Outcomes of extracranial stereotactic body radiation therapy for induced oligometastatic non-small cell lung cancer on novel systemic therapy.

Background: Stereotactic body radiation therapy (SBRT) is often delivered in patients with oligometastatic disease (OMD). However, the specific subset of patients with polymetastatic non-small cell lung cancer (NSCLC) on novel systemic therapies who develop induced oligopersistant disease (OpersisD) or oligoprogressive disease (OprogD), as defined by the European Organisation for Research and Treatment of Cancer (EORTC) OMD classification, has not been well described. This study explores the outcomes of patients treated with this strategy. Methods: Patients with stage IV NSCLC being treated with osimertinib or immune checkpoint inhibitors (ICIs) who received extracranial SBRT for OpersisD or OprogD were identified in our retrospective analysis. Outcomes reported include progression-free survival (PFS), time to change of systemic treatment (TTCST), overall survival (OS), local control (LC) and treatment-related toxicity. Results: Forty-nine patients received SBRT for OpersisD (34.7%) or OprogD (65.3%) at a median of 5.8 and 15.3 months after start of systemic therapy, respectively. 55.1% received concurrent osimertinib and 44.9% received ICI. Seventy-seven extracranial lesions were treated with various fractionation schemas. At a median of 18.8 months follow-up from first SBRT, LC was achieved in 92.2% of total lesions treated (71). The 1-year OS was 91.7% for OpersisD and 83.3% for OprogD. OpersisD compared to OprogD had a longer median PFS (18.3 vs. 6.1 months) and longer median TTCST (23.6 vs. 13.5 months), median OS was not reached for either cohort. On multivariate analysis, patients treated with osimertinib had shorter PFS (HR: 2.20; 95% CI: 1.01-4.82; P=0.048) and shorter TTCST (HR: 2.83; 95% CI: 1.09-7.33; P=0.032). One patient (2%) experienced grade 3 pneumonitis after SBRT, and no grade 4-5 toxicities were reported with SBRT treatment. Conclusions: This study indicates that SBRT for OpersisD or OprogD in Stage IV NSCLC patients on osimertinib or ICIs is safe, very well tolerated, and may prolong the time before needing a shift in systemic therapy. Further prospective research is needed to validate and expand upon these findings.

Pancreatic cancer outcome-local treatment with radiation using MRI-LINAC.

Introduction: Stereotactic MR-guided on-table adaptive radiotherapy (SMART) allows the precise delivery of high-dose radiation to tumors in great proximity to radiation-sensitive organs. The aim of this study is to evaluate the toxicity and clinical outcome in locally advanced or recurrent pancreatic tumors, with or without prior irradiation, treated with SMART. Methods: Patients were treated for pancreatic cancer (PC) using SMART technology to a prescribed dose of 50 Gy (BED10, 100 Gy) in five fractions, with daily on-table adaptation of treatment plan. Endpoints were acute and late toxicities, local control, local disease-free period, and overall survival. Results: A total of 54 PC patients were treated between August 2019 and September 2022, with a median follow-up of 8.9 months from SMART. The median age was 70.4 (45.2-86.9) years. A total of 40 patients had upfront inoperable PC (55% were locally advanced and 45% metastatic), and 14 had local recurrence following prior pancreatectomy (six patients also had prior adjuvant RT). Of the patients, 87% received at least one chemotherapy regimen (Oxaliplatin based, 72.2%), and 25.9% received ≥2 regimens. Except from lower CA 19-9 serum level at the time of diagnosis and 6 weeks prior to SMART in previously operated patients, there were no significant differences in baseline parameters between prior pancreatectomy and the inoperable group. On-table adaptive replanning was performed for 100% of the fractions. No patient reported grade ≥2 acute GI toxicity. All previously irradiated patients reported only low-grade toxicities during RT. A total of 48 patients (88.9%) were available for evaluation. Complete local control was achieved in 21.7% (10 patients) for a median of 9 months (2.8-28.8); three had later local progression. Eight patients had regional or marginal recurrence. Six- and 12-month OS were 75.0% and 52.1%, respectively. Apart from mild diarrhea 1-3 months after SMART and general fatigue, there were no significant differences in toxicity and outcomes between post-pancreatectomy and inoperable groups. Conclusion: SMART allows safe delivery of an ablative dose of radiotherapy, with minimal treatment-related toxicity, even in previously resected or irradiated patients. In this real-world cohort, local control with complete response was achieved by 20% of the patients. Further studies are needed to evaluate long-term outcome and late toxicity.

