Dosimetric Evaluation Between the Conventional Volumetrically Modulated Arc Therapy (VMAT) Total Body Irradiation (TBI) and the Novel Simultaneous Integrated Total Marrow Approach (SIMBa) VMAT TBI.

Purpose The purpose of this study was to assess the treatment planning feasibility of volumetrically modulated arc therapy total body irradiation (VMAT TBI) using a simultaneous integrated marrow and body approach (SIMBa). We also aimed to compare SIMBa TBI with the more conventional VMAT TBI approach using the entire body as the target. The goal of using an integrated approach like SIMBa is to balance the known clinical benefit of TBI with the toxicity decrease of Total Marrow Irradiation (TMI) using two prescription volumes. In anticipation of a clinical trial to investigate a novel conditioning regimen that uses SIMBa, our institution retrospectively analyzed the dosimetric differences between 20 clinical VMAT TBI which were re-planned using SIMBa. Methods Twenty patients who previously received conventional VMAT TBI at our institution with a dose of 12 Gy in six fractions were re-planned using SIMBa with a planning aim of delivering a uniform dose of 12 Gy to at least 90% of the PTV_BodyEval. The planning aims of SIMBa were to deliver a uniform dose of 12 Gy to at least 90% of the PTV_Marrow and 8 Gy to at least 90% of the PTV_TotalBody while limiting the mean lung dose to less than 8 Gy. The plans were normalized so that 100% of the PTV_Marrow received at least 90% of the dose with the PTV_TotalBody optimized to stay as close to 100% at 90% as possible. Results All 20 patient plans achieved 12 Gy/8 Gy to at least 90% of the PTV_Marrow and PTV_TotalBody, respectively, with max doses of <16 Gy (130%). As compared with the delivered TBI, the following reductions in mean dose were notable: small bowel 21.3±4.2%, lung 16.3±7.9%, heart 25.3±8.6%, and kidney 16.4±6.2%. Coverage of the sanctuary sites was maintained despite a significant reduction to sensitive organs at risk (OARs). Conclusion This study supports that VMAT TBI treatment planning with SIMBa is feasible. In this sample, SIMBa provided dosimetrically similar doses to marrow and sanctuary site doses as TBI while achieving lower doses to OARs. A clinical trial is needed to investigate the clinical implications of VMAT TBI with SIMBa.

Students' Perspectives and Concerns for the 2020 to 2021 Radiation Oncology Interview Season.

PURPOSE: Recently, the Coalition for Physician Accountability Work Group on Medical Students in the Class of 2021 recommended limiting visiting medical student rotations, conducting virtual residency interviews, and delaying the standard application timeline owing to the ongoing corona virus disease 2019 (COVID-19) pandemic. These changes create both challenges and opportunities for medical students and radiation oncology residency programs. We conducted a comprehensive needs assessment to prepare for a virtual recruitment season, including a focus group of senior medical students seeking careers in oncology. METHODS AND MATERIALS: A single 1.5-hour focus group was conducted with 10 third- and fourth-year medical students using Zoom videoconferencing software. Participants shared opinions relating to visibility of residency programs, virtual clerkship experiences, expectations for program websites, and remote interviews. The focus group recording was transcribed and analyzed independently by 3 authors. Participants' statements were abstracted into themes via inductive content analysis. RESULTS: Inductive content analysis of the focus group transcript identified several potential challenges surrounding virtual recruitment, including learning the culture of a program and/or city, obtaining accurate information about training programs, and uncertainty surrounding the best way to present themselves during a virtual interview season. In the present environment, the focus group participants anticipate relying more on departmental websites and telecommunications because in-person interactions will be limited. In addition, students perceived that the educational yield of a virtual clerkship would be low, particularly if an in-person rotation had already been completed at another institution. CONCLUSIONS: With the COVID-19 crisis limiting visiting student rotations and programs transitioning to hosting remote interviews, we recommend programs focus resources toward portraying the culture of their program and city, accurately depicting program information, and offering virtual electives or virtual interaction to increase applicant exposure to residency program culture.

