Pharmacokinetic study of oxaliplatin iv chronomodulated infusion combined with 5-fluorouracil iv continuous infusion in the treatment of advanced colorectal cancer

We investigated the pharmacokinetics (PK), preliminary clinical results and toxicity of chronomodulated oxaliplatin (OHP) plus 5-fluorouracil (5-FU) without folinic acid (FA) in 13 patients with metastatic colorectal cancer. 5-FU (200 mg/m2/day as 14-day continuous iv infusion for six cycles) plus OHP at increasing doses (25-30-35 mg/m2/day, as 12 h chronomodulated iv infusion on days 1-2-3-4, every 14 days for six cycles) were administered to reach maximum tolerated dose (MTD). At MTD (30 mg/m2/day), a PK study of 5-FU and OHP (in total and ultrafiltered-UF plasma) was performed. 5-FU plasma levels were fairly stable, below that reported in similar studies and closely related to the lack of the most typical 5-FU toxicities. OHP Cmax occurred 7 h after infusion start; a progressive accumulation of free Pt and ultrafiltered Pt (UF-OHP) through cycles 1-6 was noted. A marked difference between total plasma and UF Pt was seen in the elimination phase. OHP plasma clearance decrease was related to Vz (volume of distribution of late elimination phase), whereas in UF-OHP was due to a change in Ke or t1/2. In conclusion, the association of 5-FU with chronomodulated OHP do not seem to influence PK parameters of either drugs. Toxicity was modest/acceptable and clinical efficacy good: preliminary data showed a threshold neurotoxicity at total plasma Pt concentrations >1500 ng/ml and UF plasma Pt concentrations >150 ng/ml.     

Phase II trial of 5-fluorouracil, folinic acid and recombinant alpha-2a-interferon in patients with advanced colorectal cancer

A clinical trial regimen modulating 5-fluorouracil (5-FU) with both folinic acid (FA) and recombinant alpha-2a-interferon (ralpha-2a-IFN) was noted to have a response rate of 54% and median survival of 16.3 months (Grem et al., J Clin Oncol 1993, 11: 1737-45). Reported herein is a phase II trial performed to further examine this regimen in metastatic colorectal cancer. Fifty-one patients with histologically proven, measurable advanced colorectal cancer with no prior therapy for metastatic disease were enrolled. ralpha-2a-IFN, 5 MIU/m2/day was given s.c. on days 1-7. FA, 500 mg/m2/day, and 5-FU, 370 mg/m2/day, were given i.v. on days 2-6. Cycles were repeated at 3 week intervals. Three complete and 12 partial responses were observed for an overall response rate of 29% (95% confidence interval: 18-45%). The median time to treatment failure and median survival were 4.6 and 15.5 months, respectively. Dose-limiting toxicities encountered were gastrointestinal, and included diarrhea, stomatitis, nausea and vomiting. These results do not support the concept of using concurrent ralpha-2a-IFN and FA as biochemical modulators of 5-FU. We observed increased toxicity and similar efficacy compared to using either modulator separately with 5-FU.     

Dramatic tumor response of bulky liver metastases following treatment with CPT-11 and a chronomodulated 4-day infusion of 5-fluorouracil, folinic acid and oxaliplatin every 2 weeks in a colorectal cancer patient

