Meta-analysis of randomized clinical evidence of chemotherapy, radiotherapy and endocrine therapy in breast cancer
Abstract: Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death in females worldwide. Despite the growing body of randomized controlled trials (RCTs) regarding the use of various treatment strategies (chemotherapy, endocrine therapy, radiotherapy) in breast cancer, the efficacy of some strategies remains unclear and questionable. A meta-analysis, by combining the results of all available trials that studied the same question, could help to reduce the level of uncertainty and provide reliable conclusions about the role of various therapeutic choices for breast cancer patients.Objective: The purpose of this thesis was to identify controversial therapeutic strategies in the treatment of breast cancer and to perform, when possible, meta-analyses to find out which of these strategies are valuable in breast cancer therapy. We conducted 7 separate meta-analyses in order to answer to 7 different clinical questions. We choose 7 topics with controversial results in the therapeutic strategy of breast cancer patients, namely the role of bisphosphonates as antitumor therapy and as preventive agents against fractures in adjuvant setting, the risk of osteonecrosis of the jaw (ONJ) with the use of bisphosphonates in adjuvant setting, the use of fulvestrant in advanced breast cancer, the safety of partial breast irradiation (PBI) compared with whole-breast radiotherapy (WBRT), the role of bevacizumab in advanced breast cancer and finally the value of trastuzumab as neoadjuvant therapy in Her2-positive breast cancer patients.Materials and Methods: In all 7 meta-analyses we used the same basic principles of meta-analysis, with some minor but necessary changes in order to fit our methodology to specific aims of each trial. In general, we conducted systematic reviews of all English and non-English medical literature using MEDLINE, the Cochrane Controlled Trials Register and ISI Web of Knowledge. We set no year restriction. The references of all eligible trials were also searched in order to find any potentially eligible trial that it was not identified by our searching algorithm. Abstracts of major meetings were also searched. Eligible studies were identified according to prespecified criteria for each meta-analysis. Data extraction was conducted independently by two investigators. In case of discrepancy, consensus was reached by involvement of a third investigator. When data on the outcome were not available from trials, we contacted the primary investigators of the eligible trials. Data synthesis was perfomed by choosing the appropriate effect size measure (Odds Ratio, Risk Ratio or Hazard Ratio) for each outcome and by combining the results using fixed- or random-effects models.Results: Regarding bisphosphonates in adjuvant setting, pooled results showed no statistical significant differences with the use of bisphosphonates in early breast cancer versus non-use for the overall number of deaths (summary OR, 0.708; 95% CI, 0.482–1.041; p-value =0.079), disease recurrences(summary OR, 0.843; 95% CI, 0.602–1.181; p-value =0.321), and bone metastases (summary OR, 0.925; 95% CI, 0.768–1.114; p-value =0.413). Subgroup analyses for disease recurrences according to the type of bisphosphonate used showed a statistically significant lower risk for disease recurrences with zoledronic acid (6 trials, OR, 0.675; 95% CI, 0.479–0.952; p-value = 0.025). In addition, bisphosphonates did not reduce fracture rate (OR=0.99, 95% CI=0.73–1.34) neither in postmenopausal women (OR=0.82, 95% CI=0.55–1.20) nor in women with breast cancer receiving aromatase inhibitors (OR=0.79, 95% CI=0.53–1.17). Overall, treatment with bisphosphonates was significantly associated with the occurrence of osteonecrosis of the jaw (ONJ) (OR = 3.23, 95% CI = 1.7–8) compared with no use but it was a rare event, occurring in 13 (0.24%) of the 5,312 patients receiving bisphosphonates.Considering fulvestrant, we found no difference between fulvestrant versus other hormonal agents regarding overall survival (HR: 1.047, 95% CI: 0.688–1.592; p-value = 0.830) and time to tumor progression (HR: 0.994, 95% CI: 0.691–1.431; p-value = 0.975).Partial breast irradiation (PBI) did not influence survival (OR 0.912, 95% CI, 0.674–1.234, p-value = 0.550) compared with WBRT but it was found to lead to statistically significant higher risk for developing local recurrences (pooled OR 2.150, 95% CI, 1.396–3.312; p-value = 0.001) and axillary recurrences (pooled OR 3.430, 95% CI, 2.058–5.715; p-value < 0.0001).The combination of bevacizumab and chemotherapy resulted in a statistically significant improvement in progression-free survival compared with chemotherapy alone (HR = 0.70, 95% CI = 0.60–0.82, p-value = 9.3x10-6), especially when bevacizumab was combined with taxanes. However, the pooled HR for overall survival did not show significant advantage for the use of bevacizumab compared to placebo arm (pooled HR = 0.90, 95% CI 0.80–1.03, p-value = 0.119).Finally, the use of trastuzumab as neoadjuvant therapy lead to higher absolute pathologic complete response (pCR) rate (38% in trastuzumab arm in comparison with 21% in no trastuzumab arm) (RR 1.85, 95% CI: 1.39-2.46; p-value < 0.001). Two out of 217 (0.9%) patients in the trastuzumab arms presented congestive heart failure compared with none in the chemotherapy alone arms.Conclusions: The meta-analysis of bisphosphonates in adjuvant breast cancer therapy showed that currently available randomized evidence does not support the hypothesis that using bisphosphonates in adjuvant treatment of early breast cancer alters the natural course of the disease. In addition bisphosphonates do not seem to prevent bone fractures. However, ONJ is a rare event in breast cancer patients treated with adjuvant use of bisphosphonates.Our meta-analysis of fulvestrant suggests that fulvestrant 250 mg is similar to other hormonal agents with respect to efficacy measures with equal or even better tolerability profile compared with other hormonal agents.Our meta-analysis of PBI, despite the fact that it is based on limited randomized evidence, suggests that PBI is a safe treatment modality as it does not seem to jeopardize survival compared with standard WBRT. Nevertheless, the issue of locoregional recurrence needs to be further addressed.The results of the meta-analysis of bevacizumab show that the addition of bevacizumab to chemotherapy offers a statistically significant improvement in progression free survival in patients with metastatic breast cancer but does not benefit overall survival. In addition, clinical significance of this improvement is questionable. As a result, bevacizumab treatment cannot be suggested for treatment of 1st line metastatic breast cancer,Finally, the meta-analysis of trastuzumab as neoadjuvant treatment underscores the beneficial effects of trastuzumab treatment in neoadjuvant regimens among HER2-positive breast cancer patients in terms of pCR. Of interest, no additional cardiotoxicity was documented in the trastuzumab arms.
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