A phase II study of irinotecan alternated with five days bolus of 5-fluorouracil and leucovorin in first-line chemotherapy of metastatic colorectal cancer

Purpose: This multicenter phase II study was designed to assess the efficacy of the alternating schedule of irinotecan (CPT-11) with bolus 5-fluorouracil (5-FU) and leucovorin (LV) in first-line chemotherapy for metastatic colorectal cancer (CRC).Patients and methods: Patients with histologically proven metastatic colorectal cancer, and at least one bidimensionally measurable lesion, aged 18–70, with performance status 2, normal baseline biological values and no prior chemotherapy (or only adjuvant chemotherapy completed 6 months before study entry) were selected. Treatment was irinotecan 350 mg/m2, i.v., day 1, alternating with leucovorin 20 mg/m2 i.v. and 5-FU 425 mg/m2, i.v. daily for five consecutive days, day 22–26 (Mayo Clinic regimen). One alternating cycle was to be performed every six weeks. Patients were evaluated for efficacy every alternating cycle. Treatment was administered until five alternating cycles, disease progression, unacceptable toxicity or patient refusal.Results: Thirty-three patients (28 chemotherapy-naïve and five with prior adjuvant treatment completed >1 year prior to accrual) were enrolled. The objective response rate (RR) was 30% (95% CI: 16–49; 10 patients/33; nine partial response and one complete response). All responses were reviewed by an independent external review committee. An additional 49% of patients had stable disease. The median survival was 16 months, the one year survival amounted to 58% and the median progression free survival was 7.2 months. Relative dose intensity was nearly 90% for both drugs. Grade 3–4 diarrhea and neutropenia were the most frequent severe toxic events, seen in 24% and 64% of patients, respectively.Conclusions: The alternating schedule of CPT-11 350 mg/m2 with five days bolus of 5-FU and low dose LV is an active and feasible regimen as front-line therapy for metastatic CRC. It is well tolerated, without evidence of overlapping toxicity. The response rate appears promising with regard to that expected with either single agent. This regimen warrants further assessment in randomized trials.     

A phase II study with CPT-11 plus leucovorin and bolus IV 5-fluorouracil in patients with advanced colorectal carcinoma

Standard chemotherapy in advanced colorectal carcinoma (CRC) has not yet been established. The present study was conducted to assess the efficacy and toxicity profile of CPT-11, leucovorin (LV), and bolus 5-fluorouracil (5-FU) in a weekly schedule. Fifty-five patients were entered with no prior chemotherapy for advanced disease or adjuvant treatment ended at least 6 months preceding study entry, and 45 were assessable for response. Patients were treated with CPT-11 80 mg/m² (7 patients) or 70 mg/m² (48 patients). After completion of CPT-11 infusion, LV 200 mg/m² was administered over 2 hr followed immediately by 5-FU 450 mg/m², IV bolus, weekly for 6 weeks followed by a 2-week rest period. Treatment was continued for four cycles. Because of grade 3 and 4 diarrhea in four of the first seven patients, the study was amended to reduce the starting dose of CPT-11 from 80 to 70 mg/m² weekly. Four complete and 10 partial responses were observed (response rate: 25.5%), the median time to progression (TTP) was 7.7 months, 1-year survival rate was 62.3%, and the median overall survival was 15.0 months. Grade 3 and 4 diarrhea occurred in seven patients (12.7%), four of them treated with CPT-11 80 mg/m². Grade 3 myelotoxicity occurred in five patients (9.0%). Toxic death because of diarrhea, neutropenia, bacteremia, and sepsis occurred in a patient treated with CPT-11 80 mg/m². Our results confirm the efficacy of CPT-11, LV, and 5-FU in a weekly schedule in patients with advanced CRC. Further studies are needed to compare the present regimen with higher doses of CPT-11 with LV plus different schedules of 5-FU administration in the treatment of metastatic CRC.     

A phase I, dose-finding study of irinotecan (CPT-11) short i.v. infusion combined with fixed dose of 5-fluorouracil (5-FU) protracted i.v. infusion in adult patients with advanced solid tumours

