Irinotecan (CPT-11) combined with bolus 5-fluorouracil/leucovorin (Saltz regimen) as first-line chemotherapy of patients with advanced colorectal cancer

Concerns about the safety of irinotecan (CPT-11) plus bolus 5-fluorouracil (5-FU)/leucovorin (LV) (the so-called Saltz regimen) have been previously reported. This prospective, multicenter, non-randomized study evaluated the anti-tumoral effect and toxicity of the Saltz regimen as first-line chemotherapy of 130 patients with advanced colorectal cancer (CRC). The median numbers of treatment cycles and infusions received per patient were 3 and 12, respectively. Eight (6.1) and 37 patients (28.5%) showed complete and partial responses, respectively [overall response rate=34.6% (95% confidence interval=20.7-48.5%)]. After a median follow up period of 9 months, 70 patients had died. The median progression-free survival and overall survival were 6.78 (0.3-33.8) and 8.26 months (range 0.3-33.8), respectively. The combined CPT-11/5-FU/LV treatment was well tolerated and no toxic deaths were reported. The most common grade 3/4 hematological toxicity was neutropenia (28% of patients and 3% of infusions), but no febrile neutropenia was reported. Delayed diarrhea was the most reported grade 3/4 non-hematological toxicity (21% of patients and 2% of infusions). Other non-hematological toxicities showed very low incidences. During the study five patients died due to factors not associated with disease progression. We conclude that the Saltz regimen administered on an outpatient basis was safe and well tolerated in patients with advanced CRC. Close monitoring of external patients together with an early treatment of toxicity was found to be essential to prevent severe and potentially fatal gastrointestinal or thromboembolic events previously reported with this CPT-11 combined regimen.     

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.     

Cisplatin plus continuous infusion of 5-fluorouracil for 5 days effective for patients with advanced gastric cancer.

Seventeen consecutively treated patients with advanced gastric cancer were prescribed every 3 weeks intravenous cisplatin (20 mg/m2/day) and a continuous infusion of 5-fluorouracil (5-FU) (750 mg/m2/day) for 5 days. Twelve (71%) patients had been treated previously with other anticancer drugs. Seven (42%) patients showed a partial response and these responses persisted for over 4.4 months. Stabilization of the disease occurred in eight (47%) patients, and in two (12%) the disease progressed. At the time of analysis, mean survival of the responders was 8.2 months, while that of non-responders was 5.0 months. The toxicities were within acceptable limits and only a few had a grade III toxicity. This combined administration of cisplatin and 5-FU for 5 days is safe and effective for patients with advanced gastric cancer.     

Irinotecan (CPT-11) in metastatic colorectal cancer patients resistant to 5-fluorouracil (5-FU): a phase II study

The efficacy and toxicity of irinotecan (CPT-11) 350 mg/m(2) i.v. once every 3 weeks was assessed in 60 patients with advanced colorectal cancer (CRC) showing failure to 5-fluorouracil (5-FU) treatment. The overall objective response rate was 13.6% (1 complete response and 4 partial responses) and 25 patients (42.4%) showed stable disease; the median time to disease progression was 4.4 months and the median survival was 10.5 months. The main non-hematological toxicities were alopecia (80.3% of patients), diarrhea (75.0%), and nausea/vomiting (71.7%); neutropenia was the main hematological toxicity. Grade 3 or 4 diarrhea appeared in 21 of 131 cycles (16.1%), whereas grade 3 or 4 neutropenia appeared in 78 cycles (25.0%). In conclusion, the present phase II study confirms that CPT-11 350 mg/m(2) every 3 weeks is active and well tolerated as second-line chemotherapy for CRC in 5-FU resistant patients.     

