A Phase 1 Trial of Salvage Stereotactic Body Radiation Therapy for Radiorecurrent Prostate Cancer After Brachytherapy.

PURPOSE: NCT03253744 is a phase 1 trial with the primary objective to identify the maximum tolerated dose (MTD) of salvage stereotactic body radiation therapy (SBRT) in patients with local prostate cancer recurrence after brachytherapy. Additional objectives included biochemical control and imaging response. METHODS AND MATERIALS: This trial was initially designed to test 3 therapeutic dose levels (DLs): 40 Gy (DL1), 42.5 Gy (DL2), and 45 Gy (DL3) in 5 fractions. Intensity modulation was used to deliver the prescription dose to the magnetic resonance imaging and prostate-specific membrane antigen-based positron emission tomography imaging-defined gross tumor volume while simultaneously delivering 30 Gy to an elective volume defined by the prostate gland. This phase 1 trial followed a 3+3 design with a 3-patient expansion at the MTD. Toxicities were scored until trial completion at 2 years post-SBRT using Common Terminology Criteria for Adverse Events version 5.0. Escalation was halted if 2 dose limiting toxicities occurred, defined as any persistent (>4 days) grade 3 toxicity occurring within the first 3 weeks after SBRT or any grade ≥3 genitourinary (GU) or grade 4 gastrointestinal toxicity thereafter. RESULTS: Between August 2018 and January 2023, 9 patients underwent salvage SBRT and were observed for a median of 22 months (Q1-Q3, 20-43 months). No grade 3 to 5 adverse events related to study treatment were observed; thus, no dose limiting toxicities occurred during the observation period. Escalation was halted by amendment given excellent biochemical control in DL1 and DL2 in the setting of a high incidence of clinically significant late grade 2 GU toxicity. Therefore, the MTD was considered 42.5 Gy in 5 fractions (DL2). One- and 2-year biochemical progression-free survival were 100% and 86%, representing a single patient in the trial cohort with biochemical failure (prostate-specific antigen [PSA] nadir + 2.0) at 20 months posttreatment. CONCLUSIONS: The MTD of salvage SBRT for the treatment of intraprostatic radiorecurrence after brachytherapy was 42.5 Gy in 5 fractions producing an 86% 2-year biochemical progression-free survival rate, with 1 poststudy failure at 20 months. The most frequent clinically significant toxicity was late grade 2 GU toxicity.

2023 Radiation oncology highlights.

Radiation oncology plays an important role in the local treatment of cancers. Understanding recent advances in the application of radiation therapy to solid tumors is important for all disciplines. The radiation oncology section editors for this journal have selected the following articles for their overall significance, relevance to surgical oncologists, and to illustrate important concepts within the practice of radiation oncology.

A Phase 1 Trial of Focal Salvage Stereotactic Body Radiation Therapy for Radiorecurrent Prostate Cancer.

PURPOSE: NCT03253744 was a phase 1 trial to identify the maximum tolerated dose (MTD) of image-guided, focal, salvage stereotactic body radiation therapy (SBRT) for patients with locally radiorecurrent prostate cancer. Additional objectives included biochemical control and imaging response. METHODS AND MATERIALS: The trial design included 3 dose levels (DLs): 40 Gy (DL1), 42.5 Gy (DL2), and 45 Gy (DL3) in 5 fractions delivered ≥48 hours apart. The prescription dose was delivered to the magnetic resonance- and prostate-specific membrane antigen imaging-defined tumor volume. Dose escalation followed a 3+3 design with a 3-patient expansion at the MTD. Toxicities were scored until 2 years after completion of SBRT using Common Terminology Criteria for Adverse Events, version 5.0, criteria. Escalation was halted if 2 dose-limiting toxicities occurred, defined as any persistent (>4 days) grade 3 toxicity occurring within the first 3 weeks after SBRT and any grade 3 genitourinary (GU) or grade 4 gastrointestinal (GI) toxicity thereafter. RESULTS: Between August 2018 and May 2022, 8 patients underwent salvage focal SBRT, with a median follow-up of 35 months. No dose-limiting toxic effects were observed on DL1. Two patients were enrolled in DL2 and experienced grade 3 GU toxicities, prompting de-escalation and expansion (n = 6) at the MTD (DL1). The most common toxicities observed were grade ≥2 GU toxicities, with only a single grade 2 GI toxicity and no grade ≥3 GI toxicities. One patient experienced biochemical failure (prostate-specific antigen nadir + 2.0) at 33 months. CONCLUSIONS: The MTD for focal salvage SBRT for isolated intraprostatic radiorecurrence was 40 Gy in 5 fractions, producing a 100% 24-month biochemical progression free survival, with 1 poststudy failure at 33 months. The most frequent clinically significant toxicity was late grade ≥2 GU toxicity.

