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Charles S Fuchs

Publications and source records attributed to Charles S Fuchs.

At least 73 records · Page 4Linked to original sources
PubMed2005

Associations between plasma insulin-like growth factor proteins and C-peptide and quality of life in patients with metastatic colorectal cancer.

OBJECTIVE: Predictors of quality of life (QOL) in patients with metastatic colorectal cancer are lacking. The insulin-like growth factor (IGF) family of proteins is associated with QOL in noncancer populations. We sought to study whether these proteins are associated with QOL in patients with colorectal cancer. METHOD: We used a cohort of 526 patients with metastatic colorectal cancer treated with combination chemotherapy. Plasma samples of IGF-I, IGF-II, IGF binding protein-3, and C-peptide were collected before initiation of chemotherapy. QOL was measured by the uniscale instrument and the Symptom Distress Scale at baseline and throughout treatment. RESULTS: Baseline plasma levels of IGF-I and IGF-II before initiation of chemotherapy were significantly associated with several important baseline QOL measures in patients with metastatic colorectal cancer. Patients with lower levels of IGF-I reported increased distress with regard to appearance, appetite, cough, and nausea intensity after adjustment for potential confounders. Similarly, decreased levels of IGF-II were predictive of worse quality related to appearance, appetite, fatigue, nausea frequency and intensity, pain frequency, and composite Symptom Distress Scale score. IGF binding protein-3 and C-peptide were not predictive of baseline QOL. Baseline biomarkers were not associated with subsequent changes in QOL during treatment. Higher body mass index was significantly associated with superior baseline QOL in several areas; nonetheless, the association of IGF-I and IGF-II with baseline QOL measures remained significant even after controlling for baseline body mass index. CONCLUSION: Baseline plasma IGF-I and IGF-II are significantly associated with symptom distress. Whether this association is simply reflective of patient nutritional status and/or disease burden or represents an independent biological effect of IGFs on QOL remains uncertain. Nonetheless, these data suggest that molecular biomarkers may be useful predictors of QOL in cancer patients.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2005

Sugar-sweetened soft drink consumption and risk of pancreatic cancer in two prospective cohorts.

BACKGROUND: A history of diabetes mellitus and a diet high in glycemic load are both potential risk factors for pancreatic cancer. Sugar-sweetened soft drinks are a prevalent source of readily absorbable sugars and have been associated with an increased risk of obesity and diabetes. We investigated whether higher consumption of sugar-sweetened soft drinks increases the risk of pancreatic cancer. METHODS: We examined the relation between consumption of sugar-sweetened soft drinks and the development of pancreatic cancer in the Nurses' Health Study and the Health Professionals Follow-up Study. Among 88,794 women and 49,364 men without cancer at baseline, we documented 379 cases of pancreatic cancer during up to 20 years of follow-up. Soft drink consumption was first assessed at baseline (1980 for the women, 1986 for the men) and updated periodically thereafter. RESULTS: Compared with participants who largely abstained from sugar-sweetened soft drinks, those who consumed more than three sugar-sweetened soft drinks weekly experienced overall a multivariate relative risk (RR) of pancreatic cancer of 1.13 [95% confidence interval (95% CI), 0.81-1.58; P for trend = 0.47]. Women in the highest category of sugar-sweetened soft drink intake did experience a significant increase in risk (RR, 1.57; 95% CI, 1.02-2.41; P for trend = 0.05), whereas there was no association between sweetened soft drink intake and pancreatic cancer among men. Among women, the risk associated with higher sugar-sweetened soft drink was limited to those with elevated body mass index (>25 kg/m(2); RR, 1.89; 95% CI, 0.96-3.72) or with low physical activity (RR, 2.02; 95% CI, 1.06-3.85). In contrast, consumption of diet soft drinks was not associated with an elevated pancreatic cancer risk in either cohort. CONCLUSION: Although soft drink consumption did not influence pancreatic cancer risk among men, consumption of sugar-sweetened soft drinks may be associated with a modest but significant increase in risk among women who have an underlying degree of insulin resistance.

