Factors influencing medical oncology referral in Dukes' C colonic cancer

Aim: Colorectal cancer (CRC) is one of the most common malignancies worldwide and adjuvant chemotherapy is proven to improve survival in patients with Dukes' C CRC. The purpose of this study was to analyze factors influencing referral to medical oncology in patients with Dukes' C colonic cancer in our institutions. Methods: Patients who underwent resection for Dukes' C colonic cancer were assessed for factors that influence the pattern of postoperative referral to the medical oncology department, including demographic and perioperative data. Results: Overall, 466 patients were identified to have Dukes' C colonic cancer, with 53.9% of these being female. Referral to medical oncology occurred for 58.4% patients. Multivariable logistic regression modeling identified age, elective admission and resection in private hospitals as factors. The likelihood of medical oncology referral in patients who had elective resection was 63% versus 41% in those who had emergency resection and resection in private hospitals was 69% versus 50% in public hospitals. Conclusion: Referral to a postoperative medical oncology clinic for adjuvant chemotherapy in Dukes' C colonic cancer was more likely in younger patients, those who underwent elective resection and those treated in private hospitals.     

Medical Student Knowledge of Oncology and Related Disciplines: a Targeted Needs Assessment

Despite increasing numbers of cancer survivors, non-oncology physicians report discomfort and little training regarding oncologic and survivorship care. This pilot study assesses medical student comfort with medical oncology, surgical oncology, radiation oncology, hospice/palliative medicine, and survivorship care. A survey was developed with input from specialists in various fields of oncologic care at a National Cancer Institute-designated comprehensive cancer center. The survey included respondent demographics, reports of experience with oncology, comfort ratings with oncologic care, and five clinical vignettes. Responses were yes/no, multiple choice, Likert scale, or free response. The survey was distributed via email to medical students (MS1–4) at two US medical schools. The 105 respondents were 34 MS1s (32 %), 15 MS2s and MD/PhDs (14 %), 26 MS3s (25 %), and 30 MS4s (29 %). Medical oncology, surgical oncology, and hospice/palliative medicine demonstrated a significant trend for increased comfort from MS1 to MS4, but radiation oncology and survivorship care did not. MS3s and MS4s reported the least experience with survivorship care and radiation oncology. In the clinical vignettes, students performed the worst on the long-term chemotherapy toxicity and hospice/palliative medicine questions. Medical students report learning about components of oncologic care, but lack overall comfort with oncologic care. Medical students also fail to develop an increased self-assessed level of comfort with radiation oncology and survivorship care. These pilot results support development of a formalized multidisciplinary medical school oncology curriculum at these two institutions. An expanded national survey is being developed to confirm these preliminary findings.     

Immunohistochemical dihydropyrimidine dehydrogenase expression is a good prognostic indicator for patients with Dukes' C colorectal cancer

BACKGROUND: Dihydropyrimidine dehydrogenase (DPD) is an enzyme that catabolizes 5-fluorouracil (5-FU), which is widely used for chemotherapy in patients with advanced colorectal cancer (CRC). However, the clinical importance of tumor dihydropyrimidine dehydrogenase (DPD) expression in patients with CRC treated with 5-FU remains unclear. MATERIALS AND METHODS: We investigated DPD activities in normal mucosa (N) and tumors (T) by enzyme-linked immunosorbent assay (ELISA) in 64 surgically resected patients with Dukes' C CRC who were treated orally with postoperative adjuvant FU-based chemotherapy. We also immunohistochemically investigated DPD expression in these specimens. The clinicopathological importance of DPD activity and expression was evaluated in the patients. RESULTS: Positive DPD expression was detected in 28 tumors (43.8%) and tumor DPD activity significantly correlated with tumor DPD immunoreactivity (p=0.0121). Further, tumor DPD activity and immunoreactivity also correlated with lymph node metastatic status (p=0.0409). The disease-free survival rate of patients with positive-tumor DPD expression was significantly worse than that of patients with negative-tumor DPD expression (39.3% vs. 72.2%, p=0.0127). However, DPD activity in tumors or normal mucosa did not correlate with patient prognosis. Tumor DPD expression appeared to be an important poor prognostic factor in patients with Dukes' C CRC by multivariate analysis (p=0.013). CONCLUSION: Immunohistochemical DPD expression in tumors is a useful prognostic parameter in patients with Dukes' C CRC treated with postoperative adjuvant FU-based chemotherapy.     