Outcome of the first 200 patients with prostate cancer treated with MRI-Linac at Assuta MC.

Background: We present our experience with MR-guided stereotactic body radiotherapy (SBRT) for 200 consecutive patients with prostate cancer with minimum 3-month follow-up. Methods: Treatment planning included fusion of the 0.35-Tesla planning MRI with multiparametric MRI and PET-PSMA for Group Grade (GG) 2 or higher and contour review with an expert MRI radiologist. No fiducials or rectal spacers were used. Prescription dose was 36.25 Gy in 5 fractions over 2 weeks to the entire prostate with 3-mm margins. Daily plan was adapted if tumor and organs at risk (OAR) doses differed significantly from the original plan. The prostate was monitored during treatment that was automatically interrupted if the target moved out of the PTV range. Results: Mean age was 72 years. Clinical stage was T1c, 85.5%; T2, 13%; and T3, 1.5%. In addition, 20% were GG1, 50% were GG2, 14.5% were GG3, 13% were GG4, and one patient was GG5. PSA ranged from 1 to 77 (median, 6.2). Median prostate volume was 57cc, and 888/1000 (88%) fractions required plan adaptation. The most common acute GU toxicity was Grade I, 31%; dysuria and acute gastrointestinal toxicity were rare. Three patients required temporary catheterization. Prostate size of over 100cc was associated with acute fatigue, urinary hesitance, and catheter insertion. Prostate Specific Antigen (PSA) decreased in 99% of patients, and one patient had regional recurrence. Conclusion: MR-guided prostate SBRT shows low acute toxicity and excellent short-term outcomes. Real-time MRI ensures accurate positioning and SBRT delivery.

Pegylated Liposomal Mitomycin C Lipidic Prodrug in Combination With External Beam Radiation Therapy in Patients With Advanced Cancer: A Phase 1B Study.

PURPOSE: The aim of this study was to evaluate a formulation of pegylated liposomal mitomycin C lipidic prodrug (PL-MLP) in patients concomitantly undergoing external beam radiation therapy (RT). METHODS AND MATERIALS: Patients with metastatic disease or inoperable primary solid tumors requiring RT for disease control or symptom relief were treated with 2 courses of PL-MLP (1.25, 1.5, or 1.8 mg/kg) at 21-day intervals, along with 10 fractions of conventional RT or 5 stereotactic body RT fractions initiated 1 to 3 days after the first PL-MLP dose and completed within 2 weeks. Treatment safety was monitored for 6 weeks, and disease status was re-evaluated at 6-week intervals thereafter. MLP levels were analyzed 1 hour and 24 hours after each PL-MLP infusion. RESULTS: Overall, 19 patients with metastatic (18) or inoperable (1) disease received combination treatment, with 18 completing the full protocol. Most patients (16) had diagnoses of advanced gastrointestinal tract cancer. One grade 4 neutropenia event possibly related to study treatment was reported; other adverse events were mild or moderate. Of the 18 evaluable patients, 16 were free of RT target lesion progression at first re-evaluation. Median survival of the entire patient population was 63.3 weeks. Serum MLP level correlated with dose increases and similar long circulating profiles were observed before and after RT. CONCLUSIONS: PL-MLP up to 1.8 mg/kg in combination with RT treatment is safe, with a high rate of tumor control. Drug clearance is not affected by radiation. PL-MLP is potentially an attractive option for chemoradiation therapy that warrants further evaluation in randomized studies in the palliative and curative settings.

Comparison of intravenous 5-Fluorouracil with Oral Capecitabine in the Treatment of Anal Squamous Cell Carcinoma Using Modern Radiation Techniques.

