Fluorouracil plus leucovorin as effective adjuvant chemotherapy in curatively resected stage III colon cancer: results of the trial adjCCA-01.

PURPOSE: Adjuvant postoperative treatment with fluorouracil (5-FU) and levamisole in curatively resected stage III colon cancer significantly reduces the risk of cancer recurrence and improves survival. Biochemical modulation of 5-FU with leucovorin has resulted in increased remission rates in metastatic colorectal cancer, thus reflecting an increased tumor-cell kill. The impact of 5-FU plus leucovorin on survival and tumor recurrence was analyzed in comparison with the effects of 5-FU plus levamisole in the prospective multicentric trial adjCCA-01. PATIENTS AND METHODS: Patients with a curatively resected International Union Against Cancer stage III colon cancer were stratified according to T, N, and G category and randomly assigned to receive one of the two adjuvant treatment schemes: 5-FU 400 mg/m(2) body-surface area intravenously in the first chemotherapy course, then 450 mg/m(2) x 5 days; 12 cycles, plus leucovorin 100 mg/m(2) (arm A), or 5-FU plus levamisole (Moertel scheme; arm B). RESULTS: Six hundred eighty (96.9%) of 702 patients enrolled onto this study were eligible. After a median follow-up time of 46.5 months, the 5-FU plus leucovorin combination significantly improved disease-free survival (P =.037) and significantly decreased overall mortality (P =.0089) in comparison with 5-FU plus levamisole. In a multivariate proportional hazards model, adjuvant chemotherapy emerged as a significant prognostic factor for survival (P =.0059) and disease-free survival (P =.03). Adjuvant treatment with 5-FU plus levamisole as well as with 5-FU plus leucovorin was generally well tolerated; only a minority of patients experienced grade 3 and 4 toxicities. CONCLUSION: After a curative resection of a stage III colon cancer, adjuvant treatment with 5-FU plus leucovorin is generally well tolerated and significantly more effective than 5-FU plus levamisole in reducing tumor relapse and improving survival.     

Adjuvant sequential methotrexate --> 5-fluorouracil vs 5-fluorouracil plus leucovorin in radically resected stage III and high-risk stage II colon cancer

The aim of the study was to determine whether modulation of 5-fluorouracil (FU) by methotrexate (MTX) improves survival compared to FU+6-s-leucovorin (LV) following potentially curative resection of stage II and III colon cancer. Within 8 weeks from surgery, 1945 patients with stage III (44%) or high-risk stage II (55%) colon cancer were randomly assigned to receive either 6 monthly cycles of FU 370 mg m(-2) i.v. bolus preceded by LV 100 mg m(-2) i.v. bolus on days 1-5, or 6 monthly cycles of sequential MTX 200 mg m(-2) i.v. days 1 and 15 and FU 600 mg m(-2) i.v. on days 2 and 16 followed by LV rescue (15 mg given p.o. q 6 h x 6 doses). Levamisole 50 mg p.o. t.i.d. on days 1-3, every 14 days for 6 months, was planned to be given in both arms. After a median follow-up of 4.2 years, 568 patients have relapsed and 403 have died. Survival was similar with MTX --> FU and FU+LV (77 vs 77% at 5 years; P = 0.90), as were 5-year disease-free survivals (67 vs 63%; P = 0.44). Efficacy results were similar for both stage III and II patients. There were two toxic deaths, two in the MTX --> FU arm (0.2%) and zero in the control arm. We conclude that biochemical modulation of FU with LV or with MTX produces similar results in the adjuvant setting of colon cancer.     

Redefining adjuvant chemotherapy in patients with stage III colon cancer: X-ACT trial

The current standard adjuvant chemotherapy for suitable patients with stage III colon cancer is the combination of oxaliplatin and 5-fluorouracil plus folinic acid (5-FU/LV). However, until recently and for many years prior to this, the accepted standard adjuvant chemotherapy was 6–8 months of bolus 5-FU/LV. However, bolus treatment was associated with significant toxicity, namely stomatitis, diarrhea and neutropenia, in addition to multiple hospital visits for drug administration for patients. The X-ACT trial (Xeloda in Adjuvant Colon Cancer Therapy) compared traditional bolus 5-FU/LV (as per the Mayo Clinic regimen) with capecitabine, in the adjuvant treatment of 1987 stage III colon cancer patients. The main safety, efficacy and pharmacoeconomic results have all been published, and the updated 5-year efficacy results have also recently been presented. This trial demonstrated that capecitabine was at least as effective as bolus 5-FU/LV in terms of disease-free and overall survival, with trends towards superiority for both. Moreover, there was much less toxicity associated with capecitabine, apart from hand–foot syndrome which was significantly more prevalent. On the basis of the X-ACT trial, capecitabine was approved by the US FDA, the National Institute for Clinical Excellence and the Scottish Medicines Consortium as monotherapy for the adjuvant treatment of stage III colon cancer.     

