Ultra-fast confocal fluorescence microscopy for neck lymph node imaging in head and neck cancer.

OBJECTIVES: We evaluated ultra-fast confocal fluorescence microscopy (UFCM) as a new modality for pathology practice in head and neck cancer (HNC). This was assessed through an ex vivo study to estimate the accuracy, specificity, and sensitivity of interpretation of UFCM images by pathologists for the detection of metastatic lymph nodes in HNC patients undergoing sentinel lymph node biopsy or selective or complete neck dissection. MATERIALS AND METHODS: 44 patients with 32 cN0 and 12 cN+ HNC were included. The macroscopically non-invaded fresh bisected lymph nodes were stained with acridine orange and imaged with Histolog® Scanner (UFCM). Two pathologists interpreted independently the UFCM images postoperatively and gave a consensus diagnosis in case of disagreement. The gold standard was the diagnosis based on hematoxylin-eosin-saffron (HES) sections. RESULTS: 201 lymph nodes were imaged by UFCM. Thirty nodes (15 %) were invaded on final histology: 3 with micrometastases and 27 with macrometastases. The concordance rate between the pathologists on the UFCM images was 192/201 = 95.5 % and the Cohen kappa coefficient was 0.80. The accuracy of UFCM was 95.5 % (95 %CI: 91.7 %-97.9 %) with a high specificity at 98.8 % (95 %CI: 95.8 %-99.9 %) but an insufficient sensitivity at 76.7 % (95 %CI: 57.7 %-90.1 %). The three micrometastases and four of the 27 macrometastases were missed on UFCM images. CONCLUSION: The UFCM is providing promising detection values with a very good specificity and moderate sensitivity carrying room for improvement.

Adapted EXTREME regimen in the first-line treatment of fit, older patients with recurrent or metastatic head and neck squamous cell carcinoma (ELAN-FIT): a multicentre, single-arm, phase 2 trial.

BACKGROUND: A standard treatment for fit, older patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) is yet to be established. In the previous EXTREME trial, few older patients were included. We aimed to evaluate the efficacy and tolerance of an adapted EXTREME regimen in fit, older patients with recurrent or metastatic HNSCC. METHODS: This single-arm, phase 2 study was done at 22 centres in France. Eligible patients were aged 70 years or older and assessed as not frail (fit) using the ELAN Geriatric Evaluation (EGE) and had recurrent or metastatic HNSCC in the first-line setting that was not eligible for local therapy (surgery or radiotherapy), and an Eastern Cooperative Oncology Group performance status of 0-1. The adapted EXTREME regimen consisted of six cycles of fluorouracil 4000 mg/m2 on days 1-4, carboplatin with an area under the curve of 5 on day 1, and cetuximab on days 1, 8, and 15 (400 mg/m2 on cycle 1-day 1, and 250 mg/m2 subsequently), all intravenously, with cycles starting every 21 days. In patients with disease control after two to six cycles, cetuximab 500 mg/m2 was continued once every 2 weeks as maintenance therapy until disease progression or unacceptable toxicity. Granulocyte colony-stimulating factor was systematically administered and erythropoietin was recommended during chemotherapy. The study was based on the two-stage Bryant and Day design, combining efficacy and toxicity endpoints. The primary efficacy endpoint was objective response rate at week 12 after the start of treatment, assessed by central review (with an unacceptable rate of ≤15%). The primary toxicity endpoint was morbidity, defined as grade 4-5 adverse events, or cutaneous rash (grade ≥3) that required cetuximab to be discontinued, during the chemotherapy phase, or a decrease in functional autonomy (Activities of Daily Living score decrease ≥2 points from baseline) at 1 month after the end of chemotherapy (with an unacceptable morbidity rate of >40%). Analysis of the coprimary endpoints, and of safety in the chemotherapy phase, was based on the per-protocol population, defined as eligible patients who received at least one cycle of the adapted EXTREME regimen. Safety in the maintenance phase was assessed in all patients who received at least one dose of cetuximab as maintenance therapy. The study is registered with ClinicalTrials.gov, NCT01864772, and is completed. FINDINGS: Between Sept 27, 2013, and June 20, 2018, 85 patients were enrolled, of whom 78 were in the per-protocol population. 66 (85%) patients were male and 12 (15%) were female, and the median age was 75 years (IQR 72-79). The median number of chemotherapy cycles received was five (IQR 3-6). Objective response at week 12 was observed in 31 patients (40% [95% CI 30-51]) and morbidity events were observed in 24 patients (31% [22-42]). No fatal adverse events occurred. Four patients presented with a decrease in functional autonomy 1 month after the end of chemotherapy versus baseline. During chemotherapy, the most common grade 3-4 adverse events were haematological events (leukopenia [22 patients; 28%], neutropenia [20; 26%], thrombocytopenia [15; 19%], and anaemia [12; 15%]), oral mucositis (14; 18%), fatigue (11; 14%), rash acneiform (ten; 13%), and hypomagnesaemia (nine; 12%). Among 44 patients who received cetuximab during the maintenance phase, the most common grade 3-4 adverse events were hypomagnesaemia (six patients; 14%) and acneiform rash (six; 14%). INTERPRETATION: The study met its primary objectives on objective response and morbidity, and showed overall survival to be as good as in younger patients treated with standard regimens, indicating that the adapted EXTREME regimen could be used in older patients with recurrent or metastatic HNSCC who are deemed fit with use of a geriatric evaluation tool adapted to patients with head and neck cancer, such as the EGE. FUNDING: French programme PAIR-VADS 2011 (sponsored by the National Cancer Institute, the Fondation ARC, and the Ligue Contre le Cancer), Sandoz, GEFLUC, and GEMLUC. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

