overall rate of 14% (95% confidence interval, 10%-18%, based on 21 studies). Among these cases with PIF, the proportion of symptomatic patients was 61% (95% confidence interval, 52%-69%, based on 14 studies). The total number of PIFs was 704 (mean, 1.72 PIFs per each patient to develop PIF, based on 14 studies). More recent series (P = .0074) and the use of intensity modulated radiation therapy (P = .0299) were associated with lower fracture rates. The most common fracture sites were sacroiliac joint (39.7%), body of the sacrum (33.9%), pubis (13%), lumbar vertebra (7%), iliac bone (2.8%), acetabulum (2.1%), and femoral head/neck (1.5%). The median time to fracture was 7.1 to 19 months after radiation therapy. Conclusions The incidence of PIF after radiation therapy for gynecologic cancers is high (14%), with the majority affecting the sacral bone or joint (73.6%), although this risk appears to be lower with intensity modulated radiation therapy. Posttreatment bone surveillance is warranted in this population because nearly 40% of patients were asymptomatic at the time of PIF diagnosis.

Letter from Switzerland.

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Bridging Radiation Therapy Before Commercial Chimeric Antigen Receptor T-Cell Therapy for Relapsed or Refractory Aggressive B-Cell Lymphoma

Abstract: Purpose CD19-targeting chimeric antigen receptor T-cell (CART) therapy has emerged as a promising treatment for relapsed/refractory aggressive B-cell lymphoma (r/rABL), culminating in 2 US Food and Drug Administration–approved therapies: tisagenlecleucel (tisa-cel) and axicabtagene ciloleucel (axi-cel). Following leukapheresis and in preparation for CART infusion, contemporary bridging and lymphodepletion regimens rely mostly on cytotoxic chemotherapy. Here, in a cohort of patients treated with commercial tisa-cel and axi-cel, we show that bridging-RT may offer a supplemental approach. Methods and Materials Thirty-one patients receiving commercial tisa-cel (n = 13) or axi-cel (n = 18) between August 2018 and February 2019 for r/rABL were retrospectively reviewed. Patients were categorized into 2 groups: (1) bridging-RT within 30 days of CART infusion or (2) nonbridging-RT (NBRT), in which patients received either remote RT greater than 30 days before CART infusion or no prior RT. Results Five patients received bridging-RT within 30 days of CART infusion. Median bridging-RT dose was 37.5 Gy and was completed a median of 13 days before infusion. No grade 3 (G3) or higher RT-toxicities occurred. No patients in the bridging-RT group experienced G3 or higher CART-related toxicities (CRS or neurotoxicity), and 23% (n = 6) and 15% (n = 4) experienced G3-5 CRS and G3-5 neurotoxicity in the NBRT group, respectively. Overall treatment response in the bridging-RT and NBRT groups was 80% and 64%, respectively. The axi-cel CART product was associated with CRS (odds ratio [OR] = 26.67, P = .001) and CRS correlated with neurotoxicity (OR = 12.22, P = .028). There was a trend toward an association for CRS with metabolic tumor volume (OR = 1.06/mL, P = .141) and TLG (OR = 1.01/mL x standard uptake value, P = .099). Conclusions Bridging-RT before commercial CART does not appear to increase the risk for CART-related toxicities or negatively affect outcomes in r/rABL patients. No G3 or higher RT-toxicities occurred in this series. Pretreatment metabolic tumor burden may be associated with CART-associated CRS; however, larger patient numbers are required to elucidate significant associations. Future work to prospectively assess the value of bridging-RT is warranted.

A Prospective Study of 18F-DCFPyL PSMA PET/CT Restaging in Recurrent Prostate Cancer following Primary External Beam Radiotherapy or Brachytherapy