The addition of low-dose leucovorin to the combination of 5-fluorouracil- levamisole does not improve survival in the adjuvant treatment of Dukes' C colon cancer. IKN Colon Trial Group.

Purpose:To assess the effect of the addition of leucovorin to thecombination of 5-fluorouracil (5-FU)–levamisole on recurrence risk andoverall survival in patients after a resection with curative intent of aDukes' C colon cancer. Patients and methods:Five hundred patients with Dukes' C coloncancer were randomly assigned to adjuvant treatment for one year with5-fluorouracil (450 mg/m² i.v. weekly) and levamisole (150 mg p.o.every two weeks), the C-group or with leucovorin (20 mg/m² i.v.),5-fluorouracil and levamisole, the L-group. The median follow-up for patientsstill alive is 36 months. Four patients were ineligible because of advanceddisease at the time of randomisation. Results:Sixty percent of the patients have completed all coursesof chemotherapy. Of the remaining 40% of the patients who did notcomplete one-year treatment with chemotherapy, 46% discontinued becauseof toxic and/or emotional reasons. They were equally divided over bothtreatment arms. The addition of leucovorin increased toxicity (especiallymucositis and conjunctivitis) without a significant increase in treatmentwithdrawal. Five-year disease-free interval (C-group: 49%, L-group:46%; log-rank test, P = 0.86) and overall survival (C-group:55%, L-group: 59%, log-rank test: P = 0.96) were verysimilar in both treatment arms. Conclusions:The addition of low dose leucovorin to thecombination of 5-fluorouracil and levamisole in a 12-month adjuvant therapyfor curatively resected Dukes' C colon cancer patients does not improvedisease-free interval nor overall survival. The addition of leucovorin to thecombination of 5-FU–levamisole increases toxicity. Thereforeleucovorin–5-FU–levamisole is not recommended in a 12 monthsadjuvant regime of Dukes' C colon cancer.     

A prospective randomised phase III trial of adjuvant chemotherapy with 5-fluorouracil and leucovorin in patients with stage II colon cancer

The purpose of this trial was to investigate the efficacy of adjuvant chemotherapy with 5-fluorouracil (5-FU) and leucovorin (LV) in stage II colon cancer. Patients with stage II colon cancer were randomised to either adjuvant chemotherapy with 5-FU/LV (100 mg m(-2) LV+450 mg m(-2) 5-FU weekly, weeks 1-6, in 8 weeks cycles x 7) or surveillance only. Five hundred patients were evaluable for analyses. After a median follow-up of 95.6 months, 55 of 252 patients (21.8%) have died in the 5-FU/LV arm and 58 of 248 patients (23.4%) in the surveillance arm. There was no statistically significant difference in overall survival (OS) between the two treatment arms (hazard ratios, HR 0.88, 95% CI 0.61-1.27, P=0.49). The relative risk for tumour relapse was higher for patients on the surveillance arm than for those on the 5-FU/LV arm; however, this difference was not statistically significant (HR 0.69, 95% CI 0.45-1.06, P=0.09). Consequently, disease-free survival (DFS) was not significantly different between the two trial arms. In conclusion, results of this trial demonstrate a trend to a lower risk for relapse in patients treated with adjuvant 5-FU/LV for stage II colon cancer. However, in this study with limited power to detect small differences between the study arms, adjuvant chemotherapy failed to significantly improve DFS and OS.     

Randomized trial of adjuvant chemotherapy versus control after curative resection for gastric cancer: 5-year follow-up

Adjuvant chemotherapy of gastric cancer after curative resection is still subject to discussion. In this study 137 patients with gastric adenocarcinoma, all with positive nodes, were randomized after curative resection so that 69 received epidoxorubicin (EPI), leucovorin (LV) and 5-fluorouracil (5-FU) on days 1-3 every 3 weeks for 7 months, whereas the remaining 68 did not. After a follow-up period of 5 years, 21 of the 69 treated patients (30%) and nine controls (13%) were still alive; median survival time was 18 months for the controls and 31 months for the patients treated with adjuvant chemotherapy (P< 0.01).     

