Results of a Prospective Non-Interventional Post-Authorization Safety Study of Idelalisib in Germany.

BACKGROUND: In pivotal studies, idelalisib demonstrated remarkable efficacy and manageable tolerability in patients with chronic lymphocytic leukemia (CLL) and follicular lymphoma (FL). This prospective, multicenter, non-interventional post-authorization study assessed the characteristics, clinical management, and outcome of CLL and FL patients receiving idelalisib in routine clinical practice in Germany. PATIENTS: Observational study in CLL and FL patients treated with idelalisib between September 2015 and December 2020. RESULTS: A total of 147 patients with CLL and FL were included with a median age of 75 and 71 years, respectively. More than 80% of patients presented with comorbidity and many CLL patients with documented high-risk genetic features, including del(17p)/TP53 mutation or unmutated IGHV. The median progression-free survival (PFS) and overall survival (OS) were not reached in the CLL cohort irrespective of del(17p)/TP53 or unmutated IGHV. The estimated 6-month PFS and OS rates in CLL were 82% and 92%. The estimated 6-month PFS and OS rates for FL were 32.2% and 77.2%. Overall response rates in the CLL and FL cohorts were 70.4% and 36.4%, with the presence of high-risk genetics having no negative impact. No unexpected adverse events were observed. Most frequently reported adverse drug reactions (ADRs) were diarrhea, nausea, pneumonia, rash, and fatigue. CONCLUSION: This real-world study shows that idelalisib is an effective therapy for CLL and FL, regardless of age and high-risk genetic features, consistent with results from previous clinical trials. Collected safety data and the pattern of ADRs reflect those from previous studies.

[Larynx preservation up to T4 laryngeal cancer?] / Larynxorganerhalt bis zum T4­Larynxkarzinom?

Could primary chemoradiotherapy (pCRT) possibly be viewed as an alternative standard therapy to upfront total laryngectomy (TL)? According to the new German S3 guideline, despite higher rates of local recurrence, there would be no survival disadvantage and salvage surgery would be a curative option. In several large database studies and case series, statistically significant survival disadvantages of more than 30% between pCRT and TL have been reported for T4 laryngeal cancer. According to the literature, the success rate of salvage TL for T4 laryngeal cancer is only about 25-50%. Larynx preservation (LP) studies which could qualify the recommendation of pCRT as an alternative standard therapy to TL in T4 carcinomas should 1) evaluate T4a cancers within the T4 category; 2) perform subgroup analysis of laryngeal and hypopharyngeal cancers; 3) be sufficiently highly powered; 4) provide long-term outcomes of at least 5 years; 5) with oncological and 6) functional outcomes (duration of the need for tracheostomy and/or feeding tube dependency; necessity and success of salvage laryngectomies). 7) Specification of the criteria of the respective T4 classification (invasion through the outer cortex of the cartilage, or infiltration of which extralaryngeal structures) and 8) evaluation of pretreatment laryngeal function (at least: tracheostomy, feeding tube dependency). Collection of all the aforementioned data of T4 patients treated with pCRT in a large prospective observational cohort study in German-speaking countries is suggested. In case of rejection of TL by T4 laryngeal cancer patients, differentiation between primary spontaneous reluctance and a definitive, carefully considered decision is important. This distinction should be achieved by sensitive discussions. Not only oncological but also functional outcome probabilities should be included in the overall decision-making process.

[Larynx preservation: recommendations for decision-making in T3 laryngeal cancer patients]. / Organerhalt: Entscheidungskriterien für Patienten mit T3-Larynxkarzinom.

BACKGROUND: By today's standard, the optimal treatment of every individual tumor patient is discussed and determined in an interdisciplinary tumor board. According to the new S3 guidelines, larger volume T3 laryngeal cancers which are no longer safely resectable with larynx-sparing surgery are ideal candidates for a larynx preservation approach using primary chemoradiation (pCRT). So far, no clear criteria have been defined under what circumstances primary radiotherapy alone (pRT) might be acceptable in case chemotherapy (CT) is prohibited or in what cases, even in T3, upfront total laryngectomy with risk-adapted adjuvant treatment (TL±a[C]RT) should be recommended. METHOD: The literature was searched for parameters chosen as criteria for an inclusion in the surgical rather than the conservative arm in non-randomized LP studies or which proved to be significant prognostic markers after conservative treatment. Development of a counselling tool for therapeutic decision making. RESULTS: Significant prognostic markers were tumor volume (< 3.5 ccm/< 6 ccm vs. 6-12 ccm vs. > 12 ccm), presence and kind of vocal cord fixation (none vs. Succo I/II vs. Succo III/IV), extent of cartilage infiltration (none vs. minimal vs. multiple/gross), nodal status (N0­1 vs. N2-3), and laryngeal dysfunction (pretreatment necessity of feeding tube or tracheostomy). CONCLUSION: For T3 laryngeal cancers, pRT could be acceptable when the tumor volume is < 3.5 ccm for glottic and < 6 ccm for supraglottic tumors and there are no further risk factors. pCRT can be regarded as the standard for LP for tumors between 6 ccm and 12 ccm, vocal cord fixation Succo pattern I/II, only minimal cartilage infiltration and a high nodal burden. For tumor > 12 ccm, vocal cord fixation Succo pattern III/IV, gross or multiple cartilage infiltration or clinically relevant laryngeal dysfunction, upfront TL±a[C]RT should be considered.

