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.

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.

Breast Cancer, Version 4.2017, NCCN Clinical Practice Guidelines in Oncology.

Ductal carcinoma in situ (DCIS) of the breast represents a heterogeneous group of neoplastic lesions in the breast ducts. The goal for management of DCIS is to prevent the development of invasive breast cancer. This manuscript focuses on the NCCN Guidelines Panel recommendations for the workup, primary treatment, risk reduction strategies, and surveillance specific to DCIS.

Postmastectomy Radiotherapy: An American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology Focused Guideline Update.

PURPOSE: A joint American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology panel convened to develop a focused update of the American Society of Clinical Oncology guideline concerning use of postmastectomy radiotherapy (PMRT). METHODS: A recent systematic literature review by Cancer Care Ontario provided the primary evidentiary basis. The joint panel also reviewed targeted literature searches to identify new, potentially practice-changing data. RECOMMENDATIONS: The panel unanimously agreed that available evidence shows that PMRT reduces the risks of locoregional failure (LRF), any recurrence, and breast cancer mortality for patients with T1-2 breast cancer with one to three positive axillary nodes. However, some subsets of these patients are likely to have such a low risk of LRF that the absolute benefit of PMRT is outweighed by its potential toxicities. In addition, the acceptable ratio of benefit to toxicity varies among patients and physicians. Thus, the decision to recommend PMRT requires a great deal of clinical judgment. The panel agreed clinicians making such recommendations for individual patients should consider factors that may decrease the risk of LRF, attenuate the benefit of reduced breast cancer-specific mortality, and/or increase risk of complications resulting from PMRT. When clinicians and patients elect to omit axillary dissection after a positive sentinel node biopsy, the panel recommends that these patients receive PMRT only if there is already sufficient information to justify its use without needing to know additional axillary nodes are involved. Patients with axillary nodal involvement after neoadjuvant systemic therapy should receive PMRT. The panel recommends treatment generally be administered to both the internal mammary nodes and the supraclavicular-axillary apical nodes in addition to the chest wall or reconstructed breast.

NCCN Guidelines Update: Evolving Radiation Therapy Recommendations for Breast Cancer.

In the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Breast Cancer, among adjuvant radiotherapy options for whole-breast irradiation after breast-conserving surgery, hypofractionation is preferred. For the use of accelerated partial-breast irradiation, the NCCN Guidelines have adopted the updated definition of "suitability" used by the American Society for Radiation Oncology. Regional nodal irradiation is indicated-either in the setting of breast-conserving surgery or after mastectomy-for women with ≥4 positive nodes and should be strongly considered for 1 to 3 positive lymph nodes and select patients with node-negative disease deemed at high risk for recurrence.

NCCN Guidelines Insights: Breast Cancer, Version 1.2017.

These NCCN Guidelines Insights highlight the important updates/changes to the surgical axillary staging, radiation therapy, and systemic therapy recommendations for hormone receptor-positive disease in the 1.2017 version of the NCCN Guidelines for Breast Cancer. This report summarizes these updates and discusses the rationale behind them. Updates on new drug approvals, not available at press time, can be found in the most recent version of these guidelines at NCCN.org.

NCCN Guidelines Update: Breast Cancer.

The updates to management of early invasive breast cancer in 2016 are minor but have important treatment implications for patients. The NCCN Guidelines Panel for Breast Cancer has added endocrine therapy to its recommendations for the neoadjuvant treatment of patients with ER-rich tumors. For women who are premenopausal at diagnosis, the NCCN Guidelines suggest tamoxifen for 5 years, with or without ovarian suppression, or an aromatase inhibitor for 5 years combined with ovarian suppression or ablation. For HER2-positive patients, neoadjuvant pertuzumab is acceptable, and in advanced estrogen receptor-positive disease, palbociclib can be given with endocrine therapy. Hypofractionation is now the preferred approach for whole-breast irradiation after breast-conserving therapy. Regional nodal irradiation should be strongly considered for women with 1 to 3 positive lymph nodes and is indicated for those with 4 or more positive nodes.

Invasive Breast Cancer Version 1.2016, NCCN Clinical Practice Guidelines in Oncology.

Breast cancer is the most common malignancy in women in the United States and is second only to lung cancer as a cause of cancer death. The overall management of breast cancer includes the treatment of local disease with surgery, radiation therapy, or both, and the treatment of systemic disease with cytotoxic chemotherapy, endocrine therapy, biologic therapy, or combinations of these. This article outlines the NCCN Guidelines specific to breast cancer that is locoregional (restricted to one region of the body), and discusses the management of clinical stage I, II, and IIIA (T3N1M0) tumors. For NCCN Guidelines on systemic adjuvant therapy after locoregional management of clinical stage I, II and IIIA (T3N1M0) and for management for other clinical stages of breast cancer, see the complete version of these guidelines at NCCN.org.

Retroperitoneal sarcoma (RPS) high risk gross tumor volume boost (HR GTV boost) contour delineation agreement among NRG sarcoma radiation and surgical oncologists.