5-Fluorouracil-based chemotherapy for advanced colorectal cancer in elderly patients: a north central cancer treatment group study

Although 5-fluorouracil (5-FU)-based chemotherapy is commonly used in patients with advanced colorectal cancer (CRC), little data exist on the tolerability and benefit of therapy in elderly patients. To compare toxicity, dose intensity, response rate, time to tumor progression, and overall survival for older and younger patients, we conducted a pooled analysis of 1748 patients, divided into 4 quartile-based age groups, from 4 North Central Cancer Treatment Group trials testing 5-FU with or without leucovorin for advanced CRC. Patients aged > 65 years had modestly higher rates of severe toxicity (grade >/= 3) overall (53% vs. 46%) and higher rates of diarrhea (21% vs. 16%), stomatitis (17% vs. 13%), and infection (4% vs. 2%). Toxicity rates were similar between patients aged 66-70 years and patients aged > 70 years. The response rate did not differ by age group (2-sided; P = 0.90); it was significantly lower for patients with higher performance status scores (30% for score of 0/1; 17% for 2/3; 2-sided; P = 0.001). Performance status, not age, was predictive of time to tumor progression and overall survival. The older patients with CRC treated with 5-FU have modestly higher rates of severe toxicity, mainly diarrhea and stomatitis. Supportive measures to control diarrhea and stomatitis may be particularly important in elderly patients. Age alone should not be used to determine whether older patients are treated, because performance status is predictive of dose intensity, response rate, time to tumor progression, and overall survival.     

Adjuvant or palliative chemotherapy for colorectal cancer in patients 70 years or older.

PURPOSE: The surgical treatment of colorectal cancer (CRC) in elderly patients (age 70 years or older) has improved, but data on adjuvant and palliative chemotherapy tolerability and benefits in this growing population remain scarce. Elderly patients are underrepresented in clinical trials, and results for older patients are seldom reported separately. PATIENTS AND METHODS: Using a prospective database, we analyzed demographics, chemotherapy toxicity, response rates, failure-free survival (FFS), and overall survival (OS) of CRC patients receiving chemotherapy at the Royal Marsden Hospital. The cutoff age was 70 years. RESULTS: A total of 844 patients received first-line chemotherapy with various fluorouracil (5-FU)-containing regimens or raltitrexed for advanced disease, and 543 patients were administered adjuvant, protracted venous infusion 5-FU or bolus 5-FU/folinic acid (FA) chemotherapy. Of the 1,387 patients, 310 were 70 years or older. There was no difference in overall or severe (Common Toxicity Criteria III to IV) toxicity between the two age groups, with the exception of more frequent severe mucositis in older patients receiving adjuvant bolus 5-FU/FA. For patients receiving palliative chemotherapy, no difference in response rates (24% v 29%, P =.19) and median FFS (164 v 168 days) were detected when the elderly were compared with younger patients. Median OS was 292 days for the elderly group and 350 days for the younger patients (P =.04), and 1-year survival was 44% and 48%, respectively. The length of inpatient hospital stay was identical. CONCLUSION: Elderly patients with good performance status tolerated adjuvant and palliative chemotherapy for CRC as well as did younger patients and had similar benefits from palliative chemotherapy.     