Adult↗
PubMed2005

Dietary glycemic load, carbohydrate, sugar, and colorectal cancer risk in men and women.

Hyperinsulinemia may explain excess colorectal cancer among individuals who are overweight or inactive. Recent studies have observed elevated colorectal cancer risk among individuals with elevated insulin levels 2 hours after oral glucose challenge or with elevated plasma C-peptide levels. The effect of consuming a high glycemic diet on colorectal risk, however, remains uncertain. Two prospective cohort studies, the Nurses' Health Study and the Health Professionals Follow-up Study, contributed up to 20 years of follow-up. After exclusions, 1,809 incident colorectal cancers were available for analyses. Dietary glycemic load (GL) was calculated as a function of glycemic index (postprandial blood glucose response as compared with a reference food), carbohydrate content, and frequency of intake of individual foods reported on food frequency questionnaires. Multivariable Cox proportional hazards models were used to adjust for potential confounders. Intakes of dietary carbohydrate, GL, overall glycemic index, sucrose, and fructose were not associated with colorectal cancer risk in women. A small increase in risk was observed in men with high dietary GL (multivariate relative risk, 1.32; 95% confidence interval, 0.98-1.79; highest versus lowest quintile), sucrose or fructose (multivariate relative risk, 1.37; 95% confidence interval, 1.05-1.78; highest versus lowest quintile of fructose, P = 0.008). Associations were slightly stronger among men with elevated body mass index (> or =25 kg/m(2)). Results among women were similar after stratifying by body mass index or physical activity. High intakes of GL, fructose, and sucrose were related to an elevated colorectal cancer risk among men. For women, however, these factors did not seem to increase the risk of colorectal cancer.

Adult↗
PubMed2005

Angiogenesis inhibition in the treatment of colorectal cancer Part 3 of a 3-part series: targeting VEGF--current and future research directions.

Treatment options for advanced colorectal have improved substantially in recent years as a number of agents have been developed that have different targets and mechanisms of action. Significant improvements in outcomes have been observed by combining multiple chemotherapeutic agents instead of the single-agent approach. Some debate still remains regarding which combination is most effective and in what order regimens should be given. In addition to cytotoxic chemotherapy drugs, targeted biologic agents have been developed to inhibit tumor angiogenesis, which may hamper the viability of the tumor. There may also be a synergistic effect between antiangiogenic agents and chemotherapy. Regulation of tumor angiogenesis may actually improve blood flow throughout the tumor, which could enhance delivery of chemotherapy through the circulation. One antiangiogenic agent currently approved for the treatment of advanced colorectal cancer is bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor, a ligand known to be important for angiogenesis. The other currently approved biologic agent, cetuximab, targets the epidermal growth factor receptor. The combination of bevacizumab plus cetuximab has a biologic rationale. Randomized trials incorporating combination chemotherapy regimens plus both bevacizumab and cetuximab are currently underway, as are preliminary studies withnovel angiogenesis inhibitors.

Angiogenesis Inhibitors↗
PubMed2004

Two schedules of second-line irinotecan for metastatic colon carcinoma.

