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.
To examine the influence of dose and duration of aspirin use in the primary prevention of colorectal adenoma.
Prospective cohort study.
Nurses' Health Study.
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.
1368 cases of confirmed distal colorectal adenoma were diagnosed between 1980 and 1998. Self-reported data on aspirin use were collected from biennial questionnaires.
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).
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.
Purpose.
To determine the efficacy and toxicity of weekly neoadjuvant cetuximab combined with irinotecan, cisplatin, and radiation therapy in patients with locally advanced esophageal or ...gastroesophageal junction cancer.
Methods and Materials.
Patients with stage IIA–IVA esophageal or gastroesophageal junction cancer were enrolled in a Simon's two‐stage phase II study. Patients received weekly cetuximab on weeks 0–8 and irinotecan and cisplatin on weeks 1, 2, 4, and 5, with concurrent radiotherapy (50.4 Gy on weeks 1–6), followed by surgical resection.
Results.
In the first stage, 17 patients were enrolled, 16 of whom had adenocarcinoma. Because of a low pathologic complete response (pCR) rate in this cohort, the trial was discontinued for patients with adenocarcinoma but squamous cell carcinoma patients continued to be enrolled; two additional patients were enrolled before the study was closed as a result of poor accrual. Of the 19 patients enrolled, 18 patients proceeded to surgery, and 16 patients underwent an R0 resection. Three patients (16%) had a pCR. The median progression‐free survival interval was 10 months, and the median overall survival duration was 31 months. Severe neutropenia occurred in 47% of patients, and severe diarrhea occurred in 47% of patients. One patient died preoperatively from sepsis, and one patient died prior to hospital discharge following surgical resection.
Conclusions.
This schedule of cetuximab in combination with irinotecan, cisplatin, and radiation therapy was toxic and did not achieve a sufficient pCR rate in patients with localized esophageal adenocarcinoma to undergo further evaluation.
摘要
目的. 明确每周一次西妥昔单抗、伊立替康、顺铂新辅助化疗联合放疗用于局部晚期食管癌或胃食管交界癌患者的疗效与毒性反应。
材料与方法. Simon II期研究分两阶段进行，纳入IIA ∼ IVA期食管癌或胃食管交界癌患者。患者接受每周一次西妥昔单抗（第0 ∼ 8周）、伊立替康与顺铂（第1、2、4、5周），以及同步放疗（50.4 Gy，第1 ∼ 6周），继以手术切除。
结果. 在第一阶段，17例患者入组，其中16例为腺癌。由于这一队列的病理学完全缓解（pCR）率较低，对腺癌患者的试验中止，仍继续纳入鳞癌患者；最终研究因受试者招募速度过慢而停止，之前又多纳入2例患者。19例患者中，18例患者进行了手术，16例为R0切除。3例患者（16%）获得pCR。中位无进展生存时间为10个月，中位总生存时间为31个月。47%的患者发生重度中性粒细胞减少，47%的患者发生重度腹泻。1例患者术前因败血症死亡，1例患者在手术切除后尚未出院之前死亡。
结论. 对于局部食管腺癌患者，西妥昔单抗、伊立替康、顺铂以及放疗的联合治疗方案具有毒性，且并未达到足够的pCR率，因而未能按照研究计划开展进一步的评估。
The efficacy and toxicity of weekly neoadjuvant cetuximab combined with irinotecan, cisplatin, and radiation therapy in patients with locally advanced esophageal or gastroesophageal junction cancer were evaluated. This schedule was toxic and did not achieve a sufficient pathologic complete response rate in patients with localized esophageal adenocarcinoma to undergo further evaluation.