Cetuximab versus methotrexate in first-line treatment of older, frail patients with inoperable recurrent or metastatic head and neck cancer (ELAN UNFIT): a randomised, open-label, phase 3 trial.

BACKGROUND: At present, there is no established standard treatment for frail older patients with recurrent or metastatic head and neck squamous cell carcinoma. We aimed to compare the efficacy and safety of cetuximab to those of methotrexate (the reference regimen) in this population. METHODS: This randomised, open-label, phase 3 trial was done at 20 hospitals in France. Patients aged 70 years or older, assessed as frail by the ELAN Geriatric Evaluation, with recurrent or metastatic head and neck squamous cell carcinoma in the first-line setting and with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 were eligible for inclusion. Patients were randomly assigned (1:1) to receive cetuximab 500 mg/m2 intravenously every 2 weeks or methotrexate 40 mg/m2 intravenously every week, with minimisation by ECOG performance status, type of disease evolution, Charlson Comorbidity Index score, serum albumin concentration, and geriatrician consultation. To avoid deterministic minimisation and assure allocation concealment, patients were allocated with a probability of 0·80 to the treatment that most reduced the imbalance. Treatment was continued until disease progression or unacceptable toxicity, whichever occurred first. The primary endpoint was failure-free survival (defined as the time from randomisation to disease progression, death, discontinuation of treatment, or loss of 2 or more points on the Activities in Daily Living scale, whichever occurred first) and was analysed in the intention-to-treat population. 151 failures expected out of 164 patients were required to detect a hazard ratio (HR) of 0·625 with 0·05 alpha error, with 80% power. A futility interim analysis was planned when approximately 80 failures were observed, based on failure-free survival. Safety analyses included all patients who received at least one dose of the study drug. This study is registered on ClinicalTrials.gov (NCT01884623) and was stopped for futility after the interim analysis. FINDINGS: Between Nov 7, 2013, and April 23, 2018, 82 patients were enrolled (41 to the cetuximab group and 41 to the methotrexate group); 60 (73%) were male, 37 (45%) were aged 80 years or older, 35 (43%) had an ECOG performance status of 2, and 36 (44%) had metastatic disease. Enrolment was stopped for futility at the interim analysis. At the final analysis, median follow-up was 43·3 months (IQR 30·8-52·1). At data cutoff, all 82 patients had failure; failure-free survival did not differ significantly between the groups (median 1·4 months [95% CI 1·0-2·1] in the cetuximab group vs 1·9 months [1·1-2·6] in the methotrexate group; adjusted HR 1·03 [95% CI 0·66-1·61], p=0·89). The frequency of patients who had grade 3 or worse adverse events was 63% (26 of 41) in the cetuximab group and 73% (30 of 41) in the methotrexate group. The most common grade 3-4 adverse events in the cetuximab group were fatigue (four [10%] of 41 patients), lung infection (four [10%]), and rash acneiform (four [10%]), and those in the methotrexate group were fatigue (nine [22%] of 41), increased gamma-glutamyltransferase (seven [17%]), natraemia disorder (four [10%]), anaemia (four [10%]), leukopenia (four [10%]), and neutropenia (four [10%]). The frequency of patients who had serious adverse events was 44% (18 of 41) in the cetuximab group and 39% (16 of 41) in the methotrexate group. Four patients presented with a fatal adverse event in the cetuximab group (sepsis, decreased level of consciousness, pulmonary oedema, and death of unknown cause) as did two patients in the methotrexate group (dyspnoea and death of unknown cause). INTERPRETATION: The study showed no improvement in failure-free survival with cetuximab versus methotrexate. Patients with an ECOG performance status of 2 did not benefit from these systemic therapies. New treatment options including immunotherapy should be explored in frail older patients with recurrent or metastatic head and neck squamous cell carcinoma, after an initial geriatric evaluation, such as the ELAN Geriatric Evaluation. FUNDING: French programme PAIR-VADS 2011 (sponsored by the National Cancer Institute, the Fondation ARC and the Ligue Contre le Cancer), GEMLUC, GEFLUC, and Merck Santé. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

Cost-effectiveness analysis alongside the inter-B-NHL ritux 2010 trial: rituximab in children and adolescents with B cell non-Hodgkin's lymphoma.

