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Charles S Fuchs

Publications and source records attributed to Charles S Fuchs.

At least 37 records · Page 2Linked to original sources

Fruit and vegetable consumption and colorectal adenomas in the Nurses' Health Study.

Consumption of fruits and vegetables may confer protection from colorectal adenomas, but the limited observational and interventional evidence is inconclusive. We examined the association between fruit and vegetable consumption and the prevalence and incidence of adenomas of the distal colon and rectum in the Nurses' Health Study (NHS). We used data from 34,467 women in the NHS who had undergone colonoscopy or sigmoidoscopy during follow-up between 1980 and 1998. Consumption of fruits and vegetables was assessed in 1980, 1984, 1986, 1990, and 1994 using a semiquantitative food frequency questionnaire; 1,720 prevalent cases of adenoma of the distal colon and rectum were diagnosed between 1980 and 1998. Frequent consumption of fruit was inversely related to the risk of being diagnosed with polyps, whereas little association was found for vegetable consumption. Women who reported consuming five or more servings of fruit a day had an odds ratio (OR) of 0.60 [95% confidence interval (95% CI), 0.44-0.81] for developing colorectal adenomas compared with women who consumed only one or fewer servings of fruit per day, after adjustment for relevant covariates (P(trend) = 0.001). The respective OR for vegetable consumption was 0.82 (95% CI, 0.65-1.05; P(trend) = 0.1). Women who consumed four or more servings of legumes per week had a lower incidence of colorectal adenomas than women who reported consuming one serving per week or less (OR, 0.67; 95% CI, 0.51-0.90; P(trend) = 0.005). Frequent consumption of fruit may reduce the risk of colorectal adenomas.

Adenoma↗

Nonsteroidal antiinflammatory drugs, acetaminophen, and the risk of cardiovascular events.

BACKGROUND: Although randomized trials of cyclooxygenase-2 (COX-2) inhibitors have shown increased cardiovascular risk, studies of nonselective, nonsteroidal antiinflammatory drugs (NSAIDs) and acetaminophen have been inconsistent. METHODS AND RESULTS: We examined the influence of NSAIDs and acetaminophen on the risk of major cardiovascular events (nonfatal myocardial infarction, fatal coronary heart disease, nonfatal and fatal stroke) in a prospective cohort of 70,971 women, aged 44 to 69 years at baseline, free of known cardiovascular disease or cancer, who provided medication data biennially since 1990. During 12 years of follow-up, we confirmed 2041 major cardiovascular events. Women who reported occasional (1 to 21 d/mo) use of NSAIDs or acetaminophen did not experience a significant increase in the risk of cardiovascular events. However, after adjustment for cardiovascular risk factors, women who frequently (> or =22 d/mo) used NSAIDs had a relative risk (RR) for a cardiovascular event of 1.44 (95% CI, 1.27 to 1.65) compared with nonusers, whereas those who frequently consumed acetaminophen had a RR of 1.35 (95% CI, 1.14 to 1.59). The elevated risk associated with frequent NSAID use was particularly evident among current smokers (RR=1.82; 95% CI, 1.38 to 2.42) and was absent among never smokers (Pinteraction=0.02). Moreover, we observed significant dose-response relations: Compared with nonusers, the RRs for a cardiovascular event among women who used > or =15 tablets per week were 1.86 (95% CI, 1.27 to 2.73) for NSAIDs and 1.68 (95% CI, 1.10 to 2.58) for acetaminophen. CONCLUSIONS: Use of NSAIDs or acetaminophen at high frequency or dose is associated with a significantly increased risk for major cardiovascular events, although more moderate use did not confer substantial risk.

Acetaminophen↗

Phase II study of temozolomide and thalidomide in patients with metastatic neuroendocrine tumors.

