Summary Background Previous phase 2 studies have shown antitumour activity with gemcitabine and oxaliplatin (GEMOX) in patients with advanced biliary-tract cancers (BTCs). In this phase 2 study, we ...assessed the efficacy and safety of combined bevacizumab with GEMOX (GEMOX-B) in patients with advanced BTCs, and investigated how changes in 18-fluorodeoxyglucose (18 FFDG)-PET correlate with clinical outcome. Methods Patients with advanced measurable BTCs were given the following treatment on days 1 and 15 of a 28-day cycle: bevacizumab 10 mg/kg, followed by gemcitabine 1000 mg/m2 (10 mg/m2 per min) and oxaliplatin 85 mg/m2 (2-h infusion). 18 FFDG-PET scans were obtained at baseline and after completion of the second cycle. The primary endpoint was progression-free survival (PFS). Efficacy and safety analyses were by intention to treat. This trial is registered with ClinicalTrials.gov , number NCT00361231. Findings 35 patients were enrolled and evaluable for efficacy and toxicity. Median PFS was 7·0 months (95% CI 5·3–10·3), and PFS at 6 months was 63% (47–79), which was below the targeted rate of 70%. Grade 3–4 toxic effects included neutropenia (n=7), raised alanine aminotransferase concentrations (n=5), peripheral neuropathy (n=5), and hypertension (n=5). 18 FFDG-PET scans showed a significant decrease in maximum standardised uptake value (SUVmax ) after two cycles of treatment (5·72 SD 2·01 at baseline; 3·73 SD 1·88 after two cycles; p<0·0001). These changes were more pronounced in patients with partial response or stable disease than those with progressive disease (24 patients, −2·80 SD 1·95 vs five patients, 1·41 SD 3·13; p=0·009). Change in SUVmax was a significant predictor of PFS (HR 1·35, 1·14–1·60, p=0·0006) and overall survival (1·25, 1·05–1·50, p=0·01). Interpretation GEMOX-B showed antitumour activity with tolerable safety in patients with advanced BTCs. Decreases in SUVmax on 18 FFDG-PET scans after treatment were associated with disease control and increases in PFS and overall survival. Funding Genentech Oncology and Sanofi-Aventis.
Background
Previous studies have established that higher baseline quality of life (QOL) scores are associated with improved survival in patients with metastatic colorectal cancer (mCRC). We examined ...the relationship between overall survival (OS) and baseline QOL.
Patients and Methods
A total of 1 247 patients with mCRC participating in N9741 (comparing bolus 5-FU/LV, irinotecan IFL vs infusional 5-FU/leucovorin LV/oxaliplatin FOLFOX vs. irinotecan/oxaliplatin IROX) provided data at baseline on overall QOL using a single-item linear analogue self-assessment (LASA) 0–100 point scale. The association of OS according to clinically deficient (defined as CD-QOL, score 0–50) vs not clinically deficient (nCD-QOL, score 51–100) baseline QOL scores was tested. A multivariable analysis using Cox proportional hazards modeling was performed to adjust for the effects of multiple baseline factors. An exploratory analysis was performed evaluating OS according to baseline QOL status among patients who did or did not receive second-line therapy.
Results
Baseline QOL was a strong predictor of OS for the whole cohort (CD-QOL vs nCD-QOL: 11.2 months vs 18.4 months, P < .0001), and in each arm IFL 12.4 vs 15.1 months, FOLFOX 11.1 months vs 20.6 months, and IROX 8.9 months vs 18.1 months. Baseline QOL was associated with baseline performance status (PS) (P < .0001). After adjusting for PS and treatment arm, baseline QOL was still associated with OS (P = .017).
Conclusions
Baseline QOL is an independent prognostic factor for OS in patients with mCRC. The demonstration that patient-assessed QOL and PS are independent prognostic indicators suggests that these assessments provide important complementary prognostic information.
