Bruce Kupelnick

Colorectal Cancer Risk and Dietary Intake of Calcium, Vitamin D, and Dairy Products: A Meta-Analysis of 26,335 Cases From 60 Observational Studies

In vivo and in vitro studies suggest that dairy products, calcium, and dietary vitamin D inhibits the development of colorectal cancer (CRC). A meta-analysis was performed to evaluate this relationship in observational studies. Data from 60 epidemiological studies enrolling 26,335 CRC cases were pooled using a general variance-based meta-analytic method. Summary relative risk (RR) estimates and 95% confidence intervals (CIs) were calculated for the highest vs. the lowest intake categories. Sensitivity analyses tested the robustness of these summary effect measures and the statistical heterogeneity. The summary RR for high milk and dairy product intake, respectively, on colon cancer risk was 0.78 (95% CI = 0.67–0.92) and 0.84 (95% CI = 0.75–0.95). Milk intake was unrelated to rectal cancer risk. High calcium intake had a greater protective effect against tumors of the distal colon and rectal cancer vs. proximal colon. The risk reduction associated with calcium was similar for dietary and supplemental sources. Vitamin D was associated with a nonsignificant 6% reduction in CRC risk. Higher consumption of milk/dairy products reduces the risk of colon cancer, and high calcium intake reduces the risk of CRC. Low vitamin D intake in the study populations may limit the ability to detect a protective effect if one exists.

Use of Topical Sunscreens and the Risk of Malignant Melanoma: A Meta-Analysis of 9067 Patients From 11 Case–Control Studies

OBJECTIVES This study examined the methodology of epidemiological studies that suggest use of topical sunscreen preparations is associated with increased risk of malignant melanoma. METHODS We pooled data from observational studies using a general variance-based meta-analytic method that employed confidence intervals (previously described). The outcome of interest was a summary relative risk (RR) reflecting the risk of melanoma associated with sunscreen use versus nonuse. Sensitivity analyses were performed when necessary to explain any observed statistical heterogeneity. RESULTS Combining studies that used non-heterogeneous data yielded a summary RR of 1.01, indicating no association between sunscreen use and development of malignant melanoma. CONCLUSIONS The available epidemiological data do not support the existence of a relationship between topical sunscreen use and an increased risk of cutaneous malignant melanoma.

Smoking as a Risk Factor for Prostate Cancer: A Meta-Analysis of 24 Prospective Cohort Studies

OBJECTIVES We evaluated the relationship between smoking and adenocarcinoma of the prostate. METHODS We pooled data from 24 cohort studies enrolling 21 579 prostate cancer case participants for a general variance-based meta-analysis. Summary relative risks (RRs) and 95% confidence intervals (CIs) were calculated separately for mortality and incidence studies. We tested the robustness of effect measures and evaluated statistical heterogeneity with sensitivity analyses. RESULTS In the pooled data, current smokers had no increased risk of incident prostate cancer (RR = 1.04; 95% CI = 0.87, 1.24), but in data stratified by amount smoked they had statistically significant elevated risk (cigarettes per day or years: RR = 1.22; 95% CI = 1.01, 1.46; pack years of smoking: RR = 1.11; 95% CI = 1.01, 1.22). Former smokers had an increased risk (RR = 1.09; 95% CI = 1.02, 1.16). Current smokers had an increased risk of fatal prostate cancer (RR = 1.14; 95% CI = 1.06, 1.19). The heaviest smokers had a 24% to 30% greater risk of death from prostate cancer than did nonsmokers. CONCLUSIONS Observational cohort studies show an association of smoking with prostate cancer incidence and mortality. Ill-defined exposure categories in many cohort studies suggest that pooled data underestimate risk.

Combined chemoradiation versus radiation therapy alone in locally advanced nasopharyngeal carcinoma: results of a meta-analysis of 1,528 patients from six randomized trials.

