A Phase II Basket Trial of Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors (DART SWOG 1609) in Patients with Nonpancreatic Neuroendocrine Tumors.

PURPOSE: Immune checkpoint blockade has improved outcomes across tumor types; little is known about the efficacy of these agents in rare tumors. We report the results of the (nonpancreatic) neuroendocrine neoplasm cohort of SWOG S1609 dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART). PATIENTS AND METHODS: We performed a prospective, open-label, multicenter phase II clinical trial of ipilimumab plus nivolumab across multiple rare tumor cohorts, with the (nonpancreatic) neuroendocrine cohort reported here. Response assessment by grade was not prespecified. The primary endpoint was overall response rate [ORR; RECIST v1.1; complete response (CR) and partial response (PR)]; secondary endpoints included progression-free survival (PFS), overall survival (OS), stable disease >6 months, and toxicity. RESULTS: Thirty-two eligible patients received therapy; 18 (56%) had high-grade disease. Most common primary sites were gastrointestinal (47%; N = 15) and lung (19%; N = 6). The overall ORR was 25% [95% confidence interval (CI) 13-64%; CR, 3%, N = 1; PR, 22%, N = 7]. Patients with high-grade neuroendocrine carcinoma had an ORR of 44% (8/18 patients) versus 0% in low/intermediate grade tumors (0/14 patients; P = 0.004). The 6-month PFS was 31% (95% CI, 19%-52%); median OS was 11 months (95% CI, 6-∞). The most common toxicities were hypothyroidism (31%), fatigue (28%), and nausea (28%), with alanine aminotransferase elevation (9%) as the most common grade 3/4 immune-related adverse event, and no grade 5 events. CONCLUSIONS: Ipilimumab plus nivolumab demonstrated a 44% ORR in patients with nonpancreatic high-grade neuroendocrine carcinoma, with 0% ORR in low/intermediate grade disease.

Efficacy of VDT PACE-like regimens in treatment of relapsed/refractory multiple myeloma.

Experience with intensive chemotherapy for relapsed/refractory multiple myeloma (RRMM) using VDT PACE regimen and its modifications (VDT PACE-like regimens: VPLRs) outside TOTAL THERAPY trials is limited. We analyzed the outcomes of 141 patients with RRMM who received VPLRs at our center between 2006 and 2017 in an intent-to-treat analysis. Median age was 59.7 years and 66.7% of patients were male. A median of 2.2 years (range 0.02-11.4) separated diagnosis of myeloma and inititation of VPLR. High-risk cytogenetics were present in 52.4% patients. Patients received a median of 4 (range 1-14) prior therapies, including stem cell transplant (SCT) in 66.7% patients. Ninety-five (67.4%) patients received VDT PACE, 20 (14.2%) patients received VD PACE and 26 (18.4%) patients received other VPLRs. Patients received a median of 1 cycle (range 1-9) of VPLR. We observed ≥ minimal response in 68.4%, ≥ partial response (PR) in 54.4% and ≥ very good PR in 10.3% patients. Median progression-free survival was 3.1 months (95% CI, 1.9-3.9) and median overall survival (OS) was 8.1 months (CI, 6.2-9.9). One-hundred and sixteen (82.3%) patients received some therapy after VPLR; 71 (61.2%) received systemic chemotherapy, while 45 (38.8%) underwent SCT. Median OS for those who received SCT after VPLR was 15.1 months (CI, 10.3-20.8). Age ≥ 60 years (hazard ratio [HR] 2.3 [CI, 1.4-3.7]; P = 0.0008) and R-ISS III stage (HR- 2.4 [CI, 1.3-4.0]; P = 0.003) predicted shorter OS in patients receiving VPLR. VPLRs are effective in heavily pre-treated RRMM. In fit patients, SCT can be used to consolidate the response to VPLR.

Biological agents in gastrointestinal cancers: adverse effects and their management.

