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In the H10 and RAPID randomised trials, chemotherapy+radiotherapy (combined modalities treatment, CMT) was compared with chemotherapy (C) in limited-stage Hodgkin lymphoma (HL), with negative early positron emission tomography (ePETneg). We analysed patterns of relapses in the H10 trial, validated findings in the RAPID trial and performed a combined analysis stratified by trial. The impact of radiotherapy (RT) on risk of relapse was studied using adjusted Cox models, with time-varying effects. In H10, 1,059 ePETneg patients were included (465 European Organisation for Research and Treatment of Cancer (EORTC) favourable [F], 594 unfavourable [U]). Among the F patients, 2/227 (1%) relapsed after CMT, 30/238 (13%) after C: of these relapses, 21/30 (70%) occurred in less than 2 years and 25/30 (83%) affected originally involved areas. Among the U group, 16/292 (5%) relapsed after CMT: 8/16 (50%) in less than 2 years, 11/16 (69%) in originally involved areas. After C 30/302 (10%) relapsed: 27/30 (90%) in less than 2 years, and 26/30 (87%) in originally involved areas. Similar results were observed in 419 ePETneg RAPID patients (241 F, 128 U, 50 unclassified): among F patients, 6/118 (5%) relapsed after CMT; 13/123 (11%) after C: 11/13 (85%) in less than 2 years and 11/13 (85%) affecting originally involved areas. In U patients, 3/65 (5%) relapsed after CMT and 5/63 (8%) after C. In both trials, omitting RT in ePETneg HL resulted in more early relapses, mainly affecting originally involved areas. RT significantly reduced risk of early relapses in the combined stratified analysis.

Involved Node Radiotherapy (INRT) was introduced in the EORTC/LYSA/FIL H10 trial, a large multicenter trial in early stage Hodgkin Lymphoma (HL). The current study aimed to evaluate the quality of INRT in this trial. A retrospective, descriptive study was initiated to evaluate INRT in a representative sample encompassing approximately 10% of all irradiated patients in the H10 trial. Sampling was stratified by academic group, year of treatment, size of treatment center and treatment arm and it was done proportional to the size of the strata. The sample was completed for all patients with known recurrences to enable future research on relapse pattern. Radiotherapy principle, delineation and coverage of the target volume and applied technique and dose were evaluated using the EORTC Radiotherapy Quality Assurance (RTQA) platform. Each case was reviewed by two reviewers and, in case of disagreement, also by an adjudicator for a consensus evaluation. Data was retrieved for 66 out of 1294 irradiated patients (5.1%). Data collection and analysis were hampered by changes in archiving of diagnostic imaging and treatment planning systems during the running period of the trial, more than anticipated. Review could be performed in 61 patients. The INRT principle was applied in 86.6%. Overall, 88.5% of cases were treated according to protocol. Unacceptable variations were predominately due to geographical misses of the target volume delineations. The rate of unacceptable variations decreased during trial recruitment. The principle of INRT was applied in most of the reviewed patients. Almost 90% of the evaluated patients were treated according to the protocol. The current results should, however, be interpreted with caution because the number of patients evaluated was limited. In future trials, individual case reviews should be done in a prospective fashion. RTQA tailored to the clinical trial objectives is strongly recommended.

OBJECTIVES: We aimed to assess patterns of care delivered to older patients with locally advanced head and neck squamous cell carcinoma (LA-HNSCC), and to analyze the use of geriatric assessment (GA) and assessment of quality of life (QoL).MATERIALS AND METHODS: Members of the head and neck cancer group and the older task force of the European Organisation for Research and Treatment of Cancer (EORTC), members the European Head and Neck Society and members of national groups in Europe were asked to complete a questionnaire about treatment delivered, use of GA, and QoL assessment in older patients with LA-HNSCC.RESULTS: Investigators from 111 centers replied, including 90 (81.1%) academic centers, 16 (14.4%) community hospitals, and 5 (4.5%) private clinics. Large differences in treatment patterns were found. For instance, for oropharyngeal carcinoma, one third of the centers indicated that they treat 40% of older patients with chemoradiation. Fourteen centers (12.6%) routinely perform GA, while 43 centers (38.7%) never do, and 39 centers (35.1%) sometimes do. QoL is assessed on a routine basis in one fifth of the centers.CONCLUSIONS: Large differences exist across institutions in the patterns of care delivered to older patients with LA-HNSCC. Prospective studies are required to learn how GA can guide treatment decisions, and how QoL and treatment outcome can be improved. For that, consensus on standard of care is essential.

The purpose of this study is to evaluate the influence of the extent of surgery and radiation therapy (RT) on the rates and sites of local (LR) and regional recurrences (RR) in the EORTC 22922/10925 trial. Patients and methods: All data were extracted from the trial's individual patients’ case report forms (CRF) and analysed with a median follow-up of 15.7 years. Cumulative incidence curves were produced for LR and RR accounting for competing risks: an exploratory analysis of the effect of the extent of surgical and radiation treatments on LR rate was conducted using the Fine & Gray model accounting for competing risks and adjusted for baseline patient and disease characteristics. The significance level was set at 5%, 2-sided. Frequency tables were used to describe the spatial location of LR and RR. Results: Out of 4004 patients included in the trial, 282 (7%) patients experienced LR and 165 (4.1%) RR, respectively. Cumulative incidence rate of LR at 15 years was lower after mastectomy (3.1%) compared to BCS + RT (7.3%) (F&G: HR (Hazard Ratio) = 0.421, 95%CI = 0.282–0.628, p-value < 0.0001). LR were similar up to 3 years for both mastectomy and BCS but continued to occur at a steady rate for BCS + RT, only. The spatial location of the recurrence was related to the locoregional therapy applied and the absolute gain of RT correlated to stage of disease and extent of surgery. Conclusions: The extent of locoregional therapies impacts significantly on LR and RR rates and spatial location.

