Bolus fluorouracil and leucovorin with oxaliplatin as first-line treatment in metastatic colorectal cancer.

PURPOSE: A phase II trial investigated the activity and toxicity of a bolus administration schedule of oxaliplatin, fluorouracil (5-FU), and leucovorin (LV) therapy in patients with untreated advanced colorectal cancer. PATIENTS AND METHODS: Forty-five patients in this multicenter, open, nonrandomized study received oxaliplatin 130 mg/m(2) on the first day of each course and 5-FU and LV 350 mg/m(2) and 20 mg/m(2), respectively, as a daily bolus for 5 days, every 21 days, for a maximum of six courses. RESULTS: Partial responses occurred in 18 patients, giving an intent-to-treat response rate of 40.0%. Median time to response was 12.7 weeks; median duration of response was 18.4 weeks. Median progression-free survival was 5.9 months; median survival was 14 months. The independent prognostic factors for improved overall survival were good performance status and negative carcino-embryonic antigen blood level. Incidences of adverse effects were reduced after the 5-FU dose was reduced to 300 mg/m(2). Reversible neurologic toxicity occurred in 44.4% of patients. CONCLUSION: Bolus administration of oxaliplatin, 5-FU, and LV as first-line therapy for untreated advanced colorectal cancer is efficacious and safe. In addition to a more favorable safety profile, the 300 mg/m(2) dosage offered improved dose-intensity compared with the initial dosage.     

Phase II study of capecitabine and oxaliplatin as first-line treatment in advanced colorectal cancer.

BACKGROUND: Capecitabine and oxaliplatin are both active anticancer agents in the treatment of patients with advanced colorectal cancer. The aim of this phase II study is to determine the efficacy and tolerability of combining oxaliplatin with capecitabine in the treatment of advanced non-pretreated colorectal cancer. PATIENTS AND METHODS: Forty-three chemotherapy-na?ve patients were enrolled. Capecitabine 2500 mg/m(2)/day was administered orally twice a day continuously for 14 days and oxaliplatin 120 mg/m(2) was administered as a 2-h infusion on day 1, repeated every 3 weeks. RESULTS: Forty-three patients were assessable for toxicity and 39 for clinical activity: the main toxicity was grade 3 or 4 diarrhea, which occurred in 28% of the patients. The response rates were 44% [95% confidence interval (CI), 29.3% to 59.0%] and 48.7% (95% CI 33.0% to 64.4%) (intention-to-treat and per protocol analysis, respectively). The median overall survival was 20 months (95% CI 12-28). CONCLUSIONS: Combining capecitabine and oxaliplatin yields promising activity in advanced colorectal cancer; therefore, the capecitabine dose we utilized is probably too high. The main toxicity is diarrhea, which is manageable with appropriate dose reductions.This combination may be preferable compared to a standard combination with infusional fluorouracil/leucovorin as it is more convenient and practical with similar efficacy. Thus, phase III trials are needed to clarify its role in the treatment of chemotherapy-na?ve advanced colorectal cancer patients.     

替吉奥联合奥沙利铂一线治疗晚期结直肠癌的临床分析

目的：比较替吉奥联合奥沙利铂一线治疗晚期结直肠癌的临床疗效及安全性。方法回顾性分析48例晚期结直肠癌患者。对照组20例,采用奥沙利铂（85 mg／m2加入5％葡萄糖注射液500 mL静脉滴注,25 d为1个周期）联合卡培他滨[2500 mg／（m2·d）,口服,2次／d,21 d 为1个周期]治疗;观察组28例,采用替吉奥（20 mg／d,25 d为1个周期）联合奥沙利铂（85 mg／m2加入5％葡萄糖注射液500 mL静脉滴注,20 d为1个周期）一线治疗。比较治疗前与治疗后25 d的临床疗效及安全性。结果治疗后25 d,观察组临床有效率及疾病控制率均高于对照组（48．8％、66．6％ vs 33．6％、50．3％,均P＜0．05）。在安全性方面,观察组血小板降低发生率低于对照组,差异具有统计学意义（35．5％ vs 62．3％,P＜0．05）;贫血、呼吸道反应及肝功能受损发生率与对照组比较差异均无统计学意义（45．5％、46．8％、43．5％ vs 47．2％、47．4％、45．8％,均P＞0．05）。结论与奥沙利铂联合卡培他滨比较,替吉奥联合奥沙利铂一线治疗晚期结直肠癌临床疗效和安全性更优。     