Sofosbuvir and risk of estimated glomerular filtration rate decline or end-stage renal disease in patients with renal impairment.

BACKGROUND: Sofosbuvir, a prodrug nucleoside inhibitor of hepatitis C virus, has a predominant circulating metabolite that is renally eliminated. Whether sofosbuvir is associated with chronic kidney disease (CKD) progression is not well understood. METHODS: We performed a retrospective analysis of patients with estimated glomerular filtration rate (eGFR) 30-89 mL/min/1.73 m2 treated with sofosbuvir in 76 Phase 2/3 registrational trials. We evaluated eGFR at each study visit. Separately, we performed a retrospective analysis of an administrative claims database (IQVIA PharMetrics Plus™) to compare the risk of incident end-stage renal disease (ESRD) associated with the use of sofosbuvir or non-sofosbuvir regimens among patients with CKD using propensity score methods. Exposure, CKD status and outcomes were determined using diagnosis and medication claim codes. Cox proportional hazards methods were used to estimate ESRD risk. RESULTS: Among 4642 trial participants with baseline stage 2 CKD (eGFR 60-89 ml/min/1.73 m2 ) and 682 trial participants with stage 3 CKD (eGFR 30-59 ml/min/1.73 m2 ) mean (SD) eGFR improved from baseline to 4 weeks post-treatment (+0.7 [9.3] and +2.6 [8.8] ml/min/1.73 m2 , respectively; p < 0.001 each). In the second analysis, among 2042 patients with CKD receiving sofosbuvir-based regimens compared to 431 receiving non-sofosbuvir-based regimens, after adjusting for baseline covariates and weighting based on treatment propensity scores, there was no significant difference in risk of ESRD (adjusted HR = 0.85, 95% CI: 0.51-1.42). CONCLUSIONS: Clinical trial participants with CKD did not experience worsening eGFR during sofosbuvir-based treatment, and sofosbuvir was not associated with an increased risk of ESRD in patients with CKD in a nationally-representative administrative claims database.

Risk of hepatocellular carcinoma in treatment-naïve chronic hepatitis B patients receiving tenofovir disoproxil fumarate versus entecavir in the United States.

BACKGROUND: Entecavir (ETV) and tenofovir disoproxil fumarate (TDF) are the first-line treatment agents for chronic hepatitis B virus (HBV). Recently, whether the degree to which the risk of hepatocellular carcinoma (HCC) may be reduced by ETV vs TDF has been debated. We compared the incidence of HCC among treatment-naïve patients receiving TDF vs ETV in the United States. METHODS: From a large administrative medical claims database of commercially insured patients, we identified 166,933 adults with a diagnosis of chronic hepatitis B and a minimum of 12 months of prior enrolment, of whom 3934 and 6127 initiated ETV and TDF respectively. Fine-Gray hazard regression models incorporating treatment propensity scores (PS) were used to estimate the risk of HCC incidence associated with TDF vs ETV; variables considered for adjustment included demographic characteristics, concomitant medication use and baseline comorbidities, as well as competing events including liver transplantation and medication changes. RESULTS: After PS weighting, the TDF and ETV groups were well-matched. During the follow-up, 90 patients developed HCC, including 50 receiving ETV and 40 receiving TDF, giving rise to crude incidence rates of 0.62 per 100 person-years (PY) and 0.30 per 100 PY respectively. In PS-weighted, multivariable analysis, TDF was associated with a subdistribution hazard ratio for HCC of 0.58 (95% confidence interval [CI]: 0.38-0.89) compared to ETV. Results were similar when patients ≥40 years and men and women were analysed separately. CONCLUSION: Among commercially insured, treatment-naïve patients with chronic hepatitis B in the United States, treatment with TDF was associated with significantly lower risk of HCC than ETV.