Purpose Irinotecan (CPT-11) and 5-fluorouracil (5-FU) are effective cytotoxic agents in the treatment of solid tumours. Continuous i.v. infusion (CI) of 5-FU is significantly more active and better tolerated than bolus i.v. 5-FU. This phase I pharmacokinetic and clinical study evaluated escalating CPT-11 doses administered every 3 weeks combined with a fixed dose of 5-FU CI over 14 days to find the maximum tolerated dose (MTD) of this combined chemotherapy.Patients and methods Patients with solid tumours showing failure with previous standard treatment or for whom no established curative therapy existed received CPT-11 i.v. over 90 min (six dose levels were evaluated: 150, 175, 200, 250, 300 and 350 mg/m²) plus a fixed dose of 5-FU CI 250 mg/m² per day over 14 days. If the MTD was not reached at CPT-11 level 6, then 5-FU was increased to 300 mg/m². In step 2, 5-FU was administered as a true protracted infusion at the recommended dose found during step 1. In step 3, the recommended dose of CPT-11 was divided and administered in a weekly schedule for 4 weeks combined with a fixed dose of 5-FU CI 250 mg/m², and then followed by 2–5 weeks rest.Results Neutropenia and diarrhoea were the main toxicities, leading to early termination of infusion in three of six patients in level 7. Therefore, CPT-11 350 mg/m² + 5-FU 250 mg/m² CI over 14 days was identified as the recommended dose. In step 2, CPT-11 dose had to be reduced to 300 mg/m² due to toxicity. The weekly schedule of CPT-11 75 mg/m² + 5-FU 250 mg/m² CI was feasible with only one patient experiencing severe diarrhoea. No interactions were found in the kinetics parameters of CPT-11 or 5-FU for the different dose levels studied.Conclusion CPT-11 300 mg/m² + 5-FU 250 mg/m² protracted infusion is the recommended dose for phase II trials, neutropenia and diarrhoea being the dose-limiting toxicities.     

A phase II study of irinotecan alternated with a weekly schedule of high-dose leucovorin and 48-hour 5-fluorouracil infusion in patients with metastatic colorectal cancer

PURPOSE: To evaluate the activity and safety of an alternating schedule of irinotecan (CPT-11) with high-dose 5-fluorouracil (5-FU) given as a weekly 48-hour infusion in combination with leucovorin (LV) in the first-line treatment of metastatic colorectal cancer (MCRC) patients. PATIENTS AND METHODS: We tested the activity of a regimen consisting of a four times per week schedule of high-dose LV (150 mg/m2) followed by a 48-hour 5-FU infusion (2,600 mg/m2) alternated with CPT-11 (350 mg/m2). An alternating cycle was to be performed every 8 weeks. Treatment was administered until disease progression, unacceptable toxicity or patient refusal occurred. Thirty-five consecutive patients with measurable MCRC, aged 18-80, with a performance status < or =2, were entered into our study from May 1998 to January 2000. RESULTS: Four complete and 9 partial responses were observed (objective response rate was 37%; 95% confidence interval, CI: 21.5-55.1%); an additional 46% of the patients had stable disease. The median duration of response was 6.2 months, median time to progression 8 months (95% CI: 5.9-10.1%), and overall survival was 18.5 months (95% CI: 15.1-21.9%). The 1-year survival was 68%. No toxic deaths occurred. The incidence of grade 3-4 toxicity per patient in any cycle was: mucositis 9% and diarrhea 11% for the infusional 5-FU part, nausea/vomiting 3%, diarrhea 14%, and neutropenia 43% for the CPT-11 part of regimen. CONCLUSIONS: Our alternating schedule of 5-FU/LV and CPT-11 is a well-tolerated outpatient treatment as front-line therapy for MCRC with comparable efficacy to regimens with both drugs given together.     

5-Fluorouracil and folinic acid with or without CPT-11 in advanced colorectal cancer patients: A multicenter randomised phase II study of the Southern Italy Oncology Group

Purpose:The combination regimen CPT-11 plus bolus and infusion5-fluorouracil (5-FU) with high-dose leucovorin (hybrid regimen LV5FU2) hasbeen tested for activity and toxicity against advanced colorectal carcinomain a randomised, multicenter phase II trial. Patients and methods:A total of 102 chemotherapy-naïvepatients were randomised in a 1 : 2 fashion to receive: leucovorin 100mg/m² administered as a two-hour infusion before 5-FU 400mg/m² as an intravenous bolus, and FU 600 mg/m² as a22-hour infusion immediately after 5-FU bolus injection repeated on days 1 and2 (LV5FU2 regimen, arm A, 34 patients) or CPT-11 at 180 mg/m² (150mg/m² for patients of age 70 and <75 years) only on day 1immediately before LV5FU2 therapy (LV5FU2 + CPT-11 regimen, arm B 68patients). Both treatments were repeated every two weeks. The presence of acalibration arm assured consistency and more realistic evaluation of resultsachieved with the LV5FU2 + CTP-11 regimen. Results:Thirty-three and sixty-four patients were evaluable inarm A and B, respectively. The overall response rate was 18% in arm A(95% CI: 7%–34%) and 40% in arm B(95% CI: 28%–52%). Median time to progression,median duration of response and survival were similar in both groups.Responders (CR + PR) survived statistically longer than non-responders onlyin arm B (20 vs. 10 months, P = 0.0016). All patients were evaluablefor toxicity which was mild in both groups; gastrointestinal disturbances werethe most common. There were no treatment-related deaths. Grade 3–4toxicity was uncommon in both arms. Conclusions:The addition of CPT-11 to the hybrid LV5FU2 regimenprovided a significant overall response rate (40%) with relatively mildtoxicity. The overall response rate was 18% in patients treated withLV5FU2 alone in the calibration arm. Thus, considering other encouraging datafrom the literature, the CPT-11 + FU–LV combination therapy can beregarded as a new, very effective treatment option for first-line treatmentof advanced colorectal cancer patients.     