BACKGROUND: Anal squamous cell carcinoma (ASqCC) is a rare malignancy, traditionally treated with combined chemoradiation, with a continuous infusion of 5-fluorouracil (5-FU) and mitomycin C (MMC). Replacing intravenous (IV) 5-FU with oral capecitabine (oral fluoropyrimidine) has been reported as a non-inferior treatment option. However, these data are scarce, with variable results. OBJECTIVES: To examine the outcome of patients with ASqCC treated with either IV 5-FU or capecitabine concomitantly with radiation therapy. To compare treatment side effects, local recurrence, and general outcome. METHODS: We reviewed charts of patients who were diagnosed with stage I-III ASqCC. All participating patients received chemoradiation at the Assuta Medical Center between 2011 and 2019. RESULTS: In this study, 43 patients with ASqCC were eligible; 14 received 5-FU and 29 were treated with capecitabine. Basic characteristics were similar between the two groups, with longer follow-up for the 5-FU group. Six months following treatment, 100% (13/13 with adequate follow-up) of the 5-FU group had complete clinical response, compared to 84% in the capecitabine group (21/24), P = 0.143. The local recurrence incidence was higher in the 5-FU group at 23% (7, 10, 26 months following therapy, and none in the capecitabine group (P = 0.088). Although local and hematological toxicities were similar between groups, one patient receiving capecitabine died during chemoradiotherapy. CONCLUSIONS: Oral capecitabine demonstrated non-inferior disease control in ASqCC treated with chemoradiotherapy. We recommend oral capecitabine over continuous IV 5-FU in locally and locally advanced ASqCC. Close monitoring of side effects is required to reduce major toxicity.

Ways to improve breast cancer patients' management and clinical outcome: The 2020 Assisi Think Tank Meeting.

We report on the third Assisi Think Tank Meeting (ATTM) on breast cancer, a brainstorming project which involved European radiation and clinical oncologists who were dedicated to breast cancer research and treatment. Held on February 2020, the ATTM aimed at identifying key clinical questions in current clinical practice and "grey" areas requiring research to improve management and outcomes. Before the meeting, three key topics were selected: 1) managing patients with frailty due to either age and/or multi-morbidity; 2) stereotactic radiation therapy and systemic therapy in the management of oligometastatic disease; 3) contralateral breast tumour prevention in BCRA-mutated patients. Clinical practice in these areas was investigated by means of an online questionnaire. In the lapse period between the survey and the meeting, the working groups reviewed data, on-going studies and the clinical challenges which were then discussed in-depth and subjected to intense brainstorming during the meeting; research protocols were also proposed. Methodology, outcome of discussions, conclusions and study proposals are summarized in the present paper. In conclusion, this report presents an in-depth analysis of the state of the art, grey areas and controversies in breast cancer radiation therapy and discusses how to confront them in the absence of evidence-based data to guide clinical decision-making.

Clinical adoption patterns of 0.35 Tesla MR-guided radiation therapy in Europe and Asia.

BACKGROUND: Magnetic resonance-guided radiotherapy (MRgRT) utilization is rapidly expanding, driven by advanced capabilities including better soft tissue imaging, continuous intrafraction target visualization, automatic triggered beam delivery, and the availability of on-table adaptive replanning. Our objective was to describe patterns of 0.35 Tesla (T)-MRgRT utilization in Europe and Asia among early adopters of this novel technology. METHODS: Anonymized administrative data from all 0.35T-MRgRT treatment systems in Europe and Asia were extracted for patients who completed treatment from 2015 to 2020. Detailed treatment information was analyzed for all MR-linear accelerators (linac) and -cobalt systems. RESULTS: From 2015 through the end of 2020, there were 5796 completed treatment courses delivered in 46,389 individual fractions. 23.5% of fractions were adapted. Ultra-hypofractionated (UHfx) dose schedules (1-5 fractions) were delivered for 63.5% of courses, with 57.8% of UHfx fractions adapted on-table. The most commonly treated tumor types were prostate (23.5%), liver (14.5%), lung (12.3%), pancreas (11.2%), and breast (8.0%), with increasing compound annual growth rates (CAGRs) in numbers of courses from 2015 through 2020 (pancreas: 157.1%; prostate: 120.9%; lung: 136.0%; liver: 134.2%). CONCLUSIONS: This is the first comprehensive study reporting patterns of utilization among early adopters of a 0.35T-MRgRT system in Europe and Asia. Intrafraction MR image-guidance, advanced motion management, and increasing adoption of on-table adaptive RT have accelerated a transition to UHfx regimens. MRgRT has been predominantly used to treat tumors in the upper abdomen, pelvis and lungs, and increasingly with adaptive replanning, which is a radical departure from legacy radiotherapy practices.