Chemoradiotherapy but Not Radiotherapy Alone for Larynx Preservation in T3. Considerations from a German Observational Cohort Study.

For advanced laryngeal cancers, after randomized prospective larynx preservation studies, nonsurgical therapy has been applied on a large scale as an alternative to laryngectomy. For T4 laryngeal cancer, poorer survival has been reported after nonsurgical treatment. Is there a need to fear worse survival also in T3 tumors? The outcomes of 121 T3 cancers treated with pCRT, pRT alone, or surgery were evaluated in an observational cohort study in Germany. In a multivariate Cox regression of the T3 subgroup, no survival difference was noted between pCRT and total laryngectomy with risk-adopted adjuvant (chemo)radiotherapy (TL ± a(C)RT) (HR 1.20; 95%-CI: 0.57-2.53; p = 0.63). However, survival was significantly worse after pRT alone than after TL ± a(C)RT (HR 4.40; 95%-CI: 1.72-11.28, p = 0.002). A literature search shows that in cases of unfavorable prognostic markers (bulky tumors of 6-12 ccm, vocal cord fixation, minimal cartilage infiltration, or N2-3), pCRT instead of pRT is indicated. In cases of pretreatment dysphagia or aspiration requiring a feeding tube or tracheostomy, gross or multiple cartilage infiltration, or tumor volume > 12 ccm, outcomes after pCRT were significantly worse than those after TL. In these cases, and in cases where pCRT is indicated but the patient is not suitable for the addition of chemotherapy, upfront total laryngectomy with stage-appropriate aRT is recommended even in T3 laryngeal cancers.

A retrospective observational study to evaluate the clinical outcomes and routine management of patients with chronic lymphocytic leukaemia treated with idelalisib and rituximab in the UK and Ireland (RETRO-idel).

Idelalisib (IDL) is an oral first-in-class phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitor approved for chronic lymphocytic leukaemia (CLL) alongside rituximab (R) since 2014. However, little data exist on routine practice. The RETRO-idel was a protocol-led, retrospective study of 110 patients [n = 27 front-line (1L)] who received IDL-R. The primary end-point was clinical overall response rate (ORR). The median (range) follow-up of the whole cohort was 30·2 (0·1-51·9) months. The median (range) age was 72 (48-89) years. Tumour protein p53-disruption was common [100% 1L, 32·5% relapsed/refractory (R/R)]. The best ORR (intention-to-treat) was 88·2% (1L 96·3%, R/R 85·5%). Overall, the median event-free survival (mEFS) was 20·3 months and time-to-next treatment was 29·2 months. The mEFS for 1L patients was 18·7 months and R/R patients was 21·7 months. The 3-year overall survival was 56·1% (95% confidence interval 45·7-65·3). IDL was discontinued in 87·3% (n = 96). More patients discontinued due to adverse events in the front-line setting (1L 63·0% vs. R/R 44·6%) and due to progressive disease in R/R patients (20·5% vs. 3·7% in 1L). Lower respiratory tract infection/pneumonia were reported in 34·5% (Grade ≥3, 19·1%), diarrhoea in 30·9% (Grade ≥3, 6·4%), and colitis in 9·1% (Grade ≥3, 5·5%). Overall, these data describe clear efficacy for IDL-R in routine practice. No new safety signals were identified, although careful management of known toxicities is required.

Could Primary Chemoradiotherapy in T2 Glottic Cancers Yield Results Comparable to Primary Radiotherapy in T1? Considerations from 531 German Early Stage Patients.

T1 glottic cancer is a highly treatable disease with local control (LC) rates over 90% by either primary radiotherapy (pRT) or transoral laser microsurgery (TLM). LC of T2 glottic cancers is 15 percent points poorer on average. However, salvage after pRT entails more than 50% total laryngectomy. Therefore, there is a need for enhanced LC. Altered fractionation regimens improved LC in T1 but not in T2. For this reason, for T2, alternative strategies must be considered. In a large observational cohort study including 531 early-stage laryngeal cancers, a small number of patients were treated with primary chemoradiotherapy (pCRT). In multivariable analysis, factors associated with significantly poorer outcomes included age, comorbidities, supraglottic localization, and T category. While there was a significant difference between pRT and surgery (HR 1.79; 95%-CI: 1.15-2.79), there was none between pCRT and surgery (HR 0.70; 95%-CI: 0.33-1.51). There is evidence from the literature that pCRT in early glottic cancers could yield results that surpass the limits so far experienced in radiotherapy alone with acceptable toxicity. Thus, prospective randomized studies with larger numbers of patients are warranted.

