Therapeutic vaccines for advanced non-small cell lung cancer.

BACKGROUND: New strategies in immunotherapy with specific antigens that trigger an anti-tumour immune response in people with lung cancer open the possibility of developing therapeutic vaccines aimed at boosting the adaptive immune response against cancer cells. OBJECTIVES: To evaluate the effectiveness and safety of different types of therapeutic vaccines for people with advanced non-small cell lung cancer. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, Wanfang Data, and China Journal Net (CNKI) up to 22 August 2023. SELECTION CRITERIA: We included parallel-group, randomised controlled trials evaluating a therapeutic cancer vaccine, alone or in combination with other treatments, in adults (> 18 years) with advanced non-small cell lung cancer (NSCLC), whatever the line of treatment. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Our primary outcomes were overall survival, progression-free survival, and serious adverse events; secondary outcomes were three- and five-year survival rates and health-related quality of life. MAIN RESULTS: We included 10 studies with 2177 participants. The outcome analyses included only 2045 participants (1401 men and 644 women). The certainty of the evidence varied by vaccine and outcome, and ranged from moderate to very low. We report only the results for primary outcomes here. TG4010 The addition of the vector-based vaccine, TG4010, to chemotherapy, compared with chemotherapy alone in first-line treatment, may result in little to no difference in overall survival (hazard ratio (HR) 0.83, 95% confidence interval (CI) 0.65 to 1.05; 2 studies, 370 participants; low-certainty evidence). It may increase progression-free survival slightly (HR 0.74, 95% CI 0.55 to 0.99; 1 study, 222 participants; low-certainty evidence). It may result in little to no difference in the proportion of participants with at least one serious treatment-related adverse event, but the evidence is very uncertain (risk ratio (RR) 0.70, 95% CI 0.23 to 2.19; 2 studies, 362 participants; very low-certainty evidence). Epidermal growth factor vaccine Epidermal growth factor vaccine, compared to best supportive care as switch maintenance treatment after first-line chemotherapy, may result in little to no difference in overall survival (HR 0.82, 95% CI 0.66 to 1.02; 1 study, 378 participants; low-certainty evidence), and in the proportion of participants with at least one serious treatment-related adverse event (RR 1.32, 95% CI 0.88 to 1.98; 2 studies, 458 participants; low-certainty evidence). hTERT (vx-001) The hTERT (vx-001) vaccine compared to placebo as maintenance treatment after first-line chemotherapy may result in little to no difference in overall survival (HR 0.97, 95% CI 0.70 to 1.34; 1 study, 190 participants). Racotumomab Racotumomab compared to placebo as a switch maintenance treatment post-chemotherapy was assessed in one study with 176 participants. It may increase overall survival (HR 0.63, 95% CI 0.46 to 0.87). It may make little to no difference in progression-free survival (HR 0.73, 95% CI 0.53 to 1.00) and in the proportion of people with at least one serious treatment-related adverse event (RR 1.03, 95% CI 0.15 to 7.18). Racotumomab versus docetaxel as switch maintenance therapy post-chemotherapy was assessed in one study with 145 participants. The study did not report hazard rates on overall survival or progression-free survival time, but the difference in median survival times was very small - less than one month. Racotumomab may result in little to no difference in the proportion of people with at least one serious treatment-related adverse event compared with docetaxel (RR 0.89, 95% CI 0.44 to 1.83). Personalised peptide vaccine Personalised peptide vaccine plus docetaxel compared to docetaxel plus placebo post-chemotherapy treatment may result in little to no difference in overall survival (HR 0.80, 95% CI 0.42 to 1.52) and progression-free survival (HR 0.78, 95% CI 0.43 to 1.42). OSE2101 The OSE2101 vaccine compared with chemotherapy, after chemotherapy or immunotherapy, was assessed in one study with 219 participants. It may result in little to no difference in overall survival (HR 0.86, 95% CI 0.62 to 1.19). It may result in a small difference in the proportion of people with at least one serious treatment-related adverse event (RR 0.95, 95% CI 0.91 to 0.99). SRL172 The SRL172 vaccine of killed Mycobacterium vaccae, added to chemotherapy, compared to chemotherapy alone, may result in no difference in overall survival, and may increase the proportion of people with at least one serious treatment-related adverse event (RR 2.07, 95% CI 1.76 to 2.43; 351 participants). AUTHORS' CONCLUSIONS: Adding a vaccine resulted in no differences in overall survival, except for racotumomab, which showed some improvement compared to placebo, but the difference in median survival time was very small (1.4 months) and the study only included 176 participants. Regarding progression-free survival, we observed no differences between the compared treatments, except for TG4010, which may increase progression-free survival slightly. There were no differences between the compared treatments in serious treatment-related adverse events, except for SRL172 (killed Mycobacterium vaccae) added to chemotherapy, which was associated with an increase in the proportion of participants with at least one serious treatment-related adverse event, and OSE2101, which may decrease slightly the proportion of people having at least one serious treatment-related adverse event. These conclusions should be interpreted cautiously, as the very low- to moderate-certainty evidence prevents drawing solid conclusions: many vaccines were evaluated in a single study with small numbers of participants and events.