Background: This study was designed to test the hypothesis that the effectiveness of intensive treatment for locoregionally advanced head and neck cancer (LAHNC) depends on the proportion of patients' overall event risk attributable to cancer. / Methods: This study analyzed 22,339 patients with LAHNC treated in 81 randomized trials testing altered fractionation (AFX; Meta‐Analysis of Radiotherapy in Squamous Cell Carcinomas of Head and Neck [MARCH] data set) or chemotherapy (Meta‐Analysis of Chemotherapy in Head and Neck Cancer [MACH‐NC] data set). Generalized competing event regression was applied to the control arms in MARCH, and patients were stratified by tertile according to the ω score, which quantified the relative hazard for cancer versus competing events. The classifier was externally validated on the MACH‐NC data set. The study tested for interactions between the ω score and treatment effects on overall survival (OS). / Results: Factors associated with a higher ω score were a younger age, a better performance status, an oral cavity site, higher T and N categories, and a p16‐negative/unknown status. The effect of AFX on OS was greater in patients with high ω scores (hazard ratio [HR], 0.92; 95% confidence interval [CI], 0.85‐0.99) and medium ω scores (HR, 0.91; 95% CI, 0.84‐0.98) versus low ω scores (HR, 0.97; 95% CI, 0.90‐1.05; P for interaction = .086). The effect of chemotherapy on OS was significantly greater in patients with high ω scores (HR, 0.81; 95% CI, 0.75‐0.88) and medium ω scores (HR, 0.86; 95% CI, 0.78‐0.93) versus low ω scores (HR, 0.96; 95% CI, 0.86‐1.08; P for interaction = .011). / Conclusions: LAHNC patients with a higher risk of cancer progression relative to competing mortality, as reflected by a higher ω score, selectively benefit from more intensive treatment.

Purpose We explored the potential overall survival (OS) benefit of bleomycin, etoposide, doxorubicin (Adriamycin), cyclophosphamide, vincristine (Oncovin), procarbazine, and prednisone (BEACOPP) over doxorubicin (Adriamycin), bleomycin, vinblastine, and dacarbazine (ABVD) in a pooled analysis of four randomized trials. Patients and methods Primary objective was to evaluate the OS impact of BEACOPP using individual patient data. Secondary objectives were progression‐free survival (PFS), secondary cancers, and use of autologous stem cell transplantation (ASCT). Results About 1227 patients were included. The 7‐year OS was 84.3% (95% CI 80.8‐87.2) for ABVD vs 87.7% (95% CI 84.5‐90.2) for BEACOPP. Two follow‐up periods were identified based on survival curves and hazard ratio (HR) over time. For the first 18 months, there was no difference. For the second period of ≥18 months, ABVD patients had a higher death risk (HRABVD vs BEACOPP = 1.59; 95% CI 1.09‐2.33). A Cox model stratified by trial and evaluating the effect of treatment and International Prognostic Index (IPI) score as fixed effects showed that both were statistically significant (treatment, P = .0185; IPI score, P = .0107). The 7‐year PFS was 71.1% (95% CI 67.1‐74.6) for ABVD vs 81.1% (95% CI 77.5‐84.2) for BEACOPP (P, Advanced Hodgkin lymphoma (HL) are treated with two different chemotherapy regimens (doxorubicin [Adriamycin], bleomycin, vinblastine, and dacarbazine [ABVD] or bleomycin, etoposide, doxorubicin [Adriamycin], cyclophosphamide, vincristine [Oncovin], procarbazine, and prednisone [BEACOPP]) that have two different toxicity profiles. In this pooled analysis of four randomized trials comparing these two regimens, and with a median follow‐up of 7 years, progression‐free survival is significantly superior with the BEACOPP regimen. The 7 years overall survival was 84.3% for ABVD and 87.7% for BEACOPP. The main cause of death after ABVD is HL, but second malignancy including 10 myeloid malignancies after BEACOPP.

Contains fulltext : 238276.pdf (Publisher’s version ) (Closed access) BACKGROUND: In the TAX 323 (EORTC 24971) phase III trial enrolling patients with unresectable locoregionally advanced squamous cell carcinoma of the head and neck (LA-SCCHN), the addition of docetaxel (T) to cisplatin and 5-fluorouracil (PF)-based induction chemotherapy prior to definite radiotherapy significantly improved progression-free survival (PFS) and overall survival (OS). METHODS: The data were updated for PFS, OS and treatment-related long-term side-effects. Baseline clinical and laboratory data of 17 variables were collected and subjected to univariate and multivariate prognostic factor analyses for OS. RESULTS: All 358 patients randomised between 1999 and 2002 were included in the long-term analysis with a median follow-up of 8.6 years. The primary end-point of PFS remained significantly improved with TPF compared with PF (adjusted hazard ratio [HR], 0.70; 95% CI, 0.56-0.88, p = 0.002), translating into a persisting benefit in OS (adjusted HR, 0.75; 95% CI, 0.60-0.95, p = 0.015). Long-term side-effects in the TPF/PF arms comprised tracheostomy (7%/5%), feeding tube dependency (3%/6%) and gastrostomy (11%/11%). Second malignancy occurred in 8%/3%, respectively. Out of 177 patients randomised to the TPF arm, 160 were included in the multivariate analysis. Grade 2 or more dysphagia (p = 0.002) and grade 2 or more pain (p = 0.004) at baseline were identified as independent negative prognostic factors. In addition, OS differed across primary tumour sites (p = 0.027) and was worse in patients with a higher N-stage (p = 0.025). CONCLUSIONS: In LA-SCCHN patients treated with sequential chemoradiotherapy, TPF induction chemotherapy demonstrated long-lasting efficacy, superior to the PF regimen. Higher-grade dysphagia and pain are unfavourable prognosticators.

Introduction The current phase III EORTC 1420 Best-of trial (NCT02984410) compares the swallowing function after transoral surgery versus intensity modulated radiotherapy (RT) in patients with early-stage carcinoma of the oropharynx, supraglottis and hypopharynx. We report the analysis of the Benchmark Case (BC) procedures before patient recruitment with special attention to dysphagia/aspiration related structures (DARS). Materials and methods Submitted RT volumes and plans from participating centers were analyzed and compared against the gold-standard expert delineations and dose distributions. Descriptive analysis of protocol deviations was conducted. Mean Sorensen-Dice similarity index (mDSI) and Hausdorff distance (mHD) were applied to evaluate the inter-observer variability (IOV). Results 65% (23/35) of the institutions needed more than one submission to achieve Quality assurance (RTQA) clearance. OAR volume delineations were the cause for rejection in 53% (40/76) of cases. IOV could be improved in 5 out of 12 OARs by more than 10 mm after resubmission (mHD). Despite this, final IOV for critical OARs in delineation remained significant among DARS by choosing an aleatory threshold of 0.7 (mDSI) and 15 mm (mHD). Conclusions This is to our knowledge the largest BC analysis among Head and neck RTQA programs performed in the framework of a prospective trial. Benchmarking identified non-common OARs and target delineations errors as the main source of deviations and IOV could be reduced in a significant number of cases after this process. Due to the substantial resources involved with benchmarking, future benchmark analyses should assess fully the impact on patients’ clinical outcome.