Occupational socioeconomic risk associations for head and neck cancer in Europe and South America: individual participant data analysis of pooled case-control studies within the INHANCE Consortium.

BACKGROUND: The association between socioeconomic disadvantage (low education and/or income) and head and neck cancer is well established, with smoking and alcohol consumption explaining up to three-quarters of the risk. We aimed to investigate the nature of and explanations for head and neck cancer risk associated with occupational socioeconomic prestige (a perceptual measure of psychosocial status), occupational socioeconomic position and manual-work experience, and to assess the potential explanatory role of occupational exposures. METHODS: Pooled analysis included 5818 patients with head and neck cancer (and 7326 control participants) from five studies in Europe and South America. Lifetime job histories were coded to: (1) occupational social prestige-Treiman's Standard International Occupational Prestige Scale (SIOPS); (2) occupational socioeconomic position-International Socio-Economic Index (ISEI); and (3) manual/non-manual jobs. RESULTS: For the longest held job, adjusting for smoking, alcohol and nature of occupation, increased head and neck cancer risk estimates were observed for low SIOPS OR=1.88 (95% CI: 1.64 to 2.17), low ISEI OR=1.74 (95% CI: 1.51 to 1.99) and manual occupations OR=1.49 (95% CI: 1.35 to 1.64). Following mutual adjustment by socioeconomic exposures, risk associated with low SIOPS remained OR=1.59 (95% CI: 1.30 to 1.94). CONCLUSIONS: These findings indicate that low occupational socioeconomic prestige, position and manual work are associated with head and neck cancer, and such risks are only partly explained by smoking, alcohol and occupational exposures. Perceptual occupational psychosocial status (SIOPS) appears to be the strongest socioeconomic factor, relative to socioeconomic position and manual/non-manual work.

An Observational Cohort Study on 194 Supraglottic Cancer Patients: Implications for Laser Surgery and Adjuvant Treatment.

Supraglottic laryngeal cancer is characterized by poor prognosis. In contrast, excellent outcomes have been published in early-stage supraglottic cancers after laser surgery in single-institutional series in centers of excellence. Are these results reproducible in the normal clinical practice of less specialized facilities? As part of an observational cohort study, the outcomes of 194 supraglottic cancer patients were assessed after treatment by larynx-preserving surgery (transoral laser microsurgery [TLM] or open partial laryngectomy [OPL]) or total laryngectomy (TL), with each having risk-adopted adjuvant treatment, or primary (chemo-)radiotherapy (pCRT or pRT). In early-stage supraglottic cancers, TLM achieved a 5-year overall survival (5-year OS) of 62.0%. No significant survival difference could be discerned between patients with and without adjuvant treatment (HR 1.47; 95% CI: 0.80 2.69). The comparison between pCRT and pRT patients suggests that CRT is more effective in supraglottic cancer. The 5-year OS rate achieved in our multiinstitutional setting is comparable to that reached in laser surgery centers of excellence (59.4-76.0%). According to our data and supported by the literature, adjuvant RT (aRT) is not sufficiently effective in supraglottic cancers. In case adjuvant therapy is indicated, adjuvant chemoradiation (aCRT) could be recommended.

Treatment with tenofovir disoproxil fumarate or entecavir in chronic hepatitis B virus-infected patients with renal impairment: results from a 7-year, multicentre retrospective cohort study.