BACKGROUND: In a recently reported, randomized trial, it was found that a regimen of irinotecan once every 3 weeks for patients with advanced colorectal carcinoma was associated with a lower incidence of severe diarrhea compared with weekly treatment, and both regimens had similar efficacy. METHODS: Resource utilization was captured prospectively for all 291 patients who were included in the trial. Utilities were estimated by transformation of the global quality-of-life (QOL) item on the Eastern Organization for Research and Treatment of Cancer QLQ-C30 instrument. RESULTS: Patients in the every-3-week arm incurred an average incremental cost of $1362, because they received higher average weekly doses and because the every-3-week regimen resulted in less toxicity, allowing delivery of 97% of the planned doses compared with delivery of only 75% of the planned doses in the weekly arm. This lower toxicity also resulted in offsetting savings from decreased hospitalization and less requirement for supportive medications. Non-chemotherapy-related treatment administration costs also were lower, because the every-3-week regimen could be delivered with half the number of infusions. Utility declined less in the every-3-week arm, resulting in a saving of 6.3 quality-adjusted days. The base-case cost:utility ratio was $78,627 per quality-adjusted life year for patients on the every-3-week schedule. However, that ratio was very sensitive to the cost of irinotecan. CONCLUSIONS: The schedule of irinotecan once every 3 weeks schedule was more costly but achieved lower toxicity, resulting in modestly improved utility. The cost-per-utility ratio was comparable to other commonly accepted contemporary treatments.

Aged↗
PubMed2004

Mortality associated with daily bolus 5-fluorouracil/leucovorin administered in combination with either irinotecan or oxaliplatin: results from Intergroup Trial N9741.

BACKGROUND: Intergroup Trial N9741 evaluated 5-fluorouracil (5-FU)/leucovorin (LV) administered in conjunction with either irinotecan or oxaliplatin in the first-line treatment of advanced colorectal carcinoma (CRC). The current report describes two treatment arms that were withdrawn from the protocol due to unexpected treatment-related toxicities and a high mortality rate. The complications observed in these arms highlight the importance of aggressive and immediate supportive care in the management of digestive toxicity. METHODS: In Trial N9741, patients were randomly assigned to receive one of the following six regimens: 1) irinotecan plus bolus 5-FU/LV (Arm A); 2) sequential irinotecan plus bolus 5-FU/LV (Arm B); 3) bolus 5-FU/LV only (Mayo Clinic regimen; Arm D); 4) oxaliplatin plus bolus 5-FU/LV (Arm E); 5) oxaliplatin plus infusional 5-FU/LV (Arm F); or 6) oxaliplatin plus irinotecan (Arm G). In the current study, the authors investigated treatment-related toxicity in patients who received either of the two combination regimens containing daily bolus 5-FU (i.e., patients in Arm B or Arm E). RESULTS: Sixty-one and 47 patients were enrolled in Arm B and Arm E, respectively. Diarrhea and neutropenia were the most common toxicities in both groups. Five patients in Arm B (8.2%) and 4 patients in Arm E (8.5%) died within 60 days of study entry. All fatal toxicities occurred within 15 days of treatment administration, and all deaths were associated with the simultaneous occurrence of multiple symptoms, which were dominated by Grade > or = 3 diarrhea. CONCLUSIONS: Combination regimens containing daily bolus 5-FU/LV and oxaliplatin or irinotecan can be associated with severe gastrointestinal toxicity and high mortality rates. Therefore, the authors recommend the use of more tolerable infusional 5-FU-based regimens in the treatment of metastatic CRC.

Adult↗
PubMed2004

A Phase II trial of gemcitabine for metastatic neuroendocrine tumors.

BACKGROUND: Treatment with traditional cytotoxic chemotherapy regimens containing streptozocin or dacarbazine has resulted in only marginal benefit for patients with metastatic neuroendocrine tumors. The use of these regimens has been further limited by their potential toxicity. Gemcitabine is generally well tolerated and possesses demonstrated activity against a wide range of malignancies. The authors assessed the efficacy of gemcitabine in the treatment of patients with metastatic neuroendocrine tumors. METHODS: Eighteen patients with metastatic neuroendocrine tumors were treated with gemcitabine administered on a standard weekly schedule. Patients were followed for evidence of toxicity, response, and survival. RESULTS: Gemcitabine was well tolerated. However, no radiologic or biochemical responses were observed. Although the majority of patients (65%) experienced disease stabilization as their best response to therapy, the overall median survival duration was only 11.5 months. CONCLUSIONS: The minimal activity of gemcitabine highlighted the need for novel treatment approaches.