Irinotecan (CPT-11)-based chemotherapy as induction treatment for advanced colorectal cancer

The role of irinotecan-based chemotherapy as induction treatment of non-resectable advanced colorectal cancer (ACRC) is currently being elucidated. The objective of this retrospective study was to determine complete resection (R0), response rate, time to progression (TTP) and overall survival (OS) in patients with non-resectable ACRC after being treated with neoadjuvant irinotecan-based chemotherapy. Thirty-six patients with ACRC were selected, of whom 23 (64%) were treated with irinotecan (250 mg/m2 on day 1), UFT (300 mg/m2/day for 14 days) plus leucovorin (45 mg/day for 14 days) every 3 weeks. Another 13 (36%) received the FOLFIRI schedule of irinotecan plus 5-fluorouracil/leucovorin. A total of 214 cycles of irinotecan/UFT/LV (median 8, range 1-15) and 97 cycles of the FOLFIRI schedule (median 9, range 1-30) were administered. The overall response rate was 58% (95% confidence interval 42-74), with six complete and 15 partial responses, whereas seven patients (19%) showed stable disease. Laparotomy was performed in 12 patients, of whom eight (22%) achieved R0 and two (6%) a pathological complete response. Median TTP was 10.0 months and median OS was 38.0 months for all patients. After a median follow-up of 20 months (range 1-49), median TTP in patients with R0 was not reached (mean TTP, 33.1 months), whereas median TTP in non-resected patients was 7.5 months (p=0.016). Toxicity was manageable and no toxic deaths occurred. This retrospective study showed a high resectability rate, and a prolonged TTP and OS in patients with ACRC after induction treatment with irinotecan-based chemotherapy. Both toxicity profile and postoperative complications were acceptable. Nevertheless, the definitive role of irinotecan as induction treatment should be confirmed in future clinical trials.     

Safety and efficacy of outpatient treatment with CPT-11 plus bolus folinic acid/5-fluorouracil as first-line chemotherapy for metastatic colorectal cancer

The combination of irinotecan (CPT-11), bolus 5-fluorouracil (5-FU) and folinic acid (FA) (Saltz regimen) has recently been questioned as first-line chemotherapy for metastatic colorectal cancer after high early death rates due to gastrointestinal and thromboembolic events were reported in two US trials. Therefore, we carefully evaluated the safety and efficacy of this regimen, with high value placed on the management of delayed diarrhea. Forty-six patients with metastatic colorectal cancer received this first-line treatment in nine German outpatient clinics. Dose reductions were mandatory from the first cycle in case of toxicity grade >2. Chemotherapy was administered only to diarrhea-free patients. During a total of 175 cycles administered treatments were delayed for 1 week in 11.6% and given at a reduced dose in 14.5%. All and 40 patients were evaluable for toxicity and response, respectively. Grade 3/4 toxicities included diarrhea (n=10), leukopenia (n=9), neutropenia (n=3) and anemia (n=4). One non-fatal pulmonary embolism occurred. Four complete responses (CR) and 10 partial responses were seen, for an overall response rate of 35%. In addition, 16 patients (40%) had stable disease. Resectability of liver metastases was achieved in three patients, including one pathologically confirmed CR. Median progression-free and overall survival were 5 and 13 months, respectively. We conclude that outpatient treatment with the Saltz regimen was well tolerated. Severe gastrointestinal toxicity and thromboembolic events were rarely observed and never fatal. As down-staging was possible, combinations of CPT-11 and FA/5-FU should be further investigated in neoadjuvant protocols.     

Weekly irinotecan plus UFT and leucovorin as first-line chemotherapy of patients with advanced colorectal cancer

Summary We evaluated the antitumoral efficacy and safety of CPT-11 125 mg/m² (weekly 90 min i.v. infusion; days 1, 8 and 15) combined with UFT (oral combination of tegafur and uracil) 200 mg/m²/day plus leucovorin (LV) 45 mg/m²/day (both divided into three separate oral doses every 8 h, days 1–21) every 4 weeks as first-line chemotherapy of metastatic colorectal cancer (CRC). Fifty-three patients 18 years old with histologically confirmed diagnosis of advanced CRC and bidimensionally measurable disease were enrolled. Three patients (6%) showed CR and 8 patients (15%) showed PR (ORR = 21% (95% CI, 10–32). Stable disease was reported in 19 patients (36%) [tumor control rate = 57% (95% CI, 43–70)]. The median time to progression and overall survival were 7.9 and 18.2 months, respectively (1-year rate = 74%; 2-years rate = 26%). CPT-11/UFT/LV treatment was well tolerated: the most reported grade 3/4 toxicities were neutropenia (11% of patients) and delayed diarrhea (28% of patients). No significant differences in response rate, survival or toxicity were found between younger (65 years) and older patients (> 65 years). Weekly CPT-11 plus UFT/LV was found effective and safe as first-line chemotherapy for metastatic CRC. The addition of CPT-11 to UFT/LV doubled the response rate compared to the results previously reported with UFT/LV, while myelosuppression remained low.     

