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Debio 1143 is an orally available antagonist of inhibitor of apoptosis proteins with the potential to enhance the antitumour activity of cisplatin and radiotherapy. The radiosensitising effect of Debio 1143 is mediated through caspase activation and TNF, IFNγ, CD8 T cell-dependent pathways. We aimed to investigate the efficacy and safety of Debio 1143 in combination with standard chemoradiotherapy in patients with high-risk locally advanced squamous cell carcinoma of the head and neck. This double-blind, multicentre, randomised, phase 2 study by the French Head and Neck Radiotherapy Oncology Group (GORTEC) was run at 19 hospitals in France and Switzerland. Eligible patients were aged 18–75 years with locoregionally advanced, squamous cell carcinoma of the head and neck (characterised as non-metastatic, measurable stage III, IVa, or IVb [limited to T ≥2, N0–3, and M0] disease), Eastern Cooperative Oncology Group performance status of 0 or 1, a history of heavy tobacco smoking (>10 pack-years) with no previous or current treatment for invasive head and neck cancer, and no previous treatment with inhibitor of apoptosis protein antagonists. Patients were randomly assigned (1:1) to receive oral Debio 1143 (200 mg per day on days 1–14 of 21-day cycles, for three cycles) or oral placebo (20 mg/mL, administered at the same dosing schedule) using a stochastic minimisation technique according to node involvement and primary tumour site, and HPV-16 status in patients with an oropharyngeal primary tumour site. All patients received standard high-dose cisplatin chemoradiotherapy. The primary endpoint was the proportion of patients with locoregional control 18 months after chemoradiotherapy, analysed in the intention-to-treat population (primary analysis), and repeated in the per-protocol population. Responses were assessed according to Response Evaluation Criteria in Solid Tumors (version 1.1). This trial is registered with ClinicalTrials.gov, NCT02022098, and is still active but not recruiting. Between Jan 25, 2016, and April 24, 2017, 48 patients were randomly assigned to the Debio 1143 group and 48 to the placebo group (one patient in the placebo group did not receive the study drug and was not included in the safety analysis). Median duration of follow-up was 25·0 months (IQR 19·6–29·4) in the Debio 1143 group and 24·2 months (6·6–26·8) in the placebo group. Locoregional control 18 months after chemoradiotherapy was achieved in 26 (54%; 95% CI 39–69) of 48 patients in the Debio 1143 group versus 16 (33%; 20–48) of 48 patients in the placebo group (odds ratio 2·69 [95% CI 1·13–6·42], p=0·026). Grade 3 or worse adverse events were reported in 41 (85%) of 48 patients in the Debio 1143 group and in 41 (87%) of 47 patients in the placebo group. The most common grade 3–4 adverse events were dysphagia (in 24 [50%] patients in the Debio 1143 group vs ten [21%] in the placebo group), mucositis (in 15 [31%] vs ten [21%]), and anaemia (in 17 [35%] vs 11 [23%]). Serious treatment-emergent adverse events were recorded in 30 (63%) of 48 patients in the Debio 1143 group and 28 (60%) of 47 in the placebo group. In the placebo group, two (4%) deaths were due to adverse events (one multiple organ failure and one asphyxia; neither was considered to be related to treatment). No deaths due to adverse events occurred in the Debio 1143 group. To our knowledge, this is the first treatment regimen to achieve superior efficacy in this disease setting against a high-dose cisplatin chemoradiotherapy comparator in a randomised trial. These findings suggest that inhibition of inhibitor of apoptosis proteins is a novel and promising approach in this poor prognostic population and warrant confirmation in a phase 3 study with the aim of expanding the therapeutic options for these patients. Debiopharm.

How radiotherapy counters immune evasion In conventional radiotherapy (RT), the relative biologic effectiveness of radiation is influenced by radiobiological determinants, the so-called ‘5Rs’: Repair, Repopulation, Redistribution, Reoxygenation, and Radiosensitivity.1 A linear-quadratic model prevails to describe the radiation response of the tumor, in which the α/β ratio is used to characterize the sensitivity of a particular tissue type to fractionation. Fractionation serves to decrease acute, and especially late, toxicity to surrounding normal tissue exposed to RT. Commonly, curative RT is delivered in daily doses of 1.8–2.2 Gy for 5–8 weeks, whereas hypofractionation is defined as a delivery of greater than 2.2 Gy per fraction. With sophisticated advances in RT technologies, delivering higher doses of RT per fraction [i.e. increased biologically effective dose (BED)] in a shorter timeframe appears a safe option. Indeed, increased BED could be achieved with larger fraction sizes relative to conventionally fractionated RT. While early radiobiological studies had found that the major mechanisms of action of radiation were related to DNA damage and subsequent cell death of dividing cells, novel insights on radiation effects have uncovered the immunomodulatory properties of ionizing radiation.2

