Dietary beta-carotene intake and the risk of epithelial ovarian cancer: a meta-analysis of 3,782 subjects from five observational studies.

OBJECTIVE: The etiology of epithelial ovarian cancer is unknown. Prior work suggests that high dietary beta-carotene intake is associated with a decreased risk of this tumor although this association remains speculative. A meta-analysis was performed to evaluate this suspected relationship. METHODS: Using previously described methods, a protocol was developed for a meta-analysis examining the association between high dietary beta-carotene intake versus low intake and the risk of epithelial ovarian cancer. Literature search techniques, study inclusion criteria and statistical procedures were prospectively defined. Data from observational studies were pooled using a general variance based meta-analytic method employing confidence intervals previously described by Greenland. The outcome of interest was a summary relative risk (RRs) reflecting the risk of ovarian cancer associated with high beta-carotene intake versus low dietary intake. Sensitivity analyses were performed when necessary to evaluate any observed statistical heterogeneity. RESULTS: Five observational studies enrolling 3,782 subjects were initially pooled in a meta-analysis subsequent to an analysis showing a lack of statistical heterogeneity. The meta-analysis showed a summary relative risk of 0.84 with a 95% confidence interval of 0.75-0.94, a statistically significant result. These data suggest that high (versus low) dietary intake of beta-carotene is associated with a sixteen percent decrease in ovarian cancer risk. Sensitivity analyses showed no impact of study design or differences in quantitative measure of beta-carotene intake across studies on the summary relative risk. CONCLUSIONS: High dietary intake of beta-carotene appears to represent a protective factor for the development of ovarian cancer although its magnitude is modest. Further work is needed to clarify factors that may modify the effects of beta-carotene in vivo.

Impact of intravesical chemotherapy on recurrence rate of recurrent superficial transitional cell carcinoma of the bladder: results of a meta-analysis.

BACKGROUND: The impact of in tranvesical chemotherapy on preventing recurrence of superficial transitional cell carcinoma of the bladder is controversial. The objective of this report is to present a meta-analysis of the available clinical trial data to quantify the effect of intravesical chemotherapy on tumor recurrence following trans-urethral resection (TURB) in patients with recurrent superficial bladder cancer. METHODS: A prospective study protocol outlining a meta-analysis was developed followed by a thorough search of the existing published literature using strict eligibility criteria. Eight randomized trials were found which met protocol specifications. These studies contained data on 1,609 patients which were statistically combined using a fixed effects model (Peto). The outcome of interest was the proportion of patients with tumor recurrence at one, two and three years post-TURB. RESULTS: Combining all 8 studies using 1 year recurrence as the outcome measure yielded a Peto odds ratio (ORp) of 0.62, demonstrating a 38% reduction in one year recurrence among patients treated with intravesical chemotherapy versus TURB alone. Using 2 and 3 year recurrence as the outcome measure yielded ORp's of 0.46 and 0.35 respectively, favoring TURB + intravesical chemotherapy versus TURB alone. A statistical test for heterogeneity (Q) showed the 2 and 3 year outcome data to be heterogeneous (i.e. the studies are not measuring an effect of the same magnitude). Sensitivity analyses showed that drug type appeared to account for the observed heterogeneity with a stratified analysis demonstrating that adriamycin is less effective in reducing subsequent tumor recurrences than all other drugs studied. CONCLUSION: Intravesical chemotherapy appears to have a major impact on decreasing the chance of recurrence of recurrent superficial bladder cancer. Three year recurrence is decreased by as much as 70% when compared with TURB alone. These data are in contrast to prior analyses suggesting only modest efficacy of such treatment in this clinical setting.

Single-agent DTIC versus combination chemotherapy with or without immunotherapy in metastatic melanoma: a meta-analysis of 3273 patients from 20 randomized trials.

