[Clinical research in radiation oncology]. / La recherche clinique en oncologie-radiothérapie : acquis et perspectives.

Clinical research is summarizing scientific trials performed in human aiming to improve biological and medical knowledges. The management of such an activity has to be conducted in a secured environment in terms of expertise, competency and professionalism of involved actors. In the field of cancer, multidisciplinarity is key in the treatment of malignant disease and plays a major role sequentially or concomitantly. In the 90s, clinical research in radiation oncology obtained historical successes, which remain validated guidelines for national societies in a significant number of clinical situations. They concern not only technological improvements but also combined modality treatments with chemotherapy, hormonal therapy and potentially new targeted agents. Radiotherapy, in a palliative or in a curative setting, benefited from dramatic technological improvements aiming to address patient quality of life after radiation therapy. Actually, the emergence of artificial intelligence is willing to modify our current practice historically based on old concepts of clinical evaluation.

La recherche clinique correspond aux études scientifiques réalisées sur la personne humaine en vue du développement des connaissances biologiques et médicales. Sa conduite doit désormais être assurée dans des environnements garantissant l'expertise, la compétence et le professionnalisme des acteurs impliqués. Dans le traitement du cancer, la pluridisciplinarité, garante de la meilleure prise en charge des tumeurs malignes, fait intervenir, de manière séquentielle ou concomitante, de nombreuses spécialités. La recherche clinique en oncologie-radiothérapie a permis d'obtenir des acquis historiques qui restent, dans leur grande majorité, des référentiels de la prise en charge de la maladie reconnus par les sociétés nationales. Elles portent sur la validation des acquis technologiques, mais également sur des associations avec la chimiothérapie, l'hormonothérapie et, demain, les nouveaux agents de thérapie ciblée. La radiothérapie à visée palliative ou curative a considérablement bénéficié des évolutions technologiques et informatiques pour améliorer la qualité de vie des patients après traitement. L'émergence de l'intelligence artificielle permet d'envisager d'améliorer les pratiques basées sur une appréciation du bénéfice-risque. On peut espérer que l'intelligence artificielle devienne supérieure à l'appréciation clinique établie sur les anciens critères retenus au cours de l'histoire.

Vulvar Carcinoma: Standard of Care and Perspectives.

PURPOSE: Treatment of vulvar carcinoma (VC) is challenging. The objectives of this review were to describe for clinicians the epidemiologic and clinical aspects of VC, the standard of care in terms of primary local treatment and systemic therapies, and the recent innovations and perspectives emerging from translational research in immuno-oncology. DESIGN: We conducted a comprehensive review outlying the clinical aspects and biologic background of vulvar cancer, highlighting modern treatment strategies on the basis of a personalized approach. RESULTS: Epidemiologic data showed a recent rise in incidence of VC, attributed to human papillomavirus. Surgery is the mainstay of primary treatment, but multimodal approaches are frequently required in the presence of adverse prognosis histopathologic factors. Chemoradiation is indicated when organ-sparing surgery is not feasible. However, inability to achieve high locoregional control rates in advanced cases and the morbidity associated with local treatments are still key issues. Recent clinical data showed the benefit of individualized strategies combining organ-sparing surgical strategies, less invasive lymph node staging procedures, and refinement in radiotherapy modalities. Among the most important research area, there is a sound rationale for testing modern systemic approaches such as immune checkpoint inhibitors in selected patients with recurrent and/or metastatic tumors. Although no specific data exist for VC, the role of supportive care and post-treatment rehabilitation strategies is also crucial. CONCLUSION: There are still insufficient studies dedicated to patients with VC. Public health programs for prevention, screening, and early diagnosis are required, and clinical research should be strengthened to provide high-quality clinical evidence and improve patients' oncologic and functional outcomes.

A multi-centric evaluation of self-learning GAN based pseudo-CT generation software for low field pelvic magnetic resonance imaging.

Purpose/objectives: An artificial intelligence-based pseudo-CT from low-field MR images is proposed and clinically evaluated to unlock the full potential of MRI-guided adaptive radiotherapy for pelvic cancer care. Materials and method: In collaboration with TheraPanacea (TheraPanacea, Paris, France) a pseudo-CT AI-model was generated using end-to-end ensembled self-supervised GANs endowed with cycle consistency using data from 350 pairs of weakly aligned data of pelvis planning CTs and TrueFisp-(0.35T)MRIs. The image accuracy of the generated pCT were evaluated using a retrospective cohort involving 20 test cases coming from eight different institutions (US: 2, EU: 5, AS: 1) and different CT vendors. Reconstruction performance was assessed using the organs at risk used for treatment. Concerning the dosimetric evaluation, twenty-nine prostate cancer patients treated on the low field MR-Linac (ViewRay) at Montpellier Cancer Institute were selected. Planning CTs were non-rigidly registered to the MRIs for each patient. Treatment plans were optimized on the planning CT with a clinical TPS fulfilling all clinical criteria and recalculated on the warped CT (wCT) and the pCT. Three different algorithms were used: AAA, AcurosXB and MonteCarlo. Dose distributions were compared using the global gamma passing rates and dose metrics. Results: The observed average scaled (between maximum and minimum HU values of the CT) difference between the pCT and the planning CT was 33.20 with significant discrepancies across organs. Femoral heads were the most reliably reconstructed (4.51 and 4.77) while anal canal and rectum were the less precise ones (63.08 and 53.13). Mean gamma passing rates for 1%1mm, 2%/2mm, and 3%/3mm tolerance criteria and 10% threshold were greater than 96%, 99% and 99%, respectively, regardless the algorithm used. Dose metrics analysis showed a good agreement between the pCT and the wCT. The mean relative difference were within 1% for the target volumes (CTV and PTV) and 2% for the OARs. Conclusion: This study demonstrated the feasibility of generating clinically acceptable an artificial intelligence-based pseudo CT for low field MR in pelvis with consistent image accuracy and dosimetric results.