Multiple-target chemotherapy (LV-modulated 5-FU bolus and continuous infusion, oxaliplatin, CPT- 11) in advanced 5-FU-refractory colorectal cancer: MTD definition and efficacy evaluation. A phase I-II study

AIMS AND BACKGROUND: To identify the maximum tolerated doses and to define the activity of a regimen incorporating leucovorin (LV)-modulated 5-fluorouracil (5-FU) bolus and continuous infusion, oxaliplatin (I-OHP) and irinotecan (CPT-11) in patients with advanced, 5-FU-refractory colorectal cancer (CRC). PATIENTS AND METHODS: Starting doses: LV 100 mg/m2 as a 2-hour infusion followed by 5-FU 300 mg/m2 bolus administration followed by 5-FU 500 mg/m2 as a 22-hour infusion on days 1 and 2; I-OHP 65 mg/m2 as a 2-hour infusion concomitantly with LV on day 1; CPT-11 90 mg/m2 concomitantly with LV on day 2. Planned cycle interval: 2 weeks. RESULTS: Two hundred twenty-six cycles were administered to 27 patients. Recommended doses were 5-FU bolus 300 mg/m2, 5-FU protracted infusion 500 mg/m2, I-OHP 75 mg/m2, and CPT-11 150 mg/m2. Among 25 patients evaluable for response we observed 13 disease stabilizations (52%; 95% CI: 33-71%), 6 instances of disease progression and 6 responses (24%; 95% CI: 7-41%). Median time to progression and overall survival were 24 and 60 weeks, respectively. A cycle delay > 3 days was observed in 134/199 cycles (67%). CONCLUSIONS: This study confirms the feasibility of triplet chemotherapy in patients with advanced 5-FU-refractory CRC.     

Irinotecan (CPT-11) as first-line monotherapy in patients with advanced, metastatic colorectal cancer refractory to 5-fluorouracil adjuvant chemotherapy: a multicenter phase II study

Irinotecan (CPT-11) is active against colorectal cancer (CRC) refractory to 5-fluorouracil. Further information is needed to confirm whether CPT-11 monotherapy is more effective against tumors than 5-FU monotherapy or if there is cross-resistance of CPT-11 with 5-FU. This study assessed the efficacy and toxicity of CPT-11 350 mg/m² iv, once every 3 weeks, in patients with unsuccessfully pretreated advanced CRC. Thirty-two patients were enrolled and overall 152 cycles were administered. The total objective response rate was 17.9% and the disease stabilized in 11 patients (39.3%). Median time to progression was 3.8 months and me-dian survival was 8.2 months. Grade 3/4 diarrhea was observed in 9 cycles (5.9%) and 6 patients (18.8%), and grade 3/4 neutropenia in 5 cycles (3.3%) and 4 patients (12.5%). CPT-11 monotherapy is an active and well-tolerated first-line chemotherapy for CRC in 5-FU pretreated patients.     

Dose escalation of CPT-11 in combination with oxaliplatin using an every two weeks schedule: A phase I study in advanced gastrointestinal cancer patients

Background:To determine the dose-limiting toxicity of CPT-11 incombination with oxaliplatin, and the maximal tolerated dose (MTD) and therecommended dose (RD) of CPT-11 using an every two weeks schedule. Patients and methods:The study was designed to evaluate escalateddoses of CPT-11 starting at 100 mg/m² with a fixedclinically-relevant dose of 85 mg/m² oxaliplatin given every twoweeks. Results:Twenty-three patients and 186 cycles were evaluable fortoxicity (median per patient: 7, range: 1–13). Grade 3oxaliplatin-induced neurotoxicity was cumulative and limiting in 39%(9 of 23) of patients. The MTD of CPT-11 was 200 mg/m², withincomplete neutrophil recovery at day 15 as limiting toxicity. At the RD (175mg/m² of CPT-11): no grade 4 neutropenia was seen in the two firstcycles; 30% of patients experienced grade 3–4 diarrhea. Febrileneutropenia (3.2% of all cycles) was 3-fold more frequent inperformance status (PS) 2 than in PS 0–1 patients. Among elevencolorectal cancer (CRC) patients, three complete and four partial responseswere documented, including in three 5-fluorouracil (5-FU) refractory patients. Conclusion:To combine CPT-11 175 mg/m² and oxaliplatin85 mg/m² every two weeks is feasible in an outpatient setting, andvery active in 5-FU resistant CRC patients. A dose of 150 mg/m²CPT-11 is recommended in PS 2 patients.     