Biological therapy comprises agents that by virtue of their unique mechanisms of action, are able to specifically incite a response against or target malignant cells. They differ from conventional chemotherapy with regard to mechanisms of action, indications and side effect profile. Biologic agents have revolutionized therapy for a number of malignancies. In the setting of gastrointestinal (GI) malignancies, agents targeting vascular endothelial growth factor (VEGF), human epidermal growth factor receptor 2 (Her2/Neu) and epidermal growth factor receptor (EGFR) have proven to be invaluable additions to chemotherapy. However, these agents bring with them a set of side effects attributable to their unique mechanisms of action. The anti VEGF agents-bevacizumab, aflibercept and ramucirumab, can result in renal and vascular complications such as hypertension, arterial thrombotic events (ATE), proteinuria and GI perforations. The anti EGFR agents classically cause dermatological toxicities, in addition to hypomagnesemia, which can be dose limiting for patients. Trastuzumab, a monoclonal antibody that targets Her2/Neu, is known to cause cardiotoxicity, especially when used with anthracyclines. Use of immunotherapy agents such as nivolumab is associated with the development immune related adverse events (irAEs). The use of these agents is expected to increase over the next few years and it is crucial that patients and practitioners are aware of their adverse effects and current management strategies. This review highlights the adverse events associated with the use of biologic and immunologic therapies in GI cancers, their incidence and current management strategies.

Premorbid body mass index and mortality in patients with lung cancer: A systematic review and meta-analysis.

OBJECTIVES: We aimed to assess the association between premorbid obesity, measured using body mass index (BMI) and lung cancer-related mortality, through a systematic review and meta-analysis. MATERIALS AND METHODS: Observational studies reporting statistical measures of association between premorbid BMI categories and lung cancer-related mortality were included in our study. We estimated hazard ratios (aHR) with 95% confidence intervals (CI), comparing lung cancer-related mortality across BMI categories. The main outcome measure was lung cancer-related mortality in obese (BMI≥30kg/m2) and overweight participants (BMI 25.0-29.9kg/m2), compared with normal BMI participants. RESULTS: We included 14 studies (including 2 pooled cohort studies) comprising 3,008,137 cancer-free participants at inception, reporting 28,592 lung cancer-related deaths. On meta-analysis, we observed a significantly lower lung cancer-related mortality in overweight (aHR, 0.76; 95% CI, 0.68-0.85) and obese (aHR, 0.68, 95% CI; 0.57-0.81) participants as compared to participants with normal BMI, with considerable heterogeneity; after excluding one study with large effect size, a more conservative and consistent association was observed between BMI and lung cancer-related mortality (overweight vs. normal BMI: aHR, 0.84; 95% CI, 0.79-0.90; obese vs. normal BMI: aHR, 0.81; 95% CI, 0.75-0.87), with moderate heterogeneity. Were similar in men vs. women, non-smokers vs. smokers, and Western vs Asia-Pacific populations. CONCLUSIONS: Based on meta-analysis, we observed an independent protective association between premorbid obesity and lung cancer-related mortality. This association was observed across sex, smoking status and geographic region. Further studies are needed to prospectively study this association.

Relationship Between Metformin Use and Recurrence and Survival in Patients With Resected Stage III Colon Cancer Receiving Adjuvant Chemotherapy: Results From North Central Cancer Treatment Group N0147 (Alliance).