Background and purposeThe Meta-Analysis of Chemotherapy in squamous cell Head and Neck Cancer (MACH-NC) demonstrated that concomitant chemotherapy (CT) improved overall survival (OS) in patients without distant metastasis. We report the updated results.Materials and methodsPublished or unpublished randomized trials including patients with non-metastatic carcinoma randomized between 1965 and 2016 and comparing curative loco-regional treatment (LRT) to LRT+CT or adding another timing of CT to LRT+CT (main question), or comparing induction CT+radiotherapy to radiotherapy+concomitant (or alternating) CT (secondary question) were eligible. Individual patient data were collected and combined using a fixed-effect model. OS was the main endpoint.ResultsFor the main question, 101 trials (18951 patients, median follow-up of 6.5years) were analyzed. For both questions, there were 16 new (2767 patients) and 11 updated trials. Around 90% of the patients had stage III or IV disease. Interaction between treatment effect on OS and the timing of CT was significant (p&nbsp

Contains fulltext : 235407.pdf (Publisher’s version ) (Closed access) 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 (CLRT(P)) 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 CLRT(P) (P score 78%): induction chemotherapy with taxane, cisplatin, and fluorouracil followed by locoregional therapy (IC(TaxPF)-LRT; 89%), accelerated radiotherapy with concomitant chemotherapy (82%), and IC(TaxPF) followed by CLRT (80%). INTERPRETATION: The results of this network meta-analysis suggest that further intensifying chemoradiotherapy, using HFCRT or IC(TaxPF)-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.

Purpose: Monalizumab is a monoclonal antibody targeting the inhibitory natural killer group 2A (NKG2A) receptor localised on natural killer (NK) and T cells. Its ligand, the human leukocyte antigen E (HLA-E), is overexpressed in squamous cell carcinoma of the head and neck (SCCHN). By targeting the HLA-E-NKG2A pathway, monalizumab may enhance NK and T cell activity. Experimental design: The UPSTREAM trial is a biomarker-driven umbrella trial studying targeted therapies and immunotherapies in patients with recurrent/metastatic (R/M) SCCHN progressing after platinum therapy. The immunotherapy 1 (I1) cohort was a phase II, single-arm substudy evaluating monalizumab (10 mg/kg intravenously on day 1 of a 14 day cycle). The primary end-point was the objective response (OR) rate (Response Evaluation Criteria in Solid Tumours 1.1) over the first 16 weeks. A two-stage Simon design was used (H1 15%, H0 3%, a 8%, power 90%) with pre-planned interruption of accrual if no OR was observed after the first 25 patients. Results: Twenty-six eligible patients were enrolled. Seventeen (65%) patients had received >2 previous lines of systemic treatment, and 15 (58%) patients were PD(-L)1 inhibitor pretreated. No OR was observed. Stable disease was observed in 6 patients (23%) with a median duration of 3.8 months (95% confidence interval [CI]: 2.7 -NE). The median progression-free survival and overall survival were 1.7 months (95% CI: 1.5-1.8) and 6.7 months (95% CI: 3.0-9.6), respectively. The most frequent treatment-related adverse event was grade I/II fatigue (19%). Conclusions: Monalizumab monotherapy has limited activity in R/M SCCHN. The I1 cohort did not meet its primary objective. Monalizumab combined with durvalumab is under investigation within UPSTREAM. (c) 2021 Elsevier Ltd. All rights reserved.

Purpose To externally validate previously published Normal Tissue Complication Probability (NTCP) models developed by separate teams for grade 3 oral mucositis (g3OM). Materials and methods Two models were validated: a logistic model, based on 144 head and neck cancer (HNC) patients receiving induction chemotherapy followed by chemo-IMRT; a multivariable logistic model for prediction of g3OM for 253 patients receiving radical treatment for the head and neck squamous cell carcinoma (HNSCC). The EORTC HNCG-ROG 1219 DAHANCA trial dataset, consisting of 169 patients was used as the validation cohort. This cohort was treated with accelerated fractionated chemo-IMRT, with/without the hypoxic radiosensitizer Nimorazole for HNSCC. External validity was assessed using the scaled Brier score. Calibration was assessed in terms of calibration curves as well as measures of mean and weak calibration. Hosmer-Lemeshow was used for goodness-of-fit test. Discrimination was calculated using the area under the receiver operating curve (AUC-ROC). Results The prevalence of g3OM in the validation cohort (35.5%) was similar to that of two development cohorts, i.e. 38.7% and 31.9% for Bhide logistic and Otter multivariable logistic models respectively. The scaled Brier scores showed good overall model performance. Perfect calibration was observed in the prevalence range of 20% to 40%. AUC-ROC was acceptable in external validation (0.67). The Hosmer-Lemeshow test showed good agreement between predicted and observed outcomes for two models. Conclusion The NTCP models were validated and lead to valid predictions in a wide range of diverse treatment techniques and patient characteristics, also when Nimorazole is added as hypoxic radiosensitizer.