PURPOSE: Standard, intravenous chemotherapy regimens for neuroendocrine tumors have been associated with limited response rates and significant toxicity. We evaluated the efficacy of an oral regimen of temozolomide and thalidomide in patients with metastatic carcinoid, pheochromocytoma, or pancreatic neuroendocrine tumors. PATIENTS AND METHODS: Twenty-nine patients were treated with a combination of temozolomide, administered at a dose of 150 mg/m2 for 7 days, every other week, and thalidomide at doses of 50 to 400 mg daily. Patients were followed for evidence of toxicity, biochemical response, radiologic response, and survival. RESULTS: Treatment with temozolomide and thalidomide was associated with an objective biochemical (chromogranin A) response rate of 40%, and a radiologic response rate of 25% (45% among pancreatic endocrine tumors, 33% among pheochromocytomas, and 7% among carcinoid tumors). The median duration of response was 13.5 months, 1-year survival was 79%, and 2-year survival was 61%. The median administered dose of temozolomide was 150 mg/m(2), and the median administered dose of thalidomide was 100 mg daily. Grade 3-4 toxicities were uncommon, with the exception of grade 3-4 lymphopenia, which developed in 69% of the patient population. Opportunistic infections occurred in three patients (10%) during the time of lymphopenia, and included single cases of Pneumocystis carinii pneumonia, disseminated varicella zoster virus, and herpes simplex virus. CONCLUSION: Orally administered temozolomide and thalidomide seems to be an active regimen for the treatment of neuroendocrine tumors. In this 29-patient study, this regimen appeared more active in pancreatic endocrine tumors than in carcinoid tumors.

Adrenal Gland Neoplasms↗

A phase II trial of irinotecan and cisplatin in patients with metastatic neuroendocrine tumors.

The role of systemic chemotherapy in the treatment of patients with metastatic neuroendocrine tumors is controversial. While combination regimens containing cisplatin and etoposide have activity against more aggressive neuroendocrine tumor variants, such regimens appear to have little efficacy in patients with well-differentiated neuroendocrine tumor subtypes. The combination of irinotecan and cisplatin is active both against small cell lung cancer and in upper gastrointestinal malignancies but has not been prospectively evaluated in patients with metastatic neuroendocrine tumors. We therefore assessed the efficacy of an irinotecan/cisplatin combination in patients with this disease. Eighteen patients with metastatic neuroendocrine tumors (excluding small cell carcinoma) were treated with irinotecan, 65 mg/m2, and cisplatin, 30 mg/m2, administered weekly for 2 of every 3 weeks. Patients were followed for evidence of toxicity, response, and survival. The toxicities associated with this regimen were mild and included myelosuppression, nausea, and diarrhea. Only one radiologic response was observed among four patients with poorly differentiated neuroendocrine tumors. No radiologic responses were observed in 14 patients with well-differentiated tumors. The median overall survival duration of patients treated with this regimen was 11.4 months. We conclude that while the combination of irinotecan and cisplatin may have activity in aggressive neuroendocrine tumor subtypes, this combination is inactive in patients with well-differentiated neuroendocrine tumors.

Adult↗

Distinct molecular features of colorectal carcinoma with signet ring cell component and colorectal carcinoma with mucinous component.

