Retrospective Comparison of Two Different Schedules of Irinotecan, 5-Fluorouracil and Folinic Acid in Previously Untreated Patients with Advanced Colorectal Carcinoma: A Single Institution Experience

Abstract

Purpose: To compare efficacy and tolerability of weekly irinotecan combined with 5-fluorouracil (5-FU) bolus and folinic acid (FA) regimen (IFL) versus biweekly irinotecan with infusional 5-FU and FA (FOLFIRI) in patients (pts) with advanced stage colorectal cancer.

Patients and Methods: Treatments outcome of 86 pts (IFL - 38 pts, FOLFIRI - 48 pts) was evaluated. Chemotherapy regimens were as follows: IFL - intravenous (i.v.) infusion irinotecan 125 mg/m² over 90 min and 5-FU 500 mg/m² preceded by FA 20 mg/m² both given by i.v. bolus injection, all repeated on days 1, 8, 15 and 22 every 6 weeks; FOLFIRI - i.v. irinotecan 180 mg/m² on days 1 and 15 with subsequent FA 200 mg/m² administered as a 2-hour infusion and i.v. bolus injection of 400 mg/m² 5-FU immediately followed by 22-hour i.v. infusion of 600 mg/m² 5-FU on days 1, 2, 15 and 16 every 4 weeks. Treatment continued until disease progression or unacceptable toxicity.

Results: A total of 152 (mean - 4) IFL cycles and 328 (mean - 6) FOLFIRI cycles were administered. Average dose intensity was 0.8 and 0.78 respectively. Toxicities were mild and manageable for both regimens evaluated. Overall response rate was 36.8% in IFL arm and 44.7 % in FOLFIRI arm. At the median follow-up of 16 months in IFL arm and 14 months in FOPFIRI arm the two year survival was 38% and 45%, the median survival was 18 months and 21.5 months, and the median progression free survival was 6 months and 9.4 months respectively.

Conclusions: In our experience, both IFL and FOLFIRI regimens have acceptable toxicity at a similar level of dose intensity. Compared to IFL, FOLFIRI seems to improve progression-free survival.     

Retrospective comparison of two different schedules of irinotecan, 5-fluorouracil and folinic acid in previously untreated patients with advanced colorectal carcinoma: a single institution experience

PURPOSE: To compare efficacy and tolerability of weekly irinotecan combined with 5-fluorouracil (5-FU) bolus and folinic acid (FA) regimen (IFL) versus biweekly irinotecan with infusional 5-FU and FA (FOLFIRI) in patients (pts) with advanced stage colorectal cancer. PATIENTS AND METHODS: Treatments outcome of 86 pts (IFL - 38 pts, FOLFIRI - 48 pts) was evaluated. Chemotherapy regimens were as follows: IFL - intravenous (i.v.) infusion irinotecan 125 mg/m(2) over 90 min and 5-FU 500 mg/m(2) preceded by FA 20 mg/m(2) both given by i.v. bolus injection, all repeated on days 1, 8, 15 and 22 every 6 weeks; FOLFIRI - i.v. irinotecan 180 mg/ m(2) on days 1 and 15 with subsequent FA 200 mg/m(2) administered as a 2-hour infusion and i.v. bolus injection of 400 mg/m(2) 5-FU immediately followed by 22-hour i.v. infusion of 600 mg/m(2) 5-FU on days 1, 2, 15 and 16 every 4 weeks. Treatment continued until disease progression or unacceptable toxicity. RESULTS: A total of 152 (mean - 4) IFL cycles and 328 (mean - 6) FOLFIRI cycles were administered. Average dose intensity was 0.8 and 0.78 respectively. Toxicities were mild and manageable for both regimens evaluated. Overall response rate was 36.8% in IFL arm and 44.7% in FOLFIRI arm. At the median follow-up of 16 months in IFL arm and 14 months in FOPFIRI arm the two year survival was 38% and 45%, the median survival was 18 months and 21.5 months, and the median progression free survival was 6 months and 9.4 months respectively. CONCLUSIONS: In our experience, both IFL and FOLFIRI regimens have acceptable toxicity at a similar level of dose intensity. Compared to IFL, FOLFIRI seems to improve progression-free survival.     

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.     