Abstract Purpose To evaluate the influence of alcohol consumption on the risk of colorectal cancer according to folic acid fortification period in the United States. Methods We evaluated the ...association between alcohol consumption and colorectal cancer by fortification period (before 1998 vs. after 1998) in 2 prospective cohort studies, the Nurses’ Health Study (NHS) of women and the Health Professionals Follow-up Study (HPFS) of men, in which 2793 cases of invasive colorectal cancer were documented. Results Alcohol consumption was associated with an increased risk of colorectal cancer. Among nonusers of multivitamins and/or folic acid supplements, the pooled multivariate relative risk for ≥30 g/d drinkers versus nondrinkers was 1.36 (95% confidence interval 95% CI, 1.09–1.70; P for trend, 0.02). The effect of alcohol consumption was slightly stronger in the prefolic acid fortification period (1980 NHS/1986 HPFS-1998) than in the postfortification period (1998–2008); the pooled multivariate relative risks for ≥30 g/d drinkers versus nondrinkers were 1.31 (95% CI, 1.00–1.71; P for trend, 0.10) in the prefortification period and 1.07 (95% CI, 0.69–1.65; P for trend, 0.67) in the postfortification period. Conclusions Folic acid fortification may attenuate the adverse effect of high alcohol consumption on the risk of colorectal cancer.
Abstract Introduction Hydrochlorothiazide, an effective antihypertensive medication commonly prescribed to blacks, decreases urinary calcium excretion. Blacks have significantly higher rates of ...hypertension and lower levels of 25-hydroxyvitamin D. Thus, they are more likely to be exposed to vitamin D supplementation and thiazide diuretics. The risk for hypercalcemia among blacks using vitamin D and hydrochlorothiazide is undefined. Methods We assessed the frequency of hypercalcemia in hydrochlorothiazide users in a post hoc analysis of a randomized, double-blind, dose-finding trial of 328 blacks (median age 51 years) assigned to either placebo, or 1000, 2000, or 4000 international units of cholecalciferol (vitamin D3) daily for 3 months during the winter (2007-2010). Results Of the 328 participants, 84 reported hydrochlorothiazide use and had serum calcium levels assessed. Additionally, a comparison convenience group of 44 enrolled participants who were not taking hydrochlorothiazide had serum calcium measurements at 3 months, but not at baseline. At 3 months, hydrochlorothiazide participants had higher calcium levels (0.2 mg/dL, P <.001) than nonhydrochlorothiazide participants, but only one participant in the hydrochlorothiazide group had hypercalcemia. In contrast, none of the nonhydrochlorothiazide participants had hypercalcemia. In a linear regression model adjusted for age, sex, 25-hydroxyvitamin D at 3 months, and other covariates, only hydrochlorothiazide use (Estimate SE: 0.05 0.01, P = .01) predicted serum calcium at 3 months. Conclusion In summary, vitamin D3 supplementation up to 4000 IU in hydrochlorothiazide users is associated with an increase in serum calcium but a low frequency of hypercalcemia. These findings suggest that participants of this population can use hydrochlorothiazide with up to 4000 IU of vitamin D3 daily and experience a low frequency of hypercalcemia.
An increased risk of malignancy was reported with simvastatin/ezetimibe in 1,873 patients in the SEAS (Simvastatin and Ezetimibe in Aortic Stenosis) trial.
The purpose of this study was to clarify ...this unexpected finding in a larger sample size of patients stabilized after acute coronary syndrome, we conducted a prospective systematic analysis of malignancy events in IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial).
Within IMPROVE-IT, 17,708 patients post–acute coronary syndrome were randomized to either ezetimibe 10 mg or matching placebo on a background of simvastatin 40 mg who took ≥1 dose of the study drug. Suspected tumors (benign and malignant) reported by investigators or identified from a review of adverse events were adjudicated by oncologists without knowledge of drug assignment. The primary malignancy endpoint included new, relapsing, or progressive malignancies (excluding nonmelanotic skin malignancies). The secondary endpoint was death due to malignancy.
In this trial, 1,470 patients developed the primary malignancy endpoint during a median 6 years of follow-up. The most common malignancy locations were prostate (18.9%), lung (16.8%), and bladder (8.8%) with no differences by treatment group (p > 0.05 for each location). Kaplan-Meier 7-year rates of malignancies were similar with ezetimibe and placebo (10.2% vs. 10.3%; hazard ratio: 1.03; 95% confidence interval: 0.93 to 1.14; p = 0.56), as were the rates for malignancy death (3.8% vs. 3.6%; hazard ratio: 1.04; 95% confidence interval: 0.88 to 1.23; p = 0.68).
