Evaluation of oxaliplatin dose intensity in bimonthly leucovorin and 48-hour 5-fluorouracil continuous infusion regimens (FOLFOX) in pretreated metastatic colorectal cancer

Background:studies of bimonthly 48-hour regimens of high-doseleucovorin (LV) (FOLinic acid), 5-fluorouracil (5-FU) by continuous infusioncombined with OXaliplatin (FOLFOX) in pretreated patients with metastaticcolorectal cancer suggest that oxaliplatin dose intensity is an importantprognostic factor for response rate and progression-free survival (PFS). Tohelp define the optimal dose schedule for oxaliplatin in pretreated metastaticcolorectal cancer, we retrospectively analyzed data from three phase IIstudies using different FOLFOX regimens (FOLFOX2, 3 and 6). Patients and methods:Data on 126/161 patients were analyzed.FOLFOX2 included oxaliplatin 100 mg/m²; FOLFOX3, 85mg/m²; and FOLFOX6, 100 mg/m² (added to a simplifiedLV–5-FU regimen), all as two-hour infusions. A total of 47 patientsreceived low dose intensity oxaliplatin (LDI: 85 mg/m²/2 weeks)and 79 patients high dose intensity oxaliplatin (HDI: >85mg/m²/2 weeks). Results:Objective responses occurred in 31 (39%) HDIpatients and 9 (19%) LDI patients (P = 0.03). Median PFS was28 weeks, with 52% of HDI patients progression free at 6 months, and26 weeks with 36% of LDI patients progression free at six months(P = 0.02). Increased oxaliplatin dose intensity was not associatedwith increased neurotoxicity or other toxicities. FOLFOX are among the mosteffective regimens for treating LV–5-FU-resistant metastatic colorectalcancer. Conclusions:This study shows that oxaliplatin doseintensification significantly improves response rate and PFS in pretreatedmetastatic disease without increasing severe toxicity.     

Whole-body hyperthermia (41.8 degrees C) combined with bimonthly oxaliplatin, high-dose leucovorin and 5-fluorouracil 48-hour continuous infusion in pretreated metastatic colorectal cancer: a phase II study.

BACKGROUND: Second- and third-line treatments remain a challenge in advanced colorectal cancer. Studies of bimonthly regimens of high-dose leucovorin (LV) and 5-fluorouracil (5-FU) by continuous infusion combined with oxaliplatin (L-OHP) have shown encouraging response rates in patients not responding to a bimonthly LV/5-FU regimen. Hyperthermic enhancement of L-OHP efficiency by increased DNA adduct formation has been demonstrated in vitro. This study was designed to address feasibility, toxicity and efficacy issues of whole-body hyperthermia (WBH) as an adjunct to L-OHP/LV/5-FU in pretreated patients after progression to first- and second-line treatments with LV/5-FU by continuous infusion and irinotecan. PATIENTS AND METHODS: Forty-four patients with advanced colorectal cancer, who had progressed during or within 3 months after completion of chemotherapy with LV/5-FU 24-h infusion (LV/5-FU(24h)) (eight patients) or irinotecan combined with or after LV/5-FU(24h )(36 patients), were treated with L-OHP 85 mg/m(2), 2-h intravenous (i.v.) infusion, followed by LV 200 mg/m(2), 1-h i.v. infusion, and 5-FU 3 g/m(2), 48-h continuous infusion. Every second cycle of the biweekly regimen was combined with WBH, thus allowing a comparison of toxicity with and without WBH in the same patient. Whole-body hyperthermia was administered by a humidified radiant heat device. The target temperature of 41.8 degrees C was maintained for 60 min. L-OHP (2-h infusion) was started at a core body temperature of 39 degrees C. RESULTS: All patients could be evaluated for toxicity, and 41 patients were evaluable for response. A total of 273 L-OHP-containing regimens were administered, 130 with and 143 without WBH. Hyperthermic treatment combined with L-OHP/LV/5-FU showed no unexpected toxicities. WHO grade 3 toxicities were rare and evenly balanced between cycles given with or without WBH. One early death occurred due to sepsis and tumor lysis. The overall response rate was 20%, with two complete and six partial responses. Twenty-three patients (56%) had stable disease and nine patients (22%) progressive disease. With a median observation time of 70 weeks, the median time to progression was 21 weeks [95% confidence interval (CI) 17-25 weeks] and the median survival was 50 weeks (95% CI 39-61 weeks) from the start of therapy. CONCLUSIONS: This trial suggests some advantage of combining L-OHP/LV/5-FU with WBH. Results compare favorably with the activity of similar regimens without WBH in less extensively pretreated patients. These data support further evaluation and warrant phase III studies.     