Treatments for non-small cell lung cancer: a systematic quality assessment of clinical practice guidelines

Aim To evaluate the methodological quality of clinical practice guidelines (CPGs) on treatments for non-small cell lung cancer (NSCLC). Methods We searched MEDLINE, CPG developer websites, lung cancer societies, and oncology organizations to identify CPGs providing recommendations on treatments for NSCLC. The methodological quality for each CPG was determined independently by three appraisers using the AGREE II (Appraisal of Guidelines for Research and Evaluation II) instrument. Results Twenty-two CPGs met the eligibility criteria. The median scores per AGREE II domain were: scope and purpose 90.7% (64.8–100%), stakeholder involvement 76.9% (27.8–96.3%); rigor of development 80.9% (27.1–92.4%); clarity of presentation 89.8% (50–100%); applicability 46.5% (12.5–87.5%); and editorial independence 91.7% (27.8–100%). Most of the CPGs (54.5%) were rated as “recommended with modifications” for clinical use. Conclusions Overall, the methodological quality of CPGs proving recommendations on the management of NSCLC is moderate, but there is still room for improvement in their development and implementation (AU)

Treatments for non-small cell lung cancer: a systematic quality assessment of clinical practice guidelines.

AIM: To evaluate the methodological quality of clinical practice guidelines (CPGs) on treatments for non-small cell lung cancer (NSCLC). METHODS: We searched MEDLINE, CPG developer websites, lung cancer societies, and oncology organizations to identify CPGs providing recommendations on treatments for NSCLC. The methodological quality for each CPG was determined independently by three appraisers using the AGREE II (Appraisal of Guidelines for Research and Evaluation II) instrument. RESULTS: Twenty-two CPGs met the eligibility criteria. The median scores per AGREE II domain were: scope and purpose 90.7% (64.8-100%), stakeholder involvement 76.9% (27.8-96.3%); rigor of development 80.9% (27.1-92.4%); clarity of presentation 89.8% (50-100%); applicability 46.5% (12.5-87.5%); and editorial independence 91.7% (27.8-100%). Most of the CPGs (54.5%) were rated as "recommended with modifications" for clinical use. CONCLUSIONS: Overall, the methodological quality of CPGs proving recommendations on the management of NSCLC is moderate, but there is still room for improvement in their development and implementation.

Drugs for preventing lung cancer in healthy people.