It is currently unclear whether any combination therapy for the treatment of metastatic melanoma is superior to standard single-agent dacarbazine (DTIC) in terms of tumour response and overall survival. The available randomized clinical trial data were combined in a meta-analysis to address this question. Initially a thorough MEDLARS search was conducted covering the time period from January 1970 to January 1999. This literature search was supplemented by manual searches of study bibliographies (including review articles) and review of relevant textbooks. The meta-analysis was performed according to a prospective protocol using strict study eligibility criteria. Data derived from randomized controlled trials comparing single-agent DTIC with combination chemo/immunotherapy were combined using a fixed effects model. Data were stratified into three combination therapy groups: DTIC-containing regimens, non-DTIC-containing therapy, and chemotherapy plus immunotherapy. The primary outcome of interest was the proportion of patients demonstrating a complete or partial response to treatment. A total of 20 randomized trials comprising 3273 patients were initially combined in a meta-analysis. This yielded an odds ratio (OR) of 1.23 (95% confidence interval [CI] 1.02-1.48), demonstrating that combination drug therapies are associated with a 23% increase in response rate compared with single-agent DTIC. The combination of DTIC plus interferon-alpha produced a tumour response rate 53% greater (95% CI 1.10-2.13) than that seen with DTIC alone. This increase was greater than that seen with DTIC-containing multi-drug regimens, which had an OR of 1.33 (95% CI 0.99-1.78). No difference in overall survival was demonstrated. Non-DTIC-containing treatment programmes showed no advantage over DTIC in terms of tumour response rate (OR = 0.77, 95% CI 0.45-1.32). The combination of DTIC and interferon-alpha appears more active than standard single-agent DTIC in metastatic melanoma. Further randomized clinical trials employing a DTIC plus interferon arm are necessary to confirm these results.

Dietary fat intake and risk of epithelial ovarian cancer: a meta-analysis of 6,689 subjects from 8 observational studies.

The etiology of epithelial ovarian cancer is unknown. Prior work suggests that high dietary fat intake is associated with an increased risk of this tumor, although this association remains speculative. A meta-analysis was performed to evaluate this suspected relationship. Using previously described methods, a protocol was developed for a meta-analysis examining the association between high vs. low dietary fat intake and the risk of epithelial ovarian cancer. Literature search techniques, study inclusion criteria, and statistical procedures were prospectively defined. Data from observational studies were pooled using a general variance-based meta-analytic method employing confidence intervals (CI) previously described by Greenland. The outcome of interest was a summary relative risk (RRs) reflecting the risk of ovarian cancer associated with high vs. low dietary fat intake. Sensitivity analyses were performed when necessary to evaluate any observed statistical heterogeneity. The literature search yielded 8 observational studies enrolling 6,689 subjects. Data were stratified into three dietary fat intake categories: total fat, animal fat, and saturated fat. Initial tests for statistical homogeneity demonstrated that hospital-based studies accounted for observed heterogeneity possibly because of selection bias. Accounting for this, an RRs was calculated for high vs. low total fat intake, yielding a value of 1.24 (95% CI = 1.07-1.43), a statistically significant result. That is, high total fat intake is associated with a 24% increased risk of ovarian cancer development. The RRs for high saturated fat intake was 1.20 (95% CI = 1.04-1.39), suggesting a 20% increased risk of ovarian cancer among subjects with these dietary habits. High vs. low animal fat diet gave an RRs of 1.70 (95% CI = 1.43-2.03), consistent with a statistically significant 70% increased ovarian cancer risk. High dietary fat intake appears to represent a significant risk factor for the development of ovarian cancer. The magnitude of this risk associated with total fat and saturated fat is rather modest. Ovarian cancer risk associated with high animal fat intake appears significantly greater than that associated with the other types of fat intake studied, although this requires confirmation via larger analyses. Further work is needed to clarify factors that may modify the effects of dietary fat in vivo.

Paternal smoking during pregnancy and the risk of childhood brain tumors: results of a meta-analysis.