Three active antitumor agents, i.e. 5-fluorouracil (5-FU), oxaliplatin and CPT-11, are available for the treatment of advanced colorectal cancer (CRC) patients and have been successfully combined in two-drug regimens. Hence, CRC has become a chemosensitive disease, but the optimal combination of these agents in first-line treatment remains to be determined. We report the first case of the combination of CPT-11 with oxaliplatin, 5-FU and folinic acid (FA) as first-line chemotherapy for a patient with a pre-occlusive sigmoid adenocarcinoma and synchronous bulky liver metastases. CPT-11 was given at 125 mg/m2, prior to the start of a chronomodulated 4-day infusion of oxaliplatin 25 mg/m2/day, 5-FU 800 mg/m2/day and FA 300 mg/m2/day repeated every 2 weeks. The doses could be escalated to 150 mg/m2 for CPT-11 and 900 mg/m2/day for 5-FU. After six cycles of chemotherapy 70% reduction in tumor size was documented in the liver. The primary tumor was no longer detectable by barium enema. The toxicity included three episodes of grade 4 neutropenic fever, and two episodes of severe diarrhea and vomiting with dehydration. A cumulative grade 2 neurosensory toxicity was observed after six cycles. Following surgery of the primary tumor, because of the major hepatic tumor response and of the absence of extra-hepatic metastases, the patient might be registered for a liver transplantation program. This first report of combining the three active agents in CRC every 2 weeks led to a high dose intensity of each agent and was associated with a dramatic tumor response of a very advanced disease in a patient with already altered performance status. The antitumor activity in this patient suggests that a three-drug intensified regimen might be feasible and active. A prospective study appears warranted to further examine the efficacy and toxicity of this therapeutic approach, and to determine whether it may increase the fraction of advanced CRC patients becoming resectable. This aggressive chemotherapy program may contribute to a re-examination of the usefulness of liver transplantation in patients with metastatic CRC confined to the liver.     

Biweekly oxaliplatin plus irinotecan and folinic acid-modulated 5-fluorouracil: a phase II study in pretreated patients with metastatic colorectal cancer

Oxaliplatin (OXA) and irinotecan (IRI) are active drugs for metastatic colorectal cancer, their toxicity profiles are not overlapping, and both drugs have shown at least additivity with folinic acid-modulated 5-fluorouracil (5FU). We carried out this phase II study to assess the activity and toxicity of a biweekly regimen including OXA plus IRI on day 1, and levo-folinic acid (LFA) plus 5FU on day 2 (OXIRIFAFU) in pretreated patients with metastatic colorectal cancer. Forty-one patients, all previously treated with adjuvant and/or palliative 5FU-based chemotherapy (16 of them already exposed to IRI, OXA or both), were enrolled into this trial. On the basis of sensitivity to previous treatment, 19 patients were considered as chemo-resistant and 14 patients as chemo-refractory. OXA 110 mg/m (over 2 h) and IRI 175 mg/m (over 1 h) were delivered on day 1, followed by LFA 250 mg/m (2-h infusion) plus 5FU 800 mg/m as intravenous bolus on day 2. Cycles were repeated every 2 weeks. A total of 348 cycles were delivered, with a median of nine cycles per patient (range, 1-12 cycles per patient). Five complete and 13 partial responses were reported on 40 assessable patients, giving a response rate of 45% [95% confidence interval (CI), 29-62%]; eight of 19 (42%) resistant patients and five of 14 (36%) refractory patients achieved a major response, which was also obtained in four of eight (50%) patients pretreated with IRI and in three of eight (38%) patients pretreated with OXA. Grade 3 or higher neutropenia occurred in 68% of patients, but febrile neutropenia or infections affected only seven (17%) patients. No episodes of grade 3 or higher thrombocytopenia or anemia were recorded. Occurrence of severe non-hematologic toxicities by patients were: diarrhea, 34%; vomiting, 17%; peripheral cumulative neuropathy, 15%; stomatitis, 10%; acute cholinergic syndrome, 7%. Actually delivered dose intensities of all three drugs resulted in about two-thirds of the planned ones. After a follow-up of 39 months, median progression-free survival was 7.5 months. Median overall survival was 14.4 (95% CI, 10.4-18.4) months from the start of OXIRIFAFU and 25.3 (95% CI, 18.1-32.5) months from the diagnosis of metastatic disease. This OXIRIFAFU triplet regimen was highly effective in resistant/refractory colorectal cancer patients. A slight dose reduction of all cytotoxic drugs could be advisable in order to improve the tolerability of this regimen without jeopardizing its activity.     

