Are comorbidities associated with long-term survival of lung cancer? A population-based cohort study from French cancer registries.

BACKGROUND: Survival rates of lung cancer remains poor and the impact of comorbidities on the prognosis is discussed. The objective of this study was to assess if the Charlson Comorbidity Index (CCI) was associated with 8-year survival rates by histological type. METHODS: A cohort study was conducted using randomly selected cases from 10 French cancer registries. Net survival rates were computed using the Pohar-Perme estimator of the net cumulative rate. Three Cox models were independently built for adenocarcinomas, squamous cell and small cell cancers to estimate prognostic factors including CCI grade. RESULTS: A total of 646 adenocarcinomas, 524 squamous cell and 233 small cell cancers were included in the analysis. The net 8-year survival rate ranged from 12.6% (95% CI: 9.8-15.4%) for adenocarcinomas and 13.4% (95% CI: 10.1-16.7%) for squamous cell carcinomas, to 3.7% (95% CI: 1.1-6.3%) for small cell cancers. Observed and net survival rates decreased for CCI grades ≥3 for all histological group considered. After adjustment for sex, age group, stage and diagnostic mode, CCI grades 1 (HR = 1.6 [95% CI: 1.1-2.3]), 2 (HR = 1.7 [95% CI: 1.1-2.7]) and ≥ 3 (HR = 2.7 [95% CI: 1.7-4.4]) were associated with lower survival rates only for small cell cancers. CONCLUSION: After adjustment for age, sex, stage and diagnostic mode, the presence of comorbidity based on CCI grades 1-2 and ≥ 3 was associated with lower survival rates for small cell cancers whereas no differences were observed for adenocarcinomas and squamous cell cancers.

Merkel cell carcinoma in France: a registries-based, comprehensive epidemiological survey.

BACKGROUND: Merkel cell carcinoma (MCC) is a rare primary cutaneous neuroendocrine carcinoma. Owing to its low incidence, epidemiological data are scarce and have never been analysed in France to identify the main epidemiological trends. METHODS: Data from MCC patients diagnosed between 1998 and 2010 were obtained from 11 French cancer registries in the FRANCIM network. The main epidemiological characteristics of MCC were investigated between 2006 and 2010 because comprehensive data were only available for this period. The main focus was tumour incidence and mortality over time. RESULTS: Between 1998 and 2010, 562 cases of MCC were reported in the registries. From 2006 to 2010 (290 cases), European- and world-standardized incidence rates were 0.26 and 0.43 per 100,000 person-years in men and 0.24 and 0.38 per 100,000 person-years in women. MCC is more frequent in females in France (56.9%) with male/female ratio 1.1. Relative survival rates were 84%, 56% and 42% at one, three and 5 years, respectively. CONCLUSIONS: The incidence of MCC clearly increased over time in all areas under focus. The standardized incidence in France was comparable to the incidence observed in other countries for the same period, but French data are too recent to conclude on an increase in MCC incidence. Prognosis remains poor in all countries in which data are available.

Are dietary reports in a case-control study on thyroid cancer biased by risk perception of Chernobyl fallout?

BACKGROUND: In retrospective case-control studies performed following nuclear tests or nuclear accidents, individual thyroid radiation dose reconstructions are based on fallout and meteorological data from the residential area, demographic characteristics, and lifestyle as well as dietary information. Collecting the latter is a controversial step, as dietary declarations may be affected by the subjects' beliefs about their risk behavior. This report analyses the potential for such bias in a case-control study performed in eastern France. METHODS: The study included 765 cases of differentiated thyroid carcinoma matched with 831 controls. Risk perceptions and beliefs of cases and controls were compared using Chi2 tests and differences in dietary reports were analyzed using a two-way ANOVA. RESULTS: In general, atmospheric pollution and living near a nuclear power plant were the two major risks that may influence thyroid cancer occurrence cited by cases and controls. When focusing in particular on the consequences of the Chernobyl accident, cases were more likely to think that the consequences were responsible for thyroid cancer occurrence than controls. Vegetable consumption during the two months after the Chernobyl accident was correlated with the status of subjects, but not to their beliefs. Conversely, consumption of fresh dairy products was not correlated with the status or beliefs of subjects. CONCLUSION: We found no evidence of systematic bias in dietary reports according to the status or beliefs held by subjects about the link between thyroid cancer occurrence and Chernobyl fallout. As such, these dietary reports may be used in further studies involving individual dosimetric reconstructions.

