Normofractionated Radiotherapy Research Articles

Online Adaptive MR-Guided Ultrahypofractionated Radiotherapy of Prostate Cancer on a 1.5 T MR-Linac: Clinical Experience and Prospective Evaluation.

The use of hypofractionated radiotherapy in prostate cancer has been increasingly evaluated, whereas accumulated evidence demonstrates comparable oncologic outcomes and toxicity rates compared to normofractionated radiotherapy. In this prospective study, we evaluate all patients with intermediate-risk prostate cancer treated with ultrahypofractionated (UHF) MRI-guided radiotherapy on a 1.5 T MR-Linac within our department and report on workflow and feasibility, as well as physician-recorded and patient-reported longitudinal toxicity. A total of 23 patients with intermediate-risk prostate cancer treated on the 1.5 T MR-Linac with a dose of 42.7 Gy in seven fractions (seven MV step-and-shoot IMRT) were evaluated within the MRL-01 study (NCT04172753). The duration of each treatment step, choice of workflow (adapt to shape-ATS or adapt to position-ATP) and technical and/or patient-sided treatment failure were recorded for each fraction and patient. Acute and late toxicity were scored according to RTOG and CTC V4.0, as well as the use of patient-reported questionnaires. The median follow-up was 12.4 months. All patients completed the planned treatment. The mean duration of a treatment session was 38.2 min. In total, 165 radiotherapy fractions were delivered. ATS was performed in 150 fractions, 5 fractions were delivered using ATP, and 10 fractions were delivered using both ATS and ATP workflows. Severe acute bother (G3+) regarding IPS-score was reported in five patients (23%) at the end of radiotherapy. However, this tended to normalize and no G3+ IPS-score was observed later at any point during follow-up. Furthermore, no other severe genitourinary (GU) or gastrointestinal (GI) acute or late toxicity was observed. One-year biochemical-free recurrence survival was 100%. We report the excellent feasibility of UHF MR-guided radiotherapy for intermediate-risk prostate cancer patients and acceptable toxicity rates in our preliminary study. Randomized controlled studies with long-term follow-up are warranted to detect possible advantages over current state-of-the-art RT techniques.

Abstract PO5-21-03: Cosmetic assessment in the UNICANCER HypoG-01 trial: a deep learning approach

Abstract Introduction Cosmetic evaluation after breast cancer treatment is a clinical indicator of toxicity. User bias and inter-subject variability hamper this objective. To address this limitation, a deep learning approach was developed on the basis of the HYPOG-01 trial (NCT03127995), a phase III trial comparing hypo to normo-fractionated radiotherapy (RT) in breast cancer patients requiring nodal irradiation. Material and Methods Cosmetic outcomes using the Harris scale were assessed by a radiation oncologist using a 4-level rating system from excellent to poor. This evaluation involved photographs from 581 female patients included in the intention-to-treat population of the HYPOG-01 study analysis (mastectomy/pamectomy and non-usable cases excluded). Front images were taken with the arms along the body at baseline, 3-weeks after radiotherapy start, end of treatment, then 6 months and every year after randomization up to 5 years. Comparing manual landmark annotation with the semi-automated software BCCT.core©, the agreement rate was moderate, with an intra-class correlation coefficient (ICC) of 0.66 (95%CI 0.57-0.73). The dataset consisted of 2,348 images, which were divided into exclusive patient-based training (1,661), validation (308), and testing (377) datasets. The distribution of Harris scores in the dataset was highly imbalanced: 7% excellent, 33% good, 45% fair, and 15% poor. Nipple landmarks were used as landmarks to address picture acquisition variations by cropping and resizing images to 224 × 224 resolution. Feature extraction was performed using a Swin-TransformerV2, an advanced attention-based vision model initially trained on ImageNet. Newly integrated fully connected layers categorized the extracted features. The model was trained for 300 epochs, and the highest F1-score model was selected. Asymmetry in texture, marks, and breast geometry played a crucial role in Harris scoring. To improve the model's performance, we generated symmetrical images from the region of interest, averaging them with the original images, and we incorporated the timestamps from image captures as an additional influencing factor. We employed techniques such as contrast modulation, lighting adjustments, and geometric transformations to augment the dataset, introducing additional variations and enhancing the model's generalization and accuracy. Results The performance of our model was evaluated using balanced binary classification, multi-class accuracy, and F1-score. Comparatively, our model performed similarly to BCCT in terms of overall accuracy but demonstrated better performance in separating multiple classes, as indicated in Table 1. In Table 2, we present a confusion matrix that provides insights into the model's performance Conclusion The proposed solution simplifies and accelerates the evaluation process by utilizing only two nipple landmarks, surpassing manual and semi-automated tools. This advancement opens doors for automated, large-scale cosmetic toxicity evaluation. Continuous improvement and validation contribute to its robustness and reinforce its significant impact in assessing cosmetic outcomes after breast cancer treatment. Table. Evaluation of performance on the test set (only on cases with evaluation by BCCT (327 images)). Table. Confusion matrix between our predictions and the labels on the test set (only on cases with evaluation by BCCT (327 images)). Citation Format: Alexandre Cafaro, Amandine Ruffier, Gabriele Bielinyte, Youlia Kirova, Séverine Racadot, Mohamed Benchalal, Jean-Baptiste Clavier, Claire Charra-Brunaud, Marie-Eve Chand-Fouche, Delphine Argo-Leignel, Karine Peignaux, Ahmed Benyoucef, David Pasquier, Philippe Guilbert, Julien Blanchecotte, Agnès Tallet, Adeline Petit, Guillemette Bernadou, Xavier Zasadny, Claire Lemanski, Jacques Fourquet, Emmanuelle Malaurie, Honorine Kouto, Carole Massabeau, Alexandre Henni, Pauline Regnault, Aurélie Belliere, Yazid Belkacemi, Magali Le Blanc-Onfroy, Julien Geffrelot, Jean-Briac Prevost, Eleni Karamouza, Stefan Michiels, Marie Bergeaud, Assia Lamrani-Ghaouti, Sami Romdhani, Alexis Bombezin-Domino, Nikos Paragios, Sofia Rivera. Cosmetic assessment in the UNICANCER HypoG-01 trial: a deep learning approach [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-21-03.