Bimonthly Chemotherapy with Oxaliplatin,Irinotecan, Infusional 5-Fluorouracil/Folinic Acid in Patients with Metastatic Colorectal Cancer Pretreated with Irinotecan- or Oxaliplatin-Based Chemotherapy

Abstract

This study was conducted to assess the tolerability and efficacy of a ternary bi-monthly irinotecan (CPT-11) - oxaliplatin (OHP) - infusional 5-fluorouracil (5-FU)/folinic acid (FA) combination in advanced colorectal cancer patients who had received prior CPT-11 and/or OHP-based chemotherapy regimen. Colorectal cancer patients were given bimonthly CPT-11 as a 90-min infusion, followed by OHP (85 mg/m²), FA (200 mg/m²) 2-h infusions and 5-FU (48-h infusion). CPT-11 and 5-FU doses were escalated as reported below. 26 patients were recruited. Fourteen patients had received a prior CPT-11-, 6 patients a prior OHP-based chemotherapy regimen and 6 patients both regimens. Three dose levels were investigated: CPT-11 100, 120 and 140 mg/m² and 5-FU 1500, 1800 and 2100 mg/m² in 6, 12 and 8 patients, respectively. All patients were evaluable for toxicity, 24 for antitumor activity. At all dose levels toxicity was ac-ceptable. Grade 4 toxicity occurred in two patients only (neutropenia in one case and stomatitis in another one, 3.8%). Grade 3 toxicities included nausea and vomiting (34.6%), asthenia (26.9%), neurosensory toxicity (15.4%), neutropenia (3.8%) and di-arrhea (3.8%). Hematological toxicity was infrequent and generally mild. At the third dose level, a higher, although not significantly different incidence of hematological and neurosensory toxicity (both occurring in 62.5% of cases, all grades) was observed compared to the other two, while nausea and vomiting were significantly less frequent (37.5% vs 100%). Overall, we observed 2 complete responses, 9 partial responses (OR 45.8%), 8 stable disease (33.3%), and 5 disease progression (20.8%). Median overall survival was 18 months and median time-to-progression 5.5 months. This combination showed moderate toxicity and promising antitumor activity in CPT-11 and/or OHP pretreated colorectal cancer patients. The second dose level using CPT-11 at 120 mg/m² and 5-FU at 1800 mg/m² is recommended for further phase II studies in this patient population.     

Retrospective Comparison of Single-Agent Chemotherapy with Weekly 5-Fluorouracil or Weekly Irinotecan in Previously Treated Patients with Metastatic Colorectal Cancer

Abstract

This study is a retrospective analysis of response, toxicity and freedom from progression of two single-agent chemotherapy regimens in patients with previously treated metastatic colorectal cancer. Thirty-five patients with histological-ly confirmed measurable metastatic colorectal cancer received chemotherapy after failure of first-line 5-fluorouracil (5-FU) and leucovorin treatment. The median age was 61 years. Twenty-seven patients had liver metastases, 6 had local recurrence, 1 had retroperitoneal lymph node metastases and 1 had lung metastases. Eighteen patients received weekly 2600 mg/m² 5-FU and 17 patients received weekly 125 mg/m² irinotecan (CPT-11). Treatment was given until disease progression. Total number of cycles was 202 for 5-FU and 248 for CPT-11. The relative dose intensity was 1.0 for 5-FU and 0.84 for CPT-11. No grade 3-4 toxicity was registered in patients who received 5-FU. Grade 3- 4 toxicity rates were as follows in those who received CPT-11: vomiting 1 (5.9%) patient in 1 cycle, diarrhea 3 (17.7%) patients in 3 cycles and neutropenia in 3 (17.7%) patients in 3 cycles. No patients manifested febrile neutropenia. Two patients (11.8%) needed hospital admission because of toxicity: 1 for vomiting and 1 for diarrhea. No objective responses were observed in the 5-FU group of patients. Three patients (17.6%) who received CPT-11, achieved partial response with a median duration of 8 months. Stable disease was registered in 3 (17.6%) and 9 (52.9%) patients in 5-FU and CPT-11 groups respectively (p=0.05). Median time to progression was 3.3 months for patients who received 5-FU and 4.2 months for those treated with CPT-11 (not significant). One-year survival was 22.2% and 54.3% respectively (p=0.05).     