A Multicenter Phase 2 Study of Ultrahypofractionated Stereotactic Boost After External Beam Radiotherapy in Intermediate-risk Prostate Carcinoma: A Very Long-term Analysis of the CKNO-PRO Trial.

Background: Genitourinary (GU) or gastrointestinal (GI) complications and tumor relapse can occur in the long term after radiotherapy for prostate cancer. Objective: To assess the late tolerance and relapse-free survival (RFS) in patients undergoing hypofractionated stereotactic boost therapy after external beam radiotherapy (EBRT) for intermediate-risk prostate cancer. Design setting and participants: Seventy-six patients with intermediate-risk prostate carcinoma between August 2010 and April 2013 were included. The first course delivered a dose of 46 Gy by conventional fractionation; the second course was a boost of 18 Gy (3 × 6 Gy) within 10 d. Outcome measurements and statistical analysis: GU and GI toxicities were evaluated as the primary outcomes. The secondary outcomes were overall survival and RFS. The cumulative incidence of toxicity was calculated using a competing-risk approach. Overall survival and RFS were estimated using the Kaplan-Meier method. Results and limitations: The median follow-up period was 88 mo (range, 81-99 mo). Sixty (79%) patients were treated with the CyberKnife and 16 (21%) using a linear accelerator. The cumulative incidences of GU and GI grade ≥2 toxicities at 120 mo were 1.4% (95% confidence interval [CI]: 0.1-6.6%) and 11.0% (95% CI: 5.1-19.4%), respectively. The overall survival and RFS rates at 8 yr were 89.1% (95% CI: 77-95%) and 76.9% (95% CI: 63.1-86.1), respectively. Conclusions: A very long follow-up showed low GU and GI toxicities after a hypofractionated stereotactic boost after EBRT for intermediate-risk prostate cancer. Dose escalation of the boost delivered by hypofractionated radiation therapy appears safe for use in future trials. Patient summary: We found low toxicity and good survival rates after a short and high-precision boost after external beam radiotherapy for intermediate-risk prostate cancer, with a long-term follow-up of 88 mo. This long-term treatment is safe and should be considered in future trials.

Biochemical Recurrence Surrogacy for Clinical Outcomes After Radiotherapy for Adenocarcinoma of the Prostate.

PURPOSE: The surrogacy of biochemical recurrence (BCR) for overall survival (OS) in localized prostate cancer remains controversial. Herein, we evaluate the surrogacy of BCR using different surrogacy analytic methods. MATERIALS AND METHODS: Individual patient data from 11 trials evaluating radiotherapy dose escalation, androgen deprivation therapy (ADT) use, and ADT prolongation were obtained. Surrogate candidacy was assessed using the Prentice criteria (including landmark analyses) and the two-stage meta-analytic approach (estimating Kendall's tau and the R2). Biochemical recurrence-free survival (BCRFS, time from random assignment to BCR or any death) and time to BCR (TTBCR, time from random assignment to BCR or cancer-specific deaths censoring for noncancer-related deaths) were assessed. RESULTS: Overall, 10,741 patients were included. Dose escalation, addition of short-term ADT, and prolongation of ADT duration significantly improved BCR (hazard ratio [HR], 0.71 [95% CI, 0.63 to 0.79]; HR, 0.53 [95% CI, 0.48 to 0.59]; and HR, 0.54 [95% CI, 0.48 to 0.61], respectively). Adding short-term ADT (HR, 0.91 [95% CI, 0.84 to 0.99]) and prolonging ADT (HR, 0.86 [95% CI, 0.78 to 0.94]) significantly improved OS, whereas dose escalation did not (HR, 0.98 [95% CI, 0.87 to 1.11]). BCR at 48 months was associated with inferior OS in all three groups (HR, 2.46 [95% CI, 2.08 to 2.92]; HR, 1.51 [95% CI, 1.35 to 1.70]; and HR, 2.31 [95% CI, 2.04 to 2.61], respectively). However, after adjusting for BCR at 48 months, there was no significant treatment effect on OS (HR, 1.10 [95% CI, 0.96 to 1.27]; HR, 0.96 [95% CI, 0.87 to 1.06] and 1.00 [95% CI, 0.90 to 1.12], respectively). The patient-level correlation (Kendall's tau) for BCRFS and OS ranged between 0.59 and 0.69, and that for TTBCR and OS ranged between 0.23 and 0.41. The R2 values for trial-level correlation of the treatment effect on BCRFS and TTBCR with that on OS were 0.563 and 0.160, respectively. CONCLUSION: BCRFS and TTBCR are prognostic but failed to satisfy all surrogacy criteria. Strength of correlation was greater when noncancer-related deaths were considered events.

