Davide Mauri

Multiple-Treatments Meta-analysis of Chemotherapy and Targeted Therapies in Advanced Breast Cancer

BACKGROUND Many systemic nonhormonal regimens have been evaluated across several hundreds of randomized trials in advanced breast cancer. We aimed to quantify the relative merits of these regimens in prolonging survival. METHODS We performed a systematic review of all trials that compared different regimens involving chemotherapy and/or targeted therapy in advanced breast cancer (1973-2007). Regimens were categorized a priori into different treatment types. We performed multiple-treatments meta-analysis and calculated hazard ratios for each treatment category relative to monotherapy with old agents (ie, regimens not including anthracyclines, anthracenediones, vinorelbine, gemcitabine, capecitabine, taxanes, marimastat, thalidomide, trastuzumab, lapatinib, or bevacizumab). RESULTS We identified 370 eligible randomized trials (54,189 patients), of which 172 (31,552 patients) compared different types of treatment. Survival data from 148 comparisons pertaining to 128 of the 172 trials (26,031 patients, 22 different types of treatment) were available for inclusion in the multiple-treatments meta-analysis. Compared with single-agent chemotherapy with old nonanthracycline drugs, anthracycline regimens achieved 22%-33% relative risk reductions in mortality (ie, hazard ratio [HR] for standard-dose anthracycline-based combination: 0.67, 95% credibility interval [CrI] 0.57-0.78). Several newer regimens achieved further benefits (eg, HR [95% CrI] 0.67 [0.55-0.81] for single-drug taxane, 0.64 [0.53-0.78] for combination of anthracyclines with taxane, 0.49 [0.37-0.67] for taxane-based combination with capecitabine or gemcitabine), and similar benefits were seen with several regimens including molecular targeted treatments. Most regimens had very similar efficacy profiles (<5% difference in HR) as first- and subsequent-line therapies. CONCLUSIONS Stepwise improvements in efficacy of chemotherapy and targeted treatments cumulatively have achieved major improvements in the survival of patients with advanced breast cancer. Many options that can be used in first and subsequent lines of therapy have comparable efficacy profiles.

Obstetric outcomes after treatment of periodontal disease during pregnancy: systematic review and meta-analysis

Objective To examine whether treatment of periodontal disease with scaling and root planing during pregnancy is associated with a reduction in the preterm birth rate. Design Systematic review and meta-analysis of randomised controlled trials. Data sources Cochrane Central Trials Registry, ISI Web of Science, Medline, and reference lists of relevant studies to July 2010; hand searches in key journals. Study selection Randomised controlled trials including pregnant women with documented periodontal disease randomised to either treatment with scaling and root planing or no treatment. Data extraction Data were extracted by two independent investigators, and a consensus was reached with the involvement a third. Methodological quality of the studies was assessed with the Cochrane’s risk of bias tool, and trials were considered either high or low quality. The primary outcome was preterm birth (<37 weeks). Secondary outcomes were low birthweight infants (<2500 g), spontaneous abortions/stillbirths, and overall adverse pregnancy outcome (preterm birth <37 weeks and spontaneous abortions/stillbirths). Results 11 trials (with 6558 women) were included. Five trials were considered to be of high methodological quality (low risk of bias), whereas the rest were low quality (high or unclear risk of bias). Results among low and high quality trials were consistently diverse; low quality trials supported a beneficial effect of treatment, and high quality trials provided clear evidence that no such effect exists. Among high quality studies, treatment had no significant effect on the overall rate of preterm birth (odds ratio 1.15, 95% confidence interval 0.95 to 1.40; P=0.15). Furthermore, treatment did not reduce the rate of low birthweight infants (odds ratio 1.07, 0.85 to 1.36; P=0.55), spontaneous abortions/stillbirths (0.79, 0.51 to 1.22; P=0.28), or overall adverse pregnancy outcome (preterm births <37 weeks and spontaneous abortions/stillbirths) (1.09, 0.91 to 1.30; P=0.34). Conclusion Treatment of periodontal disease with scaling and root planing cannot be considered to be an efficient way of reducing the incidence of preterm birth. Women may be advised to have periodical dental examinations during pregnancy to test their dental status and may have treatment for periodontal disease. However, they should be told that such treatment during pregnancy is unlikely to reduce the risk of preterm birth or low birthweight infants.