Although genome-wide association studies (GWAS) have separately identified many genetic susceptibility loci for ulcerative colitis (UC), Crohn's disease (CD) and colorectal cancer (CRC), there has ...been no large-scale examination for pleiotropy, or shared genetic susceptibility, for these conditions. We used logistic regression modeling to examine the associations of 181 UC and CD susceptibility variants previously identified by GWAS with risk of CRC using data from the Genetics and Epidemiology of Colorectal Cancer Consortium and the Colon Cancer Family Registry. We also examined associations of significant variants with clinical and molecular characteristics in a subset of the studies. Among 11794 CRC cases and 14190 controls, rs11676348, the susceptibility single nucleotide polymorphism (SNP) for UC, was significantly associated with reduced risk of CRC (P = 7E-05). The multivariate-adjusted odds ratio of CRC with each copy of the T allele was 0.93 (95% CI 0.89-0.96). The association of the SNP with risk of CRC differed according to mucinous histological features (P heterogeneity = 0.008). In addition, the (T) allele was associated with lower risk of tumors with Crohn's-like reaction but not tumors without such immune infiltrate (P heterogeneity = 0.02) and microsatellite instability-high (MSI-high) but not microsatellite stable or MSI-low tumors (P heterogeneity = 0.03). The minor allele (T) in SNP rs11676348, located downstream from CXCR2 that has been implicated in CRC progression, is associated with a lower risk of CRC, particularly tumors with a mucinous component, Crohn's-like reaction and MSI-high. Our findings offer the promise of risk stratification of inflammatory bowel disease patients for complications such as CRC.
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.
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.
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.
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.
Few prospective studies have examined the associations between blood levels of folate, in conjunction with methylenetetrahydrofolate reductase (MTHFR) polymorphisms, and colorectal cancer. We ...evaluated the associations between plasma folate, MTHFR C677T, and A1298C, and colorectal cancer in three large prospective studies: the Nurses' Health Study, the Health Professionals Follow-up Study, and the Physicians' Health Study. A total of 602 incident cases were identified and individually matched to controls who provided blood specimens. We used conditional logistic regression to calculate the relative risk (RR) and 95% confidence interval (95% CI) and then pooled the estimates using a random effects model. We found a lower risk of colorectal cancer among participants with low plasma folate levels: compared with the lowest quartile, RRs (95% CIs) for each successively higher quartile of plasma folate levels were 1.55 (1.14-2.11), 1.37 (1.00-1.88), and 1.47 (1.07-2.01; P for trend = 0.10). For the MTHFR polymorphisms, RRs (95% CIs) were 0.62 (0.44-0.90) for 677TT versus CC/CT and 0.68 (0.31-1.51) for 1298CC versus AC/AA, and these lower-risk genotypes were associated with lower circulating plasma folate levels. When we partitioned the variation in plasma folate levels, variation due to folate intake was not positively associated with colorectal cancer risk. We found that low plasma folate levels were associated with lower risk of colorectal cancer. The reasons underlying a lower risk of colorectal cancer with low plasma folate levels require elucidation because plasma folate levels can reflect dietary intake, genetic influences, and other factors.
Familial clustering of colorectal cancer is generally believed to occur even when the cases are not part of a defined genetic syndrome. At least 12 retrospective studies have suggested that a history ...of colorectal cancer in a first-degree relative (a parent or sibling) elevates a person's lifetime risk of colorectal cancer 1.8-fold to 8.0-fold.
1
–
12
However, the strength of the association is uncertain because of the retrospective design of these analyses and their failure to control for other important risk factors.
In aggregate, prior analyses suggest that among people with a family history of colorectal cancer, those who are younger, . . .
Less than 5% of patients with cancer enroll in a clinical trial, partly due to financial and logistic burdens, especially among underserved populations. The COVID-19 pandemic marked a substantial ...shift in the adoption of decentralized trial operations by pharmaceutical companies.
To assess the current global state of adoption of decentralized trial technologies, understand factors that may be driving or preventing adoption, and highlight aspirations and direction for industry to enable more patient-centric trials.
The Bloomberg New Economy International Cancer Coalition, composed of patient advocacy, industry, government regulator, and academic medical center representatives, developed a survey directed to global biopharmaceutical companies of the coalition from October 1 through December 31, 2022, with a focus on registrational clinical trials. The data for this survey study were analyzed between January 1 and 31, 2023.
Adoption of decentralized clinical trial technologies.
The survey measured (1) outcomes of different remote monitoring and data collection technologies on patient centricity, (2) adoption of these technologies in oncology and all therapeutic areas, and (3) barriers and facilitators to adoption using descriptive statistics.
