Adjuvant chemotherapy in stage III colon cancer with 5-fluorouracil and levamisole versus 5-fluorouracil and leucovorin

BACKGROUND: Adjuvant chemotherapy for colon cancer has been established during the past decade. From 1990 until recently treatment with 5- fluorouracil (5-FU) and levamisole (LEV) lasting 12 months was recommended as standard treatment. At the initiation of this study in 1993 improvement of adjuvant therapy was expected by the modulation of 5-FU with folinic acid (FA). Therefore, we decided to perform a prospective randomized multicenter trial to compare standard 5-FU/LEV to 5-FU/FA for either 6 or 12 months. PATIENTS AND METHODS: Patients with stage III colon cancer after curative en bloc resection were randomized in 3 treatment groups: arm A (5-FU/LEV, weekly, 12 months), arm B (5-FU/FA, days 1-5, every 4 weeks, 12 months) and arm C (like B, 6 months). RESULTS: Between March 1993 and November 1997, 180 patients were randomized into the study, 155 were eligible for further evaluation. The interim analysis in November 2000 showed no significant difference for recurrence and disease-free survival in arm B and C, therefore the data from both 5-FU/FA treatment arms (B+C) were combined for comparison with 5-FU/LEV-treatment (A). Most pronounced toxicity in all treatment arms was mild nausea, loss of appetite and leukopenia. A tendency for more diarrhea and stomatitis was observed in arm B+C. After a median follow-up of 36.2 months no significant difference was seen for disease free survival (p = 0.9) and overall survival (p = 1.0). 3-year recurrence rates were 39.6% in arm A and 39.1% in arm B+C, 3-year survival rates amounted to 74.1% in arm A and 74.9% in arm B+C. CONCLUSION: Only a limited number of patients could be recruited in this study. The observed data support the results of other studies, which concluded that 6 months (or 12 months) treatment with 5-FU/FA is equivalent to 12 months treatment with 5-FU/LEV. Therefore the 6 months treatment with 5-FU/FA can be supported as standard for adjuvant therapy of stage III colon cancer.     

A case of recurrent colon cancer with complete response to modulation chemotherapy using low-dose leucovorin and 5-fluorouracil]

We experienced a case of lymph node recurrence from colon cancer with complete response to modulation chemotherapy using low-dose leucovorin and 5-FU. The patient was a 68-year-old male. He underwent sigmoid colon resection for sigmoid colon cancer in October 1993. In June 1994, he complained of left lower abdominal pain. Swelling of retroperitoneal lymph node was detected by CT scan and cytology revealed cancer cells in urine. He was diagnosed as having lymph node recurrence. He then was given modulation chemotherapy of 30 mg of leucovorin and 500 mg of 5-FU that were bolus injected intravenously for 5 days. After 2 cycles of this regimen, the recurrent mass disappeared completely for further examination. Until May 1998, he had received 14 cycles. Since this regimen started, his survival period has been 46 months, and his response duration 42 months.     

Chemoradiotherapy with 5-fluorouracil/leucovorin, surgery and adjuvant chemotherapy for locally advanced rectal cancer

The aim of this study was to demonstrate a pathologic complete response (pCR) rate of at least 10% with an acceptable toxicity achieved by preoperative chemoradiotherapy with 5-fluorouracil (5-FU)/leucovorin in patients with locally advanced rectal cancer. Patients were treated by radiotherapy targeting 50 Gy and 5-FU/leucovorin intravenously during the 1st, 4th and 7th week after start of radiotherapy followed by surgery and adjuvant chemotherapy. In 71 evaluable patients, the pCR rate was 14.1% (95% CI, 6.0-22.2); the local relapse rate, 6.1%; the 5-year disease-free survival, 54% and the overall 5-year survival, 68%. The most severe adverse events were neutropenia (17%), diarrhoea (17%), infection (8%) and fatal cardiovascular function (1%). This therapy yielded a high rate of pCR, a low rate of local relapse and a long disease-free and overall survival. To increase its feasibility, radiation dose reduction to 45 Gy and administration of only two preoperative cycles of chemotherapy is recommended.     

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.     

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.     

Effects of 5-fluorouracil adjuvant treatment of colon cancer

Since the late 1980s and early 1990s, 5-fluorouracil-based chemotherapy has been the standard adjuvant treatment for Stage III colon cancer. After the initial introduction of 5-fluorouracil in standard treatment protocols, several changes have been made based on results of randomized studies on various treatment regimens, including new cytotoxic agents. In Stage II patients, the role of adjuvant chemotherapy is debatable. However, there might be a role for adjuvant treatment in certain high-risk patients. Following a search of the Medline database, the results of randomized studies on 5-fluorouracil-based adjuvant therapy are reviewed, and future therapeutic options are discussed.     

