Comparative Effectiveness of Gemcitabine plus Nab-Paclitaxel and FOLFIRINOX in the First-Line Setting of Metastatic Pancreatic Cancer: A Systematic Review and Meta-Analysis.

Gemcitabine and nab-paclitaxel (GEM-NAB) and the combination of 5-fluorouracil, oxaliplatin, and irinotecan (FOLFIRINOX) are valid first-line options for advanced or metastatic pancreatic cancer (mPC). However, no randomized trials comparing the two schemes have been performed. This meta-analysis aims to compare GEM-NAB and FOLFIRINOX in terms of safety and effectiveness, taking into account data from real-life studies on mPC. We systematically searched PubMed, EMBASE and Cochrane library up to November 2018 to identify retrospective or cohort studies on mPC comparing GEM-NAB and FOLFIRINOX. We included 16 retrospective studies, including 3813 patients (2123 treated with GEM-NAB and 1690 treated with FOLFIRINOX). Despite a median weighted overall survival (OS) difference in favor of FOLFIRINOX (mean difference: 1.15, 95% confidence interval CI 0.08⁻2.22, p = 0.03), in whole population OS was similar (hazard ratio (HR = 0.99, 95% CI 0.84⁻1.16; p = 0.9). PFS was also not different between the two arms (HR = 0.88, 95% CI 0.71⁻1.1; p = 0.26). The overall response rate was similar (25 vs. 24% with GEM-NAB and FOLFIRINOX). Among grade 3⁻4 toxicities, neutropenia, febrile neutropenia, and nausea were lower with GEM-NAB, while neurotoxicity and anemia were lower with FOLFIRINOX. In conclusion, despite a numerically longer median OS with FOLFIRINOX as compared to GEM-NAB, the overall risk of death and progression were similar. Their toxicity was different with less nausea, neutropenia, and febrile neutropenia with GEM-NAB, as compared to less neurotoxicity and anemia with FOLFIRINOX. Therefore, analysis of non-randomized "real world" studies to date has not provided evidence of a major benefit of one regimen over the other.

A systematic review and meta-analysis of second-line therapies for treatment of mesothelioma.

INTRODUCTION: Advanced malignant pleural mesothelioma (MPM) is generally treated with platinum/pemetrexed-based first-line therapy. Once the disease progresses, evidence for the efficacy of palliative treatments is lacking, and platinum re-challenge or single-agent chemotherapy are commonly used. To assess the effects of cytostatic or targeted therapy for treating MPM, we performed a systematic review and meta-analysis. MATERIAL AND METHODS: PubMed, the Cochrane Library, and Embase databases were searched to identify published articles on second-line treatments for recurrent or advanced mesothelioma. Inclusion criteria were publication in the English language, describing clinical trials with 20 or more patients, and evaluability for efficacy and for receiving second-line systemic therapies. Data were pooled using number of events/number of evaluable patients, median overall survival (OS) and progression-free survival (PFS), according to a fixed or random effect model. Pooled median OS was the primary endpoint. RESULTS: A total of 49 eligible studies (n = 3938 patients; range, 12-400) were identified. Median progression-free survival (PFS) was 3.4 months (95%CI 2.87-3.93). Median pooled OS was 7.86 (95%CI 7.01-8.72). The pooled overall response rate (ORR) was 8.63% (95%CI 6-11.26), and the pooled disease control rate (DCR) was 54.8% (95%CI 48.9-60.6). Median pooled OS with platinum- and pemetrexed-based chemotherapy were 7.93 and 7.78 months, respectively. CONCLUSIONS: There remains uncertainty about the ideal second-line agent for MPM. Based on this meta-analysis, palliative chemotherapy or other experimental agents can be considered for patients with MPM who desire further treatment after their disease has progressed, during or after first-line therapy.

Salvage treatment for testicular cancer with standard- or high-dose chemotherapy: a systematic review of 59 studies.

