Patterns of Care for Breast Radiotherapy in Italy: Breast IRRadiATA (Italian Repository of Radiotherapy dATA) Feasibility Study.

Aim. Breast IRRADIATA (Italian Repository of RADIotherapy dATA) is a collaborative nationwide project supported by the Italian Society of Radiotherapy and Clinical Oncology (AIRO) and the Italian League Against Cancer (LILT). It focuses on breast cancer (BC) patients treated with radiotherapy (RT) and was developed to create a national registry and define the patterns of care in Italy. A dedicated tool for data collection was created and pilot tested. The results of this feasibility study are reported here. Methods. To validate the applicability of a user-friendly data collection tool, a feasibility study involving 17 Italian Radiation Oncology Centers was conducted from July to October 2021, generating a data repository of 335 BC patients treated between January and March 2020, with a minimum follow-up time of 6 months. A snapshot of the clinical presentation, treatment modalities and radiotherapy toxicity in these patients was obtained. A Data Entry Survey and a Satisfaction Questionnaire were also sent to all participants. Results. All institutions completed the pilot study. Regarding the Data Entry survey, all questions achieved 100% of responses and no participant reported spending more than 10 min time for either the first data entry or for the updating of follow-up. Results from the Satisfaction Questionnaire revealed that the project was described as excellent by 14 centers (82.3%) and good by 3 (17.7%). Conclusion. Current knowledge for the treatment of high-prevalence diseases, such as BC, has evolved toward patient-centered medicine, evidence-based care and real-world evidence (RWE), which means evidence obtained from real-world data (RWD). To this aim, Breast IRRADIATA was developed as a simple tool to probe the current pattern of RT care in Italy. The pilot feasibility of IRRADIATA encourages a larger application of this tool nationwide and opens the way to the assessment of the pattern of care radiotherapy directed to other cancers.

Radiation dose and fraction in immunotherapy: one-size regimen does not fit all settings, so how does one choose?

Recent evidence indicates that ionizing radiation can enhance immune responses to tumors. Advances in radiation delivery techniques allow hypofractionated delivery of conformal radiotherapy. Hypofractionation or other modifications of standard fractionation may improve radiation's ability to promote immune responses to tumors. Other novel delivery options may also affect immune responses, including T-cell activation and tumor-antigen presentation changes. However, there is limited understanding of the immunological impact of hypofractionated and unique multifractionated radiotherapy regimens, as these observations are relatively recent. Hence, these differences in radiotherapy fractionation result in distinct immune-modulatory effects. Radiation oncologists and immunologists convened a virtual consensus discussion to identify current deficiencies, challenges, pitfalls and critical gaps when combining radiotherapy with immunotherapy and making recommendations to the field and advise National Cancer Institute on new directions and initiatives that will help further development of these two fields.This commentary aims to raise the awareness of this complexity so that the need to study radiation dose, fractionation, type and volume is understood and valued by the immuno-oncology research community. Divergence of approaches and findings between preclinical studies and clinical trials highlights the need for evaluating the design of future clinical studies with particular emphasis on radiation dose and fractionation, immune biomarkers and selecting appropriate end points for combination radiation/immune modulator trials, recognizing that direct effect on the tumor and potential abscopal effect may well be different. Similarly, preclinical studies should be designed as much as possible to model the intended clinical setting. This article describes a conceptual framework for testing different radiation therapy regimens as separate models of how radiation itself functions as an immunomodulatory 'drug' to provide alternatives to the widely adopted 'one-size-fits-all' strategy of frequently used 8 Gy×3 regimens immunomodulation.

Worldwide Access to Stereotactic Radiosurgery.

Stereotactic radiosurgery is a safe and effective technology that can address a variety of neurosurgical conditions, but in many parts of the world, access remains an issue. Although the technology is increasingly available in the United States, Canada, Europe, and parts of Asia, poor access to central nervous system (CNS) imaging and inadequate treatment equipment in other parts of the world limit the availability of radiosurgery as a treatment option. In addition, epidemiologic data about cancer and CNS metastases in low-income countries are sparse and much less complete than in more developed countries, and the need for radiosurgery may be underestimated as a result. Current radiosurgical platforms can be expensive to install and require a substantial amount of personnel training for safe operation. Socioeconomic and political forces are relevant to limitations to and opportunities for improving access to care. Here we examine the current barriers to access and propose areas for future efforts to improve global availability of radiosurgery for neurosurgical conditions.

Gender, Professional Experiences, and Personal Characteristics of Academic Radiation Oncology Chairs: Data to Inform the Pipeline for the 21st Century.

