结肠癌全身辅助化疗的进展

Ⅲ期结肠癌的术后辅助化疗具有明显的生存效益,主要采用以5-FU为基础的全身化疗方案,包括5-FU/Lev、Mayo(FU/LV)方案、持续小剂量灌注(PVI)5-FU、口服氟尿嘧啶类抗癌药(UFT、Xeloda)等;5-FU合用草酸铂可以进一步提高疗效,与依立替康合用的疗效有待于进一步研究。Ⅱ期结肠癌术后辅助化疗的生存效益目前尚有争议,对高危Ⅱ期肠癌患者也应考虑行术后辅助化疗。本文综述了近年来结肠癌术后辅助化疗的进展。     

Adjuvant Chemotherapy and Prognostic Factors in Stage II Colon Cancer - Izmir Oncology Group Study

Background: Although adjuvant chemotherapy is a standard treatment in stage III colon cancer, its benefitis not as clear for stage II patients. In this retrospective analysis, we aimed to evaluate the survival of patientswith low-risk stage II colon cancer, the efficacy of adjuvant chemotherapy in high-risk stage II colon cancerpatients, and prognostic factors in stage II disease. Materials and Methods: One hundred and seventeen patientswho were diagnosed with stage II colon cancer between January 2006 and December 2011 were included inthe study. Patients were stratified into two groups as being low-risk and high-risk according to risk factorsfor stage II disease. Adjuvant 5-fluorouracil-based chemotherapy were administered to the patients with riskfactors. Results: Ninety-four patients were treated with adjuvant chemotherapy due to high risk factors and 23were monitored without treatment. Median follow-up time was 43 months. In terms of disease free survival andoverall survival, adjuvant chemotherapy did not provide a statistically significant difference. Univariate analysisdemonstrated that bowel obstruction was the major risk factor for shortened disease-free survival, while bowelperforation and perineural invasion were both negative prognostic factors for overall survival. Conclusions:The recommendation of adjuvant chemotherapy for stage II colon cancer is not clear. In our study, it was foundthat adjuvant chemotherapy did not contribute to survival in high-risk stage II patients. Due to the fact thatprognosis of stage II patients is good, many more patients will be needed for statistically significant differences insurvival. Adjuvant chemotherapy containing 5 fluorouracil is being used to high-risk stage II patients althoughit is not a standard treatment approach.     

Adjuvant Chemotherapy for Colon Cancer: Guidelines and Clinical Trials in Japan

In Japan, adjuvant chemotherapy for colon cancer was mainly developed using oral fluoropyrimidines. However, all Japanese studies to date have failed to demonstrate a statistically significant survival benefit of adjuvant chemotherapy with a combination of uracil and tegafur (UFT) monotherapy over surgery alone in patients with stage II or III colon cancer. The non-inferiority trials comparing different oral fluoropyrimidine monotherapies showed any fluoropyrimidine except S-1 was comparable in patients with stage III colon cancer. Japanese guideline plays an important role in the distribution of the optimal adjuvant treatment. In addition, the tolerability of oxaliplatin-based adjuvant chemotherapy was confirmed, and a multigene assay was validated in Japanese patients. A global collaboration is ongoing to test whether disease-free survival with 3 months of oxaliplatin-based adjuvant chemotherapy was non-inferior to that with 6 months of identical chemotherapy in patients with stage III or high-risk stage II colon cancer and is one of the best model task forces for the coordination of future adjuvant chemotherapy regimens in patients with colon cancer. These findings and further research will help define treatment duration and patient selection criteria for the personalization of adjuvant chemotherapy for colon cancer.     