A prospective randomised trial to study the role of levamisole and interferon alfa in an adjuvant therapy with 5-FU for stage III colon cancer

The purpose of this trial was to examine the efficacy of the addition of levamisole (LEV) or interferon alfa (IFN) to an adjuvant chemotherapy with 5-fluorouracil (5-FU) in patients with stage III colon cancer. According to a 2 x 2 factorial study design, 598 patients were randomly assigned to one of four adjuvant treatment arms. Patients in arm one received 5-FU weekly for 1 year, patients in arm two 5-FU plus LEV, in arm three 5-FU plus IFN and patients in arm four 5-FU, LEV and IFN. The relative risk of relapse and the relative risk of death were significantly higher for patients treated with LEV compared with those without LEV treatment (HR 1.452, 95% CI 1.135-1.856, P=0.0028; HR 1.506, 95% CI 1.150-1.973, P=0.0027, respectively). No significant impact on survival was observed for therapy with IFN in the univariate analysis. The addition of LEV to adjuvant 5-FU significantly worsened the prognosis of patients with stage III colon cancer. Interferon alfa had no significant influence on survival when combined with adjuvant 5-FU, but increased the toxicity of therapy substantially.     

Pharmacoeconomic analysis of adjuvant oral capecitabine vs intravenous 5-FU/LV in Dukes' C colon cancer: the X-ACT trial

Oral capecitabine (Xeloda) is an effective drug with favourable safety in adjuvant and metastatic colorectal cancer. Oxaliplatin-based therapy is becoming standard for Dukes' C colon cancer in patients suitable for combination therapy, but is not yet approved by the UK National Institute for Health and Clinical Excellence (NICE) in the adjuvant setting. Adjuvant capecitabine is at least as effective as 5-fluorouracil/leucovorin (5-FU/LV), with significant superiority in relapse-free survival and a trend towards improved disease-free and overall survival. We assessed the cost-effectiveness of adjuvant capecitabine from payer (UK National Health Service (NHS)) and societal perspectives. We used clinical trial data and published sources to estimate incremental direct and societal costs and gains in quality-adjusted life months (QALMs). Acquisition costs were higher for capecitabine than 5-FU/LV, but higher 5-FU/LV administration costs resulted in 57% lower chemotherapy costs for capecitabine. Capecitabine vs 5-FU/LV-associated adverse events required fewer medications and hospitalisations (cost savings pound3653). Societal costs, including patient travel/time costs, were reduced by >75% with capecitabine vs 5-FU/LV (cost savings pound1318), with lifetime gain in QALMs of 9 months. Medical resource utilisation is significantly decreased with capecitabine vs 5-FU/LV, with cost savings to the NHS and society. Capecitabine is also projected to increase life expectancy vs 5-FU/LV. Cost savings and better outcomes make capecitabine a preferred adjuvant therapy for Dukes' C colon cancer. This pharmacoeconomic analysis strongly supports replacing 5-FU/LV with capecitabine in the adjuvant treatment of colon cancer in the UK.     

Severe enteropathy among patients with stage II/III colon cancer treated on a randomized trial of bolus 5-fluorouracil/leucovorin plus or minus oxaliplatin: a prospective analysis

BACKGROUND: Cases of severe gastrointestinal toxicity were monitored prospectively during NSABP C-07, a randomized clinical trial of adjuvant therapy for patients with stage II/III colon cancer. METHODS: Patients were treated with weekly bolus 5-fluorouracil (5-FU) and leucovorin (FL; "Roswell Park Regimen") or the same regimen plus oxaliplatin (FLOX). RESULTS: Of 1857 patients, 79 (4.3%) developed a syndrome of bowel wall injury (BWI, small or large) characterized by hospitalization for the management of severe diarrhea or dehydration and radiographic or endoscopic evidence of bowel wall thickening or ulceration. Fifty-one (64.6%) of these adverse events occurred in patients treated with FLOX and 28 (35.4%) in those treated with FL (P < .01). Enteric sepsis (ES), characterized by grade 3 or greater diarrhea and grade 4 neutropenia with or without proven bacteremia occurred in 22 patients treated with FLOX, versus 8 in those treated with FL (P = .01). Patients >60 years were at higher risk for BWI after treatment with FLOX (6.7%) versus treatment with FL (2.9%, P < .01). Female patients had a higher incidence of BWI with FLOX (9.1%) than with FL (3.9%, P < .01). Severe gastrointestinal toxicity usually occurred during the third or fourth week on the first cycle of therapy, required hospitalization, and was managed with fluids, antidiarrheals, and antibiotics. There were 5 deaths (0.3%) due to enteropathy, 2 related to ES and 3 related to both BWI and ES. Seventy-one percent of patients resumed treatment with FL after recovery. CONCLUSIONS: Patients treated with adjuvant FL should be closely monitored for diarrhea and aggressively managed, especially if oxaliplatin has been added to the regimen. Society.     