PURPOSE: Curative intent management of retroperitoneal sarcoma (RPS) requires gross total resection. Preoperative radiotherapy (RT) often is used as an adjuvant to surgery, but recurrence rates remain high. To enhance RT efficacy with acceptable tolerance, there is interest in delivering "boost doses" of RT to high-risk areas of gross tumor volume (HR GTV) judged to be at risk for positive resection margins. We sought to evaluate variability in HR GTV boost target volume delineation among collaborating sarcoma radiation and surgical oncologist teams. METHODS: Radiation planning CT scans for three cases of RPS were distributed to seven paired radiation and surgical oncologist teams at six institutions. Teams contoured HR GTV boost volumes for each case. Analysis of contour agreement was performed using the simultaneous truth and performance level estimation (STAPLE) algorithm and kappa statistics. RESULTS: HRGTV boost volume contour agreement between the seven teams was "substantial" or "moderate" for all cases. Agreement was best on the torso wall posteriorly (abutting posterior chest abdominal wall) and medially (abutting ipsilateral para-vertebral space and great vessels). Contours varied more significantly abutting visceral organs due to differing surgical opinions regarding planned partial organ resection. CONCLUSIONS: Agreement of RPS HRGTV boost volumes between sarcoma radiation and surgical oncologist teams was substantial to moderate. Differences were most striking in regions abutting visceral organs, highlighting the importance of collaboration between the radiation and surgical oncologist for "individualized" target delineation on the basis of areas deemed at risk and planned resection.

NCCN Guidelines Insights Breast Cancer, Version 1.2016.

These NCCN Guideline Insights highlight the important updates to the systemic therapy recommendations in the 2016 NCCN Guidelines for Breast Cancer. In the most recent version of these guidelines, the NCCN Breast Cancer Panel included a new section on the principles of preoperative systemic therapy. In addition, based on new evidence, the panel updated systemic therapy recommendations for women with hormone receptor-positive breast cancer in the adjuvant and metastatic disease settings and for patients with HER2-positive metastatic breast cancer. This report summarizes these recent updates and discusses the rationale behind them.

Breast Cancer Version 2.2015.

Breast cancer is the most common malignancy in women in the United States and is second only to lung cancer as a cause of cancer death. The overall management of breast cancer includes the treatment of local disease with surgery, radiation therapy, or both, and the treatment of systemic disease with cytotoxic chemotherapy, endocrine therapy, biologic therapy, or combinations of these. This portion of the NCCN Guidelines discusses recommendations specific to the locoregional management of clinical stage I, II, and IIIA (T3N1M0) tumors.

Neoadjuvant chemotherapy for primary cutaneous/soft tissue angiosarcoma: Determining tumor behavior prior to surgical resection.

BACKGROUND: Given the propensity for hematogenous metastases, neoadjuvant chemotherapy (NAC) could treat occult metastatic disease early, potentially improving survival and better defining which primary angiosarcomas (AS) benefit from surgical resection. METHODS: A retrospective comparison was performed of 23 patients with resectable, localized cutaneous/soft tissue primary AS treated with surgery alone (S, n = 13) or NAC followed by surgery (NAC-S, n = 12). RESULTS: Primary sites included breast/chest (n = 9), head/neck (n = 9), extremity (n = 3), and other (n = 2). 23% S versus 40% NAC-S had prior radiation (RT). NAC regimens were paclitaxel (n = 6) or gemcitabine/docetaxel (n = 4). Seventy percent were high grade. Distant metastases were found in 17% after NAC. Non-primary wound closure was required in 54 %S versus 30%NAC-S (P = 0.4). R0 resections were achieved in 85% S versus 80% NAC-S (30% had a complete pathologic response). Two-year local recurrence (LR)-free, disease-free, and overall survivals were 67.1, 38.5, and 61.5% for S versus 68.6, 54.9, and 68.6% for NAC-S (P = 0.52, 0.67, and 0.58). The mean number of surgical resections/patient to maintain local control was 1.8 S versus 1.3 NAC-S (P = 0.06). CONCLUSIONS: NAC for primary AS was well tolerated. Although there was no statistically significant survival benefit, NAC helped define who would benefit from surgical resection.

Breast cancer version 3.2014.

Breast cancer is the most common malignancy in women in the United States and is second only to lung cancer as a cause of cancer death. The overall management of breast cancer includes the treatment of local disease with surgery, radiation therapy, or both, and the treatment of systemic disease with cytotoxic chemotherapy, endocrine therapy, biologic therapy, or combinations of these. The NCCN Guidelines specific to management of large clinical stage II and III tumors are discussed in this article. These guidelines are the work of the members of the NCCN Breast Cancer Panel. Expert medical clinical judgment is required to apply these guidelines in the context of an individual patient to provide optimal care. Although not stated at every decision point of the guidelines, patient participation in prospective clinical trials is the preferred option of treatment for all stages of breast cancer.

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.

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.

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).

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.

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.

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.