Modified de Gramont with oxaliplatin in the first-line treatment of advanced colorectal cancer

We previously reported high activity for oxaliplatin and a modified de Gramont regimen (OxMdG) in a single centre study of patients with metastatic colorectal cancer. We now report results with a further 56 patients treated at 14 centres. Low rates of grade 3 and 4 toxicity were seen, with no toxic deaths. Objective response rates were CR/PR=53%; NC=34.7%; PD=12.2%. Median time to progression was 8.3 months and overall survival was 14.5 months. This regimen is more convenient than those based around the conventional de Gramont regimen but is highly active and well tolerated; it forms part of a current UK MRC phase 3 trial.     

Two different first-line 5-fluorouracil regimens with or without oxaliplatin in patients with metastatic colorectal cancer

Background: Oxaliplatin, 5-fluorouracil (5-FU), and leucovorin(LV) are standard first-line treatments for patients with metastaticcolorectal cancer (mCRC). The aim of this multicentre, open-label,phase IIIb study was to assess the addition of oxaliplatin totwo different 5-FU regimens. Patients and methods: Patients with previously untreated mCRCwere randomised to arm A [two-weekly oxaliplatin 85 mg/m² +either continuous intravenous infusion (CIV) of 5-FU withoutLV or two-weekly bolus and CIV 5-FU + LV (LV5FU2)] or arm B(5-FU CIV or LV5FU2 alone). Irinotecan monotherapy was plannedon progression. Results: A total of 725 patients were enrolled. After a fixedfollow-up of 2 years for each patient, 2-year survival rateswere 27.3% and 24.8% in arms A and B, respectively (hazard ratio0.93; 95% confidence interval 0.78–1.10). The additionof oxaliplatin significantly improved response rates (54.1 versus29.8%; P < 0.0001) and median progression-free survival (7.9versus 5.9 months; P < 0.0001). The most common grade 3–4toxic effects were neutropenia (arm A, 33%; arm B, 5%), diarrhoea(arm A, 14%; arm B, 8%), and fatigue (arm A, 9%; arm B, 8%). Conclusions: Despite improved rates of tumour control, theseresults failed to demonstrate a survival benefit from the additionof oxaliplatin to infused 5-FU and lend further support to theuse of sequential monotherapy in some patients with mCRC. Key words: colorectal cancer, 5-fluorouracil, leucovorin, metastatic, oxaliplatin, phase III Received for publication May 12, 2008. Revision received July 16, 2008. Accepted for publication August 22, 2008.     

Safety and toxicity analysis of oxaliplatin combined with fluorouracil or as a single agent in patients with previously treated advanced colorectal cancer.

PURPOSE: Two consecutive compassionate use studies of oxaliplatin were conducted in the United States and Canada in more than 5000 patients with locally advanced or metastatic colorectal carcinoma who had experienced treatment failure after at least one prior chemotherapy regimen. PATIENTS AND METHODS: The main focus was safety. Patients were assigned to treatment with either single-agent oxaliplatin or oxaliplatin in combination with fluorouracil (FU) and with or without leucovorin (LV) in various regimens. Response data collection was not a trial objective, but time to treatment failure (TTF) was recorded in the first cohort (1370 patients). RESULTS: All treatment regimens were well tolerated, with an overall incidence of grade 3 or 4 hematologic toxicity of 23.2%, grade 3 or 4 treatment-related gastrointestinal toxicity of 26.4% (including diarrhea, vomiting, and mucositis), and grade 3 neurosensory toxicity 3.9%. Similar results were reported in the second cohort (3806 patients), in which the eligibility criteria were much less restrictive. In the first cohort (in which 83% received prior irinotecan), median TTF was 14 weeks, and was similar for the five regimens combining oxaliplatin and FU with or without LV, but significantly shorter for the single-agent oxaliplatin arm. The overall dose-intensity of oxaliplatin was maintained at 85.5% (range, 80.6% to 94.3%) of that prescribed by protocol (average 36.7 mg/m2/wk). CONCLUSION: These data in a heavily pretreated patient population confirm that oxaliplatin is safe when used as a single agent or with a variety of FU-based regimens as salvage therapy in patients with advanced colorectal cancer.     