It is currently unclear whether the addition of chemotherapy to standard radiation therapy improves clinical outcome in patients with locoregionally advanced nasopharyngeal cancer. A meta-analysis was performed to evaluate the impact of integrating chemotherapy with external beam radiation therapy in this clinical setting. Using previously described methods, a protocol was developed outlining a meta-analysis examining the influence of chemoradiation versus radiation alone (control arm) in locoregionally advanced nasopharyngeal carcinoma. The outcomes of interest were disease-free/progression-free and overall survival. Literature search techniques, study inclusion criteria, and statistical procedures were prospectively defined. Data from all available randomized controlled trials was pooled using a fixed effects model (Peto). Results were expressed as summary relative risks. Statistical tests for heterogeneity were performed. If statistical heterogeneity was demonstrated, sensitivity analyses were performed to evaluate possible sources of heterogeneity across the included studies. The literature search identified six randomized controlled trials enrolling more than 1,500 patients. All trials compared standard radical external beam radiation therapy (control arm) with radiation plus chemotherapy delivered either adjuvantly, neoadjuvantly, or concurrently with radiation. Pooling all six studies using disease-free/progression-free survival as the endpoint demonstrated that the addition of chemotherapy to radiation therapy increased disease-free/progression-free survival by 37% at 2 years, 40% at 3 years, and 34% at 4 years after treatment. Likewise, the summary relative risk for overall survival at 2 years after treatment with the addition of chemotherapy to the treatment regimen was 0.80 (0.63-1.02), reflecting a 20% increase in 2-year survival. This finding was marginally non-statistically significant. Three- and 4-year survival was increased by 19% and 21%, respectively, with the data for 4-year survival being statistically significant. The addition of chemotherapy to standard radical radiation therapy for locoregionally advanced nasopharyngeal cancer increases both disease-free/progression-free and overall survival by 19 to 40% at 2 to 4 years after treatment, depending on the endpoint of interest. Future trials are needed to confirm these results and determine the most effective regimen for integrating chemotherapy with radiation therapy in this setting.

Impact of dairy products and dietary calcium on bone-mineral content in children: Results of a meta-analysis

OBJECTIVE Although calcium is essential for maintaining bone health in children, the optimum dietary intake of calcium in this age group, particularly in the form of dairy foods, is not well defined. A meta-analysis was conducted to examine the impact of dietary calcium/dairy supplementation on bone mineral content in this age group. METHODS Data were pooled from randomized controlled intervention trials and observational studies using previously described methods. The outcome of interest was a summary mean difference bone mineral content. Sensitivity analyses were employed to evaluate any observed statistical heterogeneity and to examine the influence of specific study characteristics on the summary estimate of effect. RESULTS Initially combining data from twenty-one randomized controlled trials (RCTs) using total body bone mineral content (TB-BMC) as the outcome of interest, yielded a non-statistically significant increase in TB-BMC of 2 g (supplemented versus controls). These data demonstrated substantial statistical heterogeneity with sensitivity analyses revealing that among study subjects with normal or near normal baseline dietary calcium/dairy intakes, supplemental dairy/calcium showed little impact on bone mineral content. Sensitivity analyses suggested that baseline calcium intake could potentially account for the statistical heterogeneity. Pooling the three reports utilizing low intake subjects yielded a statistically significant summary mean BMC of 49 g (24.0-76-6). Pooling two RCTs using calcium/dairy supplement plus vitamin D was also associated with an increase in lumbar spine BMC of, on average, 35 g (-6.8-41.8). The lack of data using BMC measurements at other anatomic sites as well as sparse data from non-randomized studies, precluded further statistical pooling. CONCLUSION Increased dietary calcium/dairy products, with and without vitamin D, significantly increases total body and lumbar spine BMC in children with low base-line intakes.

Dairy Products, Dietary Calcium and Vitamin D Intake as Risk Factors for Prostate Cancer: A Meta-Analysis of 26,769 Cases From 45 Observational Studies

In this study, we examined the available evidence and sources of heterogeneity for studies of dairy products, calcium, and vitamin D intake and the risk of prostate cancer. We pooled data from 45 observational studies using a general variance-based, meta-analytic method employing CIs. Summary relative risks (RRs) were calculated for specific dairy products such as milk and dairy micronutrients. Sensitivity analyses were performed to test the robustness of these summary measures of effect. Cohort studies showed no evidence of an association between dairy [RR = 1.06; 95% confidence interval (CI) = 0.92–1.22] or milk intake (RR = 1.06; 95% CI = 0.91–1.23) and risk of prostate cancer. This was supported by pooled results of case-control analyses (RR = 1.14; 95% CI = 1.00–1.29), although studies using milk as the exposure of interest were heterogeneous and could not be combined. Calcium data from cohort studies were heterogeneous. Case-control analyses using calcium as the exposure of interest demonstrated no association with increased risk of prostate cancer (RR = 1.04; 95% CI = 0.90–1.15). Dietary intake of vitamin D also was not related to prostate cancer risk (RR = 1.16; 95% CI = 0.98–1.38). The data from observational studies do not support an association between dairy product use and an increased risk of prostate cancer.