Are clinical guidelines applied in routine daily practice?: a French regional survey of physicians' clinical practices in lung cancer management (EPOTRA)

Background: In 2003 the French government initiated a large cancer plan. This program requested the latest edition of local guidelines in each of France's administrative regions. Since their creation, none of these guidelines has been assessed in the conditions of daily clinical practice. Method: A survey was performed to assess physicians' integrated knowledge of local guidelines in the Rhône-Alpes region in France. It included 4 patient cases with accompanying multiple-choice questions. Responses were judged as appropriate or inappropriate according to the 2007 edition of local guidelines. Results: Four hundred one physicians were contacted. The response rate was 56%. Among the responding physicians, 71 were eligible for analysis (those who were board certified in oncology and pulmonology and practiced thoracic oncology only). The rate of physicians who applied guidelines was 55%, 54%, 63%, and 25% for cases 1 to 4, respectively. There were no major differences in the responses between oncologists and pulmonologists. However significant differences were noted between physicians working in public health centers (cases 1 and 2) and those who practiced in private centers (cases 3 and 4) (appropriate response rate, 68% [case 3] vs. 36% [case 1] [P = .0494] for case 1; 28% [case 4] vs. 9% [case 2] (P = .0022)). Finally, no differences in physician responses were found in the administrative departments within the administrative region. Conclusion: The results of the survey illustrate that regional guidelines are not routinely applied in daily clinical practice. This nonapplication of regional guidelines by physicians may be due to either a lack of knowledge of updates to guidelines or a lack of agreement with them.     

CpG island methylator phenotype is an independent predictor of survival benefit from 5-fluorouracil in stage III colorectal cancer.

PURPOSE: The CpG island methylator phenotype (CIMP) is observed in approximately 30% of colorectal cancer (CRC) cases and is characterized by the concurrent methylation of multiple CpG islands in tumor DNA. This phenotype (CIMP+) is more frequently observed in tumors with proximal location, microsatellite instability, and normal p53. Because it has previously been observed that each of these features is associated with a good survival benefit from 5-fluorouracil (5-FU)-based adjuvant chemotherapy, we investigated in the present study whether CIMP+ has independent predictive value. Experimental Design: CIMP+ status was evaluated in 103 stage III CRCs from patients treated with surgery alone and for an additional 103 cases from patients treated with surgery and adjuvant 5-FU-based chemotherapy. The two cohorts were randomly pair-matched for age, sex, and tumor site, and the median length of follow-up time was 39 months. RESULTS: CIMP+ status predicted survival benefit from 5-FU treatment independently of microsatellite instability and p53 mutation status (relative risk = 0.22; 95% confidence interval, 0.06-0.84; P = 0.027). Unmeasured, high-risk confounding factors could only account for this association if they were unequally distributed between the two patient cohorts by a factor of at least 2-fold. CONCLUSIONS: CIMP+ has independent predictive significance for the survival benefit from 5-FU chemotherapy in CRC. This molecular marker should be incorporated into prospective clinical trials of fluorouracil-based therapies to confirm its clinical value.     

Irinotecan (CPT-11) as first-line monotherapy in patients with advanced, metastatic colorectal cancer refractory to 5-fluorouracil adjuvant chemotherapy: a multicenter phase II study

Irinotecan (CPT-11) is active against colorectal cancer (CRC) refractory to 5-fluorouracil. Further information is needed to confirm whether CPT-11 monotherapy is more effective against tumors than 5-FU monotherapy or if there is cross-resistance of CPT-11 with 5-FU. This study assessed the efficacy and toxicity of CPT-11 350 mg/m² iv, once every 3 weeks, in patients with unsuccessfully pretreated advanced CRC. Thirty-two patients were enrolled and overall 152 cycles were administered. The total objective response rate was 17.9% and the disease stabilized in 11 patients (39.3%). Median time to progression was 3.8 months and me-dian survival was 8.2 months. Grade 3/4 diarrhea was observed in 9 cycles (5.9%) and 6 patients (18.8%), and grade 3/4 neutropenia in 5 cycles (3.3%) and 4 patients (12.5%). CPT-11 monotherapy is an active and well-tolerated first-line chemotherapy for CRC in 5-FU pretreated patients.     