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

OBJECTIVES: To evaluate the safety and efficacy of irinotecan (CPT-11) alternated with a weekly treatment for 4 weeks of oxaliplatin (L-OHP), high-dose leucovorin (LV) and a 48-hour 5-fluorouracil infusion (5-FU 48 h) as first-line chemotherapy for patients with advanced colorectal cancer (ACC). Patients and METHODS: Previously untreated patients with ACC received chemotherapy consisting of a weekly treatment for 4 weeks of L-OHP (65 mg/m2), high-dose LV (150 mg/m2) followed by a 5-FU 48 h infusion (2,300 or 1,800 mg/m2) alternated with CPT-11 (350 mg/m2). A cycle was to be performed every 8 weeks. Treatment was continued up to tolerance, disease progression or patient refusal. Forty consecutive patients with measurable ACC, aged 26-70, performance status < or =2, entered our study. RESULTS: Six complete and 17 partial responses were observed (overall response rate, 57.5%; 95% confidence interval, CI: 38.8-71.1%); an additional 35% of the patients had stable disease. The median duration of response was 10.9 months (range, 6.5-30+ months). The median time to progression and the median overall survival time were 11.4 (95% CI: 10.4-12.3) and 20.3 (95% CI: 16.4-23.7) months, respectively. At the median follow-up period of 24 months, 17 patients (42.5%) are still alive. After a median number of 4 cycles, one toxic death occurred. The incidence of grade 3-4 toxicity per patient in any cycle was: stomatitis 7.5%, nausea/vomiting 2.5% and diarrhea 45% for the infusional part, neutropenia 37.5%, anemia 2.5%, thrombocytopenia 5%, alopecia 5% and diarrhea 10% for the CPT-11 part of the regimen. Gastrointestinal toxicity was different according to the dose of 5-FU. Serious adverse events occurred most frequently when 5-FU was given at a dose of 2,300 mg/m2 with a high incidence of grade 3-4 diarrhea (72.2%) and stomatitis (16.6%), and led to dose reduction of 5-FU in 13 of 18 patients (72.2%). For 22 patients who started 5-FU at a dose of 1,800 mg/m2, a dose reduction of 5-FU was necessary only 5 times (22.7%). No patient discontinued treatment because of severe neurotoxicity. CONCLUSIONS: The activity of our alternating regimen of L-OHP/LV/5-FU 48 h and CPT-11 for not previously treated ACC patients is counterbalanced by a high toxicity and a inconvenient schedule.     

A multicenter phase II study of irinotecan (CPT-11) alternated with 5-fluorouracil and leucovorin as first-line treatment of patients with metastatic colorectal cancer

Purpose In this multicenter phase II study the efficacy and safety of the alternating schedule of irinotecan (CPT-11) with bolus 5-fluorouracil (5-FU) and leucovorin (LV) were assessed as first-line chemotherapy in patients with metastatic colorectal cancer (CRC).Patients and methods Enrolled in the study were 43 patients with advanced CRC. They received CPT-11 350 mg/m² i.v. on day 1, alternating with LV 20 mg/m² i.v. and 5-FU 425 mg/m² i.v. daily for five consecutive days, on days 22–26 (Mayo Clinic regimen). One cycle consisted of 6 weeks.Results A total of 179 cycles were administered with a median of four per patient (range one to nine). Efficacy was analyzed on an intention-to-treat basis. The overall objective response rate was 30% (95% CI 16–44), with four complete responses and nine partial responses, whereas 20 patients (4%) showed stable disease. The median time to disease progression was 9.0 months and median survival was 18.5 months. Grade 3/4 diarrhea was mainly related to CPT-11 rather than to 5-FU (9.3% vs 4.7% of patients), whereas grade 3/4 neutropenia was higher during 5-FU administration (16.3% vs 7.0% of patients).Conclusions The alternating schedule of CPT-11 with 5 days bolus of 5-FU and low-dose LV showed a clinical benefit in terms of tumor growth control as first-line treatment of patients with metastatic CRC. The overall safety data confirmed this alternating combination as a well-tolerated treatment.     