Phase II study of UFT and oxaliplatin in first-line treatment of advanced colorectal cancer

The purpose of this study was to evaluate the efficacy, assessed as response rate, and toxicity of UFT (Tegafur-Uracil) in combination with oxaliplatin as first-line treatment of advanced colorectal cancer (CRC). In all, 84 patients with recurrent or metastatic CRC with measurable disease were included. Treatment consisted of oxaliplatin 85 mg m(-2) in 120-min intravenous (i.v.) infusion on days 1 and 15; i.v. l,leucovorin (l,LV) 250 mg m(-2) given in 2 h on day 1, followed by oral UFT 390 mg m(-2) on days 1-14, and oral l,LV 7.5 mg/12 h on days 2-14. Cycles were repeated every 28 days. A total of 492 cycles of chemotherapy were delivered with a median of six per patient (range 1-12). There was one complete response (1%) and 28 partial responses (34%) for an overall response rate of 35% (95% confidence interval (CI): 24-46%). A total of 36 patients (44%) had stable disease, whereas 17 (21%) had a progression. The median time to progression was 7.3 months and the median overall survival was 16.8 months. A prescheduled preliminary analysis was performed after inclusion of 16 patients who detected a high gastrointestinal toxicity, which led to a reduction of the UFT dose to 300 mg m(-2). With this new dosage, grade 3-4 diarrhoea and grade 3-4 nausea/vomiting dropped to 21 and 14% of patients, respectively. Other grade 3-4 toxicities were stomatitis in one (1%), anaemia in three (5%), neutropenia in two (3%), thrombocytopenia in one(1%), fatigue in six (9%), peripheral sensory neuropathy in nine (14%) and laryngopharyngeal dysesthesia in two patients (2%). The combination of oxaliplatin and UFT-l,LV is an active, easy-to-administer regimen with moderate toxicity. Hence, this regimen is worthy of further investigation.     

Multicenter phase II study of Nordic fluorouracil and folinic acid bolus schedule combined with oxaliplatin as first-line treatment of metastatic colorectal cancer.

PURPOSE: This Nordic multicenter phase II study evaluated the efficacy and safety of oxaliplatin combined with the Nordic bolus schedule of fluorouracil (FU) and folinic acid (FA) as first-line treatment in metastatic colorectal cancer. PATIENTS AND METHODS: Eighty-five patients were treated with oxaliplatin 85 mg/m(2) as a 2-hour infusion on day 1, followed by a 3-minute bolus injection with FU 500 mg/m(2) and, 30 minutes later, by a bolus injection with FA 60 mg/m(2) every second week. The same doses of FU and FA were also given on day 2. RESULTS: Fifty-one of 82 assessable patients achieved a complete (n = 4) or partial (n = 47) response, leading to a response rate of 62% (95% CI, 52% to 72%). Nineteen patients showed stable disease, and 12 patients had progressive disease. Thirty-eight of the 51 responses were radiologically confirmed 8 weeks later (confirmed response rate, 46%; 95% CI, 36% to 58%). The estimated median time to progression was 7.0 months (95% CI, 6.3 to 7.7 months), and the median overall survival was 16.1 months (95% CI, 12.7 to 19.6 months) in the intent-to-treat population. Neutropenia was the main adverse event, with grade 3 to 4 toxicity in 58% of patients. Febrile neutropenia developed in seven patients. Nonhematologic toxicity consisted mainly of neuropathy (grade 3 in 11 patients and grade 2 in another 27 patients). CONCLUSION: Oxaliplatin combined with the bolus Nordic schedule of FU+FA (Nordic FLOX) is a well-tolerated, effective, and feasible bolus schedule as first-line treatment of metastatic colorectal cancer that yields comparable results compared with more complex schedules.     