Survival in Patients With Brain Metastases: Summary Report on the Updated Diagnosis-Specific Graded Prognostic Assessment and Definition of the Eligibility Quotient.

PURPOSE: Conventional wisdom has rendered patients with brain metastases ineligible for clinical trials for fear that poor survival could mask the benefit of otherwise promising treatments. Our group previously published the diagnosis-specific Graded Prognostic Assessment (GPA). Updates with larger contemporary cohorts using molecular markers and newly identified prognostic factors have been published. The purposes of this work are to present all the updated indices in a single report to guide treatment choice, stratify research, and define an eligibility quotient to expand eligibility. METHODS: A multi-institutional database of 6,984 patients with newly diagnosed brain metastases underwent multivariable analyses of prognostic factors and treatments associated with survival for each primary site. Significant factors were used to define the updated GPA. GPAs of 4.0 and 0.0 correlate with the best and worst prognoses, respectively. RESULTS: Significant prognostic factors varied by diagnosis and new prognostic factors were identified. Those factors were incorporated into the updated GPA with robust separation (P < .01) between subgroups. Survival has improved, but varies widely by GPA for patients with non-small-cell lung, breast, melanoma, GI, and renal cancer with brain metastases from 7-47 months, 3-36 months, 5-34 months, 3-17 months, and 4-35 months, respectively. CONCLUSION: Median survival varies widely and our ability to estimate survival for patients with brain metastases has improved. The updated GPA (available free at brainmetgpa.com) provides an accurate tool with which to estimate survival, individualize treatment, and stratify clinical trials. Instead of excluding patients with brain metastases, enrollment should be encouraged and those trials should be stratified by the GPA to ensure those trials make appropriate comparisons. Furthermore, we recommend the expansion of eligibility to allow for the enrollment of patients with previously treated brain metastases who have a 50% or greater probability of an additional year of survival (eligibility quotient > 0.50).

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.

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 < .01), despite the subtype distribution becoming less favorable. PF significant for survival were tumor subtype, Karnofsky Performance Status, age, number of BCBMs, and extracranial metastases (all P < .01). MS for GPA 0 to 1.0, 1.5-2.0, 2.5-3.0, and 3.5-4.0 was 6, 13, 24, and 36 months, respectively. Between cohorts B and C, the proportion of human epidermal receptor 2 + subtype decreased from 31% to 18% (P < .01) and MS in this subtype increased from 18 to 25 months (P < .01). 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.

Estrogen/progesterone receptor and HER2 discordance between primary tumor and brain metastases in breast cancer and its effect on treatment and survival.

BACKGROUND: Breast cancer treatment is based on estrogen receptors (ERs), progesterone receptors (PRs), and human epidermal growth factor receptor 2 (HER2). At the time of metastasis, receptor status can be discordant from that at initial diagnosis. The purpose of this study was to determine the incidence of discordance and its effect on survival and subsequent treatment in patients with breast cancer brain metastases (BCBM). METHODS: A retrospective database of 316 patients who underwent craniotomy for BCBM between 2006 and 2017 was created. Discordance was considered present if the ER, PR, or HER2 status differed between the primary tumor and the BCBM. RESULTS: The overall receptor discordance rate was 132/316 (42%), and the subtype discordance rate was 100/316 (32%). Hormone receptors (HR, either ER or PR) were gained in 40/160 (25%) patients with HR-negative primary tumors. HER2 was gained in 22/173 (13%) patients with HER2-negative primary tumors. Subsequent treatment was not adjusted for most patients who gained receptors-nonetheless, median survival (MS) improved but did not reach statistical significance (HR, 17-28 mo, P = 0.12; HER2, 15-19 mo, P = 0.39). MS for patients who lost receptors was worse (HR, 27-18 mo, P = 0.02; HER2, 30-18 mo, P = 0.08). CONCLUSIONS: Receptor discordance between primary tumor and BCBM is common, adversely affects survival if receptors are lost, and represents a missed opportunity for use of effective treatments if receptors are gained. Receptor analysis of BCBM is indicated when clinically appropriate. Treatment should be adjusted accordingly. KEY POINTS: 1. Receptor discordance alters subtype in 32% of BCBM patients.2. The frequency of receptor gain for HR and HER2 was 25% and 13%, respectively.3. If receptors are lost, survival suffers. If receptors are gained, consider targeted treatment.