Randomised phase II study of standard versus chronomodulated CPT-11 plus chronomodulated 5-fluorouracil and folinic acid in advanced colorectal cancer patients

In this study, a randomised phase II trial explored the effects of 6-h chronomodulated CPT-11 infusion in advanced colorectal cancer patients. Sixty-eight pre-treated patients were randomly assigned to CPT-11 administered at 180 mg/m2 on day 1, by 1-h infusion (Arm A) or 6-h sinusoidal infusion with peak timing at 5:00 a.m. (Arm B). All patients also received chronomodulated folinic acid/5-fluorouracil (FA/5-FU). Patients in Arm B obtained a 25.7% response rate for 7.0 months duration, a progression-free survival for 8.0 months and a median survival of 28 months. The same data in Arm A were 18.2%, 4.5, 6.0 and 18 months, respectively. No differences in drugs dose-intensity or increased toxicity with prolonged chronomodulated infusion were detected. Major grade 3-4 toxicity was diarrhoea: 10 patients in Arm A and 13 in Arm B. In conclusion, this study has shown that chronomodulated infusion of CPT-11 and FA/5-FU is safe, active and can be integrated with oxaliplatin (EORTC 05011) for the treatment of advanced colorectal cancer.     

复治性晚期结直肠癌多通道编程输液泵IFL方案时辰化疗临床观察

目的：探讨伊立替康（CPT-11）联合氟尿嘧啶（5FU）及亚叶酸钙（LV）组成的IFL方案时辰化疗治疗晚期结直肠癌的疗效和毒副作用,与常规FOLFIRI方案化疗进行比较。方法：2009—04—01—2012—05—30中南大学湘雅医学院附属肿瘤医院83例晚期结直肠癌复治患者分别采用IFL方案时辰化疗和FOLFIRI方案常规化疗。时辰组（42例）采用Melodie多通道编程输液泵,CPT-11160mg／m2,d1,2：00--8：00持续静脉滴入,高峰为凌晨5：00;5-FU600mg／（m2·d）,d2～d5,22：00～10：00持续静脉滴入,高峰为凌晨4：00;LV200mg／（m2·d）,d2～d5,用法同5-Fu。常规组（41例）白天给药：CPT-11160mg／m2静脉滴入,d1;LV200mg／（m2·d）,静脉滴入2h,d1～d2;5-FU400mg／（m2·d）静脉推注,d1～d2;5-FU600mg／（m2·d）,持续静脉滴入22h,d1～d2。结果：时辰化疗方案和FOLFIRI方案的总有效率（RR）分别为26．2％和71．4％,疾病控制率（DCR）分别为19．5％和63．4％;时辰化疗方案的中位无进展生存（PFS）为4．9个月,中位总生存时间（OS）为9．3个月;FOLFIRI方案的PFS为4．1个月,OS为8．6个月,两组比较差异均无统计学意义,P〉0．05。两方案常见的毒副作用为恶心呕吐、中性粒细胞减少和脱发,但多以1～2级为主;3～4级毒副作用在时辰化疗方案中的发生率低于FOLFIRI方案,P〈0．05。结论：IFL方案时辰化疗毒副作用发生率较低,患者耐受性较好,可作为晚期结直肠癌患者的二线治疗选择方案。     

A novel biweekly pancreatic cancer treatment schedule with gemcitabine, 5-fluorouracil and folinic acid

Pancreatic adenocarcinoma is a common disease considered to be poorly responsive to antiblastic treatment. Recent clinical and preclinical results suggest that a combined treatment of gemcitabine (GEM), 5-flurouracil (5-FU) and folinic acid (FA) offers a clinical benefit in patients with advanced pancreas adenocarcinoma. The aim of this phase II clinical trial was to evaluate the antitumour activity and toxicity of a novel biweekly schedule of this combination in patients with pancreatic adenocarcinoma. A total of 42 patients received a 30 min infusion of FA (100 mg m(-2)) and 5-FU (400 mg m(-2)) (FUFA) on days 1-3, and GEM 1000 mg m(-2) on day 1 every 15 days. We observed 13 objective responses (two complete, 11 partial) and 23 stable diseases. The median time to progression was 9.75 months (95% Confidence Interval (CI), 6.88-12.62) and the median overall survival was 13.10 months (95% CI 9.64-16.56). There were seven cases of each grade III gastroenteric and haematological toxicity. The GEM plus FUFA combination appears to be well tolerated and very active in patients with pancreatic carcinoma.     