BACKGROUND: Preclinical and epidemiological data suggest that metformin might have antineoplastic properties against colon cancer (CC). However, the effect of metformin use on patient survival in stage III CC after curative resection is unknown. The survival outcomes were comparable regardless of the duration of metformin use. PATIENTS AND METHODS: Before randomization to FOLFOX (folinic acid, 5-fluorouracil, oxaliplatin) with or without cetuximab, 1,958 patients with stage III CC enrolled in the N0147 study completed a questionnaire with information on diabetes mellitus (DM) and metformin use. Cox models were used to assess the association between metformin use and disease-free survival (DFS), overall survival (OS), and the time to recurrence (TTR), adjusting for clinical and/or pathological factors. RESULTS: Of the 1,958 patients, 1,691 (86%) reported no history of DM, 115 reported DM with metformin use (6%), and 152 reported DM without metformin use (8%). The adjuvant treatment arms were pooled, because metformin use showed homogeneous effects on outcomes across the two arms. Among the patients with DM (n = 267), DFS (adjusted hazard ratio [aHR], 0.90; 95% confidence interval [CI], 0.59-1.35; p = .60), OS (aHR, 0.99; 95% CI, 0.65-1.49; p = .95), and TTR (aHR, 0.87; 95% CI, 0.56-1.35; p = .53) were not different for the metformin users compared with the nonusers after adjusting for tumor and patient factors. The survival outcomes were comparable regardless of the duration of metformin use (<1, 1-5, 6-10, ≥11 years) before randomization (ptrend = .64 for DFS, ptrend = .84 for OS, and ptrend = .87 for TTR). No interaction effects were observed between metformin use and KRAS, BRAF mutation status, tumor site, T/N stage, gender, or age. CONCLUSIONS: Patients with stage III CC undergoing adjuvant chemotherapy who used metformin before the diagnosis of CC experienced DFS, OS, and TTR similar to those for non-DM patients and DM patients without metformin use. IMPLICATIONS FOR PRACTICE: The present study did not find any relationship between metformin use or its duration and disease-free survival, time to recurrence, and overall survival in a large cohort of patients with resected stage III colon cancer receiving adjuvant FOLFOX (folinic acid, fluorouracil, oxaliplatin)-based chemotherapy. This relationship was not modified by KRAS or BRAF mutation or DNA mismatch repair status. Metformin use did not increase or decrease the likelihood of chemotherapy-related grade 3 or higher adverse events.

Premorbid Obesity and Mortality in Patients With Pancreatic Cancer: A Systematic Review and Meta-analysis.

BACKGROUND & AIMS: Obesity is associated with an increased risk for pancreatic cancer, but it is unclear whether it affects mortality. We performed a systematic review and meta-analysis to assess the association between premorbid obesity and mortality from pancreatic cancer. METHODS: We performed a systematic search through January 2015 and identified studies of the association between premorbid obesity (at least 1 year prior to pancreatic cancer diagnosis) and pancreatic cancer-related mortality. We estimated summary adjusted hazard ratio (aHR) with 95% confidence interval (CI), comparing data from obese (body mass index [BMI] ≥30 kg/m(2)) and overweight subjects (BMI, 25.0-29.9 kg/m(2)) with those from individuals with a normal BMI (controls) by using random-effects model. RESULTS: We identified 13 studies (including 3 studies that pooled multiple cohorts); 5 studies included only patients with pancreatic cancer, whereas 8 studies evaluated pancreatic cancer-related mortality in cancer-free individuals at inception. In the meta-analysis, we observed increase in pancreatic cancer-related mortality among overweight (aHR, 1.06; 95% CI, 1.02-1.11; I(2) = 0) and obese individuals (aHR, 1.31; 95% CI, 1.20-1.42; I(2) = 43%), compared with controls; the association remained when we analyzed data from only subjects with pancreatic cancer. Each 1 kg/m(2) increase in BMI was associated with 10% increase in mortality (aHR, 1.10; 95% CI, 1.05-1.15) with minimal heterogeneity (I(2) = 0). In the subgroup analysis, obesity was associated with increased mortality in Western populations (11 studies; aHR, 1.32; 95% CI, 1.22-1.42) but not in Asia-Pacific populations (2 studies; aHR, 0.98; 95% CI, 0.76-1.27). CONCLUSIONS: In a systematic review and meta-analysis, we associated increasing level of obesity with increased mortality in patients with pancreatic cancer in Western but not Asia-Pacific populations. Strategies to reduce obesity-induced metabolic abnormalities might be developed to treat patients with pancreatic cancer.

Immune checkpoints and immunotherapy for colorectal cancer.