OBJECTIVES: The randomized controlled trial Inter-B-NHL ritux 2010 showed overall survival (OS) benefit and event-free survival (EFS) benefit with the addition of rituximab to standard Lymphomes Malins B (LMB) chemotherapy in children and adolescents with high-risk, mature B cell non-Hodgkin's lymphoma. Our aim was to assess the cost-effectiveness of rituximab-chemotherapy versus chemotherapy alone in the French setting. METHODS: We used a decision-analytic semi-Markov model with four health states and 1-month cycles. Resource use was prospectively collected in the Inter-B-NHL ritux 2010 trial (NCT01516580). Transition probabilities were assessed from patient-level data from the trial (n = 328). In the base case analysis, direct medical costs from the French National Insurance Scheme and life-years (LYs) were computed in both arms over a 3-year time horizon. Incremental net monetary benefit and cost-effectiveness acceptability curve were computed through a probabilistic sensitivity analysis. Deterministic sensitivity analysis and several sensitivity analyses on key assumptions were also conducted, including one exploratory analysis with quality-adjusted life years as the health outcome. RESULTS: OS and EFS benefits shown in the Inter-B-NHL ritux 2010 trial translated into the model by rituximab-chemotherapy being the most effective and also the least expensive strategy over the chemotherapy strategy. The mean difference in LYs between arms was 0.13 [95% CI 0.02; 0.25], and the mean cost difference € - 3 710 [95% CI € - 17,877; € 10,525] in favor of rituximab-chemotherapy group. For a € 50,000 per LY willingness-to-pay threshold, the probability of the rituximab-chemotherapy strategy being cost-effective was 91.1%. All sensitivity analyses confirmed these findings. CONCLUSION: Adding rituximab to LMB chemotherapy in children and adolescents with high-risk mature B-cell non-Hodgkin's lymphoma is highly cost-effective in France. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01516580.

Season of radiotherapy and outcomes of head & neck cancer patients in the MACH-NC & MARCH meta-analyses.

BACKGROUND: A single institution retrospective study suggested that head and neck squamous cell cancer (HNSCC) patients receiving radiotherapy (RT) during "dark" season (fall/winter) may have better outcomes than those treated during "light" season (spring/summer), possibly secondary to seasonal variations in cell cycle progression. We investigated the impact of season of RT in two large, multi-institutional, prospective datasets of randomized trials. METHODS: Individual patient data from the MACH-NC and MARCH meta-analyses were analyzed. Dark season was defined as mid-radiotherapy date during fall or winter and light the reverse, using equinoxes to separate the two periods. Primary endpoint was progression-free survival (PFS) and secondary endpoint was locoregional failure (LRF). The effect of season was estimated with a Cox model stratified by trial and adjusted on sex, tumor site, stage, and treatment. Planned sensitivity analyses were performed on patients treated around solstices, who received "complete radiotherapy", patients treated with concomitant radio-chemotherapy and on trials performed in Northern countries. RESULTS: 11320 patients from 33 trials of MARCH and 6276 patients from 29 trials of MACH-NC were included. RT during dark season had no benefit on PFS in the MARCH (hazard ratio[HR]: 1.01 [95%CI 0.97;1.05],p=0.72) or MACH-NC dataset (HR:1.00 [95%CI 0.94;1.06],p=1.0. No difference in LRF was observed in the MARCH (HR:1.00 [95%CI 0.94;1.06,p=0.95) or MACH-NC dataset (HR:0.99 [95%CI 0.91; 1.07],p=0.77). Sensitivity analyses showed similar results. CONCLUSION: Season of RT had no impact on PFS or LRF in two large databases of HNSCC.

Role of chemotherapy in patients with nasopharynx carcinoma treated with radiotherapy (MAC-NPC): an updated individual patient data network meta-analysis.