Prognostic Value of TSPO PET Before Radiotherapy in Newly Diagnosed IDH-Wild-Type Glioblastoma.

The 18-kDa translocator protein (TSPO) is gaining recognition as a relevant target in glioblastoma imaging. However, data on the potential prognostic value of TSPO PET imaging in glioblastoma are lacking. Therefore, we investigated the association of TSPO PET imaging results with survival outcome in a homogeneous cohort of glioblastoma patients. Methods: Patients were included who had newly diagnosed, histologically confirmed isocitrate dehydrogenase (IDH)-wild-type glioblastoma with available TSPO PET before either normofractionated radiotherapy combined with temozolomide or hypofractionated radiotherapy. SUVmax on TSPO PET, TSPO binding affinity status, tumor volumes on MRI, and further clinical data, such as O 6-alkylguanine DNA methyltransferase (MGMT) and telomerase reverse transcriptase (TERT) gene promoter mutation status, were correlated with patient survival. Results: Forty-five patients (median age, 63.3 y) were included. Median SUVmax was 2.2 (range, 1.0-4.7). A TSPO PET signal was associated with survival: High uptake intensity (SUVmax > 2.2) was related to significantly shorter overall survival (OS; 8.3 vs. 17.8 mo, P = 0.037). Besides SUVmax, prognostic factors for OS were age (P = 0.046), MGMT promoter methylation status (P = 0.032), and T2-weighted MRI volume (P = 0.031). In the multivariate survival analysis, SUVmax in TSPO PET remained an independent prognostic factor for OS (P = 0.023), with a hazard ratio of 2.212 (95% CI, 1.115-4.386) for death in cases with a high TSPO PET signal (SUVmax > 2.2). Conclusion: A high TSPO PET signal before radiotherapy is associated with significantly shorter survival in patients with newly diagnosed IDH-wild-type glioblastoma. TSPO PET seems to add prognostic insights beyond established clinical parameters and might serve as an informative tool as clinicians make survival predictions for patients with glioblastoma.

OS06.5.A Investigating safety and efficacy of TTFields prior and concomitant to radiotherapy in newly diagnosed glioblastoma - the PriCoTTF phase I/II trial

Abstract Background The EF-14 phase III trial demonstrated improved survival for patients with newly diagnosed glioblastoma (nGBM) when TTFields therapy was added to adjuvant temozolomide chemotherapy. TTFields at 200 kHz are applied to the tumor utilizing arrays on the patients’ scalp. In preclinical studies, a synergistic inhibiting effect on glioblastoma cell proliferation was found for the combination of TTFields and radiotherapy. Based on these findings, we conduct the phase I/II PriCoTTF trial in adult nGBM patients to investigate the safety and efficacy of TTFields therapy initiated prior and concomitant to radiochemotherapy. Material and Methods Per study protocol, TTFields therapy is initiated following surgery and completed wound healing. Continuing throughout radiochemotherapy and adjuvant chemotherapy, TTFields therapy is used for approximately 9 months in total with TTFields rechallenge allowed at recurrence. Radiotherapy is conducted with arrays applied on the patients’ scalp. A total recruitment of 33 patients was sought, with 20 patients in arm A receiving normo-fractionated radiotherapy, and 13 elderly patients in arm B receiving hypo-fractionated radiotherapy. Safety and tolerance are the study’s primary endpoint, analyzed by a selection of pre-specified treatment-limiting toxicities (TLTs). Results A total of 33 patients have been enrolled. Patients' characteristics were mostly typical for glioblastoma, except for a rather low fraction of patients with gross total resection (GTR, 22.5%). The distribution of adverse events of common toxicity criteria (CTC) grade 3 or higher was comparable to that of established glioblastoma trials. Notably, skin toxicity of CTC grade 3 or higher was quite uncommon (n=2, 6%). As no patient developed TLTs, the study's primary endpoint was met. Median TTFields treatment duration was 8.4 months. Overall survival data was not mature enough (event rate 48%) to allow for a definite conclusion. Notably, on multivariable Cox regression, the number of days with TTFields adherence of more than 23 hours was independently associated with overall survival (HR 0.96, 95% confidence interval 0.93 - 0.99, p=0.008). Conclusion The PriCoTTF trial met its primary endpoint indicating that combined TTFields and radiotherapy is safe and well tolerated. High-grade skin toxicity was quite uncommon and the patients with high TTFields adherence seem to perform particularly well. An extended follow-up is required to provide first estimates regarding putative efficacy. At that point in time, the reduced overall TTFields duration and fraction of patients with GTR need to be factored in.