Randomized controlled trial of the efficacy of adjuvant immunochemotherapy and adjuvant chemotherapy for colorectal cancer, using different combinations of the intracutaneous streptococcal preparation OK-432 and the oral pyrimidines 1-hexylcarbamoyl-5-fluorouracil and uracil/tegafur

Background We investigated the efficacy and safety of adjuvant immunochemotherapy and adjuvant chemotherapy for colorectal cancer, using different combinations of the intracutaneous streptococcal preparation OK-432 and the oral pyrimidines 1-hexylcarbamoyl-5-fluorouracil (carmofur, HCFU) and uracil/tegafur (UFT).Methods Patients with stage II, III, or IV (Dukes B, C) colorectal cancer were enrolled and randomly assigned to one of three groups: an immunochemotherapy group (mitomycin C [MMC] + 5-fluorouracil [5-FU] + HCFU + OK-432), a chemotherapy group (MMC + 5-FU + HCFU), and a control group (surgery alone) for those with colon cancer (study 1); and an immunochemotherapy group (MMC + 5-FU + UFT + OK-432), a chemotherapy group (MMC + 5-FU + UFT), and a control group (surgery alone) for those with rectal cancer (study 2).Results A total of 760 patients with colon cancer and 669 patients with rectal cancer were entered into this randomized clinical trial (RCT). The incidence of side-effects was in the order of: immunochemotherapy group chemotherapy group control group in both the cohort of patients with colon cancer and the cohort with rectal cancer. In particular, the frequency of leucopenia and skin disorders was significantly higher than control groups. There were no severe adverse events such as death related to the adjuvant therapy. In both the colon cancer and rectal cancer cohorts, no significant difference in the 5-year survival rate and disease-free survival rate was noted among the three groups.Conclusion The results of an RCT demonstrated that the combination of MMC + 5-FU + HCFU + OK-432 for colon cancer and that of MMC + 5-FU + UFT + OK-432 for rectal cancer could not prolong the survival of patients with surgically resected colorectal cancer, but that both combinations were well tolerated as adjuvant therapy.     

Randomized phase III trial of treatment duration for oral uracil and tegafur plus leucovorin as adjuvant chemotherapy for patients with stage IIB/III colon cancer: final results of JFMC33-0502

BackgroundWhile adjuvant chemotherapy is preferable for high-risk colon cancer, treatment duration is controversial. Oral uracil and tegafur (UFT)/leucovorin (LV) is widely used as a standard adjuvant chemotherapy for colon cancer in Japan. We conducted a phase III trial to investigate the optimal duration of adjuvant chemotherapy for stage IIB/III colon cancer.Patients and methodsPatients with curatively resected stage IIB/III colon cancer were eligible for enrollment in this trial. Patients were registered within 6 weeks after surgery and were randomly assigned to receive UFT/LV for 28 of 35 days for 6 months in the control group or for 5 consecutive days per week for 18 months in the study group. The primary end point was the disease-free survival (DFS), and the secondary end points were overall survival (OS) and safety.ResultA total of 1071 patients were registered from 233 centers. A statistically significant difference in DFS was not observed between the study group and the control group; the 5-year DFS was 69% in the study group and 69% in the control group. The 5-year OS was 85% in the study group and 85% in the control group.ConclusionEighteen-month treatment with UFT/LV did not improve DFS or OS compared with 6-month UFT/LV treatment in patients with stage IIB/III colon cancer. The important finding from this study is that not 18 months but 6 months of treatment is enough for postoperative UFT/LV for stage IIB/III colon cancer.Clinical trial numberUMIN-CTR C000000245.     

A randomized phase III trial comparing S-1 versus UFT as adjuvant chemotherapy for stage II/III rectal cancer (JFMC35-C1: ACTS-RC)