Phase II study of irinotecan, 5-fluorouracil and leucovorin as first-line therapy for advanced colorectal cancer

BACKGROUND: We evaluated the efficacy and tolerability of a modified biweekly irinotecan, 5-fluorouracil and leucovorin regimen (modified Douillard regimen) as the first-line therapy in patients with advanced colorectal cancer. METHODS: A total of 80 patients (41 male, 39 female) with recurrent or metastatic colorectal cancer were enrolled between April 2001 and December 2003. The treatment cycle consisted of irinotecan 150 mg/m(2) as a 90 min infusion on day 1, leucovorin 20 mg/m(2) intravenous bolus, immediately followed by a 48 h continuous infusion of 5-fluorouracil 3000 mg/m(2) on day 1. The primary end-point was response rate, and the secondary end-points were time to progression and toxicity profile. RESULTS: An overall objective response rate of 38.7% [95% confidence interval (CI) 27.84-49.66%] was achieved. The median time to progression was 6.1 months (95% CI 4.63-7.57 months) and the median overall survival time was 20.2 months (95% CI 15.50-24.90 months). The median duration of follow-up for patients was 16.9 months. The toxicity profile was more favorable than for the conventional Douillard regimen. CONCLUSION: We conclude that the modified Douillard regimen may be a practical and more tolerable treatment option in patients with advanced colorectal cancer.     

Oxaliplatin plus high-dose leucovorin and 5-fluorouracil in pretreated advanced breast cancer: a phase II study.

BACKGROUND: The purpose of this study was to evaluate the efficacy and toxicity of oxaliplatin plus 5-fluorouracil (5-FU) and leucovorin (LV) in patients with metastatic breast cancer (MBC) previously treated with anthracyclines and taxanes. PATIENTS AND METHODS: Fifty anthracycline- and taxane-pretreated MBC patients were treated with oxaliplatin 85 mg/m(2) as a 2-h infusion on day 1, LV 200 mg/m(2)/day as a 2-h infusion followed by bolus 5-FU 400 mg/m(2)/day and a 22-h infusion of 5-FU 600 mg/m(2)/day for 2 consecutive days. Treatment was repeated every 3 weeks. Patients were evaluated for response every two cycles. RESULTS: The median age was 51 years (range 34-75). Twenty patients (40%) had received three or more chemotherapeutic regimens, 64% had three or four metastatic sites and 78% had visceral metastases. All patients had prior exposure to anthracyclines and taxanes. Based on an intention-to-treat analysis, one patient (2%) achieved a complete response and 16 (32%) a partial response, for a 34% overall response rate. Twenty-one patients (42%) had stable disease and 12 (24%) progressive disease. The median time to tumor progression was 5.3 months (range 0.5-12.8) and the median overall survival was 12.3 months (range 0.5-19.2). Toxicity was mild to moderate. Grade 3/4 neutropenia and thrombocytopenia occurred in 32% and 18%, respectively. Febrile neutropenia was experienced by three patients (6%), who were successfully treated. Grade 3/4 neurotoxicity was reported in 14% of the patients and gradually declined after treatment discontinuation. Cycle delays were reported in 28% of patients and dose reductions in 26%. Alopecia, nausea-vomiting, diarrhea and mucositis were not significant. There were no treatment-related deaths. CONCLUSION: The combination of oxaliplatin plus 5-FU/LV seems to be an active regimen in patients with MBC and prior exposure to anthracyclines and taxanes with a good safety profile. The incidence of severe toxicity was quite low and the compliance of patients to the treatment was satisfactory. The results obtained with this regimen could be considered encouraging in this heavily pretreated group of breast cancer patients with a high incidence of visceral metastases.     