Potent effects of adjuvant chemotherapy using 5-fluorouracil + leucovorin on DNA aneuploid colorectal cancer

Background The relationship between DNA ploidy of colorectal cancer cells and sensitivity to adjuvant chemotherapy, using 5-fluorouracil+leucovorin was investigated. Methods Seventy-five patients with Duke's B or C colorectal cancer, who underwent potentially curative resection, were randomly allocated to 2 groups. Thirty-eight patients received adjuvant chemotherapy using 5-fluorouracil+leucovorin (chemotherapy group), and 37 patients received no adjuvant chemotherapies (no-chemotherapy group). Tumor cell ploidy of all patients was analyzed using paraffin-embedded samples. Results There was no statistically significant difference in overall survival between patients who received chemotherapy and those who did not. Among the patients with diploid tumors (n=39), there was no significant difference in survival between the chemotherapy group (n=20, 5-year survival rate of 34.3%) and the no-chemotherapy group (n=19, 5-year survival rate of 27.1%). By contrast, among the aptients with aneuploid tumors (n=36), the survival rate was significantly better in the chemotherapy group (n=18, 5-year survival rate of 77.8%), than in the no-chemotherapy group (n=18, 5-year survival rate of 43.7%) (P=0.023). Conclusion These results suggest that aneuploid tumors are more sensitive to adjuvant chemotherapy, using 5-fluorouracil+leucovorin, than are diploid tumors.     

Failure to complete adjuvant chemotherapy is associated with adverse survival in stage III colon cancer patients

Two recent North American studies have shown that completion of 5-fluorouracil (5FU)-based adjuvant chemotherapy is a major prognostic factor for the survival of elderly stage III colon cancer patients. The aim of the present study was to confirm this finding in a population-based series from Australia. The study cohort comprised 851 stage III colon cancer patients treated by surgery alone and 461 who initiated the Mayo chemotherapy regime. One-third of patients who initiated chemotherapy failed to complete more than three cycles of treatment. Independent predictors for failure to complete were treatment in district or rural hospitals, low socioeconomic index and treatment by a low-volume surgeon. Patients who failed to complete chemotherapy showed worse cancer-specific survival compared not only to those who completed treatment (HR=2.24; 95% confidence interval (CI) (1.66-3.03), P<0.001) but also to those treated by surgery alone (HR=1.37; 95% CI (1.09-1.72), P=0.008). The current and previous studies demonstrate the importance of completing adjuvant 5-FU-based chemotherapy for colon cancer. Further prospective studies are required to identify better the physiological and socioeconomic factors responsible for failure to complete chemotherapy so that appropriate improvements in health service delivery can be made.     

Cost-effectiveness of adjuvant chemotherapy with uracil-tegafur for curatively resected stage III rectal cancer

Recently, the National Surgical Adjuvant Study of Colorectal Cancer in Japan, a randomised controlled trial of oral uracil-tegafur (UFT) adjuvant therapy for stage III rectal cancer, showed remarkable survival gains, compared with surgery alone. To evaluate value for money of adjuvant UFT therapy, cost-effective analysis was carried out. Cost-effectiveness analysis of adjuvant UFT therapy was carried out from a payer's perspective, compared with surgery alone. Overall survival and relapse-free survival were estimated by Kaplan-Meier method, up to 5.6 years from randomisation. Costs were estimated from trial data during observation. Quality-adjusted life-years (QALYs) were calculated using utility score from literature. Beyond observation period, they were simulated by the Boag model combined with the competing risk model. For 5.6-year observation, 10-year follow-up and over lifetime, adjuvant UFT therapy gained 0.50, 0.96 and 2.28 QALYs, and reduced costs by $2457, $1771 and $1843 per person compared with surgery alone, respectively (3% discount rate for both effect and costs). Cost-effectiveness acceptability and net monetary benefit analyses showed the robustness of these results. Economic evaluation of adjuvant UFT therapy showed that this therapy is cost saving and can be considered as a cost-effective treatment universally accepted for wide use in Japan.     