Strategy for Oligometastatic Recurrence of Cardia Adenocarcinoma: Liver Radiofrequency Ablation Associated with PIPAC Inducing Response Permitting Cytoreductive Surgery and HIPEC.

Management of oligometastatic disease (OMD) in esophagogastric junction cancer is complex due to anatomical location and adenocarcinoma pathway. Specific curative strategy is mandatory to increase survival. A multimodal approach combining surgery, systemic and peritoneal chemotherapy, radiotherapy, and radiofrequency could be envisaged. We report a strategy proposed for a 61-year-old male with cardia adenocarcinoma, initially treated with chemotherapy and superior polar esogastrectomy. He developed at later stage an OMD with peritoneal metastasis, single liver metastasis, and single lung metastasis. Considering that peritoneal metastases were unresectable at first, he was given multiple Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) with oxaliplatin, associated with intravenous docetaxel. Percutaneous radiofrequency ablation was performed during the first PIPAC procedure. Peritoneal response allowed a secondary Cytoreductive Surgery with Hyperthermic Intraperitoneal Chemotherapy.

Predictive value of health-related quality of life on radiotherapy-related toxicities in patients with head and neck cancer.

PURPOSE: Little is known about whether baseline health-related quality of life (HRQoL) scores also could predict occurrence radiotherapy-related toxicities, which we aim to assess in this study. METHODS: This study analyzed data from 200 patients enrolled in randomized study investigating the utility of HRQoL. HRQOL was assessed at baseline and during follow up using QLQ-C30 questionnaire and major toxicity was considered as adverse event ≥ 3 according to NCI-CTCAE classification. Cox regressions adjusting for clinical and sociodemographic data were used to assess prognostic significance of HRQOL scores. RESULTS: In multivariable analyses adjusted on clinical and sociodemographic data, every 10-point improvement in physical (HR = 0.74), role (HR = 0.87) and social (HR = 0.88) functioning was associated with 24%, 13% and 12% lower hazard of occurrence of major toxicity respectively while every 10 point-increase in dyspnea (HR = and loss appetite was associated with 15% and 16% increased hazard of major toxicity. CONCLUSION: Certain baseline HRQoL scores were found to be significantly associated with the occurrence of major toxicity.

ESTRO-ACROP recommendations for evidence-based use of androgen deprivation therapy in combination with external-beam radiotherapy in prostate cancer.

BACKGROUND AND PURPOSE: There is no consensus concerning the appropriate use of androgen deprivation therapy (ADT) during primary and postoperative external-beam radiotherapy (EBRT) in the management of prostate cancer (PCa). Thus, the European Society for Radiotherapy and Oncology (ESTRO) Advisory Committee for Radiation Oncology Practice (ACROP) guidelines seeks to present current recommendations for the clinical use of ADT in the various indications of EBRT. MATERIAL AND METHODS: A literature search was conducted in MEDLINE PubMed that evaluated EBRT and ADT in prostate cancer. The search focused on randomized, Phase II and III trials published in English from January 2000 to May 2022. In case topics were addressed in the absence of Phase II or III trials, recommendations were labelled accordingly based on the limited body of evidence. Localized PCa was classified according to D'Amico et al. classification in low-, intermediate and high risk PCa. The ACROP clinical committee identified 13 European experts who discussed and analyzed the body of evidence concerning the use of ADT with EBRT for prostate cancer. RESULTS: Key issues were identified and are discussed: It was concluded that no additional ADT is recommended for low-risk prostate cancer patients, whereas for intermediate- and high-risk patients four to six months and two to three years of ADT are recommended. Likewise, patients with locally advanced prostate cancer are recommended to receive ADT for two to three years and when ≥ 2 high-risk factors (cT3-4, ISUP grade ≥ 4 or PSA ≥ 40 ng/ml) or cN1 is present ADT for three years plus additional Abiraterone for two years is recommended. For postoperative patients no ADT is recommended for adjuvant EBRT in pN0 patients whereas for pN1 patients adjuvant EBRT with long-term ADT is performed for at least 24 to 36 months. In the setting of salvage EBRT ADT is performed in biochemically persistent PCa patients with no evidence of metastatic disease. Long-term ADT (24 months) is recommended in pN0 patients with high risk of further progression (PSA ≥ 0.7 ng/ml and ISUP grade group ≥ 4) and a life expectancy of over ten years, whereas short-term ADT (6 months) is recommended in pN0 patients with lower risk profile (PSA < 0.7 ng/ml and ISUP grade group 4). Patients considered for ultra-hypofractionated EBRT as well as patients with image based local recurrence within the prostatic fossa or lymph node recurrence should participate in appropriate clinical trials evaluating the role of additional ADT. CONCLUSION: These ESTRO-ACROP recommendations are evidence-based and relevant to the use of ADT in combination with EBRT in PCa for the most common clinical settings.

Sequencing of Androgen-Deprivation Therapy of Short Duration With Radiotherapy for Nonmetastatic Prostate Cancer (SANDSTORM): A Pooled Analysis of 12 Randomized Trials.