Relapsed germ cell tumor (GCT) is a highly curable cancer with standard-dose platinum-based chemotherapy (CT); however, high-dose CT (HDCT) is seldom used as salvage therapy instead or after conventional CT. We conducted a systematic review of published trials to compare outcomes between standard-dose CT and HDCT in patients with relapsed GCT after first-line therapy for advanced disease. A literature search was carried out in multiple electronic databases (PubMed, Embase, Scopus, Web of Science, and The Cochrane Library), and studies reporting salvage treatment of relapsed GCT with standard-dose or carboplatin-etoposide-based HDCT were selected. Overall response rate, median overall survival (OS), and the 1-, 2-, 3-, and 5-year OS rates were pooled, and the significance of difference between arms was assessed with a Chi-square test. Twenty-nine standard-dose and 31 HD studies were included in the meta-analysis. For standard-dose CT versus HDCT, there was no significant difference in median OS (14.8 months and 24.09 months, respectively; P = 0.09) or in 1-, 2-, 3-, or 5-year survival rate (standard-dose CT, 64.2, 63.6, 45.1, and 43%, respectively; HDCT, 63.7, 51.2, 46.7, and 45%, respectively; P = 0.9, P = 0.4, P = 0.75, and P = 0.06). Conventional dose regimens and HDCT were associated with comparable efficacy when used as salvage therapies in relapsed GCTs as second-line therapy or beyond. However, the selection of ideal candidates for more or less intensive treatments deserves further research in the near future.

Early analysis of surrogate endpoints for metastatic melanoma in immune checkpoint inhibitor trials.

Recent major phase III trials led to the approval of immune checkpoint inhibitors (ipilimumab, pembrolizumab, and nivolumab) in metastatic malignant melanoma (MM). We aim to assess whether median progression-free survival, and 1 and 2-year overall survival (OS) rates are reliable surrogate endpoints for median OS through a meta-analysis of published trials involving immunotherapy. A systematic literature search in PubMed, EMBASE, Web of Science, and SCOPUS of published phase II to III trials with immunotherapy as the treatment for MM was conducted. Adjusted weighted linear regression was used to calculate Pearson correlations (R) between surrogates and median OS, and between treatment effects on surrogates and median OS. A total of 13 studies involving 3373 patients with MM were identified. The correlation of progression-free survival with OS was not significant (R = 0.45, P = .11). Conversely, the correlation between 1-year OS and median OS was very strong (R = 0.93, 95% confidence interval [CI] 0.84-0.96, P < .00001), as was the correlation between 2-year OS and OS (R = 0.79, 95% CI 0.51-0.91, P = .0001). The correlation between the treatment effects on 1-year OS and OS was also significant (R = -0.86, 95% CI -0.3 to 0.97, P = .01). Similar results were obtained for 2-year OS. According to the available study data, 1-year OS rate could be regarded as a potential surrogate for median OS in novel immunotherapy trials of metastatic MM. Waiting for ongoing studies (e.g., pembrolizumab), we suggest that this intermediate endpoint could be considered as a potential primary endpoint in future clinical trials.

Cytoreductive Nephrectomy in Metastatic Renal Cell Carcinoma Treated With Targeted Therapies: A Systematic Review With a Meta-Analysis.

Cytoreductive nephrectomy (CN) in metastatic renal cell carcinoma (mRCC) (resection of the primary tumor for debulking purposes) was considered to be an important part of oncological treatment when used with cytokines, and was associated with an overall survival (OS) benefit. However, the role of CN in the targeted therapy era is not well-defined. We conducted a systematic review and meta-analysis to determine the prognostic role of CN performed during the course of advanced disease in patients with mRCC treated with molecular agents. We searched PubMed, EMBASE, the Web of Science, Google Scholar, CINAHL, LILACS, the Cochrane Library, and SCOPUS for studies reporting survival data for participants who underwent CN with targeted therapy (CN+) versus those treated with targeted therapy alone (CN-). In a multivariate analysis, data were aggregated using hazard ratios with 95% confidence intervals for OS related to CN+. Twelve studies involving 39,953 patients were identified. In 11 publications with OS data available, the patients treated with CN+ had a reduced risk of death compared with those treated with targeted therapies alone (hazard ratio, 0.46; 95% confidence interval, 0.32-0.64; P < .01; I2 = 99%). Based on these results, CN+ reduces the risk of death in mRCC by more than 50% and should be discussed and included in the therapeutic armamentarium, as it still plays a therapeutic role, even in the post-cytokine era.