OBJECTIVE: Prior epidemiological studies suggest a possible association between paternal smoking during pregnancy and risk of childhood brain tumors (CBT). A meta-analysis was performed statistically pooling all available observational studies on this topic in order to evaluate this suspected association. METHODS: Using previously described methods, a protocol was developed for a meta-analysis examining the association between paternal smoking during pregnancy and subsequent development of primary brain tumors in their offspring. Literature search techniques study inclusion criteria and statistical procedures were prospectively defined. Data from epidemiological studies were pooled using a general variance based meta-analytic method employing confidence intervals previously described by Greenland. The outcome of interest was a summary relative risk (RRs) reflecting the risk of childhood brain tumor development associated with father's smoking during the index pregnancy. Sensitivity analyses were performed when necessary to explain any observed statistical heterogeneity and/or to evaluate the impact of demographic or study characteristics on the summary estimate of effect. RESULTS: Seven observational studies meeting protocol specified inclusion criteria were obtained via a comprehensive literature search. These studies enrolled a total of 3,600 patients. Analysis for homogeneity demonstrated that the data were homogeneous (P = 0.52) and could be statistically combined. Pooling all seven reports yielded a RRs of 1.29 (1.07-1.53), a statistically significant result suggesting a 29% increased risk of brain tumor development associated with paternal smoking during pregnancy. An analysis of father's smoking impact on CBT risk based on "ever" versus "never" smoking history gave a RRs of 1.14 (0.98-1.34), a marginally non-statistically significant result. CONCLUSION: The available epidemiological data suggest an association between paternal smoking during pregnancy and pediatric brain tumor development. Although this association is biologically plausible, limitations in study designs limit definitive conclusions based on available data.

Chemoembolization of liver tumor in a rabbit model: assessment of tumor cell death with diffusion-weighted MR imaging and histologic analysis.

PURPOSE: To assess the efficacy of chemoembolization of liver tumors by determining the fraction of viable tumor cells remaining after treatment with use of diffusion magnetic resonance (MR) imaging and histologic analysis. MATERIALS AND METHODS: VX2 tumor was grown in the livers of 12 rabbits. Animals were divided into a chemoembolization group and an untreated group. Conventional, perfusion, and diffusion MR imaging was performed on all rabbits. Histopathologic analysis of explanted livers was performed to document tumor cell death and measure Bcl-2 levels (inhibitor of apoptosis). RESULTS: Diffusion-weighted MR imaging delineated zones of tumor cell death as regions of lower signal intensity in both groups. Apparent diffusion coefficients were significantly greater in the area of tumor necrosis than in the area of viable tumor. Histologic analysis demonstrated a significantly lower percentage of viable cells in the treated group (<1%) than in the control group (55%). Bcl-2 expression detected within the viable areas of the tumor was greater in the treated group than in the control group. CONCLUSIONS: Chemoembolization causes extensive tumor cell destruction. Diffusion MR imaging can detect tumor cell death and can be used to assess the efficacy of chemoembolization. Bcl-2 was expressed in the treated group, suggesting an apoptotic pathway of cell death.

Use of topical sunscreen and the risk of malignant melanoma. Results of a meta-analysis of 9,067 patients.

PURPOSE: Prior epidemiological studies suggest that the use of sunscreen preparations is associated with increased risk of cutaneous malignant melanoma (CMM) although the data are conflicting. A meta-analysis was performed to evaluate this suspected association.METHODS: A protocol was developed for a meta-analysis examining the association between frequent sunscreen use versus non-use and the development of CMM. Data from observational studies were pooled using a general variance based meta-analytic method employing confidence intervals. The outcome of interest was a summary relative risk (RRs) reflecting the risk of melanoma associated with sunscreen use versus non-use. Sensitivity analyses were performed when necessary to explain any observed statistical heterogeneity.RESULTS: Eleven case-control studies enrolling 9,067 patients were combined in a meta-analysis. This yielded a RRs of 1.11 (CI = 0.37-3.32), a non-statistically significant result, (i.e. no association between sunscreen use and melanoma risk). Since the data were found to be heterogeneous, i.e. Q = 42.0 (p < 0.001), a series of sensitivity analyses were performed to explore possible sources of heterogeneity. Stratifying studies based on study design, i.e. hospital based versus population based, showed that hospital derived data were highly heterogeneous (Q = 36.9, p < 0.001) while the population registry data were not (Q = 4.9, p = 0.18). Combining those studies using population based data gave a RRs of 1.01 (95% CI = 0.46-2.28) indicating no association between sunscreen use and the development of CMM.CONCLUSIONS: The available epidemiological data do not support the existence of a relationship between topical sunscreen use and an increased risk of CMM.

Intravesical chemotherapy prophylaxis in primary superficial bladder cancer: a meta-analysis of 3703 patients from 11 randomized trials.