Adult↗
PubMed2004

A prospective study of folate intake and the risk of pancreatic cancer in men and women.

Laboratory and human studies suggest that folate intake may influence the risk of some cancers. However, prospective information about the relation between folate intake and the risk of exocrine pancreatic cancer is limited. The authors examined the relation of dietary folate intake to the risk of pancreatic cancer in two large prospective US cohorts. Folate intake was assessed by food frequency questionnaire in 1984 in women and in 1986 in men. Multivariate relative risks were adjusted for age, energy intake, cigarette smoking, body mass index, diabetes, and height. During 14 years' follow-up in each cohort, 326 incident cases of pancreatic cancer were identified. Compared with participants in the lowest category of folate intake, participants in increasing 100- micro g categories of total energy-adjusted folate intake had pooled multivariate relative risks for pancreatic cancer of 1.08, 1.10, and 1.03 (95% confidence interval: 0.74, 1.43; p(trend) = 0.99). For energy-adjusted folate from food, the pooled relative risks for increasing 100- micro g categories of intake were 0.81, 0.89, and 0.66 (95% confidence interval: 0.42, 1.03; p(trend) = 0.12). There was no statistical interaction between folate intake and methionine, alcohol, fat, or caffeine. The results from these two large prospective cohorts do not support a strong association between energy-adjusted folate intake and the risk of pancreatic cancer.

Adult↗
PubMed2004

A prospective study of dietary lactose and ovarian cancer.

The milk sugar lactose is an hypothesized risk factor for epithelial ovarian cancer because of possible direct toxic effects of its metabolites on oocytes or by compensatory gonadotropin stimulation. Women are presently encouraged to consume dairy products as a source of calcium to prevent osteoporosis. The objective of our study was to prospectively assess lactose, milk and milk product consumption in relation to ovarian cancer risk among 80326 participants in the Nurses' Health Study who had no history of cancer other than nonmelanoma skin cancer. Participants in the Nurses' Health Study reported on known and suspected ovarian cancer risk factors in questionnaires mailed biennially from 1976 to 1996. Food frequency questionnaires were included in the years 1980, 1984, 1986 and 1990. Newly reported ovarian cancer was documented by review of medical records. During 16 years of follow-up (1980-1996), 301 cases of invasive epithelial ovarian cancer were confirmed. Pooled logistic regression was used to control for age, body mass index (kg/m(2)), caffeine intake, oral contraceptive use, smoking history, parity and tubal ligation. For all subtypes of invasive ovarian cancer combined, we observed a nonsignificant 40% greater risk for women in the highest category of lactose consumption compared to the lowest (multivariate relative risk (RR) 1.40, 95% confidence interval (CI), 0.98-2.01). We observed a 2-fold higher risk of the serous ovarian cancer subtype among those in the highest category of lactose consumption compared to the lowest (RR 2.07, 95% CI, 1.27-3.40). For each 11-gram increase in lactose consumption (the approximate amount in one glass of milk), we observed a 20% increase in risk of serous cancers (RR 1.20, 95% CI, 1.04-1.39). Skim and low-fat milk were the largest contributors to dietary lactose. Women who consumed one or more servings of skim or low-fat milk daily had a 32% higher risk of any ovarian cancer (RR 1.32, 95% CI, 0.97-1.82) and a 69% higher risk of serous ovarian cancer (RR 1.69, 95% CI, 1.12-2.56) compared to women consuming 3 or less servings monthly. Controlling for fat intake did not change our findings. Our findings provide some support for the hypothesis that lactose intake increases risk of epithelial ovarian cancer. However, the observed excess risk appeared limited to the serous subtype of ovarian cancer in our study.

Adult↗
PubMed2004

Relationship of baseline serum bilirubin to efficacy and toxicity of single-agent irinotecan in patients with metastatic colorectal cancer.