Neoadjuvant dose-dense chemotherapy for locally advanced breast cancer: a meta-analysis of published studies.

Large operable or locally advanced breast cancers (BCs) are usually treated with neoadjuvant chemotherapy (CT) before surgery. However, there is no evidence to support an improvement in efficacy with dose-dense (DD) CT in this setting. We, therefore, carried out a meta-analysis to investigate whether DD-CT was more effective than the reference (every 3 weeks anthracyclines±taxanes) standard-dose CT as neoadjuvant treatment for BC. We searched Pubmed, SCOPUS, EMBASE, the Web of Science, CINAHL, and the Cochrane Central Register of Controlled Trials for randomized trials comparing conventional versus DD neoadjuvant CT for BC. Odds ratios (ORs) for pathologic complete responses (ypT0N0M0: pCR) and hazard ratios (HRs) of death and recurrence [overall survival (OS), and disease-free survival (DFS)] were estimated and pooled. A QUADAS-2 report for all studies included in the final analysis was tabulated for the risk of bias and applicability. A total of six randomized trials fulfilled the inclusion criteria. The pooled rates of the pCR were 13.5 and 9.2% in the experimental and control arms. A significant increase in the pCR [OR=1.55, 95% confidence interval (CI) 1.18-2.02, P=0.001] was noted with neoadjuvant DD-CT. However, the patients who received DD-CT did not have significantly better DFS and OS rates (DFS: HR=0.88, 95% CI 0.76-1.01, P=0.06; OS: HR=0.89, 95% CI 0.78-1.02, P=0.08). Even with the limitation of a relatively short follow-up period, this meta-analysis shows that DD neoadjuvant CT, despite not leading to a significant increase in survival, increases by 46.7% the possibility of achieving a pCR in operable and locally advanced BC. This treatment should thus be considered one of the backbone treatments of choice when neoadjuvant therapy is planned.

Predictive Factors for Reclassification and Relapse in Prostate Cancer Eligible for Active Surveillance: A Systematic Review and Meta-analysis.

OBJECTIVE: To systematically evaluate the evidence on the predictors of the upgrading and biochemical recurrence of prostate cancer (PC) in those patients with low-risk disease assigned to active surveillance (AS). MATERIALS AND METHODS: An electronic search of the PubMed, SCOPUS, Web of Science, CINAHL, Cochrane Library, Google Scholar, and Embase databases was performed for all reports that included detailed results of multivariate analyses of the predictors of PC reclassification and biochemical relapse during AS. Cumulative analyses of available hazard ratios (HRs) and their corresponding 95% confidence intervals were conducted using the RevMan 5.3 software to assess the potential predictors of PC upgrading and recurrence. Both random-effect model meta-analysis and Hartung-Knapp-Sidik-Jonkman meta-analysis method were applied to obtain the pooled HR for each covariate. RESULTS: In the 32 articles analyzed, encompassing about 24,236 patients with early-stage PC, the 3 clinicopathological variables significantly associated with histological progression during AS were: prostate-specific antigen-density (HR 2.46; P = .0001); 2 positive cores (HR 1.54; P = .006); and race (HR 2; P = .04). Age, prostate-specific antigen levels, and suspicion on magnetic resonance imaging were not significantly associated with increased risk of progression of PC. CONCLUSION: We identified 3 strong predictors for the upgrading of PC during AS. These should be systematically evaluated to enable patients with low-risk disease to be treated with AS.

Prognostic factors after R0 resection of colorectal cancer liver metastases: A systematic review and pooled-analysis.