[Prostate cancer incidence and mortality trends in France from 1980 to 2011]. / Le cancer de la prostate, évolution de l'incidence et de la mortalité en France entre 1980 et 2011.

UNLABELLED: The prostate cancer became for two decades the most frequent cancer in men. We describe the evolution of its incidence and mortality from 1980 to 2011 for France. METHODS: Incidence data were collected from registries and national incidence estimates were based on the use of mortality as a correlate of incidence. RESULTS: After a very strong increase of incidence between 1980 (24.8/100,000) and 2005 (124.5/100,000), we observe a net decline since (97.7/100,000, in 2011). The reduction began earlier for the old patients. The evolution of mortality is very different. We observe a regular reduction since the end of 1990s (from 18.0/100,000 in 1990 to 10.5/100,000 in 2011). The reduction began earlier for the young patients. CONCLUSION: This pattern of evolution is observed in all the countries where the use of the PSA had caused an important increase of the diagnosis of prostate cancer. LEVEL OF EVIDENCE: 3.

Trends in breast cancer incidence and mortality in France 1990-2008.

The objective of this work was to detail the incidence and mortality trends of invasive and in situ breast cancer (BC) in France, especially regarding the development of screening, over the 1990-2008 period. Data issued from nine population-based cancer registries were studied. The incidence of invasive BC increased annually by 0.8 % from 1990 to 1996 and more markedly by 3.2 % from 1996 to 2003, and then sharply decreased until 2006 (-2.3 % per year), especially among women aged 50-69 years (-4.9 % per year). This trend was similar whatever the introduction date of the organized screening (OS) program in the different areas. The incidence of ductal carcinoma in situ steadily increased between 1990 and 2005, particularly among women aged 50-69 years and 70 and older. At the same time, the mortality from BC decreased annually by 1.1 % over the entire study period. This decrease was more pronounced in women aged 40-49 and 50-69 and, during the 1990-1999 period, in the areas where OS began in 1989-1991. The similarity in the incidence trends for all periods of implementation of OS in the different areas was striking. This suggests that OS alone does not explain the changes observed in incidence rate. Our study highlights the importance of closely monitoring the changes in incidence and mortality indicators, and of better understanding the factors causing variation.

Asthma among workers in healthcare settings: role of disinfection with quaternary ammonium compounds.

INTRODUCTION: An increased incidence of asthma has been reported among healthcare workers. The role of quaternary ammonium compounds (QACs), commonly used in cleaning/disinfection products, has not been clearly defined. The aim of this study was to analyse associations between asthma and occupational exposure to disinfectants, especially QACs. METHODS: The study was performed on a stratified random sample of the various healthcare departments of 7 healthcare settings. The study included: questionnaire, physical examination and specific IgE assays. Occupational exposure assessment was performed by means of a work questionnaire, workplace studies and a review of products ingredients. Data were analysed by logistic regression. RESULTS: Response rate was 77%; 543 workers (89% female) participated; 37.1% were registered nurses (RNs), 16.4% auxiliary nurses (ANs), 17.3% cleaners; 32.8% were atopic. 335 participants were exposed to QACs. Nursing professionals reported a significantly higher risk of reported physician-diagnosed asthma and, for RNs, of nasal symptoms at work than administrative staff working in healthcare sector. This risk was particularly marked during disinfection tasks and when exposure to QACs. Exposure to QACs increased significantly the risk of reported physician-diagnosed asthma and nasal symptoms at work (adjusted OR = 7.5 and 3.2, respectively). No significant association was found with other exposures such as latex glove use, chlorinated products/bleach or glutaraldehyde. CONCLUSION: RNs and ANs presented a higher risk of reported asthma than administrative staff. The highest risk was associated with tasks involving dilution of disinfection products by manual mixing, suggesting possible exposure to repeated peaks of concentrated products known to be strong respiratory irritants. Workplace interventions should be conducted to more clearly determine QAC exposure and improve disinfection procedures.

Role of thyroid surgery in the obstructive sleep apnea syndrome.