Signet ring cell carcinoma and mucinous carcinoma are distinct subtypes of colorectal adenocarcinoma. The morphologic and molecular spectra of colorectal carcinomas with various signet ring cell components and colorectal carcinomas with various mucinous components, compared to non-mucinous adenocarcinomas, have not been examined. The study groups consisted of 39 carcinomas with various signet ring cell components ('the signet group'), 167 carcinomas with various mucinous components ('the mucinous group'), and 457 nonmucinous adenocarcinoma. We visually estimated the amounts of signet ring cell and mucinous components in tumors, and subclassified the signet and mucinous groups according to the amount of each component (< or = 19, 20-49, and > or = 50%). We sequenced BRAF and KRAS, analyzed for microsatellite instability (MSI) and 18q loss of heterozygosity (LOH), and performed immunohistochemistry for TP53, cyclooxygenase-2 (COX2), MLH1, O-6-methylguanine DNA methyltransferase (MGMT), p16 (CDKN2A), and fatty acid synthase (FASN). Signet ring cell carcinoma (> or = 50% signet ring cell tumors) and < or = 49% signet ring cell tumors showed similar molecular features. Except for MSI and MGMT, > or = 50% mucinous tumors and < or = 49% mucinous tumors also showed similar molecular features. BRAF mutations, MSI, and MLH1 loss were more frequent in both the signet and mucinous groups than nonmucinous carcinoma. More frequent KRAS mutations and less frequent p16 loss and TP53 positivity were observed in the mucinous group than nonmucinous carcinoma. 18q LOH and COX2 overexpression were less common in the signet group than nonmucinous carcinoma. FASN levels were highest in the mucinous group, followed by nonmucinous carcinoma, and lowest in the signet group. In conclusion, a minor (< or = 49%) signet ring cell or mucinous component in colorectal carcinoma suggests molecular features similar to > or = 50% signet ring cell or mucinous carcinoma, respectively. Signet ring cell carcinoma and mucinous carcinoma are related subtypes of colorectal adenocarcinoma, but have molecular features distinct from each other.

Adaptor Proteins, Signal Transducing↗

The combination of capecitabine and thalidomide in previously treated, refractory metastatic colorectal cancer.

BACKGROUND: With the increasing survival of patients with metastatic colorectal cancer (CRC) there is a growing need for effective second- and third-line agents. We conducted a multicenter, phase II study to examine the combination of capecitabine and thalidomide (Cape/Thal) in patients with refractory metastatic CRC. METHODS: Patients with previously treated stage IV CRC were eligible. Treatment consisted of capecitabine at 1,000 mg/m2 po BID for 14 days every 3 weeks and thalidomide, starting at 200 mg po QD continuously. Thalidomide was escalated individually to 600 mg po QD as tolerated. We analyzed overall survival (OS), progression-free survival, response, and toxicity rates. RESULTS: Thirty-four eligible patients were enrolled. The median age was 57 years, and most patients had a normal performance status (65%). All patients had received prior chemotherapy and 19 (56%) had received 2 or 3 prior regimens. The median number of Cape/Thal cycles administered was 3 (range, 1-15). Grade 3/4 toxicities included fatigue (15%), venous thromboembolic events (12%), somnolence (12%), and constipation (9%). Grade 2 hand-foot syndrome occurred in 5 (15%) patients. There were no radiographic responses; 13 patients (38%) achieved stable disease. The median PFS was 2.6 months (95% confidence interval [CI] = 2.2-3.9) and the median OS was 7.1 month (95% CI = 5.2-12.0). CONCLUSIONS: Though well-tolerated, the combination of capecitabine and thalidomide was not associated with objective tumor responses in a population of patients with previously treated metastatic CRC.

Administration, Oral↗

Correlation of pathologic features with CpG island methylator phenotype (CIMP) by quantitative DNA methylation analysis in colorectal carcinoma.

Extensive gene promoter methylation in colorectal carcinoma has been termed the CpG island methylator phenotype (CIMP). Previous studies on CIMP used primarily methylation-specific polymerase chain reaction (PCR), which, unfortunately, may detect low levels of methylation that has little or no biological significance. Utilizing quantitative real-time PCR (MethyLight), we measured DNA methylation in a panel of 5 CIMP-specific gene promoters (CACNA1G, CDKN2A (p16), CRABP1, MLH1, and NEUROG1) in 459 colorectal carcinomas obtained from 2 large prospective cohort studies. CIMP was defined as tumors that showed methylation in >or=4/5 promoters. CIMP was significantly associated with the presence of mucinous or signet ring cell morphology, marked Crohn's-like lymphoid reaction, tumor infiltrating lymphocytes, marked peritumoral lymphocytic reaction, tumor necrosis, tumor cell sheeting, and poor differentiation. All these features have previously been associated with microsatellite instability (MSI). Therefore, we divided the 459 colorectal carcinomas into 6 subtypes, namely, MSI-high (MSI-H)/CIMP, MSI-H/non-CIMP, MSI-low (MSI-L)/CIMP, MSI-L/non-CIMP, microsatellite stable/CIMP, and micro satellite sstable/non-CIMP. Compared with MSI-H/non-CIMP, MSI-H/CIMP was associated with marked tumor infiltrating lymphocytes, tumor necrosis, sheeting, and poor differentiation (all P<or=0.05). Compared with MSI-L/non-CIMP, MSI-L/CIMP was associated with tumors that had <50% signet ring cell component, marked tumor infiltrating lymphocytes, and poor differentiation (all P<0.05). In conclusion, several pathologic features that have previously been shown to be associated with MSI are also significantly associated with CIMP. Both MSI and CIMP appear to play a role in the pathogenesis of specific morphologic patterns of colorectal carcinoma.