国产奥沙利铂联合氟尿嘧啶和亚叶酸钙治疗晚期结直肠癌的临床观察

目的评价奥沙利铂(L-OHP)联合氟尿嘧啶(5-Fu)、亚叶酸钙(CF)方案治疗晚期结直肠癌的疗效与毒副反应.方法奥沙利铂130 mg/m2,静滴4 h,第1天;亚叶酸钙200 mg静脉滴注2 h,5-Fu 300 mg/m2,持续静滴6～8 h,第1～5天(亚叶酸钙滴完后用);21 d为1周期,行2周期治疗后评价疗效.结果全组完全缓解(CR)1例,部分缓解(PR)12例,总有效率(CR PR)为43.3%.毒性反应以骨髓抑制、感觉性神经毒性为主,多为Ⅰ～Ⅱ度,其中白细胞减少发生率为46.7%,感觉性神经毒性发生率为77.7%,无化疗相关死亡.结论奥沙利铂联合氟尿嘧啶、亚叶酸钙治疗晚期结直肠癌疗效肯定,毒副反应能耐受.     

Randomized multicenter phase II trial of oxaliplatin plus irinotecan versus raltitrexed as first-line treatment in advanced colorectal cancer.

PURPOSE: Irinotecan and oxaliplatin are two new agents with promising activity in advanced colorectal cancer. Based on preclinical and clinical evidence that both drugs act synergistically, a randomized phase II study was initiated to investigate the therapeutic potential and tolerance of this combination in the front-line setting. PATIENTS AND METHODS: Ninety-two patients with previously untreated, measurable disease were randomized to receive biweekly oxaliplatin 85 mg/m(2) plus irinotecan 175 mg/m(2) or raltitrexed 3 mg/m(2) given on day 1 every 3 weeks. Upon development of progressive disease, second-line treatment with the opposite arm was effected. RESULTS: Patients allocated to oxaliplatin/irinotecan had a significantly better radiologically confirmed response rate (43.5% v 19.6%; P =.0025) and longer progression-free survival (median, 7.1 v 5.0 months; P =.0033). Improvement in overall survival, however, did not reach the level of significance (median, 16.0 v 16.5 months; P =.3943). The response rate after cross-over was 33.3% (eight of 24) for assessable patients treated with oxaliplatin/irinotecan compared with 14.2% (three of 21) for those treated with second-line raltitrexed. Oxaliplatin/irinotecan caused more hematologic and gastrointestinal toxicities, necessitating dose reductions in 10 of the first 20 patients. After adjustment of the irinotecan starting dose from 175 to 150 mg/m(2), tolerance of treatment was acceptable; the most commonly encountered events (all grades) were neutropenia (81%), alopecia (65%), nausea/emesis (62%), peripheral sensory neuropathy (62%), and diarrhea (46%). CONCLUSION: Oxaliplatin/irinotecan seems beneficial as first-line therapy in advanced colorectal cancer, with an acceptable toxicity profile at the reduced irinotecan dose level. Its promising therapeutic potential is supported by the high response activity noted in the raltitrexed control arm after cross-over, which may also explain the lack of a difference in overall survival.     

Pharmacogenetic approach for capecitabine or 5-fluorouracil selection to be combined with oxaliplatin as first-line chemotherapy in advanced colorectal cancer

We studied the role of TS (5’VNTR, 5’SNP and 3’UTR), XRCC1-399, XPD-751, ERCC1-118 and XRCC3-241 genetic polymorphisms in tailoring fluroropyrimidine/oxaliplatin treatment. For this purpose, 110 XELOX (capecitabine/oxaliplatin)- or FUOX (fluorouracil/oxaliplatin)-treated metastatic colorectal cancer patients were selected prospectively for genotyping. In the FUOX group, TS-3’UTR +6 bp/+6 bp (hazards ratio, HR = 2.62, p = 0.007) and ERCC1-118 C/T or C/C (HR = 1.96, p = 0.050) genotypes correlated with a shorter progression free survival (PFS). When analysed jointly, the higher the number of favourable genotypes (FG) the longer the PFS (6.8 m, 9.6 m and 25.8 m for 0, 1 or 2 FG; p = 0.005). Disease-control rate was 100% in patients with 2 FG (87% and 38.5% for 1 or 0 FG; p = 0.001). In the multivariate analysis, ERCC1-118 (HR = 2.12, p = 0.0037) and TS-3’UTR (HR = 2.68, p = 0.006) were strong independent prognostic factors. According to this, patients harbouring TS-3’UTR +6 bp/+6 bp and ERCC1-118 C/T or C/C genotypes may better receive capecitabine instead of 5FU in an oxaliplatin-based first-line treatment.     