Background: 10-year results from several studies showed improved disease-free survival and distant metastasis-free survival, reduced breast cancer-related mortality, and variable effects on overall survival with the addition of partial or comprehensive regional lymph node irradiation after surgery in patients with breast cancer. We present the scheduled 15-year analysis of the European Organisation for Research and Treatment of Cancer (EORTC) 22922/10925 trial, which aims to investigate the impact on overall survival of elective internal mammary and medial supraclavicular (IM-MS) irradiation. Methods: EORTC 22922/10925, a randomised, phase 3 trial done across 46 radiation oncology departments from 13 countries, included women up to 75 years of age with unilateral, histologically confirmed, stage I–III breast adenocarcinoma with involved axillary nodes or a central or medially located primary tumour. Surgery consisted of mastectomy or breast-conserving surgery and axillary staging. Patients were randomly assigned (1:1) centrally using minimisation to receive IM-MS irradiation at 50 Gy in 25 fractions (IM-MS irradiation group) or no IM-MS irradiation (control group). Stratification was done for institution, menopausal status, site of the primary tumour within the breast, type of breast and axillary surgery, and pathological T and N stage. Patients and investigators were not masked to treatment allocation. The primary endpoint was overall survival analysed according to the intention-to-treat principle. Secondary endpoints were disease-free survival, distant metastasis-free survival, breast cancer mortality, any breast cancer recurrence, and cause of death. Follow-up is ongoing for 20 years after randomisation. This study is registered with ClinicalTrials.gov, NCT00002851. Findings: Between Aug 5, 1996, and Jan 13, 2004, we enrolled 4004 patients, of whom 2002 were randomly assigned to the IM-MS irradiation group and 2002 to the no IM-MS irradiation group. At a median follow-up of 15·7 years (IQR 14·0–17·6), 554 (27·7%) patients in the IM-MS irradiation group and 569 (28·4%) patients in the control group had died. Overall survival was 73·1% (95% CI 71·0–75·2) in the IM-MS irradiation group and 70·9% (68·6–72·9) in the control group (HR 0·95 [95% CI 0·84–1·06], p=0·36). Any breast cancer recurrence (24·5% [95% CI 22·5–26·6] vs 27·1% [25·1–29·2]; HR 0·87 [95% CI 0·77–0·98], p=0·024) and breast cancer mortality (16·0% [14·3–17·7] vs 19·8% [18·0–21·7]; 0·81 [0·70–0·94], p=0·0055) were lower in the IM-MS irradiation group than in the control group. No significant differences in the IM-MS irradiation group versus the control group were seen for disease-free survival (60·8% [95% CI 58·4–63·2] vs 59·9% [57·5–62·2]; HR 0·93 [95% CI 0·84–1·03], p=0·18), or distant metastasis-free survival (70·0% [67·7–72·2] vs 68·2% [65·9–70·3]; 0·93 [0·83–1·04], p=0·18). Causes of death between groups were similar. Interpretation: The 15-year results show a significant reduction of breast cancer mortality and any breast cancer recurrence by IM-MS irradiation in stage I–III breast cancer. However, this is not converted to improved overall survival. Funding: US National Cancer Institute, Ligue Nationale contre le Cancer, and KWF Kankerbestrijding.

Objectives There are more than 12 million long-term survivors of cancer in Europe. Yet, research on outcomes of cancer treatment has not reached its full potential due to operational, regulatory and methodological constrains. The current study aims to show the complementary roles between clinical research and population-based cancer registry in this research field. Methods The authors used an empirical case study to show the level of agreement of variables between two databases of the same patients diagnosed with Hodgkin Lymphoma treated in the European Organisation for Research and Treatment of Cancer (EORTC) H1-H9 trials: one database is the clinical trial database from the EORTC and the other is the Netherlands Cancer Registry (IKNL). Results The study showed a high level of agreement between the two datasets in most of the variables. However the vital status was more complete in the registry database, in particular for survivors diagnosed with cancer more than 10 years ago whereas treatment registration was more complete and in the EORTC clinical trial database. Conclusion The current case study is based on one single disease area and one cancer registry, which needs further research to prove its feasibility in other settings. Nevertheless the authors have envisagedseveral actionable collaboration activities between clinical research organizations and population-based registries in long-term outcome studies in the future, including data linkage, joint methodology development, data quality cross-check and improvement program.

Background: EORTC 24971 was a phase III trial demonstrating superiority of induction regimen TPF (docetaxel, cisplatin, 5-fluorouracil) over PF (cisplatin/5-fluorouracil), in terms of progression-free (PFS) and overall survival (OS) in locoregionally advanced unresectable head and neck squamous cell carcinomas. We conducted a retrospective analysis of prospectively collected data aiming to evaluate whether only HPV(-) patients (pts) benefit from adding docetaxel to PF, in which case deintensifying induction treatment in HPV(+) pts could be considered. Patients and methods: Pretherapy tumor biopsies (blocks or slides) were assessed for high-risk HPV by p16 immunohistochemistry, PCR and quantitative PCR. HPV-DNA+and/or p16+tumors were subjected to in situ hybridization (ISH) and HPV E6 oncogene expression qRT-PCR analysis. Primary and secondary objectives were to evaluate the value of HPV/p16 status as predictive factor of treatment benefit in terms of PFS and OS. The predictive effect was analyzed based on the model used in the primary analysis of the study with the addition of a treatment by marker interaction term and tested at two-sided 5% significance level. Results: Of 358, 119 pts had available tumor samples and 58 of them had oropharyngeal cancer. Median follow-up was 8.7 years. Sixteen of 119 (14%) evaluable samples were p16+and 20 of 79 (25%) evaluable tumors were HPV-DNA+. 13 of 40 pts (33%) assessed with HPV-DNA ISH and 12 of 28 pts (43%) assessed for HPV E6 mRNA were positive. The preplanned analysis showed no statistical evidence of predictive value of HPV/p16 status for PFS (P=0.287) or OS (P=0.118). Conclusions: The incidence of HPV positivity was low in the subset of EORTC 24971 pts analyzed. In this analysis only powered to detect a large treatment by marker interaction, there was no statistical evidence that treatment effect found overall was different in magnitude in HPV(+) or HPV(-) pts. These results do not justify selection of TPF versus PF according to HPV status., SCOPUS: ar.j, info:eu-repo/semantics/published

Background: Our aim was to test the safety of cetuximab added to chemoradiation with either cisplatin or carboplatin after prior induction chemotherapy. Methods: Patients with stage III/IV unresectable, squamous cell carcinoma of the head and neck received up to four cycles of TPF-E (cisplatin and docetaxel 75 mg/m(2) on day 1 followed by 5-FU 750 mg/m(2)/day as a continuous infusion on days 1-5 plus cetuximab at a loading dose of 400 mg/m(2) followed by a weekly dose of 250 mg/m(2)), with prophylactic antibiotics but no growth factors. Patients not progressing after four cycles of TPF-E were randomly assigned to radiotherapy (70 Gy over 7 weeks in 2 Gy fractions) and weekly cetuximab with either weekly cisplatin 40 mg/m(2) or carboplatin, AUC of 1.5 mg/ml/min. Primary endpoint was feasibility. Results: Forty-seven patients were recruited. One patient did not start TPF (hypersensitivity reaction during the cetuximab loading dose). Induction TPF-E was discontinued in 12 patients due to toxicity (6 patients), medical decision (2), death (1), patient refusal (1), protocol violation (1), co-morbidity (1). Three further patients were not randomized [progressive disease (1), protocol violation (1), toxicity and co-morbidity (1)]. Of particular interest are three patients who suffered from bowel perforation, one patient who died as results of pneumonia and septic shock, and a second patient who was found dead at home 12 days after starting TPF-E (cause of death unknown). Weekly cisplatin and carboplatin was stopped early in seven and four patients, respectively. Radiotherapy was stopped in two patients with cisplatin and interrupted in one patient with cisplatin and four patients with carboplatin. Conclusions: The addition of cetuximab to full dose TPF induction chemotherapy led to unacceptable complications and premature closing of the study. Only 34 out of 46 patients completed four cycles of TPF-E and only 30 started biochemoradiation.