Radiothérapie des cancers du col de l'utérus de stade IVA dans le service de Radiothérapie de l'Hôpital Aristide le Dantec de Dakar

INTRODUCTION: The management of stage IVA cervical cancer is based on radio-chemotherapy followed by utero-vaginal brachytherapy. In this study, we evaluate the results of external radiotherapy on stage IVA cervical cancer. MATERIALS AND METHODS: This was a retrospective, descriptive study. It covered all patients with stage IVA carcinoma of the cervix who received external radiotherapy at the Joliot Curie Institute of the Aristide Le Dantec Hospital from January 2018 to December 2019. RESULTS: We found 164 clinical records of patients, of which 24 patients had stage IVA, (14.3% of all cases). The average age of our patients was 51 years ± 12.13. Seventeen patients (70.9%) had an altered general condition on admission. The predominant histological type was squamous cell carcinoma found in 22 cases (91.6%). Anemia was found in 14 patients, (58.4%). Neo-adjuvant chemotherapy was performed in 21 of our patients (87.5%). Radiotherapy was exclusive in 20 patients (83.3%) and concomitant radio-chemotherapy was performed in 4 patients (16.7%). Normo-fractionated radiotherapy with curative intent was performed in 13 patients (54.2%), and hypo-fractionated radiotherapy with palliative intent was performed in the other 11 patients (45.8%). An objective response was found in 17 cases (70.8%) including 8 in patients who received hypo-fractionated radiotherapy and 9 in patients treated with normo-fractionated radiotherapy at a curative dose. Five patients (20.8%) had acute toxicity and 7 (29.2%) late toxicity. After 3 years of follow-up, 5 patients (29.2%) had loco-regional progression, 9 patients (37.5%) presented loco-regional recurrence and 4 patients (16.7%) presented distant metastases. Overall survival was 26.8% at 3 years. CONCLUSION: Normo-fractionated radiotherapy does not seem superior to palliative hypo-fractionated radiotherapy in terms of clinical response in stage IVA cervical cancer. KEYWORDS: Carcinoma; Uterine cervix; External radiotherapy.

Prospective Comparison of Hypofractionated Versus Normofractionated Intensity-Modulated Radiotherapy in Breast Cancer: Late Toxicity Results of the Non-Inferiority KOSIMA Trial (ARO2010-3).

PurposeTo compare the late toxicity profile of hypofractionation and normofractionation for whole-breast radiotherapy in breast cancer (BC) patients after conserving surgery.MethodsSixty-year-old or older patients with pTis-pT3, pN0-pN1a, M0 BC were recruited and stratified to hypofractionated (arm R-HF) or normofractionated (arm L-NF) intensity-modulated radiotherapy (IMRT), for right- and left-sided BC, respectively, in this single-center, non-randomized, non-inferiority trial. A boost was allowed if indicated. The primary outcome was the cumulative percentage of patients developing grade III fibrosis, grade I telangiectasia, and/or grade II hyperpigmentation after 2 years, with a pre-specified non-inferiority margin of 15% increase from an expected 2-year toxicity rate of 20%.ResultsThe Median follow-up was 4.93 (0.57–8.65) years for R-HF and 5.02 (0.65–8.72) years for L-NF (p=0.236). The median age was 68 (60–83 and 60–80) years, respectively. In total, 226 patients were recruited (107 for R-HF and 119 for L-NF), with 100 and 117 patients suitable for assessment, respectively. A boost was delivered in 51% and 53% of each arm, respectively. Median PTV volumes were 1013.6 (273–2805) cm3 (R-HF) and 1058.28 (315–2709) cm3 (L-NF, p=0.591). The 2-year primary endpoint rate was 6.1% (95% CI 1.3-11.7, n=5 of 82) and 13.3% (95% CI 7-20.2, n=14 of 105), respectively (absolute difference -7.2%, one-sided 95% CI ∞ to -0.26, favoring R-HF). No local recurrence-free- or overall-survival differences were found.ConclusionIn this prospective non-randomized study, hypofractionation did not have higher toxicity than normofractionated whole-breast IMRT.

Favorable safety profile of moderate hypofractionated over normofractionated radiotherapy in breast cancer patients: a multicentric prospective real-life data farming analysis