BACKGROUND: The meta-analysis of chemotherapy for nasopharynx carcinoma (MAC-NPC) collaborative group previously showed that the addition of adjuvant chemotherapy to concomitant chemoradiotherapy had the highest survival benefit of the studied treatment regimens in nasopharyngeal carcinoma. Due to the publication of new trials on induction chemotherapy, we updated the network meta-analysis. METHODS: For this individual patient data network meta-analysis, trials of radiotherapy with or without chemotherapy in patients with non-metastatic nasopharyngeal carcinoma that completed accrual before Dec 31, 2016, were identified and updated individual patient data were obtained. Both general databases (eg, PubMed and Web of Science) and Chinese medical literature databases were searched. Overall survival was the primary endpoint. A frequentist network meta-analysis approach with a two-step random effect stratified by trial based on hazard ratio Peto estimator was used. Global Cochran Q statistic was used to assess homogeneity and consistency, and p score to rank treatments, with higher scores indicating higher benefit therapies. Treatments were grouped into the following categories: radiotherapy alone, induction chemotherapy followed by radiotherapy, induction chemotherapy without taxanes followed by chemoradiotherapy, induction chemotherapy with taxanes followed by chemoradiotherapy, chemoradiotherapy, chemoradiotherapy followed by adjuvant chemotherapy, and radiotherapy followed by adjuvant chemotherapy. This study is registered with PROSPERO, CRD42016042524. FINDINGS: The network comprised 28 trials and included 8214 patients (6133 [74·7%] were men, 2073 [25·2%] were women, and eight [0·1%] had missing data) enrolled between Jan 1, 1988, and Dec 31, 2016. Median follow-up was 7·6 years (IQR 6·2-13·3). There was no evidence of heterogeneity (p=0·18), and inconsistency was borderline (p=0·10). The three treatments with the highest benefit for overall survival were induction chemotherapy with taxanes followed by chemoradiotherapy (hazard ratio 0·75; 95% CI 0·59-0·96; p score 92%), induction chemotherapy without taxanes followed by chemoradiotherapy (0·81; 0·69-0·95; p score 87%), and chemoradiotherapy followed by adjuvant chemotherapy (0·88; 0·75-1·04; p score 72%), compared with concomitant chemoradiotherapy (p score 46%). INTERPRETATION: The inclusion of new trials modified the conclusion of the previous network meta-analysis. In this updated network meta-analysis, the addition of either induction chemotherapy or adjuvant chemotherapy to chemoradiotherapy improved overall survival over chemoradiotherapy alone in nasopharyngeal carcinoma. FUNDING: Institut National du Cancer and Ligue Nationale Contre le Cancer.

Post-therapeutic surveillance of HPV-driven oropharyngeal cancers: are we ready to change our practices?

PURPOSE: Although HPV-positive and negative oropharyngeal cancers are two distinct diseases, Post-Therapeutic Surveillance (PTS) modalities are similar. Adjusting PTS strategies to HPV status will represent a massive practice change that raises the issue of its acceptability, by both physicians and patients. METHODS: Two distinct surveys were designed and submitted, respectively, to HPV-positive patients and physicians (surgeons, radiation and medical oncologists) involved in head and neck cancer treatment. RESULTS: 133 patients and 90 physicians have participated to the study. Most patients were reluctant to embrace new PTS options (remote consultations, nurse consultations and smart phone applications). However, 84% of patients would be favorable to use HPV Circulating DNA (HPV Ct DNA) measurement to guide surveillance modalities. 57% of physicians acknowledged that our current PTS strategy is improvable and most of them would accept the use of new monitoring options from the third year of follow-up. 87% of physicians would be interested to participate to a trial comparing the current PTS strategy to a new approach, where monitoring modalities (number of visits, imaging prescription) would depend on HPV Ct DNA level. CONCLUSIONS: Patients and physicians are aware that PTS modalities should depend on HPV status. Their adhesion is a prerequisite to any potential changes. Strategies based on HPV Ct DNA measurement should be assessed within a randomized clinical trial.

Effect of rituximab on immune status in children with mature B-cell non-Hodgkin lymphoma: a prespecified secondary analysis of the Inter-B-NHL Ritux 2010 trial.