Integrating the anti-VEGF-A humanized monoclonal antibody bevacizumab with chemotherapy in advanced colorectal cancer

Recent advances in the treatment of colorectal cancer (CRC) include the incorporation of new drugs to treat a disease where only one drug was known to be active. Oxaliplatin and irinotecan have been incorporated into 5-fluorouracil (5-FU)-based regimens where they have increased response rates and survival. Targeted therapies against the epidermal growth factor pathway and the vascular endothelial growth factor (VEGF) pathway are also on the forefront of oncology research, and are beginning to play a role in the treatment of CRC. Current research efforts are trying to optimize the integration of targeted therapies into chemotherapy regimens such as IFL (irinotecan/bolus 5-FU/leucovorin [LV]), FOLFIRI (irinotecan/infusional 5-FU/LV), and FOLFOX (oxaliplatin/infusional 5-FU/LV). In this article, the incorporation of the monoclonal antibody bevacizumab into the IFL regimen will be reviewed in detail. Bevacizumab targets VEGF-A, an important angiogenesis signaling factor commonly expressed in metastatic CRC. The addition of bevacizumab to the IFL regimen significantly increased response rates, median time to progression, and overall survival in patients receiving first-line treatment for CRC, thus leading the Food and Drug Administration to approve bevacizumab for the treatment of CRC in combination with 5-FU-based regimens. Bevacizumab treatment is associated with an increased rate of hypertension. In addition, there may be slight (1%-2%) but relevant increased risks related to gastrointestinal perforations and cardiovascular events. A modest increased risk of wound healing complications was observed in patients who underwent surgery while still receiving, or shortly after receiving, bevacizumab. Bevacizumab plus 5-FU is also a highly active first-line regimen. The role of bevacizumab with other first-line combination regimens, as well as its activity in the second-line setting, is now being determined by ongoing clinical trials.     

调强放疗结合诱导化疗或同期加辅助化疗治疗局部晚期鼻咽癌的疗效比较

目的:比较诱导化疗加调强放疗和同期放化疗加辅助化疗治疗局部晚期鼻咽癌的疗效。方法:收集2004年1 月至2008年12月中山大学肿瘤医院收治的经病理证实的局部晚期鼻咽癌240 例,其中采用顺铂+ 5-FU 诱导化疗加调强放疗（诱导组）117 例,采用顺铂、调强放疗同期放化疗加顺铂+ 5-FU 辅助化疗（同期组）123 例。应用Kaplan-Meier 和Log-rank 法计算和比较两组患者的生存率。结果:诱导组和同期组的5 年总生存率、无瘤生存率、无转移生存率、无鼻咽复发生存率和无颈部复发生存率分别为78.0% 和78.7% 、68.9% 和67.5% 、79.0% 和77.0% 、91.6% 和91.0% 、95.3% 和93.7% ,两组比较差异无统计学意义（P>0.05）。 同期组Ⅲ、Ⅳ级恶心呕吐和白细胞减少的发生率明显高于诱导组。多因素分析结果显示N 分期和年龄是影响局部晚期鼻咽癌患者总生存的预后独立因素。结论:诱导化疗加调强放疗治疗局部晚期鼻咽癌的疗效达到同期放化疗加辅助化疗的水平,远处转移是局部晚期鼻咽癌治疗失败的主要原因。      

晚期结直肠癌内科治疗进展

晚期转移性结直肠癌的5年生存率低于10％。5-FU／LV方案治疗的中位生存期大约12个月。最近化疗方案的更新延长了患者的中位生存期。研究发现奥沙利铂、伊立替康联合5-FU／LV或者卡培他滨等化疗方案使中位生存期延长到20个月。奥沙利铂，伊立替康联合5-FU／LV比传统的单药5-FU／LV使生活质量改善时间延长。目前转移性结直肠癌标准的一线治疗方案为FOLFOX和FOLFIRI。正在进行的研究关注新的分子靶向药物（molecular targeted therapy）联合化疗治疗转移性结直肠癌，且部分试验取得了较好的疗效。本文将对5-FU、新一代化疗药物以及分子靶向药物在转移性结肠癌治疗的演进及新进展作一综述。     

Randomised study of tegafur and oral leucovorin versus intravenous 5-fluorouracil and leucovorin in patients with advanced colorectal cancer