BackgroundModerately hypofractionated whole-breast radiotherapy (HFRT) has proven to be as safe and efficient as normofractionated radiotherapy (NFRT) in randomized trials resulting in major changes in clinical practice. Toxicity rates observed in selected clinical trial patients may differ from those observed in unselected patients with possible comorbidities and frailty in real-life. This study aimed to examine the influence of HFRT versus NFRT on acute toxicity and identify risks factors of dermatitis in real-life patients.Materials and methodsProspective data from breast cancer patients, treated with locoregional radiotherapy were collected between November 2015 and February 2020 in 3 comprehensive cancer centers. Through a systematic data-farming strategy, acute toxicity evaluation forms (CTCAEv4.0) were prospectively completed and extracted electronically. The results from each center were then anonymously merged into a single database for analysis. A Chi-2 test was used to compare HFRT and NFRT. Furthermore, risk factors of dermatitis were identified in a sub-study (622 patients) by multivariate logistic regression analysis.ResultsIn total, 3518 T0-4 N0-3 mostly M0 (85.8%) breast cancer patients with a median age of 60.7 (24–96 years old) were analyzed. Acute grade 2–3 dermatitis, grade 1–3 breast oedema, and grade 1–2 hyperpigmentation were less frequent with HFRT versus NFRT: respectively 8.9% versus 35.1% (Chi-2 = 373.7; p < 0.001), 29.0% versus 37.0% (Chi-2 = 23.1; p < 0.001) and 27.0% versus 55.8% (Chi-2 = 279.2; p < 0.001). Fewer patients experienced pain with HFRT versus NFRT: 33.4% versus 53.7% respectively (Chi-2 = 137.1; p < 0.001). Factors such as high BMI (OR = 2.30 [95% CI, 1.28–4.26], p < 0.01), large breast size (OR = 1.88 [95% CI, 1.07–3.28], p < 0.01) and lumpectomy over mastectomy (OR = 0.52 [95% CI, 0.27–0.97], p < 0.05) were associated with greater risk factors of grade 2–3 dermatitis in multivariate analysis regardless of NFRT or HFRT.ConclusionThe results of this study suggests that breast HFRT may be a better option even for patients with a high BMI or large breast size. Acute toxicity was low to mild, and lower with HFRT compared to NFRT. Results from real-life data were robust, and support the use of HFRT beyond randomized study populations. Long-term real-life data awaits further investigation.

Optimizing Postoperative Adjuvant Therapy in Elderly Patients with Newly Diagnosed Glioblastoma: Single-Institution Audit of Clinical Outcomes from a Tertiary-Care Comprehensive Cancer Center in India

There is lack of consensus regarding optimal adjuvant therapy in elderly glioblastoma (GBM). We have been treating elderly (≥60 years) GBM patients with normofractionated or hypofractionated radiotherapy (RT) plus temozolomide (TMZ) based on Karnofsky performance status (KPS). Herein we report clinical outcomes in this cohort treated at our institute using this approach. Medical records of elderly GBM patients (≥60 years) treated between 2013 and 2017 with either normofractionated RT (59.4-60 Gy/30-33 fractions/6-6.5 weeks) or hypofractionated RT (35 Gy/10 fractions/2 weeks) plus TMZ were reviewed retrospectively. Outcomes of interest included progression-free survival (PFS), overall survival (OS), and ≥grade 3 myelotoxicity. Time-to-event outcomes were analyzed with Kaplan-Meier methods, compared using log-rank test, and reported as point estimates with 95% confidence interval (CI). The normofractionated cohort (n= 126) was characterized by a higher proportion of patients younger than age 65 years, KPS ≥70, methylated O6-methylguanine DNA methyltransferase (MGMT), and receiving adjuvant TMZ including extended adjuvant TMZ (>6 cycles) compared with the hypofractionated cohort (n= 20), confirming selection bias. At a median follow-up of 13 months, 1-year Kaplan-Meier estimates of PFS and OS were 43% (95% CI: 36%-52%) and 56% (95% CI: 48%-64%), yielding median PFS and OS of 11.0 months and 13.1 months, respectively. Higher KPS, methylated MGMT, normofractionated RT, and extended adjuvant TMZ emerged as favorable prognostic factors. TMZ was well tolerated with a low risk of ≥grade 3 myelotoxicity. Our single-institution clinical audit confirms poor survival in elderly GBM with suboptimal performance status but demonstrates acceptably fair outcomes in patients with preserved KPS comparable with the nonelderly cohort.

Accelerated hyper-versus normofractionated radiochemotherapy with temozolomide in patients with glioblastoma: a multicenter retrospective analysis

Background and purposeThe standard treatment of glioblastoma patients consists of surgery followed by normofractionated radiotherapy (NFRT) with concomitant and adjuvant temozolomide chemotherapy. Whether accelerated hyperfractionated radiotherapy (HFRT) yields comparable results to NFRT in combination with temozolomide has only sparsely been investigated. The objective of this study was to compare NFRT with HFRT in a multicenter analysis.Materials and methodsA total of 484 glioblastoma patients from four centers were retrospectively pooled and analyzed. Three-hundred-ten and 174 patients had been treated with NFRT (30 × 1.8 Gy or 30 × 2 Gy) and HFRT (37 × 1.6 Gy or 30 × 1.8 Gy twice/day), respectively. The primary outcome of interest was overall survival (OS) which was correlated with patient-, tumor- and treatment-related variables via univariable and multivariable Cox frailty models. For multivariable modeling, missing covariates were imputed using multiple imputation by chained equations, and a sensitivity analysis was performed on the complete-cases-only dataset.ResultsAfter a median follow-up of 15.7 months (range 0.8–88.6 months), median OS was 16.9 months (15.0–18.7 months) in the NFRT group and 14.9 months (13.2–17.3 months) in the HFRT group (p = 0.26). In multivariable frailty regression, better performance status, gross-total versus not gross-total resection, MGMT hypermethylation, IDH mutation, smaller planning target volume and salvage therapy were significantly associated with longer OS (all p < 0.01). Treatment differences (HFRT versus NFRT) had no significant effect on OS in either univariable or multivariable analysis.ConclusionsSince HFRT with temozolomide was not associated with worse OS, we assume HFRT to be a potential option for patients wishing to shorten their treatment time.