Objective To evaluate the effect of chemotherapy added to a surgical locoregional treatment (LRT) for patients with locally advanced head and neck squamous cell carcinoma (HNSCC). Materials and Methods We studied the sub-group of trials with surgical LRT included in the meta-analysis on chemotherapy in head and neck cancer (MACH-NC). Data from published and unpublished randomized trials comparing the addition of chemotherapy to LRT in HNSCC patients were sought using electronic database searching for the period 1965–2000, hand searching and by contacting experts in the field. Trials with less than 60 patients, or preoperative radiotherapy or where the type of LRT could not be individually determined were excluded. All individual patient data were checked for internal consistency, compared with published reports, and validated with trialists. Data were pooled using a fixed-effect model. Heterogeneity was assessed using Cochrane test and I 2 statistic. Results Twenty-four trials were eligible (5000 patients). Chemotherapy improved overall survival (HR = 0.92 [95%CI: 0.85–0.99] p = 0.02). There was a significant interaction between treatment effect and timing of chemotherapy (p = 0.08 at pre-specified threshold of 0.10) with a greater effect for concomitant chemotherapy (HR = 0.79, 95%CI: 0.69–0.92). The benefit of chemotherapy was greater in women (HR women = 0.63, 95%CI: 0.50–0.80) compared to men (HR men = 0.96, 95%CI: 0.89–1.04; p for interaction = 0.001). Conclusions This analysis confirmed the benefit of concomitant chemotherapy added to surgical LRT. The role of induction therapy as yet to be determined as it did not improve OS. Women may benefit more than men from chemotherapy.

Background: Predictors to identify which patients with locoregionally advanced head and neck cancer (LAHNC) benefit from intensive treatment are lacking. We sought to test the hypothesis that patients with a higher risk of cancer recurrence relative to competing mortality (ω score) selectively benefit from altered fractionation (AFX; MARCH data) and/or chemotherapy (MACH-NC data). Methods: We analyzed 22,339 LAHNC patients treated on 81 randomized trials testing AFX (MARCH data set) or chemotherapy (MACH-NC dataset). We applied generalized competing event regression to the control arms in MARCH, stratifying patients by tertile according to ω score. Model covariates were age, performance status (PS), sex, site, T and N category, p16 status, and smoking history. We externally validated the classifier on the MACH-NC dataset. We tested for interactions between ω score and treatment effects on overall survival (OS). Findings: Factors associated with a higher ω score were lower age, better PS, oral cavity site, higher T/N category, and p16 negative/unknown status. The effect of AFX on OS was greater in patients with high (hazard ratio [HR], 0.92; 95% CI, 0.85 to 0.99) and medium (HR, 0.91; 95% confidence interval [CI], 0.84 to 0.98) vs. low ω score (HR, 0.97; 95% CI, 0.90 to 1.05; p=0.086 for interaction). The effect of chemotherapy on OS was significantly greater in patients with high (HR, 0.81; 95% CI, 0.75 to 0.88) and medium (HR, 0.86; 95% CI, 0.78 to 0.88) vs. low ω score (HR, 0.96; 95% CI, 0.86 to 1.08; p=0.011 for interaction). Interpretation: LAHNC patients with a higher risk of cancer progression relative to competing mortality - as reflected by a higher ω score - selectively benefit from more intensive treatment. Funding Statement: Ligue National Contre le Cancer, Institut National du Cancer (PHRC-K 10-02-58; PHRC-K-15-189), Programme d'Actions Integrees de Recherche (2011-1-VADS-04), UC San Diego Head and Neck Cancer Center. Declaration of Interests: KZ, BL, LKV, QTL, VG, JO, AH, BZ, MKBP, BB, MGG, GS, BO, CF, JB, HS, JH, SM, JPP, LKM – none; FR is an employee of Innate Pharma, Marseille (France). Ethics Approval Statement: Analysis and reporting conformed to the transparent reporting of a multivariable prediction model for individual prognosis or diagnosis (TRIPOD) guidelines, and followed a pre-specified protocol for the analysis.

A recent review in this Journal, which criticizes NCCN’s recommendations based, in part, on the RTOG 9501 and the EORTC 22931 trials, warrants comment. We herein provide additional data addressing many of the points and misinterpretations raised in that review which convincingly supports the use of concomitant chemotherapy and radiotherapy in patients with good performance status and high-risk pathologic features after surgery for mucosal head and neck squamous cell carcinoma.

The long-term results of the EORTC 24954 trial comparing sequential versus alternating chemotherapy and radiotherapy (RT) for patients with locally advanced laryngeal and hypopharyngeal cancer are reported. From 1996 to 2004, 450 patients were randomly assigned (1-1) to a sequential arm (SA = induction cisplatin-5fluorouracil followed by a 70Gy-RT for the responders or a total laryngectomy and post-operative RT for the non-responders) and an alternating arm (AA = cisplatin-5fluorouracil alternated with three 2-week courses of 20 Gy-RT for a total dose of 60 Gy). Median follow-up was 10.2 years. Ten-year survival with functional larynx (primary end-point) and overall survival were similar in both arms (18.7% and 33.6% in SA versus 18.3% and 31.6% in AA). Late toxicity was also similar; however, a trend for higher larynx preservation and better laryngeal function was observed in AA. (C) 2016 Elsevier Ltd. All rights reserved.

Item does not contain fulltext We tested baseline positron emission tomography (PET)/computed tomography (CT) as a measure of total tumor burden to better identify high-risk patients with early-stage Hodgkin lymphoma (HL). Patients with stage I-II HL enrolled in the standard arm (combined modality treatment) of the H10 trial (NCT00433433) with available baseline PET and interim PET (iPET2) after 2 cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine were included. Total metabolic tumor volume (TMTV) was measured on baseline PET. iPET2 findings were reported negative (DS1-3) or positive (DS4-5) with the Deauville scale (DS). The prognostic value of TMTV was evaluated and compared with baseline characteristics, staging classifications, and iPET2. A total of 258 patients were eligible: 101 favorable and 157 unfavorable. The median follow-up was 55 months, with 27 progression-free survival (PFS) and 12 overall survival (OS) events. TMTV was a prognosticator of PFS (P < .0001) and OS (P = .0001), with 86% and 84% specificity, respectively. Five-year PFS and OS were 71% and 83% in the high-TMTV (>147 cm(3)) group (n = 46), respectively, vs 92% and 98% in the low-TMTV group (147+DS1-3; 5-year PFS, 81.6%), high-intermediate (TMTV147+DS4-5; 5-year PFS, 25%). TMTV improves baseline risk stratification of patients with early-stage HL compared with current staging systems and the predictive value of early PET response as well.