This randomised, open-label trial compared oral tegafur (FT)/leucovorin (LV) with the intravenous bolus 5-fluorouracil (5-FU)/LV as first-line chemotherapy for advanced colorectal cancer (CRC). Patients were randomised to receive oral FT 750 mg/m2/day for 21 days and LV 15 mg/m2 every 8 h in cycles repeated every 28 days (n=114), or intravenous LV 20 mg/m2 followed by 5-FU 425 mg/m2 daily for 5 days every 4 weeks for 2 cycles, and later every 5 weeks (n=123). Response rate was significantly higher in the FT/LV arm (27%, 95% CI 19-35) than in the 5-FU/LV arm (13%, 95% CI 7-19) (p<0.004). The median time to progression was 5.9 months (95% CI, 5.3-6.5; FT/LV arm) and 6.2 months (95% CI, 5.4-6.9; 5-FU/LV arm). Median overall survival was 12.4 months (95% CI, 10.3-14.5 months; FT/LV arm) and 12.2 months (95% CI, 8.9-15.7 months; 5-FU/LV arm) (p=n.s.; hazard ratio FT/LV:5-FU/LV=1.02). 5-FU/LV showed a higher incidence of grade 3/4 neutropenia (4.1 vs. 0%). Non-hematological toxicities showed similar incidences in the two treatment arms. Oral FT/LV was more active than IV 5-FU/LV in terms of objective response rate with similar overall survival, and with a favorable toxicity profile. This makes FT/LV a valid alternative to the IV 5-FU schedule in CRC patients.     

Second-line chemotherapy use in metastatic colon cancer varies by disease responsiveness

BACKGROUND: Improved survival of patients with metastatic colorectal cancer (CRC) has been shown to correlate with increased utilization of the 3 active cytotoxic chemotherapeutic agents: 5-fluorouracil (5-FU), irinotecan, and oxaliplatin, usually administered in 2 lines of therapy. However, it is unclear which patient, disease, and treatment characteristics are associated with the utilization of a second-line regimen. PATIENTS AND METHODS: We performed a retrospective chart review. Patients with metastatic CRC treated with bevacizumab outside of a clinical trial and any infusional 5-FU/leucovorin (LV) regimen off-protocol (ie, 5-FU/LV/irinotecan [FOLFIRI]/bevacizumab or 5-FU/LV/oxaliplatin [FOLFOX]/bevacizumab) at the University of Texas M. D. Anderson Cancer Center between February 2004 and September 2005 were included. Prespecified characteristics of age, tumor burden, severe toxicity, and front-line regimen efficacy were compared with exploratory analyses of additional patient, disease, and treatment characteristics. RESULTS: Eighty-seven sequential patients treated with the specified front-line regimens were identified. Seventy-six percent of the eligible patients were treated with a second-line regimen. Despite equal treatment durations, patients with a better response of stable disease were significantly less likely to receive a third cytotoxic agent than patients with a partial response (68% vs. 95%; odds ratio, 8.2; P = .02) due to declining performance status (86%) or patient preference (14%). This was associated with a decreased 2-year overall survival (86% vs. 55%). Neither age, tumor burden, nor development of toxicities were associated with a different utilization of a second-line regimen. CONCLUSION: Failure to obtain a response to initial chemotherapy for metastatic disease appears to be associated with decreased utilization of a second-line regimen.     

A multicenter phase II study of irinotecan (CPT-11) alternated with 5-fluorouracil and leucovorin as first-line treatment of patients with metastatic colorectal cancer

Purpose In this multicenter phase II study the efficacy and safety of the alternating schedule of irinotecan (CPT-11) with bolus 5-fluorouracil (5-FU) and leucovorin (LV) were assessed as first-line chemotherapy in patients with metastatic colorectal cancer (CRC).Patients and methods Enrolled in the study were 43 patients with advanced CRC. They received CPT-11 350 mg/m² i.v. on day 1, alternating with LV 20 mg/m² i.v. and 5-FU 425 mg/m² i.v. daily for five consecutive days, on days 22–26 (Mayo Clinic regimen). One cycle consisted of 6 weeks.Results A total of 179 cycles were administered with a median of four per patient (range one to nine). Efficacy was analyzed on an intention-to-treat basis. The overall objective response rate was 30% (95% CI 16–44), with four complete responses and nine partial responses, whereas 20 patients (4%) showed stable disease. The median time to disease progression was 9.0 months and median survival was 18.5 months. Grade 3/4 diarrhea was mainly related to CPT-11 rather than to 5-FU (9.3% vs 4.7% of patients), whereas grade 3/4 neutropenia was higher during 5-FU administration (16.3% vs 7.0% of patients).Conclusions The alternating schedule of CPT-11 with 5 days bolus of 5-FU and low-dose LV showed a clinical benefit in terms of tumor growth control as first-line treatment of patients with metastatic CRC. The overall safety data confirmed this alternating combination as a well-tolerated treatment.     