BackgroundsPreventing distant recurrence and achieving local control are important challenges in rectal cancer treatment, and use of adjuvant chemotherapy has been studied. However, no phase III study comparing adjuvant chemotherapy regimens for rectal cancer has demonstrated superiority of a specific regimen. We therefore conducted a phase III study to evaluate the superiority of S-1 to tegafur–uracil (UFT), a standard adjuvant chemotherapy regimen for curatively resected stage II/III rectal cancer in Japan, in the adjuvant setting for rectal cancer.Patients and methodsThe ACTS-RC trial was an open-label, randomized, phase III superiority trial conducted at 222 sites in Japan. Patients aged 20–80 with stage II/III rectal cancer undergoing curative surgery without preoperative therapy were randomly assigned to receive UFT (500–600 mg/day on days 1–5, followed by 2 days rest) or S-1 (80–120 mg/day on days 1–28, followed by 14 days rest) for 1 year. The primary end point was relapse-free survival (RFS), and the secondary end points were overall survival and adverse events.ResultsIn total, 961 patients were enrolled from April 2006 to March 2009. The primary analysis was conducted in 480 assigned to receive UFT and 479 assigned to receive S-1. Five-year RFS was 61.7% [95% confidence interval (CI) 57.1% to 65.9%] for UFT and 66.4% (95% CI 61.9% to 70.5%) for S-1 [P = 0.0165, hazard ratio (HR): 0.77, 95% CI 0.63–0.96]. Five-year survival was 80.2% (95% CI 76.3% to 83.5%) for UFT and 82.0% (95% CI 78.3% to 85.2%) for S-1. The main grade 3 or higher adverse events were increased alanine aminotransferase and diarrhea (each 2.3%) in the UFT arm and anorexia, diarrhea (each 2.6%), and fatigue (2.1%) in the S-1 arm.ConclusionOne-year S-1 treatment is superior to UFT with respect to RFS and has therefore become a standard adjuvant chemotherapy regimen for stage II/III rectal cancer following curative resection.     

Risk assessment and adjuvant systemic therapy in resected stage II colon cancer

Adjuvant chemotherapy following surgical resection of stage III colon cancer has become the standard of care based on numerous large randomized trials that have demonstrated benefit in overall survival. For patients with stage II colon cancer, the picture is more uncertain. Although clinical trials have not reported a significant survival benefit for adjuvant chemotherapy in stage II disease, patients with certain high-risk clinical and pathologic features may warrant postoperative treatment. Molecular markers, such as 18q loss of heterozygosity and mi crosatellite instability, may also help to prognosticate patients with stage II colon cancer, although data supporting their role have been largely retrospective. The role of these markers in stage II disease is being prospectively investigated. Continued enrollment in clinical trials and further risk stratification will help clarify the optimal management of patients with stage II colon cancer.     

An overview of adjuvant systemic chemotherapy for colon cancer

This article summarizes the progress of adjuvant systemic chemotherapy of colon cancer. The study by Moertel et al that showed that the combination of 5-fluorouracil (5-FU) and levamisole in the adjuvant setting reduced mortality by 33% in stage III colon cancer; 5-FU/leucovorin (LV) became the standard of care in the adjuvant treatment of colon cancer after it showed superiority to 5-FU/levamisole. However, no standard schedule of 5-FU/LV has been established. The fortnightly regimen of bolus 5-FU/LV and continuous infusion 5-FU (LV5FU2) has the same efficacy as and is less toxic than the monthly regimen of bolus 5-FU/LV. Oxaliplatin combined with 5-FU and LV (FOLFOX4) is the first combination to demonstrate significant superiority in 3-year disease-free survival as compared with 5-FU/LV in the adjuvant treatment of colon cancer. Three-year disease-free survival is an excellent predictor of 5-year overall survival and, in future studies, can serve as a reliable endpoint that is associated with reproducible 5-year overall survival. Results of studies testing irinotecan combined with 5-FU and LV are not yet available. Adjuvant chemotherapy for patients with stage II colon cancer is a controversial subject. Because the available data suggest that stage II patients benefit from adjuvant chemotherapy, although to a lesser extent than patients with stage III disease, all patients with stage III and high-risk stage II disease should be offered adjuvant treatment with the new standard of care, FOLFOX4. Future studies in adjuvant therapy for colon cancer will explore oxaliplatin and 5-FU with or without antiangiogenesis or anti-epidermal growth factor agents.     

Safety of UFT/LV and S-1 as adjuvant therapy for stage III colon cancer in phase III trial: ACTS-CC trial

Background:

The Adjuvant Chemotherapy Trial of TS-1 for Colon Cancer (ACTS-CC) is a phase III trial designed to validate the non-inferiority of S-1 to UFT/leucovorin (LV) as postoperative adjuvant chemotherapy for stage III colon cancer. We report the results of a planned safety analysis.