Activity of weekly irinotecan (CPT-11) in patients with advanced non-small cell lung cancer pretreated with platinum and taxanes

Irinotecan (CPT-11), a semisynthetic derivative of camptothecin, is active in the treatment of non-small cell lung cancer (NSCLC). In this report we describe our experience with this drug when used as a single agent in patients with advanced NSCLC refractory to chemotherapy with platinum and taxanes. Nineteen NSCLC patients (thirteen males and six females; 53% adenocarcinoma and 26% squamous cell carcinoma) with a median age of 52 years (range 34–71) and a Karnofsky performance status of 60% (60–80%) were included in the study. At baseline, the patients had a median of two disease sites and had been treated with a median of two prior regimens. Irinotecan was given at a dose of 100mg/m² i.v.) weekly for 4 weeks followed by 1 week of rest. A total of 123 weekly infusions were administered, and each patient received a median of 4 weeks of treatment (range 1–32). All patients were evaluated by intention-to-treat analysis for efficacy and safety. Main toxicities reported were grade 3 neutropenia (10% of patients), diarrhea (10% of patients), and grade 4 thrombocytopenia (5% of patients). The overall clinical response rate was 16% (95% CI: 8–24) with three partial responses and 9 (47%) patients with stable disease. The median time to progression and the median survival time were 7 and 15 weeks, respectively. In conclusion, weekly irinotecan showed antitumoral activity and minimum toxicity in NSCLC patients refractory to platinum and taxanes.     

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.     

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.     

伊立替康联合5-Fu/亚叶酸钙治疗FOLFOX化疗失败的晚期结直肠癌的疗效

目的评价我国晚期结直肠癌伊立替康联合5-Fu/亚叶酸钙(FOLFIRI方案)治疗FOLFOX化疗失败的临床疗效和毒副反应。方法 FOLFIRI方案二线治疗62例晚期结直肠癌。方法 :伊立替康180 mg/m2,第一天静脉滴注90 min;亚叶酸钙400 mg/m2,第一天滴注2 h;5-Fu 2.6g/m2,亚叶酸钙滴注结束后,立即持续泵入46 h。14 d为一周期,每3周期按RESIST标准评价疗效,所有患者至少接受3周期化疗,最多达12周期。结果 62例患者一共接受346个周期的化疗,所有患者均可评价疗效。部分缓解8例(12.9%),稳定32例(51.6%),总有效率为12.9%。无完全缓解病例。进展22例(35.5%),中位进展时间4.5个月。二线化疗后中位生存时间9.2个月。最常见的不良反应为非血液学毒性,Ⅲ级呕吐反应为6例(9.7%),Ⅲ~Ⅳ级迟发性腹泻为8例(12.9%),3例(4.8%)出现Ⅲ级乙酰胆碱能综合征,13例(20.9%)发生Ⅲ~Ⅳ级粒细胞减少,2例(3.2%)伴发热;无化疗相关性死亡病例。结论 FOLFIRI方案二线治疗FOLFOX化疗失败的晚期结直肠癌疗效确切,不良反应轻。     

Association of ATP-binding cassette, sub-family C, number 2 (ABCC2) genotype with pharmacokinetics of irinotecan in Japanese patients with metastatic colorectal cancer treated with irinotecan plus infusional 5-fluorouracil/leucovorin (FOLFIRI)