Among 17,708 patients receiving simvastatin 40 mg daily, those randomized to ezetimibe 10 mg daily had a similar incidence of malignancy and deaths due to malignancy compared with those receiving placebo during a median follow-up of 6 years (96,377 patient-years). (IMPROVE-IT: Examining Outcomes in Subjects With Acute Coronary Syndrome: Vytorin Ezetimibe/Simvastatin vs Simvastatin P04103; NCT00202878)
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SummaryBackgroundPre-clinical and clinical evidence suggests that simultaneous blockade of VEGF receptor-2 (VEGFR-2) and PD-1 or PD-L1 enhances antigen-specific T-cell migration, antitumour activity, ...and has favourable toxicity. In this study, we aimed to assess the safety and preliminary antitumour activity of ramucirumab (an IgG1 VEGFR-2 antagonist) combined with pembrolizumab (an IgG4 PD-1 antagonist) in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma, non-small-cell lung cancer, or urothelial carcinoma. MethodsWe did a multicohort, non-randomised, open-label, phase 1a/b trial at 16 academic medical centres, hospitals, and clinics in the USA, France, Germany, Spain, and the UK. We enrolled adult patients aged 18 years or older with histologically confirmed gastric or gastro-oesophageal junction adenocarcinoma (cohorts A and B), non-small-cell lung cancer (cohort C), or urothelial carcinoma (cohort D), whose disease had progressed on one or two lines of previous therapy (for those with gastric or gastro-oesophageal junction adenocarcinoma) or one to three lines of previous therapy (for those with non-small-cell lung cancer and urothelial carcinoma) that included platinum (for all tumour types) or fluoropyrimidine or both (for gastric or gastro-oesophageal junction adenocarcinoma). Eligibility criteria included presence of measurable disease and an Eastern Cooperative Oncology Group performance status of 0–1. Patients with previously untreated gastric or gastro-oesophageal junction adenocarcinoma and non-small-cell lung cancer were also enrolled (in two additional separate cohorts); the results for these cohorts will be reported separately. The first 21-day treatment cycle was a dose-limiting toxicity observation period (phase 1a; safety run-in), followed by a phase 1b cohort expansion stage. Pembrolizumab 200 mg was administered intravenously on day 1, and intravenous ramucirumab was administered at 8 mg/kg on days 1 and 8 for cohort A or at 10 mg/kg on day 1 for cohorts B, C, and D, every 3 weeks, until disease progression or other discontinuation criteria were met. The primary endpoint was the safety and tolerability of ramucirumab in combination with pembrolizumab assessed by the incidence of adverse events in both phase 1a and 1b and as dose-limiting toxicities during phase 1a. The safety and activity analysis set included all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT02443324, and is no longer enrolling patients. FindingsBetween July 30, 2015 and June 24, 2016, we enrolled and treated 92 patients (41 with gastric or gastro-oesophageal junction adenocarcinoma, 27 with non-small-cell lung cancer, and 24 with urothelial carcinoma). Median follow-up was 32·8 months (IQR 28·1–33·6). During the first cycle of treatment (phase 1a safety run-in; n=11), one patient with gastro-oesophageal junction adenocarcinoma who received the 8 mg/kg dose of ramucirumab had grade 3 abdominal pain, colitis, hepatitis, interstitial lung disease, and jaundice, and grade 4 cholestasis, and died on treatment on day 40; the death was deemed related to progressive disease. No additional dose-limiting toxicities occurred and the decision was made to maintain the full planned doses of ramucirumab and pembrolizumab in phase 1b (n=81). Treatment-related adverse events occurred in 75 (82%) of 92 patients, the most common of which was fatigue (in 33 patients 36%), predominantly of grade 1 or 2 severity. 22 patients (24%) had one or more treatment-related adverse events of grade 3 or worse, most commonly hypertension (six patients; 7%) and colitis (five patients; 5%). Serious adverse events occurred in 53 (58%) of 92 patients, and were deemed related to treatment in 22 (24%) patients. The most common treatment-related serious adverse events were abdominal pain in patients with gastric or gastro-oesophageal junction adenocarcinoma (in three 7% of 41 patients); asthenia and myocardial infarction in patients with non-small-cell lung cancer (two 7% of 27 patients), and colitis in patients with urothelial carcinoma (two 8% of 24 patients). Six (7%) of 92 patients discontinued treatment because of treatment-related adverse events, and one death (from pulmonary sepsis in a patient with gastric or gastro-oesophageal junction adenocarcinoma) was deemed related to treatment. The number of patients achieving an objective response was three (7%; 95% CI 1·5–19·9) of 41 in the gastric or gastro-oesophageal junction adenocarcinoma cohort, eight (30%; 13·8–50·2) of 27 in the non-small-cell lung cancer cohort, and three (13%, 2·7–32·4) in the urothelial carcinoma cohort. InterpretationRamucirumab in combination with pembrolizumab showed a manageable safety profile with favourable antitumour activity in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma, non-small-cell lung cancer, and urothelial carcinoma. Our results contribute to the growing evidence that supports dual inhibition of the VEGF–VEGFR2 and PD-1–PD-L1 pathways. This combination could be further explored with or without chemotherapy, especially for patients with tumours for which single-agent checkpoint inhibitors have shown no additional benefit over chemotherapy. FundingEli Lilly and Company, and Merck and Co.