BACKGROUND: Survival of children and adolescents with high-risk, mature B-cell non-Hodgkin lymphoma is improved by the addition of rituximab to chemotherapy. The effect of rituximab on immune reconstitution after therapy has not been well described. Herein, we evaluate the immune effects of the addition of rituximab to intensive chemotherapy, a prespecified secondary aim of the Inter-B-NHL Ritux 2010 trial. METHODS: The Inter-B-NHL Ritux 2010 trial was an international, open-label, randomised, phase 3 trial in children (age 6 months to 18 years) with high-risk, mature B-cell non-Hodgkin lymphoma, comparing chemotherapy alone or chemotherapy with rituximab. Measures of immune status were completed at baseline, 1 month from the end of treatment, and 1 year from the start of therapy, and yearly thereafter until normalised. For this secondary analysis, we report on the proportions of patients with low lymphocyte counts and immunoglobulin concentrations at these timepoints with total lymphocyte count, B-cell count, and IgG concentration as the main endpoints. Other endpoints of interest included exposure to immunoglobulin replacement therapy and vaccine serologies. The population assessed for immune endpoints was the eligible per-protocol population with at least one immune parameter at one timepoint. Comparisons of immune status were made between the randomised treatment groups. Safety in the post-therapy period was assessed in the population eligible for the immunity study who were followed up at least 3 months after the end of treatment and without cancer-related events. The Inter-B-NHL Ritux 2010 study was registered with ClinicalTrials.gov, NCT01516580; status completed, with analyses of secondary aims ongoing. FINDINGS: From Dec 19, 2011, to June 13, 2017, 421 patients (344 [82%] boys and 77 [18%] girls; mean age was 8·8 years [SD 4·1]) were enrolled and had immune data at baseline during follow-up, or both. The study population included randomly assigned patients (n=289) and a non-randomised cohort enrolled after the planned interim analysis (n=132). At baseline, 99 (34%) of 290 patients with available data (excluding patients with bone marrow disease with peripheral blast cells) had lymphopenia, and 178 (48%) of 368 had hypogammaglobulinemia. 1 month from the end of therapy, patients who received chemotherapy with rituximab were more likely than those who received chemotherapy alone to have lymphopenia (86 [81%] of 106 vs 53 (60%) of 89, odds ratio [OR] 2·92 [95% CI 1·53-5·57], p=0·0011), B-cell lymphopenia (72 [96%] of 75 vs 36 [64%] of 56, OR 13·33 [3·71-47·84], p<0·0001), and hypogammaglobulinemia (67 [71%] of 95 vs 37 [47%] of 79, OR 2·72 [1·45-5·07], p=0·0017). Differences remained at 1 year for hypogammaglobulinemia only (52 [55%] of 94 vs 16 [25%] of 63, OR 3·64 [1·81-7·31], p=0·0003). Patients in the chemotherapy with rituximab group were more likely than those in the chemotherapy group to receive immunoglobulin replacement (26 [16%] 164 vs nine [7%] of 158, hazard ratio [HR] 2·63 [95% CI 1·23-5·62], p=0·010), mainly due to low immunoglobulin concentration. In the combined treatment groups, including non-randomly assigned patients, the proportion of patients who had loss of protective serologies to a vaccine preventable infection varied from four (9%) of 47 for polio to 21 (42%) of 50 for Streptococcus pneumoniae (pneumococcus). One patient (chemotherapy with rituximab group) had a life-threatening infectious event of polymicrobial bacterial sepsis reported 2 months after the final chemotherapy administration. INTERPRETATION: Children with high-risk mature B-cell non-Hodgkin lymphoma receiving chemotherapy with rituximab were at risk of prolonged hypogammaglobulinemia, although severe infections were rare. Strategies for immunoglobulin replacement and revaccination are needed. FUNDING: Clinical Research Hospital Program of the French Ministry of Health, Cancer Research UK, National Institute for Health Research Clinical Research Network in England, Children's Cancer Foundation Hong Kong, US National Cancer Institute, F Hoffmann-La Roche.

Improving outcomes of childhood and young adult non-Hodgkin lymphoma: 25 years of research and collaboration within the framework of the European Intergroup for Childhood Non-Hodgkin Lymphoma.

The European Intergroup for Childhood Non-Hodgkin Lymphoma (EICNHL) was established 25 years ago with the goal to facilitate clinical trials and research collaborations in the field both within Europe and worldwide. Since its inception, much progress has been made whereby major improvements in outcomes have been achieved. In this Review, we describe the different diagnostic entities of non-Hodgkin lymphoma in children and young adults describing key features of each entity and outlining clinical achievements made in the context of the EICNHL framework. Furthermore, we provide an overview of advances in biopathology with an emphasis on the role of biological studies and how they have shaped available treatments. Finally, for each entity, we describe future goals, upcoming clinical trials, and highlight areas of research that require our focus going forward.

Rituximab in addition to LMB-based chemotherapy regimen in children and adolescents with primary mediastinal large B-cell lymphoma: results of the French LMB2001 prospective study.

