Preclinical Model of Stereotactic Ablative Lung Irradiation Using Arc Delivery in the Mouse: Is Fractionation Worthwhile?

Lung stereotactic body radiation therapy is characterized by a reduction in target volumes and the use of severely hypofractionated schedules. Preclinical modeling became possible thanks to rodent-dedicated irradiation devices allowing accurate beam collimation and focal lung exposure. Given that a great majority of publications use single dose exposures, the question we asked in this study was as follows: in incremented preclinical models, is it worth using fractionated protocols or should we continue focusing solely on volume limitation? The left lungs of C57BL/6JRj mice were exposed to ionizing radiation using arc therapy and 3 × 3 mm beam collimation. Three-fraction schedules delivered over a period of 1 week were used with 20, 28, 40, and 50 Gy doses per fraction. Lung tissue opacification, global histological damage and the numbers of type II pneumocytes and club cells were assessed 6 months post-exposure, together with the gene expression of several lung cells and inflammation markers. Only the administration of 3 × 40 Gy or 3 × 50 Gy generated focal lung fibrosis after 6 months, with tissue opacification visible by cone beam computed tomography, tissue scarring and consolidation, decreased club cell numbers and a reactive increase in the number of type II pneumocytes. A fractionation schedule using an arc-therapy-delivered three fractions/1 week regimen with 3 × 3 mm beam requires 40 Gy per fraction for lung fibrosis to develop within 6 months, a reasonable time lapse given the mouse lifespan. A comparison with previously published laboratory data suggests that, in this focal lung irradiation configuration, administering a Biological Effective Dose ≥ 1000 Gy should be recommended to obtain lung fibrosis within 6 months. The need for such a high dose per fraction challenges the appropriateness of using preclinical highly focused fractionation schedules in mice.

Dose-Response Effect and Dose-Toxicity in Stereotactic Radiotherapy for Brain Metastases: A Review

For more than two decades, stereotactic radiosurgery has been considered a cornerstone treatment for patients with limited brain metastases. Historically, radiosurgery in a single fraction has been the standard of care but recent technical advances have also enabled the delivery of hypofractionated stereotactic radiotherapy for dedicated situations. Only few studies have investigated the efficacy and toxicity profile of different hypofractionated schedules but, to date, the ideal dose and fractionation schedule still remains unknown. Moreover, the linear-quadratic model is being debated regarding high dose per fraction. Recent studies shown the radiation schedule is a critical factor in the immunomodulatory responses. The aim of this literature review was to discuss the dose–effect relation in brain metastases treated by stereotactic radiosurgery accounting for fractionation and technical considerations. Efficacy and toxicity data were analyzed in the light of recent published data. Only retrospective and heterogeneous data were available. We attempted to present the relevant data with caution. A BED10 of 40 to 50 Gy seems associated with a 12-month local control rate >70%. A BED10 of 50 to 60 Gy seems to achieve a 12-month local control rate at least of 80% at 12 months. In the brain metastases radiosurgery series, for single-fraction schedule, a V12 Gy < 5 to 10 cc was associated to 7.1–22.5% radionecrosis rate. For three-fractions schedule, V18 Gy < 26–30 cc, V21 Gy < 21 cc and V23 Gy < 5–7 cc were associated with about 0–14% radionecrosis rate. For five-fractions schedule, V30 Gy < 10–30 cc, V 28.8 Gy < 3–7 cc and V25 Gy < 16 cc were associated with about 2–14% symptomatic radionecrosis rate. There are still no prospective trials comparing radiosurgery to fractionated stereotactic irradiation.