Summary Background Vascular endothelial growth factor (VEGF) and VEGF receptor-2 (VEGFR-2)-mediated signalling and angiogenesis can contribute to the pathogenesis and progression of gastric cancer. ...We aimed to assess whether ramucirumab, a monoclonal antibody VEGFR-2 antagonist, prolonged survival in patients with advanced gastric cancer. Methods We did an international, randomised, double-blind, placebo-controlled, phase 3 trial between Oct 6, 2009, and Jan 26, 2012, at 119 centres in 29 countries in North America, Central and South America, Europe, Asia, Australia, and Africa. Patients aged 24–87 years with advanced gastric or gastro-oesophageal junction adenocarcinoma and disease progression after first-line platinum-containing or fluoropyrimidine-containing chemotherapy were randomly assigned (2:1), via a central interactive voice-response system, to receive best supportive care plus either ramucirumab 8 mg/kg or placebo, intravenously once every 2 weeks. The study sponsor, participants, and investigators were masked to treatment assignment. The primary endpoint was overall survival. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov , number NCT00917384. Findings 355 patients were assigned to receive ramucirumab (n=238) or placebo (n=117). Median overall survival was 5·2 months (IQR 2·3–9·9) in patients in the ramucirumab group and 3·8 months (1·7–7·1) in those in the placebo group (hazard ratio HR 0·776, 95% CI 0·603–0·998; p=0·047). The survival benefit with ramucirumab remained unchanged after multivariable adjustment for other prognostic factors (multivariable HR 0·774, 0·605–0·991; p=0·042). Rates of hypertension were higher in the ramucirumab group than in the placebo group (38 16% vs nine 8%), whereas rates of other adverse events were mostly similar between groups (223 94% vs 101 88%). Five (2%) deaths in the ramucirumab group and two (2%) in the placebo group were considered to be related to study drug. Interpretation Ramucirumab is the first biological treatment given as a single drug that has survival benefits in patients with advanced gastric or gastro-oesophageal junction adenocarcinoma progressing after first-line chemotherapy. Our findings validate VEGFR-2 signalling as an important therapeutic target in advanced gastric cancer. Funding ImClone Systems.
Summary Overexpression of fatty acid synthase (FASN), a key enzyme for de novo lipogenesis, is observed in many cancers including colorectal cancer and is associated with poor clinical outcomes. ...Cellular FASN expression is physiologically upregulated in a state of energy excess. Obesity and excess energy balance have been known to be risk factors for colorectal cancer. High degree of microsatellite instability (MSI-H) is a distinct phenotype in colorectal cancer, associated with CpG island methylator phenotype (CIMP). Previous data suggest that obesity or altered energy balance may potentially modify risks for MSI-H cancers and microsatellite stable (MSS) cancers differently. However, the relationship between MSI and FASN overexpression has not been investigated. Using 976 cases of population-based colorectal cancer samples from 2 large prospective cohort studies, we correlated FASN expression (by immunohistochemistry) with MSI, KRAS and BRAF mutations, p53 expression (by immunohistochemistry), and CIMP status determined by MethyLight for 8 CIMP-specific gene promoters including CACNA1G , CDKN2A (p16), CRABP1 , IGF2 , MLH1 , NEUROG1 , RUNX3 , and SOCS1 . Marked (2+) FASN overexpression was observed in 110 (11%) of the 976 tumors and was significantly more common in MSI-H tumors (21% 28/135) than MSI-low (5.6% 4/72, P = .004) and MSS tumors (11% 72/678, P = .001). The association between FASN overexpression and MSI-H persisted even after stratification by CIMP status. In contrast, FASN overexpression was not correlated with CIMP after stratification by MSI status. Fatty acid synthase overexpression was not significantly correlated with sex, tumor location, p53, or KRAS / BRAF status. In conclusion, FASN overexpression in colorectal cancer is associated with MSI-H, independent of CIMP status.