A Prospective Randomized Study of Irinotecan (CPT-11), Leucovorin (LV) and 5-Fluorouracil (5FU) versus Leucovorin and 5-Fluorouracil in Patients with Advanced Colorectal Carcinoma

Abstract

The purpose of this study was to compare the activity and toxicity of an irinotecan (CPT-11), leucovorin (LV) and 5-fluorouracil (5FU) combination with a standard regimen of 5FU and LV, in patients with advanced colorectal carcinoma.

One hundred and sixty patients were randomized; 80 patients (group A) received LV 20 mg/m² bolus i.v. and 5FU 425 mg/m² bolus i.v. on days 1-5, every 28 days; 80 patients (group B) received CPT-11 80 mg/m² (30-90 min i.v. infusion), followed by LV 20 mg/m² bolus i.v. and 5FU 425 mg/m² bolus i.v. on days 1, 8, 15, 22, 29, and 36, every 8 weeks.

The overall response rate was 30% and 47.5% in groups A and B respectively. Progression-free survival was significantly higher in the triple-drug combination arm (median 7.5 vs. 4.5 months; p= 0. 0335). However, overall survival did not differ significantly between the two arms (15 months vs. 14 months for the groups B and A respectively; p=0.3531). The main grade 3 adverse events were diarrhea (19%, in group A vs. 35% in group B; p=0.032) and mucositis (2% vs. 14%; p=0.017).

The regimen containing irinotecan showed activity in advanced colorectal cancer. The overall safety data confirm this combination as a well-tolerated treatment.     

Randomised study of tegafur and oral leucovorin versus intravenous 5-fluorouracil and leucovorin in patients with advanced colorectal cancer

This randomised, open-label trial compared oral tegafur (FT)/leucovorin (LV) with the intravenous bolus 5-fluorouracil (5-FU)/LV as first-line chemotherapy for advanced colorectal cancer (CRC). Patients were randomised to receive oral FT 750 mg/m2/day for 21 days and LV 15 mg/m2 every 8 h in cycles repeated every 28 days (n=114), or intravenous LV 20 mg/m2 followed by 5-FU 425 mg/m2 daily for 5 days every 4 weeks for 2 cycles, and later every 5 weeks (n=123). Response rate was significantly higher in the FT/LV arm (27%, 95% CI 19-35) than in the 5-FU/LV arm (13%, 95% CI 7-19) (p<0.004). The median time to progression was 5.9 months (95% CI, 5.3-6.5; FT/LV arm) and 6.2 months (95% CI, 5.4-6.9; 5-FU/LV arm). Median overall survival was 12.4 months (95% CI, 10.3-14.5 months; FT/LV arm) and 12.2 months (95% CI, 8.9-15.7 months; 5-FU/LV arm) (p=n.s.; hazard ratio FT/LV:5-FU/LV=1.02). 5-FU/LV showed a higher incidence of grade 3/4 neutropenia (4.1 vs. 0%). Non-hematological toxicities showed similar incidences in the two treatment arms. Oral FT/LV was more active than IV 5-FU/LV in terms of objective response rate with similar overall survival, and with a favorable toxicity profile. This makes FT/LV a valid alternative to the IV 5-FU schedule in CRC patients.     

Phase II Study of Irinotecan plus Leucovorin and Bolus 5-Fluorouracil as First- or Second-Line Chemotherapy in Patients with Advanced Gastric or Esophageal-Gastric Junction Adenocarcinoma

Abstract

The aim of this study was to evaluate the activity and safety of 5-fluorouracil (5-FU) / leucovorin (LV) and irinotecan as first- or second-line treatment in patients with advanced gastric adenocarcinoma. Treatment consisted of irinotecan 80 mg/m² intravenously (i.v.), followed by LV 200 mg/m² (i.v.) and 5-FU 450 mg/m² as an i.v. bolus, administered weekly for 6 weeks, followed by a 2-week rest period. Thirty-one patients (23 chemo-naïve, 8 chemo-exposed) were enrolled. The overall response rate was 22.6% and the disease control rate was 38.7%. Among the patients who received the regimen as first-line treatment, objective response rate was 30.4% and the disease control rate was 52.1%. However, progression of the disease was recorded in all the patients receiving the combination as second-line chemotherapy. The median time to disease progression (TTP) was 4 months and the median duration of survival was 7 months. The median TTP was 6 months for patients treated with first-line chemotherapy and 2.5 for those who received study treatment as second line. Furthermore, the median survival duration was 8 months and 6 months, respectively. The most frequent grade 3 toxicity was febrile neutropenia. Grade 3 non-hematological toxicities were rare. There were no treatmentrelated deaths.

The combination of 5-FU/LV and irinotecan as first-line treatment was found to be well tolerated and effective in patients with advanced gastric cancer. Further investigation would be worthwhile, particularly in elderly or debilitated patients who cannot tolerate aggressive chemotherapy.     