Postoperative cisplatin and radiotherapy is the standard of care for high-risk resected locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN). The NIVOPOST-OP trial aimed to assess the efficacy and safety of programmed death 1 blockade by nivolumab added to cisplatin and radiotherapy in this setting. This open-label, phase 3 trial evaluated adding nivolumab to cisplatin and radiotherapy after surgery for LA-SCCHN with high-risk pathological features. The main inclusion criteria were age 19–74 years, an Eastern Cooperative Oncology Group performance status 0–1, squamous cell carcinoma of the oral cavity, oropharynx, larynx, or hypopharynx resected with macroscopic complete resection, and at least one high-risk pathological feature: nodal extracapsular extension, microscopically positive margins, four or more cervical nodal involvements without extracapsular extension, and multiple perineural invasions. 680 participants recruited in 82 sites across six countries (France, Spain, Poland, Belgium, Greece, and Switzerland) were randomly assigned 1:1 to receive cisplatin and radiotherapy (66 Gy, cisplatin 100 mg/m2 intravenously once every 3 weeks, for three cycles); or nivolumab 240 mg intravenously, followed by cisplatin and radiotherapy with three cycles of concomitant nivolumab 360 mg once every 3 weeks, and six cycles of adjuvant nivolumab 480 mg once every 4 weeks. The primary endpoint was disease-free survival as per investigator assessment in the intention-to-treat population. 230 disease-free survival events (relapses or deaths) were required to detect a hazard ratio of 0·65 with 0·05 two-sided α error, with 90% power. The trial is registered at ClinicalTrials.gov (NCT03576417) and is active, but not recruiting. The 680 patients were recruited from Oct 15, 2018, to July 3, 2024. The analysis was based on 666 participants randomly assigned until the cutoff date (April 30, 2024), at which point the required number of events was reached (median follow-up 30·3 months). Disease-free survival was significantly improved with nivolumab, cisplatin, and radiotherapy versus cisplatin and radiotherapy alone, irrespective of programmed death ligand 1 expression (HR 0·76; 95% CI 0·60–0·98; stratified log-rank test p value=0·034). There was an increase in the rate of participants with treatment-related grade 4 adverse events with nivolumab, cisplatin, and radiotherapy compared with cisplatin and radiotherapy (30 [10%] of 312 vs 16 [5%] of 306). Treatment-related deaths occurred in two participants in each group. Nivolumab added to cisplatin and radiotherapy in high-risk resected LA-SCCHN improves disease-free survival with moderate toxic effect increase, and can be proposed as a new standard treatment. Groupe Oncologie Radiotherapie Tete Et Cou (GORTEC) and Bristol Myers Squibb.

PurposeNaloxegol, an oral once-daily peripherally acting mu-opioid receptor antagonist, is indicated for the treatment of opioid-induced constipation (OIC) with inadequate response to laxative(s), in cancer and non-cancer patients. This study mainly aimed to assess in real-life conditions the efficacy and safety of naloxegol in cancer pain patients and the evolution of their quality of life.MethodsA non-interventional, 4-week follow-up study was conducted in 24 French oncology and pain centers between 2018 and 2019. Eligible patients were aged ≥ 18 years, treated with opioids for cancer pain, and started naloxegol for OIC with inadequate response to laxatives. The rate of the response to naloxegol (primary criterion) was assessed at W4. The evolution of quality of life was measured using the Patient Assessment of Constipation Quality of Life (PAC-QOL).ResultsA total of 124 patients were included (mean age, 62 ± 12 years; ECOG ≤ 2, 79%; primary cancer, lung 18%, breast 16%, prostate 11%, head and neck 9%, digestive 9%…; metastatic stage, 80%). At inclusion, the median opioid dosage was 60 mg of oral morphine or equivalent. At W4, the response rate was 73.4% (95% CI [63.7–83.2%]), and 62.9% (95% CI [51.5–74.2%]) of patients had a clinically relevant change in quality of life (decrease in PAC-QOL score ≥ 0.5 point). Adverse events related to naloxegol were reported in 8% of patients (7% with gastrointestinal events; one serious diarrhea).ConclusionThis real-world study shows that naloxegol is effective and well tolerated in cancer pain patients with OIC and that their quality of life improves under treatment.