Cell Differentiation↗

C-peptide, insulin-like growth factor binding protein-1, glycosylated hemoglobin, and the risk of distal colorectal adenoma in women.

BACKGROUND: Determinants of insulin secretion and insulin-like growth factors (IGF) have been directly associated with risk for colorectal cancer. However, few studies have evaluated whether these factors are also associated with risk of colorectal adenoma, the main precursor lesion to colorectal cancer. METHODS: We identified 380 distal colorectal adenoma cases diagnosed between 1989 and 1998 and 380 controls among nondiabetic women from the cohort of 32,826 women, nested in the Nurses' Health Study, who provided blood samples in 1989 to 1990. Cases and controls were individually matched on year of birth, time period of and indication(s) for endoscopy, and date of blood draw. RESULTS: High concentrations of C-peptide, an indicator of insulin secretion, were statistically significantly associated with risk of distal colorectal adenoma [multivariable relative risk (MVRR) top versus bottom quartile, 1.63; 95% confidence interval (95% CI), 1.01-2.66; P = 0.01], even after including body mass index and physical activity in the statistical model. Fasting IGF binding protein-1 (IGFBP-1) concentrations did not show any clear association with risk for adenoma (MVRR top versus bottom quartile, 1.08; 95% CI, 0.56-2.07). These associations did not differ significantly by size/stage of adenoma. Glycosylated hemoglobin (HbA1c) was associated with a nonstatistically significant increased risk of colorectal adenoma (MVRR top versus bottom quartile, 1.47; 95% CI, 0.89-2.44). CONCLUSIONS: High HbA1c and low IGFBP-1 were not clearly associated with increased risk of distal colorectal adenoma. However, our current results and previous associations between C-peptide and colorectal cancer suggest that hyperinsulinemia may play a role throughout the development of colorectal neoplasia.

Adenoma↗

Vitamin D intake and the risk for pancreatic cancer in two cohort studies.

Vitamin D and its analogues exhibit potent antitumor effects in many tissues, including the pancreas. Normal and malignant pancreatic tissues were recently shown to express high levels of vitamin D 1-alpha-hydroxylase, which converts circulating 25-hydroxyvitamin D to active 1,25-dihydroxyvitamin D. We examined associations between dietary intake of vitamin D, calcium, and retinol and subsequent risk for pancreatic cancer. We conducted prospective studies in cohorts of 46,771 men ages 40 to 75 years as of 1986 (the Health Professionals Follow-up Study), and 75,427 women ages 38 to 65 years as of 1984 (the Nurses' Health Study), documenting incident pancreatic cancer through the year 2000. Diet was ascertained by semiquantitative food-frequency questionnaire. We identified 365 incident cases of pancreatic cancer over 16 years of follow-up. Compared with participants in the lowest category of total vitamin D intake (<150 IU/d), pooled multivariate relative risks for pancreatic cancer were 0.78 [95% confidence interval (95% CI), 0.59-1.01] for 150 to 299 IU/d, 0.57 (95% CI, 0.40-0.83) for 300 to 449 IU/d, 0.56 (95% CI, 0.36-0.87) for 450 to 599 IU/d, and 0.59 (95% CI, 0.40-0.88) for >/=600 IU/d (P(trend) = 0.01). These associations may be stronger in men than women. After adjusting for vitamin D intake, calcium and retinol intakes were not associated with pancreatic cancer risk. In two U.S. cohorts, higher intakes of vitamin D were associated with lower risks for pancreatic cancer. Our results point to a potential role for vitamin D in the pathogenesis and prevention of pancreatic cancer.