Triplet combination with irinotecan plus oxaliplatin plus continuous-infusion fluorouracil and leucovorin as first-line treatment in metastatic colorectal cancer: a multicenter phase II trial.

PURPOSE: To evaluate the efficacy and tolerance of irinotecan (CPT-11) in combination with oxaliplatin (L-OHP) plus fluorouracil (5-FU)/leucovorin (LV) (de Gramont regimen) as first-line treatment of metastatic colorectal cancer (MCC). PATIENTS AND METHODS: Thirty-one patients with MCC who had not received prior therapy for metastatic disease were enrolled. Their median age was 60 years; performance status (World Health Organization) was 0 in 12, 1 in 14, and 2 in five patients; 19 patients (61%) had prior surgery, and 14 (45%) had adjuvant chemotherapy. CPT-11 was administered on day 1 at 150 mg/m(2) as a 90-minute intravenous (IV) infusion; L-OHP was administered on day 2 at 65 mg/m(2) as a 2-hour IV infusion; and on days 2 and 3, LV 200 mg/m(2) preceded 5-FU administration of 400 mg/m(2)/d initial IV bolus dose followed by 600 mg/m(2)/d 22-hour IV continuous infusion. The regimen was repeated every 2 weeks. RESULTS: All patients were assessable for toxicity and 30 for response to treatment. Complete response was achieved in two patients (6.5%) and partial response in 16 (51.6%) (overall response rate, 58.1%; 95% confidence interval, 40.7% to 75.4%); eight patients (25.8%) had stable disease, and five (16.1%) had disease progression. The median duration of response was 9 months, and the median time to disease progression was 13 months. Neutropenia grade 3 to 4 occurred in 14 patients (45%) and febrile neutropenia in two (6%). Diarrhea grade 3 to 4 was observed in 10 patients (32%), neurotoxicity grade 3 to 4 in three (9%), and asthenia grade 3 in two (10%). No treatment-related death has occurred. CONCLUSION: The triplet combination of 5-FU/LV + CPT-11 + L-OHP is a highly active regimen with manageable toxicity as front-line treatment in MCC.     

Irinotecan or oxaliplatin combined with leucovorin and 5-fluorouracil as first-line treatment in advanced colorectal cancer: a multicenter, randomized, phase II study.

BACKGROUND: Irinotecan (IRI) and oxaliplatin (OXA) are effective in the treatment of colorectal cancer. Previously untreated patients with advanced colorectal carcinoma (CRC) were randomly assigned to receive IRI plus leucovorin (LV)/5-fluorouracil (5-FU), or OXA plus LV/5-FU in order to compare the response rates, time-to-tumor progression, overall survival rates, and toxicity profiles of these two agents. MATERIALS AND METHODS: From January 1999 to February 2002, 295 patients were randomized to receive either IRI/LV/5-FU or OXA/LV/5-FU. The treatment schedules consisted of weekly IRI 70 mg/m(2) or OXA 45 mg/m(2) plus LV 200 mg/m(2) followed immediately by intravenous bolus 5-FU 450 mg/m(2) for 6 weeks, followed by a 2-week rest period. Treatment was continued for up to four cycles or until disease progression, unacceptable toxicity or patient refusal. RESULTS: There were no significant differences between the study arms in the overall response rate (33% with IRI/LV/5-FU versus 32% with OXA/LV/5-FU based on responses demonstrated on a single evaluation; 23% with IRI/LV/5-FU versus 22.3% with OXA/LV/5-FU based on responses confirmed according to WHO criteria) median time to progression (8.9 versus 7.6 months), and median overall survival (17.6 versus 17.4 months). Toxicity profiles (grades 3 and 4) were similar in the IRI and OXA arms (diarrhea 12.3% and 9.8%, neutropenia 8.2% and 4.9%, and febrile neutropenia 1.4% and 1.4%, respectively), with the exception of grade 3 sensory neuropathy, which almost exclusively occurred in the OXA arm (0% versus 5.6%; P=0.003, Fisher's exact test). CONCLUSION: The IRI/LV/5-FU and OXA/LV/5-FU regimens demonstrated equally substantial efficacies and manageable toxicity profiles in the first-line treatment of patients with advanced CRC. However, IRI/LV/5-FU may be the preferable regimen to avoid significant neurotoxicity associated with OXA-LV/5-FU.     