BACKGROUND: This is the second update of this Cochrane Review. Some studies have suggested a protective effect of antioxidant nutrients and higher dietary levels of fruits and vegetables on lung cancer. OBJECTIVES: To determine whether vitamins and minerals and other potential agents, alone or in combination, reduce lung cancer incidence and lung cancer mortality in healthy populations. SEARCH METHODS: We searched CENTRAL, MEDLINE and Embase from 1974 to May 2019 and screened references included in published studies and reviews. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing vitamins or mineral supplements with placebo, administered to healthy people with the aim of preventing lung cancer. DATA COLLECTION AND ANALYSIS: Four review authors independently selected the trials to be included in the review, assessed their methodological quality and extracted data. For dichotomous outcomes we calculated risk ratios (RRs) and 95% confidence intervals (CIs) and pooled results using the random-effects model. We assessed the risk of bias using Cochrane's 'Risk of bias' assessment tool and certainty of evidence using the GRADE approach. MAIN RESULTS: In this update, we identified three new trials for a total of 12 studies. Six analysed vitamin A, three vitamin C, three combined vitamin D3 + calcium, four vitamin E combined with other products, one selenium supplements and nine studied combinations of two or more products. Four studies included only men and five only women. Vitamin A results in little to no difference in lung cancer incidence (RR 1.09, 95% CI 1.00 to 1.19; 5 RCTs, 212314 participants; high-certainty evidence) and lung cancer mortality (RR 1.06, 95% CI 0.81 to 1.38; 3 RCTs, 190118 participants; high-certainty evidence). But in smokers or asbestos workers vitamin A increases the risk of lung cancer incidence (RR 1.10, 95% CI 1.01 to 1.20; 3 RCTs, 43995 participants; high-certainty evidence), lung cancer mortality (RR 1.18, 95% CI 1.01 to 1.38; 2 RCTs, 29426 participants; high-certainty evidence) and all-cause mortality (RR 1.09, 95% CI 1.05 to 1.13; 2 RCTs, 32883 participants; high-certainty evidence). Vitamin A increases the risk of minor side effects, such as yellowing of the skin and minor gastrointestinal symptoms (high-certainty evidence). Vitamin C likely results in little to no difference in lung cancer incidence (RR 1.29, 95% CI 0.67 to 2.49; 2 RCTs, 14953 participants; moderate-certainty evidence). In women, vitamin C increases the risk of lung cancer incidence (RR 1.84, 95% CI 1.14 to 2.95; 1 RCT, 7627 participants; high-certainty evidence). In men, vitamin C results in little to no difference in mortality for lung cancer (RR 0.81, 95% CI 0.53 to 1.23; 1 RCT, 7326 participants; high-certainty evidence). Vitamin D + calcium may result in little to no difference in lung cancer incidence in postmenopausal women (RR 0.90, 95% CI 0.39 to 2.08; 3 RCTs, 37601 women; low-certainty evidence). Vitamin E results in little to no difference in lung cancer incidence (RR 1.01, 95% CI 0.90 to 1.14; 3 RCTs, 36841 participants; high-certainty evidence) or to lung cancer mortality (RR 0.96, 95% CI 0.77 to 1.18; 2 RCTs, 29214 participants; high-certainty evidence), but increases the risk of haemorrhagic strokes (hazard ratio (HR), 1.74, 95% CI 1.04 to 2.91; 1 RCT, 14641 participants; high-certainty evidence). Calcium results in little to no difference in lung cancer incidence in postmenopausal women (RR 0.65, 95% CI 0.13 to 3.18; 1 RCT, 733 participants) or in risk of renal calculi (RR 1.94, 95% CI 0.20 to 18.57; 1 RCT, 733 participants; low-certainty evidence). Selenium in men results in little to no difference in lung cancer incidence (RR 1.11, 95% CI 0.80 to 1.54; 1 RCT, 17448 participants; high-certainty evidence) and lung cancer mortality (RR 1.09, 95% CI 0.72 to 1.66; 1 RCT, 17448 participants; high-certainty evidence) and increases the risk for grade 1 to 2 dermatitis (RR 1.16, 95% CI 1.04 to 1.31; 1 RCT, 17448 participants; high-certainty evidence) and for alopecia (RR 1.28, 95% CI 1.07 to 1.53; 1 RCT, 17448 participants; high-certainty evidence). The combination of vitamins A, C, E + selenium + zinc results in little to no difference in lung cancer incidence (RR 0.64, 95% CI 0.28 to 1.48; 1 RCT, 12741 participants; high-certainty evidence). AUTHORS' CONCLUSIONS: Well-designed RCTs have shown no beneficial effect of supplements for the prevention of lung cancer and lung cancer mortality in healthy people. Vitamin A supplements increase lung cancer incidence and mortality in smokers or persons exposed to asbestos. Vitamin C increases lung cancer incidence in women. Vitamin E increases the risk of haemorrhagic strokes.

