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Considering clinical benefits of new combination therapies for metastatic renal-cell carcinoma (mRCC), this study aims to calculate the number needed to treat (NTT) and the cost of preventing an event (COPE) for pembrolizumab plus axitinib (P + A), and nivolumab plus ipilimumab (N + I) as first-line treatments, from the Brazilian private perspective. Overall survival (OS) and progression-free survival (PFS) data for intermediate- and poor-risk groups were obtained from KEYNOTE-426 and CHECKMATE-214 trials for P + A and N + I, respectively, versus sunitinib as mRCC first-line treatment. Considering a 12-month time horizon, 6 patients should be treated with P + A to prevent one death with sunitinib use, resulting in a COPE of 3,893,903 BRL. Using N + I, NNT for 12-month OS rate was 13 compared to sunitinib, with a COPE of 6,357,965 BRL. Regarding PFS data, NNT was also 6 when comparing P + A versus sunitinib, with an estimated COPE of 3,893,903 BRL. Estimated NNT was 20 comparing N + I and sunitinib, resulting in a COPE of 10,172,744 BRL. Cost differences between two treatment options, reached more than 6 million BRL for PFS, and 2 million BRL for OS. At the 12-month landmark, P + A suggests better economic scenario versus N + I as first-line mRCC treatment option for intermediate- and poor-risk groups, through an indirect comparison using sunitinib as a common comparator.

680 Background: To perform a systematic review and meta-analysis of all randomized controlled trials (RCTs) comparing the efficacy of adjuvant VEGFRi in locally advanced, non-metastatic clear renal-cell carcinoma (RCC). Methods:Several databases were searched, including MEDLINE, EMBASE, LILACS, and CENTRAL. We included studies that compared the addition of VEGFRi versus placebo, after nephrectomy. Analyzed endpoints were overall survival (OS) and disease-free survival (DFS). The data extracted from the studies were combined by using Hazard Ratio (HR) or Risk Ratio (RR) with their corresponding Confidence Intervals of 95% (CI95%). Results: Overall, 121 references were identified and screened. The final analysis included 5 trials (S-TRAC, ATLAS, ASSURE, PROTECT and SORCE) comprising 6,128 patients that underwent previous nephrectomy for RCC. The DFS was similar in patients who received VEGFRi (fixed effect: HR=0.94, CI95%=0.87 to 1.03; p=0.19), with no heterogeneity (Chi2 = 4.33, df = 5 (P=0.50); I2 = 0%). Overall survival also was not statistically better in patients who received VEGFR inhibitors (HR=1.01, CI95%=0.90 to 1.15; p=0.84), with no heterogeneity (Chi2= 3.57, df = 5 (P=0.61); I2 = 0%). In the final combined analysis of the higher-risk disease group (pT3, pT4, or N+ disease), patients who received VEGFRi had a longer DFS (fixed effect: HR=0.85, CI95%=0.74 to 0.97; p=0.02), with no heterogeneity (Chi2 = 2.46, df = 3 (P=0.48); I2 = 0%). Overall survival was not statistically different for these higher-risk disease patients (fixed effect: HR=0.93, CI95%=0.74 to 1.16; p=0.5). Conclusions: This is the first meta-analysis including the five available RCTs in the literature (the previous meta-analysis reviewed only four), comparing adjuvant VEGFRi versus placebo in patients submitted to nephrectomy with a locally advanced, non-metastatic RCC. Adjuvant VEGFRi did not increase the OS in this group of patients. Amodest benefit of DFS with the use of adjuvant VEGFR inhibitors was restricted to patients with the highest risk of relapse.