BACKGROUND: Prognostic variables associated with outcome after curative (R0) Resection of Colorectal Cancer (CRC) liver metastases are paramount in identifying high-risk patients after surgery. The aim of this study was to identify risk factors related to Overall Survival (OS) after R0 resection of CRC liver metastases. METHODS: A literature search on prognostic factors after resection of liver metastases was performed. Studies were eligible if covariates associated with OS were reported in patients with R0 resected CRC liver metastases. Independent prognostic factors associated with OS were identified using multivariate analysis. RESULTS: Twenty-four publications with a total of 4855 patients were eligible. In multivariate analyses, a disease-free interval < 12 months (hazard ratio [HR] 1.47, P = 0.0002), the size of the largest metastasis (HR 1.56, P < 0.0001), the total number of metastases (HR 1.73, P < 0.00001), a primary tumor with node-positive status (HR 1.56, P = 0.002), a rectal primary tumor (HR 1.48, P < 0.00001), a high carcinoembryonic antigen level (HR 1.49, P = 0.02), a high tumor grade (HR 2.42, P < 0.00001), and extrahepatic disease (HR 2.03, P < 0.00001) were associated with an increased risk of death after R0 resection of CRC liver metastases in at least 3 studies. CONCLUSION: We identified 9 clinicopathological prognostic factors that could help identify high-risk patients and guide further treatment and follow up decisions. In particular burden of liver and extrahepatic metastases and grade are those associated with a higher risk of death.

Optimal treatment of poor-risk renal cell carcinoma patients with mTOR inhibitors and anti-VEGFR agents.

Poor-risk metastatic renal cell carcinoma (RCC) includes a subgroup of patients with unfavorable prognosis, according to both the Motzer and Heng criteria. Overall, owing to the poor prognosis of these patients, the approach is still a challenge for the first and subsequent lines of treatment, particularly for rare histologies other than clear cell renal cell carcinoma. In this review, we investigated the present treatment option of poor-risk metastatic RCC. Areas covered are data with first and further line of therapy with mTOR inhibitors and other agents but without cytoreductive nephrectomy or rare histologies. The current data on systemic therapy in poor-risk metastatic RCC maintain temsirolimus as the preferred first-line therapy. New agents targeting immune checkpoints are being developed in clinical trials.

Long response to eribulin in breast cancer: a case report.

No definitive cure is available for metastatic breast cancer and current therapies mainly focus on symptom control and minimization of adverse events to extend survival and maintain a good quality of life. Current treatment options include hormonal and chemotherapeutic agents which are characterized by different toxicity profiles and are selected based on patients' performance status and prior therapies. Eribulin is a microtubule dynamic inhibitor which acts by sequestering tubulin molecules into aggregates, thus preventing microtubule growth and causing apoptosis. Many studies show that heavily pretreated metastatic breast cancer patients benefit from eribulin treatment both in terms of efficacy and for the favorable toxicity profile. In the Phase III EMBRACE study, eribulin treatment resulted in a significant improvement in overall survival. We report here the case of a patient who experienced a time to progression of several months with eribulin after three lines of chemotherapy and two lines of hormonal therapy.

Hepatic resection for gastric cancer liver metastases: A systematic review and meta-analysis.

BACKGROUND: Resection of liver metastases from gastric cancer (GC) is rarely performed, and the outcome after hepatic surgery has not been systematically evaluated in the literature. The aim of this study was to perform a systematic review of outcome and prognostic factors for survival after liver metastasectomy for GC. METHODS: We performed a meta-analysis of published studies that focused on long-term outcomes (5-year overall survival [OS]) after surgical management of liver metastases from GC, and included more than 10 patients each. Pooled hazard ratios (HRs) were calculated for variables considered as potential prognostic factors for OS in at least three publications. RESULTS: Twenty-three studies comprising a total of 870 patients were considered in this analysis. The pooled weighted median OS was 22 months (95%CI 17.6-27.2). The pooled 5-year OS after liver resection was 23.8% (95%CI 19-29.3%). The pooled 5-year OS rates for metachronous and synchronous metastases were 30% (95%CI 24.7-35.8%) and 22.6% (95%CI 14-34.4%), respectively. Parameters associated with poor survival were (i) multiple metastases, and (ii) large size of metastases. CONCLUSIONS: Hepatic resection of GC liver metastases is associated with an acceptable 5-year OS, in particular after surgery of metachronous lesions, and could be offered to selected patients.

Prognostic role of lactate dehydrogenase in solid tumors: a systematic review and meta-analysis of 76 studies.