Methods:

Patients aged 20–80 years with curatively resected stage III colon cancer were randomly assigned to receive UFT/LV (UFT, 300 mg m⁻² per day as tegafur; LV, 75 mg per day on days 1–28, every 35 days, 5 courses) or S-1 (80, 100, or 120 mg per day on days 1–28, every 42 days, 4 courses). Treatment status and safety were evaluated.

Results:

Of 1535 enrolled patients, a total of 1504 (756 allocated to S-1 and 748 to UFT/LV) were analysed. The completion rate of protocol treatment was 77% in the S-1 group and 73% in the UFT/LV group. The overall incidence of adverse events (AEs) were 80% in S-1 and 74% in UFT/LV. Stomatitis, anorexia, hyperpigmentation, and haematological toxicities were common in S-1, whereas increased alanine aminotransferase and aspartate aminotransferase were common in UFT/LV. The incidences of ⩾grade 3 AEs were 16% and 14%, respectively.

Conclusion:

Although AE profiles differed between the groups, feasibility of the protocol treatment was good. Both S-1 and UFT/LV could be safely used as adjuvant chemotherapy.     

American Society of Clinical Oncology recommendations on adjuvant chemotherapy for stage II colon cancer.

PURPOSE: To address whether all medically fit patients with curatively resected stage II colon cancer should be offered adjuvant chemotherapy as part of routine clinical practice, to identify patients with poor prognosis characteristics, and to describe strategies for oncologists to use to discuss adjuvant chemotherapy in practice. METHODS: An American Society of Clinical Oncology Panel, in collaboration with the Cancer Care Ontario Practice Guideline Initiative, reviewed pertinent information from the literature through May 2003. RESULTS: A literature-based meta-analysis found no evidence of a statistically significant survival benefit of adjuvant chemotherapy for stage II patients. Recommendations The routine use of adjuvant chemotherapy for medically fit patients with stage II colon cancer is not recommended. However, there are populations of patients with stage II disease that could be considered for adjuvant therapy, including patients with inadequately sampled nodes, T4 lesions, perforation, or poorly differentiated histology. CONCLUSION: Direct evidence from randomized controlled trials does not support the routine use of adjuvant chemotherapy for patients with stage II colon cancer. Patients and oncologists who accept the relative benefit in stage III disease as adequate indirect evidence of benefit for stage II disease are justified in considering the use of adjuvant chemotherapy, particularly for those patients with high-risk stage II disease. The ultimate clinical decision should be based on discussions with the patient about the nature of the evidence supporting treatment, the anticipated morbidity of treatment, the presence of high-risk prognostic features on individual prognosis, and patient preferences. Patients with stage II disease should be encouraged to participate in randomized trials.     

S-1 as adjuvant chemotherapy for stage III colon cancer: a randomized phase III study (ACTS-CC trial)

BackgroundS-1 is an oral fluoropyrimidine whose antitumor effects have been demonstrated in treating various gastrointestinal cancers, including metastatic colon cancer, when administered as monotherapy or in combination chemotherapy. We conducted a randomized phase III study investigating the efficacy of S-1 as adjuvant chemotherapy for colon cancer by evaluating its noninferiority to tegafur–uracil plus leucovorin (UFT/LV).Patients and methodsPatients aged 20–80 years with curatively resected stage III colon cancer were randomly assigned to receive S-1 (80–120 mg/day on days 1–28 every 42 days; four courses) or UFT/LV (UFT: 300–600 mg/day and LV: 75 mg/day on days 1–28 every 35 days; five courses). The primary end point was disease-free survival (DFS) at 3 years.ResultsA total of 1518 patients (758 and 760 in the S-1 and UFT/LV group, respectively) were included in the full analysis set. The 3-year DFS rate was 75.5% and 72.5% in the S-1 and UFT/LV group, respectively. The stratified hazard ratio for DFS in the S-1 group compared with the UFT/LV group was 0.85 (95% confidence interval: 0.70–1.03), demonstrating the noninferiority of S-1 (noninferiority stratified log-rank test, P < 0.001). In the subgroup analysis, no significant interactions were identified between the major baseline characteristics and the treatment groups.ConclusionAdjuvant chemotherapy using S-1 for stage III colon cancer was confirmed to be noninferior in DFS compared with UFT/LV. S-1 could be a new treatment option as adjuvant chemotherapy for colon cancer.ClinicalTrials.govNCT00660894.     