Pathologic Complete Response and Clinical Outcomes in Patients With Localized Soft Tissue Sarcoma Treated With Neoadjuvant Chemoradiotherapy or Radiotherapy: The NRG/RTOG 9514 and 0630 Nonrandomized Clinical Trials.

Importance: Pathologic complete response (pCR) may be associated with prognosis in patients with soft tissue sarcoma (STS). Objective: We sought to determine the prognostic significance of pCR on survival outcomes in STS for patients receiving neoadjuvant chemoradiotherapy (CT-RT) (Radiation Therapy Oncology Group [RTOG] 9514) or preoperative image-guided radiotherapy alone (RT, RTOG 0630) and provide a long-term update of RTOG 0630. Design, Setting, and Participants: RTOG has completed 2 multi-institutional, nonrandomized phase 2 clinical trials for patients with localized STS. One hundred forty-three eligible patients from RTOG 0630 (n = 79) and RTOG 9514 (n = 64) were included in this ancillary analysis of pCR and 79 patients from RTOG 0630 were evaluated for long-term outcomes. Intervention: Patients in trial 9514 received CT interdigitated with RT, whereas those in trial 0630 received preoperative RT alone. Main Outcomes and Measures: Overall and disease-free survival (OS and DFS) rates were estimated by the Kaplan-Meier method. Hazard ratios (HRs) and P values were estimated by multivariable Cox model stratified by study, where possible; otherwise, P values were calculated by stratified log-rank test. Analysis took place between December 14, 2016, to April 13, 2017. Results: Overall there were 42 (53.2%) men; 68 (86.1%) were white; with a mean (SD) age of 59.6 (14.5) years. For RTOG 0630, at median follow-up of 6.0 years, there was 1 new in-field recurrence and 1 new distant failure since the initial report. From both studies, 123 patients were evaluable for pCR: 14 of 51 (27.5%) in trial 9514 and 14 of 72 (19.4%) in trial 0630 had pCR. Five-year OS was 100% for patients with pCR vs 76.5% (95% CI, 62.3%-90.8%) and 56.4% (95% CI, 43.3%-69.5%) for patients with less than pCR in trials 9514 and 0630, respectively. Overall, pCR was associated with improved OS (P = .01) and DFS (HR, 4.91; 95% CI, 1.51-15.93; P = .008) relative to less than pCR. Five-year local failure rate was 0% in patients with pCR vs 11.7% (95% CI, 3.6%-25.1%) and 9.1% (95% CI, 3.3%-18.5%) for patients with less than pCR in 9514 and 0630, respectively. Histologic types other than leiomyosarcoma, liposarcoma, and myxofibrosarcoma were associated with worse OS (HR, 2.24; 95% CI, 1.12-4.45). Conclusions and Relevance: This ancillary analysis of 2 nonrandomized clinical trials found that pCR was associated with improved survival in patients with STS and should be considered as a prognostic factor of clinical outcomes for future studies. Trial Registration: ClinicalTrials.gov Identifiers: RTOG 0630 (NCT00589121); RTOG 9514 (NCT00002791).

Overcoming Burnout and Promoting Wellness in Radiation Oncology: A Report From the ACR Commission on Radiation Oncology.

Burnout, defined by the presence of emotional exhaustion, depersonalization, and decreased sense of personal accomplishment, impacts a significant portion of radiation oncologists. This has been exacerbated by the COVID-19 pandemic, is notably worse for women, and has been identified as an international concern. Key contributors to burnout within radiation oncology include inadequate clinical and administrative support, imbalanced personal and professional lives including time with family and for self-care, decreased job satisfaction secondary to increased electronic medical record and decreased patient time, unsupportive organizational culture, lack of transparency from leadership and inclusion in administrative decisions, emotionally intensive patient interactions, challenges within the radiation oncology workforce, financial security related to productivity-based compensation and increasing medical training-related debt, limited education on wellness, and fear of seeking mental health services due to stigma and potential negative impacts on the trajectory of one's career. Limited data exist to quantify the impacts of these factors on the overall levels of burnout within radiation oncology specifically, and additional efforts are needed to understand and address root causes of burnout within the field. Strategies should focus on improving the systems in which physicians work and providing the necessary skills and resources to thrive in high-stress, high-stakes work environments.

A Primer on Radiopharmaceutical Therapy.