Colorectal cancer (CRC) remains one of the major causes of death worldwide, despite steady improvement in early detection and overall survival over the past decade. Current treatment paradigms, with chemotherapy and biologics, appear to have reached their maximum benefit. Immunotherapy, especially with checkpoint inhibitors, has shown considerable clinical benefit in various cancers, including mismatch-repair-deficient CRC. This has led to the planning and initiation of several clinical trials evaluating novel immunotherapy agents-as single agents, combinations and in conjunction with chemotherapy-in patients with CRC. This article reviews biological and preclinical data for checkpoint inhibitors and discusses various immunotherapy trials in CRC, as well as current efforts in CRC immunotherapy.

Prevalence, risk factors, and outcomes of interval colorectal cancers: a systematic review and meta-analysis.

OBJECTIVES: We performed meta-analysis to estimate pooled prevalence, risk factors, and outcomes of interval colorectal cancers (CRCs). METHODS: Systematic literature search through October 2013, identified population-based studies, reporting prevalence of interval CRCs (CRCs diagnosed within 6-36 months of colonoscopy). We estimated the pooled prevalence, patient, endoscopist, and tumor-related risk factors, as well as outcomes of interval CRCs, as compared with detected CRCs (CRCs diagnosed at or within 6 months of colonoscopy). RESULTS: Twelve studies reporting on 7,912 interval CRCs were included. Pooled prevalence of interval CRCs was 3.7% (95% confidence interval (CI)=2.8-4.9%). These cancers were 2.4 times more likely to arise in the proximal colon (6.5%; 95% CI=4.9-8.6%) as compared with distal colon (2.9%; 95% CI=2.0-4.2%). Patients with interval CRCs were older (age >65-70 years vs. <65-70 years: odds ratio (OR)=1.15; 95% CI=1.02-1.30), have more comorbidities (high Charlson comorbidity index: OR=2.00; 95% CI=1.77-2.27), and have diverticular disease (OR=4.25; 95% CI=2.58-7.00). There was a nonsignificant time trend of declining prevalence of interval CRCs from 4.8% in 1990s to 4.2% between 2000 and 2005 and 3.7% beyond 2005. Patients with interval CRCs were less likely to present at an advanced stage (OR=0.79; 95% CI=0.67-0.94), although there was no survival benefit. Considerable heterogeneity was observed in most of the analyses. CONCLUSIONS: Based on meta-analysis, approximately 1 in 27 CRCs are interval CRCs, although the confidence in these estimates is low because of the heterogeneity among the studies. These are more likely to arise in the proximal colon and are diagnosed in older patients, patients with comorbidities or diverticular disease.

Acid-suppressive medications and risk of oesophageal adenocarcinoma in patients with Barrett's oesophagus: a systematic review and meta-analysis.

BACKGROUND AND AIMS: Acid-suppressive medications, particularly proton pump inhibitors (PPIs), may decrease the risk of oesophageal adenocarcinoma (OAC) in patients with Barrett's oesophagus (BO). We performed a systematic review with meta-analysis of studies evaluating the association between acid-suppressive medications (PPIs and histamine receptor antagonists (H2RAs)) and risk of OAC or high-grade dysplasia (BO-HGD) in patients with BO. METHODS: We performed a systematic search of multiple electronic databases and conference proceedings up to June 2013 to identify studies reporting the association between use of acid-suppressive medications and risk of OAC and/or BO-HGD in patients with BO. Summary ORs with 95% CIs were estimated. RESULTS: We identified seven observational studies (2813 patients with BO, 317 cases of OAC or BO-HGD, 84.4% PPI users). On meta-analysis, PPI use was associated with a 71% reduction in risk of OAC and/or BO-HGD in patients with BO (adjusted OR 0.29; 95% CI 0.12 to 0.79). There was a trend towards a dose-response relationship with PPI use for >2-3 years protective against OAC or BO-HGD (three studies; PPI use >2-3 years vs <2-3 years: OR 0.45 (95% CI 0.19 to 1.06) vs 1.09 (0.47 to 2.56)). Considerable heterogeneity was observed. Two studies reported the association between H2RA use and risk of OAC and/or BO-HGD (1352 patients with BO, 156 cases of OAC, 25.4% on H2RAs), and both studies did not show a significant effect. CONCLUSIONS: Based on meta-analysis of observational studies, the use of PPIs is associated with a decreased risk of OAC and/or BO-HGD in patients with BO. None of the studies showed an increased risk of OAC. PPI use should be considered in BO, and chemopreventive trials of PPIs in patients with BO are warranted.