366 Background: To perform a systematic review and meta-analysis of all randomized controlled trials (RCTs) comparing efficacy of adjuvant radiotherapy (AR) versus expectant management (EM) in men who undergo radical prostatectomy for localized prostate cancer (CaP). Methods: To perform this review and meta-analysis,several databases were searched, including MEDLINE, EMBASE, LILACS, and CENTRAL. We included all the studies that compared AR versus EM after radical surgery for CaP. The primary endpoints analyzed were biochemical progression-free survival (bPFS), metastasis-free survival (MPFS), prostate cancer-specific survival (CSS), overall survival (OS) and side effects. The data extracted from the studies were combined by using the Hazard Ratio (HR) or Risk Ratio (RR) with their corresponding Confidence Intervals of 95% (CI95%). Results: Overall, 68 studies were identified and screened. The final analysis included 7 trials (EORTC 22911, SWOG 8794, ARO 96-02/AUO AP 09/95, RAVES, FINNISH, GETUG-AFU 17 and RADICALS-RT) comprising 4,221 patients. The bPFS was higher in patients who received AR (fixed effect: HR = 0.58, CI95% = 0.52 to 0.66; p < 0.00001) but with significant heterogeneity (Chi2 = 40.34, df = 6 (P < 0.00001); I2 = 85%). We performed a random-effect model analysis to better explore this heterogeneity: in this analysis, the result remained in favor of AR (random effect: HR = 0.64, CI95% = 0.45 to 0.90; p = 0.01). The MPFS also was higher in patients who received AR (HR = 0.77, CI95% = 0.65 to 0.91; p = 0.002). The CSS and OS were not statistically different in patients with or without adjuvant radiotherapy (HR = 0.79, CI95% = 0.47 to 1.32; p = 0.36 and HR = 0.92, CI95% = 0.77 to 1.11; p = 0.38, respectively). The incidence of adverse events (gastrointestinal and genitourinary) were higher in the AR group. Conclusions: This is the first meta-analysis including the seven available RCTs in the literature (the previous meta-analysis reviewed only three), comparing adjuvant radiotherapy versus expectant management following radical prostatectomy for CaP. Adjuvant radiotherapy statistically increased the bPFS and MPFS, but did not have an impact on the OS or CSS.

Objective To perform a systematic review and meta-analysis of randomized controlled trials that compared the efficacy of targeted therapy to conventional chemotherapy (CT) in patients with metastatic triple-negative breast cancer (TNBC). Methods Several databases were searched, including Medline, Embase, LILACS, and CENTRAL. The primary end point was progression-free survival (PFS). We performed a meta-analysis of the published data. The results are expressed as hazard ratio (HR) or risk ratio, with their corresponding 95% confidence intervals (95% CIs). Results The final analysis included twelve trials comprising 2,054 patients with TNBC, which compared conventional CT alone against CT combined with targeted therapy (bevacizumab [Bev], sorafenib [Sor], cetuximab, lapatinib, and iniparib). PFS was superior in previously untreated patients with TNBC who received Bev plus CT compared to CT alone (fixed effect, HR 0.62, 95% CI 0.51–0.75; P

BACKGROUND This paper reports a systematic review and meta-analysis of all randomized controlled trials comparing the efficacy of lapatinib plus chemotherapy or endocrine therapy (CET) versus CET alone in human epidermal growth factor receptor 2-overexpressing (HER-2+) locally advanced or metastatic breast cancer. METHODS Several databases were searched, including MEDLINE, EMBASE, LILACS, and CENTRAL. The primary endpoints were progression-free survival and overall survival. The side effects of each treatment were analyzed. The data extracted from the studies were combined by using the hazard ratio or risk ratio with their corresponding 95% confidence interval (CI). RESULTS A total of 113 references were identified and screened. The final analysis included four trials comprising 1,073 patients with HER-2+. The overall response rate was higher in patients who received the combination of CET plus lapatinib (risk ratio 0.78; 95% CI 0.71-0.85; P < 0.00001) but with significant heterogeneity (χ(2) = 15.61, df = 3; P = 0.001; I(2) = 81%). This result remained favorable to the use of lapatinib when a random-effects model analysis was performed (risk ratio 0.76; 95% CI 0.62-0.94; P = 0.01). Progression-free survival was also higher in patients who received CET plus lapatinib (hazard ratio 0.57; 95% CI 0.49-0.66; P < 0.00001) with no heterogeneity detected on this analysis (χ(2) = 3.05; df = 3; P = 0.38; I(2) = 1%). Overall survival was significantly longer in patients who received CET plus lapatinib (hazard ratio 0.80; 95% CI 0.69-0.92; P = 0.002) without heterogeneity on this analysis (χ(2) = 1.26; df = 3; P = 0.74; I(2) = 0%). Regarding adverse events and severe toxicities (grade ≥3), the group receiving CET plus lapatinib had higher rates of neutropenia (risk ratio 2.08; 95% CI 1.64-2.62; P < 0.00001), diarrhea (risk ratio 4.82; 95% CI 3.14-7.41; P < 0.00001), and rash (risk ratio 8.03; 95% CI 2.46-26.23; P = 0.0006). CONCLUSION The combination of CET plus lapatinib increased the overall response rate, progression-free survival, and overall survival in patients with HER-2+ locally advanced or metastatic breast cancer.