奥沙利铂联合亚叶酸钙和氟尿嘧啶治疗晚期大肠癌的临床观察

目的评价奥沙利铂联合亚叶酸钙和大剂量氟尿嘧啶（5-FU）持续48 h静脉滴注治疗晚期大肠癌的疗效和安全性。方法32例大肠癌患者采用静脉滴注奥沙利铂100 mg/m^2,亚叶酸钙200 mg/m^2,亚叶酸钙滴注之后用5-FU 0．5 g静注,接着用5-FU 3．0 g/m^2持续静脉滴注48h,每2周1次,2次为1个周期。结果32例病例中,平均疗程数为4个周期,其中完全缓解（CR）1例,部分缓解（PR）15例,稳定（SD）12例,进展（PD）4例,总有效率（CR＋PR）为50%。不良反应为恶心、呕吐和骨髓抑制,但多为Ⅰ～Ⅱ度,一过性感觉异常。结论奥沙利铂联合亚叶酸钙和氟尿嘧啶治疗晚期大肠癌疗效较高,不良反应轻而且安全,患者容易耐受,值得推广使用。     

5-fluorouracil alone versus 5-fluorouracil plus folinic acid in the treatment of colorectal carcinoma: meta-analysis

OBJECTIVE: Innovative techniques in the field of artificial intelligence could help to resolve several methodological problems. A model taking into account all the parameters involved in a therapy can foresee the results of each type of treatment or therapeutic protocol on patients at different stages of a disease. We used a Computer Decision Support System in order to verify the reliability and efficacy of this method on chemotherapy of colorectal carcinoma. MATERIAL AND METHODS: We analyzed 8 randomized clinical trials employing 5-fluorouracil alone (5-FU) or 5-fluorouracil (5-FU) plus leucovorin (FA) in the management of advanced colorectal carcinoma. Computer Decision Support System (CDSS) was used to perform four basic tasks: data acquisition and organization; data recruitment; combination of the various principles and specific data; user-friendly display of the analysis results and responses to treatment. RESULTS: In the majority of the studies examined, the death rates were lower in patients treated with 5-FU + FA than in those on 5-FU alone, even though the difference was not statistically significant. However, there were wide fluctuations in the efficacy/tolerability ratio between the two protocols investigated, depending on the patients' clinical status. Our data showed that a strong attack using 5-FU + FA is feasible whenever the patients' clinical conditions are not particularly severe, whereas a moderate attack using 5-FU alone is recommended as the patients' clinical condition worsens. CONCLUSION: The use of CDSS in the management of colorectal carcinoma indicates which therapy is the best in terms of efficacy, overall survival and incidence of side effects.     

Biweekly bolus 5-fluorouracil and leucovorin plus oxaliplatin in pretreated patients with advanced colorectal cancer: a dose-finding study

The primary objective of this study was to determine the maximum tolerable dose (MTD) and dose-limiting toxicity (DLT) for bolus 5-fluorouracil (5-FU) administered on a biweekly schedule and in combination with fixed doses of leucovorin (LV) and oxaliplatin. The secondary objectives were to evaluate the toxicity profile and antitumor activity of this regimen for pre-treated patients with advanced colorectal cancer. A total of 26 patients with documented fluoropyrimidine-resistant, advanced colorectal cancer were enrolled into this phase I study. Fixed dose of oxaliplatin (85 mg/m2) was delivered as an i.v. infusion over 2 h, followed by LV (20 mg/m2) and 5-FU bolus every 2 weeks. The starting dose of 5-FU was 600 mg/m2, which was then incremented by 100 mg/m2 for each dose level. The DLT was determined for the first two treatment cycles, while toxicity and efficacy were evaluated throughout treatment. Six dose levels were tested. The MTD of 5-FU was deemed to be 1000 mg/m2 since dose-limiting fatigue was noted for three of the five-patient cohort during the first two cycles of chemotherapy at dose level 6. The most frequent treatment-related toxicities during the study were neutropenia, vomiting, diarrhea, fatigue and neuropathy. In an intent-to-treat analysis, the objective response rate was 30.8% (95% confidence interval 11.8-49.8%) for the 26 patients. The combination of bolus 5-FU/LV and oxaliplatin every 2 weeks is a feasible and effective treatment at the recommended dosages. A phase II study, to more-precisely define activity and toxicity, is ongoing.     

