Lucas Vieira dos Santos

Neurokinin-1 Receptor Antagonists for Chemotherapy-Induced Nausea and Vomiting: A Systematic Review

BACKGROUND The addition of neurokinin-1 receptor (NK1R) antagonists to antiemetic regimens has substantially reduced chemotherapy-induced nausea and vomiting (CINV). We sought to systematically review the overall impact of NK1R antagonists on CINV prevention. METHODS We systematically searched the MEDLINE, EMBASE, and CENTRAL databases, and meeting proceedings for randomized controlled trials (RCTs) that evaluated NK1R antagonists plus standard antiemetic therapy for CINV prevention. Complete response (CR) to therapy was defined as the absence of emesis and the absence of rescue therapy. The endpoints were defined as CR in the overall phase (during the first 120 hours of chemotherapy), CR in the acute phase (first 24 hours), and the delayed phase (24-120 hours) after chemotherapy, nausea, and toxicity. Subgroup analyses evaluated the type of NK1R antagonist used, the emetogenic potential of the chemotherapy regimen, and prolonged use of 5-HT3 (serotonin) receptor antagonists, a class of standard antiemetic agents. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using a random-effects model. Statistical tests for heterogeneity were one-sided; statistical tests for effect estimates and publication bias were two-sided. RESULTS Seventeen trials (8740 patients) were included in this analysis. NK1R antagonists increased the CR rate in the overall phase from 54% to 72% (OR = 0.51, 95% CI = 0.46 to 0.57, P < .001). CR and nausea were improved in all phases and subgroups. The expected side effects from NK1R antagonists did not statistically significantly differ from previous reports; however, this analysis suggests that the incidence of severe infection increased from 2% to 6% in the NK1R antagonist group (three RCTs with a total of 1480 patients; OR = 3.10; 95% CI = 1.69 to 5.67, P < .001). CONCLUSIONS NK1R antagonists increased CINV control in the acute, delayed, and overall phases. They are effective for both moderately and highly emetogenic chemotherapy regimens. Their use might be associated with increased infection rates; however, additional appraisal of specific data from RCTs is needed.

Optimal duration of first-line chemotherapy for advanced non-small cell lung cancer: a systematic review with meta-analysis

BACKGROUND The optimal duration of first-line chemotherapy for advanced non-small cell lung cancer (NSCLC) has been a matter for debate for nearly 20 years. In order to elucidate this issue, a meta-analysis comparing the different durations of same treatments was performed. METHODS We searched for all published randomised controlled trials (RCTs) comparing different durations of first-line treatment of advanced NSCLC. The MEDLINE, EMBASE, LILACS and CENTRAL databases were searched for RCTs comparing a defined number of cycles of chemotherapy versus continuing treatment until disease progression, or a defined number of cycles versus a higher number of cycles of the same chemotherapy. Trials including biological agents were excluded. RESULTS Seven trials that included 1559 patients were analysed. Treatment for more than 4 cycles was associated with a non-statistically significant decrease in the hazard of mortality relative to shorter treatment (hazard ratio (HR)=0.97; 95% confidence interval (CI)=0.84-1.11; P=.65). In those treated with third-generation chemotherapy through the whole study time, treatment for more than 4 cycles was associated with a non-statistically significant increase in mortality (HR=1.08; 95% CI=0.90-1.28; P=.28). Patients receiving more chemotherapy had significant longer progression-free survival (HR=.75; 95% CI=0.60-0.85; P<0.0001) than the group with shorter duration of treatment. In an intent-to-treat analysis, there was no difference in the overall response rate between the groups (odds ratio (OR)=0.78; 95% CI=0.60-1.01; P=.96). Longer treatment was associated with more severe leucopaenia but with no significant increase in non-haematological toxicities. CONCLUSIONS In patients with advanced NSCLC the use of more than 4 cycles of first-line chemotherapy with third-generation regimens significantly increases progression-free survival but not overall survival and is associated with higher incidence of adverse events. There is no evidence to support continuous chemotherapy until progression in patients with lung cancer.