Background Low-level laser therapy (LLLT) also called Photobiomodulation therapy (PBMT) could reduce oral mucositis (OM) incidence and severity in head and neck cancer patients treated by chemoradiotherapy, however randomised data about efficacy and safety are missing with curative dose 4 J/cm 2 . Methods This phase III trial was conducted in patients with oral cavity, or oro/hypopharyngeal cancers (stage III or IV). Patients were treated by lasertherapy on OM lesions grade ≥ 2 (4 J/cm 2 or placebo), during chemoradiotherapy and until recovery. Severity of OM (incidence and duration of grades ≥3) was used as primary endpoint and blindly assessed. Results Among 97 randomised patients, 83 patients (85.6%) could be assessed finally (erroneous inclusions, chemoradiotherapy interruptions) and 32 patients had no lasertherapy because of unreachable OM lesions. Randomisation and population characteristics (sex ratio, age, chemoradiotherapy procedures, toxicities incidence) were still comparable between the two LLLT/PBMT groups. An acute OM (grade ≥ 3) was observed in 41 patients (49.4%): 23 patients (54.8%) of the active laser group versus 18 (43.9%) in the control group (modified intend to treat, p  = 0.32). Median time before occurrence of OM ≥ grade 3 in half of the patients was 8 weeks in active laser group (vs. 9 weeks in control group). However, 95% of patients exhibited a very good tolerance of LLLT/PBMT. Conclusions This study assessed LLLT/PBMT according to the Multinational Association of Supportive care in Cancer recommendations but lacked power. LLLT/PBMT was well tolerated with a good safety profile, which promotes its use in clinical routine for severe OM treatment. Trial registration ClinicalTrials.gov Identifier: NCT01772706 . Title: Laser Mucite ORL: Effectiveness of Laser Therapy for Mucositis Induced by a Radio-chemotherapy in Head and Neck Cancer (LaserMucite). Study Start Date: October 2008. Primary Completion Date: October 2016. Responsible Party: Institut de Cancérologie de l’Ouest – Paul Papin. Principal Investigator: Eric Jadaud, M.D., Institut de Cancérologie de l’Ouest – Paul Papin. Funding: French Ministry of Health, French national funding scheme (PHRC 2008).

To date, no study has evaluated the detection rate of head and neck squamous cell carcinoma (HNSCC) in cause-of-death records in Europe. Our objectives were to compare the number of deaths attributable to HNSCC from two national databases in France and to identify factors associated with under-reporting of HNSCC in cause-of-death records. The national hospital discharge database and the national underlying cause-of-death records were compared for all HNSCC-attributable deaths in adult patients from 2008 to 2012 in France. Factors associated with under-reporting of HNSCC in cause-of-death records were assessed using multivariate Poisson regression. A total of 41,503 in-hospital deaths were attributable to HNSCC as compared to 25,647 deaths reported in national UCoD records (a detection rate of 62%). Demographics at death were similar in both databases with respect to gender (83% men), age (54% premature deaths at 25-64 years), and geographic distribution. In multivariate Poisson regression, under-reporting of HNSCC in cause-of-death records significantly increased in 2012 compared to 2010 (+7%) and was independently associated with a primary HNSCC site other than the larynx, a former primary or second synchronous cancer other than HNSCC, distant metastasis, palliative care, and death in hospitals other than comprehensive cancer care centers. The main study results were robust in a sensitivity analysis which also took into account deaths outside hospital (overall, 51,129 HNSCC-attributable deaths; a detection rate of 50%). For the year 2012, the age-standardized mortality rate for HNSCC derived from underlying cause-of-death records was less than half that derived from hospital discharge summaries (14.7 compared to 34.1 per 100,000 for men and 2.7 compared to 6.2 per 100,000 for women). HNSCC is largely under-reported in cause-of-death records. This study documents the value of national hospital discharge databases as a complement to death certificates for ascertaining cancer deaths.

The severity of breakthrough cancer pain (BTcP) impacts patients' quality of life, increases the risk of anxiety and depression, lowers functional capacities, and may lead to poor compliance with cancer treatments. The aim of the current study was to assess, in a real-life setting, patient satisfaction with a fentanyl-pectin-nasal-spray (FPNS) for BTcP management in head and neck (H&N) cancer patients treated by radiotherapy. This non-interventional, prospective study was conducted in 92 adult H&N-cancer patients undergoing radiotherapy and who started FPNS treatment for BTcP. Throughout the radiotherapy period, the patients completed self-diaries to assess their BTcP episodes, FPNS use, satisfaction on FPNS efficiency (primary outcome), tolerability and ease of use. Prior to FPNS treatment, 86% of the patients were experiencing ≤4 BTcP episodes/day. During the radiotherapy period, the BTcP episodes were treated with a median dose of 100µg of FPNS. Patients were \"satisfied/very-satisfied\" with the efficiency (73% of assessments), ease of use (87% of assessments) and tolerability (87% of assessments) of FPNS. In total, 27% of patients reported at least one adverse event related to FPNS and 4% of patients discontinued treatment due to adverse events. None of the adverse events were serious. Patient quality of life was maintained throughout the radiotherapy period. This study showed, in a real-life setting, that a clear majority of H&N cancer patients treated with FPNS for BTcP throughout radiotherapy expressed satisfaction with this analgesic treatment.

