Paclitaxel plus Bevacizumab versus Paclitaxel Alone for Metastatic Breast Cancer

Miller, Kathy D.; Wang, Molin; Gralow, Julie R.; Dickler, Maura N.; Cobleigh, Melody A.; Perez, Edith A.; Shenkier, Tamara; Cella, David; Davidson, Nancy E.

doi:10.1056/nejmoa072113

Cited by 2,835 publications

(1,913 citation statements)

References 22 publications

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“…Although the goal of cancer treatment is to improve the quantity and quality of life,1 2 3 clinical trials designed to gain regulatory approval for new drugs often evaluate indirect or “surrogate” measures of drug efficacy. These endpoints show that an agent has biological activity, but they are not reliable surrogates for improved survival4 5 6 7 8 9 10 11 or quality of life4 6 11 12 13 in all settings, and two recent systematic reviews suggest that the strength of association between surrogates in cancer clinical trials and life extension is generally low 814 Moreover, there is growing concern that the benefits offered by many new treatments for cancer—often discussed and promoted as “breakthroughs”15 16 17 18—are marginal and might not be clinically meaningful to patients, despite rapidly escalating costs 19…”

Section: Introductionmentioning

confidence: 99%

Availability of evidence of benefits on overall survival and quality of life of cancer drugs approved by European Medicines Agency: retrospective cohort study of drug approvals 2009-13

Davis

Naci

Gurpinar

et al. 2017

BMJ

478

415

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Objective To determine the availability of data on overall survival and quality of life benefits of cancer drugs approved in Europe. Design Retrospective cohort study. Setting Publicly accessible regulatory and scientific reports on cancer approvals by the European Medicines Agency (EMA) from 2009 to 2013. Main outcome measures Pivotal and postmarketing trials of cancer drugs according to their design features (randomisation, crossover, blinding), comparators, and endpoints. Availability and magnitude of benefit on overall survival or quality of life determined at time of approval and after market entry. Validated European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS) used to assess the clinical value of the reported gains in published studies of cancer drugs. Results From 2009 to 2013, the EMA approved the use of 48 cancer drugs for 68 indications. Of these, eight indications (12%) were approved on the basis of a single arm study. At the time of market approval, there was significant prolongation of survival in 24 of the 68 (35%). The magnitude of the benefit on overall survival ranged from 1.0 to 5.8 months (median 2.7 months). At the time of market approval, there was an improvement in quality of life in seven of 68 indications (10%). Out of 44 indications for which there was no evidence of a survival gain at the time of market authorisation, in the subsequent postmarketing period there was evidence for extension of life in three (7%) and reported benefit on quality of life in five (11%). Of the 68 cancer indications with EMA approval, and with a median of 5.4 years’ follow-up (minimum 3.3 years, maximum 8.1 years), only 35 (51%) had shown a significant improvement in survival or quality of life, while 33 (49%) remained uncertain. Of 23 indications associated with a survival benefit that could be scored with the ESMO-MCBS tool, the benefit was judged to be clinically meaningful in less than half (11/23, 48%). Conclusions This systematic evaluation of oncology approvals by the EMA in 2009-13 shows that most drugs entered the market without evidence of benefit on survival or quality of life. At a minimum of 3.3 years after market entry, there was still no conclusive evidence that these drugs either extended or improved life for most cancer indications. When there were survival gains over existing treatment options or placebo, they were often marginal.

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Section: Introductionmentioning

confidence: 99%

Availability of evidence of benefits on overall survival and quality of life of cancer drugs approved by European Medicines Agency: retrospective cohort study of drug approvals 2009-13

Davis

Naci

Gurpinar

et al. 2017

BMJ

478

415

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“…Median survival of these patients is in the range of 16-24 months and is determined by several factors, including number and site of metastatic lesions, and tumor characteristics such as hormone receptor and HER2neu status [2,3]. During the last decades, the treatment of metastatic breast cancer has undergone considerable changes, with taxanes and thirdgeneration aromatase-inhibitors being introduced in the nineties of the previous century and, among others, trastuzumab and bevacizumab in the current decade [4][5][6].…”

Section: Introductionmentioning

confidence: 99%

Impact of breast surgery on survival in patients with distant metastases at initial presentation: a systematic review of the literature