Effects of 5-fluorouracil adjuvant treatment of colon cancer

Since the late 1980s and early 1990s, 5-fluorouracil-based chemotherapy has been the standard adjuvant treatment for Stage III colon cancer. After the initial introduction of 5-fluorouracil in standard treatment protocols, several changes have been made based on results of randomized studies on various treatment regimens, including new cytotoxic agents. In Stage II patients, the role of adjuvant chemotherapy is debatable. However, there might be a role for adjuvant treatment in certain high-risk patients. Following a search of the Medline database, the results of randomized studies on 5-fluorouracil-based adjuvant therapy are reviewed, and future therapeutic options are discussed.     

Protracted continuous infusion of 5-fluorouracil and low-dose leucovorin in patients with metastatic colorectal cancer resistant to 5-fluorouracil bolus-based chemotherapy: a phase II study

Continuous-infusion (c.i.) 5-fluorouracil (5-FU) can overcome resistance to bolus 5-FU, and leucovorin (LV) enhances the cytotoxic effects of 5-FU, mainly when the duration of exposure to the latter is prolonged. The main objective of this study was therefore to determine the activity of a prolonged infusion schedule of 5-FU + LV in patients with metastatic colorectal cancer resistant to a 5-FU bolus-based chemotherapy. Only patients with metastatic measurable disease in progression during or within 2 months of the end of a 5-FU bolus ± LV-based chemotherapy were eligible for the study. 5-FU and l-LV were given as a 14-day c.i. every 28 days, the 5-FU dose being 200 mg/m² per day and the l-LV dose being 5 mg/m² per day. A total of 59 patients entered the study, of which 48 were resistant to 5-FU + LV and 11, to 5-FU + levamisole. Treatment was well tolerated, and WHO grade 3–4 toxicities were uncommon (11% of patients developed stomatitis and 7%, diarrhea). According to an intent-to-treat analysis, 10 of 59 patients obtained an objective response (1 complete response, 9 partial responses), for an objective response rate of 16% (95% confidence interval 8–25%). The median progression-free survival and overall survival were 4 and 9 months, respectively. The protracted 5-FU + LV c.i. schedule used in the present study is a well-tolerated and moderately active regimen in metastatic colorectal cancer patients resistant to 5-FU bolus ± LV. Only randomized studies can determine whether this palliative treatment has advantages in comparison with other second-line therapies such as 5-FU c.i. without LV, irinotecan, or oxaliplatin. Received: 22 September 1998 / Accepted: 5 January 1999     

Weekly 5-fluorouracil and leucovorin: achieving lower toxicity with higher dose-intensity in adjuvant chemotherapy after colorectal cancer resection.

BACKGROUND: Current standard therapy following resection of high-risk colon cancer is intravenous bolus 5-fluorouracil (5-FU) with leucovorin (LV), but there is no consensus on the optimum regimen of these drugs: practice ranges from the high toxicity Mayo Clinic schedule to the very low toxicity weekly QUASAR schedule. We present data for a weekly schedule that aims to provide moderately dose-intense treatment with low toxicity. PATIENTS AND METHODS: One hundred and sixty-two patients were studied: 60% male; median age 65 years (36% over 70 years); 94% colorectal primary. Treatment was intravenous bolus (5 min) 5-FU 425 mg/m(2) plus D,L-LV 45 mg flat rate once weekly, for a planned 24 weeks. Data for toxicity, dose-reductions, delays and stoppages were collected. RESULTS: Overall, 20% of patients experienced any grade > or = 3 toxicity, most commonly diarrhoea (14% patients). Dose reductions were made in 35% of patients (although only 21% required 20% or more reduction); toxicity contributed to a decision to stop treatment before 24 weeks in 16% of patients. Median delivered dose intensity (DI) was 96% of planned (407 mg/m(2)/week) during treatment, and 91% of planned (385 mg/m(2)/week) over the full 24 week treatment plan. Female sex and age >70 years were significantly associated with higher rates of toxicity and dose adjustment, and lower delivered DI. CONCLUSIONS: Weekly treatment at these doses is convenient and well-tolerated for the large majority of patients, and achieves DI comparable with the 5 days a month QUASAR schedule and other more toxic standard regimens.     