Phase II trial of a biweekly regimen of fluorouracil and leucovorin plus irinotecan in patients with previously untreated advanced gastric cancer

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/m(2) (2-hour i.v. infusion) followed by 5-FU 400 mg/m(2) (bolus) and 5-FU 600 mg/m(2) (22-hour continuous infusion) on therapeutic days 1 and 2 plus CPT-11 180 mg/m(2) (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.     

Multicenter phase II trial evaluating a three-weekly schedule of irinotecan plus raltitrexed in patients with 5-fluorouracil-refractory advanced colorectal cancer.

BACKGROUND: Irinotecan (CPT-11) and raltitrexed are active against advanced colorectal cancer (ACC), act through different mechanisms, and have only partially overlapping toxicity profiles. Phase I studies have shown that single-agent full doses of both drugs can be safely combined. The aim of this multicenter study was to assess the efficacy and toxicity of the combination in patients with 5-fluorouracil (5-FU)-refractory ACC. PATIENTS AND METHODS: Between October 1999 and December 2000, 52 patients (31 males, 21 females) with a median age of 62 years (range 39-75) were included and received CPT-11 (350 mg/m(2) as a 60-min infusion) plus raltitrexed (3 mg/m(2) as a 15-min infusion, 1 h after CPT-11), with courses repeated every 21 days. Objective response was assessed after every three courses, and treatment maintained until tumor progression or unacceptable toxicity. RESULTS: A total of 313 cycles were administered, with a median of six cycles per patient (range 1-14). Seven patients (13.5%) achieved a partial response and one a complete response (1.9%), for an overall intention-to-treat response rate of 15.4% (95% confidence interval 6.1% to 27.2%). The incidence of grade 3/4 toxicity was 23.1% for diarrhea, 21.2% for asthenia, 17.3% for neutropenia, 13.4% for emesis and 7.7% for infection. There were no treatment-related deaths. With a median follow-up of 20 months, median survival was 11.9 months and median time to progression was 4.6 months. CONCLUSIONS: CPT-11 plus raltitrexed is active in patients with 5-FU-refractory ACC, at the expense of moderate toxicity.     

A phase II study of ifosfamide, 5-fluorouracil and leucovorin in patients with recurrent nasopharyngeal carcinoma previously treated with platinum chemotherapy

The aim of this study was to evaluate the efficacy and toxicity of ifosfamide, 5-fluorouracil (5-FU) and leucovorin (IFL) as a second-line chemotherapy regimen in patients with recurrent undifferentiated nasopharyngeal carcinoma (NPC) previously treated with platinum/5-FU. Between June 1997 and February 1999, 18 patients were entered into the study. 3 patients had loco-regional recurrence, 12 had distant metastases and 3 had both loco-regional recurrence and distant metastases. All patients had previously received platinum/5-FU as adjuvant or palliative treatments. The IFL regimen consisting of ifosfamide 1.2 g/m(2) (with mesna), 5-FU 375 mg/m(2) and leucovorin 20 mg/m(2) for 5 days and was repeated every 21 days. The dose of ifosfamide was escalated to 1.4 and 1.6 g/m(2) in subsequent cycles according to the bone marrow toxicity, and the dose of 5-FU to 450 and 525 mg/m(2) according to the severity of mucositis. Patients received a median of 3 cycles of IFL (range: 2-6), with a median total ifosfamide dose of 21 g/m(2) (range: 13-46) and a median total 5-FU dose of 6.75 g/m(2) (range: 4.1-14.7). The median follow-up was 10 months (range: 4-25). 9 patients (50%) achieved a partial response and 1 patient (6%) achieved a complete response, with an overall response rate of 56% (95% confidence interval (CI): 32-80%). For those patients who responded to IFL, 8 had subsequent disease progression on follow-up, with a median response duration of 7.1 months (95% CI: 5.3-8.9). The median time to progression for all patients was 6.5 months (95% CI: 4.2-8.7). 12 patients are still alive with an estimated 1-year survival probability rate of 51%. Treatments were well tolerated, only 1 patient had grade 3 emesis. None of the patients had grade 3/4 anaemia, leucopenia or thrombocytopenia, although IFL was discontinued in 1 patient because of persisting thrombocytopenia. IFL is an effective second-line regimen in patients with recurrent NPC and is well tolerated with mild toxicity. Combining platinum and IFL in chemona?ve patients may further improve the overall response rate and duration and is worth investigating in future trials.     