A Comprehensive Prospective Comparison of Acute Skin Toxicity after Hypofractionated and Normofractionated Radiation Therapy in Breast Cancer.

The current study aims to determine whether hypofractionated radiotherapy (HF) leads to lower rates of acute radiodermatitis compared to conventional normofractionated radiotherapy (CF). A total of 166 patients with invasive breast cancer or DCIS were included in a prospective cohort study. Evaluation of acute radiodermatitis was obtained before radiotherapy, at the end of the treatment (T1), and 6 weeks after the treatment (T2) using CTCAE (v5.0) scores, the Skindex-16 questionnaire, and ultrasound measurement of the skin. CTCAE and Skindex-16 scores in the CF-group were significantly higher compared to the HF group indicating more pronounced side effects at the end of the treatment (CTCAE: CF-RT 1.0 (IQR: 0.0) vs. HF-RT 0.0 (0.25); p = 0.03; Skindex-16: CF: 20.8 (IQR: 25.8); HF: 8.3 (27.1); p = 0.04). At 6 weeks after the treatment, no significant differences between the two fractionation schemes were observed. Ultrasound based assessment showed that the skin thickness in the treated breast was higher compared to the healthy breast at all time-points. However, no significant difference between HF and CF was seen either at T1 or T2. The current study complements and confirms pre-existing evidence that HF leads to a lower degree of acute radiodermatitis and better patient reported outcome compared to CF at the end of treatment. This should be considered whenever fractionation of adjuvant breast cancer treatment is being discussed.

CTNI-38. PriCoTTF TRIAL: A PHASE I/II TRIAL OF TTFIELDS PRIOR AND CONCOMITANT TO RADIOTHERAPY IN NEWLY DIAGNOSED GLIOBLASTOMA

Abstract TTFields therapy is applied at 200 kHz by arrays that are placed at the patients’ scalp. In the phase 3 EF-14 trial, survival rates were significantly improved when adding tumor-treating fields (TTFields) to adjuvant temozolomide-based chemotherapy in patients with newly diagnosed glioblastoma (nGBM). Preclinical studies showed that combination of TTFields and radiotherapy synergistically impaired glioblastoma cell growth. Here, we present the PriCoTTF trial, which is enrolling nGBM patients and will assess the safety and efficacy of TTFields initiated prior and concomitant to radiochemotherapy. Following surgery and wound-healing, TTFields therapy is initiated in adult nGBM patients. TTFields therapy continues throughout radiochemotherapy and adjuvant chemotherapy for a total of approximately 9 months. During radiotherapy, the arrays - through which TTFields is delivered - remain on the patients’ scalp. Totally, thirty-three patients are planned to be enrolled in two treatment arms. In arm A, 20 patients receive normo-fractionated radiotherapy, whereas in the elderly arm, arm B, 13 patients receive hypo-fractionated radiotherapy. The primary endpoint of this trial is safety and tolerance that will be gauged by a set of pre-specified treatment-limiting toxicities. Secondary endpoints include the frequency of adverse events, progression-free survival (PFS), and overall survival (OS). The trial is currently enrolling patients at four sites in Germany. At the time of abstract submission, 9 patients enrolled in Arm B. Patient recruitment for arm A has been completed with. We will present initial practical experiences as well as preliminary safety and tolerance data. There is a biological rationale for combining TTFields and radiotherapy to further improve survival of GBM patients. In the presented phase I/II trial, the safety and efficacy of TTFields initiated prior and concomitant to RT in nGBM will be assessed. In addition, initial efficacy data (phase II) may serve as a rationale for a putative randomized phase III trial.

P14.64 PriCoTTF Trial: A phase I/II trial of TTFields prior and concomitant to radiotherapy in newly diagnosed glioblastoma

Abstract BACKGROUND TTFields therapy is applied at 200 kHz by arrays that are placed at the patients’ scalp. In the phase 3 EF-14 trial, survival rates were significantly improved when adding tumor-treating fields (TTFields) to adjuvant temozolomide-based chemotherapy in patients with newly diagnosed glioblastoma (nGBM). In preclinical studies, the combination of TTFields and radiotherapy synergistically impaired proliferation and growth of glioblastoma cells. Here, we present the PriCoTTF trial, which is enrolling nGBM patients and will assess the safety and efficacy of TTFields initiated prior and concomitant to radiochemotherapy. MATERIAL AND METHODS Following surgery and complete wound-healing, TTFields therapy is initiated in adult nGBM patients. TTFields therapy continues throughout radiochemotherapy and adjuvant chemotherapy for a total of approximately 9 months. During radiotherapy, the arrays - through which TTFields is delivered - remain on the patients’ scalp. Totally, thirty-three patients are planned to be enrolled in two treatment arms. In arm A, 20 patients receive normo-fractionated radiotherapy, whereas in the elderly arm, arm B, 13 patients receive hypo-fractionated radiotherapy. Concomitant and adjuvant chemotherapy follow institutional standards and interdisciplinary tumor conference recommendations. RESULTS The primary endpoint of this trial is safety and tolerance that will be gauged by a set of pre-specified treatment-limiting toxicities. Secondary endpoints include the frequency of adverse events, progression-free survival (PFS), and overall survival (OS). The trial is currently enrolling patients at four sites in Germany. At the time of abstract submission, 9 patients enrolled in Arm B. Patient recruitment for arm A has been completed with 20 patients enrolled. We will present initial practical experiences as well as preliminary safety and tolerance data. CONCLUSION There is a biological rationale for combining TTFields and radiotherapy to further improve survival of GBM patients. In the presented phase I/II trial, the safety and efficacy of TTFields initiated prior and concomitant to RT in nGBM will be assessed. In addition, initial efficacy data (phase II) may serve as a rationale for a putative randomized phase III trial.