BACKGROUND: Limited data exist regarding tenofovir disoproxil fumarate (TDF) safety and effectiveness in chronic hepatitis B virus-infected (CHB) patients with renal impairment (RI). AIMS: To compare real-world data on renal safety and effectiveness of TDF vs entecavir (ETV) in CHB patients with moderate-to-severe RI. METHODS: Retrospective, non-interventional, cohort study analysing medical records for TDF/ETV-treated CHB patients (54 European centres). Included patients experienced moderate-to-severe RI (creatinine clearance 20-60 mL/min [Cockcroft-Gault]) either before TDF/ETV initiation ('before' subgroup [baseline = treatment initiation]) or after TDF/ETV initiation ('after' subgroup [baseline = first RI occurrence]). The primary objective was TDF safety, particularly renal-related adverse events of special interest (AESI). TDF and ETV safety and effectiveness were compared and multivariate analyses were performed using inverse probability treatment weighting. RESULTS: 'Before' subgroup included 107 TDF- and 91 ETV-treated patients; 'after' subgroup included 212 TDF- and 77 ETV-treated patients. Mean baseline creatinine clearance was higher for TDF- vs ETV-treated patients (both subgroups). Median follow-up was 3.1 years (both treatments). AESI were more frequent with TDF vs ETV ('before': 18.7% vs 8.8%; 'after': 9.9% vs 3.9%); however, differences were not significant by multivariate analysis. Only TDF-treated patients experienced renal tubular dysfunction (6.5% 'before'; 1.9% 'after') as well as renal adverse events leading to treatment discontinuation (8.4% 'before'; 7.1% 'after'). Effectiveness was similar between treatments. CONCLUSIONS: Overall safety was similar for TDF vs ETV (both subgroups). Given that renal tubular dysfunction occurred with TDF and not with ETV, renal safety concerns may be greater with TDF in CHB patients with RI.

Laryngeal Cancer Risks in Workers Exposed to Lung Carcinogens: Exposure-Effect Analyses Using a Quantitative Job Exposure Matrix.

INTRODUCTION: Various established occupational lung carcinogens are also suspected risk factors for laryngeal cancer. However, individual studies are often inadequate in size to investigate this relatively rare outcome. Other limitations include imprecise exposure assessment and inadequate adjustment for confounders. METHODS: This study applied a quantitative job exposure matrix (SYN-JEM) for four established occupational lung carcinogens to five case-control studies within the International Head and Neck Cancer Epidemiology Consortium. We used occupational histories for 2256 laryngeal cancer cases and 7857 controls recruited from 1989 to 2007. We assigned quantitative exposure levels for asbestos, respirable crystalline silica, chromium-VI, and chromium-VI and nickel combined (to address highly correlated exposures) via SYN-JEM. We assessed effects of occupational exposure on cancer risk for males (asbestos, respirable crystalline silica, chromium-VI, and chromium-VI and nickel combined) and females (asbestos and respirable crystalline silica), adjusting for age, study, tobacco smoking, alcohol consumption, and asbestos exposure where relevant. RESULTS: Among females, odds ratios (ORs) were increased for ever versus never exposed. Among males, P values for linear trend were <0.05 for estimated cumulative exposure (all agents) and <0.05 for exposure duration (respirable crystalline silica, chromium-VI, and chromium-VI and nickel combined); strongest associations were for asbestos at >90th percentile cumulative exposure (OR = 1.3, 95% confidence interval [CI] = 1.0, 1.6), respirable crystalline silica at 30+ years duration (OR = 1.4, 95% CI = 1.2, 1.7) and 75th-90th percentile cumulative exposure (OR = 1.4, 95% CI = 1.1, 1.8), chromium-VI at >75th percentile cumulative exposure (OR = 1.9, 95% CI = 1.2, 3.0), and chromium-VI and nickel combined at 20-29 years duration (OR = 1.5, 95% CI = 1.1, 2.2). CONCLUSIONS: These findings support hypotheses of causal links between four lung carcinogens (asbestos, respirable crystalline silica, chromium-VI, and nickel) and laryngeal cancer.

Age at start of using tobacco on the risk of head and neck cancer: Pooled analysis in the International Head and Neck Cancer Epidemiology Consortium (INHANCE).

BACKGROUND: Tobacco use is a well-established risk factor for head and neck cancer (HNC). However, less is known about the potential impact of exposure to tobacco at an early age on HNC risk. METHODS: We analyzed individual-level data on ever tobacco smokers from 27 case-control studies (17,146 HNC cases and 17,449 controls) in the International Head and Neck Cancer Epidemiology (INHANCE) consortium. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using random-effects logistic regression models. RESULTS: Without adjusting for tobacco packyears, we observed that younger age at starting tobacco use was associated with an increased HNC risk for ever smokers (OR<10 years vs. ≥30 years: 1.64, 95% CI: 1.35, 1.97). However, the observed association between age at starting tobacco use and HNC risk became null after adjusting for tobacco packyears (OR<10 years vs. ≥30 years: 0.97, 95% CI: 0.80, 1.19). In the stratified analyses on HNC subsites by tobacco packyears or years since quitting, no difference in the association between age at start and HNC risk was observed. CONCLUSIONS: Results from this pooled analysis suggest that increased HNC risks observed with earlier age at starting tobacco smoking are largely due to longer duration and higher cumulative tobacco exposures.