A randomized phase III trial of post-operative adjuvant oral fluoropyrimidine versus sequential paclitaxel/oral fluoropyrimidine; and UFT versus S1 for T3/T4 gastric carcinoma: the Stomach Cancer Adjuvant Multi-institutional Trial Group (Samit) Trial

Paclitaxel, S1 and their combined sequential administration is proposed to be examined installing UFT as an active control of adjuvant chemotherapy for curatively resected T3-4 gastric cancer in a multicenter Phase III trial. The primary endpoint is disease-free survival and the secondary endpoints are incidence of adverse events, overall survival and compliance. The sample size is 370 per treatment arm (1480 in total) for two hypotheses of the superiority of sequential use of paclitaxel followed by oral fluoropyrimidines to fluoropyrimidines (UFT/S1) alone and the non-inferiority of S1 to UFT to be tested by two-by-two factorial design. Abdominal CT or US is performed every 3 months in the first 2 years and every 6 months thereafter for 3 years in total to ensure recurrence data collection. This trial could appraise sequential combination therapy and efficacy of new drugs as adjuvant for gastric cancer treatment.     

Adjuvant systemic chemotherapy for Stage II and III colon cancer after complete resection: an updated practice guideline

Aims

The standard adjuvant therapy for resected stage III colon cancer has been intravenous 5-fluorouracil. However, newer chemotherapy agents, such as capecitabine, oxaliplatin and irinotecan, have been investigated in clinical trials since the publication of the original guidelines. The Gastrointestinal Cancer Disease Site Group (DSG) conducted a systematic review of the evidence for the use of adjuvant systemic chemotherapy for patients with resected stage II and III colon cancer and developed an updated practice guideline based on that evidence and expert consensus. The following research questions were addressed: Should patients with stage II or III colon cancer receive adjuvant systemic chemotherapy? What are the preferred adjuvant systemic chemotherapy options for patients with completely resected stage II or III colon cancer? Outcomes of interest were disease-free survival, overall survival, adverse effects and quality of life.

Materials and methods

A systematic search of published studies was conducted for the time period following the publication of the original guidelines to identify relevant randomised trials and syntheses of evidence in the form of meta-analyses. Recommendations were based on that evidence, evidence contained in the original guidelines and consensus of the Gastrointestinal Cancer DSG. The systematic review and practice guideline were externally reviewed through a mailed survey of practitioners in Ontario, Canada.

Results

Recommendations were drafted based on the available evidence and expert consensus.

Conclusions

The routine use of adjuvant chemotherapy for all patients with stage II colon cancer is not recommended. However, a subset of patients with high-risk stage II disease should be considered for adjuvant therapy. Patients with completely resected stage III colon cancer should be offered adjuvant chemotherapy. Treatment should depend on factors such as patient suitability and preference, and patients and clinicians must work together to determine the optimal course of treatment.     

