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There is no strong and reliable predictive biomarker in head and neck squamous cell carcinoma (HNSCC) for EGFR inhibitors. We aimed to identify predictive and pharmacodynamic biomarkers of efficacy of afatinib, a pan-HER tyrosine kinase inhibitor, in a window-of-opportunity trial (NCT01415674). Multi-omics analyses were carried out on pre-treatment biopsy and surgical specimen for biological assessment of afatinib activity. Sixty-one treatment-naïve and operable HNSCC patients were randomised to afatinib 40 mg/day for 21–28 days versus no treatment. Afatinib produced a high rate of metabolic response. Responders had a higher expression of pERK1/2 ( P  = 0.02) and lower expressions of pHER4 ( P  = 0.03) and pRB1 ( P  = 0.002) in pre-treatment biopsy compared to non-responders. At the cellular level, responders displayed an enrichment of tumor-infiltrating B cells under afatinib ( P  = 0.02). At the molecular level, NF-kappa B signaling was over-represented among upregulated genes in non-responders ( P  < 0.001; FDR = 0.01). Although exploratory, phosphoproteomics-based biomarkers deserve further investigations as predictors of afatinib efficacy.

Goals of work Patients with low-risk neutropenic fever as defined by the Multinational Association of Supportive Care in Cancer (MASCC) score might benefit from ambulatory treatment. Optimal management remains to be clearly defined, and new oral antibiotics need to be evaluated in this setting. Materials and methods Cancer patients with febrile neutropenia and a favorable MASCC score were randomized between oral moxifloxacin and intravenous ceftriaxone. All were fit for early hospital discharge. The global success rate was related to the efficacy of monotherapy, as well as to the success of ambulatory monitoring. Main results The trial was closed prematurely because of low accrual. Ninety-six patients were included (47 in the ceftriaxone arm and 49 in the moxifloxacin arm). A total of 65% were women, 30.2% had lymphoma, 34.4% had metastatic, and 35.4% had non-metastatic solid tumors. The success rates of home antibiotics were 73.9% and 79.2% for ceftriaxone and moxifloxacin, respectively. Seven patients were not discharged, and 14 required re-hospitalization. There were 17% of microbiologically documented infections that were, in most cases, susceptible to oral monotherapy. Conclusions These results suggest that MASCC is a valid and useful tool to select patients for ambulatory treatments and that oral moxifloxacin monotherapy is safe and effective for the outpatient treatment of cancer patients with low-risk neutropenic fever.

Concomitant chemoradiotherapy and accelerated radiotherapy independently improve outcomes for patients with locally advanced head and neck squamous-cell carcinoma (HNSCC). We aimed to assess the efficacy and safety of a combination of these approaches. In our open-label phase 3 randomised trial, we enrolled patients with locally advanced, stage III and IV (non-metastatic) HNSCC and an Eastern Cooperative Oncology Group performance status of 0–2. We randomly allocated patients centrally with a computer program (with centre, T stage, N stage, and localisation as minimisation factors) in a 1:1:1 ratio to receive conventional chemoradiotherapy (70 Gy in 7 weeks plus three cycles of 4 days' concomitant carboplatin-fluorouracil), accelerated radiotherapy-chemotherapy (70 Gy in 6 weeks plus two cycles of 5 days' concomitant carboplatin-fluorouracil), or very accelerated radiotherapy alone (64·8 Gy [1·8 Gy twice daily] in 3·5 weeks). The primary endpoint, progression-free survival (PFS), was assessed in all enrolled patients. This trial is completed. The trial is registered with ClinicalTrials.gov, number NCT00828386. Between Feb 29, 2000, and May 9, 2007, we randomly allocated 279 patients to receive conventional chemoradiotherapy, 280 to accelerated radiotherapy-chemotherapy, and 281 to very accelerated radiotherapy. Median follow-up was 5·2 years (IQR 4·9–6·2); rates of chemotherapy and radiotherapy compliance were good in all groups. Accelerated radiotherapy-chemotherapy offered no PFS benefit compared with conventional chemoradiotherapy (HR 1·02, 95% CI 0·84–1·23; p=0·88) or very accelerated radiotherapy (0·83, 0·69–1·01; p=0·060); conventional chemoradiotherapy improved PFS compared with very accelerated radiotherapy (0·82, 0·67–0·99; p=0·041). 3-year PFS was 37·6% (95% CI 32·1–43·4) after conventional chemoradiotherapy, 34·1% (28·7–39·8) after accelerated radiotherapy-chemotherapy, and 32·2% (27·0–37·9) after very accelerated radiotherapy. More patients in the very accelerated radiotherapy group had RTOG grade 3–4 acute mucosal toxicity (226 [84%] of 268 patients) compared with accelerated radiotherapy-chemotherapy (205 [76%] of 271 patients) or conventional chemoradiotherapy (180 [69%] of 262; p=0·0001). 158 (60%) of 265 patients in the conventional chemoradiotherapy group, 176 (64%) of 276 patients in the accelerated radiotherapy-chemotherapy group, and 190 (70%) of 272 patients in the very accelerated radiotherapy group were intubated with feeding tubes during treatment (p=0·045). Chemotherapy has a substantial treatment effect given concomitantly with radiotherapy and acceleration of radiotherapy cannot compensate for the absence of chemotherapy. We noted the most favourable outcomes for conventional chemoradiotherapy, suggesting that acceleration of radiotherapy is probably not beneficial in concomitant chemoradiotherapy schedules. French Ministry of Health.