Chemopreventive strategies in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the third most common cause of death from cancer. The incidence and mortality of HCC are increasing in most Western countries as a result of an ageing cohort infected with chronic hepatitis C, and are expected to continue to rise as a consequence of the obesity epidemic. Chemopreventive strategies aimed at decreasing the risk or delaying the onset of HCC are needed. Universal immunization against HBV and antiviral therapy against HBV and HCV in patients with established disease has consistently been associated with reduced HCC risk, especially in patients who achieve sustained virologic response. However, the cost-effectiveness of antiviral therapy for primary HCC prevention is not known. Several commonly prescribed medications seem promising as chemopreventive agents against HCC, including statins, antidiabetic medications and aspirin. Dietary agents such as coffee, vitamin E and fish oil as well as phytochemicals might also be associated with reduced risk of HCC. Though randomized controlled trials are ideally needed to firmly establish efficacy, such chemoprevention trials are logistically and ethically challenging. Well-designed, prospective, population-based cohort studies might provide the best evidence for chemopreventive efficacy of these agents.

Antidiabetic medications and the risk of colorectal cancer in patients with diabetes mellitus: a systematic review and meta-analysis.

BACKGROUND: Antidiabetic medications (ADM) may modify colorectal cancer risk in patients with diabetes mellitus. We performed a systematic review and meta-analysis, evaluating the effect of metformin, thiazolidinediones (TZD), sulfonylureas, and insulin on colorectal cancer risk in diabetic patients. METHODS: We conducted a systematic search of multiple bibliographic databases, up to September 2012, for articles that evaluated exposure to metformin, TZD, sulfonylureas, and insulin, reported colorectal cancer risk in patients with diabetes mellitus, and reported OR or provided data for their estimation. Summary OR estimates with 95% confidence intervals (CI) were estimated using the random-effects model. RESULTS: Fifteen studies reporting 13,871 cases of colorectal cancer in 840,787 patients with diabetes mellitus were included. Meta-analysis of observational studies showed an 11% reduction in colorectal cancer risk associated with metformin use (n = 9 studies; OR, 0.89; 95% CI, 0.81-0.99), whereas TZD use was not associated with colorectal cancer risk (n = 5 studies; OR, 0.96; 95% CI, 0.87-1.05). Conversely, a trend toward higher colorectal cancer risk was observed with sulfonylurea (n = 7 studies; OR, 1.11; 95% CI, 0.97-1.26) and insulin (n = 9 studies; OR, 1.33; 95% CI, 0.91-1.94) use, although these associations were not statistically significant. There was considerable heterogeneity across studies, partly explained by study location and adjustment for concomitant use of other ADMs. Post-hoc analysis of randomized controlled trials did not reveal any significant association between ADM and colorectal cancer risk. CONCLUSIONS: Meta-analysis of published studies supports a protective association between metformin use and colorectal cancer risk in patients with diabetes mellitus. IMPACT: Clinical trials on the chemopreventive effect of metformin against colorectal cancer are warranted.

Statin a day keeps cancer at bay.