Tobias Engel Ayer Botrel,1 Otávio Clark,1 Antônio Carlos Lima Pompeo,2 Francisco Flávio Horta Bretas,2 Marcus Vinicius Sadi,2 Ubirajara Ferreira,2 Rodolfo Borges dos Reis21CoBEU and Evidencias, 2Comitê Brasileiro de Estudos em Uro-Oncologia – CoBEU, BrazilBackground: The purpose of this work was to conduct a systematic review and meta-analysis of all randomized controlled trials comparing the efficacy and side effect profile of hypofractionated versus conventional external-beam radiation therapy for prostate cancer.Methods: Several databases were searched, including Medline, EmBase, LiLACS, and Central. The endpoints were freedom from biochemical failure and side effects. We performed a meta-analysis of the published data. The results are expressed as the hazard ratio (HR) or risk ratio (RR), with the corresponding 95% confidence interval (CI).Results: The final analysis included nine trials comprising 2702 patients. Freedom from biochemical failure was reported in only three studies and was similar in patients who received hypofractionated or conventional radiotherapy (fixed effect, HR 1.03, 95% CI 0.88–1.20; P = 0.75), with heterogeneity [χ2 = 15.32, df = 2 (P = 0.0005); I2 = 87%]. The incidence of acute adverse gastrointestinal events was higher in the hypofractionated group (fixed effect, RR 2.02, 95% CI 1.45–2.81; P < 0.0001). We also found moderate heterogeneity on this analysis [χ2 = 7.47, df = 5 (P = 0.19); I2 = 33%]. Acute genitourinary toxicity was similar among the groups (fixed effect, RR 1.19, 95% CI 0.95–1.49; P = 0.13), with moderate heterogeneity [χ2 = 5.83, df = 4 (P = 0.21); I2 = 31%]. The incidence of all late adverse events was the same in both groups (fixed effect, gastrointestinal toxicity, RR 1.17, 95% CI 0.79–1.72, P = 0.44; and acute genitourinary toxicity, RR 1.16, 95% CI 0.80–1.68, P = 0.44).Conclusion: Hypofractionated radiotherapy in localized prostate cancer was not superior to conventional radiotherapy and showed higher acute gastrointestinal toxicity in this meta-analysis. Because the number of published studies is still small, future assessments should be conducted to clarify better the true role of hypofractionated radiotherapy in patients with prostate cancer.Keywords: hypofractionated, radiotherapy, prostate cancer, systematic review, acute radiation effects

Objective Prostate cancer is the most common nonskin cancer and second most common cause of cancer mortality in older men in the United States (USA) and Western Europe. Androgen-deprivation therapy alone (ADT) remains the first line of treatment in most cases, for metastatic disease. We performed a systematic review and meta-analysis of all randomized controlled trials (RCT) that compared the efficacy and adverse events profile of a chemohormonal therapy (ADT ± docetaxel) for metastatic hormone-naive prostate cancer (mHNPC). Methods Several databases were searched, including MEDLINE, EMBASE, LILACS, and CENTRAL. The primary endpoint was overall survival. Data extracted from the studies were combined by using the hazard ratio (HR) or risk ratio (RR) with their corresponding 95% confidence intervals (95% CI). Results The final analysis included 3 trials comprising 2,264 patients (mHNPC). Patients who received the chemohormonal therapy had a longer clinical progression-free survival interval (HR = 0.64; 95% CI: 0.55 to 0.75; p