OBJECTIVES: To study the impact of thyroid surgery on obstructive sleep apnea syndrome (OSAS) evaluated by the apnea/hypopnea index (AHI) was studied. Secondary objectives were to evaluate the impact on the positional component of OSAS and to highlight possible predictors of improvement of OSAS after thyroidectomy. METHODS: Twenty-eight patients with OSAS are included in this monocentric study: they underwent total thyroidectomy (n = 26) or left loboisthmectomy. Postoperative assessment involves a nocturnal control polysomnography as of 60 days after surgery. RESULTS: The mean age at the time of surgery is 61.3 years (standard deviation ±7.3) and average body mass index is 29.6 kg/m2 (±7.3). Continuous positive airway pressure (CPAP) treatment is introduced preoperatively in 82% of patients. The statistical analysis shows a significant decrease of 33% in postoperative AHI for the total population (p = 0.001), 77% in patients under CPAP (p = 0.05), and 27% in patients without CPAP (p = 0.02). CPAP therapy could be released in four patients. Given the limited number of subjects studied, the surgery did not impact on the positional component of the OSAS. Statistical analysis failed to link a predictive factor to AHI reduction. CONCLUSIONS: We propose thyroid surgery as an alternative or as a complement to CPAP treatment for the patients with goitre: it allows a significant decrease in postoperative AHI, allowing adaptation of the CPAP treatment downward, or even a release in some cases. These results need to be confirmed on a larger series of patients in a prospective study with standardized criteria for polysomnography and multivariate analysis.

Response shift effects on measuring post-operative quality of life among breast cancer patients: a multicenter cohort study.

PURPOSE: To characterize response shift effects in patients with breast cancer (BC). METHODS: The QLQ-C30, BR23, and EurQOL-EQ-5D were assessed at baseline and at the end of the first hospitalization. We used the then-test approach to characterize changes in internal standards by calculating the mean difference between the then-test (retrospective measure) and pre-test baseline QoL assessments. The Ideal Scale Approach was also used to assess changes in standards by comparing health and QoL expectancies between baseline and the end of the first hospitalization. Successive Comparison Approach was used to assess changes in values through the longitudinal assessment of the relative importance of EuroQOL dimensions. RESULTS: The results of this study showed that recalibration RS effects occurred early after the first hospitalization for 6/15 dimensions of QLQ-C30 (emotional, cognitive, fatigue, insomnia, appetite loss, diarrhea) and 2/8 of BR-23 (future perspective, systemic therapy side effects). Moreover, health and QoL expectancies changed between the baseline and the end of the first hospitalization, and changes in values were seen for the self-care and usual activities dimensions of the EuroQOL-EQ-5D. CONCLUSIONS: The occurrence of RS early after the first hospitalization suggests that it needs to be taken into account to interpret QoL changes in BC.

[Incidence and mortality of urological cancers in 2012 in France]. / Projection de l'incidence et de la mortalité par cancer urologique en France en 2012.

OBJECTIVES: Present national estimations of the incidence and mortality trends in urological cancers in France between 1980 and 2012. MATERIAL AND METHODS: Francim database and French Register of Cancers. RESULTS: Analysis of the current data shows a regular increase of the incidence of renal cancer in men and women (7,781 cases in men and 3,792 in women in 2012). For bladder cancer, trends are divergent. There is a small reduction in incidence for men and an increase for women (9,549 cases in men and 2,416 in women in 2012). Testicular cancer is still increasing slightly (2,317 incidental cases in 2012). The incidence of prostate cancer experienced a huge increase up until 2005, and thereafter it decreased sharply, though it is difficult to discern whether this drop (which was observed up until 2008) continued at the same rate after that point (56,841 incidences in 2012 based on the rates calculated for 2009). CONCLUSION: The analyses by organ database show that there are significant variations in the incidence of urological cancers, particularly for prostate cancer, which shows that both the natural history of urological tumours and the methods of detection have an impact on incidence.

Evaluation of continuous ampicillin/sulbactam infusion in critically ill patients.