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

PurposeVarious 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.MethodsA 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.ResultsFourteen 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.ConclusionAlthough 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.

Radiotherapy planning parameters correlate with changes in the peripheral immune status of patients undergoing curative radiotherapy for localized prostate cancer

PurposeThe influence of radiotherapy on patient immune cell subsets has been established by several groups. Following a previously published analysis of immune changes during and after curative radiotherapy for prostate cancer, this analysis focused on describing correlations of changes of immune cell subsets with radiation treatment parameters.Patients and methodsFor 13 patients treated in a prospective trial with radiotherapy to the prostate region (primary analysis) and five patients treated with radiotherapy to prostate and pelvic nodal regions (exploratory analysis), already published immune monitoring data were correlated with clinical data as well as radiation planning parameters such as clinical target volume (CTV) and volumes receiving 20 Gy (V20) for newly contoured volumes of pelvic blood vessels and bone marrow.ResultsMost significant changes among immune cell subsets were observed at the end of radiotherapy. In contrast, correlations of age and CD8+ subsets (effector and memory cells) were observed early during and 3 months after radiotherapy. Ratios of T cells and T cell proliferation compared to baseline correlated with CTV. Early changes in regulatory T cells (Treg cells) and CD8+ effector T cells correlated with V20 of blood vessels and bone volumes.ConclusionsPatient age as well as radiotherapy planning parameters correlated with immune changes during radiotherapy. Larger irradiated volumes seem to correlate with early suppression of anti-cancer immunity. For immune cell analysis during normofractionated radiotherapy and correlations with treatment planning parameters, different time points should be looked at in future projects.Trial registration number:NCT01376674, 20.06.2011

Evaluation of practical experiences of German speaking radiation oncologists in combining radiation therapy with checkpoint blockade

The results of this survey reveal current clinical practice in the handling of combined radioimmunotherapy with Immune Checkpoint Inhibitors (RT + ICI). We aim to provide a basis to open a discussion for clinical application of RT + ICI by analyzation of experts’ assessment. We conducted a survey with 24 items with a focus on side effects of RT + ICI, common practice of scheduling and handling of adverse events. After pilot testing by radiation oncology experts the link to the online survey was sent to all members of the German Society of Radiation Oncology (DEGRO). In total, 51 radiation oncologists completed the questionnaire. Pulmonary toxicity under RT + ICI with ICIs was reported most frequently. Consensus was observed for bone and soft tissue RT of the limbs in favor for no interruption of ICIs. For cranial RT half of the participants do not suspend ICIs during normofractionated radiotherapy (nfRT) or stereotactic hypofractionated RT (SRT). More participants pause ICIs for central than for peripheral thoracic region. Maintenance therapy with ICIs is mostly not interrupted prior to RT. For management of RT associated pneumonitis under durvalumab the majority of 86.3% suggest corticosteroid therapy and 76.5% would postpone the next cycle of ICI therapy. The here obtained assessment and experiences by radiation oncologists reveal a large variability in practical handling of combined RT + ICI. Until scientific evidence is available a discussion for current clinical application of RT + ICI should be triggered. Interdisciplinary consensus guidelines with practical recommendations are required.

Radiothérapie et toxicité médullaire : actualités et perspectives

Radiation-induced myelopathy is a devastating late effect of radiotherapy. Fortunately, this late effect is exceptional. The clinical presentation of radiation myelopathy is aspecific, typically occurring between 6 to 24 months after radiotherapy, and radiation-induced myelopathy remains a diagnosis of exclusion. Magnetic resonance imaging is the most commonly used imaging tool. Radiation oncologists must be extremely cautious to the spinal cord dose, particularly in stereotactic radiotherapy and reirradiation. Conventionally, a maximum dose of 50Gy is tolerated in normofractionated radiotherapy (1.8 to 2Gy per fraction). Repeat radiotherapies lead to consider cumulative doses above this recommendation to offer individualized reirradiation. Several factors increase the risk of radiation-induced myelopathy, such as concomitant or neurotoxic chemotherapy. The development of predictive algorithms to prevent the risk of radiation-induced myelopathy is promising. However, radiotherapy prescription should be cautious, regarding to ALARA principle (as low as reasonably achievable). As the advent of immunotherapy has improved patient survival data and the concept of oligometastatic cancer is increasing in daily practice, stereotactic treatments and reirradiations will be increasingly frequent indications. Predict the risk of radiation-induced myelopathy is therefore a major issue in the following years, and remains a daily challenge for radiation oncologists.