Comparison of adverse events during 5-fluorouracil versus 5-fluorouracil/oxaliplatin adjuvant chemotherapy for stage III colon cancer: a population-based analysis

BACKGROUND:

In clinical trials, combined 5‐fluorouracil (5FU) plus oxaliplatin improves the survival of patients who have resected, stage III colon cancer with manageable toxicity. However, the tolerability of this in the general population of patients with colon cancer is uncertain.

METHODS:

Adverse outcomes were compared in patients with stage III colon cancer who received either 5FU or 5FU/oxaliplatin within 120 days of undergoing resection versus a control group of patients with stage II colon cancer who did not receive chemotherapy in the Surveillance, Epidemiology, and End Results (SEER)‐Medicare database and in data from the New York State Cancer Registry linked to Medicare and Medicaid. Hospitalizations, emergency room (ER) visits, and outpatient adverse events (AEs) were measured in claims from 30 days to 9 months after patients underwent resection. Multiple logistic regression was used to calculate adjusted odds ratios of events by treatment. Propensity score matching was used to minimize selection bias.

RESULTS:

Adverse outcomes were more frequent for chemotherapy recipients. AE rates were higher in patients who received 5FU/oxaliplatin (81%) compared with patients who received 5FU alone (72%), in the SEER‐Medicare data. The effect of oxaliplatin on AEs was greater in older patients: The odds ratio was 2.10 (95% confidence interval, 1.53‐2.87) for patients aged ≥75 years versus 1.75 (95% confidence interval, 1.39‐2.21) for patients aged <75 years. ER use was high in Medicaid patients (83% of those who received chemotherapy), but neither ER use nor hospitalization was increased by oxaliplatin. The 60‐day mortality rate was 1% to 3% for patients who received 5FU alone and 1% to 2% for patients who received combined 5FU/oxaliplatin.

CONCLUSIONS:

The incremental harms of adjuvant chemotherapy with 5FU/oxaliplatin versus 5FU alone were modest in patients with stage III colon cancer who were insured by Medicare and Medicaid. The additional harms in patients aged ≥75 years largely were restricted to outpatient events and did not extend to an increased rate of hospitalization or early death. Cancer 2012. © 2012 American Cancer Society     

Modulation of 5-fluorouracil as adjuvant systemic chemotherapy in colorectal cancer: the IGCS-COL multicentre, randomised, phase III study

The aims of this multicentre, randomised phase III trial were to evaluate: (1) the role of levamisol (LEV); and (2) the role of folinic acid (FA), added to 5-fluorouracil (5FU) in the adjuvant treatment of colorectal cancer. Patients with histologically proven, radically resected stage II or III colon or rectal cancer were eligible. The study had a 2x2 factorial design with four treatment arms: (a) 5FU alone, (b) 5FU+LEV, (c) 5FU+FA, (d) 5FU+LEV+FA, and two planned comparisons, testing the role of LEV and of FA, respectively. From March 1991, to September 1998, 1327 patients were randomised. None of the two comparisons resulted in a significant disease-free (DFS) or overall (OAS) survival advantage. The hazard ratio (HR) of relapse was 0.89 (95% confidence intervals (CI): 0.73-1.09) for patients receiving FA and 0.99 (95% CI 0.80-1.21) for those receiving LEV; corresponding HRs of death were 1.02 (95% CI: 0.80-1.30) and 0.94 (95% CI 0.73-1.20). Nonhaematological toxicity (all grade vomiting, diarrhoea, mucositis, congiuntivitis, skin, fever and fatigue) was significantly worse with FA, while all other toxicities were similar. In the present trial, there was no evidence that the addition of FA or LEV significantly prolongs DFS and OAS of radically resected colorectal cancer patients.     