Oncology Treatments during the COVID-19 Pandemic in Israel: the ONCOR Study.

BACKGROUND: The increased susceptibility of cancer patients to coronavirus disease-2019 (COVID-19) infections and complications calls for special precautions while treating cancer patients during COVID-19 pandemics. Thus, oncology departments have had to implement a wide array of prevention measures. OBJECTIVES: To address issues associated with cancer care during the COVID-19 pandemic and to assess the implementation of measures aimed at containment of COVID-19 diffusion while allowing continuation of quality cancer care. METHODS: A national survey among oncology departments in Israel was conducted between 12 April 2020 and 14 April 2020. Eighteen heads of hospital-based oncology departments completed a self-report questionnaire regarding their institute's preparedness for treatment of cancer patients during the COVID-19 pandemic. RESULTS: In this national survey, prevention measures against COVID-19 spread were taken prior to patients' arrival and at arrival or while staying in the departments. Most participants (78-89%) reported using a quick triage of patients and caregivers prior to their entrance to the oncology units, limiting the entrance of caregivers, and reducing unnecessary visits to the clinic. Switching to oral therapies rather than intravenous ones when possible was considered by 82% and shortage in personal protective equipment was reported by five (28%) heads of oncology departments. Some differences between large and small/medium sized medical centers were observed regarding issues related to COVID-19 containment measures and changes in treatment. CONCLUSIONS: Oncology departments in Israel were able to prepare and adapt their services to guidelines and requirements related to the COVID-19 pandemic with little harm to their treatment capacity.

Clinical oncology module for the ESTRO core curriculum.

INTRODUCTION: Clinical oncologists are physicians with the competencies to manage cancer patients through the entire disease pathway combining the competencies of radiation and medical oncologists. The 4th edition of the European Society for Radiotherapy and Oncology Core Curriculum for Radiation Oncology/Radiotherapy (ESTRO curriculum) has received wide support by the clinical oncology community. The aim was to develop a clinical oncology module that could be combined with the ESTRO curriculum to enable clinical oncology trainees to follow a single curriculum. MATERIALS AND METHODS: A range of stakeholders including National Society representatives, an oncologist from a low- middle-income country, and a recently appointed specialist, developed and commented on iterations of the curriculum. Further modifications were made by the ESTRO Education Council. RESULTS: The module is based on the CanMEDS 2015 framework and identifies 20 enabling competencies in the Medical Expert role that are required in addition to the ESTRO curriculum for the training of clinical oncologists. Recommendations are made for the levels of Entrustable Professional Activities (EPAs) to be attained by the end of training. CONCLUSIONS: The Clinical Oncology module, when combined with the ESTRO curriculum, covers the entire cancer pathway rather than being modality specific. It is hoped it will aid in the development of comparable standards of training in clinical oncology across Europe and may also have utility in low- and middle-income countries as well as providing a single curriculum for trainees.

The 2018 assisi think tank meeting on breast cancer: International expert panel white paper.

We report on the second Assisi Think Tank Meeting (ATTM) on breast cancer which was held under the auspices of the European Society for RadioTherapy & Oncology (ESTRO). In discussing in-depth current evidence and practice it was designed to identify grey areas in diverse forms of the disease. It aimed at addressing uncertainties and proposing future trials to improve patient care. Before the meeting, three key topics were selected: 1) primary systemic therapy, mastectomy, breast reconstruction and post-mastectomy radiation therapy, 2) therapeutic options in ductal carcinoma in situ, and 3) therapy de-escalation in early stage breast cancer. Clinical practice in these areas was investigated by means of an online questionnaire. The time lapse period between the survey and the meeting was used to review the literature and on-going clinical trials. At the ATTM both were discussed in depth and research protocols were proposed.