Comparison of Techniques for Involved-Site Radiation Therapy in Patients With Lower Mediastinal Lymphoma.

PURPOSE: Patients with lower mediastinal lymphoma (LML) benefit dosimetrically from proton therapy (PT) compared with intensity modulated radiation therapy (IMRT). The added dosimetric benefit of deep-inspiration breath-hold (DIBH) is unknown; therefore, we evaluated IMRT versus PT and free-breathing (FB) versus DIBH among patients with LML. METHODS AND MATERIALS: Twenty-one patients with LML underwent 4-dimensional computed tomography and 3 sequential DIBH scans at simulation. Involved-site radiation therapy target volumes and organ-at-risk contours were developed for both DIBH and FB scans. FB-IMRT, DIBH-IMRT, FB-PT, and DIBH-PT plans were generated for each patient for comparison. RESULTS: The median difference in lung volume between the DIBH and FB scans was 1275 mL; the average difference in clinical target volume was 5.7 mL. DIBH-IMRT produced a lower mean lung dose (10.8 vs 11.9 Gy; P < .001) than FB-IMRT, with no difference in mean heart dose (MHD; 16.1 vs 15.0 Gy; P = .992). Both PT plans produced a significantly lower mean dose to the lung, heart, left ventricle, esophagus, and nontarget body than DIBH-IMRT. DIBH-PT reduced the median MHD by 4.2 Gy (P < .0001); left ventricle dose by 5.1 Gy (P < .0001); and lung V5 by 26% (P < .0001) versus DIBH-IMRT. The 2 PT plans were comparable, with DIBH-PT reducing mean lung dose (7.0 vs 7.7 Gy; P = .063) and with no difference in MHD (10.3 vs 9.5 Gy; P = .992). CONCLUSIONS: Among patients with LML, DIBH (IMRT or PT) improved lung dosimetry over FB but had little influence on MHD. PT (DIBH and FB) significantly reduced lung, heart, esophagus, and nontarget body dose compared with DIBH IMRT, potentially reducing the risk of late complications.

Incidence, features and management of radionecrosis in melanoma patients treated with cerebral radiotherapy and anti-PD-1 antibodies.

BACKGROUND: Brain radiotherapy is used in the management of melanoma brain metastases (MBM) and can result in radionecrosis. Anti-PD-1 is active in the brain and may increase the risk of radionecrosis when combined with radiotherapy. We studied the incidence, associated factors and management of radionecrosis in longer-term survivors with MBM treated with this combination. METHODS: Patients with MBM treated with radiotherapy and anti-PD-1 who survived >1 year were identified to determine radionecrosis incidence (Cohort A, n = 135). Cohort A plus additional radionecrosis cases were examined for factors associated with radionecrosis and management (Cohort B, n = 148). RESULTS: From Cohort A, 17% developed radionecrosis, with a cumulative incidence at 2 years of 18%. Using Cohort B, multivariable analysis confirmed an association between radionecrosis and elevated lactate dehydrogenase (p = 0.0496) and prior treatment with ipilimumab (p = 0.0319). Radionecrosis was diagnosed based on MRI (100%), symptoms (69%) and pathology (56%). Treatment included corticosteroids, bevacizumab and neurosurgery. CONCLUSIONS: Radionecrosis is a significant toxicity in longer-term melanoma survivors with MBM treated with anti-PD-1 and radiotherapy. Identification of those at risk of radionecrosis who may avoid radiotherapy is required.