Cost-effectiveness analysis of irinotecan plus fluorouracil/folinic acid compared with fluorouracil/folinic acid alone as first-line treatment for advanced colorectal cancer

Introduction

An economic evaluation was conducted to test whether irinotecan in combination with fluorouracil and folinic acid was as cost-effective (within the Spanish Health Service) as fluorouracil and folinic acid alone in the first-line treatment of advanced colorectal cancer.

Material and methods

Efficacy data from the study by Douillard et al were used. Data on resource use for the two groups of patients were collected for 41 Spanish patients and the assigned costs were from various Spanish sources. The incremental cost-effectiveness ratios of the alternatives were calculated by comparing costs in relation to survival.

Results

Douillard's trial showed an improved median survival of 2.80 months (0.233 years) in patients in the irinotecan group compared to the control group. Cumulative drug costs and other resource consumption per patient (e.g. average number of cycles per treatment) were higher in the irinotecan group. Patients in the control group required greater additional chemotherapy following the trial period. The average cost per patient was ©22,280 and ©14,016 in the irinotecan and control groups, respectively. The incremental cost per life-year gained in the basic case was ©35,416.

Conclusions

The results indicate that the combination of irinotecan with fluorouracil and folinic acid can be considered cost-effective as first-line treatment of advanced colorectal cancer in the Spanish setting.     

Activity and safety of oxaliplatin with weekly 5-fluorouracil bolus and low-dose leucovorin as first-line treatment for advanced colorectal cancer

This study was designed to evaluate the safety and tolerability of oxaliplatin combined with weekly boluses of 5-fluorouracil (5-FU) and low doses of leucovorin (LV) and to determine objective response, progression-free survival, and overall survival of patients with previously untreated advanced colorectal cancer. Seventy-nine patients enrolled in an observational, multicenter, prospective, open-label phase II study received intravenous (I.V.) infusions of oxaliplatin 85 mg/m2 over the course of 2 hours on days 1 and 14 and LV 20 mg/m2 over the course of 2 hours and 5-FU 500 mg/m2 as a bolus on days 1, 7, and 14 every 4 weeks until disease progression or unacceptable toxicity occurred. Seventy-nine patients were evaluable for safety, and data from 70 patients were used for efficacy analysis. The objective response rate was 51.4%. Complete responses occurred in 7 patients (10%), and partial responses occurred in 29 patients (41.4%). Disease control, defined as response or stable disease, was obtained in 56 of 70 patients (80%). The median duration of response was 8.34 weeks (range, 7.3-11.5 weeks). The median time to progression was 7.13 months (range, 6.28-7.72 months), and median overall survival time was 15 months (range, 12.32-18.37 months). Acute dose-limiting toxicities were grade 3/4 diarrhea and neutropenia, which occurred in 10.5% and 3.9% of patients, respectively. Among the 70 patients who experienced neurosensory toxicity, it was estimated that only 1.3% had grade 3 symptoms. Preliminary data showed that the regimen is at least as active as other regimens combining oxaliplatin and infusional schedules of 5-FU and might be more convenient for patients because it avoids the need for I.V. catheter implantation.     

A genotype-directed phase I-IV dose-finding study of irinotecan in combination with fluorouracil/leucovorin as first-line treatment in advanced colorectal cancer

Background:

Infusional fluorouracil/leucovorin (FU/LV) plus irinotecan (FOLFIRI) is one of the standard first-line options for patients with metastatic colorectal cancer (mCRC). Irinotecan is converted into 7-ethyl-10-hydroxycamptothecin (SN-38) by a carboxylsterase and metabolised through uridine diphosphate glucuronosyl transferase (UGT1A1). The UGT1A1^*28 allele has been associated with the risk of developing severe toxicities. The present trial was designed to define the maximum tolerated dose according to UGT1A1 genotype. This report focuses on the results of tolerance to different escalated doses of FOLFIRI first-line of chemotherapy.