The practice of regular physical activity can reduce the incidence of certain cancers (colon, breast, and prostate) and improve overall survival after treatment by reducing fatigue and the risk of relapse. This impact on survival has only been demonstrated in active patients with lymphoma before and after treatment. As poor general health status reduces the chances of survival and these patients are most likely to also have sarcopenia, it is important to be able to improve their physical function through adapted physical activity (APA) as part of supportive care management. Unfortunately, APA is often saved for patients with advanced blood cancer. As a result, there is a lack of data regarding the impact of standardized regular practice of APA and concomitant chemotherapy as first-line treatment on lymphoma survival. This study aimed to assess the impact of a new and open rehabilitation program suitable for a frail population of patients treated for diffuse large B-cell lymphoma (DLBCL). PHARAOM (Physical Activity Program for the Survival of Elderly Patients with Lymphoma) is a phase 3 randomized (1:1) study focusing on a frail population of patients treated for DLBCL. The study will include 186 older adult patients with DLBCL (aged >65 years) receiving rituximab and chemotherapy. Overall, 50% (93/186) of patients (investigational group) will receive APA along with chemotherapy, and they will be supervised by a dedicated qualified kinesiologist. The APA program will include endurance and resistance training at moderate intensity 3 times a week during the 6 months of chemotherapy. The primary end point of this study will be event-free survival of the patients. The secondary end points will include the overall survival, progression-free survival, prevalence of sarcopenia and undernutrition, and patients' quality of life. This study will be conducted in accordance with the principles of the Declaration of Helsinki. Recruitment, enrollment, and data collection began in February 2021, and 4 participants have been enrolled in the study as of July 2022. Data analysis will begin after the completion of data collection. Future outcomes will be published in peer-reviewed health-related research journals and presented at national congress, and state professional meetings. This publication is based on protocol version 1.1, August 3, 2020. The PHARAOM study focuses on highlighting the benefits of APA intervention on survival during the period of first-line treatment of patients with DLBCL. This study could also contribute to our understanding of how an APA program can reduce complications such as sarcopenia in patients with lymphoma and improve their quality of life. By documenting the prevalence and relationship between sarcopenia and exercise load, we might be able to help physicians plan better interventions in the care of patients with DLBCL. ClinicalTrials.gov NCT04670029; https://clinicaltrials.gov/ct2/show/NCT04670029. DERR1-10.2196/40969.

Introduction As part of French residents' radiotherapy training, delineation workstations were available at a national teaching course. We report a prospective comparative study of a non small cell lung cancer (NSCLC) case delineated by 120 residents before and after a radioanatomy/radiotherapy lecture. Materials and methods The case of a patient with right upper lobe non small cell lung cancer (NSCLC) was provided for delineation to 32 groups of residents before and after a radiation therapy lecture about thoracic delineation. GTV, CTV and PTV was asked to each group. In a second step, the GTV, CTV and PTV were compared with those of 9 groups of senior physicians. Finally the consequences for treatment planning between each group before and after the course were explored. Results The expert's average GTV, CTV and PTV were 89.1 cm 3 , 242.3 cm 3 and 293.9 cm 3 respectively. For residents, those volumes were 103.4 cm 3 , 242.3 cm 3 and 457.9 cm 3 before teaching, compared to 99.5 cm 3 , 224.2 cm 3 and 412.5 cm 3 after teaching. The overlap (OV) and kappa (KI) indices before and after education were respectively 0.58 and 0.73. Compared to senior physicians, OV and KI indices were lower in the residents group (p = 0.039 and p = 0.043). An increased dose to the lung is noted for the residents' dosimetry compared to the experts' (V20: 23.2% versus 36.5%) due to the larger PTV delineated. No significant difference was observed for other organs at risk. Conclusion There were no significant differences for the delineation of the GTV and CTV before and after the course, although the differences tended to decrease after the course. The good initial quality of the contours could explain the lack of difference. V20 for lung was higher in the residents group compared to the experts group (23.2% vs 36.5%). No other treatment planning consequences were observed for other critical organs.