大肠癌的靶向治疗

大肠癌是最常见的恶性肿瘤之一,全世界每年大约有近100万的新发病例,至少有50万患者因其而死亡[1].大肠癌的传统治疗方法主要有手术治疗、放射治疗、化学药物治疗.目前,大肠癌的靶向治疗已经成为其第4种治疗方法,同时也是临床研究的热点和争论较多的问题.现就近年来大肠癌的靶向治疗进展综述如下.     

Colorectal cancer. Are adjuvant therapies beneficial?

The American Cancer Society's recommendations for screening the population at normal risk for colorectal cancer have been promoted since 1983. Additional study of the effectiveness of these recommendations is in progress, but the medical community has generally endorsed them and urges their implementation in office practice. To date, chemotherapy is not clearly indicated as adjuvant therapy, but enrollment of patients in cooperative group protocols is recommended. Use of second-look surgery to resect selected recurrent tumors has increased in recent years, in part because of the contribution of the computed tomographic scan and carcinoembryonic antigen assay to follow-up of postoperative patients. For advanced disease, technologic advances have improved the technique of hepatic artery perfusion with chemotherapeutic agents, but evidence of a survival advantage afforded by this method is still lacking. Single-agent chemotherapy with fluorouracil remains the best choice for palliating advanced disease, but hepatic artery perfusion with floxuridine also may relieve liver-dominant disease.     

Capecitabine: a new adjuvant option for colorectal cancer

Colorectal cancer continues to pose a major public health threat in the United States. Without postsurgical adjuvant therapy, approximately 50% of patients will have recurrent disease and die within five years. Since 1990, five new chemotherapy agents have been added to the therapeutic armamentarium for management of colorectal cancer, and agents traditionally used to treat metastatic and advanced disease increasingly are being applied in the adjuvant setting. One such treatment, capecitabine, offers patients the benefit of oral dosing and permits at-home self-management. A phase III randomized trial, Xeloda in Adjuvant Colorectal Cancer Treatment, demonstrated that treatment with single-agent capecitabine was equivalent to bolus 5-fluorouracil with leucovorin with respect to disease-free survival and overall survival, with significantly less diarrhea, stomatitis, neutropenia, nausea and vomiting, and alopecia. This article reviews the findings and discusses how oncology nurses can help provide effective education and monitoring for patients using oral treatment in the adjuvant setting.     

结直肠癌患者术后辅助化疗依从性的影响因素分析及对策

目的探讨Ⅱ期或Ⅲ期结直肠癌患者术后辅助化疗依从性的影响因素，提出相应对策。方法对2005年1月-2007年1月在本科室行结直肠癌根治术后行辅助化疗的138例患者进行术后随访，分析患者化疗依从性的影响因素。结果138例患者中失访26例，112例随访患者中依从43例，部分依从40例，不依从29例。不同文化程度、付费方式、病理分期、知情程度、化疗方案的结直肠癌患者术后辅助化疗依从性的差异有统计学意义（均P〈0．05）。结论针对患者的个性特点对其进行有针对性的健康教育、采用多渠道方式缓解患者经费困难、进行合理的资金分配、重视患者的知情权．充分告知等是提高结直肠癌根治术后辅助化疗依从性的有效措施。     

Arterial therapies of colorectal cancer metastases to the liver

Intra-arterial therapies directed to the liver take advantage that liver tumors are fed by the hepatic artery while the liver vascularization is 30% arterial. Most common techniques of intra-arterial therapies for colorectal cancer liver metastases (CRLM) include intra-arterial hepatic chemotherapy (IAHC), transarterial chemoembolization (TACE), and radioembolization. Such treatments are used as salvage therapies because they provide response when systemic therapies are inefficient. They are also used as a first line therapy to produce maximal response in order to convert the patient from non-surgical to surgical. IAHC with FUDR or oxaliplatinum allow 90% response rate and conversion to surgery of 40% to 50% of initially inoperable patients. TACE is used in CRLM with promising response rate, namely due to the use of drug eluting beads that can be loaded with irinotecan which can elute the drug they contain after embolization in liver tumor. Radioembolization is a unique way of delivering a high tumoricidal dose of radiation (>100 Gy) to liver tumor without harming the healthy liver, and provided interesting results in salvage therapy, enough to be evaluated today in a randomized control trial in first line therapy where FOLFOX is proposed with and without additional radioembolization.     