Mortality in Critically Ill Elderly Individuals Receiving Mechanical Ventilation.

BACKGROUND: Previous studies that evaluated mortality in elderly subjects who received mechanical ventilation had conflicting results. The aim of this systematic review was to evaluate the effects of age on mortality. METHODS: A number of medical literature databases and the references listed (from 1974 to May 2015) were searched for studies that compared 2 different age groups. The primary outcome was mortality in subjects ages ≥ 65 y. The severity scores, ICU and hospital lengths of stay, and the presence of ventilator-associated pneumonia were secondary outcomes. Finally, mortality in the subjects with ARDS and of cutoff ages 70 and 80 y was assessed by subgroup analysis. Evidence quality was assessed by the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) criteria score. RESULTS: Of the 5,182 articles identified, 21 were included. Subjects ages ≥ 65 y had higher mortalities (odds ratio [OR] 1.80, 95% CI 1.56-2.08; I2 = 71%). APACHE (Acute Physiology and Chronic Health Evaluation) II revealed intergroup differences (mean difference 3.07, 95% CI 2.52-3.61; I2 = 0%), whereas neither the ICU nor hospital length of stay (mean difference 1.27, 95% CI -0.82 to 3.36, I2 = 82%, and mean difference 1.29, 95% CI -0.71 to 3.29, I2 = 0%, respectively) nor the groups in the 2 studies that assessed ventilator-associated pneumonia exhibited any difference. Subgroup analysis revealed a higher mortality in the older subjects, in the subjects with ARDS (OR 1.76, 95% CI 1.30-2.36; I2 = 0%) and in the subjects ages 70 and 80 y (OR 1.78, 95% CI 1.51-2.10, I2 = 71%; and OR 1.96, 95% CI 1.81-2.13, I2 = 0%, respectively). The quality of associated evidence was low or very low. CONCLUSIONS: Although low-quality evidence was available, we conclude that age is associated with a greater mortality in critical subjects who were receiving mechanical ventilation.

Chemotherapy versus best supportive care for extensive small cell lung cancer.