Background Febrile neutropenia is a frequent adverse event experienced by people with cancer who are undergoing chemotherapy, and is a potentially life-threatening situation. The current treatment is supportive care plus antibiotics. Colony-stimulating factors (CSFs), such as granulocyte-CSF (G-CSF) and granulocyte-macrophage CSF (GM-CSF), are cytokines that stimulate and accelerate the production of one or more cell lines in the bone marrow. Clinical trials have addressed the question of whether the addition of a CSF to antibiotics could improve outcomes in individuals diagnosed with febrile neutropenia. However, the results of these trials are conflicting. Objectives To evaluate the safety and efficacy of adding G-CSF or GM-CSF to standard treatment (antibiotics) when treating chemotherapy-induced febrile neutropenia in individuals diagnosed with cancer. Search methods We conducted the search in March 2014 and covered the major electronic databases: the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, LILACS, and SCI. We contacted experts in hematology and oncology and also scanned the citations from the relevant articles. In addition, we also searched for economic evaluations via MEDLINE(R) In-Process & Other Non-Indexed Citations, Embase, CENTRAL and NHS Economic Evaluation Database in May 2015 to support a Brief Economic Commentary (BEC). Selection criteria We searched for randomized controlled trials (RCTs) and economic evaluations that compared CSF plus antibiotics versus antibiotics alone for the treatment of chemotherapy-induced febrile neutropenia in adults and children. Data collection and analysis We used the standard methodological procedures expected by The Cochrane Collaboration. We performed meta-analysis of the selected studies using Review Manager 5 software. Main results Fourteen RCTs (15 comparisons) including a total of 1553 participants addressing the role of CSF plus antibiotics in febrile neutropenia were included. Overall mortality was not improved by the use of CSF plus antibiotics versus antibiotics alone (hazard ratio (HR) 0.74 (95% confidence interval (CI) 0.47 to 1.16) P = 0.19; 13 RCTs; 1335 participants; low quality evidence). A similar finding was seen for infection-related mortality (HR 0.75 (95% CI 0.47 to 1.20) P = 0.23; 10 RCTs; 897 participants; low quality evidence). Individuals who received CSF plus antibiotics were less likely to be hospitalized for more than 10 days (risk ratio (RR) 0.65 (95% CI 0.44 to 0.95) P = 0.03; 8 RCTs; 1221 participants; low quality evidence) and had more number of participants with a more faster neutrophil recovery (RR 0.52 (95% CI 0.34 to 0.81) P = 0.004; 5 RCTs; 794 participants; moderate quality evidence) than those treated with antibiotics alone. Similarly, participants receiving CSF plus antibiotics had shorter duration of neutropenia (standardized mean difference (SMD) -1.70 (95% CI -2.65 to -0.76) P = 0.0004; 9 RCTs; 1135 participants; moderate quality evidence), faster recovery from fever (SMD -0.49 (95% CI -0.90 to -0.09) P value = 0.02; 9 RCTs; 966 participants; moderate quality evidence) and shorter duration of antibiotics use (SMD -1.50 (95% CI -2.83 to -0.18) P = 0.03; 3 RCTs; 457 participants; low quality evidence) compared with participants receiving antibiotics alone. We found no significant difference in the incidence of deep venous thromboembolism (RR 1.68 (95% CI 0.72 to 3.93) P = 0.23; 4 RCTs; 389 participants; low quality evidence) in individuals treated with CSF plus antibiotics compared with those treated with antibiotics alone. We found higher incidence of bone or joint pain or flu-like symptoms (RR 1.59 (95% CI 1.04 to 2.42) P = 0.03; 6 RCTs; 622 participants; low quality evidence) in individuals treated with CSF plus antibiotics compared with those treated with antibiotics alone. Overall, the methodological quality of studies was moderate to low across different outcomes. The main reasons to downgrade the quality of evidence were inconsistency across the included studies and imprecision of results. No full economic evaluations were identified. Several of the included RCTs identified economic benefits regarding a reduction in overall length of stay attributable to the use of CSF plus antibiotics, however they fell short of undertaking a full economic evaluation. Authors' conclusions The use of a CSF plus antibiotics in individuals with chemotherapy-induced febrile neutropenia had no effect on overall mortality, but reduced the amount of time participants spent in hospital and improved their ability to achieve neutrophil recovery. It was not clear whether CSF plus antibiotics had an effect on infection-related mortality. Participants receiving CSFs had shorter duration of neutropenia, faster recovery from fever and shorter duration of antibiotics use. The current scarcity of relevant economic evaluations highlights an evidence gap and the need for further research fully explore the cost-effectiveness of these treatment alternatives.