Continuous infusion (CI) of beta-lactam-antibiotics may improve pharmacodynamics in critically ill patients, but resulting concentrations have not been studied. Therapeutic drug monitoring is increasingly used to ensure antibiotic concentration. The aim of this study is to evaluate therapeutic ampicillin/sulbactam concentrations of a continuous infusion regimen. METHODS: Medical records of all patients admitted to ICU between January 2019 and December 2020 were retrospectively reviewed. Each patient received a 2/1 g ampicillin/sulbactam loading dose, followed by a continuous infusion of 8/4 g per 24 h. Ampicillin serum concentrations were measured. Main outcomes were reaching of plasma concentrations breakpoint defined by minimum inhibitory concentration (MIC at 8 mg/l) and 4-fold MIC (MIC at 32 mg/l) during steady state of CI. RESULTS: In 50 patients a total of 60 concentration measurements were performed. The first concentration was measured after a median of 29 h (IQR 21-61 h). Mean ampicillin concentration was 62.6 ± 39.1 mg/l. Furthermore, serum concentrations exceeded the defined MIC breakpoint in all measurements (100 %) and were above the 4-fold MIC in 43 analyses (71.1 %). However, patients suffering from acute kidney injury exhibited significant higher serum concentrations (81.1 ± 37.7 mg/l vs. 38.2 ± 24.8 mg/l; p < 0.001). Also, there was a negative correlation between ampicillin serum concentrations and GFR (r = -0.659; p < 0.001). CONCLUSION: The described dosing regimen for ampicillin/sulbactam is safe with respect to the defined MIC breakpoints for ampicillin, and continuous subtherapeutic concentration is unlikely. However, with impaired renal function drug accumulation occurs, and with increased renal clearance, drug levels can be below the 4-fold MIC breakpoint.

Epidemiology of posttransplant lymphoproliferative disorders in adult kidney and kidney pancreas recipients: report of the French registry and analysis of subgroups of lymphomas.

A registry of posttransplant lymphoproliferative disorders (PTLD) was set up for the entire population of adult kidney transplant recipients in France. Cases of PTLD were prospectively enrolled between January 1, 1998, and December 31, 2007. Ten-year cumulative incidence was analyzed in patients transplanted after January 1, 1989. PTLD risk factors were analyzed in patients transplanted after January 1, 1998 by Cox analysis. Cumulative incidence was 1% after 5 years, 2.1% after 10 years. Multivariate analysis showed that PTLD was significantly associated with: older age of the recipient 47-60 years and >60 years (vs. 33-46 years, adjusted hazard ratio (AHR) = 1.87, CI = 1.22-2.86 and AHR = 2.80, CI = 1.73-4.55, respectively, p < 0.0001), simultaneous kidney-pancreas transplantation (AHR = 2.52, CI = 1.27-5.01 p = 0.008), year of transplant 1998-1999 and 2000-2001 (vs. 2006-2007, AHR = 3.36, CI = 1.64-6.87 and AHR = 3.08, CI = 1.55-6.15, respectively, p = 0.003), EBV mismatch (HR = 5.31, CI = 3.36-8.39, p < 0.001), 5 or 6 HLA mismatches (vs. 0-4, AHR = 1.54, CI = 1.12-2.12, p = 0.008), and induction therapy (AHR = 1.42, CI = 1-2.02, p = 0.05). Analyses of subgroups of PTLD provided new information about PTLD risk factors for early, late, EBV positive and negative, polymorphic, monomorphic, graft and cerebral lymphomas. This nationwide study highlights the increased risk of PTLD as long as 10 years after transplantation and the role of cofactors in modifying PTLD risk, particularly in specific PTLD subgroups.

The role of general practitioners in diagnosis of cutaneous melanoma: a population-based study in France.

BACKGROUND: Little data are available concerning the role of general practitioners (GPs) in the diagnosis of melanoma. OBJECTIVES: To evaluate the actual role of GPs in a population-based study covering five regions of France and 8·2 million inhabitants. MATERIALS AND METHODS: A survey of cancer registries and pathology laboratories, and questionnaires to practitioners were used to identify incident melanomas in 2008, and evaluate characteristics of patients (age, sex, area of residence, social isolation), tumours (Breslow, ulceration, location, histological type), and GPs (training, conditions of practice), and their influence on patterns of diagnosis and Breslow thickness. RESULTS: Among 898 melanomas, 376 (42%) were first diagnosed in a general practice setting (GP group). Breslow thickness was much higher in the GP group than in other melanomas (median: 0·95 vs. 0·61 mm, P < 0·0001). Multivariate analysis identified an older age, lower limb location, nodular subtype and Breslow thickness as factors associated with the GP group. Within this group, 52·5% of melanomas were detected by patients (median Breslow thickness: 1·30 mm) and 47·5% by GPs (median Breslow thickness: 0·80 mm, P = 0·0009), including 8% during a systematic full-body skin examination. Previous GP training on melanoma was associated with active detection by GPs. Male sex and social isolation of patients were associated with thicker melanomas, whereas active detection by GPs was associated with thinner CMs. CONCLUSIONS: GPs play a key role in melanoma diagnosis in France, but still frequently detect thick tumours. Increasing awareness and training of GPs and focusing attention on male and/or socially isolated patients should help to improve early detection of melanoma.