The goal of this article is to serve as a primer for the United States-based radiation oncologist who may be interested in learning more about radiopharmaceutical therapy (RPT). Specifically, we define RPT, review the data behind its current and anticipated indications, and discuss important regulatory considerations for incorporating it into clinical practice. RPT represents an opportunity for radiation oncologists to leverage 2 key areas of expertise, namely therapeutic radiation therapy and oncology, and apply them in a distinct context in collaboration with nuclear medicine and medical oncology colleagues. Although not every radiation oncologist will incorporate RPT into their day-to-day practice, it is important to understand the role for this modality and how it can be appropriately used in select patients.

Functional Imaging of Liver Cancer (FLIC): Study protocol of a phase 2 trial of 18F-DCFPyL PET/CT imaging for patients with hepatocellular carcinoma.

BACKGROUND: While prostate specific membrane antigen (PSMA) is overexpressed in high-grade prostate cancers, it is also expressed in tumor neovasculature and other malignancies, including hepatocellular carcinoma (HCC). Importantly, no functional imaging for HCC is clinically available, making diagnosis and surveillance following local therapies particularly challenging. 18F-DCFPyL binds with high affinity to PSMA yet clears rapidly from the blood pool. PET imaging with 18F-DCFPyL may represent a new tool for staging, surveillance and assessment of treatment response in HCC. The purpose of this Functional Imaging Liver Cancer (FLIC) trial is to assess the ability of 18F-DCFPyL-PET/CT to detect sites of HCC. METHODS: This is a phase II multi-site prospective imaging trial with a plan to enroll 50 subjects with suspected HCC on standard of care CT or MRI and eligible for standard local treatment. Participants will undergo a baseline 18F-DCFPyL-PET/CT, prior to therapy. Subjects will also be scanned with 18F-FDG-PET/CT within 2 weeks of 18F-DCFPyL-PET/CT. Participants will undergo histopathologic assessment and standard of care local treatment for HCC within a multidisciplinary team context. Participants with histopathologic confirmation of HCC and a positive baseline 18F-DCFPyL-PET/CT will undergo a post-treatment 18F-DCFPyL-PET/CT during the first routine follow-up, typically within 4-8 weeks. Subjects with negative baseline 18F-DCFPyL-PET/CT will not be re-scanned after treatment but will remain in follow-up. Participants will be followed for 5-years to assess for progression-free-survival. The primary endpoint is the positive predictive value of 18F-DCFPyL-PET for HCC as confirmed by histopathology. Secondary endpoints include comparison of 18F-DCFPyL-PET/CT with CT, MRI, and 18F-FDG-PET/CT, and evaluation of the value of 18F-DCFPyL-PET/CT in assessing treatment response following local treatment. Exploratory endpoints include next generation sequencing of tumors, and analysis of extracellular vesicles to identify biomarkers associated with response to therapy. DISCUSSION: This is a prospective imaging trial designed to evaluate whether PSMA-PET/CT imaging with 18F-DCFPyL can detect tumor sites, assess local treatment response in HCC patients, and to eventually determine whether PSMA-PET/CT could improve outcomes of patients with HCC receiving standard of care local therapy. Importantly, this trial may help determine whether PSMA-selective radiopharmaceutical therapies may be beneficial for patients with HCC. CLINICAL TRIAL REGISTRATION: NIH IND#133631. Submission date: 04-07-2021. Safe-to-proceed letter issued by FDA: 05.07.2021. NIH IRB #00080. ClinicalTrials.gov Identifier NCT05009979. Date of Registry: 08-18-2021. Protocol version date: 01-07-2022.

A Phase 1 Trial of Highly Conformal, Hypofractionated Postprostatectomy Radiation Therapy.