Weekly treatment with irinotecan, folinic acid and infusional 5-fluorouracil (ILF) in patients with advanced gastric cancer

Although 5-fluorouracil remains the mainstay of treatment for advanced gastric cancer (AGC), no standard chemotherapy regimen exists. Combinations of irinotecan with folinic acid and infusional 5-fluorouracil (5-FU) (ILF) have shown good efficacy with acceptable toxicity in patients with metastatic colorectal cancer. At present, only sparse data on ILF are available for AGC. Therefore we conducted a prospective study of this combination in 25 consecutive patients with metastatic gastric cancer. Median age was 63 years, 10 had received prior chemotherapy and 13 presented initially with peritoneal carcinosis. Treatment consisted of irinotecan 80 mg/m2, folinic acid 500 mg/m2 and infusional 5-FU 2.0 g/m2 over 24 h, given weekly for 6 weeks followed by a 1-week rest. Grade 3/4 hematologic toxicity occurred in six patients (anemia = 4, neutropenia = 1 and leukopenia = 1). Non-hematologic toxicity consisted mainly of nausea/vomiting (grade 3/4 in six patients) and diarrhea (grade 3/4 in 10 patients). The overall response rate was 20% for first- and second-line treatment, with two complete and three partial responses. Another nine patients (36%) had stable disease, for a tumor control rate of 56%. Median time to progression was 4 months, median overall survival and survival for patients with tumor control was 7 and 13 months, respectively. We conclude that ILF is a feasible outpatient regimen with manageable toxicity that provides tumor control in a high proportion of patients with advanced gastric cancer, even among those with unfavorable prognostic features.     

Phase I study of gemcitabine in combination with cisplatin, 5-fluorouracil and folinic acid in patients with advanced esophageal cancer

The prognosis for advanced esophageal carcinoma is poor with a median survival of 9-12 months and 5-year-survival rate of 10-20%. Combination chemotherapy with cisplatin and 5-fluorouracil (5-FU) is considered to be the standard therapy, but has a high potential of side effects and is usually not given on an ambulatory basis. This phase I study was designed to find the maximum tolerated dose (MTD) of weekly cisplatin in combination with standard doses of gemcitabine (1,000 mg/m(2), 30 min) and 5-FU (750 mg/m(2), 24 h)/folinic acid (200 mg/m(2), 30 min). All drugs were to be given on a day 1, 8, 15 and 22 of a 6-weekly cycle in an outpatient setting. Nineteen chemonaive patients with inoperable stage IIa, III and IV squamous cell carcinoma and adenocarcinoma of the esophagus were enrolled into the study. Eight, six and five patients were enrolled at cisplatin dose levels 0 (20 mg/m(2) ), I (25 mg/m(2) ) and II (30 mg/m(2)), respectively. One hundred and eighty-one out of 187 treatments (55 cycles) were given on an outpatient basis. The dose-limiting toxicities of this schedule were leukopenia and thrombocytopenia. Other side effects were mild. Dose level II (30 mg/m(2)) was defined as the MTD for cisplatin when used in this combination and schedule. Partial responses were observed in 10 of the 19 enrolled patients. The side effect profile seen in this study in combination with the preliminary evidence of efficacy justifies further testing in a phase II setting with a cisplatin dose of 25 mg/m(2) and offers a treatment option for patients in an outpatient setting.     

多西他赛联合奥沙利铂和5-氟尿嘧啶方案治疗晚期胃癌41例

目的:观察多西他赛联合奥沙利铂和5-氟尿嘧啶(5-Fu)方案治疗晚期胃癌的近期疗效、毒副反应及生存状况。方法:收集2004-2010年我院41例晚期胃癌患者,多西他赛75 mg.m-2(d 1);奥沙利铂130 mg.m-2(d 2);5-Fu 400～500 mg.m-2.d-1,[d 2～d 5或持续泵入96 h(civ 96 h)],每21 d重复1次,至少2个周期。结果:总缓解率(ORR)为26.8%,疾病控制率(DCR)为78.0%。中位无进展生存期(PFS)为5.6个月(95%CI:3.52～7.6),中位总生存(OS)为12.3个月(95%CI:2.7～21.9)。1年生存率为46.3%(19/41);2年生存率为21.9%(9/41);3年生存率为7.3%(3/41)。常见的毒副反应为骨髓抑制(主要为白细胞及中性粒细胞减少)、胃肠道反应(恶心和呕吐)、腹泻和脱发等。结论:多西他赛联合奥沙利铂和5-FU方案治疗晚期胃癌疗效显著,毒副反应可耐受。化疗近期疗效是晚期胃癌PFS和OS的独立预后因素[危害比(HR):3.6;95%CI:1.8～7.3]。     