Mitomycin-C and capecitabine as third-line chemotherapy in patients with advanced colorectal cancer: a phase II study

Purpose The aim of this study was to investigate the therapeutic value and safety of third-line treatment with mitomycin-C (MMC) and capecitabine (Xeloda) in patients with advanced colorectal cancer pretreated with combination regimens including 5-fluorouracil (5-FU), folinic acid (FA) and irinotecan (CPT-11) or 5-FU, FA and oxaliplatin (L-OHP).Patients and methods A total of 21 patients (M/F 16/5, median age 60.0 years) with advanced colorectal cancer, all of whom had developed progressive disease while receiving or within 6 months of discontinuing two sequential chemotherapy lines with 5-FU, FA and CPT-11 or 5-FU, FA and L-OHP, were accrued to this study. At the time of their relapse or progression, cytotoxic chemotherapy, consisting of intravenous MMC 7 mg/m² on therapeutic day 1 plus oral capecitabine 1000 mg/m² twice daily on days 1–14, was initiated. After rest for 7 days, capecitabine 1000 mg/m² twice daily was administered on days 22–35 followed by 7 days rest. Treatment courses were repeated every 6 weeks unless there was evidence of progressive disease, unacceptable toxicity or patient refusal of treatment.Results All the patients were assessable for toxicity and 19 for response. The median number cycles of chemotherapy was two (range one to four). Only 1 patient (4.8%) had a partial response, 4 patients (19.0%) had stable disease, and 14 patients (66.7%) progressed. The median follow-up period was 7.3 months and median time to progression was 2.6 months. The median overall survival was 6.8 months. No toxic deaths occurred. Toxicities of third-line treatment were mild and manageable. As NCI/NIH common toxicity criteria, grade 3/4 anemia, neutropenia and thrombocytopenia occurred in two, one and one patients, respectively.Conclusion Our findings suggest that the combination of MMC and capecitabine in patients with advanced colorectal cancer pretreated with combination regimens including 5-FU, FA and CPT-11 or 5-FU, FA and L-OHP is safe. However, this regimen had a poor response rate and no definitive contribution to increasing patients overall survival time. Further evaluation of other salvage regimens seems to be warranted.     

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.     

Retrospective comparison of single-agent chemotherapy with weekly 5-fluorouracil or weekly irinotecan in previously treated patients with metastatic colorectal cancer

This study is a retrospective analysis of response, toxicity and freedom from progression of two single-agent chemotherapy regimens in patients with previously treated metastatic colorectal cancer. Thirty-five patients with histologically confirmed measurable metastatic colorectal cancer received chemotherapy after failure of first-line 5-fluorouracil (5-FU) and leucovorin treatment. The median age was 61 years. Twenty-seven patients had liver metastases, 6 had local recurrence, 1 had retroperitoneal lymph node metastases and 1 had lung metastases. Eighteen patients received weekly 2600 mg/m2 5-FU and 17 patients received weekly 125 mg/m2 irinotecan (CPT-11). Treatment was given until disease progression. Total number of cycles was 202 for 5-FU and 248 for CPT-11. The relative dose intensity was 1.0 for 5-FU and 0.84 for CPT-11. No grade 3-4 toxicity was registered in patients who received 5-FU. Grade 3-4 toxicity rates were as follows in those who received CPT-11: vomiting 1 (5.9%) patient in 1 cycle, diarrhea 3 (17.7%) patients in 3 cycles and neutropenia in 3 (17.7%) patients in 3 cycles. No patients manifested febrile neutropenia. Two patients (11.8%) needed hospital admission because of toxicity: 1 for vomiting and 1 for diarrhea. No objective responses were observed in the 5-FU group of patients. Three patients (17.6%) who received CPT-11, achieved partial response with a median duration of 8 months. Stable disease was registered in 3 (17.6%) and 9 (52.9%) patients in 5-FU and CPT-11 groups respectively (p=0.05). Median time to progression was 3.3 months for patients who received 5-FU and 4.2 months for those treated with CPT-11 (not significant). One-year survival was 22.2% and 54.3% respectively (p=0.05). Conclusion: Weekly chemotherapy with CPT-11 is tolerated with acceptable toxicity and leads to a better response rate than weekly high dose 5-FU. It also significantly improves survival but does not prolong freedom from progression.     