BACKGROUND: Combination chemotherapy has been the mainstay of treatment for extensive stage small celI lung cancer (SCLC) over the last 30 years, even though it only gives a short prolongation in median survival time. The main goal for these patients should be palliation with the aim of improving their quality of life. OBJECTIVES: To determine the effectiveness of first-line chemotherapy versus placebo or best supportive care (BSC) in prolonging survival in patients with extensive SCLC at diagnosis and the effectiveness of second-line chemotherapy at relapse or progression after first-line chemotherapy compared with BSC or placebo in prolonging survival in patients with extensive SCLC; as well as to evaluate the adverse events of treatment and the quality of life of patients. SEARCH METHODS: This is the second update of the review. MEDLINE (1966 to October 2013), EMBASE (1974 to October 2013), and the Cochrane Central Register of Controlled Trials (CENTRAL) (2012, Issue 3) were searched. Experts in the field were contacted. SELECTION CRITERIA: Phase III randomised controlled trials in which any chemotherapy treatment was compared with  placebo or BSC in patients with extensive SCLC, as first-line or second-line therapy at relapse. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data and assessed study quality. We resolved disagreements by discussion. Additional information was obtained from one study author. MAIN RESULTS: Two studies of unclear risk of bias were included for first-line chemotherapy. A total of 88 men under 70 years with good performance status were randomised to receive either supportive care, placebo infusion or ifosfamide. Ifosfamide gave an extra mean survival of 78.5 days compared with supportive care or placebo infusion. Partial tumour response was greater with the active treatment. Toxicity was only seen in the chemotherapy group and quality of life was only assessed at the beginning of treatment. The quality of the evidence for overall survival and adverse effects was very low.Three studies of moderate risk of bias were included for second-line chemotherapy at relapse (one identified in the last search). A total of 932 men and women under 75 years and any performance status were randomised to receive either methotrexate-doxorubicin, topotecan, or picoplatin versus symptomatic treatment or BSC. The methotrexate-doxorubicin treatment gave a median survival of 63 days longer than in the symptomatic-treatment group for patients allocated to receive four cycles of first-line chemotherapy, and 21 days longer for patients allocated to receive eight cycles of first-line chemotherapy.Treatment with topotecan gave a median survival of 84 days longer than in the BSC group (log-rank P = 0.01). The adjusted hazard ratio (HR) for overall survival was 0.61 (95% CI 0.43 to 0.87). Treatment with picoplatin gave a median survival time of six days longer than BSC (HR 0.817, 95% CI 0.65 to 1.03, P = 0.0895). A meta-analysis of topotecan and picoplatin gave a HR of 0.73 (95% CI 0.55 to 0.96, P = 0.03; low-quality evidence).Partial or complete response in the methotrexate-doxorubicin group was 22.3%. Five patients (7%, 95% CI 2.33 to 15.67) showed a partial response with topotecan. No data were provided about tumour response in the picoplatin study. Toxicity was worst in the chemotherapy group (moderate-quality evidence). Quality of life was better in the topotecan group and was not measured in the methotrexate-doxorubicin and picoplatin studies (low-quality evidence). AUTHORS' CONCLUSIONS: Two small RCTs from the 1970s suggest that first-line chemotherapeutic treatment (based on ifosfamide) may provide a small survival benefit (less than three months) in comparison with supportive care or placebo infusion in patients with advanced SCLC. However platinum-based combination chemotherapy regimens have been shown to increase complete response rates when compared to non-platinum chemotherapy regimens with no significant difference in survival, and so these are currently the standard first-line treatment for patients with SCLC.Second-line chemotherapy at relapse or progression may prolong survival for some weeks in relation to BSC. Nevertheless, the impact of first-line chemotherapy on quality of life, older patients, women and patients with poor prognosis is unknown and the benefits of second-line chemotherapy are also unclear for older people. Globally, the evidence on which these conclusions are based is very scarce and of uncertain or low quality, which calls for well-designed, controlled trials to further evaluate the trade-offs between benefits and risks of different chemotherapeutic schedules in patients with advanced SCLC.

Drugs for preventing lung cancer in healthy people.

BACKGROUND: This is an updated version of the original review published in Issue 2, 2003. Some studies have suggested a protective effect of antioxidant nutrients on lung cancer. Observational epidemiological studies suggest an association between higher dietary levels of fruits and vegetables containing beta-carotene and a lower risk of lung cancer. OBJECTIVES: To determine whether vitamins, minerals and other potential agents, alone or in combination, reduce incidence and mortality from lung cancer in healthy people. SEARCH METHODS: For this update we have used a search strategy adapted from the design in the original review. The following electronic databases have been searched up to December 2011: MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials (CENTRAL). References included in published studies and reviews were also screened. SELECTION CRITERIA: Included studies were randomised controlled clinical trials comparing different vitamins, mineral supplements or supplements with placebo, administered to healthy people with the aim of preventing lung cancer. DATA COLLECTION AND ANALYSIS: Two authors independently selected the trials to be included in the review, assessed the methodological quality of each trial and extracted data using a standardised form. For each study, relative risk and 95% confidence limits were calculated for dichotomous outcomes and pooled results were calculated using the random-effect model. MAIN RESULTS: In the first version of this review four studies were included; in this review update, an additional five studies have been included. Four studies included only males and two only females; two studies included only participants considered at high risk, namely smokers or exposed to asbestos, and one study included people deficient in many micronutrients. Six studies analysed vitamin A, three vitamin C, four vitamin E, one selenium supplements, and six studied combinations of two or more products. All the RCTs included in this review were classified as being of low risk of bias.For people not at high risk of lung cancer and compared to placebo, none of the supplements of vitamins or minerals or their combinations resulted in a statistically significant difference in lung cancer incidence or mortality, except for a single study that included 7627 women and found a higher risk of lung cancer incidence for those taking vitamin C but not for total cancer incidence, but that effect was not seen in males or when the results for males and females were pooled.For people at high risk of lung cancer, such as smokers and those exposed to asbestos and compared to placebo, beta-carotene intake showed a small but statistically significant higher risk of lung cancer incidence, lung cancer mortality and for all-causes mortality. AUTHORS' CONCLUSIONS: There is no evidence for recommending supplements of vitamins A, C, E, selenium, either alone or in different combinations, for the prevention of lung cancer and lung cancer mortality in healthy people. There is some evidence that the use of beta-carotene supplements could be associated with a small increase in lung cancer incidence and mortality in smokers or persons exposed to asbestos.