Oxaliplatin combined with 5-fluorouracil, leucovorin regimen for patients with advanced colorectal cancer

Objective： To observe the efficacy and tolerability of continuously infusing 5-fluorouracil （5-FU） / folic acid combined with oxaliplatin （L-OHP/5-FU/LV regimen） as first line treatment in advanced colorectal cancer. Methods： 23 patients of advanced colorectal cancer were treated with 5-FU 500 mg/d, civ, d 1-d5, d8-d12, leucovorin 100 mg/d, iv gtt, d1, d8, folic acid tablet 60 mg/d, po, d2-d5, d9-d12, and oxaliplatin 65 mg/（m^2·d）, iv gtt, dl, d8, repeated every 21 days （one cycle）. The effect was evaluated after two cycles. Results： Complete response in 2 cases and partial response in 10 cases were observed with an overall response rate of 47.18%. Adverse effects were mainly grade 1-2, including nausea, vomiting, diarrhea, dental ulcer, peripheral neuritis and myelosuppression. Conclusion： L-OHP/5-FU/LV regimen is an effective and better tolerated alternative treatment in advanced colorectal cancer and yields promising clinical application.     

草酸铂联合氟尿嘧啶、醛氢叶酸治疗晚期结直肠癌的临床观察

Objective:To observe the efficacy and tolerability of continuously infusing 5-fluorouracii(5-FU)/folic acid combined with oxaliplatin(L-OHP/5-FU/Lv regimen)as first line treatment in advanced colorectal cancer.Methods:23 patients of advanced colorectal cancer were treated with 5-Fu 500mg/d,civ,d1-d5,d8-d12,leucovorin 100mg/d,iv gtt,d1,d8,folic acid tablet 60 mg/d,po,d2-d5,d9-d12,and oxaliplatin 65mg/(m2-d),iv gtt,d1,d8,repeated every 21 days(one cycle).The effect was evaluated after two cycles.Results:Complete response in 2 cases and partial response in 10 cases were observed with an overall response rate of 47.18%.Adverse effects were mainly grade 1-2,including nausea,vomiting,diarrhea,dental ulcer,peripheral neuritis and myelosuppression.Conclusion:L-OHP/5-FU/LV regimen is an effective and better tolerated alterna tive treatment in advanced colorectal cancer and yields promising clinical application.     

Bimonthly high-dose leucovorin, 5-fluorouracil infusion and oxaliplatin (FOLFOX3) for metastatic colorectal cancer resistant to the same leucovorin and 5-fluorouracil regimen

Background: FOLFOX2, a bimonthly regimen of high-dose leucovorin (LV), 48-hour continuous infusion of 5-fluorouracil (5-FU) (LV–5-FU) and oxaliplatin (100 mg/m2) produced a high response rate (46%; 95% confidence interval (95% CI): 31%–60%) in 5-FU pre-treated patients with metastatic colorectal cancer. In this phase II study, pre-treated patients were given a lower dose of oxaliplatin to reduce the toxic effects of the regimen.Patients and methods: Thirty patients with advanced colorectal adenocarcinoma and progression while receiving bimonthly LV–5-FU (LV: 500 mg/m2, 5-FU: 1.5–2 g /m2/ 22 hours, days 1–2, every two weeks), were given the same LV–5-FU schedule with the addition of oxaliplatin (85 mg/m2) every two weeks (FOLFOX3).Results: The main toxic effects were peripheral neuropathy (90%) with four severe sensitive neuropathies (WHO grade 2: 13%). The response rate was 20% (95% CI: 8%–39%). Median progression-free survival was 26 weeks, median survival was 57 weeks from the start of FOLFOX3 and median duration of the response was 37 weeks.Conclusions: Results obtained with FOLFOX3 confirmed the synergy between oxaliplatin and 5-FU in 5-FU-resistant metastatic colorectal cancer. However, the response rate seems to be lower than that obtained with FOLFOX2. Further studies to determine the best oxaliplatin dose intensity are in progress.     