An alternating regimen of irinotecan/ 5-fluorouracil/folinic acid and oxaliplatin/ 5-fluorouracil/folinic acid in metastatic colorectal cancer: a Phase II trial

OBJECTIVE: To assess the feasibility and activity of a combination schedule with irinotecan (CPT-11), oxaliplatin (L-OHP), brief infusional fluorouracil (5-FU) and folinic acid (FA) as first-line treatment in metastatic colorectal cancer (MCC) patients. METHODS: Fifty consecutive patients were treated with CPT-11 125 mg/m2 as a 90-min intravenous infusion, followed by FA 20 mg/m2 as an intravenous bolus, and 5-FU 500 mg/m2 over a 2-hour intravenous infusion on days 1 and 8. L-OHP was administered at 85 mg/m2 over 2 h on day 15, in combination with a FA 60 mg/m2 intravenous bolus and 5-FU 600 mg/m2 as a 2-hour intravenous infusion on days 15-16. The treatment was repeated every 4 weeks for a maximum of 9 cycles. RESULTS: Twenty-five of 50 assessable patients achieved a complete (n=5) or partial (n=20) response, leading to a response rate of 50% (95% CI 35-64%). Eighteen (36%) patients showed stable disease. The median time to tumor progression was 10.3 months (95% CI 9.6-10.9 months). After a median follow-up of 16.4 months, the median survival was not reached. Grade 3 neutropenia (8%), grade 3 nausea/vomiting (6%) and grade 3 diarrhea (2%) were the major adverse events. CONCLUSION: This alternating three-drug regimen is very well tolerated, manageable and effective in terms of activity and time to progression.     

Concurrent irinotecan and 5-fluorouracil plus levo-folinic acid given every other week in the first-line management of advanced colorectal carcinoma: A phase I study of the Southern Italy Cooperative Oncology Group

Objectives: To determine the maximum tolerable doses (MTDs) of irinotecan (CPT-11) and 5-fluorouracil (5-FU) plus levo-folinic acid (LFA) administered together every two weeks, to define the toxicity profile of this regimen, and to have a preliminary evidence of its activity in the first-line management of advanced colorectal cancer patients.Patients and methods: Patients with histologically proven colorectal carcinoma, no prior chemotherapy for their advanced disease, and with at least one measurable or evaluable indicator lesion, were admitted to this study. The starting dose of CPT-11 was 150 mg/m² given i.v. (90 min infusion) on day 1, followed on day 2 by a fixed dose of LFA (250 mg/m²) as a two-hour i.v. infusion plus a starting dose of 5-FU 600 mg/m² as i.v. bolus. No intra-patient dose escalation was allowed. If no dose limiting toxicity (DLT) was observed among three patients of each cohort, CPT-11 and 5-FU were alternately escalated in the subsequent cohort. Otherwise, three more patients were enrolled at the same dose level. DLT was defined as: WHO grade 3 non-haematological toxicity (except for vomiting or alopecia), grade 3 febrile neutropenia, grade 4 neutro- or thombocytopenia, or a >2-week delay in recycling. The MTDs were defined as the doses at which two of three, or four of six, patients showed the same DLT.Results: Thirty-one patients (five pretreated in adjuvant setting) were enrolled in this study, and a total number of 293 cycles (median 6/patient) were administered. Dose escalation safely proceeded to 210/950/250 mg/m² of CPT-11/5-FU/LFA. These dosages were considered as MTDs, since four of six patients showed grade 4 neutropenia, in one case associated with grade 3 stomatitis. A mild decrease of both the CPT-11 and 5-FU doses to 200 and 850 mg/m², respectively, caused different DLTs (neutropenia and diarrhoea) in two out of seven patients. At these dosages, transient grades 3 or 4 neutropenia affected two patients each during their treatment, while only one patient suffered from a severe delayed diarrhoea. Other non-haematological toxicities were mild and manageable. Therefore, we recommend this latter dose level for further study. Major responses (3 complete and 11 partial) were reported in 14 patients, for an overall response rate of 45% (95% CI: 27%–64%) according to an intent-to-treat analysis. Responses were observed from first dose level, and in four of five previously treated patients. Median failure-free and overall survivals, after a median follow-up of 39 weeks, were 42 and 55 weeks, respectively.Conclusions: The concurrent administration of CPT-11 and modulated 5-FU every two weeks is feasible at the recommended dosages. This regimen demonstrated interesting activity in the management of advanced colorectal cancer patients, and it probably better exploits the synergism between CPT-11 and 5-FU than recently tested alternating schedules. A phase II study is ongoing to more precisely define its activity and toxicity.     

FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin and irinotecan) vs FOLFIRI (folinic acid, 5-fluorouracil and irinotecan) as first-line treatment in metastatic colorectal cancer (MCC): a multicentre randomised phase III trial from the Hellenic Oncology Research Group (HORG)

To compare the efficacy and toxicity of oxaliplatin (L-OHP) in combination with irinotecan (CPT-11), 5-fluorouracil (5-FU) and leucovorin (LV) (FOLFOXIRI) vs irinotecan and 5-FU/LV (FOLFIRI) as first-line treatment of patients with metastatic colorectal cancer (MCC). A total of 283 chemotherapy-na?ve patients with MCC were enrolled (FOLFIRI arm: n=146; FOLFOXIRI arm: n=137). In the FOLFOXIRI arm, CPT-11 (150 mg m(-2)) was given on d1, L-OHP (65 mg m(-2)) on d2, LV (200 mg m(-2)) on days 2 and 3 and 5-FU (400 mg m(-2) as i.v. bolus and 600 mg m(-2) as 22 h i.v. continuous infusion) on days 2 and 3. In the FOLFIRI arm, CPT-11 (180 mg m(-2)) was given on d1 whereas LV and 5-FU were administered in the same way as in the FOLFOXIRI regimen. Both regimens were administered every 2 weeks. There was no difference in terms of overall survival (median OS: 19.5 and 21.5 months, for FOLFIRI and FOLFOXIRI, respectively; P=0.337), median time to disease progression (FOLFIRI: 6.9 and FOLFOXIRI: 8.4 months; P=0.17), response rates (33.6 and 43% for FOLFIRI and FOLFOXIRI, respectively; P=0.168). Patients treated with FOLFOXIRI had a significantly higher incidence of alopecia (P=0.0001), diarrhoea (P=0.0001) and neurosensory toxicity (P=0.001) compared with patients treated with FOLFIRI. The present study failed to demonstrate any superiority of the FOLFOXIRI combination compared with the FOLFIRI regimen, although the observed median OS is one of the best ever reported in the literature.     

Biweekly irinotecan or raltitrexed plus 6S-leucovorin and bolus 5-fluorouracil in advanced colorectal carcinoma: a Southern Italy Cooperative Oncology Group phase II-III randomized trial.

Purpose:The aim of this randomised trial was to evaluate theactivity and toxicity of a biweekly regimen including 6S-leucovorin-modulated5-fluorouracil (LFA–5-FU), combined with either irinotecan (CPT-11 +LFA–5-FU) or raltitrexed (Tomudex®) (TOM + LFA–5-FU), inadvanced colorectal cancer patients, and to make a preliminary comparison ofboth these experimental regimens with a biweekly administration ofLFA–5-FU modulated by methotrexate (MTX + LFA–5-FU). Patients and methods:One hundred fifty-nine patients withadvanced colorectal carcinoma previously untreated for the metastatic disease(34 of them previously exposed to adjuvant 5-FU) were randomly allocated toreceive: CPT-11, 200 mg/m² i.v. on day 1, followed on day 2 by LFA,250 mg/m² i.v. infusion and 5-FU, 850 mg/m² s i.v. bolus(arm A); TOM, 3 mg/m² i.v. on day 1, followed on day 2 by LFA, 250mg/m² i.v. infusion and 5-FU, 1050 mg/m² i.v. bolus (armB); or MTX, 750 mg/m² i.v. on day 1, followed on day 2 by LFA, 250mg/m² i.v. infusion and 5-FU, 800 mg/m² i.v. bolus (armC). Courses were repeated every two weeks in all arms of the trial. Responserate (RR) was evaluated after every four courses. The sample size was definedto have an 80% power to detect a 35% RR for each experimentaltreatment, and to show a difference of at least 4% in RR with thestandard treatment if the true difference is 15% or more. Results:The RRs were: 34% (95% confidence interval(95% CI): 21%–48%) in arm A, including 3 completeresponses (CRs) and 15 partial responses (PRs), 24% (95% CI:14%–38%) in arm B, including 2 CRs and 11 PRs, and24% (95% CI: 14%–38%), with 2 CRs and 11PRs, in arm C. After a median follow-up time of 62 (range 18–108) weeks,the median time to progression was 38, 25, and 27 weeks for arm A, B, and C,respectively. With 94 patients still alive, the one-year probability ofsurvival was 61%, 54%, and 59%, respectively. WHO grade3 or 4 neutropenia and diarrhoea affected 46% and 16%,respectively, of patients treated with CPT-11 + LFA–5-FU. Medianrelative dose intensity over eight cycles (DI₈) was 78% forCPT-11 and 82% for 5-FU. Severe toxicities of TOM + LFA–5-FU wereneutropenia (16%) and diarrhoea (16%), but median relativeDI₈ was 93% for TOM, and 82% for 5-FU. Conclusions:CPT-11 + LFA–5-FU compares favorably in termof activity and toxicity with other combination regimens including CPT-11 andcontinuous infusional 5-FU. The hypothesis of a RR 15% higher than theMTX + LFA–5-FU treatment can not be ruled out after this interimanalysis. The TOM + LFA–5-FU regimen showed a RR and a toxicity profilevery close to the MTX + LFA–5-FU combination, and dose not deservefurther evaluation in advanced colorectal cancer patients.     