BACKGROUND: In cancer cells, metabolism is shifted to aerobic glycolysis with lactate production coupled with a higher uptake of glucose as the main energy source. Lactate dehydrogenase (LDH) catalyzes the reduction of pyruvate to form lactate, and serum level is often raised in aggressive cancer and hematological malignancies. We have assessed the prognostic value of LDH in solid tumors. MATERIAL AND METHODS: A systematic review of electronic databases was conducted to identify publications exploring the association of LDH with clinical outcome in solid tumors. Overall survival (OS) was the primary outcome, and cancer-specific survival (CSS), progression-free survival (PFS), and disease-free survival (DFS) were secondary outcomes. Data from studies reporting a hazard ratio (HR) and 95% confidence interval (CI) were pooled in a meta-analysis. Pooled HRs were computed and weighted using generic inverse-variance and random-effect modeling. All statistical tests were two-sided. RESULTS: Seventy-six studies comprising 22 882 patients, mainly with advanced disease, were included in the analysis. Median cut-off of serum LDH was 245 U/L. Overall, higher LDH levels were associated with a HR for OS of 1.7 (95% CI 1.62-1.79; p < 0.00001) in 73 studies. The prognostic effect was highest in renal cell, melanoma, gastric, prostate, nasopharyngeal and lung cancers (all p < 0.00001). HRs for PFS was 1.75 (all p < 0.0001). CONCLUSIONS: A high serum LDH level is associated with a poor survival in solid tumors, in particular melanoma, prostate and renal cell carcinomas, and can be used as a useful and inexpensive prognostic biomarker in metastatic carcinomas.

Surveillance or Adjuvant Treatment With Chemotherapy or Radiotherapy in Stage I Seminoma: A Systematic Review and Meta-Analysis of 13 Studies.

OBJECTIVE: Testicular stage I seminoma has a remarkable cure rate with orchiectomy alone. The benefit of adjuvant therapy is questionable, and a direct comparison with active surveillance is lacking. We performed a meta-analysis to evaluate the benefit of adjuvant radiotherapy (RT) or chemotherapy (CT) compared with surveillance alone on relapse-free survival (RFS), overall survival (OS), and noncancer-related mortality in patients with stage I seminoma. METHODS: We performed a systematic search of PubMed, EMBASE, Web of Science, SCOPUS, and the Cochrane Register of Controlled Trials. Meta-analysis was performed using the fixed- or random-effects models. The primary endpoint was 5-year RFS, and secondary endpoints were 5-year OS and 5-year noncancer-related mortality, reported as odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: A total of 13 trials (11 retrospective and 2 prospective cohort series), including 12,075 patients with stage I seminoma, were analyzed. The relapse rates were 3.9% versus 14.8% in the adjuvant therapy and surveillance arms, respectively. Overall, adjuvant therapy significantly improved 5-year RFS (OR, 0.17; 95% CI, 0.1-0.29; P < .00001), but not 5-year OS (OR, 1.03; 95% CI, 0.46-2.28; P = .94). Mortality due to other causes was not significantly increased with CT or RT. CONCLUSIONS: Adjuvant RT and CT reduce recurrence risk by 80% of stage I seminoma. However, they do not increase OS or noncancer-related mortality. Both treatment options can be offered to patients with stage I seminoma, taking into consideration the side effects and high cure rate of testicular cancer at relapse.

Efficacy of fourth-line chemotherapy in advanced non-small-cell lung cancer: a systematic review and pooled analysis of published studies.

There are no agents labelled for use as fourth-line therapy for non-small-cell lung cancer, even though it is currently prescribed in about 5-10% of patients. Here, we provide a pooled analysis of published studies on the efficacy of treatments in patients who have had at least three unsuccessful lines of therapy. The literature search was performed on Pubmed, EMBASE, the Web of Science, SCOPUS, CINAHL, Google Scholar and the Cochrane Library using the terms 'lung cancer' OR NSCLC AND 'fourth line'. The response rates and disease control rates were pooled using a random-effect or a fixed-effect model according to heterogeneity. Median progression-free survival and overall survival data were also collected and aggregated to obtain pooled median values of the included studies. Overall, 14 studies (673 patients), which were almost entirely published by Asian institutions, were eligible for this pooled analysis. Among these were two phase II trials and 12 retrospective cohort series. In general, the pooled overall response rate was 13.6% [95% confidence interval (CI) 10-18.3] and the pooled overall disease control rate was 47.3% (95% CI 38-56.9). The pooled median progression-free survival for these studies was 3.34 months (95% CI 2.42-4.27). The pooled median overall survival for these studies was 10.5 months (95% CI 9.57-11.52). In conclusion, for non-small-cell lung cancer patients who have undergone three or more unsuccessful lines of therapy, fourth-line treatment could be offered in select cases to those with a good performance status.