Adult↗

Nonsynonymous polymorphisms in genes in the one-carbon metabolism pathway and associations with colorectal cancer.

The Ala(222)Val single nucleotide polymorphism (SNP) in the gene for 5,10-methylenetetrahydrofolate reductase (MTHFR), a critical enzyme in one-carbon metabolism, has been associated with colorectal cancer risk. Many enzymes are involved in one-carbon metabolism, and SNPs in the corresponding genes may play a role in colorectal carcinogenesis. We examined 24 nonsynonymous SNPs in 13 genes involved in the one-carbon metabolism pathway in relation to the risk of colorectal cancer in a case-control study nested in the Nurses' Health Study and the Health Professionals Follow-up Study cohorts. Among 376 men and women with colorectal cancer and 849 controls, a reduced risk of colorectal cancer was observed for Val/Val versus Ala carriers of MTHFR Ala(222)Val [odds ratio (OR), 0.66; 95% confidence interval (CI), 0.43-1.00]. An increased risk was suggested for the variant carrier genotypes versus homozygous wild-type for betaine hydroxymethyltransferase Arg(239)Gln (OR, 1.40; 95% CI, 1.07-1.83) and two linked SNPs in methionine synthase reductase, Ser(284)Thr (OR, 1.85; 95% CI, 1.05-3.27) and Arg(415)Cys (OR, 2.03; 95% CI, 1.15-3.56). The other SNPs were not associated with colorectal cancer risk. Also, none of the SNPs were associated with risk in subgroups of dietary methyl status or were jointly associated with colorectal cancer risk in combination with another SNP, except possibly SNPs in methionine synthase and transcobalamin II. However, these analyses of gene-diet interactions were limited in statistical power. Our results corroborate previous findings for MTHFR Ala(222)Val and suggest that other genes involved in one-carbon metabolism, particularly those that affect DNA methylation, may be associated with colorectal cancer risk.

Adult↗

Combined analysis of COX-2 and p53 expressions reveals synergistic inverse correlations with microsatellite instability and CpG island methylator phenotype in colorectal cancer.

Cyclooxygenase-2 (COX-2) overexpression and mutations of p53 (a known COX-2 regulator) are inversely associated with microsatellite instability-high (MSI-H) and CpG island methylator phenotype (CIMP) characterized by extensive promoter methylation, is associated with MSI-H. However, no studies have comprehensively examined interrelations between COX-2, p53, MSI, and CIMP. Using MethyLight, we measured DNA methylation in five CIMP-specific gene promoters [CACNA1G, CDKN2A (p16/INK4A), CRABP1, MLH1, and NEUROG1] in relatively unbiased samples of 751 colorectal cancer cases obtained from two large prospective cohorts; 115 (15%) tumors were CIMP-high (> or = 4 of 5 methylated promoters), 251 (33%) were CIMP-low (1 to 3 methylated promoters), and the remaining 385 (51%) were CIMP-0 (no methylated promoters). CIMP-high tumors were much less frequent in COX-2+/p53+ tumors (4.6%) than in COX-2+/p53- tumors (19%; P < .0001), COX-2-/p53+ tumors (17%; P = .04), and COX-2-/p53- tumors (28%; P < .0001). In addition, COX-2+/p53+ tumors were significantly less common in MSI-H CIMP-high tumors (9.7%) than in non-MSI-H CIMP-low/CIMP-0 tumors (44-47%; P < .0001). In conclusion, COX-2 and p53 alterations were synergistically inversely correlated with both MSI-H and CIMP-high. Our data suggest that a combined analysis of COX-2 and p53 may be more useful for the molecular classification of colorectal cancer than either COX-2 or p53 analysis alone.