A polymorphism in the enhancer region of the thymidylate synthase promoter influences the survival of colorectal cancer patients treated with 5-fluorouracil

High levels of thymidylate synthase (TS) expression have been associated with poor survival of colorectal cancer (CRC) patients to 5-fluorouracil (5-FU)-based chemotherapy. Recent evidence suggests that a polymorphism within the enhancer region of the TS gene promoter can influence TS expression, with the triple repeat homozygote (3R/3R) being associated with significantly higher tumour TS levels than either the double repeat homozygote (2R/2R) or heterozygotes (2R/3R). In the present study we investigated whether TS genotype was associated with the degree of survival benefit from chemotherapy in 221 Dukes' C stage CRC patients. Patients with the 3R/3R polymorphism (n = 58, 26%) showed no significant long-term survival benefit from chemotherapy (RR = 0.62, 95% CI: 0.30-1.25, P = 0.18), whereas those with the 2R/2R or 2R/3R genotype (n = 163, 74%) showed significant gains in survival from this treatment (RR = 0.52, 95% CI: 0.52-0.82, P = 0.005). These results demonstrate that a polymorphism within the TS gene, probably through its effect on TS expression levels, can influence the survival benefit obtained by CRC patients from 5-FU-based chemotherapy.     

Gender differences in the dihydropyrimidine dehydrogenase expression of colorectal cancers

Dihydropyrimidine dehydrogenase (DPD) is the initial, rate-limiting enzyme in the catabolism of 5-fluorouracil (5-FU). DPD expression levels are believed to correlate with the 5-FU sensitivity of malignant tumors. In colorectal cancer (CRC), a few previous studies demonstrated that females could benefit more from adjuvant chemotherapy. However, it is still unknown why the effectiveness of postoperative chemotherapy is affected by gender. The objective of this study was to clarify the beneficial differences in 5-FU chemotherapy between genders in patients with the CRC based on DPD expression. Ninety-seven tumor specimens and 92 adjacent normal tissue specimens from 97 patients with the CRC and no prior therapy were obtained. The DPD expression in the tissues was quantified and analyzed based on clinicopathological factors. In the tumor tissue, the DPD expression in females was significantly lower than that in males. In the normal tissues, however, there were no significant differences in DPD expression between genders. In the treatment of CRC, cases who will benefit most because of 5-FU sensitivity; i.e. cases with lower DPD expression, must be given priority. Based on DPD expression, female gender seems to be a predictive factor for a better response to chemotherapy with 5-FU.     

A novel continuous infusional 5-fluorouracil-based chemotherapy regimen compared with conventional chemotherapy in the neo-adjuvant treatment of early breast cancer: 5 year results of the TOPIC trial.