CTNI-79. PRICOTTF TRIAL: A PHASE I/II TRIAL OF TTFIELDS PRIOR AND CONCOMITANT TO RADIOTHERAPY IN NEWLY DIAGNOSED GLIOBLASTOMA

Abstract OBJECTIVE Survival rates were significantly improved when adding TTFields to adjuvant chemotherapy with temozolomide in patients with newly diagnosed glioblastoma (nGBM) in the phase 3 EF-14 trial. TTFields therapy is applied at 200 kHz by arrays that are placed at the patients’ scalp. In preclinical studies, the combination of TTFields and radiotherapy demonstrated synergistically enhanced efficacy in GBM cells. Here, we present the PriCoTTF trial, which is currently enrolling nGBM patients and will assess the safety and efficacy of TTFields initiated prior and concomitant to radiochemotherapy. METHODS After surgery and complete wound-healing, TTFields therapy will be initiated in newly diagnosed GBM patients. TTFields therapy will continue throughout radiochemotherapy and adjuvant chemotherapy for a total of approximately 9 months. Radiotherapy will be conducted through the arrays, by which TTFields therapy is delivered. Totally, thirty-three patients will be enrolled in two arms. In arm A, 20 adult patients will be enrolled to receive normo-fractionated radiotherapy and in arm B, 13 elderly patients will be treated by hypo-fractionated radiotherapy. The patients will receive chemotherapy according to institutional standard and interdisciplinary tumor conference. RESULTS Safety and tolerance based on the frequency of pre-specified treatment-limiting toxicities is defined as primary endpoint of the trial. Secondary endpoints include the frequency of adverse events, progression-free survival (PFS), and overall survival (OS). The trial is currently enrolling patients at four sites in Germany. To date, 13 patients were included (May 2020). Initial practical experiences will be presented. CONCLUSION The combination of TTFields and radiotherapy is an encouraging approach to further improve survival of GBM patients. In the presented phase I/II trial, the safety and efficacy of TTFields initiated prior and concomitant to RT in newly diagnosed GBM will be assessed. In addition, initial efficacy data (phase II) can serve as a rationale for a randomized phase III trial.

Hypofractionated Radiotherapy for Anaplastic Thyroid Cancer: Systematic Review and Pooled Analysis.

Simple SummaryAnaplastic thyroid carcinoma is an aggressive cancer subtype with a dismal prognosis. Multimodal treatment approaches consisting of surgical resection, radiation therapy (RT) and chemotherapy have resulted in longer overall survival and promising outcomes. Hypofractionated RT is an alternative to conventional RT regimens. In this study, we aim to evaluate the outcome of hypofractionated regimens, perform a systematic review concerning hypofractionated RT and pooled analysis of this treatment modality. Hypofractionated RT appears to be non-inferior compared to conventional RT concerning OS after propensity score matching. In addition, radiation dose escalation correlated with a longer OS. In conclusion, hypofractionated RT is effective with manageable toxicity and could be an integral part in multimodal treatment.Anaplastic thyroid carcinoma (ATC) is associated with a poor prognosis due to aggressive tumor growth and high treatment resistance. Hypofractionated treatment concepts may be more effective and less time consuming compared to normofractionated radiotherapy (RT). In this retrospective study, we aim to evaluate the outcome of hypofractionated regimens and perform a systematic review concerning hypofractionated RT and pooled analysis of this treatment modality. A systematic review using the MEDLINE/Pubmed and Cochrane databases was performed. Data from all eligible studies were extracted, and a pooled analysis of literature and our cohort (n = 60) was carried out to examine patient characteristics, toxicity, and outcomes of patients with ATC. As a result, median overall survival (OS) of the single center cohort was four (range 1–12) months. Survival rates at one, three, and six months were 82%, 55%, and 36%, respectively. In univariate analyses, multimodal treatment (p = 0.006) and gender (p = 0.04) were correlated with an improved OS. Six studies with a total number of 152 patients undergoing hypofractionated RT treatment were analyzed. The pooled analysis included four patient cohorts with 60 patients and showed median OS of 5.3 (range: 1–24) months. Multimodal treatment (p < 0.001) and a cumulative radiation dose ≥50 Gy in equivalent dose in 2 Gy fractions (EQD2) (p = 0.014) correlated with an improved OS. On multivariate analysis, multimodal treatment (p = 0.003, hazard ratio (HR): 0.636, 95% confidence interval (CI): 0.469–0.861) was an independent predictor for longer OS. After propensity score matching (PSM), hypofractionated RT appears to be non-inferior compared to normofractionated RT concerning OS. In conclusion, hypofractionated RT is effective with manageable toxicity. A dose escalation with ≥50 Gy (EQD2) correlated with a longer OS. Hypofractionated RT could be an integral part in multimodal treatment with a promising outcome.

Abstract OT2-03-01: A phase one trial of olaparib with radiation therapy in patients with triple negative breast cancer: RADIOPARP