Primary mediastinal large B-cell lymphoma (PMLBL) is a rare entity predominantly affecting adolescents and young adults. Recently, an international phase II trial in pediatric patients using dose-adjusted etoposide, doxorubicin, and cyclophosphamide with vincristine and prednisone plus rituximab (DA-EPOCH-R) failed to reproduce excellent survival reported in some adult studies. The optimal therapy regimen needs to be determined in this disease. The French prospective LMB2001 trial included all patients ≤18 years with mature B-cell lymphoma treated in French centers. For patients with PMLBL, treatment included four to eight courses of Lymphomes Malins B (LMB)-based chemotherapy without radiotherapy. From 2008, rituximab was added before each chemotherapy course. From 09/2001 to 03/2012, 42 patients with PMLBL were registered. The median age was 15 years (range, 8-18). Twenty-one patients were treated with chemotherapy plus rituximab. The median follow-up was 7.1 years (interquartile range, 5.8-11.1). Five-year event-free and overall survival were 88.1% (95% confidence interval (CI): 75.0-94.8) and 95.2% (95% CI: 84.0-98.7) for the whole population. The 5-year EFS was 81.0% (95% CI: 60.0-92.3) and 95.2% (95% CI: 77.3-99.2) (hazard ratio =0.24; 95% CI: 0.03- 2.2) and 5-year overall survival was 90.5% (95% CI: 71.1-97.3) and 100% for patients treated without and with rituximab, respectively. Only one of 21 patients treated with rituximab and LMB-based chemotherapy had local early treatment failure but achieved prolonged complete remission with second-line chemotherapy and radiotherapy. Intensive LMBbased chemotherapy with rituximab achieved excellent survival in children/adolescents with PMLBL. Further international prospective studies are required to confirm these results in this population.

Meta-analysis of chemotherapy in nasopharynx carcinoma (MAC-NPC): An update on 26 trials and 7080 patients.

PURPOSE: Chemotherapy, when added to radiotherapy, improves survival in locally advanced nasopharyngeal carcinoma (NPC). This article presents the second update of the Meta-Analysis of Chemotherapy in NPC. METHODS: Published or unpublished randomized trials assessing radiotherapy (±a second chemotherapy timing) with/without chemotherapy in non-metastatic NPC patients were identified. Updated data were sought for studies included in the previous rounds of the meta-analysis. The primary endpoint was overall survival. All trials were analyzed following the intent-to-treat principle using a fixed-effects model. Treatments were classified in five subsets according to chemotherapy timing. The statistical analysis plan was pre-specified. RESULTS: Eighteen new trials were identified. Individual patient data were available for seven. In total, the meta-analysis now included 26 trials and 7,080 patients. The addition of chemotherapy reduced the risk of death, with a hazard ratio (HR) of 0.79 (95% confidence interval (CI) [0.73; 0.85]), and an absolute survival increase at 5 and 10 years of 6.1% [+3.9; +8.3] and + 8.4% [+5.7; +11.1], respectively. The largest effect was observed for concomitant + adjuvant, induction (with concomitant in both arms) and concomitant chemotherapy, with respective HR [95%CI] of 0.68 [0.59; 0.79] (absolute survival increase at 5 years: 12.3% (7.0%;17.6%)), 0.73 [0.63; 0.86] (6.0% (2.5%;9.5%)) and 0.81 [0.70; 0.92] (5.2% (0.8%;9.6%)). The benefit of chemotherapy was also demonstrated by improvement in progression-free survival, cancer mortality, locoregional control and distant control. There was a significant interaction between patient age and chemotherapy effect. CONCLUSION: This updated meta-analysis confirms the benefit of concomitant chemotherapy and concomitant + adjuvant chemotherapy, and suggests that addition of induction or adjuvant chemotherapy to concomitant chemotherapy improves tumor control and survival. The benefit of chemotherapy decreases with increasing patient age.

Imaging of Skull Base and Orbital Invasion in Sinonasal Cancer: Correlation with Histopathology.

BACKGROUND: Pretreatment assessment of local extension in sinonasal cancer is essential for prognostic evaluation and surgical planning. The aim of this study was to assess the diagnostic performance of two common imaging techniques (CT and MRI) for the diagnosis of skull base and orbital invasion by comparing imaging findings to histopathological data. METHODS: This was a retrospective two-center study including patients with sinonasal cancer involving the skull base and/or the orbit operated on between 2000 and 2019. Patients were included only if pre-operative CT and/or MRI, operative and histopathologic reports were available. A double prospective blinded imaging review was conducted according to predefined radiological parameters. Radiologic tumor extension was compared to histopathological reports, which were considered the gold standard. The predictive positive value (PPV) for the diagnosis of skull base/orbital invasion was calculated for each parameter. RESULTS: A total of 176 patients were included. Ethmoidal intestinal-type adenocarcinoma was the most common type of cancer (41%). The PPV for major modification of the bony skull base was 78% on the CT scan, and 89% on MRI. MRI signs of dural invasion with the highest PPVs were: contact angle over 45° between tumor and dura (86%), irregular deformation of dura adjacent to tumor (87%) and nodular dural enhancement over 2 mm in thickness (87%). Signs of orbital invasion had low PPVs (<50%). CONCLUSIONS: This retrospective study provides objective data about the diagnostic value of pretreatment imaging in patients with sinonasal cancer.