Patients with muscle-invasive urothelial carcinoma of the bladder have poor survival after cystectomy. The EORTC 30994 trial aimed to compare immediate versus deferred cisplatin-based combination chemotherapy after radical cystectomy in patients with pT3–pT4 or N+ M0 urothelial carcinoma of the bladder. This intergroup, open-label, randomised, phase 3 trial recruited patients from hospitals across Europe and Canada. Eligible patients had histologically proven urothelial carcinoma of the bladder, pT3–pT4 disease or node positive (pN1–3) M0 disease after radical cystectomy and bilateral lymphadenectomy, with no evidence of any microscopic residual disease. Within 90 days of cystectomy, patients were centrally randomly assigned (1:1) by minimisation to either immediate adjuvant chemotherapy (four cycles of gemcitabine plus cisplatin, high-dose methotrexate, vinblastine, doxorubicin, and cisplatin [high-dose MVAC], or MVAC) or six cycles of deferred chemotherapy at relapse, with stratification for institution, pT category, and lymph node status according to the number of nodes dissected. Neither patients nor investigators were masked. Overall survival was the primary endpoint; all analyses were by intention to treat. The trial was closed after recruitment of 284 of the planned 660 patients. This trial is registered with ClinicalTrials.gov, number NCT00028756. From April 29, 2002, to Aug 14, 2008, 284 patients were randomly assigned (141 to immediate treatment and 143 to deferred treatment), and followed up until the data cutoff of Aug 21, 2013. After a median follow-up of 7·0 years (IQR 5·2–8·7), 66 (47%) of 141 patients in the immediate treatment group had died compared with 82 (57%) of 143 in the deferred treatment group. No significant improvement in overall survival was noted with immediate treatment when compared with deferred treatment (adjusted HR 0·78, 95% CI 0·56–1·08; p=0·13). Immediate treatment significantly prolonged progression-free survival compared with deferred treatment (HR 0·54, 95% CI 0·4–0·73, p<0·0001), with 5-year progression-free survival of 47·6% (95% CI 38·8–55·9) in the immediate treatment group and 31·8% (24·2–39·6) in the deferred treatment group. Grade 3–4 myelosuppression was reported in 33 (26%) of 128 patients who received treatment in the immediate chemotherapy group versus 24 (35%) of 68 patients who received treatment in the deferred chemotherapy group, neutropenia occurred in 49 (38%) versus 36 (53%) patients, respectively, and thrombocytopenia in 36 (28%) versus 26 (38%). Two patients died due to toxicity, one in each group. Our data did not show a significant improvement in overall survival with immediate versus deferred chemotherapy after radical cystectomy and bilateral lymphadenectomy for patients with muscle-invasive urothelial carcinoma. However, the trial is limited in power, and it is possible that some subgroups of patients might still benefit from immediate chemotherapy. An updated individual patient data meta-analysis and biomarker research are needed to further elucidate the potential for survival benefit in subgroups of patients. Lilly, Canadian Cancer Society Research.