Prophylactic breast irradiation reduces background parenchymal enhancement (BPE) on MRI: A secondary analysis.

PURPOSE: We recently showed that prophylactic breast irradiation (PBI) reduces the risk of contralateral breast cancer in BRCA mutation carriers undergoing treatment for early breast cancer. It has been suggested that Background Parenchymal Enhancement (BPE) may be a biomarker for increased risk of breast cancer. METHODS: For participants in the trial we reviewed the MRI prior to enrollment and following radiation treatment and scored the contralateral breast for BPE and density. RESULTS: Significant reduction of BPE was more commonly noted following PBI (p = 0.011) compared to the control group. CONCLUSION: Reduction of BPE by PBI may contribute to its prophylactic effect.

Recommended ESTRO Core Curriculum for Radiation Oncology/Radiotherapy 4th edition.

INTRODUCTION: In 2017 it was decided to revise the European Core Curriculum for Radiation Oncology/Radiotherapy to produce a 4th edition. The aims of the ESTRO curriculum are to develop comparable standards for training across Europe and to facilitate free movement of specialists across borders. It is also hoped that it will improve the level of training across Europe and will make the non-medical expert roles more explicit. MATERIALS AND METHODS: A wide range of stakeholders including National Society representatives, trainees, recently appointed specialists, members of the European Union Medical Specialists Radiotherapy section, an RTT, a radiobiologist, a physicist and lay members from ESTRO staff developed and commented on iterations of the curriculum. RESULTS: The 4th edition is based on the CanMEDS 2015 framework and identifies 14 Entrustable Professional Activities (EPAs) and the competencies required to perform these. The manager role is replaced by competencies related to leadership. The levels of proficiency required for tumour sites is defined as levels of EPAs. CONCLUSIONS: It is hoped that the inclusive method of developing the 4th edition has resulted in a document that will have utility in the wide range of environments in which radiation oncology is practised in Europe.

Real-time Online Matching in High Dose-per-Fraction Treatments: Do Radiation Therapists Perform as Well as Physicians?

PURPOSE: In our department, for high dose-per-fraction treatments such as stereotactic body radiation therapy, we require a physician to perform the pretreatment on-board imaging match. The purpose of this study was to determine whether patient-matching positioning performed by radiation therapists (RTTs) is as accurate as that performed by physicians. METHODS AND MATERIALS: Sixteen RTTs and 5 physicians participated in this study. Data were collected from 113 patients, totaling 324 measurements. A total of 60 patients were treated for bone lesions and 53 for soft-tissue lesions, such as lung and liver. Matching was performed using kV-kV imaging for bones and cone beam computed tomography for soft tissue. All treatments were delivered on Varian linear accelerators. The initial match was performed by the RTTs, and the shifts were noted. Subsequently, the match was reset, and the physician performed an independent match blinded to the RTT match. Physician shifts were applied for treatment. We used the Wilcoxon rank sum test to determine the statistical significance between RTT and physician shifts. RESULTS: The differences in patient shifts between physicians and RTTs were calculated in 3 translational 1 one rotational axis. The average vector shift was 0.88 ± 0.57 cm versus 0.91 ± 0.57 cm for RTTs versus physicians, respectively. Neither the average vector nor the individual axis shifts were statistically significantly different (P > .2). There was no significant difference when testing for bony or soft lesion matches separately. CONCLUSIONS: RTT on-board imaging matching is as accurate as physician matching for both bone and soft tissue lesions. On the basis of these results, RTTs are as qualified as physicians to perform a pretreatment match. Thus, it may be feasible for the RTTs to perform the match and the physician to review it offline after treatment without being present at the machine during treatment. Our results show that this approach does not compromise patient safety.

Chemo-Radiotherapy of Oligometastases of Colorectal Cancer With Pegylated Liposomal Mitomycin-C Prodrug (Promitil): Mechanistic Basis and Preliminary Clinical Experience.