Purpose: This phase 1 trial aimed to identify the maximally tolerated hypofractionated dose schedule for postoperative radiation therapy (PORT) after radical prostatectomy. Secondary objectives included biochemical control and quality of life (QoL) measures. Methods and Materials: Patients were treated on 1 of 3 dose levels (DLs): 56.4 Gy in 20 fractions (DL1), 51.2 Gy in 15 fractions (DL2), and 44.2 Gy in 10 fractions (DL3). Treatment was delivered to the prostate bed without pelvic nodal irradiation. Dose escalation followed a standard 3 + 3 design with an expansion for 6 additional patients at the maximally tolerated hypofractionated dose schedule. Acute dose-limiting toxicity (DLT) was defined as grade 3 toxicity lasting >4 days within 21 days of PORT completion; late DLT was defined as grade 4 gastrointestinal (GI) or genitourinary (GU) toxicity. Results: Between January 2018 and August 2019, 15 patients underwent radiation treatment: 3 on DL1, 3 on DL2, and 9 on DL3. The median follow-up was 24 months. There were no DLTs, and the maximally tolerated hypofractionated dose schedule was identified as DL3. Two of the 15 patients (13.3%) experienced biochemical failure (prostate-specific antigen >0.1). Ten of 15 patients (67%) had grade 2+ acute toxicities, consisting of transient GI toxicities. Three patients experienced late grade 2+ GI toxicity, and 5 patients experienced late grade 2+ GU toxicity. Late grade 3 GU toxicity occurred in 2 patients. There were no grade 4+ acute or late toxicities. There were no significant differences in GI measures of QoL, however, there was an increase in GU symptoms and corresponding decrease in GU QoL between 12 and 24 months. Conclusions: The maximum tolerated hypofractionated dose schedule for hypofractionated PORT to the prostate bed was determined to be 44.2 Gy in 10 daily fractions. The most frequent clinically significant toxicities were late grade 2+ GU toxicities, which corresponded to a worsening of late GU QoL.

Radiation Therapy for Soft Tissue Sarcoma: Indications, Timing, Benefits, and Consequences.

Radiation therapy is an integral component of local management with oncologic resection for soft tissue sarcoma. Radiotherapy is indicated in patients at an increased risk of local recurrence so that improved local control may be achieved. Sequencing of radiotherapy and resection should be determined by multidisciplinary input before treatment initiation. For most patients, preoperative delivery of radiation therapy is preferred. In patients initially thought to be at low risk for local recurrence and found to have unexpected adverse pathologic features at resection, postoperative radiation therapy is indicated. The use of radiation therapy for retroperitoneal sarcoma is controversial; when used, preoperative delivery of radiation is recommended.

Bowel and Bladder Reproducibility in Image Guided Radiation Therapy for Prostate Cancer: Results of a Patterns of Practice Survey.

Purpose: Optimal management of patients with prostate cancer (PCa) to achieve bowel and bladder reproducibility for radiation therapy (RT) and the appropriate planning target volume (PTV) expansions for use with modern image guidance is uncertain. We surveyed American Society of Radiation Oncology radiation oncologists to ascertain practice patterns for definitive PCa RT with respect to patient instructions and set up, daily image guidance, and subsequent PTV expansions. Methods and Materials: A pattern of practice survey was sent to American Society of Radiation Oncology radiation oncologists who self-identified as specializing in PCa. Respondents identified the fractionation regimens routinely used, and their practices regarding diet, bowel, and bladder instructions for patients with PCa before RT simulation and throughout treatment. Questions regarding PTV margins, daily set up practices, and use of image guidance were included. Results: Of 190 respondents, 158 reported using conventional fractionation (CFx), 49 moderate hypofractionation (MHFx), and 61 stereotactic body radiation therapy (SBRT). Diet modifications during RT were advised by 84% of respondents, treatment with full bladder by 96%, and bowel instructions by 78%. Prescription of bowel medication was higher for respondents using SBRT (95.1%) versus those using CFx/MHFx (55.1%; 34.7%). The most common implantable device reported was fiducial markers, with increased use in SBRT (86.0%; 68.9%) versus CFx/MHFx. Cone beam computed tomography was the most common daily imaging technique across fractionation regimens. SBRT showed correlation between PTV margin expansions, fiducial marker use, and image guidance. Conclusions: Survey results indicate heterogeneity in treatment modality, dose, patient instructions, and PTV expansions used by radiation oncologists in the treatment of patients with PCa. Further investigation to define appropriate patient instructions on bowel preparation to maximize target reproducibility in PCa is needed, as is continued guidance on evidence-based approaches for image guidance and PTV margin selection.

Role of Radiation Therapy in Retroperitoneal Sarcoma.

Retroperitoneal sarcoma comprises a small subset of all soft tissue sarcoma and includes various histopathologic subtypes, each with unique patterns of behavior and differential risks for local recurrence and hematogenous metastatic spread. The primary treatment modality is surgery, although even with complete macroscopic resection, recurrence is common. The rationale for the addition of radiotherapy to resection is to improve local control; however, the use of radiation therapy for retroperitoneal sarcoma is controversial, and existing data are suboptimal to guide management. Treatment decisions should be determined with multidisciplinary input and shared decision-making. When used in selected patients, radiation therapy should be delivered preoperatively; postoperative treatment is not recommended.

Management of neurofibromatosis type 1-associated plexiform neurofibromas.