RADT-26. PROTON VERSUS PHOTON CRANIOSPINAL IRRADIATION FOR ADULT MEDULLOBLASTOMA: A DOSIMETRIC AND TOXICITY ANALYSIS

Medulloblastoma is a posterior fossa tumor rarely diagnosed in adults. Treatment includes craniospinal irradiation (CSI). Proton CSI is increasingly utilized to decrease radiation dose to normal tissues, despite the lack of randomized data demonstrating decreased toxicity compared to photon CSI. This single institution retrospective study of 39 adult medulloblastoma patients includes nineteen patients treated with photon CSI prior to 2015, and twenty treated with proton CSI thereafter. Median age was 28 years (range 18-66). Molecular subtype was most commonly sonic hedgehog (68%). The most common fractionation schedule was 36 Gy CSI in 20 fractions (85% of photon and 58% of proton patients) with a boost to 54-55.8 Gy (92%). Proton CSI delivered significantly lower mean doses to the cochleae (median 32 Gy vs. 44 Gy), lacrimal glands (8 vs. 36 Gy), lens (2 vs. 28 Gy), parotid glands (3 vs. 26 Gy), pharyngeal constrictors (6 vs. 15 Gy), esophagus (2 vs. 29 Gy), heart (0 vs. 14 Gy), lungs (1 vs. 7 Gy), liver (0.1 vs. 7 Gy), and skin (38 vs. 51 Gy) (all p&lt; 0.001). Patients receiving proton CSI had significantly lower rates of acute dysphagia of any grade (5% vs. 35%, p= 0.044) and decreased median weight loss during radiation (+1.0 vs. -2.8 kg, p= 0.011). Acute hospitalization was associated with increased weight loss (p= 0.009). Median follow-up was 2.9 and 12.9 years for proton and photon patients, respectively, limiting late toxicity and outcome comparisons. At last follow-up five photon patients had died (two of progressive disease, three without recurrence ages 41-63) and 21% had experienced major cardiovascular events. At 10 years, 89% were alive and 82% were recurrence free. In conclusion, this study demonstrates dosimetric improvements with proton CSI, potentially leading to decreased acute toxicity including dysphagia and weight loss during treatment.

Do sustainable palliative single fraction radiotherapy practices proliferate or perish 2 years after a knowledge translation campaign?

BACKGROUND There is a paucity of data regarding the time-dependent effects of knowledge translation (KT) campaign derived Radiation Oncologist (RO) prescription behaviour. In early 2017, the XXXX and XXXX undertook a comprehensive KT campaign to improve utilization of single fraction radiotherapy (SFRT) over multiple fraction radiotherapy (MFRT) in accordance with clinical guidelines for palliative management of bone metastases. The campaign significantly increased short-term SFRT utilization. We assess the time-dependent effects of KT-derived SFRT utilization 12-24 months removed from the KT campaign in a Canadian Provincial Cancer Program. METHODS This retrospective, population-based cohort study identified all patients receiving palliative radiotherapy for bone metastases in XXXX from 1 Jan 2018 to 31 Dec 2018 using provincial radiotherapy databases. Baseline characteristics were tabulated by fractionation schedule. The proportion of patients treated with SFRT in 2018 was compared to 2017 levels overall and by prescribing RO. Logistic regression analyses identified risk factors associated with MFRT receipt. RESULTS In 2018, 1,008 patients received palliative radiotherapy for bone metastasis, of which 63.3% received SFRT, a small overall increase in SFRT use over 2017 (59.1%). However, 41.1% of ROs demonstrated year-over-year decreases in SFRT utilization, indicative of a time-dependent loss of SFRT prescription habits derived from KT. CONCLUSION Although SFRT use increased slightly overall in 2018, evidence of compliance fatigue was observed suggestive of a time-perishing property of RO prescription behaviours derived from KT methodologies. These findings highlight the need for additional longitudinal KT reinforcement practices in the years following KT campaigns.