In addition to cholesterol reduction, statins, currently the most commonly prescribed drug in the world, have been shown to have anti-neoplastic and immunomodulatory effects. Several observational studies and meta-analyses have shown reduction in risk of multiple cancers. More recently there has been an increasing interest in the potential role of statins as adjuvant therapy after cancer diagnosis and in modifying cancer mortality. Although post-hoc analyses of randomized controlled trials of statins for cardiovascular outcomes have not shown reduction in the risk of cancer mortality with statin use, these studies lack sufficient power to detect a significant difference in cancer outcomes. Recently, in a Danish nationwide population-based cohort study, Nielsen et al showed a 15% reduction in all-cause and cancer-specific mortality in statin users as compared to non-users. Improved survival with statin exposure was seen in 13/27 cancer subtypes, including the 4 most common cancers - lung, prostate, colorectal and breast. In this commentary, we examine this important study, review its implications and limitations, and briefly discuss impact of other drugs like metformin and aspirin that also exhibit anti-neoplastic effects.

Anti-diabetic medications and the risk of hepatocellular cancer: a systematic review and meta-analysis.

Several preclinical and observational studies have shown that anti-diabetic medications (ADMs) can modify the risk of hepatocellular cancer (HCC) in patients with diabetes mellitus (DM). We performed a systematic review and meta-analyses of studies evaluating the effect of metformin, thiazolidinediones (TZDs), sulfonylureas, and/or insulin on the risk of HCC. We conducted a systematic search of Medline, EMBASE, and Web of Science up to August 2012. Studies were included if they (1) evaluated and clearly defined exposure to metformin, TZDs, sulfonylureas, and/or insulin, (2) reported HCC outcomes in patients with DM, and (3) reported relative risks or odds ratio (OR) or provided data for their estimation. Summary OR estimates with 95% confidence intervals (CIs) were estimated using the random-effects model. Ten studies reporting 22,650 cases of HCC in 334,307 patients with type 2 DM were included in the analysis. Meta-analysis of observational studies showed a 50% reduction in HCC incidence with metformin use (n=8 studies; OR 0.50, 95% CI 0.34-0.73), 62% and 161% increase in HCC incidence with sulfonylurea (n=8 studies; OR 1.62, 95% CI 1.16-2.24) or insulin use (n=7; OR 2.61, 95% CI 1.46-4.65), respectively. TZDs did not modify the risk of HCC (n=4; OR 0.54, 95% CI 0.28-1.02). There was considerable heterogeneity across studies, which was partly explained by study setting, location, and whether the studies adjusted for the concomitant use of other ADMs. Post-hoc analysis of randomized controlled trials did not reveal any significant association between ADM use and risk of HCC. ADMs may modify the risk of HCC in patients with DM, especially in the Western population. However, the effect of each individual agent should be interpreted with caution owing to inherent cancer-modifying effect of the comparator group.

Anti-diabetic medications and risk of pancreatic cancer in patients with diabetes mellitus: a systematic review and meta-analysis.

OBJECTIVES: Several preclinical and observational studies have shown that anti-diabetic medications (ADMs) may modify the risk of pancreatic cancer (PaC). We performed a systematic review and meta-analysis evaluating the effect of metformin, sulfonylureas (SUs), thiazolidinediones (TZDs), and insulin on the risk of PaC in patients with diabetes mellitus (DM). METHODS: We conducted a systematic search of Medline, EMBASE, and Web of Science, up to June 2012, and published abstracts from major gastroenterology and oncology meetings from 2003 to 2012. Studies were included if they (1) evaluated and clearly defined exposure to metformin, SU, TZDs, and/or insulin, (2) reported PaC outcomes in patients with DM and (3) reported relative risks or odds ratio (OR) or provided data for their estimation. Summary OR estimates with 95% confidence intervals (CIs) were estimated using the random-effects model. RESULTS: Eleven studies (6 cohort, 3 case-control, and 2 randomized controlled trials (RCTs)) reported 1770 cases of PaC in 730,664 patients with DM. Meta-analysis of observational studies showed no significant association between metformin (n=9 studies; adjusted OR 0.76, 95% CI 0.57-1.03, P=0.073), insulin (n=7 studies; adjusted OR 1.59, 95% CI 0.85-2.96, P=0.144), or TZD (n=4 studies; adjusted OR 1.02, 95% CI 0.81-1.30, P=0.844) use and risk of developing PaC. Use of SU was associated with a 70% increase in the odds of PaC (n=8 studies; adjusted OR 1.70, 95% CI 1.27-2.28, P<0.001). There was considerable inherent heterogeneity between studies not explained by study design, setting, or comparator drug and is likely related to confounding by indication and reverse causality. The pooled analyses of the two RCTs were underpowered and provided non-significant results with wide, non-informative 95% CIs. CONCLUSIONS: Although SU seems to be associated with increased risk of PaC, meta-analysis of existing studies does not support a protective or harmful association between ADM use and risk of PaC in patients with DM. There was considerable heterogeneity across studies, and future, well-designed, prospective studies would be required to understand this association better.