Camptothecins Compared with Etoposide in Combination with Platinum Analog in Extensive Stage Small Cell Lung Cancer: Systematic Review with Meta-Analysis

Introduction: Superiority of camptothecin regimens over etoposide—both combined with platinum analogs—in extensive disease small cell lung cancer has been a matter of debate with contradictory findings in randomized trials. A systematic review was sought to elucidate this issue. Methods: Randomized controlled trials comparing first-line camptothecin-platinum doublets versus etoposide-platinum doublets in patients with extensive disease small cell lung cancer were searched in MEDLINE, EMBASE, LILACS, and CENTRAL databases, European Society of Medical Oncology, American Society of Clinical Oncology, and International Association for the Study of Lung Cancer meeting sites. Meta-analyses were performed using fixed-effects model. Subgroup analyses were undertaken comparing each type of camptothecin to etoposide-based regimens. The outcomes of interest were overall survival (OS), progression-free survival (PFS), response rate (RR), and toxicities. Results: Eight studies (3086 patients) were included. The meta-analysis of topotecan regimens (TP) was not reliable due to impending heterogeneity. Meta-analysis of trials testing irinotecan combinations (IP) versus etoposide regimens (EP; 1561 patients) stated an OS improvement in favor of IP arm, though with considerable heterogeneity, whose origin seemed to be a Japanese trial. In the analyses without that study (1407 patients left), IP brought a significant improvement in OS (hazard ratio = 0.87; 95% confidence interval 0.78–0.97; p = 0.02; I2 = 0). IP also increased PFS (hazard ratio = 0.83; 95% confidence interval 0.73–0.95; p = 0.006; I2 = 0%). There was no impact in RR (absolute RR 56% with IP; 53% with EP; p = 0.17). IP caused more diarrhea (p < 0.0001) but less hematological toxicities (p < 0.001) than EP. Conclusions: The present meta-analysis demonstrates statistically significant OS and PFS benefits of IP over EP regimens in western and eastern patients. Specific characteristics of safety profile should be taken into account when administrating IP chemotherapy.

Is there a role for consolidative radiotherapy in the treatment of aggressive and localized Non-Hodgkin Lymphoma? A systematic review with meta-analysis

BackgroundChemotherapy is the mainstay of non-Hodgkin lymphoma (NHL) treatment. Based on expert opinion, the use of radiotherapy (RT) is currently preferred in some institutions as consolidative treatment for patients with localized disease. The lack of conclusive data coming from conflicting studies about the impact of treatment demands a systematic review, which could provide the most reliable assessment for clinical decision-making. We evaluate the addition of RT post-CT, for aggressive and localized NHL (ALNHL).MethodsRandomized controlled trials (RCT) that evaluated chemotherapy alone versus chemotherapy plus RT were searched in databases. The outcomes were overall survival (OS), progression-free survival (PFS), overall response rate (ORR) and toxicity. Risk ratio (RR) and hazard ratio (HR) with their respective 95% confidence intervals (CI) were calculated using a fized-effect model.ResultsFour trials (1,796 patients) met the inclusion criteria. All trials tested the use of RT after systemic therapy comprising anthracycline-based chemotherapy. This systematic review showed that RT enhances PFS after chemotherapy (hazard ratio [HR] 0.81; 95% CI 0.67-0.98; p = 0.03), with no impact on ORR and OS. Some heterogeneity between trials could limit the conclusions about OS. Toxicity data could not be pooled due to differences in reporting adverse events.ConclusionsThis systematic review with meta-analysis shows no improvement in survival when adding RT to systemic therapy for ALNHL. Our conclusions are limited by the available data. Further evaluations of new RT technologies and its association with biologic agents are needed.