Chemotherapy of metastatic colorectal cancer: fluorouracil plus folinic acid and irinotecan or oxaliplatin

(1) Following the recent introduction of several new cytotoxic agents, a new look at the role of chemotherapy in metastatic colorectal cancer is needed. (2) In one clinical trial of first-line treatment, fluorouracil + folinic acid infusion, after an initial bolus (LV-5FU2 protocol), was more effective and better tolerated than bolus administration alone (Mayo Clinic protocol). (3) Five comparative trials failed to show that raltitrexed was more effective than fluorouracil + folinic acid in first-line treatment, and it has more serious adverse effects. (4) There are no comparative trials of capecitabine or tegafur + uracil versus fluorouracil + folinic acid (LV-5FU2 protocol) in first-line treatment. (5) In three comparative randomised trials involving previously untreated patients, adjunction of oxaliplatin to the fluorouracil + folinic acid combination (FOLFOX protocol) increased both tumour response rate and progression-free survival (by about 2 months), but it also caused more neuropathies, severe diarrhea and severe neutropenia. (6) In two comparative trials of first-line treatment, adjunction of irinotecan to fluorouracil + folinic acid (FOLFIRI protocol) increased the median survival time by about 3 months, to 15-17 months, but increased the incidence of diarrhea, neutropenia, serious cardiovascular disorders and severe thrombosis. (7) In second-line treatment, irinotecan is the only properly assessed drug with a positive impact, prolonging survival compared with appropriate palliative care (34 months after diagnosis, versus 27 months). (8) In one comparative trial, first-line treatment with the FOLFOX protocol, followed by the FOLFIRI protocol, resulted in the same median survival time (21 months) as the reverse sequence. (9) In practice, the first-line treatment for metastatic colorectal cancer appears to be the fluorouracil + folinic acid combination (LV-5FU2 protocol) plus either oxaliplatin (FOLFOX protocol) or irinotecan (FOLFIRI protocol). The reference second-line treatment is the FOLFIRI protocol (or the FOLFOX protocol if the FOLFIRI protocol has already been used). These treatments were associated with the longest survival in one trial.     

Population pharmacokinetics of oxaliplatin (85 mg/m2) in combination with 5-fluorouracil in patients with advanced colorectal cancer

Pharmacokinetic (PK) studies of oxaliplatin, using a dose regimen of 85 mg/m, are lacking. A PK model may be used in future studies to investigate the relationship between pharmacokinetics and dose limiting toxicity. The purpose of this study was to construct a population PK model to describe platinum (Pt) concentrations in plasma in 33 patients with colorectal cancer. The secondary objective was to determine the relationship between the amount of Pt in 24-hour urine and the amount of Pt in fractionated urine collection periods. Plasma and urine samples were collected from patients during their first oxaliplatin treatment course. Population PK analysis was performed with WinNonMix. The model that best described the Pt concentrations in plasma was a two-compartment PK model. The elimination clearance (CL) and the elimination clearance of the peripheral compartment (CL2) (median +/- SE) were 25.2 +/- 6.3 L/hr and 68 +/- 24.8 L/hr, respectively. The median volume of distribution (V1) was determined to be 41.6 +/- 9.4 L and the median volume of distribution of the peripheral compartment (V2) was 452.5 +/- 96.4 L. The relationship between the cumulative amount of Pt in urine in the first 12 hours compared with the amount of Pt in 24 hours urine was reflected by a correlation coefficient (r2) of 0.95. The cumulative Pt concentration in urine in the first 10 hours and the first 8 hours compared with 24 hours was reflected by correlation coefficients r2 = 0.93 and r2 = 0.897, respectively. This PK model could be useful in identifying predictors for PK and pharmacodynamic variability to individualize dosing. The results of this study suggest that fractionated urine samples can replace 24-hour urine collection.     