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.

Impact of intravesical chemotherapy versus BCG immunotherapy on recurrence of superficial transitional cell carcinoma of the bladder: metaanalytic reevaluation.

Bacille Calmette-Guérin (BCG) immunotherapy is currently considered the most effective agent in the management of superficial bladder cancer. Prior work suggests that the efficacy of intravesical chemotherapy in preventing tumor recurrence may be greater than previously suggested. This latter finding, therefore, brings into question the currently perceived superiority of BCG treatment for this disease. A metaanalysis was performed to rigorously examine existing data relevant to this relationship and to quantify the relative efficacy of both treatment modalities on tumor recurrence. A prospective protocol outlining the above-noted metaanalysis was initially developed followed by a thorough search of the existing published literature using strict eligibility criteria. Nine randomized trials were found that met protocol specifications. These reports contained data on 2,261 patients that were statistically combined using a fixed effects model (Peto). The outcome of interest was the proportion of patients with recurrence at 1, 2, and 3 years following intravesical therapy (i.e., a summary odds ratio, ORp). Combining all nine trials using 1-year recurrence as the endpoint demonstrated significant statistical heterogeneity, although the ORp favored BCG over intravesical chemotherapy (0.89 [0.74–1.07]). This precluded statistical pooling of the data and sensitivity analyses were performed to determine the source of heterogeneity. These tests showed that the prior chemotherapy treatment in a large number of the randomized trials biased study results in favor of the BCG arms. Once the data were stratified on presence or absence of prior drug treatment, intravesical chemotherapy reduced 1-, 2-, and 3-year recurrence by 21% to 82% versus BCG, depending on the endpoint of interest. The available data suggest that clinical trials directly comparing intravesical BCG to intravesical chemotherapy must stratify on the presence or absence of prior chemotherapy. Recurrences following prior intravesical chemotherapy appear less responsive to drug therapy than those in chemotherapy-naive patients. The currently perceived superiority of BCG therapy may therefore be an artifact of this phenomenon, since most randomized trials include chemotherapy failures in their chemotherapy treatment arms.

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.

The influence of intravesical therapy on progression of superficial transitional cell carcinoma of the bladder: a metaanalytic comparison of chemotherapy versus bacilli Calmette-Guerin immunotherapy.

Objective:Currently, the true impact of intravesical chemotherapy or immunotherapy (bacilli Calmette-Guerin [BCG]) on the rate of progression of superficial transitional cell carcinoma of the bladder to muscle invasive disease is unclear. A metaanalysis was performed to statistically compare the efficacy of these treatments in preventing tumor progression in this disease setting. Methods:A prospective protocol outlining the metaanalysis noted here was developed followed by a thorough search of the existing published literature using strict eligibility criteria. Eight randomized, controlled trials were found that met protocol specifications. These reports contained data on 2427 patients who were statistically pooled using a fixed-effects model (Peto). The outcome of interest was the proportion of patients progressing to muscle invasive or metastatic disease expressed as a summary odds ratio (ORp). An ORp greater than unity favored BCG versus chemotherapy. Results:Initial pooling of these 8 trials gave a nonstatistically significant summary odds ratio of 1.24 (0.95–1.61) without evidence of statistical heterogeneity. Analysis by drug type showed significant attenuation of the ORp when the effects of mitomycin C were compared with BCG, ie, 1.04 (0.76–1.42) suggesting that: 1) mitomycin is probably more active than the other chemotherapeutics used in the available trials and 2) BCG is not clearly superior to mitomycin C. Sensitivity analyses also demonstrated that failure to control for prior intravesical drug treatment in all but 2 of the analyzed studies produces a spurious result favoring BCG over intravesical chemotherapy. Conclusion:The available data fail to support a clear superiority of intravesical BCG over intravesical chemotherapy in preventing progression of superficial transitional cell carcinoma of the bladder. Mitomycin C appears more effective than the other commonly used drugs, and failure to control for prior intravesical chemotherapy in most of available studies results in a spurious finding of greater clinic effect of BCG over chemotherapy.