Hypo-fractionated radiotherapy and stereotactic body radiotherapy are viable options for treatment of oligometastases. A prodrug of mitomycin-C is under clinical testing as a pegylated liposomal formulation (Promitil) with an improved safety profile over mitomycin-C. Promitil was offered to two patients with oligometastases from colorectal cancer as radiosensitizer. Each derived durable clinical benefit from Promitil administered immediately prior to and following irradiation. Transient toxicity to normal tissues of moderate to severe degree was observed. Promitil appears to have potential clinical value in this setting. HIGHLIGHTS - Delivery of radio-sensitizing drugs with pegylated (long-circulating) liposomes is a pharmacologically rational approach which remains largely clinically untested.- A mitomycin-c prodrug delivered by pegylated liposomes (Promitil) is activated by thiol groups, which are produced in excess by radiation-damaged cells, thus potentiating the radio-sensitizing effect of Promitil.- Two durable clinical responses in patient with colorectal oligometastases to Promitil and radiotherapy suggest that this approach may be of value in cancer chemo-radiotherapy.

Stereotactic Ablative Body Radiation for Stage I Lung Cancer in Israel: A Retrospective Single-Center Report.

BACKGROUND: Stereotactic ablative radiation therapy (SABR) is the application of a very high radiation dose to a small treatment volume. It is the new standard of care in medically inoperable early-stage lung cancer. OBJECTIVES: To report the outcomes of SABR in stage I lung cancer at Sheba Medical Center since its introduction in 2009. METHODS: We conducted a retrospective chart review of patients with stage I lung cancer treated during the period 2009-2015. Survival status was retrieved from the electronic medical records and confirmed with the national registry. Local failure was defined as increased FDG uptake on PETCT scan within a 2 cm radius of the treated region. Toxicity was estimated from medical records and graded according to common toxicity criteria for adverse events (CTCAE) version 4.03. Overall survival and local control were estimated by the Kaplan-Meier method. RESULTS: During the study period 114 patients were treated for 122 stage I lung cancer lesions. Median follow-up time was 27 months (range 8.2-69.5 months), median age was 76 years. Eighty-two percent of the tumors were stage IA (size ≤ 3 cm). Median survival was 46 months; estimated 3 year overall survival was 59% (95%CI 47-69%) and local control was 88% (95%CI 78-94%). Toxicity included chest wall pain in 8.4% of patients, rib fracture in 0.9%, grade 1-2 pneumonitis in 12%, grade 3 in 12% and grade 5 (death) in 0.9%. CONCLUSIONS: SABR has been successfully implemented at Sheba Medical Center for the treatment of stage I lung cancer in inoperable patients. It is associated with excellent local control, minor toxicity and an acceptable overall survival.

Spine radiosurgery: lessons learned from the first 100 treatment sessions.

OBJECTIVE Local therapy to spine tumors has been shown to be effective in selected cases. Spinal radiosurgery (SRS) is an evolving radiotherapy regimen allowing for noninvasive, highly efficacious local treatment. The learning curve can compromise the results of any newly employed technology and should be studied to minimize its effects. In this paper the first 100 SRSs performed at several medical centers are presented and analyzed for the effects of the learning curve on outcome. METHODS A retrospective analysis was undertaken to evaluate data from patients treated with SRS at Sheba Medical Center and Assuta Medical Centers in the period from September 2011 to February 2016. Medical history, clinical and neurological findings, pathological diagnoses, SRS variables, complications, and follow-up data were collected and analyzed. Local control rates were calculated, and local treatment failure cases were qualitatively studied. RESULTS One hundred treatment sessions were performed for 118 lesions at 179 spinal levels in 80 patients. The complication rate was low and did not correlate with a learning curve. Mean follow-up time was 302 days, and the overall local control rate was 95%. The local control rate was dose dependent and increased from 87% (among 35 patients receiving a dose of 16 Gy) to 97% (among 65 patients receiving a dose of 18 Gy). The 6 treatment failure cases are discussed in detail. CONCLUSIONS Spinal radiosurgery is a safe and effective treatment. Comprehensive education of the treating team and continuous communication are essential to limit the effects of the learning curve on outcome.