BACKGROUND: To compare the efficacy of continuous infusional 5-fluorouracil (5-FU)-based chemotherapy against conventional bolus chemotherapy in the preoperative treatment of patients with large operable early breast cancer. PATIENTS AND METHODS: Four hundred and twenty-six women with histologically proven 3 cm invasive early breast cancer were randomised to receive pre-operative infusional 5-FU 200 mg/m(2) by daily 24 h continuous infusion via a Hickman line for 18 weeks with epirubicin 60 mg/m(2) intravenous (i.v.) bolus on day 1 and cisplatin 60 mg/m(2) i.v. bolus on day 1, both repeating 3-weekly (infusional ECisF), or conventional bolus doxorubicin 60 mg/m(2) i.v. on day 1 and cyclophosphamide 600 mg/m(2) i.v. on day 1, both repeating 3-weekly (AC), both schedules for six courses. Patients subsequently had local therapy (surgery or radiotherapy or both) and tamoxifen 20 mg orally daily as appropriate. RESULTS: The 5 year results for AC and infusional ECisF, respectively, were as follows: overall response, 75% and 77%; complete clinical remission, 31% and 34%; pathological complete remission (pathCR), 16% for both; and pathCR with residual ductal carcinoma in situ (DCIS), 25% and 24%. Mastectomy rates were 37% and 34%, respectively. Five-year overall survival was 74% for AC and 82% for infusional ECisF (hazard ratio 0.76, 95% confidence interval 0.51-1.13; P = 0.18). Both treatments were well tolerated. Grade III/IV lethargy, vomiting, alopecia and plantar-palmar erythema were significantly greater for infusional ECisF; grade III/IV leucopenia was significantly greater for AC. CONCLUSIONS: Preoperative continuous infusional 5-FU-based chemotherapy is no more active than conventional AC for early breast cancer; with a median 5 year follow-up, the infusion-based schedule shows a non-significant trend towards improved survival.     

Molecular determinants of response to 5-fluorouracil-based chemotherapy in colorectal cancer: The undisputable role of micro-ribonucleic acids

5-flurouracil (5-FU)-based chemotherapy is the main pharmacological therapy for advanced colorectal cancer (CRC). Despite significant progress in the treatment of CRC during the last decades, 5-FU drug resistance remains the most important cause of failure in CRC therapy. Resistance to 5-FU is a complex and multistep process. Different mechanisms including microsatellite instability, increased expression level of key enzyme thymidylate synthase and its polymorphism, increased level of 5-FU-activating enzymes and mutation of TP53 are proposed as the main determinants of resistance to 5-FU in CRC cells. Recently, micro-ribonucleic acids (miRNA) and their alterations were found to have a crucial role in 5-FU resistance. In this regard, the miRNA-mediated mechanisms of 5-FU drug resistance reside among the new fields of pharmacogenetics of CRC drug response that has not been completely discovered. Identification of the biological markers that are related to response to 5-FU-based chemotherapy is an emerging field of precision medicine. This approach will have an important role in defining those patients who are most likely to benefit from 5-FU-based chemotherapy in the future. Thereby, the identification of 5-FU drug resistance mechanisms is an essential step to predict and eventually overcome resistance. In the present comprehensive review, we will summarize the latest knowledge regarding the molecular determinants of response to 5-FU-based chemotherapy in CRC by emphasizing the role of miRNAs.     

Determination of microsatellite instability, p53 and K-RAS mutations in hepatic metastases from patients with colorectal cancer: relationship with response to 5-fluorouracil and survival

In vitro and clinical studies have suggested that high-frequency microsatellite instability (MSI-H) phenotype, p53 and K-ras mutations might influence the response to chemotherapy in a variety of tumors, including primary colorectal cancers (CRC). Unresectable hepatic metastases from CRC are commonly treated with 5-fluorouracil (5FU) and folinic acid. Since several new active drugs are now used for treating CRC, molecular determinants predictive to response to 5FU would thus be crucial for optimizing indications of chemotherapy to those patients. MSI-H phenotype, p53 and K-ras status were characterized in a prospective study of 56 patients with CRC metastatic to the liver and treated with 5FU-based chemotherapy. The objective response rate after a 3-month treatment was 32.1%. The prevalence of p53 mutations, K-ras mutations and MSI-H phenotype was 62.5%, 30.3% and 1.8%, respectively. No significant association was found between response to chemotherapy and p53 mutations (78% mutated tumors in responders vs. 55% in nonresponders; p = 0.10) and K-ras mutations (39% mutated tumors in responders vs. 26% in nonresponders; p = 0.34). Survival was longer for patients with p53-mutated metastases than for patients with unresected wild-type p53 metastases (median survival 15 months vs. 17 months; p = 0.06). The determination of the MSI-H phenotype, p53 and K-ras status in hepatic metastases from CRC does not discriminate a group of patients that should preferentially benefit from 5FU-based chemotherapy. The prognosis of patients with treated liver metastases is better when p53 is mutated.