Summary The transforming growth factor- β receptor type 2 gene ( TGFBR2 ) is mutated in most microsatellite instability-high (MSI-H) colorectal cancers. Promoter methylation of RUNX3 (runt-related ...transcription factor 3; encoding a transcription factor downstream of the TGF- β pathway) is observed in colorectal cancer with CpG island methylator phenotype (CIMP), which is characterized by extensive promoter methylation and is associated with MSI-H and BRAF mutations. However, no study to date has examined interrelationship between TGFBR2 mutation, RUNX3 methylation, and CIMP in colorectal cancer. Using 144 MSI-H colorectal cancers derived from 2 large prospective cohort studies, we analyzed a mononucleotide repeat of TGFBR2 and quantified DNA methylation (by MethyLight technology) in 8 CIMP-specific promoters ( RUNX3 , CACNA1G calcium channel, voltage-dependent, T type α -1G subunit, CDKN2A p16, CRABP1 cellular retinoic acid binding protein 1, IGF2 insulin-like growth factor 2, MLH1 , NEUROG1 neurogenin 1, and SOCS1 suppressor of cytokine signaling 1). Among the 144 MSI-H tumors, the presence of TGFBR2 mutation (overall 72% frequency) was correlated positively with CIMP-high (with ≥6/8 methylated promoters; P < .0001), RUNX3 methylation ( P = .0004), BRAF mutation ( P = .0006), and right colon ( P = .05); inversely with KRAS mutation ( P = .006); but not significantly with sex, tumor differentiation, and p53 status (assessed by immunohistochemistry). After stratification by sex, location, tumor differentiation, RUNX3 status, KRAS/BRAF status, or p53 status, CIMP-high was persistently correlated with TGFBR2 mutation. In contrast, RUNX3 , KRAS , or BRAF status was no longer correlated with TGFBR2 mutation after stratification by CIMP status. In conclusion, TGFBR2 mutation is associated with CIMP-high and indirectly with RUNX3 methylation. Our findings emphasize the importance of analyzing global epigenomic status (for which CIMP status is a surrogate marker) when correlating a single epigenetic event (eg, RUNX3 methylation) with any other molecular or clinicopathologic variables.
Summary Cytoplasmic mislocalization of p27 (CDKN1B/KIP1) is caused by activated AKT1 and has been associated with poor prognosis in various cancers. CIMP in colorectal cancer is characterized by ...extensive promoter methylation and is associated with MSI–MSI-H and BRAF mutations. We have recently shown a positive correlation between MSI/CIMP and loss of nuclear p27. However, no study has examined cytoplasmic p27 mislocalization in relation to CIMP and MSI in colorectal cancer. Using MethyLight assays, we quantified DNA methylation in 8 CIMP-specific gene promoters ( CACNA1G , CDKN2A (p16), CRABP1 , IGF2 , MLH1 , NEUROG1 , RUNX3 , and SOCS1 ) in 853 colorectal cancer samples obtained from 2 large prospective cohorts. We assessed expressions of nuclear and cytoplasmic p27 and nuclear p53 by immunohistochemistry. Cytoplasmic p27 expression was inversely associated with loss of nuclear p27 ( P < .0001), CIMP-high ( P < .0001), MSI-H ( P < .0001), and BRAF mutations ( P < .0001). The inverse association of cytoplasmic p27 with CIMP-high (or MSI-H) was independent of MSI (or CIMP) status. In addition, the inverse association of cytoplasmic p27 with CIMP-high was independent of KRAS / BRAF status. BRAF and CDKN2A (p16) methylation were not correlated with cytoplasmic p27 after stratification by CIMP status. The inverse associations of cytoplasmic p27 with MSI-H and CIMP-high were much more pronounced in p53-negative than p53-positive tumors. In conclusion, cytoplasmic p27 expression is inversely associated with MSI-H and CIMP-high, particularly in p53-negative tumors, suggesting interplay of functional losses of p27 and p53 in the development of various molecular subtypes of colorectal cancer.
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