Patients and methods:

Patients undergoing first-line treatment for mCRC and eligible for treatment with FOLFIRI were classified according to UGT1A1 genotype. A total of 94 patients were eligible for dose escalation of irinotecan. The starting dose of biweekly irinotecan was 180 mg m⁻² for the ^*1/^*1, 110 mg m⁻² for the ^*1/^*28 and 90 mg m⁻² for the ^*28/^*28 genotypes.

Results:

The dose of irinotecan was escalated to 450 mg m⁻² in patients with the ^*1/^*1 genotype, to 390 mg m⁻² in those with the ^*1/^*28 genotype and to 150 mg m⁻² in those with the ^*28/^*28 genotype. Neutropenia and diarrhoea were the most common grade 3 or 4 toxicities.

Conclusions:

Our results demonstrated that the recommended dose of 180 mg m⁻² for irinotecan in FOLFIRI is considerably lower than the dose that can be tolerated for patients with the UGT1A1 ^*1/^*1 and ^*1/^*28 genotypes. The maximum tolerable dose (MTD) in patients with a high-risk UGT1A1 ^*28/^*28 genotype is 30% lower than the standard dose of 180 mg m⁻².     

Phase II study of ACNU as first-line treatment in advanced colorectal cancer.

Thirty-two patients with metastatic colorectal cancer were entered in a phase II study of ACNU as first-line treatment. ACNU was given at a dose of 100 mg/m2 i.v. every six weeks. In 30 evaluable patients we observed partial responses lasting 5 and 8 months in 2 patients with liver metastases, and stable disease in 4 patients. The toxicity mainly consisted of leuco- and trombocytopenia. We conclude that in this dose and schedule ACNU has only very limited activity in metastatic colorectal cancer.     

Randomized multicenter phase II trial of two different schedules of capecitabine plus oxaliplatin as first-line treatment in advanced colorectal cancer.

PURPOSE: Capecitabine and oxaliplatin, two new agents with potential synergistic activity, have demonstrated promising antitumor efficacy in advanced colorectal cancer (ACC). Preclinical and clinical evidence indicating that dose intensification of the oral fluorouracil prodrug might result in improved therapeutic results led us to the present randomized multicenter phase II study. PATIENTS AND METHODS: Eighty-nine patients with bidimensionally measurable ACC previously untreated for metastatic disease were randomly allocated to receive oxaliplatin 130 mg/m(2) day 1 plus capecitabine 2,000 mg/m(2)/d days 1 to 14 every 3 weeks (arm A) or to receive oxaliplatin 85 mg/m(2) days 1 and 14 combined with capecitabine 3,500 mg/m(2) days 1 to 7 and 14 to 21 every 4 weeks (arm B). In both treatment arms, chemotherapy was continued for a total of 6 months unless there was prior evidence of progression of disease. RESULTS: Patients allocated to the high-dose capecitabine combination arm B had a higher radiologically confirmed response rate (54.5% v 42.2%) and a significantly longer median progression-free survival time than those allocated to control arm A (10.5 v 6.0 months; P =.0013). Median overall survival times cannot be calculated for either treatment arm at this point. Despite a 34% higher dose intensity of capecitabine in arm B, there was no difference in hematologic toxicity between treatment arms (neutropenia/thrombocytopenia: 60%/43% in arm B v 56%/33% in arm A). Similarly, the incidence rate and degree of nonhematologic adverse events were comparable: The most commonly encountered symptoms (all grades, arm A and arm B) included nausea/emesis (A: 58%; B: 62%), diarrhea (A: 44%; B: 31%), peripheral sensory neuropathy (A: 80%; B: 83%), and fatigue (A: 40%; B: 50%). CONCLUSION: Results of this study indicate that both combination regimens are feasible, tolerable, and clinically active. The dose-intensified bimonthly capecitabine arm, however, seems to be more effective in increasing both response rate and progression-free survival time.