PURPOSE: To examine the predictive value of baseline serum bilirubin measurement for chemotherapy-related toxicity or efficacy among patients receiving irinotecan for metastatic colorectal cancer. METHODS: We performed a secondary analysis of a cohort of 287 patients treated in a multicenter, phase III study with single-agent irinotecan administered either weekly or once every 3 weeks. Patients were grouped into three categories of baseline bilirubin measurements (0 to 0.4, 0.5 to 0.9, and 1.0 to 1.5 mg/dL). We performed analyses of overall survival, time to progression, and treatment-related toxicity based on bilirubin category, as well as using bilirubin as a continuous variable. RESULTS: With a median follow-up of 15.8 months, baseline serum bilirubin was not predictive of 1-year survival (42.4%, bilirubin 0 to 0.4; 42.3%, bilirubin 0.5 to 0.9; 48.1%, bilirubin 1.0 to 1.5 mg/dL), median overall survival (10.1, 9.7, and 15.6 months, respectively; P =.5), or median time to progression (2.8, 3.0, and 4.1 months, respectively; P =.5). Patients with elevated bilirubin had a significantly greater risk grade 3 to 4 neutropenia; however, this was limited to patients treated on a weekly schedule (P trend =.03) and not once every 3 weeks (P trend =.8). Other toxicities were not significantly different by initial bilirubin measurement. CONCLUSION: Although modest elevations of bilirubin (1.0 to 1.5 mg/dL) are associated with increased grade 3 to 4 neutropenia in patients treated with weekly irinotecan, baseline serum bilirubin does not reliably predict overall irinotecan-related toxicity or efficacy. Additional methods, including potential application of pharmacogenetic information, are needed to optimize irinotecan dosing and tailor therapy to individual patients.

Aged↗
PubMed2004

Phase I clinical trial of the farnesyltransferase inhibitor BMS-214662 given as a 1-hour intravenous infusion in patients with advanced solid tumors.

PURPOSE: BMS-214662 is a nonsedating benzodiazepine derivative that exhibits broad spectrum cytotoxicity against human solid tumor cell lines and potently inhibits farnesylation of the H-ras and K-ras oncogenic proteins. This report describes the initial Phase I clinical trial of the compound. The main objective of the study was to determine the dose-limiting toxicities and the maximum tolerated dose of BMS-214662 when administered as a single dose i.v. over 1 h every 21 days to patients with advanced solid tumors. EXPERIMENTAL DESIGN: Patients with advanced solid tumors and adequate organ function were eligible for the study. The dose was escalated according to a modified Fibonacci schedule after evaluating groups of at least three patients for toxicity during the first cycle of therapy at each dose level. Pharmacokinetic and pharmacodynamic studies were performed after administration of the two initial doses. RESULTS: The dose of BMS-214662 was escalated from 36 to 225 mg/m(2) through 5 intermediate dose levels in a total of 44 patients. Dose-limiting toxicities occurred in 3 of the 13 (23%) patients during the first cycle of treatment with 225 mg/m(2), consisting of grade 3 nausea/vomiting in 2 patients and grade 3 diarrhea in another patient. In addition, four of these patients experienced reversible grade 3 transaminitis, which was not considered to be dose-limiting. At the recommended dose for Phase II studies, 200 mg/m(2), the most common side effects were reversible transaminitis, nausea, and vomiting. Although there were no objective responses, one patient with pancreatic cancer continues to receive treatment more than 3.5 years after entering the study. BMS-214662 exhibited linear pharmacokinetics and had a mean biological half-life of 1.55 +/- 0.27 h and a total body clearance of 21.8 +/- 10.8 liters/h/m(2), with a low apparent volume of distribution at steady state (31.5 +/- 12.9 liters/m(2)). In patients treated with the recommended Phase II dose, the mean maximum plasma concentration of the drug was 6.57 +/- 2.94 microg/ml, and farnesyltransferase activity in peripheral blood mononuclear cells decreased to a nadir of 10.5 +/- 6.4% of baseline at the end of the infusion but fully recovered within 24 h. CONCLUSIONS: BMS-214662 can be delivered safely as a single 1-h i.v. infusion at a dose that results in pronounced inhibition of farnesyltransferase activity in peripheral blood mononuclear cells. However, the duration of enzyme inhibition was transient, recovering in parallel with the decline in plasma concentrations of this rapidly eliminated drug. Because indications of anticancer activity were observed in several patients, further optimization of the administration schedule for this promising new compound is warranted.