Diagnosis and Treatment of Chronic Prostatitis Caused by Chlamydia trachomatis

Abstract

To investigate the therapeutic value and safety of the biweekly regimen of 5-fluorouracil (5-FU) and leucovorin (LV) plus irinotecan (CPT-11) in patients with previously untreated advanced gastric cancer (AGC). A total of 50 patients (M/F 35/15; median age = 65) with AGC, none of whom had received chemotherapy for advanced disease, were accrued in this trial. Fifteen patients (30%) were 70 years old or older. At the time of their accrual, cytotoxic chemotherapy, consisting of LV 100 mg/m² (2-hour i.v. infusion) followed by 5-FU 400 mg/m² (bolus) and 5-FU 600 mg/m² (22-hour continuous infusion) on therapeutic days 1 and 2 plus CPT-11 180 mg/m² (1-hour infusion) on day 1, was initiated. Treatment courses were repeated every 2 weeks until evidence of progressive disease, unacceptable toxicity or withdrawal of consent. All patients were assessable for toxicity and 48 of 50 for response evaluation, having completed at least four courses of chemotherapy. Complete response was achieved in 2 patients (4%, intent to treat) and partial response in 16 (32%) (overall response rate, 36%; 95% confidence interval [CI]: 22%-50%). Twenty-four patients (48%) had stable disease and 6 patients (16%) progressed. The median time to progression was 8 months (95% CI: 6-10 months) and median overall survival 14 months (95% CI: 6-22 months). Between the subgroups of patients <70 years old and 70 or older, there were no significant differences in efficacy. One toxic death occurred. Treatment tolerance was generally mild to moderate and easy to treat. The main grade 3/4 toxicities were neutropenia (32%), diarrhea (16%), and anemia (8%). Grade 3-4 neutropenia was the only treatment-related serious adverse event significantly more common in patients older than those aged ≤70 (53.3% vs 22.8%, respectively; P = 0.03). Our data suggest that the biweekly regimen of LV and 5-FU plus CPT-11 in untreated patients with AGC is active and has an acceptable safety profile. Further evaluation of this regimen seems to be warranted in a phase III trial.     

Multicentre phase II study of bifractionated CPT-11 with bimonthly leucovorin and 5-fluorouracil in patients with metastatic colorectal cancer pretreated with FOLFOX

This multicentre phase II study was designed to evaluate the antitumour activity and toxicity of bifractionated camptothecin (CPT-11) and 5-fluorouracil/ leucovorin (5-FU/LV) in the treatment of patients with metastatic colorectal cancer (MCC) who had been pretreated with 5-FU/LV-oxaliplatin (FOLFOX regimen). In all, 35 patients were enrolled in a two-stage trial. Treatment consisted of two daily doses of CPT-11, 90 mg m2 administered over 90 min, followed by LV, 200 mg m2 administered over 2 h plus 5-FU 400 mg m2 as a bolus and 600 mg m2 as a 22-h continuous infusion administered with disposable pumps as outpatient therapy. Toxicity was closely monitored. Response was evaluated by computed tomography scans every 8 weeks. All 35 patients were assessable for toxicity and response to treatment. Seven patients had a partial response, giving an overall response rate of 20%; 11 patients had stable disease (31.4%) and 17 progressed (48.5%). The median progression-free survival was 7.1 months and median survival was 14 months. A total of 10 patients (30%) experienced grade 3-4 toxicity, including nausea (15%), diarrhoea (12%) and neutropenia (15%), while seven patients (21%) had grade 2 alopecia. The bifractionated bimonthly schedule of CPT-11 plus 5-FU/LV showed substantial antitumour activity and was well tolerated in this group of patients with a poor prognosis, pretreated with the FOLFOX regimen.     

Oxaliplatin combined with irinotecan and 5-fluorouracil/leucovorin (OCFL) in metastatic colorectal cancer: a phase I-II study.