Background To investigate the activity and safety of afatinib in the preoperative treatment of squamous cell carcinoma of the head and neck (SCCHN). Patients and methods This study was an open-label, randomized, multicenter, phase II window of opportunity trial. Treatment-naive SCCHN patients selected for primary curative surgery were randomized (5 : 1 ratio) to receive afatinib during 14 days (day –15 until day –1) before surgery (day 0) or no treatment. Tumor biopsies, 2-[fluorine-18]-fluoro-2-deoxy- d -glucose positron emission tomography (FDG-PET), and magnetic resonance imaging (MRI) were carried out at diagnosis and just before surgery. The primary end point was metabolic FDG-PET response (according to EORTC guidelines). Other end points included response assessment based on the Response Evaluation Criteria In Solid Tumors (RECIST) v1.1, dynamic contrast-enhanced (DCE)-MRI, diffusion weighted (DW)-MRI, safety, and translational research (TR). Results Thirty patients were randomized: 25 to afatinib and 5 to control arm. Of the 23 eligible patients randomized to afatinib, 16 (70%; 95% CI: 47% to 87%) patients had a partial metabolic FDG-PET response (PMR). Five patients (22%; 95% CI: 8% to 44%) showed a partial response by RECISTv1.1. Responses assessed via DCE-MRI and DWI-MRI did not show a strong association with PMR or RECIST. One patient discontinued afatinib after 11 days for grade 3 diarrhea with subsequent renal failure and 24 days delay in surgery. No grade 4 toxicities or surgical comorbidities related to afatinib were reported. TR results indicated that PMR was more frequent in the tumors with high Cluster3-hypoxia score expression and with TP53 wild type. Conclusion Afatinib given for 2 weeks to newly diagnosed SCCHN patients induces a high rate of FDG-PET partial metabolic response and partial response according to RECISTv1.1. Afatinib can be safely administered before surgery. Although exploratory, the hypoxic gene signature needs further investigations as a predictive biomarker of afatinib activity. Clinical trial registration ClinicalTrials.gov: NCT01538381

The molecular landscape of squamous cell carcinoma of the head and the neck (SCCHN) has been characterized and actionable or targetable genomic alterations have been identified. However, targeted therapies have very limited activity in unselected SCCHN, and the current treatment strategy is still based on tumor location and disease stage and not on tumor biology. Trying to select upfront the patients who will benefit from a specific treatment might be a way to improve patients' outcome. With the objective of optimizing the activity of targeted therapies and immunotherapy, we have designed an umbrella biomarker-driven study dedicated to recurrent and/or metastatic SCCHN patients (EORTC-1559-HNCG, NCT03088059). In this article, we review not only the different trial designs for biomarker-driven studies with their respective advantages and opportunities but also the potential pitfalls that led to the design of the EORTC-1559-HNCG protocol. We also discuss the scientific and logistic challenges of biomarker-driven trials.

Treatment intensification to maximize disease control and reduced intensity approaches to minimize the risk of late sequelae have been evaluated in newly diagnosed Hodgkin lymphoma. The influence of these interventions on the risk of secondary malignant neoplasms, progression-free survival and overall survival is reported in the meta-analysis herein, based on individual patient data from 9498 patients treated within 16 randomized controlled trials for newly diagnosed Hodgkin lymphoma between 1984 and 2007. Secondary malignant neoplasms were meta-analyzed using Peto's method as time-to-event outcomes. For progression-free and overall survival, hazard ratios derived from each trial using Cox regression were combined by inverse-variance weighting. Five study questions (combined-modality treatment vs. chemotherapy alone; more extended vs. involved-field radiotherapy; radiation at higher doses vs. radiation at 20 Gy; more vs. fewer cycles of the same chemotherapy protocol; standard-dose chemotherapy vs. intensified chemotherapy) were investigated. After a median follow-up of 7.4 years, dose-intensified chemotherapy resulted in better progression-free survival rates (P=0.007) as compared with standard-dose chemotherapy, but was associated with an increased risk of therapy-related acute myeloid leukemia/myelodysplastic syndromes (P=0.0028). No progression-free or overall survival differences were observed between combined-modality treatment and chemotherapy alone, but more secondary malignant neoplasms were seen after combined-modality treatment (P=0.010). For the remaining three study questions, outcomes and secondary malignancy rates did not differ significantly between treatment strategies. The results of this meta-analysis help to weigh up efficacy and secondary malignancy risk for the choice of first-line treatment for Hodgkin lymphoma patients. However, final conclusions regarding secondary solid tumors require longer follow-up.

Background Randomised trials of rituximab maintenance (MR) for patients with follicular lymphoma support improved progression-free survival (PFS), but the effect on overall survival has been inconclusive. To evaluate the effect of MR on overall survival according to patient and disease characteristics, and to explore certain adverse events, we performed an individual patient data (IPD) meta-analysis. Methods All investigators of randomised controlled trials that compared MR therapy with observation or treatment only at relapse (no MR) for patients with follicular lymphoma were invited to participate in an IPD meta-analysis. We obtained baseline patient and disease characteristics and time to progression and death for each patient. All analyses took into account the trial and original randomised treatment group. We analysed data in two ways: a two-stage analysis and a multivariate model including patient and disease characteristics. Findings Seven trials including 2315 patients were analysed. Overall survival of patients improved with MR compared with no MR (hazard ratio [HR] 0.79, 95% CI 0.66–0.96). We could not detect any patient or disease characteristics that were associated with a survival benefit with MR. In all of the models, MR had a beneficial effect on overall survival compared with observation for all types of patients, which was not shown in a particular subgroup in which the patient had already received rituximab in the induction phase and received first-line therapy. MR improved PFS compared with observation (HR 0.57, 95% CI 0.51–0.64). The risk of adverse events was higher with MR, specifically infection of any grade and grade 3–4 infections. Interpretation Based on IPD from randomised controlled trials, MR improves overall survival consistently in all patients, regardless of patient and disease characteristics when compared with observation, and should be prescribed after a successful induction with R-CVP or R-CHOP for patients with follicular lymphoma. It is still uncertain if that holds when the patient has already received rituximab in his/hers first induction. The effect of MR after bendamustine-rituximab induction compared with rituximab at progression should be further explored.