First-line 5-fluorouracil/folinic acid, oxaliplatin and irinotecan (FOLFOXIRI) does not impair the feasibility and the activity of second line treatments in metastatic colorectal cancer.

BACKGROUND: We conducted two phase II trials evaluating the combination of 5-fluorouracil/folinic acid, oxaliplatin and irinotecan (FOLFOXIRI) as first-line treatment in 74 metastatic colorectal cancer patients. Results were very promising with an overall response rate of 71% and 72%, a median PFS of 10.4 and 10.8 months and an overall survival of 26.5 and 28.4 months, respectively. A concern about the use of all three active agents up-front is the possibility that this might limit, after progression, disease control with second-line treatments. Therefore, we conducted the present analysis to evaluate the outcome of second-line treatments in these 74 patients. METHODS: Among the 71 patients so far progressed 54 (76%) received second line chemotherapy (23: FOLFIRI, 17: FOLFOXIRI, five: 5-FU protracted infusion, three: FOLFOX, three: 5-FU+MMC, two: CPT-11, one: CPT-11+LOHP, one: raltitrexed). Seventeen patients (24%) did not receive second line treatments: 10 because of deterioration of performance status (PS), four because of patient refusal and three because of death. Patients' characteristics at the time of second-line treatment were: M/F 36 of 18 patients, median age 64 yrs (range 44-75), ECOG PS>or=1 21 (39%) patients, multiple sites of disease 33 (61%) patients. RESULTS: A median of 4.1 months of second-line chemotherapy per patient were administered (range 1-8). Overall response rate (52 out of 54 evaluable patients) was 33% and stable disease were 19 (37%). Median duration of response was 8.1 months. At a median follow up of 15.1 months from the start of salvage chemotherapy median PFS and overall survival were respectively 6.7 and 15.2 months. CONCLUSIONS: First-line FOLFOXIRI does not impair the possibility to obtain objective responses and delay tumor progression with second line treatments containing the same agents used in first-line.     

A randomized phase II trial of irinotecan in combination with infusional or two different bolus 5-fluorouracil and folinic acid regimens as first-line therapy for advanced colorectal cancer.

BACKGROUND: Three different therapeutic regimens of irinotecan (CPT-11) in combination with 5-fluorouracil (5-FU) and folinic acid (FA) were evaluated for efficacy and safety in the first-line therapy of advanced colorectal cancer. PATIENTS AND METHODS: Patients were randomly assigned to receive intravenously either: CPT-11 125 mg/m(2), FA 20 mg/m(2) followed by 5-FU 500 mg/m(2) bolus, weekly for 4 weeks (arm A, Saltz regimen); or CPT-11 180 mg/m(2) day 1 then FA 200 mg/m(2) over 2 h and 5-FU 400 mg/m(2) bolus and 5-FU 600 mg/m(2) 22-h infusion on days 1 and 2, every 2 weeks (arm B, Douillard regimen); or CPT-11 350 mg/m(2) (days 1 and 43) alternating with FA 20 mg/m(2)/day followed by 5-FU bolus 425 mg/m(2)/day during 5 days (days 22-26) (arm C, Mayo Clinic regimen). RESULTS: A total of 154 patients were included in the study (arm A, 51 patients; arm B, 53; arm C, 50). Overall response rates for the intention-to-treat populations were 33% [95% confidence interval (CI) 21% to 48%], 42% (95% CI 28% to 56%) and 30% (95% CI 18% to 45%) for arms A, B and C, respectively. Median times to progression were 6, 8 and 7 months for arms A, B and C, respectively. Median survival times were 15, 12 and 17 months for arms A, B and C, respectively. Overall response rates for the evaluable patient populations were 40% (95% CI 24% to 58%) in arm A, 44% (95% CI 29% to 60%) in arm B and 31% (95% CI 17% to 47%) in arm C. Neutropenia was the main serious adverse event in arms A (30% of patients) and C (22% of patients) but occurred in only 8% of patients in arm B. Delayed diarrhea was the main severe adverse event for the three regimens, from 15% to 22%. CONCLUSION: All three regimens were highly active. The biweekly combination of CPT-11 and 5-FU/FA (arm B) was notable for its low incidence of grade 3/4 neutropenia. The incidence of grade 3/4 delayed diarrhea was equivalent for the three treatment arms.     