BACKGROUND: A phase I-II multicenter trial was conducted to define the maximal tolerated dose and describe the activity of an OCFL combination using oxaliplatin (OHP), irinotecan (CPT-11) and 5-fluorouracil (FU)/leucovorin (LV) in metastatic colorectal cancer (CRC). PATIENTS AND METHODS: CRC patients not pretreated with palliative chemotherapy, with performance status < or =1 and adequate haematological, kidney and liver function, were eligible. Treatment consisted in weekly 24-h infusion 5-FU (2300 mg/m(2))/LV (30 mg) and alternating OHP (70-85 mg/m(2), days 1 and 15) and CPT-11 (80-140 mg/m(2), days 8 and 22) repeated every 5 weeks. OHP and CPT-11 were escalated in cohorts of three to six patients. RESULTS: Thirty patients received a median of five cycles. Dose-limiting toxicity occurred at dose level 3, and the recommended dose was OHP 70 mg/m(2), CPT-11 100 mg/m(2), LV 30 mg and 5-FU 2300 mg/m(2)/24 h. Grade > or =3 toxicities were diarrhea 23%, neutropenia 20%, fatigue 7%, and neurologic 7%. Two febrile neutropenia episodes (one fatal) were recorded. Among 28 patients with measurable disease (90%), we observed two complete and 20 partial responses; overall RR was 78% (95% CI, 59% to 92%). Median time to progression and overall survival were 9.5 and 25.4 months, respectively. Seven patients underwent liver metastases resection. CONCLUSION: OCFL is an overall well tolerated regimen with very high efficacy, which makes it most suitable for tumour control before surgery of metastatic disease.     

Combination of irinotecan (CPT-11) plus 5-fluorouracil and leucovorin (FOLFIRI regimen) as first line treatment for elderly patients with metastatic colorectal cancer: a phase II trial

PURPOSE: To evaluate the efficacy and tolerance of irinotecan (CPT-11) in combination with bolus and continuous infusion of 5-fluorouracil (5-FU) and leucovorin (LV) (FOLFIRI regimen) as first-line treatment of elderly patients with metastatic colorectal cancer (MCC). METHODS: Thirty consecutive, previously untreated patients with metastatic colorectal cancer, aged (median 76 years; range 70-84) were enrolled. The performance status (WHO) was 0 in 8, 1 in 16 and 2 in 6 patients; 19 (63%) patients had prior surgery and 8 (27%) adjuvant chemotherapy. CPT-11 (180 mg/m(2) as a 90 min i.v. infusion) was administered on day 1, LV (200 mg/m(2) as a 2-hour i.v. infusion), 5-FU (400 mg/m(2)/d i.v. bolus followed by 600 mg/m(2)/d as a 22-hour i.v. continuous infusion) were given on days 1 and 2 every 2 weeks. RESULTS: Complete response was achieved in one (3.3%) patient and partial response in 10 (33.3%) (overall response rate: 36.6%; 95% C.I.: 26.6-48.4%); 11 (36.6%) patients had stable disease and, 8 (26.6%) disease progression. The median duration of response was 7.5 months and the median time to disease progression 7.0 months. After a median follow-up period of 17 months, the median overall survival was 14.5 months. Main toxicities were: grade 3-4 neutropenia (n = 6; 20%), grade 3 thrombocytopenia (n = 1; 3.3%), grade 2 anemia (n = 9; 30%), grade 3-4 diarrhea (n = 5; 17%) and grade 3 asthenia (n = 3; 10%). There was one treatment-related death due to neutropenic sepsis. CONCLUSIONS: The FOLFIRI combination is an active regimen with manageable toxicity as front-line treatment in patients above 70 years of age.     

Phase I study of CPT-11 and bolus 5-FU/<Emphasis Type="Italic">l</Emphasis>-leucovorin in patients with metastatic colorectal cancer

Background Irinotecan (CPT-11) and bolus 5-fluorouracil (5-FU)/leucovorin (LV) administered weekly for 4 weeks every 42 days (Saltz regimen) is active but substantially toxic in patients with metastatic colorectal cancer (CRC). The efficacy and toxicity of this regimen, however, have not been determined in Japanese patients with metastatic CRC.Methods We investigated the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and recommended phase II dose (RD) for CPT-11 given i.v. (90-min infusion) and bolus 5-FU plus biologically active l-LV administered weekly for 3 weeks every 28 days (modified Saltz regimen) in Japanese patients with metastatic CRC. Eighteen patients with measurable disease, Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less, and adequate organ functions were enrolled.Results At dose level 2 (CPT-11, 100mg/m²; 5-FU, 400mg/m²; and l-LV, 25mg/body), 1 of 6 patients had DLT (febrile neutropenia). At dose level 3 (CPT-11, 100mg/m²; 5-FU, 500mg/m²; and l-LV, 25mg/body), 2 of 6 patients had DLT (febrile neutropenia and grade 4 neutropenia lasting more than 4 days). To determine whether level 3 was the MTD level, an additional 3 patients were treated at this level, but no DLT was observed. Consequently, 2 of 9 patients had DLT at level 3, this level thus being considered as the RD. At this level, grade 3–4 neutropenia was common but manageable. Nonhematological toxicities were mild. Seven partial responses were observed in the 18 enrolled patients (response rate [RR], 39%), and 8 patients (44%) experienced stable disease.Conclusion This CPT-11/5-FU/l-LV regimen administered weekly for 3 weeks every 28 days has substantial antitumor activity, with manageable toxicities. A multicenter phase II study is currently underway.