Ruiterkamp

Voogd

Bosscha

et al. 2009

Breast Cancer Res Treat

103

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According to current treatment standards, patients with metastatic breast cancer at diagnosis receive palliative therapy. Local treatment of the breast is only recommended if the primary tumor is symptomatic. Recent studies suggest that surgical removal of the primary tumor has a favorable impact on the prognosis of patients with primary metastatic breast cancer. We performed a systematic review of the literature to weigh the evidence for and against breast surgery in this patient group. Ten retrospective studies were found in which the use of breast surgery in primary metastatic breast cancer and its impact on survival was examined. The hazard ratios of the studies were pooled to provide an estimate of the overall effect of surgery, and the results and conclusions of the studies were analyzed. A crude analysis, without adjustment for potential confounders, showed that surgical removal of the breast lesion in stage-IV disease was associated with a significantly higher overall survival rate in seven of the ten studies, and a trend toward a better survival in the three remaining studies. Surgery of the primary tumor appeared to be an independent factor for an improved survival in the multivariate analyses from the individual studies, with hazard ratios ranging from 0.47 to 0.71. The pooled hazard ratio for overall mortality was 0.65 (95% CI 0.59-0.72) in favor of the patients undergoing surgery. This systematic review of the literature suggests that surgery of the primary breast tumor in patients with stage-IV disease at initial presentation does have a positive impact on survival. In order to provide a definite answer on whether local tumor control in patients with primary metastatic disease improves survival, a randomized controlled trial comparing systemic therapy with and without breast surgery is needed.

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“…13 However, despite advances in the treatment of MBC, only 2 further targeted agents have shown the ability to improve progression-free (and/or overall) survival: bevacizumab and trastuzumab. 14,15 Thus, the need for improvements in personalized medicine clearly exists, and this study attempted to widen the realm of treatment regimens for patients with MBC. Unfortunately, although the study demonstrated that RP14610 is a well-tolerated agent, with a manageable adverse event profile, this agent did not demonstrate significant efficacy in this heavily pretreated patient population.…”

Section: Discussionmentioning

confidence: 99%

An open‐label, phase 2 trial of RPI.4610 (angiozyme) in the treatment of metastatic breast cancer

Morrow

Murthy

Ensor

et al. 2012

Cancer

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BACKGROUND:Serum and plasma levels of vascular endothelial growth factor (VEGF) correlate with prognosis in patients with metastatic breast cancer (MBC). VEGF binds to 2 receptors on endothelial cells, VEGFR‐1 and VEGFR‐2. RPI.4610 (Angiozyme0) is an antiangiogenic ribozyme targeting the VEGFR‐1 mRNA. Preclinical and phase 1 studies suggested that RPI.4610 is a well‐tolerated agent with clinical activity in solid tumors. The authors' trial evaluated the efficacy of RPI.4610 in the treatment of patients with progressive MBC.METHODS:This phase 2, multicenter, single‐arm study was designed to assess the objective response rate of RPI.4610 in patients with MBC who had experienced disease progression with at least 1 course of chemotherapy for MBC. Patients received daily subcutaneous injections of RPI.4610 100 mg/m2 for 12 weeks.RESULTS:Most patients (93%) had received at least 2 lines of chemotherapy previously; 69% of patients had received at least 3 lines of chemotherapy. Median follow‐up was 2.76 months (range, 0.89‐36.6 months). No partial responses nor complete responses were found. Median progression‐free survival was 1.41 months (95% confidence interval [CI], 1.35‐1.45). The median overall survival from start of treatment was 11.89 months (95% CI, 4.11‐23.66). Treatment‐related adverse events (AEs) were primarily grade 1 to 2 in intensity. Most common AEs were: injection site reactions, abdominal pain, anorexia, chromaturia, constipation, dyspnea, fatigue, headache, pain at the injection site, nausea, vomiting, and fever.CONCLUSIONS:Although RPI.4610 demonstrated a well‐tolerated safety profile, its lack of clinical efficacy precludes this drug from further development. Cancer 2012.© 2012 American Cancer Society.

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Paclitaxel plus Bevacizumab versus Paclitaxel Alone for Metastatic Breast Cancer

Abstract: Initial therapy of metastatic breast cancer with paclitaxel plus bevacizumab prolongs progression-free survival, but not overall survival, as compared with paclitaxel alone. (ClinicalTrials.gov number, NCT00028990 [ClinicalTrials.gov].).

Cited by 2,835 publications

References 22 publications

Availability of evidence of benefits on overall survival and quality of life of cancer drugs approved by European Medicines Agency: retrospective cohort study of drug approvals 2009-13

Availability of evidence of benefits on overall survival and quality of life of cancer drugs approved by European Medicines Agency: retrospective cohort study of drug approvals 2009-13

Impact of breast surgery on survival in patients with distant metastases at initial presentation: a systematic review of the literature

An open‐label, phase 2 trial of RPI.4610 (angiozyme) in the treatment of metastatic breast cancer

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