Adult↗
PubMed2004

Impact of body mass index on outcomes and treatment-related toxicity in patients with stage II and III rectal cancer: findings from Intergroup Trial 0114.

PURPOSE: To study the relationship between body mass index (BMI) and rates of sphincter-preserving operations, overall survival, cancer recurrence, and treatment-related toxicities in patients with rectal cancer. PATIENTS AND METHODS: We evaluated a nested cohort of 1,688 patients with stage II and III rectal cancer participating in a randomized trial of postoperative fluorouracil-based chemotherapy and radiation therapy. RESULTS: Obese patients were more likely to undergo an abdominoperineal resection (APR) than normal-weight patients (odds ratio, 1.77; 95% CI, 1.27 to 2.46). When analyzed by sex, increasing adiposity in men was a strong predictor of having an APR (P <.0001). Obese men with rectal cancer were also more likely than normal-weight men to have a local recurrence (hazard ratio [HR], 1.61; 95% CI, 1.00 to 2.59). In contrast, obesity was not predictive of cancer recurrence in women, nor was BMI predictive of overall mortality in either men or women. Underweight patients had an increased risk of death (HR, 1.43; 95% CI, 1.08 to 1.89) compared with normal-weight patients but no increase in cancer recurrences. Among all study participants, obese patients had a significantly lower rate of grade 3 to 4 leukopenia, neutropenia, and stomatitis and a lower rate of any grade 3 or worse toxicity when compared with normal-weight individuals. CONCLUSION: Increasing BMI in male patients with rectal cancer is associated with a decreased likelihood of sphincter preservation and a higher chance of local recurrence. For both men and women, overweight and obese patients experience less toxicity associated with adjuvant chemoradiotherapy, suggesting that actual body weight dosing of fluorouracil for obese patients is justified.

Antineoplastic Agents↗
PubMed2004

A prospective study of aspirin use and the risk for colorectal adenoma.

BACKGROUND: Randomized, double-blind, placebo-controlled trials have established that regular aspirin use reduces the risk for recurrent colorectal adenoma. However, the effect of dose and duration of use, particularly in an average-risk population, is not well understood. OBJECTIVE: To examine the influence of dose and duration of aspirin use in the primary prevention of colorectal adenoma. DESIGN: Prospective cohort study. SETTING: Nurses' Health Study. PARTICIPANTS: 27 077 women, 34 to 77 years of age, without a history of adenoma, cancer, inflammatory bowel disease, or familial polyposis, who underwent lower endoscopy between 1980 and 1998. MEASUREMENTS: 1368 cases of confirmed distal colorectal adenoma were diagnosed between 1980 and 1998. Self-reported data on aspirin use were collected from biennial questionnaires. RESULTS: After other risk factors for adenoma were adjusted, women who regularly used aspirin (> or =2 standard aspirin tablets/wk) had a multivariate relative risk for adenoma of 0.75 (95% CI, 0.66 to 0.84) compared with nonregular users. Compared with women who denied any aspirin use, the multivariate relative risks for adenoma were 0.80 (CI, 0.70 to 0.93) for women who used 0.5 to 1.5 standard tablets per week, 0.74 (CI, 0.62 to 0.88) for those who used 2 to 5 tablets per week, 0.72 (CI, 0.61 to 0.85) for those who used 6 to 14 tablets per week, and 0.49 (CI, 0.36 to 0.65) for those who used more than 14 tablets per week (P < 0.001 for trend). Similar dose-response relationships were found among regular short-term users (< or =5 years; P < 0.001) and long-term users (>5 years; P < 0.001). In contrast, after adjustments were made for dose, increasing duration of aspirin use did not confer greater risk reduction (P > 0.2). CONCLUSIONS: Regular, short-term use of aspirin is inversely associated with risk for colorectal adenoma. However, the greatest protective effect is evident at substantially higher doses (>14 tablets/wk) than those recommended for the prevention of cardiovascular disease. Before aspirin can be recommended for chemoprevention in the general adult population, these results suggest the need for a more thorough evaluation of the risks and benefits of routine aspirin use at doses not previously considered.