Independent Radiologic Review in Metastatic Colorectal Cancer: Systematic Review and Meta-Analysis

PURPOSE To perform a meta-analysis addressing evaluation bias in local radiologic assessment (LRA) of lesions when compared with independent radiologic review (IRR) in randomized controlled trials (RCTs) testing chemotherapy for metastatic colorectal cancer (CRC). MATERIALS AND METHODS MEDLINE, EMBASE, ClinicalTrials.gov, the Cochrane Library, and Web sites for major medical meetings were searched for RCTs of chemotherapy for metastatic CRC that reported response evaluation by both LRA and IRR. The risk ratios (RRs) of response in the experimental (RR(exp)) and control (RR(cont)) arms were calculated (response rate in LRA divided by response rate in IRR) for each selected study. The ratio of RR of response was calculated (RR of response of LRA divided by RR of response of IRR). The random-effects model was applied. Meta-regression was used to examine the effect of study characteristics on outcomes. RESULTS LRA and IRR results were concordant (13 studies; 7742 patients; ratio of RR of response = 0.97; 95% confidence interval [95% CI]: 0.90, 1.04; P = .35). However, LRA overestimated tumor response independently of therapy allocation (interaction test, P = .81) both in control (RR(cont), 1.163; 95% CI: 1.086, 1.246; P < .001) and experimental (RR(exp), 1.156; 95% CI: 1.093, 1.222; P < .001) therapies. Meta-regression did not show any effect of trial characteristics on effects. CONCLUSION LRA yields higher response rates in RCTs testing chemotherapy for metastatic CRC, although there was no sign of bias toward experimental therapy. The need for IRR to control evaluation bias must be reappraised.

Duration of Chemotherapy for Metastatic Non–Small-Cell Lung Cancer: More May Be Not Better

pared to best supportive care alone. 2 Trials fully published presented no gain in OS (hazard ratio [HR], 0.98; 95% CI, 0.90 to 1.07) while those presented in abstract format stated relevant gain in OS (HR, 0.79; 95% CI 0.69 to 0.91). The difference among these two groups (fully and partially published trials) cannot be overlooked (interaction P .01). Nevertheless, the main source of concern in this meta-analysis is the assumption that different therapeutic approaches were similar and could be polled. Seven trials continued all drugs used in first-line therapy, three maintained a single drug already used in first-line therapy (maintenance therapies) and three switched to a new single drug before progression (sequential therapy) in the longer therapy arms. Even though there was no relevant statistical heterogeneity, pooling all these types of trials caused an inconsistency beyond numbers. Is the use of docetaxel or pemetrexed after four cycles of platinum-based chemotherapy similar to maintaining a platinum-doublet up to six cycles? Can continuing vinorelbine after platinum doublet be considered equal to docetaxel after platinum doublets? Are six or more courses of platinum doublets better than four cycles? It is hardly believable that such specifics question could be answered by a single broad meta-analysis. Ideally, a systematic review must point to a specific direction, and this was not the case with the Soon et al metaanalysis. An appropriated answer to the optimal duration of first-line chemotherapy must be better defined. The meta-analysis presented by Soon et al 1 did not perform a straightforward comparison of duration of first-line therapy alone, it is confounded by major differences in treatment. The OS benefit identified (HR, 0.92; 95% CI 0.86 to 0.99) when all types of trials were combined merits a deeper discussion. We could speculate that not all therapeutic approaches (maintenance and sequential) contribute equally to this result. In fact, the inclusion of one large sequential trial 3 seemed to be capital for achieving this survival gain as the robust analysis pointed out. These consideration were all taken into account in other systematic review recently published. 4 This review had more restricts inclusion criteria: trials comparing early introduction of a different drug (sequential trials) were excluded to avoid confounding bias. These narrow inclusion criteria of the meta-analysis diminished the number of included trials and patients but provided an interesting clinical uniformity among trials. Prolonged use of third-generation doublets increased progressionfree survival (HR, 0.75; 95% CI, 0.65 to 0.85) but not OS (HR, 1.08; 95% CI 0.90 to 1.28). The conclusion was that three to four cycles of platinum-based doublets would provide similar benefit of longer platinum-doublets therapies with less toxicity.