Cost-effectiveness analysis of resorbable biosynthetic mesh in contaminated ventral hernia repair.

BACKGROUND: The aim of this study was to compare, in terms of cost and serious complications, the use of biosynthetic resorbable parietal mesh with biologic mesh in patients undergoing contaminated ventral hernia repair (modified Ventral Hernia Working Group grade 3). Poly-4-hydroxy-butyrate (P4HB) biosynthetic mesh has rarely been the subject of comparative studies in the context of contamination. Data are required to confirm the effects of a transition from biological mesh to biosynthetic resorbable mesh. PATIENTS AND METHODS: A cost-effectiveness analysis was conducted. It was based on a decision analysis model built with clinical and economic data issued from a before-after study that included 94 patients hospitalized for ventral hernia repair at the University Hospital of Strasbourg (France) from June 2011 to February 2018. The effectiveness endpoint was the number of patients presenting with a serious specific complication or a general complication at 6 months. Data for surgical hospitalization stays, home hospitalizations and ambulatory care costs were included. RESULTS: We found fewer serious complications with biosynthetic mesh: 21% versus 33% with biologic mesh. A cost savings of US $5146 was determined. Deterministic sensitivity analyses and a probabilistic analysis confirmed our findings and the robustness of the model. CONCLUSION: P4HB biosynthetic resorbable mesh appeared to be the most effective and the least costly option. Additional data will be needed to confirm the superiority of biosynthetic mesh in terms of the recurrence risk reduction over a longer period.

Systemically administered ligands of Toll-like receptor 2, -4, and -9 induce distinct inflammatory responses in the murine lung.

OBJECTIVE: To determine whether systemically administered TLR ligands differentially modulate pulmonary inflammation. METHODS: Equipotent doses of LPS (20 mg/kg), CpG-ODN (1668-thioat 1 nmol/g), or LTA (15 mg/kg) were determined via TNF activity assay. C57BL/6 mice were challenged intraperitoneally. Pulmonary NFκB activation (2 h) and gene expression/activity of key inflammatory mediators (4 h) were monitored. RESULTS: All TLR ligands induced NFκB. LPS increased the expression of TLR2, 6, and the cytokines IL-1αß, TNF-α, IL-6, and IL-12p35/p40, CpG-ODN raised TLR6, TNF-α, and IL12p40. LTA had no effect. Additionally, LPS increased the chemokines MIP-1α/ß, MIP-2, TCA-3, eotaxin, and IP-10, while CpG-ODN and LTA did not. Myeloperoxidase activity was highest after LPS stimulation. MMP1, 3, 8, and 9 were upregulated by LPS, MMP2, 8 by CpG-ODN and MMP2 and 9 by LTA. TIMPs were induced only by LPS. MMP-2/-9 induction correlated with their zymographic activities. CONCLUSION: Pulmonary susceptibility to systemic inflammation was highest after LPS, intermediate after CpG-ODN, and lowest after LTA challenge.

A prospective randomized study of two reminding strategies: telephone versus mail in the screening of cervical cancer in women who did not initially respond.

OBJECTIVE: To compare the efficacy and cost-effectiveness of two reminding strategies addressed to women who did not respond to a first invitation to undergo cervical cancer screening. STUDY DESIGN: A randomized study was carried out by a programme created in Alsace to organize cervical cancer screening. In total, 10,662 women who did not have a smear test 1 year after a first notice was sent, were randomly allocated to receive either a new letter with a reply coupon or a telephone call. The uptake of screening was measured using routine data. Efficacy and direct costs of the two methods were compared. RESULTS: Uptake at 8 months was 6.3% [95% confidence interval (CI) 5.6-7.0%] for telephone calls and 5.8% (95% CI 5.2-6.4%) for letters. The difference was not significant. More information was collected through telephone calls than by letters, but with less reliability. Furthermore, telephone calls were more costly. CONCLUSIONS: We found that in our region, a mail reminder was as effective as, and less expensive than, a telephone call; moreover, it was applicable to the whole population, including patients without a telephone.

