Minibeam Radiation Therapy Treatment (MBRT): Commissioning and First Clinical Implementation.

BACKGROUND: Minibeam radiation therapy (MBRT) is characterized by the delivery of submillimeter wide regions of high "peak" and low "valley" doses throughout a tumor. Preclinical studies have long shown the promise of this technique, and we report here the first clinical implementation of MBRT. METHODS: A clinical orthovoltage unit was commissioned for MBRT patient treatments using 3, 4, 5, 8, and 10 cm diameter cones. The 180 kVp output was spatially separated into minibeams using a tungsten collimator with 0.5 mm wide slits spaced 1.1 mm on center. Percentage depth dose (PDD) measurements were obtained using film dosimetry and plastic water for both peak and valley doses. PDDs were measured on central axis for offsets of 0, 0.5, and 1 cm. The peak-to-valley ratio (PVR) was calculated at each depth for all cones and offsets. To mitigate the effects of patient motion on delivered dose, patient-specific 3D printed collimator holders were created. These conformed to the unique anatomy of each patient and affixed the tungsten collimator directly to the body. Two patients were treated with MBRT, both received 2 fractions. RESULTS: Peak PDDs decreased gradually with depth. Valley PDDs initially increased slightly with depth, then decreased gradually beyond 2 cm. PVRs were highest at the surface for smaller cone sizes and offsets. In vivo film dosimetry confirmed a distinct delineation of peak and valley doses on both patients treated with MBRT with no dose blurring. Both patients experienced prompt improvement in symptoms and tumor response. CONCLUSIONS: We report commissioning results, treatment processes, and the first two patients treated with MBRT using a clinical orthovoltage unit. While demonstrating feasibility of this approach is a crucial first step toward wider translation, clinical trials are needed to further establish safety and efficacy.

Proton Craniospinal Irradiation with Immunotherapy in Two Patients with Leptomeningeal Disease from Melanoma.

Introduction: Proton craniospinal irradiation (pCSI) is a treatment option for leptomeningeal disease (LMD), which permits whole neuroaxis treatment while minimizing toxicity. Despite this, patients inevitably experience progression. Adding systemic therapy to pCSI may improve outcomes. Methods: In this single-institution retrospective case series, we present the feasibility of treatment with pCSI (30Gy, 10 fractions) and an immune checkpoint inhibitor (ICI) in two sequential patients with LMD from melanoma. Results: The first patient developed LMD related to BRAF V600E-mutant melanoma after prior ICI and BRAF-targeted therapy. After pCSI with concurrent nivolumab, the addition of relatlimab, and BRAF-targeted therapy, he remained alive 7 months after LMD diagnosis despite central nervous system progression. The second patient developed LMD related to BRAF-wildtype melanoma after up-front ICI. He received pCSI with concurrent ipilimumab and nivolumab, then nivolumab maintenance. Though therapy was held for ICI hepatitis, the patient remained progression-free 5 months after LMD diagnosis. Conclusion: Adding an ICI to pCSI is feasible for patients with LMD and demonstrates a tolerable toxicity profile. While prospective evaluation is ultimately warranted, pCSI with ICI may confer survival benefits, even after prior ICI.

Patterns of progression after immune checkpoint inhibitors for Hodgkin lymphoma: implications for radiation therapy.

ABSTRACT: Immune checkpoint inhibitors (ICIs) have demonstrated remarkable response rates in relapsed or refractory Hodgkin lymphoma (HL). Still, most patients eventually progress. Patterns of progression after ICIs are not well described and are essential to defining the role of local therapies in combination with ICIs. We identified patients who received ICIs for HL between 2013 and 2022. Fludeoxyglucose-18 positron emission tomography (FDG-PET) before initiating ICI and at progression on/after ICI were reviewed, and areas of active HL were recorded. An exploratory analysis of treatable progression included patients with ≤5 sites of disease on pre-ICI FDG-PET and progression only at pre-ICI sites. Ninety patients were identified; 69 had complete records, and of these, 32 (52%) had relapsed at ICI initiation, 17 (25%) were refractory, and 16 (23%) received ICI as first-line therapy. Forty-five of 69 patients had ≤5 sites of disease (limited) on pre-ICI FDG-PET. Patients with >5 sites of disease had a higher risk of progression, and every site of disease >5 sites conferred an additional 1.2x higher chance of progression. At a median follow-up of 4.0 years, 41 of 69 patients had progressed on/after ICIs (cumulative incidence 66.4%), and of these, 22 of 41 patients progressed only at pre-ICI sites (cumulative incidence 39.4%). In an exploratory analysis, the cumulative incidence of a treatable progression among 45 patients with limited disease was 34%. The cumulative incidence of any progression among this cohort was 58.9%. More than one-third of patients with limited disease before ICIs experienced progression only at pre-ICI sites of disease. These patients could be candidates for radiation during or after ICIs.

Detectable Postoperative Circulating Tumor Human Papillomavirus DNA and Association with Recurrence in Patients With HPV-Associated Oropharyngeal Squamous Cell Carcinoma.

PURPOSE: The purpose of our study is to determine the rate of detectability of ctHPVDNA after surgery but before adjuvant therapy in patients with human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (HPV[+]OPSCC) and to investigate whether detectable ctHPVDNA at this time point may be associated with risk of recurrence. METHODS AND MATERIALS: We examined prospectively collected samples from patients with OPSCC in a blinded fashion using a multianalyte polymerase chain reaction assay. We collected 45 samples from patients with HPV(+)OPSCC preop (before any treatment) and 159 samples postop (before or at the start of adjuvant radiation therapy). We identified samples via the radiation oncology biobank or via participation in a clinical trial. Radiation therapy consisted of 60 Gy ± cisplatin or de-escalation (30 Gy to 36 Gy in 20 bid fractions + docetaxel). For our preliminary analysis, 32 patients had paired samples available pre- and postop. We performed additional exploratory analyses including associations of patient and tumor characteristics with recurrence using Cox proportional hazards models for all 159 postop samples. We compared detectability of ctHPVDNA across groups using logistic regression. We used Kaplan-Meier to estimate recurrence-free survival. RESULTS: In a paired analysis of 32 pre- and postop timepoints, 94% of patients had detectable ctHPVDNA preop and 41% did postop. Recurrence-free survival at 18 months was 83% (95% confidence interval, 47%-95%) for patients with detectable postop ctHPVDNA compared with 100% for patients with undetectable postop ctHPVDNA (P = .094). In an exploratory analysis of nonpaired postop samples, ctHPVDNA was detectable in 26% of patients (41 of 159) (median of 22 days postop). Age (odds ratio,1.06, P = .025), lymphovascular space invasion (odds ratio, 3.17, P = .011) and extranodal extension (odds ratio = 5.67, P = .001) were associated with detectable ctHPVDNA after surgery. Detectable postop ctHPVDNA was significantly associated with recurrence-free survival (P < .001). CONCLUSION: Among patients with detectable preop ctHPVDNA, a significant proportion have detectable postop ctHPVDNA in paired postop samples collected before the initiation of adjuvant radiation therapy. Future prospective study is warranted to investigate the association of detectable postop ctHPVDNA with recurrence, including in comparison to established clinical and pathologic risk factors.