Recent advances is surgical adjuvant chemotherapy for colorectal cancer

To evaluate the significance of surgical adjuvant chemotherapy, randomized controlled trials (RCTs) of adjuvant chemotherapy after curative resection for colorectal cancer were reviewed. Several multi-drug systemic chemotherapies (MOF, MMC/FT, 5-FU, UFT p.o.) were useful as adjuvant treatment to improve survival or disease-free survival of patients with colorectal cancer. Moreover, a worldwide meta-analysis suggested that continuous intraportal 5-FU infusion improves survival. Combination chemotherapy trials utilizing 5-FU and levamisol (LEV) demonstrated a survival advantage in patients with high risk colon cancer. Recently, many RCTs have substantiated the benefits of treatment with 5-FU/Leucovorin (LV) and this treatment is widely used as adjuvant treatment for the patients with Dukes C resected colon cancer in Europe and the U.S.A. Now, with the increasing use of oral chemotherapy drugs, new trials comparing oral UFT/LV with intravenous 5-FU/LV are being implemented to investigate these drugs in terms of QOL, toxicity and cost. Furthermore, the new drug irinotecan (CPT-11) is now under investigation to see if it brings added efficacy to 5-FU/LV. In Japan, two major groups (N-SAS-CC and TAC-CR) are comparing surgery alone and UFT alone in patients with Dukes C colon and rectal cancer. From these results, surgical adjuvant chemotherapy seems to be effective in the treatment of patients with high risk colon cancer and those with rectal cancer.     

A randomized controlled trial to evaluate the effect of adjuvant oral fluoropyrimidine derivative therapy after curative resection for stage II/III rectal cancer-adjuvant chemotherapy trial of S-1 for rectal cancer (ACTS-RC):

We are conducting a prospective randomized trial to evaluate the survival benefit of adjuvant chemotherapy with S-1 (tegafur, gimeracil, oteracil potassium) and UFT (uracil-tegafur) after curative surgery for patients with Stage II and III rectal cancer. Patients are randomized to either administration of UFT (control) or S-1. UFT was orally administered for 5 days (400 mg/m2/day) followed by two days rest for a year. S-1 was orally administered for 4 weeks (80 mg/m2/day) followed by two weeks rest for a year. The primary endpoint is relapse-free survival (RFS) rate, and the secondary endpoints are overall survival time (OS) and frequency or level of adverse events. We aim to include 400 patients in each of the treatment groups and assume that the registration period will last until 2009.     

Challenges in the management of stage II colon cancer

Approximately one third of patients diagnosed with early-stage colon cancer will present with lymph node involvement (stage III) and about one quarter with transmural bowel wall invasion but negative lymph nodes (stage II). Adjuvant chemotherapy targets micrometastatic disease to improve disease-free (DFS) and overall survival (OS). While beneficial for stage III patients, the role of adjuvant chemotherapy is unestablished in stage II disease. This likely relates to the improved outcome of these patients, and the difficulties in developing studies with sufficient power to document benefit in this patient population. However, recent investigation also suggests that molecular differences may exist between stage II and III cancers and within stage II patients. Validated pathologic prognostic markers are useful at identifying stage II patients at high risk for recurrence for whom the benefit from adjuvant chemotherapy may be greater. Such high-risk features include higher T stage (T4 v T3), suboptimal lymph node retrieval, presence of lymphovascular invasion, bowel obstruction, or bowel perforation, and poorly differentiated histology. However, for the majority of patients who do not carry any of these adverse features and are classified as "average-risk" stage II patients, the benefit of adjuvant chemotherapy remains unproven. Emerging understanding of the underlying biology of stage II colon cancer has identified molecular markers that may change this paradigm and improve our risk assessment and treatment choices for stage II disease. Assessment of microsatellite stability (MSI), which serves as a marker for DNA mismatch repair (MMR) system function, has emerged as a useful tool for risk stratification of patients with stage II colon cancer. Patients with high frequency of MSI have been shown to have increased OS and limited benefit from 5-fluorouracil (5-FU)-based chemotherapy. Additional research is necessary to clearly define the most appropriate way to use this marker and others in routine clinical practice.     

Why We Should Not Treat Patients with Stage II Colon Cancer

Research assessing the worth of adjuvant chemotherapy for stage II colon cancer has been ongoing for several decades. The majority of studies have not demonstrated a significant improvement in survival. Despite this, many patients with stage II disease deemed to be at high-risk for recurrence do receive postoperative chemotherapy. The benefit of adjuvant therapy in such high-risk patients has been suggested by retrospective analyses of phase III trials. Molecular and genetic factors are being investigated to learn if they can predict those who might benefit most from adjuvant therapy. The results of randomized trials and pooled analyses will be reviewed to argue that the majority of stage II colon cancer patients should not receive adjuvant chemotherapy. Prospective studies addressing the benefit of adjuvant chemotherapy in high-risk patients are a high priority.     