PURPOSE: Understanding the pathways and gateways to leadership and challenges faced by individuals in such roles can inform efforts to promote diversity and equity. We sought to describe the professional experiences and personal characteristics of academic radiation oncology (RO) chairs and to evaluate whether differences exist by gender. METHODS AND MATERIALS: Anonymous surveys were distributed to 95 chairs of RO departments during the 2016 annual meeting of the Society of Chairs of Academic Radiation Oncology Programs. The surveys included 28 closed-ended questions and the Leadership Practices Inventory. Results were analyzed by gender using χ2 tests, rank-sum, and t tests (significance P < .05). RESULTS: A total of 72 chairs responded (61 male, 10 female, 1 declined to identify gender) for a response rate of 76%. There were no significant gender differences in age, academic rank, publications, or prior leadership positions held at the time of the first chair appointment, but female respondents held significantly greater total direct funding from extramural grants than their male counterparts (median, $1.89 million [interquartile range, $0.5-$5 million] vs $0.25 million [interquartile range, $0-$1.0 million]; P = .006). Women were more likely to have spouses employed outside the home at time of their first chair appointment than men were, with a trend toward women experiencing greater difficulty relocating. Men and women identified budgeting and resource allocation as their greatest professional challenges. There were no gender differences in the Leadership Practices Inventory-identified leadership domains or professional goals. CONCLUSIONS: Female RO chairs are as equally qualified as men in terms of productivity or leadership skills, but they face distinct challenges in the context of a gender-structured society. The observation of higher grant funding among women at the time of chair appointment suggests a possible need for interventions such as unconscious bias training to ensure that selection processes do not unnecessarily hold women to a higher standard.

Immunological Mechanisms Responsible for Radiation-Induced Abscopal Effect.

Radiotherapy has been used for more than a hundred years as a local tumor treatment. The occurrence of systemic antitumor effects manifesting as regression of tumors outside of the irradiated field (abscopal effect) was occasionally observed but deemed too rare and unpredictable to be a therapeutic goal. This has changed with the advent of immunotherapy. Remarkable systemic effects have been observed in patients receiving radiotherapy to control tumors that were progressing during immune checkpoint blockade, stimulating interest in using radiation to overcome primary and acquired cancer resistance to immunotherapy. Here, we review the immunological mechanisms that are responsible for the ability of focal radiation to promote antitumor T cell responses that mediate tumor rejection and, in some cases, result in systemic effects.

Emerging biomarkers for the combination of radiotherapy and immune checkpoint blockers.

Over the past few years, multiple immune checkpoint blockers (ICBs) have achieved unprecedented clinical success and have been approved by regulatory agencies for the treatment of an increasing number of malignancies. However, only a limited fraction of patients responds to ICBs employed as a standalone intervention, calling for the development of combinatorial regimens. Radiation therapy (RT) stands out as a very promising candidate for this purpose. Indeed, RT mediates antineoplastic effects not only by cytotoxic and cytostatic mechanisms, but also by modulating immunological functions, both locally (within the irradiated field) and systemically. As combinatorial regimens involving RT and ICBs are being developed and clinically tested at an accelerating pace, it is paramount to identify biomarkers that reliably predict the likelihood of individual patients to respond. Here, we discuss emerging biomarkers that may potentially predict the response of cancer patients to RT plus ICBs.

Activating autophagy to potentiate immunogenic chemotherapy and radiation therapy.

Autophagy is fundamental to the maintenance of intracellular homeostasis in virtually all human cells. Accordingly, defective autophagy predisposes healthy cells to undergoing malignant transformation. By contrast, malignant cells are able to harness autophagy to thrive, despite adverse microenvironmental conditions, and to resist therapeutic challenges. Thus, inhibition of autophagy has been proposed as a strategy to kill cancer cells or sensitize them to therapy; however, autophagy is also critical for optimal immune function, and mediates cell-extrinsic homeostatic effects owing to its central role in danger signalling by neoplastic cells responding to immunogenic chemotherapy and/or radiation therapy. In this Perspective, we discuss accumulating preclinical and clinical evidence in support of the all-too-often dismissed possibility that activating autophagy might be a relevant clinical objective that enables an increase in the effectiveness of immunogenic chemotherapy and/or radiation therapy.

Trial Watch: Immunotherapy plus radiation therapy for oncological indications.