Cohort Studies↗

Precision and performance characteristics of bisulfite conversion and real-time PCR (MethyLight) for quantitative DNA methylation analysis.

Assays to measure DNA methylation, which are important in epigenetic research and clinical diagnostics, typically rely on conversion of unmethylated cytosine to uracil by sodium bisulfite. However, no study has comprehensively evaluated the precision and performance characteristics of sodium bisulfite conversion and subsequent quantitative methylation assay. We developed quantitative real-time polymerase chain reaction (MethyLight) to measure percentage of methylated reference (PMR, ie, degree of methylation) for the MGMT, MLH1, and CDKN2A (p16) promoters. To measure the precision of bisulfite conversion, we bisulfite-treated seven different aliquots of DNA from each of four paraffin-embedded colon cancer samples. To assess run-to-run variation, we repeated MethyLight five times. Bisulfite-to-bisulfite coefficient of variation (CV) of PMR ranged from 0.10 to 0.38 (mean, 0.21), and run-to-run CV of PMR ranged from 0.046 to 0.60 (mean, 0.31). Interclass correlation coefficients were 0.74 to 0.84 for the three loci, indicating good reproducibility. DNA mixing study with methylated and unmethylated DNA showed good linearity of the assay. Of 272 colorectal cancers evaluated, most showed PMR either <1 or >10, and promoter methylation (PMR >4) was tightly associated with loss of respective protein expression (P < 10(-16)). In conclusion, sodium bisulfite conversion and quantitative MethyLight assays have good precision and linearity and can be effectively used for high-throughput DNA methylation analysis on paraffin-embedded tissue.

Adaptor Proteins, Signal Transducing↗

CpG island methylator phenotype-low (CIMP-low) in colorectal cancer: possible associations with male sex and KRAS mutations.

The CpG island methylator phenotype (CIMP or CIMP-high) with extensive promoter methylation seems to be a distinct epigenotype of colorectal cancer. However, no study has comprehensively examined features of colorectal cancer with less extensive promoter methylation (designated as "CIMP-low"). Using real-time polymerase chain reaction (MethyLight), we quantified DNA methylation in five CIMP-specific gene promoters [CACNA1G, CDKN2A (p16), CRABP1, MLH1, and NEUROG1] in 840 relatively unbiased, population-based colorectal cancer samples, obtained from two large prospective cohort studies. CIMP-low (defined as 1/5 to 3/5 methylated promoters) colorectal cancers were significantly more common among men (38 versus 30% in women, P = 0.01) and among KRAS-mutated tumors (44 versus 30% in KRAS/BRAF wild-type tumors, P = 0.0003; 19% in BRAF-mutated tumors, P < 0.0001). In addition, KRAS mutations were significantly more common in CIMP-low tumors (47%) than in CIMP-high tumors (with > or =4/5 methylated promoters, 12%, P < 0.0001) and CIMP-0 tumors (with 0/5 methylated promoters, 37%, P = 0.007). The associations of CIMP-low tumors with male sex and KRAS mutations still existed after tumors were stratified by microsatellite instability status. In conclusion, CIMP-low colorectal cancer is associated with male sex and KRAS mutations. The hypothesis that CIMP-low tumors are different from CIMP-high and CIMP-0 tumors needs to be tested further.

Colorectal Neoplasms↗

Efficacy of cetuximab after treatment with oral epidermal growth factor receptor tyrosine kinase inhibitor-based chemotherapy in metastatic colorectal cancer.