Weekly high-dose 5-fluorouracil as 24-h infusion and folinic acid (AIO) plus irinotecan as second- and third-line treatment in patients with colorectal cancer pre-treated with AIO plus oxaliplatin

Our objective was to evaluate the efficacy and safety of high-dose 5-fluorouracil (5-FU) as a 24-h infusion and folinic acid (FA) (AIO regimen) plus irinotecan (CPT-11) after pre-treatment with AIO plus oxaliplatin (L-OHP) in colorectal carcinoma (CRC). Twenty-six patients with non-resectable distant CRC metastases were analyzed for second- or third-line treatment with AIO plus CPT-11 after pre-treatment with AIO plus L-OHP. On an outpatient basis, the patients received a treatment regimen comprising weekly 80 mg/m2 CPT-11 in the form of a 1-h i.v. infusion and 500 mg/m2 FA as a 1- to 2-h i.v. infusion, followed by 2000 mg/m2 5-FU i.v. administered as a 24-h infusion once weekly. A single treatment cycle comprised six weekly infusions followed by 2 weeks of rest. A total of 26 patients received 344 chemotherapy applications with AIO plus CPT-11. The main symptom of toxicity was diarrhea (NCI-CTC toxicity grade 3+4) occurring in five patients (19%; 95% CI 7-39%). Nausea and vomiting presented in two patients (8%; 95% CI 1-25%). The response rate of 26 patients can be summarized as follows: partial remission: n=7 (27%; 95% CI 12-48%); stable disease: n=9 (35%; 95% CI 17-56%) and progressive disease: n=10 (38%; 95% CI 20-59%). The median progression-free survival (n=26) was 5.8 months (range 3-13), the median survival time counted from the treatment start with the AIO plus CPT-11 regimen was 10 months (range 2-24) and counted from the start of first-line treatment (n=26) was 23 months (range 10-66). We conclude that the AIO regimen plus CPT-11 is practicable in an outpatient setting and well tolerated by the patients. Tumor control was achieved in 62% of the patients. The median survival time was 10 months and the median survival time from the start of first-line treatment (n=26) was 23 months.     

The efficacy of hybrid chemotherapy with intravenous oxaliplatin and folinic acid and intra-hepatic infusion of 5-fluorouracil in patients with colorectal liver metastases: a phase II study

Summary Intra-arterial chemotherapy in patients with liver metastases from colorectal cancer has some limitations such as hepatic toxicity and extra-hepatic progression. With the aim of overcoming these limitations, a phase II trial was designed to assess the efficacy and tolerability of a hybrid chemotherapy regimen with systemic infusion of oxaliplatin and folinic acid associated with intra-arterial 5-fluorouracil. Thirty-nine patients with colorectal liver metastases were recruited. The median age was 59 years, 30 patients (77%) had synchronous metastases, and half of the patients were chemo-naive. A total of 313 chemotherapy cycles were administered (median number 8). Treatment was well tolerated and hepatic toxicity negligible. Out of 34 evaluable patients an ORR of 41%. was observed. Eight patients (21%) underwent radical liver surgery. The median time to progression (TTP) was 10 months (range 2–63) and the median overall survival (OS) 21 months (range 6–63). Extra-hepatic progression was observed in six patients. Our results suggest that this regimen is active even if technical complications are frequent. Our aim to reduce hepatic toxicity and extra-hepatic progression was reached.     

多西紫杉醇联合奥沙利铂及氟尿嘧啶治疗晚期胃癌的疗效分析

目的观察多西紫杉醇联合奥沙利铂和5-氟尿嘧啶治疗进展期胃癌的临床疗效及不良反应。方法96例进展期胃癌采用多西紫杉醇75mg/m2,第1d静脉输注1h;奥沙利铂100mg/m2,第1d静脉输注3h;亚叶酸0.2g/m2,第1d静脉输注2h;5-氟尿嘧啶2.4g/m2用便携式微量输液泵持续静脉输注48h,21d为1个周期。治疗2个周期后评价疗效和不良反应。结果96例患者均可评价,获得完全缓解（CR）3例,部分缓解（PR）39例,稳定（SD）33例,进展（PD）21例,总有效率（RR）为43.8%（42/96）,中位疾病进展时间（TTP）7.5个月,中位生存期11.4个月。主要不良反应为骨髓抑制、腹泻、四肢末梢感觉异常,其中Ⅱ～Ⅲ度白细胞减少为65.7%（63/96）,Ⅱ～Ⅲ度血小板减少为34.4%（33/96）,Ⅰ～Ⅱ度神经毒性为56.3%（54/96）,Ⅰ～Ⅱ度腹泻为18.8%（18/96）。结论多西紫杉醇联合奥沙利铂、5-氟尿嘧啶方案治疗进展期胃癌疗效肯定,且毒副反应可以耐受,患者临床受益。     