Occupations and the Risk of Head and Neck Cancer: A Pooled Analysis of the International Head and Neck Cancer Epidemiology (INHANCE) Consortium.

OBJECTIVE: To investigate the associations between head and neck cancer (HNC) risk and occupations. METHODS: We harmonized data on occupations in a pooled analysis of 8839 HNC cases and 13,730 controls in International Head and Neck Cancer Epidemiology (INHANCE) consortium. Logistic regression was used to estimate odds ratios (ORs) for associations of occupations and HNC risk. Population attributable fraction (PAF) for occupations was calculated using the formula PEC × (OR - 1)/OR. RESULTS: Trend of increasing HNC risk was found with increasing duration of employment for many occupations, including cooks (OR = 1.36; 95% confidence interval [CI] 1.09 to 1.68), cleaners (OR = 1.38; 95% CI 1.13 to 1.69), painters (OR = 1.82; 95% CI 1.42 to 2.35). The PAF for a priori occupations was 14.5% (95% CI 7.1% to 21.9%) for HNC. CONCLUSIONS: We found associations between certain occupations and HNC risks, including for subsites, with a duration-response relationship.

DNA methylation at an enhancer of the three prime repair exonuclease 2 gene (TREX2) is linked to gene expression and survival in laryngeal cancer.

BACKGROUND: Genetic aberrations in DNA repair genes are linked to cancer, but less is reported about epigenetic regulation of DNA repair and functional consequences. We investigated the intragenic methylation loss at the three prime repair exonuclease 2 (TREX2) locus in laryngeal (n = 256) and colorectal cancer cases (n = 95) and in pan-cancer data from The Cancer Genome Atlas (TCGA). RESULTS: Significant methylation loss at an intragenic site of TREX2 was a frequent trait in both patient cohorts (p = 0.016 and < 0.001, respectively) and in 15 out of 22 TCGA studies. Methylation loss correlated with immunohistochemically staining for TREX2 (p < 0.0001) in laryngeal tumors and improved overall survival of laryngeal cancer patients (p = 0.045). Chromatin immunoprecipitation, demethylation experiments, and reporter gene assays revealed that the region of methylation loss can function as a CCAAT/enhancer binding protein alpha (CEBPA)-responsive enhancer element regulating TREX2 expression. CONCLUSIONS: The data highlight a regulatory role of TREX2 DNA methylation for gene expression which might affect incidence and survival of laryngeal cancer. Altered TREX2 protein levels in tumors may affect drug-induced DNA damage repair and provide new tailored therapies.

A change in the study evaluation paradigm reveals that larynx preservation compromises survival in T4 laryngeal cancer patients.

BACKGROUND: Larynx preservation (LP) is recommended for up to low-volume T4 laryngeal cancer as an evidence-based treatment option that does not compromise survival. However, a reevaluation of the current literature raises questions regarding whether there is indeed reliable evidence to support larynx preservation for T4 tumor patients. METHODS: In an observational cohort study of 810 laryngeal cancer patients, we evaluated the outcomes of all T4 tumor patients treated with primary chemo-radiotherapy (CRT) or primary radiotherapy alone (RT) compared with upfront total laryngectomy followed by adjuvant (chemo)radiotherapy (TL + a[C]RT). Additionally, we reevaluated the studies that form the evidence base for the recommendation of LP for patients with up to T4 tumors (Pfister et al., J Clin Oncol 24:3693-704, 2006). RESULTS: The evaluation of all 288 stage III and IV patients together did not show a significant difference in overall survival (OS) between CRT-LP and TL + a(C)RT (hazard ratio (HR) 1.23; 95% confidence interval (CI): 0.82-1.86; p = 0.31) using a multivariate proportional hazard model. However, a subgroup analysis of T4 tumor patients alone (N = 107; 13.9%) revealed significantly worse OS after CRT compared with TL + a(C)RT (HR 2.0; 95% CI: 1.04-3.7; p = 0.0369). A reevaluation of the subgroup of T4 patients in the 5 LP studies that led to the ASCO clinical practice guidelines revealed that only 21-45 T4 patients had differential data on survival outcome. These data, however, showed a markedly worse outcome for T4 patients after LP. CONCLUSIONS: T4 laryngeal cancer patients who reject TL as a treatment option should be informed that their chance of organ preservation with primary conservative treatment is likely to result in a significantly worse outcome in terms of OS. Significant loss of survival in T4 patients after LP is also confirmed in recent literature.

Low frequency of cigarette smoking and the risk of head and neck cancer in the INHANCE consortium pooled analysis.