[Epidemiology of oral cavity cancers in France]. / Épidémiologie des cancers de la cavité buccale en France.

INTRODUCTION: We had for objective to describe the updated epidemiology of oral cancers in France. MATERIAL AND METHODS: Estimates made from data collected from various French cancer institutions. The distribution by topography, histology, regions, mean age, and specific incidence rates were calculated from the collected data. The survival data was taken from the Francim network studies. RESULTS: Approximately 7000 oral cavity cancers were diagnosed in France in 2005. In 2007, 1746 people died of that cancer. Standardized (world population) incidence rates are respectively, in men and women, 12.3 and 3.0 cases per 100,000 person-years. These cancers have significantly decreased in men: the standardized incidence rate decreased by 43.2% between 1980 and 2005. Among women, the trend is reversed with an increased incidence of 51.7% over the same period. CONCLUSION: In France, the incidence of oral cavity cancers has been strongly decreasing in men and strongly increasing in women. This trend should be compared to the frequency of the main risk factors: alcohol and tobacco.

Evolution of pleural cancers and malignant pleural mesothelioma incidence in France between 1980 and 2005.

The evolution of pleural cancers and malignant pleural mesothelioma incidence in France between 1980 and 2005 was analysed using data derived from the French network of cancer registries (FRANCIM) and the French National Mesothelioma Surveillance Program (PNSM). Mesothelioma proportions in pleural cancers were calculated by diagnosis year in the 1980-2000 period. Our results suggest that the incidences of pleural cancer and mesothelioma levelled off in French men since 2000 and continued to increase in French women. A decrease of the annual pleural cancer incidence average in men was noticed (-3.4% of annual rate of change) between 2000 and 2005. The proportion of pleural cancers that were mesothelioma was unchanged between 1980 and 2003 with an average of 86%. The age standardised incidence rate of pleural mesothelioma remained relatively stable between 1998 and 2005 with a slight falling trend. For women, the age standardised incidence rate of pleural cancers and mesothelioma increased during the period 1998-2005. Additionally, the proportion of pleural cancers that were mesothelioma increased during the same period of time. Finally, the increased trend observed in the incidence of pleural mesothelioma and cancers in women is credibly due to their under diagnosis in the 1980-1997 period. The comparison between the French incidence and the American and British ones shows that the decreasing trend in incidence of mesothelioma and pleural cancers in French men since 2000 is potentially associated with a lower amphibole consumption and by the implementation of safety regulations at work from 1977.

A population-based study of adjuvant chemotherapy for stage-II and -III colon cancers.

BACKGROUND: Although clinical trials have demonstrated that adjuvant chemotherapy improves survival for stage-III colon cancer, the benefits remain controversial for stage-II lesions. The objective of the present study was to determine the extent to which adjuvant chemotherapy is used for patients with stage-II and -III colon cancers. METHODS: The study population comprised 1074 patients with stage-II and -III colon cancers diagnosed in 2000 in 12 French administrative districts and recorded in population-based cancer registries. Data were collected using a standardized procedure. RESULTS: Overall, 20.4% of patients with stage II and 61.9% with stage III received adjuvant chemotherapy. Age at diagnosis was the strongest determinant of chemotherapy. Among stage-II patients, those receiving chemotherapy decreased from 57.6% in patients aged or=85. The corresponding percentages with stage III were 93.6% and 1.4%. In multivariate analyses, other factors found to be independently and significantly associated with administration of adjuvant chemotherapy for stage II were extension of the cancer (stage IIA vs. stage IIB), clinical presentation (obstruction or perforation vs. uncomplicated cancer) and discussion of the case at a multidisciplinary case-review meeting. For stage III, apart from age, discussion of the case at a multidisciplinary meeting was the only factor independently associated with administration of chemotherapy. CONCLUSION: Adjuvant chemotherapy for stage-III colon cancer is used extensively for patients under 75 years of age. However, many elderly patients do not receive such treatment. On the other hand, a substantial percentage of stage-II colon cancer patients receive adjuvant chemotherapy despite its uncertain benefits.