Curative-Intent Surgery for Pancreatic Tumors: A Review of Procedures From the Brazilian National Health System

Purpose In Brazil, a country with major health access disparities, resource limitations make management of pancreatic cancer (PC) challenging. This study evaluated curative-intent surgery for PC in the Brazilian public health care system. Methods We collected data for PC surgical procedures with curative intent in Brazil’s public health care system (DATASUS) and from the demographic database. Costs, lengths of stay, number of perioperative deaths, and PC deaths were analyzed for each state and then associated with population, gross domestic product (GDP) per capita, and number of procedures. Results A total of 37,142 patients died as a result of PC in Brazil between 2008 and 2012. The number of deaths (per 100,000 person-years) was highest in the south and southeast regions. Mortality from PC had a positive association with the number of procedures and GDP per capita. Between January 2008 and July 2014, 3,386 procedures were performed, the majority (51.2%) in the southeast region. Four hundred ninety-three patients died, which translates to an inpatient mortality rate of 14.6%. The northern states had the highest perioperative mortality (mean, 25%). The number of procedures per 100,000 residents was higher in the southeast and south. Overall, cost tended to increase as the number of procedures or population increased. For fixed GDP per capita and population, cost tended to increase as the number of procedures increased, whereas for a fixed number of procedures and GDP per capita, cost tended to decrease as population increased. The mean length of hospital stay was 16.9 days, which was higher than in major international centers. Conclusion This study is the first to our knowledge to evaluate regional disparities in PC care in Brazil. Perioperative mortality was high in the public health care system. Regionalized policies that improve care are needed.

Important Clinical Findings for Chemotherapy-Induced Nausea and Vomiting: Commentary on Molassiotis et al.

In this issue, Molassiotis et al. report the predictors of chemotherapy-induced nausea and vomiting (CINV) in the largest prospective observational study to date. The impact of Multinational Association of Supportive Care in Cancer (MASCC) guideline compliance on CINV has been reported in a previous publication using the same data set. This well-conducted study found that female gender was not a key predictor of CINV. Three other predictors of CINV emerged and must be appraised by every physician involved in cancer care. Complete response in the first cycle of chemotherapy, as defined by the study, was a determinant factor for CINV in the following cycles. This suggests that complete response in the first cycle of chemotherapy may be a more important clinical goal. Second, factors related to the patients themselves, such as anticipatory nausea and prechemotherapy anxiety, were demonstrated for the first time in a prospective study to be important risk factors for CINV. This illustrates a possible role of behavioral and symptomatic therapy during treatment planning and before the start of chemotherapy.

Japanese patients equally likely to benefit from aprepitant for chemotherapy-induced nausea and vomiting prevention.

(Cancer Sci 2011; 102: 1112)

Cisplatin plus irinotecan in the treatment of gallbladder or biliary tract cancer: A randomized phase II trial (NCT01859728).

TPS485 Background: Gallbladder and biliary tract cancer (GBTC) have an aggressive behavior and gemcitabine-platinum chemotherapy emerged as the new standard of care for advanced or metastatic GBTC. Despite optimal management, prognosis is still poor. This randomized trial aims to compare irinotecan plus cisplatin versus gembitabine plus cisplatin in advanced or metastatic GBTC. Methods: Patients with biopsy-proven, chemo-naive, unresectable or metastatic carcinoma of GBTC (gallbladder, intrahepatic biliary tract, extrahepatic biliary tract, or ampulla of Vater), ECOG 0-2, measurable disease per RECIST 1.1, adequate organ function and written informed consent are stratified by ECOG (0 or 1 vs 2) and hematogenic metastases (yes vs no) and randomized to receive Irinotecan 65mg/m² D1 and D8 q21 days plus Cisplatin 60mg/m² D1 q 21 days (IP) or Gemcitabine 1000mg/m² D1 and D8 every 21 days plus cisplatin 25mg/m² D1 and D8 every 21 days (GC), until disease progression or unacceptable toxicity, with standard hydr...