FOLFIRINOX-based neoadjuvant therapy in borderline resectable or unresectable pancreatic cancer: a meta-analytical review of published studies.

OBJECTIVE: The use of neoadjuvant chemotherapy can enable surgical resection of borderline resectable or unresectable pancreatic cancer (PC). The aim of this study was to evaluate the effectiveness of the multiagent 5-fluorouracil + oxaliplatin + irinotecan + leucovorin (FOLFIRINOX) regimen as a neoadjuvant treatment for PC. METHODS: Studies in which FOLFIRINOX with or without radiotherapy was given before surgery to patients with borderline resectable or unresectable PC were analyzed using a meta-analytical approach. The primary outcomes were resection rate and radical (R0) resection rate. Data were expressed as weighted pooled proportions with 95% confidence intervals (CIs). RESULTS: Thirteen studies, with a total of 253 patients, were included in this meta-analysis. After undergoing the treatment, 43% (95% CI, 32.8-53.8) of patients were resected and 39.4% (95% CI, 32.4-46.9) underwent R0 resection (85% of surgical specimens). In particular, among borderline resectable PCs, R0 resection was possible in 63.5% (95% CI, 49%-76%) of the cases. The rate of R0 resection in unresectable PCs was 22.5% (95% CI, 13.3-35.4). CONCLUSIONS: This meta-analysis shows that down-staging after neoadjuvant FOLFIRINOX-based therapy is noticeable in patients with borderline resectable/unresectable PC, with a total R0 resection rate of 40%.

Adjuvant dose-dense chemotherapy in breast cancer: a systematic review and meta-analysis of randomized trials.

Dose-dense (DD) chemotherapy (CT) aimed at achieving a higher rate of cancer cell destruction has been adopted as an adjuvant therapy in high-risk breast cancer (BC), with the goal being to improve outcomes. We performed an updated systematic review and meta-analysis of the existing data from randomized phase III trials regarding the efficacy and toxicity of this adjuvant DD-CT strategy in early BC. Randomized-controlled trials that compared a DD with a standard adjuvant CT schedule in adult women with resected BC were identified by searching the databases of Pubmed, the Cochrane Cancer Register of Controlled Trials, SCOPUS, EMBASE, and the Web of Science up to March 2015. Hazard ratios (HRs) of death and recurrence, and the relative risks of adverse events, were estimated and pooled. A total of 8 phase III trials encompassing 17,188 randomized patients met the inclusion criteria. The patients who received DD-CT had better overall survival (OS: HR 0.86, 95 % confidence interval [CI] 0.79-0.93, P = 0.0001) and disease-free survival (DFS: HR 0.84, 95 % CI 0.77-0.91, P < 0.0001) than those on the conventional schedule. A statistically significant OS benefit was observed in patients with hormone receptor-negative (ER-) tumors (HR 0.8, P = 0.002), but not in those with ER-positive BC (HR 0.93, 95 % CI 0.82-1.05; P = 0.25). DD-CT leads to better OS and DFS, particularly in women with ER- early BC. These results suggest that the DD strategy should be the standard care offered to high-risk ER- BC patients.

Progression-free survival as surrogate endpoint in advanced pancreatic cancer: meta-analysis of 30 randomized first-line trials.