International audience; In recent years, the number of approved and investigational agents that can be safely administered for the treatment of lymphoma patients for a prolonged period of time has substantially increased. Many of these novel agents are evaluated in early-phase clinical trials in patients with a wide range of malignancies, including solid tumors and lymphoma. Furthermore, with the advances in genome sequencing, new "basket" clinical trial designs have emerged that select patients based on the presence of specific genetic alterations across different types of solid tumors and lymphoma. The standard response criteria currently in use for lymphoma are the Lugano Criteria which are based on 18-Fluoro-deoxyglucose positron emission tomography (FDG-PET) or bidimensional tumor measurements on computerized tomography (CT) scans. These differ from the RECIST criteria used in solid tumors, which use unidimensional measurements. The RECIL group hypothesized that single dimension measurement could be used to assess response to therapy in lymphoma patients, producing results similar to the standard criteria. We tested this hypothesis by analyzing 47,828 imaging measurements from 2983 individual adult and pediatric lymphoma patients enrolled on 10 multicenter clinical trials, and developed new lymphoma response criteria (RECIL 2017). We demonstrate that assessment of tumor burden in lymphoma clinical trials can use the sum of longest diameters of a maximum of three target lesions. Furthermore, we introduced a new provisional category of a minor response. We also clarified response assessment in patients receiving novel immune therapy and targeted agents that generate unique imaging situations.

First-line escalated BEACOPP does not hinder stem cell collection and transplantation strategy in patients with relapsed/refractory Hodgkin's lymphoma

Purpose Patients who receive combined modality treatment for stage I and II Hodgkin lymphoma (HL) have an excellent outcome. Early response evaluation with positron emission tomography (PET) scan may improve selection of patients who need reduced or more intensive treatments. Methods We performed a randomized trial to evaluate treatment adaptation on the basis of early PET (ePET) after two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) in previously untreated—according to European Organisation for Research and Treatment of Cancer criteria favorable (F) and unfavorable (U)—stage I and II HL. The standard arm consisted of ABVD followed by involved-node radiotherapy (INRT), regardless of ePET result. In the experimental arm, ePET-negative patients received ABVD only (noninferiority design), whereas ePET-positive patients switched to two cycles of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPPesc) and INRT (superiority design). Primary end point was progression-free survival (PFS). Results Of 1,950 randomly assigned patients, 1,925 received an ePET—361 patients (18.8%) were positive. In ePET-positive patients, 5-year PFS improved from 77.4% for standard ABVD + INRT to 90.6% for intensification to BEACOPPesc + INRT (hazard ratio [HR], 0.42; 95% CI, 0.23 to 0.74; P = .002). In ePET-negative patients, 5-year PFS rates in the F group were 99.0% versus 87.1% (HR, 15.8; 95% CI, 3.8 to 66.1) in favor of ABVD + INRT; the U group, 92.1% versus 89.6% (HR, 1.45; 95% CI, 0.8 to 2.5) in favor of ABVD + INRT. For both F and U groups, noninferiority of ABVD only compared with combined modality treatment could not be demonstrated. Conclusion In stage I and II HL, PET response after two cycles of ABVD allows for early treatment adaptation. When ePET is positive after two cycles of ABVD, switching to BEACOPPesc + INRT significantly improved 5-year PFS. In ePET-negative patients, noninferiority of ABVD only could not be demonstrated: risk of relapse is increased when INRT is omitted, especially in patients in the F group.