Objective To perform a systematic review and meta-analysis of all randomized controlled trials comparing the efficacy of Sipuleucel-T versus placebo for asymptomatic or minimally symptomatic metastatic castration-refractory prostate cancer (mCRPC). Materials ans Methods Several databases were searched, including MEDLINE, EMBASE, LILACS, and CENTRAL. The endpoints were overall survival (OS), time to progression (TTP) and side effects. We performed a meta-analysis (MA) of the published data. The results are expressed as Hazard Ratio (HR) or Risk Ratio (RR), with their corresponding 95% confidence intervals (CI 95%). Results The final analysis included 3 trials comprising 737 patients. The TTP was similar in patients who received Sipuleucel-T or placebo (fixed effect: HR = 0.89; CI 95% = 0.75 to 1.05; p = 0.16), with no heterogeneity detected on this analysis (Chi2 = 2.14, df = 2 (P = 0.34); I2 = 6%). The results showed a higher overall survival in patients treated with Sipuleucel-T (fixed effect: HR = 0.74; CI 95% = 0.61 to 0.89; p = 0.001; NNT = 3). We found no heterogeneity on this analysis either (Chi2 = 1.46, df = 2 (P = 0.48); I2 = 0%). The incidence of adverse events (grade > 3) was the same in both groups. Conclusion Sipuleucel-T prolongs overall survival in patients with asymptomatic or minimally symptomatic mCRPC.

To perform a systematic review and meta-analysis of all randomized controlled trials comparing the efficacy of chemotherapy (CT) plus Bevacizumab (Bev) versus CT alone in previously untreated locally advanced or metastatic non-small cell lung cancer (NSCLC).Several databases were searched, including MEDLINE, EMBASE, LILACS, and CENTRAL. The endpoints were overall survival (OS), progression-free survival (PFS) and side effects. We performed a meta-analysis (MA) of the published data, using a fixed effects model and an additional random effects model, when applicable. The results of the MA are expressed as hazard ratio (HR) or risk ratio (RR), with their corresponding 95% confidence intervals (CI95%). We analyzed the use of Bev in the doses of 7.5 mg/kg and 15 mg/kg.The final analysis included 4 trials, comprising 2200 patients. The response rate was higher in patients who received the combination of CT plus Bev 7.5 mg/kg (RR=0.58; CI95%=0.46-0.74; p0.00001) and Bev 15 mg/kg (RR=0.53; CI95%=0.45-0.63; p0.00001) with moderate heterogeneity at dose of 15 mg/kg (Chi(2)=4.30, df=3 (P=0.23); I(2)=30%). The PFS length was longer in patients who received CT plus Bev 7.5 mg/kg (HR=0.78, CI95%=0.68-0.90; p=0.0005) and Bev 15 mg/kg (HR=0.72, CI95%=0.65-0.80; p0.00001) with moderate heterogeneity (Bev 7.5 mg/kg: Chi(2)=1.43, df=1 (P=0.23); I(2)=30% and Bev 15 mg/kg: Chi(2)=7.43, df=3 (P=0.06); I(2)=60%). Differences in these end points remained in favor of CT plus Bev when made the analysis by random-effects model. Overall survival was longer in patients who received CT plus Bev 15 mg/kg (HR=0.89, CI95%=0.80-1.00; p=0.04), with moderate heterogeneity (Chi(2)=5.09, df=3 (P=0.17); I(2)=41%). The random-effects model analysis for this endpoint did not confirmed the difference seen in the fixed effects model analysis (HR=0.90, CI95%=0.76-1.07; p=0.23). Severe haematologic toxicities (grade3), neutropenia and febrile neutropenia were more common among the patients that received Bev.The combination of CT plus Bev increased the response rate and progression-free survival of patients with NSCLC. With respect to overall survival the benefits of Bev remains uncertain.

Background Colorectal cancer (CRC) is the fourth most frequently diagnosed cancer and the second leading cause of neoplasm-related death in the United States. Several studies analyzed the efficacy of bevacizumab combined with different chemotherapy regimens consisting on drugs such as 5-FU, capecitabine, irinotecan and oxaliplatin. This systematic review aims to evaluate the effectiveness and safety of chemotherapy plus bevacizumab versus chemotherapy alone in patients with previously untreated advanced or metastatic colorectal cancer (mCRC). Methods Several databases were searched, including MEDLINE, EMBASE, LILACS, and CENTRAL. The primary endpoints were overall survival and progression-free survival. Data extracted from the studies were combined by using hazard ratio (HR) or risk ratio (RR) with their corresponding 95 % confidence intervals (95 % CI). Results The final analysis included 9 trials comprising 3,914 patients. Patients who received the combined treatment (chemotherapy + bevacizumab) had higher response rates (RR = 0.89; 95 % CI: 0.82 to 0.96; p = 0.003) with heterogeneity, higher progression-free survival (HR = 0.69; 95 % CI: 0.63 to 0.75; p