Abstract Background Preclinical studies have shown that breast cancer (BC) cell lines with a triple-negative phenotype are more sensitive to PARP1 inhibitors compared with non-TNBC cells. All these lines of evidence provide a strong rationale for developing a new therapeutic approach to TNBC based on targeting the DNA-repair defects via PARP inhibition in TNBC. Research hypothesis for patients with inoperable TNBC, there is a lack of systemic therapy to combine with radiotherapy (RT) in order to control the loco-regional disease. For patients with TNBC operated with residual disease (after neoadjuvant chemotherapy), a new strategy with postoperative RT in combination with new drugs could improve loco regional outcome. Rational for the study is the radiosensitization by olaparib in TNBC. The aim of the proposed phase I study is to determine the Maximal Tolerated Dose (MTD) of olaparib monotherapy administered with concurrent loco regional radiotherapy in patients who have TNBC inoperable after neoadjuvant chemotherapy or with residual disease after surgery. Primary objective: To determine the Maximal Tolerated Dose (MTD) of olaparib administered with concurrent RT in patients with TNBC. Secondary objectives • To assess the safety profile of concurrent olaparib-RT; evaluate efficacy profile and patient outcome, explore biomarkers of concurrent olaparib-RT activity. Study Overview: olaparib (orally, tablets) is administered at a starting dose of 50 mg bid. The other dose levels are: 50mg-100 mg - 150 mg-200 mg bid. Seven days prior to their first fraction of RT, patients will start olaparib at the assigned dose twice daily each day. All patients will receive RT on day 8 after the start of olaparib as following: normofractionated radiotherapy to whole breast or chest wall with or without the lymph node areas (LN). Patients will be assigned to olaparib one week before RT and during breast radiation (5 to 6 weeks). Total treatment duration will be: 6 to 7 weeks. Eligibility Women aged &amp;gt;18 years. With histologically confirmed TNBC with indication for pre or post-operative or exclusive RT; ECOG &amp;lt;2; Life expectancy &amp;gt; 6 months; Adequate hematologic, renal and hepatic function; Urine or serum negative pregnancy test; Ability to swallow and retain oral medications and affiliated to the French Social Security System. Sample size and Analysis: Phase I dose-finding based on toxicity will be conducted in a sequential and adaptive Bayesian scheme, using the method of Time-to-event Continual Reassessment Method to determine the Maximum Tolerated Dose (MTD) of olaparib associated with radiotherapy. The primary endpoint is Dose-Limiting Toxicity (DLT) occurring within 4-6 weeks after the end of the radiotherapy (12 or 13 weeks from the first drug intake, depending on the period of RT length). Dose allocation will be centrally defined, based on DLT observed in all patients previously evaluated, by modeling the probability of DLT. An empiric model will be used for the dose-toxicity relationship. No intra-patient dose-escalation is permitted. The MTD is defined as the dose associated with 25% of DLT. Four dose levels are considered as previously described. Cohort of size 3 is used with the TITE-CRM design. So, three patients will be included at the first dose level (50mg bid daily). At least three patients fully observed are required at a given dose level before dose escalation following the TITE-CRM method. Every new patient will be treated at the best current recommended dose proceed (50mg bid, 100mg bid, 150mg bid and 200mg bid daily), i.e. the dose associated with an estimated level of toxicity that is judged acceptable (25% DLT). Twenty-four to 30 patients are expected to be enrolled. Contact: youlia.kirova@curie.fr Acknowledgements: AstraZeneca for their support Citation Format: Youlia M. Kirova, Delphine Loirat, Frederique Berger, Manuel Rodrigues, Louis Bazire, Anne Chilles, Jean Yves Pierga, Francesco Ricci, Marie Paule Sablin, Anne Vincent Salomon, Fatima Laki, Claire Bertrand, Cyrine Ezzili, Laurence Raizoville, Veronique Mosseri, Souhir Neffati, Monia Ezzalfani, Alain Fourquet. A phase one trial of olaparib with radiation therapy in patients with triple negative breast cancer: RADIOPARP [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT2-03-01.

Optimal adjuvant therapy in elderly glioblastoma: results from a systematic review and network meta-analysis.

There exists lack of consensus worldwide regarding the most optimal adjuvant therapy regimen in elderly patients with newly-diagnosed glioblastoma (GBM). To identify the most optimal adjuvant therapy regimen in elderly GBM patients through systematic review and network meta-analysis. Prospective trials randomly assigning elderly GBM patients post-operatively to any adjuvant therapy regimen were included. The primary outcome measure was overall survival. Numbers of events, patients at-risk, and censored patients for survival were estimated from Kaplan-Meier survival curves in the interval of 0-12months. The total person-time at risk and the mortality × 100 person-months was also estimated. The relative ranking probability of each treatment and rankograms were used to estimate the hierarchy of each intervention in terms of overall survival. The mean rank values and the surface under the cumulative ranking (SUCRA) curves were also calculated. A systematic literature search identified 1278 abstracts, that were screened to retrieve full-text manuscripts of potentially eligible articles. After detailed assessment, data from 1569 patients in 7 randomized controlled trials (RCTs) treated with one of following regimens was extracted and analyzed: normofractionated radiotherapy (RT) delivered over 5.5-6weeks; moderately hypofractionated RT (2-3weeks) either alone or in combination with temozolomide or bevacizumab; extremely hypofractionated RT (1-week); temozolomide monotherapy; and best supportive care alone. In terms of overall survival, moderately hypofractionated RT (3-weeks) with concurrent and adjuvant temozolomide emerged as the best and second-best adjuvant therapy option with 81% probability and 99.1% probability respectively. Using SUCRA, the surface area for moderately hypofractionated RT (3-weeks) with concurrent and adjuvant temozolomide reached almost 100%, confirming it as the best intervention. As expected, best supportive care alone was ranked as the worst treatment strategy. Moderately hypofractionated RT (3-weeks) with concurrent and adjuvant temozolomide is the most optimal and preferred adjuvant therapeutic regimen in elderly GBM.