Side effects of adjuvant therapies of breast cancer: their significance for the patient

In a retrospective survey we interviewed 53 patients with respect to side effects of adjuvant therapy for breast cancer. All of them had undergone modified mastectomy and were randomly assigned to either chemotherapy, irradiation or a combination of both. Standardized questionnaires concerning the side effects and semi-structured, focusing counseling talks were the methods used in questioning the patients. Patients named significantly more side effects of severe and extreme intensity with chemotherapy, and especially in the group given combination therapy, where chemo- and radiotherapy could be directly compared by the patient. The experience was particularly threatening when several side effects occurred simultaneously. Different psychological aspects and visualisation of systemic and local side effects are discussed with respect to the patient's ability to cope with adjuvant therapy. Consequences for routine care are: continuous explanatory talks about side effects throughout the whole process, muscle relaxation and interdisciplinary cooperation.     

The value of adjuvant therapy after radical surgery for colorectal cancer.

Extensive efforts to improve survival for patients with colorectal cancer using adjuvant treatments in addition to radical surgery have long been tried but without success. Recent data from several controlled trials have, however, shown positive results. The collected information from several trials using different chemotherapy schedules indicate that overall survival is improved. The extent of this improvement is not properly known although several centres have considered it to be sufficiently large to merit routine use in certain stages. Likewise, the collected information from several trials using perioperative radiotherapy indicates that the proportion of local recurrences are reduced by about 50% but without any major influence on survival. Most evidence favours additional radiotherapy before surgery rather than after. If proper dose planning is utilized, sufficiently high doses can be given preoperatively without increasing postoperative mortality.     

76例结直肠癌患者根治术后 FOLFOX4方案辅助化疗的临床观察

目的：观察结直肠癌(CRC)根治术后患者12周期奥沙利铂(OXA)、亚叶酸钙(CF)、5-氟尿嘧啶(5-FU) FOLFOX4方案辅助化疗的完成情况,分析未完成的原因,为探索适合我国 CRC 患者的化疗剂量和化疗周期数提供依据。方法76例根治术后病理确诊为 CRC 的患者行 FOLFOX4方案辅助化疗,参见美国国立癌症研究所常见毒性反应标准3.0版本(NCI-CTCAE,v3.0)标准对化疗期间的不良反应进行分级,总结未完成化疗的原因,化疗结束后定期随访,观察无瘤生存期和复发转移发生情况。结果76例患者中10例(13.2%)未经减量完成了标准12周期FOLFOX4方案辅助化疗,全组中位化疗周期时间为7(1~12)周期,需要减量的比例31.6%(24/76),剂量调整中位周期时间为第4(2~10)周期,中止化疗的原因主要有患者依从性(30/66,45.5%)、不良反应(26/66,39.4%)等。治疗过程中的不良反应包括3~4度骨髓抑制(48/76,63.2%)、1~2度肝脏毒性(55/76,72.4%)、1~2级胃肠道反应(41/76,53.9%)、周围神经毒性(15/76,19.7%)、OXA 过敏反应(9/76,11.8%)。随访期间死亡3例,14例患者发生复发和(或)转移,其中复发4例,转移13例,3例同时复发和转移,中位复发或转移时间分别为14.0(13.8~20.5)、15.5(7.0~33.9)个月。全组患者中位无瘤生存期25.6(7.0~47.8)个月。结论 CRC 患者根治术后 FOLFOX4方案化疗可降低复发转移率,本组患者标准12周期方案完成率低,化疗期间不良事件发生率较高,需要探索适合中国人的化疗剂量和化疗周期数。     

Patients' perception of information after completion of adjuvant radiotherapy for breast cancer