The impact of intravesical chemotherapy prophylaxis on recurrence of superficial transitional cell carcinoma of the bladder is poorly defined. The objective of this report is to present a meta-analysis of the available clinical trial data to quantify the effect of intravesical chemotherapy on tumor recurrence following complete transurethral resection (TURB) in patients with newly diagnosed superficial bladder cancer. A prospective protocol outlining the above meta-analysis was initially developed followed by a thorough search of the existing published literature using strict eligibility criteria. Eleven randomized trials were found that met protocol specifications. These studies contained data on 3703 patients that were statistically combined using a fixed effects model (Peto). The outcome of interest was the proportion of patients recurring at 1, 2, and 3 years post-TURB. Combining all 11 studies using 1-year recurrence as the outcome measure yielded a Peto odds ratio (ORp) of 0.56, demonstrating a 44% reduction in 1-year recurrence among patients treated with intravesical chemotherapy versus those treated with TURB alone. A statistical test for heterogeneity (Q) showed these data to be heterogenous (the studies are not measuring an effect of the same size). Sensitivity analyses were performed to determine sources of heterogeneity. These tests suggest that chemotherapy treatment schedule may account for the wide variation in tumor recurrence rates across studies. When the available clinical trial data were stratified by duration of treatment, the meta-analysis showed that intravesical chemotherapy decreased tumor recurrence from 30% to 80% depending on the outcome of interest (i.e., recurrence at 1, 2, or 3 years post-TURB). Intravesical chemotherapy appears to have a major impact on decreasing the chance of recurrence of superficial transitional cell carcinoma of the bladder. This is in contrast to prior analyses suggesting only modest efficacy in this clinical setting (i.e., on the order of a 14% reduction in recurrence).

Prognostic significance of p53 mutations in non-small cell lung cancer: a meta-analysis of 829 cases from eight published studies.

Mutation of the p53 tumor suppressor gene is considered a possible marker of poor survival among patients with non-small cell lung cancer (NSCLC). This report presents the results of a meta-analysis of the available data addressing this issue. Using previously described methods, a protocol was developed for a meta-analysis examining the prognostic significance of p53 mutations in NSCLC. Two-year survival data derived from 829 patients in eight published studies were analyzed using a general variance-based method employing confidence intervals described by Greenland (Epidemiol. Rev. 9 (1986) 1-30). The outcome of interest was a summary relative risk (RRs) reflecting the risk of death at 2 years associated with p53 mutation positive versus p53 negative disease. Prior to calculation of a RRs, an analysis for homogeneity (Q) showed Q to equal 22.3. With 8 degrees of freedom, this yielded a P value corresponding to P<0.005. This indicated substantial heterogeneity across studies in terms of their estimate of effect. Although a RRs of 1.52 was found when all eight studies were combined (favoring a negative prognostic role for p53 mutation), the validity of this estimate is questionable since the existing heterogeneity indicates that factors other than p53 mutation account for the variability in RRs across studies. Sensitivity analyses suggested that selection bias might represent an important source of variability in that p53 mutations may differ in their effects on biological behavior of NSCL tumors. Other possible confounders include smoking history, race, geographic location of study and socio-economic status. The available data do not support a clear role for p53 mutation as a prognostic marker in NSCLC. It appears that multiple sources of bias may contribute to spurious association of p53 mutation status and survival. Future analyses must control for possible confounders in order to determine whether certain p53 mutations are truly associated with poor clinical outcome.

Epidermal growth factor receptor gene amplification as a prognostic marker in glioblastoma multiforme: results of a meta-analysis.

Amplification of the epidermal growth factor receptor (EGFR) gene occurs in approximately 40% of cases of glioblastoma multiforme (GBM) and is considered a possible marker of poor prognosis. This report presents the results of a meta-analysis of the available data addressing this issue. Using a prospective protocol, a meta-analysis was designed to assess the possible prognostic importance of EGFR gene amplification in GBM. One-year survival data derived from seven published studies were analyzed using a general variance based method employing confidence intervals described by Greenland. The outcome of interest was a summary relative risk (RRs) reflecting the risk of death at 1 year from diagnosis associated with EGFR amplification-positive versus -negative disease. Prior to calculation of a RRs, an analysis for homogeneity (Q) showed Q to equal 9.21. With 6 df this yielded a P value of 0.12, indicating that the data were homogenous and could be combined in a meta-analysis. Pooling all available studies gave a RRs of 1.13 with a 95% confidence interval of 0.71-1.80, a nonstatistically significant result. The data suggest that the available studies are insufficient for determining whether EGFR gene amplification is of prognostic value in GBM. Important potential confounding factors are the influence of underlying EFGR gene mutation on patient survival and lack of control for important known clinical prognostic indicators in many studies. Future work must incorporate these parameters in multivariate analyses to determine whether EGFR gene alterations are truly associated with poor clinical outcome.