Moderately hypofractionated radiotherapy as definitive treatment for localized prostate cancer: Pattern of practice in German-speaking countries

Purpose Various randomized phase III clinical trials have compared moderately hypofractionated to normofractionated radiotherapy (RT). These modalities showed similar effectiveness without major differences in toxicity. This project was conducted by the Prostate Cancer Expert Panel of the German Society of Radiation Oncology (DEGRO) and the Working Party on Radiation Oncology of the German Cancer Society. We aimed to investigate expert opinions on the use of moderately hypofractionated RT as a definitive treatment for localized prostate cancer in German-speaking countries. Methods A 25-item, web-based questionnaire on moderate-hypofractionation RT was prepared by an internal committee. The experts of the DEGRO were asked to complete the questionnaire. Results Fourteen active members of DEGRO completed the questionnaire. The questions described indications for selecting patients eligible to receive moderate hypofractionation based on clinical and pathological factors such as age, urinary symptoms, and risk-group. The questions also collected information on the technical aspects of selection criteria, including the definition of a clinical target volume, the use of imaging, protocols for bladder and rectal filling, the choice of a fractionation schedule, and the use of image guidance. Moreover, the questionnaire collected information on post-treatment surveillance after applying moderately hypofractionated RT. Conclusion Although opinions varied on the use of moderate-hypofractionation RT, the current survey reflected broad agreement on the notion that moderately hypofractionated RT could be considered a standard treatment for localized prostate cancer in German-speaking countries.

Variability of α/β Ratios for Prostate Cancer With the Fractionation Schedule: Caution Against Using the Linear-Quadratic Model for Hypofractionated Radiotherapy

Background: Prostate cancer (PCa) is known to be suitable for hypofractionated radiotherapy due to the very low α/β ratio (about 1.5-3 Gy). However, several randomized controlled trials have not shown the superiority of hypofractionated radiotherapy over conventionally fractionated radiotherapy. Besides, in vivo and in vitro experimental results show that the linear-quadratic (LQ) model may not be appropriate for hypofractionated radiotherapy, and we guess it may be due to the influence of fractionation schedules on the α/β ratio. Therefore, this study attempted to estimate the α/β ratio in different fractionation schedules and evaluate the applicability of the LQ model in hypofractionated radiotherapy. Methods: The maximum likelihood principle in mathematical statistics was used to fit the parameters: k, α and β values in the tumor control probability (TCP) formula derived from the LQ model. In addition, the fitting results were substituted into the original TCP formula to calculate 5-year biochemical relapse-free survival for further verification.Results: Information necessary for fitting could be extracted from a total of 23,281 PCa patients. A total of 16,442 PCa patients were grouped according to fractionation schedules. We found that, for patients who received conventionally fractionated radiotherapy, moderately hypofractionated radiotherapy, and stereotactic body radiotherapy, the average α/β ratios were 1.78 Gy (95% CI: 1.59-1.98, P < 0.001), 3.46 Gy (95% CI: 3.08-3.83, P < 0.001), and 4.24 Gy (95% CI: 4.10-4.39, P < 0.001), respectively. Hence, the calculated α/β ratios for PCa tended to become higher when the dose per fraction increased. Among all PCa patients, 14,641 could be grouped according to the risks of PCa in patients receiving radiotherapy with different fractionation schedules. The results showed that as the risk increased, the k and α values decreased, indicating that the number of effective target cells decreased and the radioresistance increased.Conclusions: The LQ model appeared to be inappropriate for high doses per fraction owing to α/β ratios tending to become higher when the dose per fraction increased. Therefore, to convert the conventionally fractionated radiation doses to equivalent high doses per fraction using the standard LQ model, a higher α/β ratio should be used for calculation.