Nuclear Maspin expression is associated with response to adjuvant 5-fluorouracil based chemotherapy in patients with stage III colon cancer

Maspin, a member of the Serpin protease inhibitor family, is overexpressed in poorly differentiated colorectal tumors and more frequently found in tumors with microsatellite instability. Immunohistochemical nuclear Maspin staining is predominantly seen in tumor cells at the invasion front of such cancers, suggesting that this molecule is associated with local tumor cell infiltration and aggressiveness. In a retrospective study, we studied nuclear Maspin expression as a potential prognostic tool in a total of 172 primary stage III colon cancers by immunohistochemistry. Of those 172 patients, 76 were treated by surgery only, and 96 patients received additional adjuvant 5-fluorouracil (5-FU) based chemotherapy. Nuclear Maspin expression was an independent adverse prognostic factor for overall survival in our patient cohort (hazard ratio 2.08; 95% CI, 1.13-3.81; p = 0.018). However, patients with primary tumors expressing Maspin in the nucleus showed a significant treatment benefit from 5-FU chemotherapy (hazard ratio 0.384; 95% CI, 0.188-0.784; p = 0.009) compared to adjuvantly treated patients whose tumors did not express this molecule. Nuclear Maspin expression is highly predictive of 5-FU chemotherapy response in patients with advanced stage colon cancer. Patients with negative immunohistochemical Maspin expression do not benefit from 5-FU treatment and may be candidates for an alternative (non-5-FU based) adjuvant therapy regime.     

Administration of adjuvant chemotherapy for stage II‐III colon cancer patients: An European population‐based study

The advantage of adjuvant chemotherapy (ACT) for treating Stage III colon cancer patients is well established and widely accepted. However, many patients with Stage III colon cancer do not receive ACT. Moreover, there are controversies around the effectiveness of ACT for Stage II patients. We investigated the administration of ACT and its association with overall survival in resected Stage II (overall and stratified by low‐/high‐risk) and Stage III colon cancer patients in three European countries including The Netherlands (2009–2014), Belgium (2009–2013) and Sweden (2009–2014). Hazard ratios (HR) for death were obtained by Cox regression models adjusted for potential confounders. A total of 60244 resected colon cancer patients with pathological Stages II and III were analyzed. A small proportion (range 9–24%) of Stage II and over half (range 55–68%) of Stage III patients received ACT. Administration of ACT in Stages II and III tumors decreased with higher age of patients. Administration of ACT was significantly associated with higher overall survival in high‐risk Stage II patients (in The Netherlands (HR; 95%CI = 0.82 (0.67–0.99), Belgium (0.73; 0.59–0.90) and Sweden (0.58; 0.44–0.75)), and in Stage III patients (in The Netherlands (0.47; 0.43–0.50), Belgium (0.46; 0.41–0.50) and Sweden (0.48; 0.43–0.54)). In Stage III, results were consistent across subgroups including elderly patients. Our results show an association of ACT with higher survival among Stage III and high‐risk Stage II colon cancer patients. Further investigations are needed on the selection criteria of Stages II and III colon cancer patients for ACT.     

A phase III randomized trial of 5-fluorouracil, doxorubicin, and mitomycin C versus 5-fluorouracil and mitomycin C versus 5-fluorouracil alone in curatively resected gastric cancer.

BACKGROUND: A phase III single-center randomized trial was performed in order to determine whether the addition of mitomycin C (MMC) and/or doxorubicin to 5-fluorouracil (5-FU) as adjuvant chemotherapy could influence survival in patients with curatively resected gastric cancer. PATIENTS AND METHODS: A total of 416 patients who had undergone curative resection for stage IB-IIIB gastric adenocarcinoma were stratified according to the stage and type of surgery, and then randomized to receive one of the three chemotherapy regimens, 5-FU alone (F) or 5-FU and MMC (FM) or 5-FU, doxorubicin and MMC (FAM) within 5 weeks after surgery. RESULTS: Of 416 patients registered, 395 (133 in F, 131 in FM and 131 in FAM) were assessable. Median follow-up duration was 91 months. Five-year overall survival rates were 67.2% for F, 67.0% for FM and 66.7% for FAM (P = 0.97). Five-year disease-free survival rates were 62.1% for F, 63.3% for FM and 62.5% for FAM (P = 0.83). Hematological toxicities were more frequent in the FM and FAM groups, whereas stomatitis was more common in the F group. CONCLUSIONS: Compared with adjuvant 5-FU alone, the addition of MMC and/or doxorubicin to 5-FU did not influence survival in patients with resected gastric cancer.     

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.