K-ras oncogene mutation as a prognostic marker in non-small cell lung cancer: a combined analysis of 881 cases.

The treatment of non-small cell lung cancer (NSCLC) remains unsatisfactory, with most patients succumbing to metastatic disease within 5 years of diagnosis. Improved selection of patients for aggressive adjuvant therapy may contribute to improved survival. Mutation of the k-ras oncogene is considered a potentially clinically useful prognostic biomarker for this purpose. This report presents the results of a meta-analysis performed to determine whether the existing data support such a role for k-ras mutations in NSCLC. Two year survival data derived from 881 NSCLC patients in eight published studies were analyzed using a general variance-based meta-analytical method employing confidence intervals. The outcome of interest was a summary relative risk (RR(s)) reflecting the risk of death at 2 years associated with k-ras mutation-positive versus k-ras mutation-negative disease. Prior to calculation of RR(s), analysis for heterogeneity showed Q to equal 15.52 (7 df, P = 0.03). This indicated heterogeneity across the analyzed studies in terms of their estimate of effect. Possible sources of heterogeneity were identified and included selection bias and various other sources of uncontrolled confounding. Although a RR(s) of 2.35 (95% CI = 1.61-3. 22) was found when all eight studies were combined (favoring a negative prognostic role for k-ras mutation), it is unclear whether the magnitude of the RR(s) would persist after adjusting for other well-established prognostic indicators (e.g. stage). The existing data suggest that k-ras mutation may be associated with shortened survival in NSCLC, although this finding awaits confirmation in well-designed multivariate analyses which adjust for the effect of known prognostic indicators.

Diagnosis of malignant pleural mesothelioma by supraclavicular lymph node biopsy.

Extrathoracic lymph node metastases in pleural mesothelioma are rare. A case of pleural mesothelioma diagnosed by supraclavicular lymph node biopsy is described. To our knowledge, this is the first reported case of pleural mesothelioma diagnosed in this manner.

Chemotherapy response rates in recurrent/progressive pediatric glioma; results of a systematic review.

The optimum treatment strategy for recurrent childhood glioma is unknown. This report presents a systematic analysis of the currently available clinical data on chemotherapeutic management of this disease. A study protocol was prospectively developed outlining the objectives and methods of analysis including literature search strategy, eligibility criteria for published trials to be included, key data elements to be extracted and a plan for statistical analysis. Summary statistics were analyzed for the primary outcome variables. Data on recognized prognostic factors were recorded in order to adjust the outcome measures for these factors. A total of 27 non-randomized clinical trails were included in the analysis. Studies were stratified into 6 chemotherapy classes based on the frequency of drug used across studies. Average median response (complete + partial) across all drug categories was approximately 14% (range 10.4-23.5%). Adding patients with stable disease to complete and partial responders at least doubled average median response rates. Time to tumor progression ranged from 29.4 weeks to 49.7 weeks. The most frequently used drugs were the platinum analogs which demonstrated a mean TTP of 42.0 = /-23.4 weeks. Small sample sizes and the overall poor quality of the available data precluded definitive conclusions regarding the clinical impact of the various drug classes on the natural history of this disease.

Planned preoperative radiation therapy in muscle invasive bladder cancer; results of a meta-analysis.