Stereotactic Body Radiotherapy for Frail Patients with Primary Renal Cell Carcinoma: Preliminary Results after 4 Years of Experience

Introduction: The aim of this study was to report the oncological outcomes and toxicity of stereotactic body radiotherapy (SBRT) to treat primary renal cell carcinoma (RCC) in frail patients unfit for surgery or standard alternative ablative therapies. Methods: We retrospectively enrolled 23 patients who had SBRT for primary, biopsy-proven RCC at our tertiary center between October 2016 and March 2020. Treatment-related toxicities were defined using CTCAE, version 4.0. The primary outcome was local control which was defined using the Response Evaluation Criteria in Solid Tumors. Results: The median age, Charlson score and tumor size were 81 (IQR 79–85) years, 7 (IQR 5–8) and 40 (IQR 28–48) mm, respectively. The most used dose fractionation schedule was 35 Gy (78.3%) in five or seven fractions. The median duration of follow-up for all living patients was 22 (IQR 10–39) months. Local recurrence-free survival, event-free survival, cancer-specific survival and overall survival were 96 (22/23), 74 (18/23), 96 (22/23) and 83% (19/23), respectively. There were no grade 3–4 side effects. No patients required dialysis during the study period. No treatment-related deaths or late complications were reported. Conclusion: SBRT appears to be a promising alternative to surgery or ablative therapy to treat primary RCC in frail patients.

A PROSPECTIVE OBSERVATIONAL STUDY TO DETERMINE RESPONSE AND QUALITY OF LIFE IN ADVANCED HEAD&NECK CANCERS FOLLOWING HYPOFRACTIONATED PALLIATIVE EXTERNAL BEAM RADIOTHERAPY.

Introduction: Squamous cell cancer of the head and neck (HNSCC) represents the sixth most common malignancy, with 6,50,000 new cases and 3,00,000 HNSCC related deaths reported annually worldwide. HNSCC constitutes approximately 90 percent of all head and neck cancers, and accounted for approximately 3 percent (about 50,000) of all new cancer cases and 2 percent (approximately 12,000) of all cancer deaths in 2010 in the United States. Overall, 57.5% of global head and neck cancers occur in Asia. Aims And Objectives: To Determine Local Control And Quality Of Life in stage III & IV Advanced HNSCC Following Hypo Fractionated Palliative Radiotherapy. To study the response with hypo fractionated external beam radio therapy treatment using RECISTcriteria (version 1.1). Materials And Methods: At the completion of treatment both the primary and the node Response was assessed as per the RECIST 1.1 Response Criteria and Quality of life with QLQ H&N 35 module. Results And Conclusion: At the completion of RT, 32.1% had CR, 50% had PR,14.3% had SD and 3.6% had PD. At 4 weeks of follow-up, 28.6% had CR, 53.6% had PR,14.3% had SD and 3.6% had PD. At 3 months of follow up 17.9% had CR, 60.7% had PR,10.7% had SD and 10.7% had PD. There is a statistically signicant improvement in distressing symptoms like pain, swallowing difculty, opening mouth difculty. This fractionation schedule allowed treatment to be completed in a short overall period with good tolerance and clinically acceptable toxicities

Radiotherapy–Immunotherapy Combination: How Will We Bridge the Gap Between Pre-Clinical Promise and Effective Clinical Delivery?

Radiotherapy (RT) is highly effective at directly killing tumor cells and plays an important part in cancer treatments being delivered to around 50% of all cancer patients. The additional immunomodulatory properties of RT have been investigated, and if exploited effectively, have the potential to further improve the efficacy of RT and cancer outcomes. The initial results of combining RT with immunomodulatory agents have generated promising data in pre-clinical studies, which has in turn led to a large number of RT and immunotherapy clinical trials. The overarching aim of these combinations is to enhance anti-tumor immune responses and improve responses rates and patient outcomes. In order to maximize this undoubted opportunity, there remain a number of important questions that need to be addressed, including: (i) the optimal RT dose and fractionation schedule; (ii) the optimal RT target volume; (iii) the optimal immuno-oncology (IO) agent(s) to partner with RT; (iv) the optimal site(s)/route(s) of administration of IO agents; and finally, the optimal RT schedule. In this review, we will summarize progress to date and identify current gaps in knowledge that need to be addressed in order to facilitate effective clinical translation of RT and IO agent combinations.