PURPOSE: The sequencing of androgen-deprivation therapy (ADT) with radiotherapy (RT) may affect outcomes for prostate cancer in an RT-field size-dependent manner. Herein, we investigate the impact of ADT sequencing for men receiving ADT with prostate-only RT (PORT) or whole-pelvis RT (WPRT). MATERIALS AND METHODS: Individual patient data from 12 randomized trials that included patients receiving neoadjuvant/concurrent or concurrent/adjuvant short-term ADT (4-6 months) with RT for localized disease were obtained from the Meta-Analysis of Randomized trials in Cancer of the Prostate consortium. Inverse probability of treatment weighting (IPTW) was performed with propensity scores derived from age, initial prostate-specific antigen, Gleason score, T stage, RT dose, and mid-trial enrollment year. Metastasis-free survival (primary end point) and overall survival (OS) were assessed by IPTW-adjusted Cox regression models, analyzed independently for men receiving PORT versus WPRT. IPTW-adjusted Fine and Gray competing risk models were built to evaluate distant metastasis (DM) and prostate cancer-specific mortality. RESULTS: Overall, 7,409 patients were included (6,325 neoadjuvant/concurrent and 1,084 concurrent/adjuvant) with a median follow-up of 10.2 years (interquartile range, 7.2-14.9 years). A significant interaction between ADT sequencing and RT field size was observed for all end points (P interaction < .02 for all) except OS. With PORT (n = 4,355), compared with neoadjuvant/concurrent ADT, concurrent/adjuvant ADT was associated with improved metastasis-free survival (10-year benefit 8.0%, hazard ratio [HR], 0.65; 95% CI, 0.54 to 0.79; P < .0001), DM (subdistribution HR, 0.52; 95% CI, 0.33 to 0.82; P = .0046), prostate cancer-specific mortality (subdistribution HR, 0.30; 95% CI, 0.16 to 0.54; P < .0001), and OS (HR, 0.69; 95% CI, 0.57 to 0.83; P = .0001). However, in patients receiving WPRT (n = 3,049), no significant difference in any end point was observed in regard to ADT sequencing except for worse DM (HR, 1.57; 95% CI, 1.20 to 2.05; P = .0009) with concurrent/adjuvant ADT. CONCLUSION: ADT sequencing exhibits a significant impact on clinical outcomes with a significant interaction with field size. Concurrent/adjuvant ADT should be the standard of care where short-term ADT is indicated in combination with PORT.

Educative Impact of Automatic Delineation Applied to Head and Neck Cancer Patients on Radiation Oncology Residents.

To evaluate the educational impact on radiation oncology residents in training when introducing an automatic segmentation software in head and neck cancer patients regarding organs at risk (OARs) and prophylactic cervical lymph node level (LNL) volumes. Two cases treated by exclusive intensity-modulated radiotherapy were delineated by an expert radiation oncologist and were considered as reference. Then, these cases were delineated by residents divided into two groups: group 1 (control group), experienced residents delineating manually, group 2 (experimental group), young residents on their first rotation trained with automatic delineation, delineating manually first (M -) and then after using the automatic system (M +). The delineation accuracy was assessed using the Overlap Volume (OV). Regarding the OARs, mean OV was 0.62 (SD = 0.05) for group 1, 0.56 (SD = 0.04) for group 2 M - , and 0.61 (SD = 0.03) for group 2 M + . Mean OV was higher in group 1 compared to group 2 M - (p = 0.01). There was no OV difference between group 1 and group 2 M + (p = 0.67). Mean OV was higher in the group 2 M + compared to group 2 M - (p < 0.003). Regarding LNL, mean OV was 0.53 (SD = 0.06) in group 1, 0.54 (SD = 0.03) in group 2 M - , and 0.58 (SD = 0.04) in group 2 M + . Mean OV was higher in group 2 M + for 11 of the 12 analysed structures compared to group 2 M - (p = 0.016). Prior use of the automatic delineation software reduced the average contouring time per case by 34 to 40%. Prior use of atlas-based automatic segmentation reduces the delineation duration, and provides reliable OARs and LNL delineations.

Long-Term Outcomes in Head and Neck Paragangliomas Managed with Intensity-Modulated Radiotherapy.

OBJECTIVES: Head & Neck Paragangliomas have been historically relying on surgery mostly, with worsened quality of life and major sequelae. Conventional external radiation therapy seems to offer an equivalent control rate with a low toxicity profile. The aim of this study was to assess the safety and efficiency of intensity-modulated radiation therapy in Head & Neck paragangliomas. METHODS: This is a retrospective monocentric study conducted in a referral center, including all patients treated with IMRT, whether as an exclusive or post-operative treatment for a tympanic and jugular, carotid, or vagal paraganglioma. Data collection was performed through the manuscript and computerized medical files, including consultation, operative, imaging, pathological analyses, delineation, and treatment planning reports. Success was defined as the complete or partial regression or stabilization without progression, or relapse in accordance with the RECIST criteria. Acute toxicities and long-term sequelae were assessed. RESULTS: Our cohort included 39 patients included between 2011 and 2021: 18 patients treated for a TJ PG (45.9%), 11 patients for a carotid PG (28.4%), and 9 for a vagal PG (23.1%). Twenty-nine patients had IMRT as an exclusive treatment (74.4%), whereas 10 patients had a post-operative complementary treatment (25.6%). Median follow-up in our cohort was 2318 days (average = 2200 days, 237-5690, sd = 1281.9). Among 39 patients, 37 were successfully controlled with IMRT (94.8%), and the toxicity profile was low without any major toxicity. CONCLUSION: IMRT seems an ideal treatment, whether exclusive or post-operative for Head & Neck paragangliomas. LEVEL OF EVIDENCE: 3 Laryngoscope, 133:607-614, 2023.