BACKGROUND: Cigarette smoking is a major risk factor for head and neck cancer (HNC). To our knowledge, low cigarette smoking (<10 cigarettes per day) has not been extensively investigated in fine categories or among never alcohol drinkers. METHODS: We conducted a pooled analysis of individual participant data from 23 independent case-control studies including 19 660 HNC cases and 25 566 controls. After exclusion of subjects using other tobacco products including cigars, pipes, snuffed or chewed tobacco and straw cigarettes (tobacco product used in Brazil), as well as subjects smoking more than 10 cigarettes per day, 4093 HNC cases and 13 416 controls were included in the analysis. The lifetime average frequency of cigarette consumption was categorized as follows: never cigarette users, >0-3, >3-5, >5-10 cigarettes per day. RESULTS: Smoking >0-3 cigarettes per day was associated with a 50% increased risk of HNC in the study population [odds ratio (OR) = 1.52, 95% confidence interval (CI): (1.21, 1.90). Smoking >3-5 cigarettes per day was associated in each subgroup from OR = 2.01 (95% CI: 1.22, 3.31) among never alcohol drinkers to OR = 2.74 (95% CI: 2.01, 3.74) among women and in each cancer site, particularly laryngeal cancer (OR = 3.48, 95% CI: 2.40, 5.05). However, the observed increased risk of HNC for low smoking frequency was not found among smokers with smoking duration shorter than 20 years. CONCLUSION: Our results suggest a public health message that low frequency of cigarette consumption contributes to the development of HNC. However, smoking duration seems to play at least an equal or a stronger role in the development of HNC.

Disaggregating health inequalities within Rio de Janeiro, Brazil, 2002-2010, by applying an urban health inequality index / Desagregando desigualdades na saúde no Rio de Janeiro, Brasil, 2002-2010, através da aplicação de um índice urbano de desigualdade de saúde / Disgregando desigualdades en el ámbito de la salud en Río de Janeiro, Brasil, 2002-2010, mediante la aplicación de un índice urbano de desigualdad en salud

Abstract An urban health index (UHI) was used to quantify health inequalities within Rio de Janeiro, Brazil, for the years 2002-2010. Eight main health indicators were generated at the ward level using mortality data. The indicators were combined to form the index. The distribution of the rank ordered UHI-values provides information on inequality among wards, using the ratio of the extremes and the gradient of the middle values. Over the decade the ratio of extremes in 2010 declined relative to 2002 (1.57 vs. 1.32) as did the slope of the middle values (0.23 vs. 0.16). A spatial division between the affluent south and the deprived north and east is still visible. The UHI correlated on an ecological ward-level with socioeconomic and urban environment indicators like square meter price of apartments (0.54, p < 0.01), low education of mother (-0.61, p < 0.01), low income (-0.62, p < 0.01) and proportion of black ethnicity (-0.55, p < 0.01). The results suggest that population health and equity have improved in Rio de Janeiro in the last decade though some familiar patterns of spatial inequality remain.

Resumo Um índice de saúde urbana foi utilizado para quantificar desigualdades na saúde no Rio de Janeiro, Brasil, 2002-2010. Oito indicadores de saúde foram gerados no nível dos bairros utilizando dados de mortalidade. Os indicadores foram combinados para formar o índice. A distribuição ordenada dos valores do índice fornece informações sobre a desigualdade entre os bairros, por meio da relação entre os extremos e o gradiente dos valores médios. Ao longo da década, a proporção dos extremos caiu em 2010 em relação a 2002 (1,57 vs. 1,32), assim como a inclinação dos valores médios (0,23 vs. 0,16). A divisão espacial entre o sul afluente e o norte carente está ainda visível. Os valores do índice correlacionam com indicadores socioeconômicos e urbanos como o preço do metro quadrado de apartamentos (0,54, p < 0,01), baixa escolaridade da mãe (-0,61, p < 0,01), baixa renda (-0,62, p < 0,01) e proporção de pretos étnicos (-0,55, p < 0,01). Os resultados sugerem que a equidade na saúde no nível da população tem melhorado no Rio de Janeiro na última década, embora padrões familiares da desigualdade espacial permaneçam.