Background Health state utility (HSU) is a core component of QALYs and cost-effectiveness analysis, although HSU is rarely estimated among a representative sample of patients. We explored the feasibility of assessing HSU in head and neck cancer from the French National Hospital Discharge database. Methods An exhaustive sample of 53,258 incident adult patients with a first diagnosis of head and neck cancer was identified in 2010–2012. We used a cross-sectional approach to define five health states over two periods: three \"cancer stages at initial treatment\" (early, locally advanced or metastatic stage); a \"relapse state\" and otherwise a \"relapse-free state\" in the follow-up of patients initially treated at early or locally advanced stage. In patients admitted in post-acute care, a two-parameter graded response model (Item Response Theory) was estimated from all 144,012 records of six Activities of Daily Living (ADLs) and the latent health state scale underlying ADLs was calibrated with the French EQ-5D-3 L social value set. Following linear interpolation between all assessments of the patient, daily estimates of utility in post-acute care were averaged by health state, patient and month of follow-up. Finally, HSU was estimated by health state and month of follow-up for the whole patient population after controlling for survivorship and selection in post-acute care. Results Head and neck cancer was generally associated with poor HSU estimates in a real-life setting. As compared to “distant metastasis at initial treatment”, mean HSU was higher in other health states, although numerical differences were small (0.45 versus around 0.54). It was primarily explained by the negative effects on HSU of an older age (38.4% aged ≥70 years in “early stage at initial treatment”) and comorbidities (> 50% in other health states). HSU estimates significantly improved over time in the “relapse-free state” (from 8 to 12 months of follow-up). Conclusions HSU estimates in head and neck cancer were primarily driven by age at diagnosis, comorbidities, and time to assessment of cancer survivors. This feasibility study highlights the potential of estimating HSU within and across severe conditions in a systematic way at the national level.

Our recently developed prone crawl position (PCP) for radiotherapy of breast cancer patients with lymphatic involvement showed promising preliminary data and it is being optimized for clinical use. An important aspect in this process is making new, position specific delineation guidelines to ensure delineation (for treatment planning) is uniform across different centers. The existing ESTRO and PROCAB guidelines for supine position (SP) were adapted for PCP. Nine volunteers were MRI scanned in both SP and PCP. Lymph node regions were delineated in SP using the existing ESTRO and PROCAB guidelines and were then translated to PCP, based on the observed changes in reference structure position. Nine PCP patient CT scans were used to verify if the new reference structures were consistently identified and easily applicable on different patient CT scans. Based on these data, a team of specialists in anatomy, CT- and MRI radiology and radiation oncology postulated the final guidelines. By taking the ESTRO and PROCAB guidelines for SP into account and by using a relatively big number of datasets, these new PCP specific guidelines incorporate anatomical variability between patients. The guidelines are easily and consistently applicable, even for people with limited previous experience with delineations in PCP.

Purpose: Management of head and neck cancers of unknown primary (HNCUP) combines neck dissection (ND) and radiotherapy, with or without chemotherapy. The prognostic value of ND has hardly been studied in HNCUP. Methods: A retrospective multicentric study assessed the impact of ND extent (adenectomy, selective ND, radical/radical-modified ND) on nodal relapse, progression-free survival (PFS) or survival, taking into account nodal stage. Results: 53 patients (16.5%) had no ND, 33 (10.2%) had lymphadenectomy, 116 (36.0%) underwent selective ND and 120 underwent radical/radical-modified ND (37.3%), 15 of which received radical ND (4.7%). With a 34-month median follow-up, the 3-year incidence of nodal relapse was 12.5% and progression-free survival (PFS) 69.1%. In multivariate analysis after adjusting for nodal stage, the risk of nodal relapse or progression was reduced with lymphadenectomy, selective or radical/modified ND, but survival rates were similar. Patients undergoing lymphadenectomy or ND had a better PFS and lowered nodal relapse incidence in the N1 + N2a group, but the improvement was not significant for the N2b or N2 + N3c patients. Severe toxicity rates exceeded 40% with radical ND. Conclusion: In HNCUP, ND improves PFS, regardless of nodal stage. The magnitude of the benefit of ND does not appear to depend on ND extent and decreases with a more advanced nodal stage.

To evaluate the clinical and economic burden of head and neck squamous cell carcinoma (HNSCC) in France. All 53,255 incident adult patients discharged with a first diagnosis of HNSCC in 2010-2012 were identified from the 2008-2013 French National Hospital Discharge (PMSI) database. We conducted a retrospective longitudinal analysis of prognosis and direct costs attributable to HNSCC. Direct medical costs attributable to HNSCC care amounted to 665 million euros in 2012 in France. The majority (62%) of incident patients were 64 years old or less at HNSCC diagnosis and incurred 1.3-fold higher mean direct costs as compared to elderly patients (41,909 vs 32,221 euros over 3 years, respectively; p<0.001). HNSCC stage at initial treatment was the major driver of mean (SD) direct costs over 3 years (p<0.001): 19,819 (23,150) euros in 31% patients diagnosed at early stage; 46,791 (34,841) euros in 60% patients diagnosed at locally advanced stage; and 43,377 (33,953) euros in 9% patients diagnosed with distant metastasis. About half patients died over 3 years at a median (IQR) age of 63 (56-75) years resulting in 10.9 years-of-life lost on average per incident patient. The present study suggests that the clinical and economic burden of HNSCC is substantial in France.