Phase 1 Study of the Combination of Escalated Total Marrow Irradiation Using Helical Tomotherapy and Fixed High-Dose Melphalan (140 mg/m²) Followed by Autologous Stem Cell Transplantation at First Relapse in Multiple Myeloma.

PURPOSE: A second intensification is an option at first relapse in multiple myeloma (MM) after more than 36 months of initial remission. Many conditioning regimens have been tested, with or without total body irradiation (TBI). Recently, it was found that TBI could be replaced by total marrow irradiation (TMI) using helical tomotherapy, with promising results. METHODS AND MATERIALS: This study was a prospective multicenter phase 1 trial that aimed to determine the maximum tolerated dose (MTD) of TMI administered in association with melphalan 140 mg/m², followed by autologous stem cell transplantation as consolidation at first relapse in MM. Four dose levels were explored: 8 Gy, 10 Gy, 12 Gy, and 14 Gy. The dose-limiting toxicity (DLT) was defined as grade 4 neutropenia >15 days, grade 4 thrombopenia >28 days, and all other grade 4 nonhematologic toxic effects except nausea, vomiting, alopecia, mucositis, and reaction to autologous stem cell infusion. RESULTS: Thirteen patients were included; only 1 DLT at the third escalated dose level (12 Gy) was observed, whereas 1 patient was treated at 14 Gy with no adverse events. The MTD was not reached. The rate of acute toxicity was low: 38% of grade 3-4 diarrhea, mucositis, or unexplained fever. Regarding the lungs, the mean dose administered was systematically less than 8 Gy. After a median follow-up of 55 months, 70% of participants were alive. Of these 13 patients, 38.5% were in very good partial response and 30.8% were in complete response. Three of them were progression-free. Six patients were long survivors, still alive after 55 months of follow-up. CONCLUSIONS: Total marrow irradiation provides good results with a good tolerance profile at first relapse in MM and makes it possible to increase the dose delivered to the planning target volume while sparing organs at risk. This technique could be discussed for all regimens before auto- or allo-stem cell rescue when TBI is required.

Local Failure Events in Prostate Cancer Treated with Radiotherapy: A Pooled Analysis of 18 Randomized Trials from the Meta-analysis of Randomized Trials in Cancer of the Prostate Consortium (LEVIATHAN).

CONTEXT: The prognostic importance of local failure after definitive radiotherapy (RT) in National Comprehensive Cancer Network intermediate- and high-risk prostate cancer (PCa) patients remains unclear. OBJECTIVE: To evaluate the prognostic impact of local failure and the kinetics of distant metastasis following RT. EVIDENCE ACQUISITION: A pooled analysis was performed on individual patient data of 12 533 PCa (6288 high-risk and 6245 intermediate-risk) patients enrolled in 18 randomized trials (conducted between 1985 and 2015) within the Meta-analysis of Randomized Trials in Cancer of the Prostate Consortium. Multivariable Cox proportional hazard (PH) models were developed to evaluate the relationship between overall survival (OS), PCa-specific survival (PCSS), distant metastasis-free survival (DMFS), and local failure as a time-dependent covariate. Markov PH models were developed to evaluate the impact of specific transition states. EVIDENCE SYNTHESIS: The median follow-up was 11 yr. There were 795 (13%) local failure events and 1288 (21%) distant metastases for high-risk patients and 449 (7.2%) and 451 (7.2%) for intermediate-risk patients, respectively. For both groups, 81% of distant metastases developed from a clinically relapse-free state (cRF state). Local failure was significantly associated with OS (hazard ratio [HR] 1.17, 95% confidence interval [CI] 1.06-1.30), PCSS (HR 2.02, 95% CI 1.75-2.33), and DMFS (HR 1.94, 95% CI 1.75-2.15, p < 0.01 for all) in high-risk patients. Local failure was also significantly associated with DMFS (HR 1.57, 95% CI 1.36-1.81) but not with OS in intermediate-risk patients. Patients without local failure had a significantly lower HR of transitioning to a PCa-specific death state than those who had local failure (HR 0.32, 95% CI 0.21-0.50, p < 0.001). At later time points, more distant metastases emerged after a local failure event for both groups. CONCLUSIONS: Local failure is an independent prognosticator of OS, PCSS, and DMFS in high-risk and of DMFS in intermediate-risk PCa. Distant metastasis predominantly developed from the cRF state, underscoring the importance of addressing occult microscopic disease. However a "second wave" of distant metastases occurs subsequent to local failure events, and optimization of local control may reduce the risk of distant metastasis. PATIENT SUMMARY: Among men receiving definitive radiation therapy for high- and intermediate-risk prostate cancer, about 10% experience local recurrence, and they are at significantly increased risks of further disease progression. About 80% of patients who develop distant metastasis do not have a detectable local recurrence preceding it.

High-dose Radiotherapy or Androgen Deprivation Therapy (HEAT) as Treatment Intensification for Localized Prostate Cancer: An Individual Patient-data Network Meta-analysis from the MARCAP Consortium.