Malignant cells succumbing to some forms of radiation therapy are particularly immunogenic and hence can initiate a therapeutically relevant adaptive immune response. This reflects the intrinsic antigenicity of malignant cells (which often synthesize a high number of potentially reactive neo-antigens) coupled with the ability of radiation therapy to boost the adjuvanticity of cell death as it stimulates the release of endogenous adjuvants from dying cells. Thus, radiation therapy has been intensively investigated for its capacity to improve the therapeutic profile of several anticancer immunotherapies, including (but not limited to) checkpoint blockers, anticancer vaccines, oncolytic viruses, Toll-like receptor (TLR) agonists, cytokines, and several small molecules with immunostimulatory effects. Here, we summarize recent preclinical and clinical advances in this field of investigation.

Breast, chest wall, and nodal irradiation with prone set-up: Results of a hypofractionated trial with a median follow-up of 35 months.

PURPOSE: To test clinical feasibility, safety, and toxicity of prone hypofractionated breast, chest wall, and nodal radiation therapy. METHODS AND MATERIALS: Following either segmental or total mastectomy with axillary node dissection, patients were treated in an institutional review board-approved prospective trial of prone radiation therapy to the breast, chest wall, and supraclavicular and level III axillary lymph nodes. A dose of 40.5 Gy/15 fractions with a concomitant daily boost to the tumor bed of 0.5 Gy (total dose, 48 Gy) was prescribed. In postmastectomy patients, the same treatment was prescribed, but without a tumor bed boost. The primary endpoint was incidence of >grade 2 acute skin toxicity. The secondary endpoints were feasibility of treatment using prone set-up, compliance with protocol-defined dosimetric constraints, and incidence of late toxicity. A dosimetric comparison was performed between protocol plans (prone) and nonprotocol plans (supine), targeting the same treatment volumes. RESULTS: Sixty-nine patients with stage IB-IIIA breast cancer enrolled in this trial. Surgery was segmental mastectomy (n = 45), mastectomy (n = 23), and bilateral mastectomy (n = 1), resulting in 70 cases. None experienced >grade 2 acute skin toxicity according to the Common Terminology Criteria for Adverse Events, v 3.0, meeting our primary endpoint. Ninety-six percent of patients could be treated with this technique prone. However, 17 plans (24%) exceeded protocol constraints to the brachial plexus. Maximum long-term toxicity was 1 grade 2 arm lymphedema, 1 grade 3 breast retraction, and no occurrence of brachial plexopathy. Dosimetric comparison of protocol with nonprotocol plans demonstrated significantly decreased lung and heart doses in prone plans. CONCLUSIONS: Prone hypofractionated breast, chest wall, and nodal radiation therapy is safe and well tolerated in this study. Although the initial pattern of local and regional control is encouraging, longer follow-up is warranted for efficacy and late toxicity assessment, particularly to the brachial plexus.

Why is partial-breast irradiation still investigational.

The investigational nature of partial breast irradiation (PBI) remains an area of controversy in the field of breast radiotherapy. While we have a long track record of conducting and strongly supporting the research in this area, we have chosen the more cautious approach of continuing to offer PBI only as part of a trial, open to selected breast cancer patients at low risk of local recurrence. This position reflects the fact that existing whole breast radiotherapy has revealed very successful in controlling local recurrences and it remains the safest choice for the patient. Our thinking has been reinforced by the recent data linking the prevention of recurrence to long term breast cancer survival: until more is known about PBI safety, its indiscriminate use may deprive some women from their best chance of fighting breast cancer. Considerations regarding the correct interpretation of the available evidence in view of the still limited duration of follow up and of the pattern of local recurrence of breast cancer sustain our position that PBI can be offered only in the context of a clinical trial. Unfortunately, more time and data are warranted for PBI to be legitimately recognized a standard radiotherapy approach in breast conservation therapy.

The role of a prone setup in breast radiation therapy.

Most patients undergoing breast conservation therapy receive radiotherapy in the supine position. Historically, prone breast irradiation has been advocated for women with large pendulous breasts in order to decrease acute and late toxicities. With the advent of CT planning, the prone technique has become both feasible and reproducible. It was shown to be advantageous not only for women with larger breasts but in most patients since it consistently reduces, if not eliminates, the inclusion of heart and lung within the field. The prone setup has been accepted as the best localizing position for both MRI and stereotactic biopsy, but its adoption has been delayed in radiotherapy. New technological advances including image-modulated radiation therapy and image-guided radiation therapy have made possible the exploration of accelerated fractionation schemes with a concomitant boost to the tumor bed in the prone position, along with better imaging and verification of reproducibility of patient setup. This review describes some of the available techniques for prone breast radiotherapy and the available experience in their application. The NYU prone breast radiotherapy approach is discussed, including a summary of the results from several prospective trials.