Effect of periodontal disease treatment during pregnancy on preterm birth incidence: a metaanalysis of randomized trials

We conducted a metaanalysis of randomized controlled trials to determine whether periodontal disease treatment with scaling and/or root planing during pregnancy may reduce preterm birth (PTB) or low birthweight (LBW) infant incidence. Treatment resulted in significantly lower PTB (odds ratio [OR], 0.55; 95% confidence interval [CI], 0.35-0.86; P = .008) and borderline significantly lower LBW (OR, 0.48; 95% CI, 0.23-1.00; P = .049), whereas no difference was found for spontaneous abortion/stillbirth (OR, 0.73; 95% CI, 0.41-1.31; P = .292). Subgroup analysis suggested significant effect of treatment in the absence of history of PTB or LBW (OR, 0.48; 95% CI, 0.29-0.77; P = .003) and less severe periodontal disease as defined by probing depth (OR, 0.49; 95% CI, 0.28-0.87; P = .014) or bleeding on probing site (OR, 0.37; 95% CI, 0.14-0.95; P = .04). If ongoing large and well-designed randomized trials support our results, we might need to reassess current practice or at least be cautious prior to rejecting treatment of periodontal disease with scaling and/or root planing during pregnancy.

Combined vitamin C and E supplementation during pregnancy for preeclampsia prevention: a systematic review.

The effect of combined vitamin C and E supplementation during pregnancy on the prevention of preeclampsia and major adverse infant outcomes has been reviewed. We searched MEDLINE and the Central Library of Controlled Trials of the Cochrane Library through August 2006 for relevant clinical trials. Interstudy heterogeneity was evaluated using the &khgr;2 statistic (Q statistic) test. Pooled relative risks (RRs) and 95% confidence intervals (CIs) were calculated with a fixed or random-effects model as appropriate. Four trials that collectively randomized 4680 pregnant women to either the combination of vitamin C and vitamin E or placebo were included in the analysis. There were no significant differences between the vitamin and placebo groups in the risk of preeclampsia, 11% versus 11.4%, RR 0.97 (95% CI 0.82–1.13), fetal or neonatal loss, 2.6% versus 2.3%, RR 1.10 (95% CI 0.78–1.57), or small for gestational age (SGA) infant, 20.6% versus 20%, RR 0.94 (95% CI 0.74–1.19). Although there was a higher risk for preterm birth in the vitamin group, 19.5% versus 18%, RR 1.07 (95% CI 0.96–1.20), this finding was not significant. Combined vitamin C and E supplementation during pregnancy does not reduce the risk of preeclampsia, fetal or neonatal loss, small for gestational age infant, or preterm birth. Such supplementation should be discouraged unless solid supporting data from randomized trials become available. Target Audience: Obstetricians & Gynecologists, Family Physicians Learning Objectives: After completion of this article, the reader should be able to recall that many methods have been used to prevent preeclampsia, state that increased oxidative stress has been postulated and many trials have used antioxidants to prevent the disease, and explain that MEDLINE analysis of the literature questions the use of vitamin C and E supplements.

Overall survival benefit for weekly vs three-weekly taxanes regimens in advanced breast cancer: a meta-analysis

BACKGROUND Taxanes have been extensively tested in patients with advanced breast cancer, but it is unclear whether their weekly use might offer any benefits against standard every three weeks administration. We therefore performed a meta-analysis of randomized controlled trials that compared weekly and every three weeks taxanes regimens in advanced breast cancer. METHODS The endpoints that we assessed were objective response rate, progression free survival (PFS) and overall survival. Efficacy data for paclitaxel and docetaxel were separately analyzed. Trials were located through PubMed and Cochrane Library searches and abstracts of major international conferences. RESULTS Omicronbjective response rate was notably better when paclitaxel was used as every three weeks regimen (7 studies, 1772 patients, fixed effect model pooled RR 1.20 95%CI 1.08-1.32 p<0.001). No difference were found for PFS (6 studies, 1610 patients, random effect model HR 1.02, 95%CI 0.81-1.30 p=0.860); while OS was statistically higher among patients receiving weekly paclitaxel (5 studies, 1471 patients, fixed effect model pooled HR 0.78, 95%CI 0.67-0.89 p=0.001). No differences were observed for the weekly compared to the every three weeks use of docetaxel either for objective response, PFS and OS. Overall, the incidence of serious adverse events, neutropenia, neutropenic fever, and peripheral neuropathy were significantly lower in weekly taxanes schedules. The incidence of nail changes and epiphora were significantly lower in the every three weeks docetaxel regimens. CONCLUSIONS Use of paclitaxel in weekly regimen give overall survival advantages compared with the standard every three weeks regimen. The observed survival benefit does not seem to stem from an increased potency of the drug with weekly regimens. The use of weekly paclitaxel regimens is therefore recommended for the treatment of locally advanced/metastatic breast cancer.