BACKGROUND: The relative benefits of radiotherapy (RT) dose escalation and the addition of short-term or long-term androgen deprivation therapy (STADT or LTADT) in the treatment of prostate cancer are unknown. OBJECTIVE: To perform a network meta-analysis (NMA) of relevant randomized trials to compare the relative benefits of RT dose escalation ± STADT or LTADT. DESIGN, SETTING, AND PARTICIPANTS: An NMA of individual patient data from 13 multicenter randomized trials was carried out for a total of 11862 patients. Patients received one of the six permutations of low-dose RT (64 to <74 Gy) ± STADT or LTADT, high-dose RT (≥74 Gy), or high-dose RT ± STADT or LTADT. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSES: Metastasis-free survival (MFS) was the primary endpoint. Frequentist and Bayesian NMAs were performed to rank the various treatment strategies by MFS and biochemical recurrence-free survival (BCRFS). RESULTS AND LIMITATIONS: Median follow-up was 8.8 yr (interquartile range 5.7-11.5). The greatest relative improvement in outcomes was seen for addition of LTADT, irrespective of RT dose, followed by addition of STADT, irrespective of RT dose. RT dose escalation did not improve MFS either in the absence of ADT (hazard ratio [HR] 0.97, 95% confidence interval [CI] 0.80-1.18) or with STADT (HR 0.99, 95% CI 0.8-1.23) or LTADT (HR 0.94, 95% CI 0.65-1.37). According to P-score ranking and rankogram analysis, high-dose RT + LTADT was the optimal treatment strategy for both BCRFS and longer-term outcomes. CONCLUSIONS: Conventionally escalated RT up to 79.2 Gy, alone or in the presence of ADT, does not improve MFS, while addition of STADT or LTADT to RT alone, regardless of RT dose, consistently improves MFS. RT dose escalation does provide a high probability of improving BCRFS and, provided it can be delivered without compromising quality of life, may represent the optimal treatment strategy when used in conjunction with ADT. PATIENT SUMMARY: Using a higher radiotherapy dose when treating prostate cancer does not reduce the chance of developing metastases or death, but it does reduce the chance of having a rise in prostate-specific antigen (PSA) signifying recurrence of cancer. Androgen deprivation therapy improves all outcomes. A safe increase in radiotherapy dose in conjunction with androgen deprivation therapy may be the optimal treatment.

Treatment related factors associated with the risk of breast radio-induced-sarcoma.

BACKGROUND AND PURPOSE: The Radiation Induced Sarcoma (RIS) is a rare but serious adverse event following radiotherapy (RT). Current RT techniques are more precise, but irradiate a larger volume at a low dose. This study aimed to describe radiation characteristics in a large series of patients suffering from RIS. MATERIALS AND METHODS: Patient-representative voxel-based anthropomorphic phantoms were used to reconstruct patient-specific RT fields for 125 patients diagnosed with RIS after primary breast cancer. For each patient, the location of the RIS onset site was determined and transferred onto the phantom as a contour. Using a treatment planning system (TPS), the dose distribution on the RIS in the phantom was calculated. RESULTS: The mean dose (Dmean) received in the area where RIS subsequently developed was 47.8 ± 11.6 Gy. The median dose in the zones where RIS later developed ranged from 11 Gy to 58.8 Gy. The median time from RT to RIS development was 8 years (range 2-32 years). Analysis for predictors of time to radiation-induced sarcoma development highlighted a significant impact of age of patient during the RT whereas in multivariable analysis chemotherapy and hormonotherapy for primary breast cancer were not associated with a significant difference in time to diagnosis of RIS. CONCLUSIONS: This study highlights that the dose received by the tissue in which the RIS developed was almost 47 Gy. These results are encouraging for the use of new RT techniques increasing volumes receiving low doses, without fear of an excess of RIS over the next 10 years.

Androgen deprivation therapy use and duration with definitive radiotherapy for localised prostate cancer: an individual patient data meta-analysis.

BACKGROUND: Randomised trials have investigated various androgen deprivation therapy (ADT) intensification strategies in men receiving radiotherapy for the treatment of prostate cancer. This individual patient data meta-analysis of relevant randomised trials aimed to quantify the benefit of these interventions in aggregate and in clinically relevant subgroups. METHODS: For this meta-analysis, we performed a systematic literature search in MEDLINE, Embase, trial registries, the Web of Science, Scopus, and conference proceedings to identify trials with results published in English between Jan 1, 1962, and Dec 30, 2020. Multicentre randomised trials were eligible if they evaluated the use or prolongation of ADT (or both) in men with localised prostate cancer receiving definitive radiotherapy, reported or collected distant metastasis and survival data, and used ADT for a protocol-defined finite duration. The Meta-Analysis of Randomized trials in Cancer of the Prostate (MARCAP) Consortium was accessed to obtain individual patient data from randomised trials. The primary outcome was metastasis-free survival. Hazard ratios (HRs) were obtained through stratified Cox models for ADT use (radiotherapy alone vs radiotherapy plus ADT), neoadjuvant ADT extension (ie, extension of total ADT duration in the neoadjuvant setting from 3-4 months to 6-9 months), and adjuvant ADT prolongation (ie, prolongation of total ADT duration in the adjuvant setting from 4-6 months to 18-36 months). Formal interaction tests between interventions and metastasis-free survival were done for prespecified subgroups defined by age, National Comprehensive Cancer Network (NCCN) risk group, and radiotherapy dose. This meta-analysis is registered with PROSPERO, CRD42021236855. FINDINGS: Our search returned 12 eligible trials that provided individual patient data (10 853 patients) with a median follow-up of 11·4 years (IQR 9·0-15·0). The addition of ADT to radiotherapy significantly improved metastasis-free survival (HR 0·83 [95% CI 0·77-0·89], p<0·0001), as did adjuvant ADT prolongation (0·84 [0·78-0·91], p<0·0001), but neoadjuvant ADT extension did not (0·95 [0·83-1·09], p=0·50). Treatment effects were similar irrespective of radiotherapy dose, patient age, or NCCN risk group. INTERPRETATION: Our findings provide the strongest level of evidence so far to the magnitude of the benefit of ADT treatment intensification with radiotherapy for men with localised prostate cancer. Adding ADT and prolonging the portion of ADT that follows radiotherapy is associated with improved metastasis-free survival in men, regardless of risk group, age, and radiotherapy dose delivered; however, the magnitude of the benefit could vary and shared decision making with patients is recommended. FUNDING: University Hospitals Seidman Cancer Center, Prostate Cancer Foundation, and the American Society for Radiation Oncology.