BACKGROUND: Progression-free survival (PFS) has not been extensively investigated as a surrogate for survival in the first-line treatments of pancreatic cancer. The aim of this review was to evaluate PFS as a potential surrogate endpoint for overall survival (OS) in advanced pancreatic cancer in trials comparing poly-chemotherapy to gemcitabine alone. DATA SOURCES: A systematic literature search in PubMed, Embase, Web of Science, and the Cochrane Central Register of Controlled Trials was conducted. The key words included randomized trial, first-line chemotherapy, pancreatic cancer, gemcitabine and poly-chemotherapy. Adjusted weighted linear regression was used to calculate RS (Spearman's rank-order correlation coefficient) between PFS and post-progression survival (PPS) with OS (RS) and between treatment effects on PFS and OS (RHR). RESULTS: A total of 30 trials including 8467 patients met the inclusion criteria. Correlation between the treatment effects on PFS and OS (RHR=0.78) and between the endpoint PFS and OS was high across all studies (RS=0.75). The slope of the regression line was 0.76+/-0.26, indicating that an agent producing a 10% risk reduction for PFS will provide a 7.6%+/-2.6% risk reduction for OS. Correlation between PPS and OS was very strong (RS=0.71) and accounted for more than 50% of the whole OS variability (R2=0.57). CONCLUSION: Because of the robust correlation with OS and the potential influence of PPS caused by the second line therapies, it may be justified to consider PFS as a surrogate endpoint in trials evaluating new cytotoxic agents when gemcitabine is the control arm.

Efficacy of oxaliplatin-based chemotherapy + bevacizumab as first-line treatment for advanced colorectal cancer: a systematic review and pooled analysis of published trials.

OBJECTIVES: Oxaliplatin and either capecitabine or infusional/bolus 5-fluorouracil (5FU)-based chemotherapy + bevacizumab (XELOX + B and FOLFOX + B) represent 2 of the approved first-line treatments for advanced colorectal cancer (CRC). However, the addition of B did not offer a survival benefit compared with FOLFOX/XELOX alone in the phase III, NO16966 trial. The aim of this review was to aggregate all published data on the efficacy of XELOX and FOLFOX-B in prospective and retrospective studies as first-line therapy for stage IV CRC. METHODS: We performed a systematic review, through PubMed and EMBASE, of all published studies exploring the efficacy of fluoropyrimidines + oxaliplatin + B-based chemotherapy as first-line chemotherapy in advanced CRC patients. Pooled estimates of the response rates, weighted medians of progression-free survival, and overall survival from all FOLFOX + B and XELOX + B arms were calculated. RESULTS: A total of 25 studies were retrieved, with a total of 7878 patients. Overall, the pooled response rates (n=20 publications) was 49.1%. The median progression-free survival and overall survival (n=21 and 22 publications, respectively) were 10.3 and 23.7 months, respectively. The pooled median rate of surgical resection of metastases (n=13 publications) was 14%. CONCLUSIONS: XELOX + B and FOLFOX + B are active combinations as first-line treatment of advanced CRC. The efficacy is confirmed for the first time from this pooled analysis of 25 trials. Both the XELOX + B and the FOLFOX + B arms represent 2 of the cornerstone combinations when B is used as first-line therapy.

Early tumour shrinkage as a prognostic factor and surrogate end-point in colorectal cancer: a systematic review and pooled-analysis.

PURPOSE: Early tumour shrinkage (ETS), defined as a reduction of at least 20% in tumour size at first reassessment, has been recently investigated retrospectively in first-line trials of metastatic colorectal cancer (CRC), and appears to be associated with better outcomes. We have performed a systematic review and meta-analysis of published trials to evaluate the prognostic value of ETS in CRC in terms of overall survival (OS) and progression-free survival (PFS). MATERIAL AND METHODS: An electronic search of the PubMed, SCOPUS, EMBASE, the Web of Science, and the Cochrane Central Register of Controlled Trial databases identified trials that compared outcomes of patients with or without ETS during first-line chemotherapy for metastatic CRC. The OS, reported as a hazard ratio (HR) with a 95% confidence interval (CI), was the primary outcome measure; the correlation coefficient (R) between ETS with median OS was also estimated. RESULTS: Twenty-one trials from 10 publications were analysed. Overall, patients with ETS were associated with a better OS (HR, 0.58; 95% CI, 0.53 to 0.64; P<0.00001) and PFS (HR, 0.57; 95% CI, 0.47-0.69; P<0.00001) compared with patients who were early non-responders. However, ETS was poorly correlated with OS in terms of surrogacy (R=0.37; 95% CI - 0.31-0.78; P=0.28). CONCLUSIONS: ETS is a good prognostic factor but an inappropriate surrogate for predicting outcome in CRC patients. These findings support ETS as prognostic tool in ascertaining earlier non-responders; however, its role as a surrogate end-point deserves further evaluation.