PURPOSE: We studied the efficacy of cetuximab therapy in patients with metastatic colorectal cancer (mCRC) previously treated with an oral inhibitor of the tyrosine kinase domain of the epidermal growth factor receptor. PATIENTS AND METHODS: We reviewed the posttrial records of 73 patients with mCRC who participated in 1 of 3 clinical trials that examined a combination of gefitinib or erlotinib with standard cytotoxic chemotherapy. Medical and pharmacy records were used to identify patients who were subsequently treated with cetuximab-based therapy. Computed tomography scans during cetuximab-based therapy were reviewed, and the clinical activity of cetuximab was assessed by response rate using Response Evaluation Criteria in Solid Tumors and progression-free survival. RESULTS: Twenty-four patients with mCRC previously treated with gefitinib or erlotinib and combination cytotoxic chemotherapy who subsequently received cetuximab-based therapy were identified. While receiving cetuximab-based therapy, no patient experienced a partial or complete response; however, 3 patients (16% of patients with available scans for formal measurements) had a minor response, defined as a 15%-29.9% decrease in the sum of longest dimensions of target lesions, and 72% had stable disease. The progression-free survival was 5.1 months for all patients and 6 months for patients who had documented progression of disease while previously receiving gefitinib- or erlotinib-based therapy. CONCLUSION: Cetuximab appears to have clinical benefit in patients with mCRC previously treated with a chemotherapy regimen that included an oral tyrosine kinase inhibitor of epidermal growth factor receptor. Whether these results apply to other cancer types is unknown but worthy of further study.

Adult↗

Phase I study of gefitinib plus FOLFIRI in previously untreated patients with metastatic colorectal cancer.

BACKGROUND: In this study, the maximum tolerated dose and toxicity profile of FOLFIRI (infusional fluorouracil [5-FU]/leucovorin/irinotecan) plus gefitinib (an oral inhibitor of the epidermal growth factor receptor) were evaluated as first-line therapy in patients with metastatic colorectal cancer. PATIENTS AND METHODS: Sixteen patients participated in this study. Oral gefitinib was administered at 250 mg or 500 mg daily in 2 dose-escalation cohorts. FOLFIRI was administered without dose escalation on a 14-day cycle with treatment on day 1 with irinotecan 180 mg/m2, leucovorin 200 mg/m2, and 5-FU 400 mg/m2 bolus, followed by 5-FU 2400 mg/m2 continuous infusion over 46 hours. RESULTS: The maximum tolerated dose of gefitinib was 250 mg, with diarrhea and neutropenia noted as the principal dose-limiting toxicities. Dose reductions in 5-FU and irinotecan were required in 4 patients because of diarrhea and 1 patient because of neutropenia. A partial response was observed in 25% of patients, and 56% had stable disease for > 12 weeks, corresponding to a disease control rate of 81%. CONCLUSION: These findings suggest that gefitinib can be safely combined with FOLFIRI as first-line treatment of metastatic CRC and support the safety of further investigations of EGFR tyrosine kinase inhibitors with multiagent chemotherapy in this patient population.

Adenocarcinoma↗

The role of targeted therapy in the treatment of colorectal cancer.

Recent years have brought significant advances in the treatment of metastatic colorectal cancer. Combination regimens with standard chemotherapeutic agents have extended survival to nearly 2 years, and recent studies suggest that chemotherapy-free intervals may be feasible in some patients without compromising survival outcomes. The most significant recent progress has centered on the use of targeted biologic therapies. The first targeted agent to show a significant benefit in metastatic colorectal cancer was bevacizumab. This monoclonal antibody is directed against vascular endothelial growth factor, a molecule known to be involved in the angiogenic process that is central to cancer growth and metastasis. In clinical trials, bevacizumab has improved survival when added to multiple chemotherapy regimens. The second targeted agent to be approved for colorectal cancer is the monoclonal antibody cetuximab, which is directed against the epidermal growth factor receptor, another key mediator of cancer growth. Cetuximab has been shown to increases the efficacy of irinotecan in irinotecan-refractory patients, indicating that cetuximab may make tumors more sensitive to chemotherapeutic agents. Bevacizumab and cetuximab continue to be evaluated alone as maintenance therapy and in combination in different settings to determine their optimal use in colorectal cancer. Additional targeted agents are also being developed and are showing promise in clinical trials.