Dose-Adjusted Etoposide, Doxorubicin, and Cyclophosphamide With Vincristine and Prednisone Plus Rituximab Therapy in Children and Adolescents With Primary Mediastinal B-Cell Lymphoma: A Multicenter Phase II Trial.

PURPOSE: A dose-adjusted etoposide, doxorubicin, and cyclophosphamide with vincristine and prednisone plus rituximab (DA-EPOCH-R) regimen has been shown to deliver excellent survival for adults with primary mediastinal large B-cell lymphoma (PMLBL) without the use of radiotherapy. No international prospective evaluation of this regimen has previously been reported in children and adolescents. PATIENTS AND METHODS: We conducted an international single-arm phase II trial involving patients younger than age 18 years with PMLBL who were to receive six courses of DA-EPOCH-R. The primary end point was event-free survival (EFS). Overall survival and toxicity were also assessed. This trial was registered (ClinicalTrials.gov identifier: NCT01516567). RESULTS: Analyses were based on 46 patients. The median age was 15.4 years (interquartile range: 14-16 years). The median follow-up was 59.0 months (interquartile range: 52.6-69.2 months). Fourteen events were observed (eight relapses or progressions (including three parenchymal CNS relapses), four residual lymphoma, and two second malignancies). The 4-year EFS was 69.6% (95% CI, 55.2 to 80.9), which did not differ from the rate observed historically (P = .59). Seven deaths occurred (six disease-related and one second malignancy). The overall survival was 84.8% (95% CI, 71.8 to 92.4). Twenty-two patients (48%) reached dose levels ≥ 4. Nonhematologic adverse events grade ≥ 3 or cardiac adverse events grade ≥ 2 occurred in 47 of 276 (17%) courses and 30 of 46 patients (65%). CONCLUSION: DA-EPOCH-R did not improve the EFS compared with a historical control in this first prospective multisite international study of children and adolescents with PMLBL. Further studies are required to determine the optimum therapy for children and adolescents with this lymphoma.

Efficacy and safety of immune checkpoint inhibitors in elderly patients (≥70 years) with squamous cell carcinoma of the head and neck.

BACKGROUND: Recent meta-analysis showed that immune checkpoint inhibitors (ICIs) have comparable activity between younger and older patients. However, little is known about efficacy and safety of ICI in elderly patients with relapsed/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). The aim of this study is to compare the efficacy of ICI for patients aged ≥70 y to that for younger patients, while taking into account potential confounding factors. METHODS: A retrospective study was conducted at four hospitals in France. Patients treated with ICI for R/M SCCHN between September 2014 and December 2018 were eligible. Patients' charts were reviewed for clinical and radiological data as well as oncologic outcomes. RESULTS: We included 226 patients, of whom 67 were aged ≥70 years. Objective response rate (ORR), median overall survival (OS) and median progression-free survival (PFS) were 23%, 9.7 months and 2.7 months, respectively, for elderly patients, compared to 13%, 8.7 months and 1.9 months for younger patients (respective p-values: 0.071, 0.87 and 0.21). After adjustment for performance status, site of progression, number of ICI drugs, time between initial diagnosis and ICI start and number of previous lines, age ≥70 years was significantly associated with a better PFS (hazard ratio [HR], 0.66; p = 0.021) but not OS (HR, 0.91; p = 0.59). Grade 3-5 adverse events (AEs) occurred in 15% of patients aged ≥70 years and in 8% of younger patients (p = 0.13). CONCLUSION: Patients aged ≥70 years with R/M SCCHN may respond to ICI similarly as younger patients in terms of ORR, OS and PFS, while maintaining comparable rate of AEs.

Impact of COVID-19 on healthcare organisation and cancer outcomes.

BACKGROUND: Changes in the management of patients with cancer and delays in treatment delivery during the COVID-19 pandemic may impact the use of hospital resources and cancer mortality. PATIENTS AND METHODS: Patient flows, patient pathways and use of hospital resources during the pandemic were simulated using a discrete event simulation model and patient-level data from a large French comprehensive cancer centre's discharge database, considering two scenarios of delays: massive return of patients from November 2020 (early-return) or March 2021 (late-return). Expected additional cancer deaths at 5 years and mortality rate were estimated using individual hazard ratios based on literature. RESULTS: The number of patients requiring hospital care during the simulation period was 13,000. In both scenarios, 6-8% of patients were estimated to present a delay of >2 months. The overall additional cancer deaths at 5 years were estimated at 88 in early-return and 145 in late-return scenario, with increased additional deaths estimated for sarcomas, gynaecological, liver, head and neck, breast cancer and acute leukaemia. This represents a relative additional cancer mortality rate at 5 years of 4.4 and 6.8% for patients expected in year 2020, 0.5 and 1.3% in 2021 and 0.5 and 0.5% in 2022 for each scenario, respectively. CONCLUSIONS: Pandemic-related diagnostic and treatment delays in patients with cancer are expected to impact patient survival. In the perspective of recurrent pandemics or alternative events requiring an intensive use of limited hospital resources, patients should be informed not to postpone care, and medical resources for patients with cancer should be sanctuarised.