Purpose of the researchThe aims of the present study were to examine patients' perceptions of received information and satisfaction with information after completion of adjuvant radiotherapy (RT) for breast cancer. Associations between satisfaction with information and health related quality of life (HRQoL), and clinical variables were also studied.Methods and sampleA total of 93 consecutive women planned for adjuvant RT were asked to complete two questionnaires (EORTC QLQ-C30 and QLQ-INFO25) in connection with their last treatment.Key resultsA total of 88 patients (95%) responded. The mean values for the information subscale scores, on a 0 to 100 point scale (QLQ-INFO25) regarding “the treatments” and “the disease” were 46 and 53 respectively. A total of 48% of the patients expressed a wish for more information. Patients treated with chemotherapy previous to RT reported statistically significant lower levels of information about “the disease”. Age was statistically significant related to satisfaction with received information. Younger women were less satisfied with the information received, and a higher proportion wanted more information (55%), as well among women treated with chemotherapy previous to RT (63%). Patients satisfied with information scored significantly higher on global health status and emotional functioning and reported less fatigue. Positive associations were found between “satisfaction with information” and HRQoL.ConclusionsImprovements of information to breast cancer patients during their treatments are needed. The results also underline the need for patient-centred information in general and that extra attention should be paid to younger women and patients undergoing combined treatment.     

Molecularly targeted therapies for colorectal cancer: Strategies for implementing translational research in clinical trials

Few breakthroughs in preclinical research have translated into meaningful benefits, either in clinical terms or quality of life, for patients with advanced colorectal cancer, despite important preclinical discoveries regarding aberrant biological pathways associated with disease development and progression. The many reasons for the slow progress are diverse, ranging from the failure to codevelop biomarkers and targeted therapies, the regulatory burdens imposed on academic investigators, and the failure to collect serial tumor biopsies during clinical trials. This review discusses promising translational research that could help reduce the disparity between preclinical discovery and patient benefit, and advocate the concentration of efforts and resources on the most promising therapeutic targets in colorectal cancer, such as EGFR, VEGF and Fcγ receptor.     

Limited sampling model for the analysis of 5-fluorouracil pharmacokinetics in adjuvant chemotherapy for colorectal cancer

BACKGROUND: Administration of 5-fluorouracil may be associated with life-threatening toxicities, resulting from a reduced drug biotransformation to the inactive metabolite 5-fluoro-5,6-dihydrouracil. Patients with severe toxicities display significant alterations of 5-fluorouracil pharmacokinetics, the monitoring of which may be made easier by the availability of a limited sampling model (LSM). METHODS: LSMs for 5-fluorouracil and 5-fluoro-5,6-dihydrouracil therapeutic monitoring have been developed in 80 patients with colorectal cancer (training set) given 5-fluorouracil, 370 mg/m(2) per day as an intravenous bolus, plus leucovorin, 100 mg/m(2) per day, for 5 days every 4 weeks. Pharmacokinetic analysis was performed on plasma levels of 5-fluorouracil and 5-fluoro-5,6-dihydrouracil obtained on day 1 of the first cycle of chemotherapy, and backward stepwise regression analysis was used to determine the optimal LSM on the basis of bias (percentage mean prediction error [MPE]) and precision (percentage root mean square prediction error [RMSE]). RESULTS: An optimal model based on 2 time points was obtained (percentage MPE = 1.99% +/- 1.41%; percentage RMSE = 12.70% +/- 1.27%), and the predicted area under the time versus plasma concentration curve (AUC) was calculated as follows: predicted AUC (h x microg/mL) = 0.119 x C(5) + 1.436 x C(45) + 2.066, in which C(5) and C(45) are plasma concentrations of 5-fluorouracil at 5 and 45 minutes after drug administration, respectively. The application of this algorithm to pharmacokinetic analysis of plasma levels of 5-fluorouracil in 80 patients (test set) allowed a precise estimation of AUC (percentage MPE = -0.09% +/- 1.37%; percentage RMSE = 12.17% +/- 1.23%). The best LSM for 5-fluoro-5,6-dihydrouracil was characterized by a percentage MPE of -0.64% +/- 0.86% and a percentage RMSE of 7.64% +/- 0.81%, and the optimal sampling time points were 45 and 180 minutes. CONCLUSION: The current LSM allows a reliable assessment of drug exposure and improves the use of therapeutic drug monitoring for treatment optimization of 5-fluorouracil in patients with cancer.     