Tailored Strategy for Locally Advanced Rectal Carcinoma (GRECCAR 4): Long-term Results From a Multicenter, Randomized, Open-Label, Phase II Trial.

BACKGROUND: Systematic preoperative radiochemotherapy and total mesorectal excision are the standard of care for locally advanced rectal carcinoma. Some patients can be over- or undertreated. OBJECTIVE: This study aimed to investigate the long-term oncological, functional, and late morbidity outcomes after tailored radiochemotherapy and induction high-dose chemotherapy. DESIGN: This is a prospective, phase II, multicenter, open-label study at 16 tertiary centers in France. SETTINGS: Patients were operated on by surgeons from the French GRECCAR group. PATIENTS: Two hundred six patients were randomly assigned to treatment: good responders after chemotherapy (≥75% tumor volume reduction) to immediate surgery (arm A) or standard radiochemotherapy (capecitabine 50) plus surgery (arm B) and poor responders to capecitabine 50 (arm C) or intensive radiochemotherapy (capecitabine 60; 60 Gy irradiation; arm D) before surgery. INTERVENTIONS: Treatment was tailored according to MRI response to induction chemotherapy. RESULTS: After induction treatment, 194 patients were classified as good (n = 30, 15%) or poor (n = 164, 85%) responders; they were included in arms A and B (16 and 14 patients) or C and D (113 and 51 patients). The primary objective was obtained: R0 resection rates (90% CI) in the 4 arms were 100% (74-100), 100% (85-100), 83% (72-91), and 88% (77-95). At 5 years, overall survival rates were 90% (47.3-98.5), 93.3% (61.3-99.0), 84.3% (71.0-91.8), and 86.1% (71.6-93.5); disease-free survival rates were 80% (40.9-94.6), 89.5% (64.1-97.3), 72.9% (58.5-82.9), and 72.8% (57.7-83.2); local recurrence rates were 0%, 0%, 2.1% (0.3-13.9), and 9.3% (3.6-23.0); and metastasis rates were 20% (5.4-59.1), 10.5% (2.7-35.9), 18% (31.8-94.6), and 18.8% (10.2-33.0). Late morbidity and quality-of-life evaluations showed no significant difference between arms. LIMITATIONS: Limitations were due to the small number of patients randomly assigned in the good responder arms, especially arm A without radiotherapy. CONCLUSION: Tailoring preoperative radiochemotherapy based on induction treatment response appears to be promising. Future prospective trials should confirm this strategy. See Video Abstract at http://links.lww.com/DCR/B761 . REGISTRATION: URL: https://www.clinicaltrials.gov ; Identifier: NCT01333709. ESTRATEGIA HECHA A MEDIDA PARA EL TRATAMIENTO DEL CARCINOMA DE RECTO LOCALMENTE AVANZADO GRECCAR RESULTADOS A LARGO PLAZO DE UN ESTUDIO ALEATRIO MULTICNTRICO Y ABIERTO DE FASE II: ANTECEDENTES:La radio-quimioterapia pré-operatoria sistemáticas y la excisión total del mesorrecto son el estándar en el tratamiento del carcinoma de recto localmente avanzado. En éste sentido, algunos pacientes podrían recibir un sobre o un infra-tratamiento.OBJETIVO:Evaluar los resultados oncológicos, funcionales y de morbilidad a largo plazo después de radio-quimioterapia personalizada y quimioterapia de inducción a dosis elevadas.DISEÑO:Estudio aleatório multicéntrico y abierto de Fase II° realizado en 16 centros terciarios en Francia.AJUSTE:Aquellos pacientes operados por cirujanos del grupo GRECCAR francés.PACIENTES:206 pacientes fueron asignados aleatoriamente al tratamiento: los buenos respondedores después de quimioterapia (reducción del volumen tumoral ≥75%) a la cirugía inmediata (brazo A) o a la radio-quimioterapia estándar (Cap 50) asociada a la cirugía (brazo B); los malos respondedores a Cap 50 (brazo C) o a la radio-quimioterapia intensiva (Cap 60 (irradiación de 60 Gy) (brazo D) previas a la cirugía.INTERVENCIONES:Tratamiento adaptado según la respuesta de la RM a la TC de inducción.RESULTADOS:Después del tratamiento de inducción, 194 pacientes fueron clasificados como buenos (n = 30, 15%) o malos (n = 164, 85%) respondedores, y se incluyeron en los brazos A y B (16 y 14 pacientes) o C y D (113 y 51 pacientes). Se alcanzó el objetivo principal: las tasas de resección R0 [intervalo de confianza del 90%] en los cuatro brazos respectivamente, fueron del 100% [74-100], 100% [85-100], 83% [72-91] y 88% [77-95]. A los 5 años, las tasas fueron: de sobrevida global 90% [47,3-98,5], 93,3% [61,3-99,0], 84,3% [71,0-91,8], 86,1% [71,6-93,5]; de sobrevida libre a la enfermedad 80% [40,9-94,6], 89,5% [64,1-97,3], 72,9% [58,5-82,9], 72,8% [57,7-83,2]; de recidiva local 0, 0, 2,1% [0,3-13,9], 9,3% [3,6-23,0]; de metástasis 20% [5,4-59,1], 10,5% [2,7-35,9], 18% [31,8-94,6], 18,8% [10,2-33,0]. La evaluación tardía de la morbilidad y la calidad de vida no mostraron diferencias significativas entre los brazos.LIMITACIONES:Debido al pequeño número de pacientes asignados al azar en los brazos de buenos respondedores, especialmente en el brazo A de aquellos sin radioterapia.CONCLUSIÓN:Parecería muy prometedor el adaptar la radio-quimioterapia pré-operatoria basada en la respuesta al tratamiento de inducción. Estudios prospectivos en el futuro podrán confirmar la presente estrategia. Consulte Video Resumen en http://links.lww.com/DCR/B761 . (Traducción-Dr. Xavier Delgadillo )IDENTIFICADOR DE CLINICALTRIALS.GOV:NCT01333709. Groupe de REcherche Chirurgicale sur le CAncer du Rectum.