ATP-binding cassette, sub-family C, number 2 (ABCC2) is involved in the biliary excretion of irinotecan and its metabolites, SN-38 and SN-38 glucuronide. Effects of the ABCC2 genotype on the pharmacokinetics (PK) of irinotecan and the metabolites were examined in Japanese patients with metastatic colorectal cancer receiving irinotecan plus infusional 5-fluorouracil/leucovorin (FOLFIRI). ABCC2 genotypes (-1549G>A, -1023G>A, -1019A>G, -24C>T, 1249G>A and 3972C>T) and haplotypes were analyzed for 67 patients with cancer. PK was also examined in a subset of 31 patients receiving FOLFIRI. Relationship between the ABCC2 genotypes or diplotypes and area under the time-concentration curve (AUC) of irinotecan and the metabolites normalized by irinotecan dose was analyzed. The lower AUC of irinotecan was seen in patients with A/A or G/A genotypes at 1249 of the ABCC2 gene than others (p=0.011, Mann-Whitney U teat). AUC of SN-38 in patients with A/A or G/A genotypes at -1023 was significantly lower than that in others (p=0.018). The haplotype I included -1023A (GAACGC) was the most frequent one with the allele frequency of 0.366. The AUC of SN-38 observed in patients with diplotypes harboring at least one haplotype I was lower than that observed in others (p=0.023). The haplotype IV consisted of 1249 (GGACAC) and was the fourth most frequent one with the allele frequency of 0.127. Patients with diplotypes carrying at least one haplotype IV showed lower AUC of irinotecan than others (p=0.011). Thus, ABCC2 genotype is one of the predictors of the variability of irinotecan PK in Japanese patients with metastatic colorectal cancer receiving FOLFIRI.     

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.     

Pharmacokinetics, metabolism, and excretion of irinotecan (CPT-11) following I.V. infusion of [(14)C]CPT-11 in cancer patients.

This study determined the disposition of irinotecan hydrochloride trihydrate (CPT-11) after i.v. infusion of 125 mg/m(2) (100 microCi) [(14)C]CPT-11 in eight patients with solid tumors. Mean +/- S.D. recovery of radioactivity in urine and feces was 95.8 +/- 2.7% (range 92.2-100.3%, n = 7) of dose. Radioactivity in blood, plasma, urine, and feces was determined for at least 168 h after dosing. Fecal excretion accounted for 63.7 +/- 6.8 (range 54.2-74.9%, n = 7) of dose, whereas urinary excretion accounted for 32.1 +/- 6.9% (range 21.7-43.8%; n = 7) of dose. One patient with a biliary T-tube excreted 30.1% of dose in bile, 14.2% in feces, and 48.2% in urine. Quantitative radiometric HPLC revealed that CPT-11 was the major excretion product in urine, bile, and feces. Aminopentane carboxylic acid (APC) and SN-38 glucuronide (SN-38G) were the most significant metabolites in urine and bile, whereas SN-38 and NPC, a primary amine metabolite, were relatively minor excretion products. SN-38 and APC were the most significant metabolites in feces. The relatively higher amount of SN-38 in feces compared with bile is presumably due to hydrolysis of SN-38G to SN-38 by enteric bacterial beta-glucuronidases. There was close correspondence between quantitative fluorescence HPLC and mass balance findings. CPT-11 was the major circulating component in plasma (55% of the mean radiochemical area under the curve), and CPT-11, SN-38, SN-38G, and APC accounted for 93% of the mean radiochemical AUC. These results show that the parent drug and its three major metabolites account for virtually all CPT-11 disposition, with fecal excretion representing the major elimination pathway.     

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.     

An economic evaluation of Tomudex (raltitrexed) and 5-fluorouracil plus leucovorin in advanced colorectal cancer.