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.     

CPT-11联合5-FU/FA方案治疗局部晚期或转移性结直肠癌的临床研究

目的评价CPT-11(开普拓)联合5-FU/FA治疗局部晚期或转移性结直肠癌的临床疗效及不良反应.方法符合收治标准者19例,可评价疗效者17例,入组Arm A方案8例,Arm B方案9例,ArmA方案:CPT-11270mg/m2静滴d1;FA200mg/m2,5-FU 425mg/m2分别静滴,均d1～5,每3周重复,两次CPT-11(6周)评价疗效.ArmB方案:CPT-11 180mg/m2静滴d1,LA200mg/m2,静滴d1～2,5-FU 400mg/m2静推,然后5-FU 600mg/m2,d1～2,每2周重复,应用3次CPT-11(6周)为一个周期.结果17例患者,CR 1例,PR 5例,SD 9例,PD 2例,总缓解率35%,稳定率52.9%,中位缓解时间7.5个月,中位稳定时间5个月.主要剂量限制毒性为迟发性腹泻及中性粒细胞减少.结论CPT-11联合5-FU/FA两种方案治疗局部晚期或转移性结直肠癌有较高的疾病缓解率和稳定率,主要剂量限制毒性为迟发性腹泻及中性粒细胞减少.     

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.     

伊立替康联合5-Fu/CF治疗晚期结直肠癌的临床受益分析

背景与目的：伊立替康（CPT-11）是喜树碱类抗癌药物，为DNA拓扑异构酶Ⅰ抑制剂。它通过CyP3A酶氧化成无活性代谢物（包括APC），并通过羟酸酯酶-2（CES-2）活化成SN-38。CPT-11具有良好的抗结直肠癌的活性本文评价CPT-11联合5-FU／CF方案治疗晚期结直肠癌的临床受益、客观疗效和毒副反应。方法：用CFT-11联俞5-FU／CF方案治疗晚期结直肠癌患者32例，包括19例患者采用CPT-11联合5-FU／CF2周方案治疗；13例患者采用CPT-11联合5-FU／CF3剧厅案治疗。结果：可评价疗效者30例，其中完全缓解（CR）2例，部分缓解（PR）11例，RR占43．3％，稳定（SD）14例，占46．7％，进展（PD）3例。临床受益率为83．3％，疼痛缓解率83．3％。中位肿瘤进展时间7．2月，中位生存期13．8月。主要副反应为迟发性腹泻和中性粒细胞减少，未出现治疗相关性死亡结论：CPT-11联合5-FU／CF方案治疗晚期结直肠癌患者有效，临床缓解率高，明显减轻患者的痛苦，提高患者的生存质量，毒副作用患者能够耐受。因此，可作为晚期结直肠癌的一线或二线治疗方案。     

Potent effects of adjuvant chemotherapy using 5-fluorouracil + leucovorin on DNA aneuploid colorectal cancer

Background The relationship between DNA ploidy of colorectal cancer cells and sensitivity to adjuvant chemotherapy, using 5-fluorouracil+leucovorin was investigated. Methods Seventy-five patients with Duke's B or C colorectal cancer, who underwent potentially curative resection, were randomly allocated to 2 groups. Thirty-eight patients received adjuvant chemotherapy using 5-fluorouracil+leucovorin (chemotherapy group), and 37 patients received no adjuvant chemotherapies (no-chemotherapy group). Tumor cell ploidy of all patients was analyzed using paraffin-embedded samples. