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Background This study reports the single-institution clinical experience of multifield pencil beam scanning (PBS) intensity-modulated proton therapy (IMPT) and dosimetric comparison to proton arc for uveal melanoma (UM) in a regular PBS gantry room. Methods Eleven consecutive UM patients were treated with IMPT to 50 Gy in 5 fractions. A customized gaze-fixation device attached to the thermoplastic mask was used to reproduce the globe position for each patient. IMPT plans were robustly optimized with perturbations of 3 mm setup and 3.5% range uncertainties using 3–4 fields without apertures. Each plan was robustly reoptimized (using the same perturbation parameters) using two non-coplanar arc fields in the RayStation treatment planning system. Treatment quality for both plans was evaluated daily using CBCT-generated synthetic CT. Target coverage, conformity, and mean/maximum doses to adjacent organs were assessed. Results Proton arc plans provided comparable plan quality compared to IMPT plans. Similar target coverage was achieved, with an average GTV D95% equal to 101.1% 1.0% and 101.4% 0.4% for IMPT and proton arc plans, respectively. Proton arc improves the conformity index (RTOG) compared to IMPT plans (average 0.96 0.23 vs. 0.88 0.18, p  = 0.11). Both modalities met all the clinical goals for organs-at-risk (OARs), while proton arc significantly reduced the maximum dose for the retina from, on average, 54.5 0.7 to 53.2 0.3 Gy ( p  < 0.01). Treatment evaluation on synthetic CT showed that the doses received by patients were highly consistent with the planned doses, with a relative target coverage (D95%) difference within 3.5% for IMPT and 3.1% for proton arc, and the D95% of actual delivery exceeding 98.7% and 98.2%, respectively. The doses delivered to OARs did not exceed clinical constraints. Conclusions This is a novel report on proton arc for ocular tumors and gantry-based multifield PBS proton treatment for these tumors. This study demonstrated that both modalities can meet the clinical goals. The IMPT is currently clinically implanted, and 2-field non-coplanar proton arc plans can achieve comparable dosimetric metrics to those of IMPT plans when the deliver technique is matured.

Nonmelanoma skin cancers (NMSCs) are some of the most commonly diagnosed malignancies. In general, early-stage NMSCs have favorable outcomes; however, a small subset of patients develop resistant, advanced, or metastatic disease, or aggressive subtypes that are more challenging to treat successfully. Recently, immune checkpoint inhibitors (ICIs) have been approved by the US Food and Drug Administration (FDA) for the treatment of Merkel cell carcinoma (MCC), cutaneous squamous cell carcinoma (CSCC), and basal cell carcinoma (BCC). Although ICIs have demonstrated activity against NMSCs, the routine clinical use of these agents may be more challenging due to a number of factors including the lack of predictive biomarkers, the need to consider special patient populations, the management of toxicity, and the assessment of atypical responses. With the goal of improving patient care by providing expert guidance to the oncology community, the Society for Immunotherapy of Cancer (SITC) convened a multidisciplinary panel of experts to develop a clinical practice guideline (CPG). The expert panel drew on the published literature as well as their own clinical experience to develop recommendations for healthcare professionals on important aspects of immunotherapeutic treatment for NMSCs, including staging, biomarker testing, patient selection, therapy selection, post-treatment response evaluation and surveillance, and patient quality of life (QOL) considerations, among others. The evidence- and consensus-based recommendations in this CPG are intended to provide guidance to cancer care professionals treating patients with NMSCs.

Importance Patients with recurrent or unresectable skin cancers have limited treatment options. Diffusing alpha-emitter radiation therapy (DaRT), a novel solid tumor management strategy using alpha-particle interstitial brachytherapy, may address this challenge. Objective To evaluate the feasibility and safety of using DaRT to manage recurrent or unresectable skin cancers. Design, Setting, and Participants This prospective cohort study of patients who received a 2-week to 3-week treatment course and were followed up for 24 weeks after treatment during 2021 and 2022 at 2 sites in the US. Patients with malignant skin tumors or soft tissue tumors were recruited if they had limited treatment options for tumors recurrent after prior surgery or external beam radiotherapy or unresectable tumors. Intervention Patients underwent DaRT to deliver a physical dose of 10 Gy (equivalent weighted dose of 200 CGE) to the tumor. Main Outcomes and Measures Feasibility of the DaRT procedure was evaluated based on the ability of investigators to successfully deliver radiation to the tumor. Patients were followed up for adverse events (AEs) for 24 weeks and for tumor response by physicians’ physical examination and imaging 12 weeks after device removal. Results This study included 10 participants with recurrent or unresectable skin cancer (median [IQR] age, 72 [68-75] years; 6 males [60%]; 4 females [40%]). Six patients (60%) had recurrent disease, and 4 (40%) had tumors that were deemed unresectable. Tumors were located on the nose, chin, eyelid, scalp, neck, trunk, and extremities. Median (range) tumor volume before treatment was 2.1 cm3(0.65-12.65 cm3). The mean (SD) prescription dose coverage of the gross tumor volume was 91% (2.8%) with all tumors having coverage of 85% or more. No device-related grade 3 AEs were noted. Common AEs were grade 1 to 2 erythema, edema, and pruritus. At 12 weeks following treatment, there was a 100% complete response rate. Nine of 10 complete responses (90%) were confirmed by CT imaging. Conclusions and Relevance This cohort study suggests the feasibility and preliminary safety of DaRT in the management of recurrent or unresectable skin cancers. The favorable safety profile and high response rates are promising. A US trial for marketing approval based on this pilot study is under way. Trial Registration ClinicalTrials.gov Identifier:NCT04377360

Breast cancer brain metastases (BCBM) are a common and devastating complication of metastatic breast cancer with conventional systemic therapies demonstrating limited effectiveness. Consequently, radiotherapy (RT) ± surgery remains the cornerstone of BCBM management. Because preclinical and clinical evidence indicate that immune checkpoint blockade (ICB) may synergize with RT to promote systemic tumor regression, we explored the safety and efficacy of RT and concurrent tremelimumab-mediated cytotoxic T-lymphocyte associated protein 4 (CTLA-4) ICB with tremelimumab ± HER2-directed therapy with trastuzumab for BCBM. Eligible patients had BCBM indicated for brain RT. A Simon two-stage design was adopted to evaluate the efficacy of tremelimumab and RT in 20 patients with human epidermal growth factor receptor normal (HER2−) BCBM. The safety of concurrent RT, tremelimumab, and trastuzumab was evaluated in a cohort of 6 HER2+ patients. The primary endpoint was 12-week non-central nervous system (CNS) disease control rate (DCR). Secondary endpoints included safety, survival, and CNS response. Exploratory correlatives included characterization of peripheral blood immune responses among exceptional responders. Tremelimumab plus RT ± trastuzumab was tolerated with no treatment-related grade 4 adverse events reported. The 12-week non-CNS DCR was 10% (2/20) in the HER2− cohort and 33% (2/6) in the HER2+ cohort. One patient with HER2+ disease experienced a durable partial response with evidence of peripheral T-cell activation. Thus, tremelimumab and RT ± trastuzumab was tolerated. Although modest clinical activity was observed in the HER2- efficacy cohort, encouraging responses were observed in the HER2+ safety cohort. Consequently, a trial to determine efficacy in HER2+ BCBM is planned.Clinical Trial Registration Number: NCT02563925.

Background Cytokine release syndrome (CRS) has been reported after immunologic manipulations, most often through therapeutic monoclonal antibodies. To our knowledge, CRS after radiation therapy (RT) for cancer has not been reported before. The development of unusual clinical signs and symptoms after RT led us to investigate the possibility of CRS after RT and review the medical literature on this topic. Case presentation A 65 year-old man with untreated chronic lymphocytic leukemia and recurrent, metastatic Merkel cell carcinoma undergoing anti-programmed death 1 (PD1) immunotherapy was referred for palliative RT to sites of progressing metastases. Within hours of each weekly dose of RT, he experienced fever, tachycardia, hypotension, rash, dyspnea, and rigors. Based on clinical suspicion for CRS, blood cytokine measurements were performed 1 h after the second and third dose of RT and demonstrated tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) levels approximately ten-fold higher than normal. These were near normal immediately prior to the third dose of RT, and resolved to normal levels 3 weeks after RT. He experienced rapid regression of irradiated tumors, with development of new sites of metastases soon thereafter. A literature review revealed no clinical cases of CRS after RT for cancer. Conclusions RT during anti-PD1 immunotherapy in a patient with underlying immune dysfunction appeared to be the putative mediator of an immune process which yielded significant increases in pro-inflammatory cytokines, and produced the clinical symptoms meeting the definition of grade 3 CRS. This case demonstrates the capability of RT to elicit immune-related adverse events.

Basal cell carcinoma (BCC) is a very common cancer in the Caucasian population. Treatment aims to eradicate the tumor with the lowest possible functional and aesthetic impact. Electronic brachytherapy (EBT) is a treatment technique currently emerging. This study aims to show the outcomes of two consecutive prospective pilot clinical trials using different radiation doses of EBT with Esteya(®) EB system for the treatment of superficial and nodular basal cell carcinoma. Two prospective, single-center, non-randomized, pilot studies were conducted. Twenty patients were treated in each study with different doses. The first group (1) was treated with 36.6 Gy in 6 fractions of 6.1 Gy, and the second group (2) with 42 Gy in 6 fractions of 7 Gy. Cure rate, acute toxicity, and late toxicity related to cosmesis were analyzed in the two treatment groups. In group 1, a complete response in 90% of cases was observed at the first year of follow-up, whereas in group 2, the complete response was 95%. The differences with reference to acute toxicity and the cosmetic results between the two treatment groups were not statistically significant. Our initial experience with Esteya(®) EB system to treat superficial and nodular BCC shows that a dose of 36.6 Gy and 42 Gy delivered in 6 fraction of 7 Gy achieves a 90% and 95% clinical cure rate at 1 year, respectively. Both groups had a tolerable toxicity and a very good cosmesis. The role of EBT in the treatment of BCC is still to be defined. It will probably become an established option for selected patients in the near future.

A patient with metastatic melanoma with slowly progressive disease while receiving ipilimumab underwent radiotherapy for a pleural-based metastasis. Tumor lesions in nonirradiated sites began to disappear, and titers of antibody against a tumor-associated antigen increased. The abscopal effect refers to a rare phenomenon of tumor regression at a site distant from the primary site of radiotherapy. 1 Localized radiotherapy has been shown to induce abscopal effects in several types of cancer, including melanoma, lymphoma, and renal-cell carcinoma. 2 – 4 The biologic characteristics underlying this effect are not completely understood, but it may be mediated by immunologic mechanisms. 5 NY-ESO-1 is an antigen expressed in 30 to 40% of patients with advanced melanoma but not present in normal adult tissues except testicular germ cells and placenta. 6 Ipilimumab (Bristol-Myers Squibb) has been shown to enhance immunity to NY-ESO-1, and patients . . .

Background. Advanced age and immune dysfunction are risk factors for cutaneous squamous cell carcinoma (cSCC) and often render patients with locally-advanced disease medically inoperable or surgically unresectable, but potentially curable with radiotherapy. Concurrent chemotherapy and radiotherapy may not be well tolerated in this population, but another systemic therapy may improve disease control. Objective. Determine the tolerance and efficacy of concurrent cetuximab and radiotherapy (CRT) for patients with locally advanced and unresectable cSCC. Methods. Retrospective analysis of 12 patients treated with CRT for locally advanced and unresectable cSCC. Results. Patients were elderly and 75% had moderate-to-severe comorbidities, while 42% had immune dysfunction. Grades 3-4 adverse events were noted in 83% of patients; 67% required hospital admission for adverse events. Complete and partial response was noted in 36% and 27% (response rate, 64%). Stable and progressive disease was noted in 3 and 1 patients, respectively (disease control rate, 91%). Median progression-free and overall survival were 6.4 and 8.0 months, respectively. Limitations. Retrospective small-cohort, single-institution analysis. Conclusion. Patients selected for CRT were elderly, with comorbidities and immune dysfunction, but treatment responses were observed. Patients selected for this treatment approach have a poor prognosis with limited capacity for therapy; more effective treatment is needed.

To the Editor: In the past 2 years, Eggermont et al. have reported the findings of two landmark trials of adjuvant immunotherapy for stage III melanoma: the European Organization for the Research and Treatment of Cancer (EORTC) 18071 trial of ipilimumab 1 and the EORTC 1325 trial of pembrolizumab (May 10 issue). 2 Both trials suggest that adjuvant immunotherapy had a smaller effect on preventing locoregional recurrence than on preventing distant metastases. Neither article provides details on regional recurrence in patients at high risk for this event, such as those with macroscopic involvement of large or multiple lymph nodes or those with . . .