Antibiotics for treating osteomyelitis in people with sickle cell disease.

BACKGROUND: Osteomyelitis (both acute and chronic) is one of the most common infectious complications in people with sickle cell disease. There is no standardized approach to antibiotic therapy and treatment is likely to vary from country to country. Thus, there is a need to identify the efficacy and safety of different antibiotic treatment approaches for people with sickle cell disease suffering from osteomyelitis. OBJECTIVES: To determine whether an empirical antibiotic treatment approach (monotherapy or combination therapy) is effective and safe as compared to pathogen-directed antibiotic treatment and whether this effectiveness and safety is dependent on different treatment regimens, age or setting. SEARCH STRATEGY: We searched The Group's Haemoglobinopathies Trials Register, which comprises references identified from comprehensive electronic database searches and handsearching of relevant journals and abstract books of conference proceedings. We also searched the LILACS database (1982 to 14 January 2009) and www.clinicaltrials.gov (June 2008).Date of most recent search of the Haemoglobinopathies Trials Register: 14 November 2008. SELECTION CRITERIA: We searched for published or unpublished randomised and quasi-randomised controlled trials. DATA COLLECTION AND ANALYSIS: Each author intended to independently extract data and assess trial quality by standard Cochrane Collaboration methodologies, but no eligible randomised controlled trials were identified. MAIN RESULTS: We were unable to find any randomised or quasi-randomised controlled trials on antibiotic treatment approaches for osteomyelitis in people with sickle cell disease. AUTHORS' CONCLUSIONS: We were unable to identify any relevant trials on the efficacy and safety of the antibiotic treatment approaches for people with sickle cell disease suffering from osteomyelitis. Randomised controlled trials are needed to establish the optimum antibiotic treatment for this condition.

Vitamin K for upper gastrointestinal bleeding in patients with liver diseases.

BACKGROUND: Upper gastrointestinal bleeding is one of the most frequent causes of morbidity and mortality in the course of liver cirrhosis. Several treatments are used for upper gastrointestinal bleeding in patients with liver diseases. One of them is vitamin K administration, but it is unknown whether it benefits or harms patients with liver disease and upper gastrointestinal bleeding. OBJECTIVES: To assess the beneficial and harmful effects of vitamin K for patients with liver disease and upper gastrointestinal bleeding. SEARCH STRATEGY: We searched The Cochrane Hepato-Biliary Group Controlled Trials Register (September 2007), which comprises references identified from comprehensive electronic database searches and handsearching of relevant journals and abstract books of conference proceedings, The Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (Issue 3, 2007), MEDLINE (1950 to September 2007), EMBASE (1980 to September 2007), Science Citation Index Expanded (1945 to September 2007), and LILACS (1982 to November 2007). Additional randomised trials were sought from two registries of clinical trials, ClinicalTrials.gov and Sistema de Información Esencial en Terapéutica y Salud, the reference lists of the trials found, and reviews identified by the electronic searches. SELECTION CRITERIA: Randomised clinical trials. DATA COLLECTION AND ANALYSIS: Data from randomised clinical trials were to be summarised by standard Cochrane Collaboration methodologies. MAIN RESULTS: We could not find any randomised trials on vitamin K for upper gastrointestinal bleeding in patients with liver diseases. AUTHORS' CONCLUSIONS: This updated review found no randomised clinical trials on the safety and efficacy of vitamin K for upper gastrointestinal bleeding in patients with liver diseases. The effects of vitamin K need to be tested in randomised clinical trials. Unless randomised clinical trials provide evidence of a treatment effect and the trade off between potential benefits and harms are established, policy-makers, clinicians, and academics should not use vitamin K for upper gastrointestinal bleeding in patients with liver diseases.