Costs incurred by patients undergoing advanced colorectal cancer therapy. A comparison of raltitrexed and fluorouracil plus folinic acid

BACKGROUND: To assess the cost effectiveness of healthcare interventions from a societal perspective, it is necessary to include costs such as patients' travel costs and the opportunity cost of patients' time spent consuming healthcare. OBJECTIVE: To analyse patients' travel and time costs associated with 2 alternative drug therapies for advanced colorectal cancer: raltitrexed and fluorouracil plus folinic acid (leucovorin) [5FU + FA]. DESIGN AND SETTING: The analysis is based on a prospective substudy within a multinational randomised controlled trial of raltitrexed versus 5FU + FA. PATIENTS AND PARTICIPANTS: 495 patients with advanced colorectal cancer were enrolled in the trial, 270 of whom completed the questionnaire on costs. METHODS: Data were collected within the trial to estimate the numbers of journeys made to and from hospital by patients and the time lost from usual activities over the period of therapy. A subset of patients were asked to complete a questionnaire to provide the information necessary to value time and travel costs in monetary terms. These data, together with UK transport costs and forgone time values, were used to value the transport and opportunity costs of time of all patients in the trial. RESULTS: The total travel cost per patient was statistically significantly higher in the 5FU + FA group (p < 0.001; median of 31.50 Pounds with raltitrexed, 96.00 Pounds with 5FU + FA; 1997 prices). Overall time cost per patient was also higher in the 5FU + FA group (p = 0.005; median of 168.80 Pounds with raltitrexed, 224.04 Pounds with 5FU + FA). Adding the two gives a median total cost per patient of 206.08 Pounds [interquartile range (IQR) 108 Pounds to 482 Pounds] among patients randomised to raltitrexed and 342.25 Pounds (IQR 214 Pounds to 555 Pounds) for those in the 5FU + FA group (p < 0.001). The sensitivity analysis showed that, even under extreme assumptions, raltitrexed imposed fewer time and travel costs on patients. These cost differences are likely, in part, to reflect the longer treatment times for 5FU + FA patients (median 16.9 vs 12.7 weeks). CONCLUSIONS: Different chemotherapy regimens for advanced colorectal cancer can impose different travel and time costs on patients. Over the period of treatment in a randomised controlled trial of 495 patients, those randomised to 5FU + FA were found to have a median travel plus time cost 136 Pounds per patient higher than those randomised to raltitrexed.     

Phase I trial of sequential raltitrexed followed by bolus 5-fluorouracil in patients with advanced colorectal cancer

Our objective was to determine the maximum tolerated dose (MTD) of sequential raltitrexed (Tomudex) and 5-fluorouracil (5-FU) by bolus administration every 3 weeks in patients with advanced colorectal cancer (aCRC) and appendiceal adenocarcinoma. This phase I dose-escalation study was carried out in three stages: (1) 5-FU fixed at 900 mg/m, raltitrexed escalated from 0.5 to 3.0 mg/m, (2) raltitrexed fixed at 3.0 mg/m, 5-FU escalated from 900 mg/m until dose-limiting toxicity (DLT) and (3) 5-FU fixed at the dose level below DLT, raltitrexed escalated from 3.0 mg/m until MTD. Seventy-one patients with measurable disease were enrolled. No DLTs were observed during stage 1 of treatment. At a fixed dose of raltitrexed 3.0 mg/m, DLT developed when 5-FU was increased to 1350 mg/m (stage 2). When 5-FU was fixed at 1200 mg/m and raltitrexed was increased to 6.0 mg/m (stage 3), DLT was dose limiting. The recommended doses for further study are 5.5 mg/m ralitrexed and 1200 mg/m 5-FU. Of the 69 patients evaluated for efficacy, one had a complete response (8.0 months) and five had partial responses (5.1-11.6 months). Thirty patients had stable disease for 5 or more cycles of therapy (mean time to progression: 3.6 months). Median survival was 11.7 months. We conclude that raltitrexed can be combined with bolus 5-FU, at raltitrexed doses that are higher than the recommended single-agent dose of 3.0 mg/m, with manageable toxicity. This combination shows encouraging activity, and survival appears promising in the pre-treated aCRC patient population. Further clinical trials are warranted.     