Palliative second-line treatment with weekly high-dose 5-fluorouracil as 24-hour infusion and folinic acid (AIO) plus oxaliplatin after pre-treatment with the AIO-regimen in colorectal cancer (CRC)

BACKGROUND AND AIMS: The aim of this work was to evaluate the efficacy and safety of second-line treatment with weekly high-dose 5-Fluorouracil (5-FU) as a 24-hour infusion (24-h inf.) and folinic acid (FA) (AIO-regimen) plus Oxaliplatin (L-OHP) after pre-treatment with the AIO regimen, focusing in particular on the efficacy of palliative first- and second-line treatment in colorectal carcinoma (CRC). PATIENTS AND METHODS: Patients with non-resectable distant CRC metastases were enrolled in a prospective phase II study for palliative second-line treatment after previous palliative first-line treatment in accordance with the AIO regimen. On an outpatient basis, the patients received a treatment regimen comprising biweekly 85 mg/m2 L-OHP in the form of a 2-hour intravenous (i.v.) infusion and 500 mg/m2 FA as a 1 to 2-hour i.v. infusion, followed by 2,600 mg/m2 5-FU administered as a 24-h inf. i.v. once weekly. A single treatment cycle comprised 6 weekly infusions followed by 2 weeks of rest. RESULTS: During second-line treatment, a total of 26 patients received 340 chemotherapy applications. As the main symptom of toxicity, diarrhoea (NCI-CTC toxicity grade 3+4) presented in 5 patients (19%; 95% CI: 4-34), followed by nausea (CTC grade 3) in one patient (4%; 95% CI: 0-11). Twenty-three patients were evaluable for treatment response. The remission data can be summarised as follows: Complete remission (CR): n=1 (4%; 95% CI: 0-13); partial remission (PR): n=3 (13%; 95% CI: 0-27); stable disease (SD): n=11 (48%; 95% CI: 27-68) and progressive disease (PD): n=8 (35%; 95% CI: 15-54). The median progression-free survival (PFS) rate (n=26) was 3.3 months (range 0-11.5), the median survival time counted from the start of second-line treatment (n=26) 11.6 months (range 2.1-33.0) and the median survival time counted from the start of first-line treatment (n=26) 19.9 months (range 7.7-49.8). CONCLUSION: Palliative second-line treatment according to the AIO regimen plus L-OHP is feasible in an outpatient setting and well tolerated by the patients. Tumour control (CR + PR + SD) was achieved in 65% of the patients, the median survival time being 11.6 months. The AIO regimen followed by the 'AIO regimen plus L-OHP' therapy sequence led to a promising median survival time of 19.9 months (range 7.7-49.8).     

Oxaliplatin, folinic acid and 5-fluorouracil (OFF) in patients with recurrent advanced head and neck cancer: a phase II feasibility study

The purpose of this phase II trial was to investigate the efficacy and toxicity of oxaliplatin combined with folinic acid (FA) and 5-FU in patients with recurrent squamous cell carcinoma of the head and neck (scchn) in advanced stage of disease. Thirty-six patients with recurrent/metastatic disease with median age of 59 years were enrolled. Patients received oxaliplatin (85mg/m(2)) and FA (200mg/m(2)) followed by 5-FU (2000mg/m(2)) as 24h continuous infusion on day 1 and 15 in a 4-week cycle. On day 8 and 22 FA (200mg/m(2)) and 5-FU (2000mg/m(2)) were administered without oxaliplatin followed by two weeks without cytotoxic treatment. Toxic effects, length of survival and tumour response were assessable in 33/36 patients. The overall response was 60.6% with 7 (21.2%) complete responders (CR) and 13 (39.4%) partial responders (PR). Eight patients (24.2%) showed stable disease (SD) and 5 (15.2%) progressed. The median time to progression (TTP) was 8.1 month (range 2-14) and median overall survival was 10.8 months (range 5-16). The 1-year survival rate was 43.2%. The incidence of haematological toxicity was low but mild paraesthesias occurred in all patients received more then 3 cycles of cytotoxic therapy and dose reduction was necessary in two patients due to diarrhoea grade 3. In this small phase II study the combination of oxaliplatin, FA and 5-FU (OFF) demonstrated relative to the standard regimen of cisplatin and 5-FU a high antitumoural activity in previously treated scchn with favourable toxicity profile.