All 8 invited coalition companies completed the survey, representing 33% of the oncology market by revenues in 2021. Across nearly all technologies, adoption in oncology trials lags that of all trials. In the current state, electronic diaries and electronic clinical outcome assessments are the most used technology, with a mean (SD) of 56% (19%) and 51% (29%) adoption for all trials and oncology trials, respectively, whereas visits within local physician networks is the least adopted at a mean (SD) of 12% (18%) and 7% (9%), respectively. Looking forward, the difference between the current and aspired adoption rate in 5 years for oncology is large, with respondents expecting a 40% or greater absolute adoption increase in 8 of the 11 technologies surveyed. Furthermore, digitally enabled recruitment, local imaging capabilities, and local physician networks were identified as technologies that could be most effective for improving patient centricity in the long term.
These findings may help to galvanize momentum toward greater adoption of enabling technologies to support a new paradigm of trials that are more accessible, less burdensome, and more inclusive.
Summary
Purpose
Resistance to cetuximab, a monoclonal antibody against the epithelial growth factor receptor (EGFR), in colorectal cancer (CRC) may result from compensatory signaling through ErbB ...receptors, ErbB2/neu/HER2 (HER2) and ErbB3/HER3 (HER3). Pertuzumab is a monoclonal antibody that blocks HER2 hetero-dimerization; thus the combination of pertuzumab and cetuximab could possibly overcome cetuximab resistance.
Patients and methods
This single-arm, open-label, multicenter phase I/II study was designed to assess the safety and efficacy of pertuzumab and cetuximab in patients with cetuximab-resistant KRAS wild type metastatic CRC. Thirteen patients were enrolled and received cetuximab in combination with pertuzumab at several dose levels in a 3 + 3 design. Patients were assessed for dose-limiting toxicity (DLT) during the first cycle. A phase II portion was planned, but not initiated due to toxicity.
Results
Six of the thirteen patients (46 %) experienced DLTs, therefore the study was terminated early. Grade 3 or higher DLTs included dermatitis with desquamation and/or acneiform rash (
n
= 6), mucositis or stomatitis (
n
= 5), and diarrhea (
n
= 2). There was one Grade 5 event (myocardial infarction) attributed to underlying disease. Among the 13 patients, seven (54 %) were evaluable for response. The objective response rate was 14 %: one patient had a partial response lasting 6 months. Two patients had stable disease (29 %), and four had progressive disease (57 %). Median progression free survival was 2.1 months (95 % CI, 1.5–4.9) and median overall survival was 3.7 months (95 % CI, 1.6–7.9).
Conclusion
Combination pertuzumab and cetuximab in refractory CRC was associated with potential antitumor activity; however, the combination was not tolerable due to overlapping toxicities.
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.
The CpG island methylator phenotype (CIMP or CIMP-high) with widespread promoter methylation is a distinct phenotype in colorectal cancer. However, the concept of CIMP-low with less extensive CpG ...island methylation is still evolving. Our aim is to examine whether density of methylation in individual CpG islands was different between CIMP-low and CIMP-high tumors. Utilizing MethyLight technology and 889 population-based colorectal cancers, we quantified DNA methylation (methylation index, percentage of methylated reference) at 14 CpG islands, including 8 CIMP-high-specific loci (CACNA1G, CDKN2A (p16), CRABP1, IGF2, MLH1, NEUROG1, RUNX3 and SOCS1). Methylation positivity in each locus was defined as methylation index>4. Low-level methylation (methylation index>0, <20) in each CIMP-high-specific locus was significantly more common in 340 CIMP-low tumors (1/8–5/8 methylation-positive loci) than 133 CIMP-high tumors (≥6/8 methylation-positive loci) and 416 CIMP-0 tumors (0/8 methylation-positive loci) (P≤0.002). In the other six loci (CHFR, HIC1, IGFBP3, MGMT, MINT31 and WRN), which were not highly specific for CIMP-high, low-level methylation, was not persistently more prevalent in CIMP-low tumors. In conclusion, compared to CIMP-high and CIMP-0 tumors, CIMP-low colorectal cancers show not only few methylated CIMP-high-specific CpG islands, but also more frequent low-level methylation at individual loci. Our data may provide supporting evidence for a difference in pathogenesis of DNA methylation between CIMP-low and CIMP-high tumors.
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