Impact of follow-up on generalized pairwise comparisons for estimating the irinotecan benefit in advanced/metastatic gastric cancer.

BACKGROUND AND OBJECTIVES: The net treatment effect (∆) is a new method to assess the treatment benefit that combines multiple time-to-event, binary and continuous endpoints according to a pre-specified sequence. It represents the net probability for a random patient treated in the experimental arm to have a better overall outcome than a random patient from the control arm does. We aimed at characterizing the impact of follow-up on ∆ estimated from both time-to-event and binary toxicity endpoints, in randomized controlled trials (RCTs) of irinotecan-based regimen in advanced/metastatic gastric cancer (AGC). STUDY DESIGN: Three RCTs are reanalysed. The net treatment effect using from one to three outcomes (i.e. overall survival, time to progression and toxicity in this order) and the hazard ratio (HR) were estimated after various cut-off dates and compared to the values obtained after complete follow-up were reported. RESULTS: In all three RCTs (897 patients), the irinotecan-based regimen was superior to the non-irinotecan containing regimen in terms of HR and ∆. This superiority was lower when the net treatment effect also accounted for toxicity. The HR was slightly less influenced by an incomplete follow-up than ∆ was, but correction proposed by Péron to account for censored observations showed quite robust results. CONCLUSIONS: The net treatment effect using Péron's correction can be used in case of interim analyses or high censoring rates. In addition to relative measures such as the hazard ratio, it provides a simple mean to evaluate the net treatment effect with and without toxicity outcomes.

Chemotherapy and radiotherapy in locally advanced head and neck cancer: an individual patient data network meta-analysis.

BACKGROUND: Randomised, controlled trials and meta-analyses have shown the survival benefit of concomitant chemoradiotherapy or hyperfractionated radiotherapy in the treatment of locally advanced head and neck cancer. However, the relative efficacy of these treatments is unknown. We aimed to determine whether one treatment was superior to the other. METHODS: We did a frequentist network meta-analysis based on individual patient data of meta-analyses evaluating the role of chemotherapy (Meta-Analysis of Chemotherapy in Head and Neck Cancer [MACH-NC]) and of altered fractionation radiotherapy (Meta-Analysis of Radiotherapy in Carcinomas of Head and Neck [MARCH]). Randomised, controlled trials that enrolled patients with non-metastatic head and neck squamous cell cancer between Jan 1, 1980, and Dec 31, 2016, were included. We used a two-step random-effects approach, and the log-rank test, stratified by trial to compare treatments, with locoregional therapy as the reference. Overall survival was the primary endpoint. The global Cochran Q statistic was used to assess homogeneity and consistency and P score to rank treatments (higher scores indicate more effective therapies). FINDINGS: 115 randomised, controlled trials, which enrolled patients between Jan 1, 1980, and April 30, 2012, yielded 154 comparisons (28 978 patients with 19 253 deaths and 20 579 progression events). Treatments were grouped into 16 modalities, for which 35 types of direct comparisons were available. Median follow-up based on all trials was 6·6 years (IQR 5·0-9·4). Hyperfractionated radiotherapy with concomitant chemotherapy (HFCRT) was ranked as the best treatment for overall survival (P score 97%; hazard ratio 0·63 [95% CI 0·51-0·77] compared with locoregional therapy). The hazard ratio of HFCRT compared with locoregional therapy with concomitant chemoradiotherapy with platinum-based chemotherapy (CLRTP) was 0·82 (95% CI 0·66-1·01) for overall survival. The superiority of HFCRT was robust to sensitivity analyses. Three other modalities of treatment had a better P score, but not a significantly better HR, for overall survival than CLRTP (P score 78%): induction chemotherapy with taxane, cisplatin, and fluorouracil followed by locoregional therapy (ICTaxPF-LRT; 89%), accelerated radiotherapy with concomitant chemotherapy (82%), and ICTaxPF followed by CLRT (80%). INTERPRETATION: The results of this network meta-analysis suggest that further intensifying chemoradiotherapy, using HFCRT or ICTaxPF-CLRT, could improve outcomes over chemoradiotherapy for the treatment of locally advanced head and neck cancer. FUNDINGS: French Institut National du Cancer, French Ligue Nationale Contre le Cancer, and Fondation ARC.