Trastuzumab combined to neoadjuvant chemotherapy in patients with HER2-positive breast cancer: A systematic review and meta-analysis

PURPOSE To perform a meta-analysis in order to quantify the actual cumulative randomized evidence for the benefit and toxicity of trastuzumab combined with neoadjuvant chemotherapy in HER2-positive breast cancer. METHODS Potentially eligible trials were located through PubMed and Cochrane Library searches and abstracts of major international conferences. The endpoints that we assessed were pathologic complete response (pCR) rate, breast-conserving surgery (BCS) rate and toxicity. RESULTS Five trials were identified with 515 eligible patients. The probability to achieve pCR was higher for the trastuzumab plus chemotherapy arm (RR 1.85, 95% CI: 1.39-2.46; p-value < 0.001). No significant difference in terms of breast-conserving surgery between the two treatment arms was observed (OR: 0.98, 95% CI: 0.80-1.19, p-value = 0.82). Regarding toxicity, the addition of trastuzumab did not increase the incidence of neutropenia, neutropenic fever, and cardiac adverse events. CONCLUSION The addition of trastuzumab in HER2-positive breast cancer in the neoadjuvant setting improves the probability of achieving higher pCR with no additional toxicity. Based on the available evidence, the use of trastuzumab combined with neoadjuvant chemothetherapy in patients with HER2-positive breast cancer seems to offer substantial benefit in terms of pCR.

Evaluating novel agent effects in multiple treatments meta-regression

Multiple-treatments meta-analyses are increasingly used to evaluate the relative effectiveness of several competing regimens. In some fields which evolve with the continuous introduction of new agents over time, it is possible that in trials comparing older with newer regimens the effectiveness of the latter is exaggerated. Optimism bias, conflicts of interest and other forces may be responsible for this exaggeration, but its magnitude and impact, if any, needs to be formally assessed in each case. Whereas such novelty bias is not identifiable in a pair-wise meta-analysis, it is possible to explore it in a network of trials involving several treatments. To evaluate the hypothesis of novel agent effects and adjust for them, we developed a multiple-treatments meta-regression model fitted within a Bayesian framework. When there are several multiple-treatments meta-analyses for diverse conditions within the same field/specialty with similar agents involved, one may consider either different novel agent effects in each meta-analysis or may consider the effects to be exchangeable across the different conditions and outcomes. As an application, we evaluate the impact of modelling and adjusting for novel agent effects for chemotherapy and other non-hormonal systemic treatments for three malignancies. We present the results and the impact of different model assumptions to the relative ranking of the various regimens in each network. We established that multiple-treatments meta-regression is a good method for examining whether novel agent effects are present and estimation of their magnitude in the three worked examples suggests an exaggeration of the hazard ratio by 6 per cent (2-11 per cent).

Safety of Pregnancy After Primary Breast Carcinoma in Young Women: A Meta-Analysis to Overcome Bias of Healthy Mother Effect Studies