Our objective was to establish the balance between costs and effects of treatment with Tomudex (raltitrexed) as an alternative to treatment with 5-fluorouracil (5-FU) plus leucovorin (LV) in patients with advanced colorectal cancer. Data were used from an international, open label randomized clinical trial. Costs were calculated by multiplying resource utilization data with Dutch estimates of unit costs. Effects have been expressed in terms of 6 months and 1 year survival, and in terms of the number of patients without severe adverse events including WHO grade 3 and 4 leucopenia, mucositis, anemia and severe asthenia. Cost effectiveness is expressed in terms of costs per additional day of survival and costs per additional patient without any severe adverse event. The clinical results did not show significant survival differences implying great uncertainty about the cost-effectiveness of raltitrexed in terms of additional costs per additional life-year gained. However, 80% of the initially higher cost of raltitrexed ($3132 per patient) is compensated by savings due to a more convenient administration scheme leading to a net cost of $626 per patient treated. Weighed against the decrease in adverse events, a cost-effectiveness ratio results of $3936 per additional patient free of any severe adverse event. More favorable estimates result when the convenience of the administration scheme is valued in positive monetary terms.     

Double-blind randomised placebo-controlled phase III study of an E. coli extract plus 5-fluorouracil versus 5-fluorouracil in patients with advanced colorectal cancer

The primary aim of this study was to evaluate the toxicity (mucositis, diarrhea and leucopenia) of a therapy with 5-fluorouracil (CAS 51-21-8; 5-FU) plus an E. coli extract (LC-Extract, Laves coli extract, Colibiogen inject, cell-free soluble fraction from lysed E. coli, Laves strain) in comparison with 5-FU plus placebo. Secondary endpoints included general toxicity, response rate according to WHO, survival time and quality of life. 164 patients with advanced colorectal cancer were enrolled in this randomised, placebo-controlled, double-blind, multicenter phase III study. The treatment consisted of 0.167 ml/kg/d LC-Extract or placebo followed by 500-750 mg/m2/d 5-FU on five consecutive days, repeated every three weeks for up to six treatment cycles. 158 (77 verum, 81 placebo) patients were evaluable for toxicity, 144 (72 verum, 72 placebo) evaluable for response. The therapy with LC-Extract was well tolerated. Adverse events that occurred during the study were mainly judged as 5-FU- or tumor-related. Toxicity from treatment with 600 mg/m2/d 5-FU in both treatment groups was very low. After treatment with 750 mg/m2/d 5-FU patients in the placebo-group experienced a higher CTC toxicity than in the LC-Extract groups. Remission rate and survival time showed a slight trend in favour of LC-Extract. These results suggest a positive benefit-risk ratio of the additional application of LC-Extract to 5-FU in the treatment of advanced colorectal cancer especially for administration of high doses of 5-FU.     

伊立替康联合草酸铂、5-氟尿嘧啶、亚叶酸钙治疗晚期胃癌的临床疗效

目的:比较伊立替康联合奥沙利铂和5-氟尿嘧啶、亚叶酸钙(FOLFOXIRI)与奥沙利铂联合CF,5-FU(FOLFOX4)治疗进展期或转移性胃癌的疗效和毒副反应。方法:经病理确诊的进展期或转移性胃癌患者78人,随机分为两组,FOLFOXIRI组36人,FOLFOX6组42人。FOLFOX4方案:L-OHP 85 mg/m2,第1天静滴,CF 200 mg/m2,5-FU 400 mg/m2,静冲,5-FU 600mg/m2,第1,2天,持续静点22h。FOLFOXIRI方案用法:CPT-11 165 mg/m2,L-OHP,CF,5-FU用法同FOLFOX4。结果:FOL-FOXIRI方案与FOLFOX4方案一线治疗进展期或转移性胃癌的缓解率分别为53.07%和28.57%(P=0.028),中位生存期分别为11.8月和9.4月(P=0.321),中位疾病进展时间为6.0月和4.8月(P=0.036)。FOLFOXIRI方案的骨髓毒性和腹泻发生率高于FOLFOX4方案。结论:本研究结果显示FOLFOXIRI方案治疗胃癌近期缓解率高于FOLFOX4方案,不良反应可以耐受,值得更深入系统地进行临床研究。