BACKGROUND: The role of pre-operative radiation therapy in the treatment of muscle invasive bladder cancer is unclear. The objective of this report is to present a meta-analysis of the published clinical trial data on this topic to determine whether pre-operative radiation improves survival in patients with this disease. METHODS: Data from 5 randomized trial were pooled using the meta-analytic techniques previously described by Peto et al. Three and five year survival were compared between patients receiving pre-operative radiation therapy followed by cystectomy versus patients treated with cystectomy alone. RESULTS: A summary odds ratio was calculated following a statistical analysis showing a lack of heterogeneity among the included studies in terms of their estimate of effect. The calculated Peto odds ratio was 0.71 favoring the use of preoperative radiation (95% CI 0.48-1.06). Due to possible biases in this original analysis due to study design deficiencies, a sensitivity analysis showed a "corrected" odds ratio of 0.94 with a 95% confidence interval of 0.57- 1.55, a non-statistically significant result. CONCLUSION: The available clinical trial data do not support a role for routine use of pre-operative radiation therapy in the treatment of muscle invasive bladder cancer. Additional well designed trials are needed to address this issue.

Meta-analytic re-evaluation of misonidazole in the treatment of high grade astrocytoma.

BACKGROUND: The clinical effects of the radiation sensitizer, misonidazole, in the treatment of high grade astrocytoma are equivocal based on available clinical trial data. A meta-analysis was performed in order to evaluate the impact of this compound on treatment outcome for this disease. METHODS: One year survival data derived from over 1,700 patients enrolled in 9 randomized clinical trials were analyzed using the meta-analytic techniques previously described by Peto et al. This analysis compared the proportion of patients surviving one year treated with misonidazole sensitized radiation therapy (+/- chemotherapy) versus radiation alone (+/- chemotherapy). RESULTS: A summary odds ratio was calculated following a statistical analysis showing a lack of heterogeneity among the included studies in terms of their estimate of effect. The calculated Peto odds ratio was 0.92 with a 95% confidence interval of 0.77-1.09. These data indicate that misonidazole treatment is associated with an approximately 8% improved 1 year survival compared with non-misonidazole treatment arms. This odds ratio increased to 0.87 when only those trials using "conventional" radiation therapy schedules were analyzed. CONCLUSION: This analysis suggests that misonidazole may contribute to improved 1 year survival in patients with high grade astrocytoma and that the magnitude of this improvement may be comparable to that seen with the use of chemotherapy in this patient group.

Treatment of recurrent high grade astrocytoma; results of a systematic review of 1,415 patients.

OBJECTIVE: The optimum treatment strategy for recurrent high grade glioma (anaplastic astrocytoma and glioblastoma multiforme) remains undefined. The objective of this report is to present a systematic analysis of the published clinical trial literature on the therapy of this disease. METHODS: A study protocol was prospectively developed outlining the objectives and methods of the analysis such as; literature search strategy, eligibility criteria for published trials to be included, key data elements to be extracted, and a plan for statistical analysis. Variables of interest were, those describing key features of the study such as publication date and geographic location of reporting institution, characteristics of study population including functional status, details of patient treatment, treatment sequencing and data on clinical outcomes of interest, i.e. time to tumor progression and overall survival. Data were analyzed using SAS version 6.11. Summary statistics were calculated for the primary outcome variables. Data on recognized prognostic variables were recorded in order to adjust the analysis for these parameters. RESULTS: A total of 40 trials (36 non-randomized controlled trials; nRCTs and 4 randomized controlled trials: RCTs) were included in the analysis. Thirty-two of the eligible trials were chemotherapy trials while 7 were radiation therapy trials. One surgical trial met eligibility criteria. A total of 47 treatment arms were analysed which included 1,415 patients. Five chemotherapy groups were studied, i.e. interferons, nitrosoureas, platinums, platinums + nitrosoureas and others. The nitrosoureas were found to significantly extend time to tumor progression compared to all other drugs (26.9 weeks). The nitrosoureas and platinums appear to be the most active agents with regard to overall survival (over 32.0 weeks) as compared with the other drug categories. Patients treated with both a nitrosourea and a platinum compound showed the longest overall survival (40.0 weeks) although this was not significantly different from these drugs used as single agents. Average median survival for patients treated with radiation therapy was 44.7 weeks although selection bias makes these data difficult to compare with those derived from studies of chemotherapy. No definite conclusions can be made regarding surgical therapy in this setting due to limited data. CONCLUSIONS: The nitrosoureas and platinums, either as single agents or as combination chemotherapy, appear to be the most active agents in this disease although few, well designed chemotherapy trials are available for analysis. Due to the limitations of the available data on radiation therapy and surgery, as outlined in this report, additional, well designed clinical trials are needed to define the appropriate role for these modalities in the treatment of recurrent high grade glioma.