The Evolving Role of Postmastectomy Radiation Therapy.

Throughout various eras of breast cancer therapy, postmastectomy radiation therapy (PMRT) has played an important role in the treatment of locally advanced breast cancer. PMRT decreases locoregional recurrence and may improve overall survival in patients with tumors over 5 cm or positive lymph nodes. As novel cancer therapies improve survival in breast cancer, the role of radiation therapy is evolving. Individualized recommendations for PMRT dependent on pathologic response after neoadjuvant systemic therapy are under investigation. This review summarizes the role of PMRT during breast cancer therapy and discusses open questions that may change the landscape of future breast cancer treatment.

Postmastectomy Radiation Therapy: Are We Ready to Individualize Radiation?

Contemporary recommendations for postmastectomy radiation have undergone a shift in thinking away from simple stage based recommendations (one size fits all) to a system that considers both tumor biology and host factors. While surgical staging has traditionally dictated indications for postmastectomy radiation therapy (PMRT), our current understanding of tumor biology, host, immunoprofiles, and tumor microenvironment may direct a more personalized approach to radiation. Understanding the interaction of these variables may permit individualization of adjuvant therapy aimed at appropriate escalation and deescalation, including recommendations for PMRT. This article summarizes the current data regarding tumor and host molecular biomarkers in vitro and in vivo that support the individualization of PMRT and discusses open questions that may alter the future of breast cancer treatment.

Chronic granulomatous dermatitis induced by talimogene laherparepvec therapy of melanoma metastases.

Talimogene laherparepvec (TVEC) is the first oncolytic viral immunotherapy approved by the FDA, for advanced melanoma consisting of genetically modified herpes simplex type 1 virus which selectively replicates causing tumor lysis, expressing granulocyte macrophage-colony stimulating factor (GM-CSF) and activating dendritic cells. Intratumoral injection of TVEC produces objective response in 41% of stage IIB-IV M1a melanoma. However, clinical response assessment can be problematic due to immune-related inflammation at established tumor sites. Herein, we report 5 cases of granulomatous dermatitis developing at sites of TVEC injection associated with pathologic complete response in 4 of 5 patients. Over 5 months, TVEC injections were administrated in a median of 20 tumors per patient for 9 median doses prior to biopsy of persistent, indurated nodules. Granulomatous dermatitis with melanophages and melanin pigment incontinence was observed in all samples without evidence of melanoma cells in 4 patients. The fifth patient was rendered melanoma-free by resection of the 1 nodule out of 4 with persistent tumor. Repetitive administration of TVEC or other oncolytic viral immunotherapies mimicking unresolved infection can produce granulomatous inflammation confounding assessment of the degree of tumor response and need for additional TVEC therapy. Tumor biopsies are encouraged after 4 to 6 months of TVEC administration to differentiate melanoma from granulomatous inflammation. Patients with confirmed granulomatous dermatitis replace continued with remained in remission after treatment discontinuation. Inflammatory nodules typically regress spontaneously.

Defining Health Across the Cancer Continuum.

Health is not defined by the absence of disease or suffering, but by response to a series of life events that can markedly alter the quality and quantity of life. Patients with cancer experience significant but dynamic physical, psychosocial, and financial challenges. With the increasing number of patients with early stage cancers transitioning to survivorship, there is a critical need to address health promotion and overall well-being. For those with advanced cancer, discussion about prognosis and early integration of palliative care can have a profound impact on the quality of life. Effective communication between healthcare providers and patients is important in aligning treatment recommendations with patient goals and preferences throughout cancer therapy. This review provides a dynamic definition of health and proposes actionable guidelines for health promotion at any point along the cancer continuum: survivorship after early cancer or when goals of care transition to improve quality at the end of life.