Effect and mechanism of orally administered leucovorin/5-fluorouracil on colon cancer

Leucovorin (LV)/5-fluorouracil combination is one of the first-line forms of chemotherapy for colorectal cancer, and in this regimen it was recommended that 5-FU be infused continuously from the venous route. However, since this regimen limits the patients' ADL, oral administration is preferable. The purpose of this study is to elucidate the mechanisms of orally-administered LV/5-FU. MATERIAL AND METHODS: The Gastrostomy was performed, and 1 x 10(6) of colon 26 was transplanted subcutaneously in CDF1 mice. In the continuous administration group, either 10, 20, 40 mg/kg of 5-FU and 100 mg/kg of LV were continuously infused for 7 days following gastrostomy using a microinfusion pump (n = 6). In the single infusion group, either 10, 20, 40 mg/kg of 5-FU was infused once a day for 7 days after gastrostomy concomitant with LV (n = 6). The other 6 animals served as the control, and LV alone was infused in this group. Tumor volume, thymidylate synthase inhibition rate (TSIR), incorporation of 5-FU into RNA (F-RNA) and body weight were measured at the end of the treatment. During the experimental period, mice were given free access to chow and water. RESULTS: The tumor volume suppression rate was significantly higher along with the amount of 5-FU. However, there was no significant difference between continuous and single infusion groups. TSIR was higher in the continuous group at the dose of 20 and 40 mg/kg. In contrast, F-RNA was higher in the single group at the dose of 20 and 40 mg/kg. Significant body weight loss was not recognized in any group. CONCLUSION: From these data, single administration of 5-FU is more effective for RNA dysfunction. On the other hand, continuous infusion is more damaging to DNA duplication. In summary, since the mechanism of the antitumor effect differs with the administration method, it is important to understand this mechanism.     

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     

Sequential chemotherapy with low-dose methotrexate and 5-fluorouracil in advanced gastric cancer

Sequential chemotherapy with low-dose methotrexate (30 mg/body) and 5-FU (750 mg/m2) was undertaken in 16 patients with advanced gastric cancer. Following the chemotherapy, leucovorin (30 mg/body) was injected intravenously. These treatment were repeated weekly for two to eight weeks. Out of 16 patients, two partial remissions and two minor responses were obtained. The overall response rate was 12.5%. There were no cases of renal or hematologic toxicity. The only adverse effect was nausea. We concluded therefore, that sequential chemotherapy with low-dose methotrexate and 5-FU is a useful method for advanced gastric cancer.     

Cost-effectiveness analysis of oxaliplatin compared with 5-fluorouracil/leucovorin in adjuvant treatment of stage III colon cancer in the US

BACKGROUND: The MOSAIC trial demonstrated that oxaliplatin/5-fluorouracil/leucovorin (FU/LV) (FOLFOX4) as adjuvant treatment of TNM stage II and III colon cancer significantly improves disease-free survival compared with 5-FU/LV alone. For stage III patients the 4-year disease-free survival (DFS) was 69% in the FOLFOX4 arm vs 61% in the LV5FU2 arm, P = .002). The cost-effectiveness of FOLFOX4 in stage III patients was evaluated from a US Medicare perspective. METHODS: By using individual patient-level data from the MOSAIC trial (median follow-up: 44.2 months), DFS and overall survival (OS) were estimated up to 4 years from randomization. DFS was extrapolated from 4 to 5 years by fitting a Weibull model and subsequent survival was estimated from life tables. OS beyond 4 years was predicted from the extrapolated DFS estimates and observed survival after recurrence. Costs were calculated from trial data and external estimates of resources to manage recurrence. RESULTS: Patients on FOLFOX4 were predicted to gain 2.00 (95% confidence interval [CI]: 0.63, 3.37) years of DFS over those on 5-FU/LV. The predicted life expectancy of stage III patients on FOLFOX4 and 5-FU/LV was 17.61 and 16.26 years, respectively. Mean total lifetime disease-related costs were $56,300 with oxaliplatin and $39,300 with 5-FU/LV. Compared with 5-FU/LV, FOLFOX4 was estimated to cost $20,600 per life-year gained and $22,800 per quality-adjusted life-year (QALY) gained, discounting costs and outcomes at 3% per annum. CONCLUSIONS: FOLFOX4 is likely to be cost-effective compared with 5-FU/LV in the adjuvant treatment of stage III colon cancer. The incremental cost-effectiveness ratio compares favorably with other funded interventions in oncology.     