Background: An increased number of women are expected to conceive after the diagnosis of early breast cancer. Most physicians recommend that pregnancy be delayed by 2 to 3 years after diagnosis of early breast cancer, but this recommendation is based on data from trials with small patient cohorts. Furthermore, a healthy mother effect (HME) selection bias may be operative in most of these studies, because women undergoing childbearing after treatment were healthier when compared with the control group. Aim: To perform a systematic review and meta-analysis of published trials corrected for HME bias so as to assess the effect of pregnancy (at least 10 months after diagnosis) versus no pregnancy on overall survival of primary breast cancer patients less than 45 years. Methods: We searched MEDLINE and Thomson Reuters (ISI) Web of Knowledge for eligible studies. From each study we extracted the relative hazard ratio or, if not provided, all the necessary data to impute it. In cases where the duration from diagnosis to pregnancy was not reported, we extracted relevant data to estimate it. Results: Our electronic search strategy yielded 1623 hits pertaining to 20 potentially eligible studies involving 49,370 premenopausal breast cancer patients. Ten studies were eligible after considering HME potential bias in matching controls. Among these, 9 studies (pregnant 1089, matched-controls 13051) contained data appropriate for analysis. Overall survival was statistically higher among patients who became pregnant compared to controls: fixed effect model estimated pooled hazard ratio for death 0.51 (95% confidence interval: 0.42–0.62). No study heterogeneity was observed: Q = 10.4, P = 0.17; I2 = 48%. Conclusion: The pooled available evidence indicates that in early breast cancer patients, pregnancy that occurs at least 10 months after diagnosis does not jeopardize prognosis and may actually confer significant survival benefit. Target Audience: Obstetricians & Gynecologists, Family Physicians Learning Objectives: After completing this CME activity, physicians should be better able to assess the effect pregnancy has on long-term survival in primary breast cancer patients under age 45; counsel patients on the safety of pregnancy after breast cancer diagnosis and treatment; and interpret how pregnancy may be associated with improved breast cancer survival.

Partial breast irradiation or whole breast radiotherapy for early breast cancer: a meta-analysis of randomized controlled trials.

Abstract:  The purpose of the study was to compare treatment outcomes in patients with breast cancer treated with partial breast irradiation (PBI) and of those treated with whole breast‐radiation therapy (WBRT). We conducted a systematic review and meta‐analysis of published randomized clinical trials comparing PBI versus WBRT. Primary outcome was overall survival and secondary outcomes were locally, axillary, supraclavicular, and distant recurrences. A search of the literature identified three trials with pooled total of 1,140 patients. We found no statistically significant difference between partial and whole breast radiation arms associated with death (OR 0.912, 95% CI 0.674–1.234, p = 0.550), distant metastasis (OR 0.740, 95% CI, 0.506–1.082, p = 0.120), or supraclavicular recurrences (pooled OR 1.415, 95% CI 0.278–7.202, p = 0.560). However, PBI was statistically significantly associated with an increased risk of both local (pooled OR 2.150, 95% CI, 1.396–3.312; p = 0.001) and axillary recurrences (pooled OR 3.430, 95% CI, 2.058–5.715; p < 0.0001) compared with whole breast‐radiation. Partial breast irradiation does not seem to jeopardize survival and may be used as an alternative to whole breast‐radiation. Nevertheless the issue of loco‐regional recurrence needs to be further addressed.

Adjuvant Therapy With Zoledronic Acid in Patients With Breast Cancer: A Systematic Review and Meta-Analysis

BACKGROUND The purpose of the study was to estimate the impact on survival and fracture rates of the use of zoledronic acid versus no use (or delayed use) in the adjuvant treatment of patients with early-stage (stages I-III) breast cancer. MATERIALS AND METHODS We performed a systematic review and meta-analysis of randomized clinical trials. Trials were located through PubMed, ISI, Cochrane Library, and major cancer scientific meeting searches. All trials that randomized patients with primary breast cancer to undergo adjuvant treatment with zoledronic acid versus nonuse, placebo, or delayed use of zoledronic acid as treatment to individuals who develop osteoporosis were considered eligible. Standard meta-analytic procedures were used to analyze the study outcomes. RESULTS Fifteen studies were considered eligible and were further analyzed. The use of zoledronic acid resulted in a statistically significant better overall survival outcome (five studies, 6,414 patients; hazard ratio [HR], 0.81; 95% confidence interval [CI], 0.70-0.94). No significant differences were found for the disease-free survival outcome (seven studies, 7,541 patients; HR, 0.86; 95% CI, 0.70-1.06) or incidence of bone metastases (seven studies, 7,543 patients; odds ratio [OR], 0.94; 95% CI, 0.64-1.37). Treatment with zoledronic acid led to a significantly lower overall fracture rate (OR, 0.78; 95% CI, 0.63-0.96). Finally, the rate of osteonecrosis of the jaw was 0.52%. CONCLUSION Zoledronic acid as adjuvant therapy in breast cancer patients appears to not only reduce the fracture risk but also offer a survival benefit over placebo or no treatment.