Introduction High risk stage IIB Hodgkin lymphoma (HL) with mediastinum-to-thorax ratio of ≥0.33 or extranodal localization are defined as a poor prognosis subset according to German Hodgkin study group (Sieber et al., Ann. of Oncol. 2000). These patients were treated consecutively in our group as limited stage in the EORTC/LYSA/FIL H10 study (André et al, JCO 2017) or advanced stage in the AHL2011 LYSA trial (Casasnovas et al., Lancet Oncol 2019). However, the relative efficacy of each of these strategies to control disease is unknown in this uncommon subset of patients. In the present retrospective study, we compared the outcome of patients with high risk stage IIB included in the H10 and AHL2011 studies, and analyzed prognostic factors. Methods We included patients with Ann-Arbor disease stage IIB with mediastinum-to-thorax (M/T) ratio of ≥0.33 or extranodal localization enrolled in the H10 or AHL2011 trials, aged between 16 and 60 years for AHL2011 and 18-60 years for H10 with newly diagnosed Hodgkin lymphoma excluding nodular lymphocyte predominant subtype, who had baseline PET and PET2 images available in the LYSA database. In H10 trial, after 2 cycles of ABVD patients received in the standard arm 2 additional cycles of ABVD plus INRT 30 Gy, in the experimental arm 2 to 4 additional cycles of ABVD;- in PET2 negative patients 4 additional cycles of ABVD (or after the trial amendment 2 additional cycles of ABVD plus INRT 30 Gy); - in PET2 positive patients 2 cycles of escalated BEACOPP plus INRT 30Gy. PET2 were reported according to IHP criteria. In AHL2011 study, after 2 upfront escalated BEACOPP patients received either 4 additional escalated BEACOPP in the standard arm and PET2 positive patients of the PET-driven arm, or 4 cycles of ABVD in PET2 negative patients of the PET-driven arm. PET2 were reported using Deauville score (DS 1-2-3 vs 4-5), DS4 being defined positive if SUVmax of the residual lesion >140% of SUVmax of the liver background. Baseline clinical and biological characteristics of patients enrolled in both studies were compared. Total metabolic tumor volume (TMTV) at baseline was calculated with the Beth Israel Fiji software based on a 41% SUVmax cutoff of each lesion. In this study, all PET2 response was reanalysed using Deauville score And PET positivity was defined according to the criteria used in the AHL2011 trial. Results 148 patients were eligible for the study, including 83 and 65 patients enrolled in the AHL2011 and H10 trials respectively. The median age was 27 years (16; 59), 51.4% of patients were treated according to the experimental arm of each trial, the median size of the bulky mass was 84 mm (20-197), the index prognostic score (IPS) was 3 or higher in 29.1% of cases (38.6% in AHL2011 and 16.9% in H10 patients), the median TMTV value was 155.5 ml (8.3-782.9). Most patients had M/T ratio of ≥0.33 (98.6%) and 10.9% had an extra-nodal involvement. 62.2 % of patients had a treatment strategy including escalated BEACOPP and 31.8% received radiotherapy. PET2 was positive in 16.9% (n=14) of AHL2011 cohort and 9.2% (n=6) in H10 cohort patients. With a median follow-up of 4.2 and 4.4 years in AHL2011 and H10 trials respectively, 16 patients (10.8%) relapsed including 7 (10.7%) patients in H10 and 9 (10.8%) in AHL2011, and five deaths occurred with three due to lymphoma progression . Eleven relapses (68.8% for all, 8 for AHL2011 and 3 for H10) were localized in mediastinum. In univariate analysis, PET2 response, baseline TMTV (155 ml cut off) and IPS (0-2 vs 3-7) significantly influenced PFS with hazard ratios of 6.26 (2.29-17.07), 3.37 (1.093-10.371), 2.89 (0.94-8.86) respectively. The strategy of treatment, either H10 or AHL2011, did not influence PFS. In multivariate analysis stratified on the study (figure 1), only the TMTV as continuous variable (HR: 1.003; 1.000-1.005) and PET2 response (HR: 5.38; 1.99-14.56) were prognostic factors. Among the thirteen patients with high TMTV and PET2 positivity, 7 relapsed (4 for AHL2011 and 3 for H10). Conclusions This is the first study comparing two strategies of treatment in high risk stage IIB lymphoma patients included in two large randomized clinical trials. PFS of these patients was 88.0% (95%CI = [81.2%; 92.4%]) at 4 years and similar regardless the study treatment. Baseline TMTV and PET2 response were the main factors influencing the outcome of high risk stage IIB lymphoma patients. Figure Disclosures André: Takeda: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers-Squibb: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Travel grants; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Roche: Other: Travel grants, Research Funding; Amgen: Other: Travel grants, Research Funding; Johnson & Johnson: Research Funding; Takeda Millenium: Research Funding; Chugai: Research Funding; Celgene: Other: Travel grants, Research Funding. Brice:Takeda France: Consultancy, Honoraria; Millennium Takeda: Research Funding; BMS: Honoraria. Stamatoullas:Takeda: Consultancy; Celgene: Honoraria. Federico:Seattle Genetics: Research Funding; Allos: Research Funding; Spectrum: Consultancy, Honoraria; Medimmune: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Teva: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Mundipharma: Consultancy, Honoraria. Casasnovas:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses; Merck Sharp and Dohme: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Purpose To compare patients with high-risk stage III to IV Hodgkin lymphoma (HL) in the phase III European Organisation for Research and Treatment of Cancer 20012 Intergroup trial (Comparison of Two Combination Chemotherapy Regimens in Treating Patients With Stage III or Stage IV Hodgkin’s Lymphoma) who were randomly assigned to either doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) or to bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP). Patients and Methods Patients with clinical stage III or IV HL, International Prognostic Score of 3 or higher, and age 60 years or younger received ABVD for eight cycles (ABVD8) or escalated-dose BEACOPP (BEACOPPescalated) for four cycles followed by baseline BEACOPP (BEACOPPbaseline) for four cycles (BEACOPP4+4) without radiotherapy. Primary end points were event-free survival (EFS), treatment discontinuation, no complete response (CR) or unconfirmed complete response (CRu) after eight cycles, progression, relapse, or death. Secondary end points were CR rate, overall survival (OS), quality of life, secondary malignancies, and disease-free survival in CR/CRu patients. Results Between 2002 and 2010, 549 patients were randomly assigned to ABVD8 (n = 275) or BEACOPP4+4 (n = 274). Other characteristics included median age, 35 years; male, 75%; stage IV, 74%; “B” symptoms, 81%; and International Prognostic Score ≥ 4, 59%. WHO performance status was 0 (34%), 1 (48%), or 2 (17%). Median follow-up was 3.6 years. CR/CRu was 82.5% in both arms. At 4 years, EFS was 63.7% for ABVD8 versus 69.3% for BEACOPP4+4 (hazard ratio [HR], 0.86; 95% CI, 0.64 to 1.15; P = .312); disease-free survival was 85.8% versus 91.0% (HR, 0.59; 95% CI, 0.33 to 1.06; P = .076), and OS was 86.7% versus 90.3% (HR, 0.71; 95% CI, 0.42 to 1.21; P = .208). Death as a result of toxicity occurred in six and five patients, early discontinuation (before cycle 5) in 12 and 26 patients, treatment crossovers in five and 10 patients, and secondary malignancies in eight and 10 patients in the ABVD8 and BEACOPP4+4 arms, respectively. Conclusion ABVD8 and BEACOPP4+4 resulted in similar EFS and OS in patients with high-risk advanced-stage HL. Because BEACOPP4+4 did not demonstrate a favorable effectiveness or toxicity ratio compared with ABVD8, treatment burden, immediate and late toxicities, and associated costs must be considered before selecting one of these regimens on which to build future treatment strategies.

Since the creation of the EORTC Headquarters in 1974, major advances have been made in the methodology used in the design and analysis of cancer clinical trials. However, the speed of these developments in the fields of biology, medicine, and statistics has greatly increased since the turn of the 21st century. These changes have all become possible because of the increased computer power now available. The landscape of therapeutic anti-cancer development changed completely with the advent of the so-called “targeted agents” that treat the underlying molecular basis of the disease rather than the symptoms of tumor proliferation. The new challenges posed by the clinical development of these numerous new agents that are expected to work in often yet-to-be-identified subgroups of patients induced a new wave of methodological developments. Some of these were readily embraced by the EORTC Headquarters statistics department, while others met with opposition. Our assessment is still in progress in many areas. Trials tend to become increasingly complex so that their planning relies on an increasing number of unknown parameters that need to be monitored during the trial itself, one development being “adaptive” design methodology. Because the knowledge required to design these new and more complex clinical trials and associated research program spans more disciplines (biology, genomics, radiology) and involves specialized knowledge within those disciplines, continued success requires further developing our partnerships with specialized departments (imaging, bio-informatics, biology, etc.) within EORTC Headquarters and in EORTC affiliated centers as well as collaborations with specialized statisticians from academia.

TPS6099Background: SGCs are rare and heterogeneous tumors ( < 1% of all malignancies in Europe). Among more than 20 histotypes, only salivary duct carcinoma (SDC) and adenocarcinoma NOS express AR....