奥沙利铂联合亚叶酸钙及氟尿嘧啶治疗晚期大肠癌的临床分析

目的观察奥沙利铂联合亚叶酸钙及氟尿嘧啶方案治疗晚期大肠癌的临床疗效及毒副反应。方法 64例晚期大肠癌患者给予化疗方案为:L-OHP 130 mg/m2静脉点滴2 h,d1;CF 200 mg/m2,静脉点滴2 h,d1;5-FU 400 mg/m2静脉推注,后2 400 mg/m2微泵持续静脉滴注48 h。每2周重复,4周为1个周期,完成2个周期后判定疗效,按WHO标准评价客观疗效和毒副反应。结果全组64例均可评价疗效,其中完全缓解8例,部分缓解24例,稳定18例,进展14例,总有效率CR+PR=50.0%。中位肿瘤进展时间为5.6个月,中位生存时间为9.5个月。毒副反应主要是骨髓抑制、胃肠道反应及外周神经毒性。结论奥沙利铂联合亚叶酸钙及氟尿嘧啶方案治疗晚期肠癌患者的近期疗效较好,毒副反应可以耐受,值得进一步研究应用。     

Irinotecan and capecitabine as second-line treatment after failure for first-line infusional 24-h 5-fluorouracil/folinic acid in advanced colorectal cancer: a phase II study

The efficacy of combination therapy with irinotecan and capecitabine has been demonstrated for the first-line treatment of metastatic colorectal cancer (MCRC). The aim of this trial was to evaluate the efficacy and safety of this combination in MCRC as second-line treatment after failure of 24-h infusional 5-fluorouracil (5-FU24h) and folinic acid (FA). Patients pre-treated with 5-FU24h/FA were recruited at two institutions to receive 6 x weekly irinotecan 70 mg/m2 and capecitabine (1000 mg/m2 b.i.d. days 1-14 and 22-35). Courses were repeated on day 50. In elderly patients (>65 years) a 20% dose reduction of both drugs was scheduled. Twenty-eight patients [M/F 20/8; median age 65 years (range 44-79); median ECOG score 1] were enrolled. The most frequent sites of metastases were liver, n=20, lymph nodes and lungs, n=10, respectively. Half of the patients had two or more metastatic sites. A total of 71 treatment courses (median 2, range 1-8) were administered. Main toxicities [worst per patient (%); CTC grade 1/2/3/4] were: anaemias 18/14/-/-; leukocytopenia 11/21/-/-; thrombocytopenia 11/-/-/-; diarrhea 18/36/21/-; nausea/vomiting 43/29/4/-; mucositis 4/11/-/-; alopecia 7/25/-/-; hand-foot syndrome 7/21/-/-; fatigue 14/14/-/-; renal insufficiency (caused by diarrhea and exsiccosis) -/-/-/7. Dose intensity in the first course was [median/mean (%)]: irinotecan 92/83; capecitabine 88/82. Twenty-three patients are evaluable for response analysis (five did not complete the first course): three patients showed partial remissions (13%) and 11 patients had stable disease (48%). Median time to progression was 3.0 months for the total population (range 1.4-17.3) and 6.5 months for responders (partial response plus no change). Seventy-four percent of the patients received a third-line therapy. Overall survival was 15.7 months calculated from the start of study treatment. Second-line therapy with irinotecan and capecitabine yielded a tumor control in 61% of patients with MCRC. Efficacy and toxicity data are comparable to 5-FU/irinotecan combinations, although the likelihood of severe diarrhea appears to be higher with capecitabine/irinotecan.