Plexiform Neurofibromas (PN) are a common manifestation of the genetic disorder neurofibromatosis type 1 (NF1). These benign nerve sheath tumors often cause significant morbidity, with treatment options limited historically to surgery. There have been tremendous advances over the past two decades in our understanding of PN, and the recent regulatory approvals of the MEK inhibitor selumetinib are reshaping the landscape for PN management. At present, there is no agreed upon PN definition, diagnostic evaluation, surveillance strategy, or clear indications for when to initiate treatment and selection of treatment modality. In this review, we address these questions via consensus recommendations from a panel of multidisciplinary NF1 experts.

Detection of failure patterns using advanced imaging in patients with biochemical recurrence following low-dose-rate brachytherapy for prostate cancer.

PURPOSE/OBJECTIVE(S): This study describes the pattern of failure in patients with biochemical (BCR) recurrence after low-dose-rate (LDR) brachytherapy as a component of definitive treatment for prostate cancer. METHODS: Patients with BCR after LDR brachytherapy ± external beam radiation therapy (EBRT) were enrolled on prospective IRB approved advanced imaging protocols. Patients underwent 3T multiparametric MRI (mpMRI); a subset underwent prostate specific membrane antigen (PSMA)-based PET/CT. Pathologic confirmation was obtained unless contraindicated. RESULTS: Between January 2011 and April 2021, 51 patients with BCR after brachytherapy (n = 36) or brachytherapy + EBRT (n = 15) underwent mpMRI and were included in this analysis. Of 38 patients with available dosimetry, only two had D90<90%. The prostate and seminal vesicles were a site of failure in 66.7% (n = 34) and 39.2% (n = 20), respectively. PET/CT (n = 32 patients) more often identified lesions pelvic lymph nodes (50%; n = 16) and distant metastases (18.8%; n = 6), than mpMRI. Isolated nodal disease (9.8%; n = 5) and distant metastases (n = 1) without local recurrence were uncommon. Recurrence within the prostate was located in the transition zone in 48.5%, central or midline in 45.5%, and anterior in 36.4% of patients. CONCLUSION: In this cohort of patients with BCR after LDR brachytherapy ± EBRT, the predominant recurrence pattern was local (prostate ± seminal vesicles) with frequent occurrence in the anterior prostate and transition zone. mpMRI and PSMA PET/CT provided complementary information to localize sites of recurrence, with PSMA PET/CT often confirming mpMRI findings and identifying occult nodal or distant metastases.

Radiation Therapy for Treatment of Soft Tissue Sarcoma in Adults: Executive Summary of an ASTRO Clinical Practice Guideline.

PURPOSE: This guideline provides evidence-based recommendations addressing the indications for radiation therapy (RT), sequencing of local therapies, and appropriate dose and planning techniques for management of primary, operable, localized, soft tissue sarcoma (STS) in adults. METHODS: The American Society for Radiation Oncology convened a task force to address 5 key questions focused on the use of RT for management of STS. These questions included indications for RT for STS of the extremity and superficial trunk; considerations for sequencing of RT with respect to surgery, dose of RT, appropriate treatment volumes and techniques; and the role of RT in management of retroperitoneal sarcoma. Recommendations were based on a systematic literature review and created using a predefined consensus-building methodology and system for grading evidence quality and recommendation strength. RESULTS: Multidisciplinary evaluation and decision making are recommended for all cases of STS. RT is recommended for patients in whom there is increased risk of local recurrence of resected STS, particularly if close or microscopically positive margins are anticipated or have occurred. When RT is indicated, preoperative RT is strongly recommended over postoperative RT. Postoperative RT is conditionally recommended in specific clinical circumstances (eg, uncontrolled pain or bleeding) or when the risk of wound complications outweighs that of late toxicity from RT. Routine use of RT in addition to oncologic resection for retroperitoneal sarcoma is conditionally not recommended. When RT is used for retroperitoneal sarcoma, preoperative RT is recommended, whereas postoperative RT is not recommended. CONCLUSIONS: Based on currently published data, the American Society for Radiation Oncology task force has proposed evidence-based recommendations regarding the use of RT for STS in adults. Future studies will ascertain whether alterations in dosing and sequencing may optimize outcomes and quality of life.

Biology of Radiation-Induced Lung Injury.

Radiation-induced lung injury encompasses radiation-induced pneumonitis, inflammation of the lung which may manifest as a dose-limiting acute or subacute toxicity, and radiation-induced lung fibrosis, a late effect of lung exposure to radiation. This review aims to highlight developments in molecular radiation biology of radiation-induced lung injury and their implications in clinical practice.