Antibodies, Monoclonal↗

Dietary fiber intake and risk of colorectal cancer: a pooled analysis of prospective cohort studies.

CONTEXT: Inconsistent findings from observational studies have continued the controversy over the effects of dietary fiber on colorectal cancer. OBJECTIVE: To evaluate the association between dietary fiber intake and risk of colorectal cancer. DESIGN, SETTING, AND PARTICIPANTS: From 13 prospective cohort studies included in the Pooling Project of Prospective Studies of Diet and Cancer, 725,628 men and women were followed up for 6 to 20 years across studies. Study- and sex-specific relative risks (RRs) were estimated with the Cox proportional hazards model and were subsequently pooled using a random-effects model. MAIN OUTCOME MEASURE: Incident colorectal cancer. RESULTS: During 6 to 20 years of follow-up across studies, 8081 colorectal cancer cases were identified. For comparison of the highest vs lowest study- and sex-specific quintile of dietary fiber intake, a significant inverse association was found in the age-adjusted model (pooled RR = 0.84; 95% confidence interval [CI], 0.77-0.92). However, the association was attenuated and no longer statistically significant after adjusting for other risk factors (pooled multivariate RR = 0.94; 95% CI, 0.86-1.03). In categorical analyses compared with dietary fiber intake of 10 to <15 g/d, the pooled multivariate RR was 1.18 (95% CI, 1.05-1.31) for less than 10 g/d (11% of the overall study population); and RR, 1.00 (95% CI, 0.85-1.17) for 30 or more g/d. Fiber intake from cereals, fruits, and vegetables was not associated with risk of colorectal cancer. The pooled multivariate RRs comparing the highest vs lowest study- and sex-specific quintile of dietary fiber intake were 1.00 (95% CI, 0.90-1.11) for colon cancer and 0.85 (95% CI, 0.72-1.01) for rectal cancer (P for common effects by tumor site = .07). CONCLUSIONS: In this large pooled analysis, dietary fiber intake was inversely associated with risk of colorectal cancer in age-adjusted analyses. However, after accounting for other dietary risk factors, high dietary fiber intake was not associated with a reduced risk of colorectal cancer.

Colorectal Neoplasms↗

Assessment of a dietary questionnaire in cancer patients receiving cytotoxic chemotherapy.

PURPOSE: Few studies have examined the influence of diet on survival and chemotherapy-associated toxicities in patients with cancer. Although several comprehensive dietary questionnaires have been validated and calibrated in healthy populations, similar studies have not been performed among cancer patients. METHODS: Two hundred patients with colorectal, breast, or neuroendocrine cancer undergoing treatment with cytotoxic chemotherapy completed a self-administered, 131-item, semiquantitative food frequency questionnaire. Using the questionnaire, we calculated dietary intakes of carotenoids, tocopherols, and fatty acids, and correlated these values with relevant biomarkers measured in simultaneously collected plasma specimens. RESULTS: The Pearson correlation coefficients for various carotenoids as measured by the questionnaire, with the corresponding measurements in plasma specimens, ranged from 0.33 to 0.44 (all P < .001), adjusted for total energy intake, body mass index, age, sex, smoking status, and total plasma cholesterol. Similarly, the adjusted correlation between self-reported total vitamin E intake and plasma alpha-tocopherol was 0.34 (P < .001). Correlations between questionnaire and plasma measurements of trans-fat, eicosapentaenoic acid, and docosahexaenoic acid were 0.55, 0.29, and 0.42 (all P < .001), respectively. These levels of correlation are consistent with those reported in similar studies of self-reported diet in otherwise healthy populations. CONCLUSION: Among patients with cancer receiving cytotoxic chemotherapy, questionnaire-based measurements of various micronutrients and dietary factors appeared to predict meaningful differences in the corresponding measurements in plasma specimens. This dietary questionnaire could offer an informative and practical means for assessing the influence of diet in cancer patients receiving chemotherapy.

Adult↗