Current practice in proton therapy delivery in adult cancer patients across Europe.

BACKGROUND AND PURPOSE: Major differences exist among proton therapy (PT) centres regarding PT delivery in adult cancer patient. To obtain insight into current practice in Europe, we performed a survey among European PT centres. MATERIALS AND METHODS: We designed electronic questionnaires for eight tumour sites, focusing on four main topics: 1) indications and patient selection methods; 2) reimbursement; 3) on-going or planned studies, 4) annual number of patients treated with PT. RESULTS: Of 22 centres, 19 (86%) responded. In total, 4233 adult patients are currently treated across Europe annually, of which 46% consists of patients with central nervous system tumours (CNS), 15% head and neck cancer (HNC), 15% prostate, 9% breast, 5% lung, 5% gastrointestinal, 4% lymphoma, 0.3% gynaecological cancers. CNS are treated in all participating centres (n = 19) using PT, HNC in 16 centres, lymphoma in 10 centres, gastrointestinal in 10 centres, breast in 7 centres, prostate in 6 centres, lung in 6 centres, and gynaecological cancers in 3 centres. Reimbursement is provided by national health care systems for the majority of commonly treated tumour sites. Approximately 74% of centres enrol patients for prospective data registration programs. Phase II-III trials are less frequent, due to reimbursement and funding problems. Reasons for not treating certain tumour types with PT are lack of evidence (30%), reimbursement issues (29%) and/or technical limitations (20%). CONCLUSION: Across European PT centres, CNS tumours and HNC are the most frequently treated tumour types. Most centres use indication protocols. Lack of evidence for PT and reimbursement issues are the most reported reasons for not treating specific tumour types with PT.

Randomized Trial Assessing the Impact of Routine Assessment of Health-Related Quality of Life in Patients with Head and Neck Cancer.

The impact of routine assessment of health-related quality of life (HRQoL) on satisfaction with care and the HRQoL of patients with head and neck cancer (HNC) treated with radiotherapy was assessed. Patients with HNC were randomly assigned to two arms, with stratification on sex, cancer localization, and stage of the disease. In the intervention arm, the patients completed the EORTC QLQ-C30 and EORTC QLQ-H&N35 questionnaires first before randomization, then before each medical appointment during radiotherapy (7 weeks), and then every 3 months until 1 year and at 2 years thereafter. In the control arm, the EORTC QLQ-C30 and EORTC QLQ-H&N35 questionnaires were completed before randomization and at 1 year and 2 years thereafter. The primary endpoint was mean change in HRQoL at score at 2 years from baseline assessed by EQ VAS from the EuroQol questionnaire. The secondary endpoint was mean change in satisfaction with care at 2 years from baseline assessed by QLQ-SAT32. Two hundred patients with head and neck cancers were involved in this study (mean age, 58.83 years (range, 36.56-87.89)), of whom 100 were assigned to the intervention arm and 100 to the control arm. Patients in the intervention arm were reported to have a statistically significant increase in EQ VAS at 2 years (p < 0.0001) and exceeded the minimal clinically important difference (mean change at 2 years from baseline = 10.46). In the two arms, mean differences between arms were not statistically significant, but minimal clinically important differences in favor of the intervention arm were found for EQ VAS (mean change difference (MD) = 5.84), satisfaction with care, in particular waiting times (MD = 10.85) and satisfaction with accessibility (MD = 6.52). Routine assessment of HRQoL improves HRQoL and satisfaction with care for patients with HNC treated with radiotherapy.