Treatment for advanced colorectal carcinoma with 5-fluorouracil plus low-dose leucovorin]

From July 1992 to May 1996, 16 patients with non-curative postoperative or recurrent colorectal carcinomas were treated with 5-fluorouracil (5-FU) plus leucovorin (LV) systemic chemotherapy. LV was given at a dose of 20 mg/m2/d immediately followed by 5-FU at 370 mg/m2/d. LV was given by rapid intravenous (i.v.) injection and 5-FU by rapid or drip i.v. for 5 consecutive days. Courses were repeated once every 4 weeks for two months and then once every 5 weeks. All patients took 3 or more courses. The toxicity was tolerable, but one patient needed hospitalization because of severe gastro-intestinal toxicity. We observed 3 PR cases, no CR and an overall response rate of 19%. The response duration was 6 to 8 months, averaging 7.3 months, and median survival was 12 months. It was possible to perform this chemotherapy on an outpatient basis, so we think this chemotherapy is superior to in-hospital chemotherapy considering the issue of quality of life. However, the response rate was low and its duration was short. We must investigate chemotherapy further with new and more powerful chemical modulations to increase the response rate and to prolong the response duration.     

A phase II study of infusional 5-fluorouracil and low-dose leucovorin with docetaxel for advanced gastric cancer

BACKGROUND: The standard chemotherapy regimen for advanced gastric cancer has not yet been established. We investigated the efficacy and the safety of the combination of docetaxel with infusional 5-fluorouracil (5-FU) and leucovorin (FLT) in advanced gastric cancer. METHODS: Patients received docetaxel 75 mg/m(2) (1-hour infusion) followed by a leucovorin bolus 20 mg/m(2) and a 24-hour infusion of 5-FU 1,000 mg/m(2) (day 1-3) every 3 weeks. The response was evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria, and the toxicity was evaluated by National Cancer Institute common toxicity criteria (NCI-CTC). RESULTS: Sixty-six patients were enrolled. Median relative dose intensity was 86%. Of 57 evaluable patients, the overall response rate was 25.7%. The response rate was 34.2% in chemona?ve patients and 14.2% in the patients who had previously received treatment. Median time to progression and overall survival duration were 5.2 and 9.7 months, respectively. The most frequent grade 3-4 toxicity was neutropenia, which was the major cause of treatment delay. Other hematological and nonhematological toxicities were rare. CONCLUSIONS: The FLT regimen showed a comparable efficacy with other second-generation regimens. Because of the low nonhematological toxicity, this could be a potential alternative to the cisplatin-containing regimens in gastric cancer.     

基于循证医学依据的结肠癌辅助化疗

目前,氟尿嘧啶仍是结肠癌辅助化疗的基本药物,含5-FU/LV/奥沙利铂(FOLFOX或FLOX)的方案是结肠癌辅助化疗的新标准,对部分患者也可以考虑选用5-FU/LV(Mayo,Roswell Park,LV5 FU2)、卡培他滨等单药辅助化疗;目前没有证据表明辅助化疗中使用伊立替康能带来额外的获益,反而会增加化疗毒性的风险,因此,不建议在结肠癌辅助化疗中使用含伊立替康的方案。Ⅲ期结肠癌是辅助化疗的主要适应证,而"高危Ⅱ期"结肠癌也应该在患者充分知情后给予辅助化疗,高危因素包括T4肿瘤、伴有肠梗阻、穿孔、肿瘤分化差、伴有神经脉管浸润以及切除或送检淋巴结<12枚。其他的Ⅱ期结肠癌不应该常规行辅助化疗。只要身体状况允许,年龄不应该是选择辅助化疗的禁忌;结肠癌辅助化疗建议在术后8周内开始,目前的标准疗程是为期6个月。     

High-dose 5-fluorouracil and leucovorin as second-line chemotherapy in patients with platinum-resistant epithelial ovarian cancer

A total of 14 patients with platinum-resistant advanced epithelial ovarian cancer were treated with a continuous infusion of high-dose 5-fluorouracil (5-FU, 1200 mg/m² per day) for 2 consecutive days weekly for 4 weeks and, thereafter, every 2 weeks in combination with a push injection of folinic acid (20 mg/m²) given just before 5-FU and after 24 h. No objective response was documented, and only five patients showed stable disease. The median survival was 6.5 months. There was minimal toxicity. This schedule of 5-FU in combination with folinic acid is not effective as second-line chemotherapy in advanced ovarian cancer.     

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。