Adenoma↗
PubMed2004

Comparison of risk factors for colon and rectal cancer.

Predictors of colorectal cancer have been extensively studied with some evidence suggesting that risk factors vary by subsite. Using data from 2 prospective cohort studies, we examined established risk factors to determine whether they were differentially associated with colon and rectal cancer. Our study population included 87,733 women from the Nurses' Health Study (NHS) and 46,632 men from the Health Professionals Follow Up Study (HPFS). Exposure information was collected via biennial questionnaires (dietary variables were collected every 4 years). During the follow-up period (NHS: 1980 to May 31, 2000; HPFS: 1986 to January 31, 2000), we identified 1,139 cases of colon cancer and 339 cases of rectal cancer. We used pooled logistic regression to estimate multivariate relative risks for the 2 outcomes separately and then used polytomous logistic regression to compare these estimates. In the combined cohort, age, gender, family history of colon or rectal cancer, height, body mass index, physical activity, folate, intake of beef, pork or lamb as a main dish, intake of processed meat and alcohol were significantly associated with colon cancer risk. However, only age and sex were associated with rectal cancer. In a stepwise polytomous logistic regression procedure, family history and physical activity were associated with statistically significant different relative risks of colon and rectal cancer. Our findings support previous suggestions that family history and physical activity are not strong contributors to the etiology of rectal cancer. Future investigations of colon or rectal cancer should take into consideration risk factor differences by subsite.

Adult↗
PubMed2004

A prospective study of aspirin use and the risk of pancreatic cancer in women.

BACKGROUND: In vitro experiments and limited animal studies suggest that aspirin and nonsteroidal anti-inflammatory drugs may inhibit pancreatic carcinogenesis. Because few studies have examined the association between aspirin use and pancreatic cancer in humans and the results have been inconsistent, we examined the relationship between aspirin use and the development of pancreatic cancer in the Nurses' Health Study. METHODS: Among 88 378 women without cancer at baseline, we documented 161 cases of pancreatic cancer during 18 years of follow-up. Aspirin use was first assessed at baseline in 1980 and updated biennially thereafter. All statistical tests were two-sided. RESULTS: Participants were classified according to history of aspirin use. In a multivariable analysis, the risk of pancreatic cancer was not associated with current regular aspirin use (defined as two or more standard tablets per week; relative risk [RR] = 1.20, 95% confidence interval [CI] = 0.87 to 1.65), compared with use of fewer than two tablets per week. Increasing duration of regular aspirin use, compared with non-use, was associated with a statistically significant increase in risk: Women who reported more than 20 years of regular aspirin use had an increased risk of pancreatic cancer (RR = 1.58, 95% CI = 1.03 to 2.43; P(trend) =.01). Among women who reported aspirin use on at least two of three consecutive biennial questionnaires compared with consistent non-users of aspirin, the risk increased with dose (one to three tablets per week: RR = 1.11, 95% CI = 0.70 to 1.76; four to six tablets per week: RR = 1.29, 95% CI = 0.70 to 2.40; seven to 13 tablets per week: RR = 1.41, 95% CI = 0.76 to 2.61; and > or = 14 tablets per week: RR = 1.86, 95% CI = 1.03 to 3.35) (P(trend) =.02). CONCLUSION: Extended periods of regular aspirin use appear to be associated with a statistically significantly increased risk of pancreatic cancer among women.