Resumen Se utilizó un índice de salud urbana para cuantificar desigualdades en el ámbito de la salud en Río de Janeiro, Brasil, 2002 a 2010. Se han generado ocho indicadores de salud a nivel de barrios, utilizando datos de mortalidad. Los indicadores fueron combinados para formar el índice. La distribución ordenada de los valores del índice ofrece información de la desigualdad, a través de la relación entre los extremos y el gradiente de los valores medios. A lo largo de la década la proporción de los extremos disminuyó en 2010, en comparación con 2002 (1,57 vs. 1,32), al igual que el gradiente de los valores medios (0,23 vs. 0,16). La división espacial entre el opulento sur y el norte desfavorecido es todavía visible. Los valores del índice se correlacionan con los indicadores socioeconómicos y urbanos, como el precio de los apartamentos (0,54, p < 0,01), la baja educación materna (-0.61, p < 0.01), baja renta (-0,62, p < 0,01) y la población afrobrasileña (-0,55, p < 0,01). Los resultados sugieren que la equidad en salud ha mejorado en Río de Janeiro en la última década, aunque los patrones familiares de desigualdad espacial permanecen.

Risk factors for head and neck cancer in young adults: a pooled analysis in the INHANCE consortium.

BACKGROUND: Increasing incidence of head and neck cancer (HNC) in young adults has been reported. We aimed to compare the role of major risk factors and family history of cancer in HNC in young adults and older patients. METHODS: We pooled data from 25 case-control studies and conducted separate analyses for adults ≤ 45 years old ('young adults', 2010 cases and 4042 controls) and >45 years old ('older adults', 17700 cases and 22 704 controls). Using logistic regression with studies treated as random effects, we estimated adjusted odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: The young group of cases had a higher proportion of oral tongue cancer (16.0% in women; 11.0% in men) and unspecified oral cavity / oropharynx cancer (16.2%; 11.1%) and a lower proportion of larynx cancer (12.1%; 16.6%) than older adult cases. The proportions of never smokers or never drinkers among female cases were higher than among male cases in both age groups. Positive associations with HNC and duration or pack-years of smoking and drinking were similar across age groups. However, the attributable fractions (AFs) for smoking and drinking were lower in young when compared with older adults (AFs for smoking in young women, older women, young men and older men, respectively, = 19.9% (95% CI=9.8%, 27.9%), 48.9% (46.6%, 50.8%), 46.2% (38.5%, 52.5%), 64.3% (62.2%, 66.4%); AFs for drinking=5.3% (-11.2%, 18.0%), 20.0% (14.5%, 25.0%), 21.5% (5.0%, 34.9%) and 50.4% (46.1%, 54.3%). A family history of early-onset cancer was associated with HNC risk in the young [OR=2.27 (95% CI=1.26, 4.10)], but not in the older adults [OR=1.10 (0.91, 1.31)]. The attributable fraction for family history of early-onset cancer was 23.2% (8.60% to 31.4%) in young compared with 2.20% (-2.41%, 5.80%) in older adults. CONCLUSIONS: Differences in HNC aetiology according to age group may exist. The lower AF of cigarette smoking and alcohol drinking in young adults may be due to the reduced length of exposure due to the lower age. Other characteristics, such as those that are inherited, may play a more important role in HNC in young adults compared with older adults.

Association of history of allergies and influenza-like infections with laryngeal cancer in a case-control study.

Prior studies suggest that history of allergy and infections early in life might be inversely associated with cancer. We explored the association between allergies, recent influenza infections and laryngeal cancer risk. We used data from a case-control study which included 229 cases of laryngeal cancer and 769 population controls matched for age and sex. History of a physician-diagnosed allergy, influenza-like infections in the past 5 years, smoking, alcohol consumption and occupational exposure to carcinogens were self-reported. Allergies were classified into two groups (Type I and Type IV), according to the underlying immunologic mechanism. Conditional logistic regression models were fitted using laryngeal cancer as the outcome, adjusting for smoking, alcohol consumption and occupational exposure and stratified for age and sex. Having any allergy was not associated significantly with laryngeal cancer. Although Type I and Type IV allergies were non-significantly associated with laryngeal cancer, Type IV allergies showed a strong inverse association after adjusting for smoking and alcohol (OR 0.50, 95 % CI 0.22-1.2). Participants who reported at least one influenza-like infection during the past 5 years were significantly less likely to have laryngeal cancer (OR 0.57, 95 % CI 0.39-0.81). After considering fever (≥38.5 °C) as a criterion for influenza infection, the association between influenza infection and laryngeal cancer was even stronger (OR 0.29, 95 % CI 0.13-0.63). We found no significant association between any allergy and laryngeal cancer, some indication of an inverse association between Type IV allergy and laryngeal cancer, whereas recent influenza infections were inversely associated with laryngeal cancer risk.