Abstract: Purpose Radio-recurrent prostate cancer is typically detected by a rising prostate-specific antigen and may reflect local or distant disease. Positron emission tomography (PET) radiotracers targeting prostate-specific membrane antigen, such as 18F-DCFPyL have shown promise in restaging men with recurrent disease postprostatectomy but are less well characterized in the setting of radio-recurrent disease. Methods and Materials A prospective, multi-institutional study was conducted to evaluate the effect of 18F-DCFPyL PET/computed tomography (CT) when added to diagnostic imaging (DI; CT abdomen and pelvis, bone scan, multiparametric magnetic resonance imaging pelvis) for men with radio-recurrent prostate cancer. All men were imaged with DI and subsequently underwent 18F-DCFPyL PET/CT with local and central reads. Tie break reads were performed as required. Management questionnaires were completed after DI and again after 18F-DCFPyL PET/CT. Discordance in patterns of disease detected with 18F-DCFPyL PET/CT versus DI and changes in management were characterized. Results Seventy-nine men completed the study. Most men had T1 disease (62%) and Gleason score Conclusions 18F-DCFPyL PET/CT identified extraprostatic disease in twice as many men with radio-recurrent prostate cancer compared with DI and detected a site of recurrence in 87% of men compared with 67% with DI. Furthermore, 18F-DCFPyL PET/CT identified potentially actionable disease (prostate only recurrence or oligometastatic disease) in 75% of men and changed proposed management in 43% of men.

Patterns and Predictors of Relapse Following Radical Chemoradiation Therapy Delivered Using Intensity Modulated Radiation Therapy With a Simultaneous Integrated Boost in Anal Squamous Cell Carcinoma.

Abstract: Purpose Our purpose was to describe the patterns and predictors of treatment failure in patients receiving definitive chemoradiation therapy (CRT) for anal squamous cell carcinoma (ASCC), delivered using intensity modulated radiation therapy (IMRT). Methods and Materials Our study was a retrospective cohort analysis of consecutive patients treated with curative intent for ASCC using CRT delivered with a standardized IMRT technique in 5 UK cancer centers. Patients were included from the start of UK IMRT guidance from February 2013 to October 31, 2017. Collected data included baseline demographics, treatment details, tumor control, sites of relapse, and overall survival. Statistical analysis to calculate outcomes and predictive factors for outcome measures were performed using SPSS and R. Results The medical records of 385 consecutive patients were analyzed. Median follow-up was 24.0 months. Within 6 months of completing CRT, 86.7% of patients achieved a complete response. Three-year disease-free survival and overall survival were 75.6% and 85.6%, respectively. Of all relapses, 83.4% occurred at the site of primary disease. There were 2 isolated relapses in regional nodes not involved at outset. Predictive factors for cancer recurrence included male sex, high N-stage, and failure to complete radiation therapy as planned. Conclusions The treatment results compare favorably to published outcomes from similar cohorts using 3-dimensional conformal CRT. The observed patterns of failure support the current UK IMRT voluming guidelines and dose levels, highlighting our prophylactic nodal dose as sufficient to prevent isolated regional relapse in uninvolved nodes. Further investigation of strategies to optimize CR should remain a priority in ASCC because the site of primary disease remains the overwhelming site of relapse.

End-of-Range Radiobiological Effect on Rib Fractures in Patients Receiving Proton Therapy for Breast Cancer.

Abstract: Purpose A prospective trial of proton therapy for breast cancer revealed an increased rib fracture rate of 7%, which is higher than the expected rate based on the literature on photon therapies. We aim to evaluate the hypothesis that the increased relative biological effectiveness (RBE) at the distal edge of proton beams is the cause. Methods and Materials We combined the cohort from the prospective clinical trial and a retrospective cohort from a database. Monte Carlo simulations were performed to recalculate the physical dose and dose-averaged linear energy transfer (LETd). The first 10 ribs and fracture areas in patients with fractures were contoured and deformably registered. The LETd-weighted dose was used as a surrogate for biological effectiveness and compared with the conventional fixed RBE of 1.1. Dose to 0.5 cm3 of the ribs (D0.5) was selected to analyze the dose-response relationship using logistic regression. We chose an alpha/beta ratio of 3 to calculate the biological effective dose in Gy3(RBE). Results Thirteen of 203 patients in the cohorts exhibited a total of 25 fractures. The LETd in fractured areas is increased (6.1 ± 2.0 keV/μm, mean ± standard deviation), suggesting possible end-of-range radiobiological effects with increased RBE. The D0.5 of the fractured ribs is 80.3 ± 9.4 Gy3(RBE) with a generic factor of 1.1 and is relatively low compared with historical photon results. On the other hand, the D0.5 of the fractured ribs is 100.0 ± 12.5 Gy3(RBE) using the LETd-based model with a dose-response curve that is more consistent with historical photon data. Conclusions The increased rib fracture rate seen in our trial is probably associated with the increased LETd and RBE at the distal edge of proton beams. This phenomenon warrants further investigation and possible integration of LETd into treatment planning and optimization in proton therapy.