Statins are associated with reduced risk of esophageal cancer, particularly in patients with Barrett's esophagus: a systematic review and meta-analysis.

BACKGROUND & AIMS: The incidence of esophageal cancer is increasing in the United States, especially among patients with Barrett's esophagus (BE). Statins might prevent this cancer. We performed a systematic review with a meta-analysis of studies that evaluated the effect of statins on the risk of esophageal cancer. METHODS: We conducted a systematic search of Medline, Embase, and Web of Science through August 2012. Studies were included if they evaluated exposure to statins, reported the development of esophageal cancer, and reported relative risks or odds ratios (OR), or provided data for their estimation. Summary OR estimates with 95% confidence intervals (CI) were calculated using the random-effects model. The analysis included 13 studies (including a post hoc analysis of 22 randomized controlled trials) reporting 9285 cases of esophageal cancer among 1,132,969 patients. RESULTS: A meta-analysis of the studies showed a significant (28%) reduction in the risk of esophageal cancer among patients who took statins (adjusted OR, 0.72; 95% CI, 0.60-0.86), although there was considerable heterogeneity among studies. In analyzing a subset of patients known to have BE (5 studies, 312 esophageal adenocarcinomas [EAC] developed in 2125 patients), statins were associated with a significant (41%) decrease in the risk of EAC, after adjusting for potential confounders (adjusted OR, 0.59; 95% CI, 0.45-0.78) with consistent results among all studies. The number needed to treat with statins to prevent 1 case of EAC in patients with BE was 389. CONCLUSIONS: Based on meta-analysis of observational studies, statin use may be associated with lower risk of esophageal cancer, particularly risk of EAC in patients with BE.

Statins are associated with a reduced risk of hepatocellular cancer: a systematic review and meta-analysis.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide. Several studies have shown that statins could have chemopreventive effects on HCC. We performed a systematic review and meta-analysis of studies that evaluated the effects of statins on the risk of HCC. METHODS: We conducted a systematic search of MEDLINE, Embase, and Web of Science through May 2012 and manually reviewed the literature. Studies were included if they evaluated and clearly defined exposure to statins, reported the incidence of HCC, and reported relative risks or odds ratios (ORs) or provided data for their estimation. Ten studies reporting 4298 cases of HCC in 1,459,417 patients were analyzed. Summary OR estimates with 95% confidence intervals (CIs) were calculated using the random effects model. Statistical heterogeneity was assessed with the Cochran's Q statistic and I(2) statistic. RESULTS: Statin users were less likely to develop HCC than statin nonusers (adjusted OR, 0.63; 95% CI, 0.52-0.76), although the results were heterogeneous (P = .01, I(2) = 59%). This heterogeneity could be accounted for by study location (Asian population [n = 4]: adjusted OR, 0.52; 95% CI, 0.42-0.64; Western population [n = 6]: adjusted OR, 0.67; 95% CI, 0.53-0.85) and design (observational studies [n = 7]: adjusted OR, 0.60; 95% CI, 0.49-0.73; clinical trials [n = 3]: adjusted OR, 0.95; 95% CI, 0.62-1.45). CONCLUSIONS: Based on meta-analysis, statin use is associated with a reduced risk of HCC, most strongly in Asian but also in Western populations. Randomized clinical trials in populations at high risk for HCC (especially in Asian populations with hepatitis B) are warranted.