Microsatellite Status and Adjuvant Chemotherapy in Patients with Stage II Colon Cancer

Colon cancers do not represent a homogeneous entity, and the two main known pathways are the microsatellite instability (MSI) and chromosomal instability pathways. Although statistically significant, the absolute improvement in overall survival with 5-fluorouracil (5-FU) adjuvant chemotherapy in patients with stage II colon cancer is small and does not support the use of adjuvant chemotherapy in all patients. Today, concordant and accumulated results of independent large studies show that microsatellite status is a robust prognostic factor in colon cancer. Moreover, patients with stage II MSI tumors do not benefit from 5-FU adjuvant chemotherapy alone. Therefore, these results do not support the use of fluoropyrimidine adjuvant chemotherapy in patients with MSI stage II colon cancer. Consequently, microsatellite status should be determined before making any decision regarding adjuvant chemotherapy in patients with stage II colon cancer.     

Application of Microsatellite Instability and Oncotype DX in Stage II Colon Cancer Adjuvant Chemotherapy

Adjuvant chemotherapy has improved the overall prognosis for patients with stage III colon cancer. However, the precise role of adjuvant chemotherapy for patients with stage II colon cancer remains a matter of ongoing debate. While patients with high-risk stage II disease derive clinical benefit from adjuvant therapy, it remains unclear as to whether patients with average or low-risk stage II disease should receive further therapy following surgical resection. Significant efforts have focused on developing and validating molecular biomarkers to further define the subset of patients with stage II disease who would derive benefit from adjuvant therapy. Herein, we review the current status of biomarker research with respect to the specific roles of microsatellite instability and genotype analysis in patients with stage II colon cancer.     

Multicenter comparative study of the recurrence-inhibitory effect of oral fluoropyrimidine drugs in patients with colorectal cancer following curative resection

HCFU and UFT were reported effective in adjuvant chemotherapy for colorectal cancer. This investigation was planned as a randomized study to compare the usefulness of combination therapies with mitomycin C (MMC)+HCFU and MMC+UFT as postoperative adjuvant chemotherapy in patients with colorectal cancer following curative resection, in terms of survival rate, recurrence rate, and adverse drug reactions. A total of 501 patients consisting of 252 patients with stage III/IV colon cancer (Colorectal Cancer Handling Rules, 4th Ed.) for which macroscopic curative resection was possible and 249 patients with stage II/III/IV rectal cancer (ibid, 4th Ed.) were registered from 40 participating institutions. The patients were randomly allocated to two groups with colon cancer and rectal cancer employed as stratification factors. Beginning on Day 14 after surgery, HCFU at 300 mg/day was administered to one group and UFT at 300 mg/day or 400 mg/day to another group, both orally and daily for one year. MMC 6 mg/m2 was administered intravenously to both groups on the day of surgery and the day following. Among the 501 patients, 496 patients (99%) were eligible. The 5-year survival rates were 77.1% for the MMC+ HCFU group and 79.2% for the MMC+UFT group, with the 5-year recurrence-free survival rates were 76.1% and 72.9%, respectively, neither showing a significant difference between the groups. Adverse drug reactions appeared in 23% of patients in the MMC+HCFU group and in 19% in the MMC+UFT group, with no serious reactions. One year after surgery the administration completion rates were good, at 82% for the MMC+HCFU group and 83% for the MMC+UFT group. No clear difference in effectiveness was noted between MMC+HCFU therapy and MMC+UFT therapy as postoperative adjuvant chemotherapy for colorectal cancer. The administration completion rates were good, and no serious adverse drug reactions were observed for either therapy. It was thus considered that both therapies could be administered safely, and both were useful as postoperative adjuvant chemotherapies for colorectal cancer. It is considered necessary to compare them with standard therapies in Western countries in the future.