Adult↗
PubMed2004

Impact of hospital procedure volume on surgical operation and long-term outcomes in high-risk curatively resected rectal cancer: findings from the Intergroup 0114 Study.

PURPOSE: Prior studies have demonstrated superior outcomes after a curative surgical resection of rectal cancer at hospitals where the volume of such surgeries is high. However, because these studies often lack detailed information on tumor and treatment characteristics as well as cancer recurrence, the true nature of this relation remains uncertain. PATIENTS AND METHODS: We studied a nested cohort of 1,330 patients with stage II and stage III rectal cancer participating in a multicenter, adjuvant chemoradiotherapy trial. We analyzed differences in rates of sphincter-preserving operations, overall survival, and cancer recurrence by hospital surgical volume. RESULTS: We observed a significant difference in the rates of abdominoperineal resections across tertiles of hospital procedure volume (46.3% for patients resected at low-volume, 41.3% at medium-volume, and 31.8% at high-volume hospitals; P <.0001), even after adjustment for tumor distance from the anal verge. However, this higher rate of sphincter-sparing operations at high-volume centers was not accompanied by any increase in recurrence rates. Hospital surgical volume did not predict overall, disease-free, recurrence-free, or local recurrence-free survival. However, among patients who did not complete the planned adjuvant chemoradiotherapy (270 patients), those who underwent surgery at low-volume hospitals had a significant increase in cancer recurrence (adjusted hazard ratio, 1.94; 95% CI, 1.01 to 3.72; P =.04 for the trend) and a nonsignificant trend toward increased overall mortality (P =.08) and local recurrence (P =.10). In contrast, no significant volume-outcome relation was noted among patients who did complete postoperative therapy. CONCLUSION: Using prospectively recorded data, we found that hospital surgical volume had no significant effect on rectal cancer recurrence or survival when patients completed standard adjuvant therapy. Sphincter-preserving surgery was more commonly performed at high-volume centers.

Adult↗
PubMed2004

A prospective study of genetic polymorphisms in the cytochrome P-450 2C9 enzyme and the risk for distal colorectal adenoma.

BACKGROUND & AIMS: Regular aspirin use is associated with a reduced risk for colorectal adenoma, whereas smoking increases risk. The cytochrome P-450 (CYP) 2C9 (CYP2C9) enzyme is involved in the metabolism of several drugs, including possibly aspirin, and such carcinogens as smoking-related polycyclic aromatic hydrocarbons. Genetic variation in this enzyme may modulate the influence of aspirin and smoking on adenoma risk. METHODS: We examined the risk for incident distal colorectal adenoma according to CYP2C9 genotype, aspirin use, and smoking in a prospective nested case-control study of women. RESULTS: Among 394 cases and 396 controls, women with at least 1 variant CYP2C9 allele had a significantly greater risk for adenoma (multivariate odds ratio [OR], 1.56; 95% confidence interval [CI], 1.13-2.15; P = 0.007). Although women who used aspirin regularly (>/=2 standard tablets/wk) experienced a lower risk for adenoma compared with non-regular users, the effect was similar irrespective of genotype. Women who smoked >20 pack-years had an OR of adenoma of 1.50 (95% CI, 1.07-2.12; P = 0.02) compared with those who smoked </=20 pack-years. Among women with at least 1 variant allele who smoked >20 pack-years, the OR of adenoma was 2.50 (95% CI, 1.44-4.38; P = 0.001) compared with women with no variant alleles who smoked </=20 pack-years. CONCLUSIONS: Polymorphisms in the CYP2C9 enzyme are associated with elevated risk for colorectal adenoma. This observation does not appear to be related to modification of the effect of aspirin on adenoma risk, but may be associated with differential metabolism of environmental carcinogens.

Adenoma↗