Heterogeneous staining for mismatch repair proteins during population-based prescreening for hereditary nonpolyposis colorectal cancer

The aim of this study was to determine the frequency of microsatellite instability (MSI(+)) in tumors from a population-based series of young colorectal cancer patients and its correlation with the loss of expression of mismatch repair (MMR) proteins. The BAT-26 mononucleotide repeat was used to screen for MSI(+) in all colorectal cancers diagnosed in Western Australia throughout a 5-year period in patients <60 years of age. MSI(+) was found in 75 of 1003 (7.5%) cases, of which six contained a concomitant mutation in BRAF and were therefore excluded from further investigations as possible hereditary nonpolyposis colorectal cancer. Immunohistochemistry was used to evaluate expression of the four major MMR proteins (MLH1, MSH2, MSH6, and PMS2) in the remaining 69 MSI(+) tumors. Complete loss of MLH1 and PMS2 expression or of MSH2 and MSH6 expression was found in 35 (51%) and 17 (25%) cases, respectively, whereas other patterns of complete loss were observed in eight cases (12%). Eight tumors (12%) were initially recorded as showing normal expression, but on review seven were reclassified as having abnormal staining because of heterogeneous patterns of MMR loss. Three of these seven cases had previously been found to have germline mutations. Because of possible misinterpretation of heterogeneous immunohistochemistry staining for MMR protein loss, MSI testing is recommended as the initial screen for population-based detection of hereditary nonpolyposis colorectal cancer.     

Combined chemotherapy of hydroxycampothecin with oxaliplatin as an adjuvant treatment for human colorectal cancer

Colorectal cancer (CRC) is a major cause of morbidity and mortality for cancer worldwide, but many patients with CRC are resistant to chemotherapy. We therefore investigated the therapeutic mechanism and clinical effect of combined chemotherapy of hydroxycampothecin (HCPT) with oxaliplatin (L-OHP) on CRC. HCPT represents a potential antitumor agent of Chinese herb. Mice carrying the xenografted human LS174T CRC cells were injected into peritoneal cavities with different drugs: HCPT + L-OHP (OH), HCPT, L-OHP, or saline. Treatment of mice with OH caused the decrease in the volume of tumor and the expression of p53, but increased the apoptotic rate and Fas-L expression, compared to those of animals treated with HCPT or L-OHP, or control animals. Thus, the combination of HCPT with L-OHP could more effectively induce the apoptosis of CRC cells. Furthermore, 56 patients with CRC were treated with HCPT and L-OHP (28 cases, OH group) or L-OHP plus leucovorin plus 5-fluorouracil (28 cases, OFL group), then reviewed the response rate, survival rate and toxicity. The one-year survival rate was 35.07% in OH group and 24.21% in OFL group. However, the occurrence of anemia (51.8%) or diarrhea (60.7%) was higher in OH group than that of 19.6% or 46.4% in OFL group. The clinical results suggest that HCPT plus L-OHP combined chemotherapy could increase the survival time of patients. Taken together, the present study indicates that the combined chemotherapy of HCPT with L-OHP could become a new adjuvant treatment for CRC.     

Faecal haemoglobin concentrations by gender and age: implications for population-based screening for colorectal cancer

Abstract Background: Faecal immunochemical tests (FIT) are becoming widely used in colorectal cancer screening. Estimation of faecal haemoglobin concentration in a large group prompted an observational study on gender and age. Methods: A single estimate of faecal haemoglobin concentration was made using quantitative automated immunoturbidimetry. Potential reference intervals were calculated for men and women and for age quintiles according to the Clinical and Laboratory Standards Institute Approved Guideline. The percentages of positive results were calculated at a number of concentrations. The percentages of individuals who fell into different risk groups were assessed. Results: The 97.5 percentiles, potential upper reference limits, were 519 ng haemoglobin/mL (90% CI: 468-575) for men and 283 ng haemoglobin/mL (90% CI: 257-316) for women. Concentrations increased with age in both genders. Decision limits have advantages over reference intervals. At any cut-off concentration, more men are declared positive than women and more older people are declared positive than younger people. Future risk of neoplasia is higher in men than in women and in older people. Conclusions: Faecal haemoglobin concentrations vary with gender and age. More tailored strategies are needed in screening programmes. Faecal haemoglobin concentration could be included in individual risk assessment scores. These data should assist in screening programme design.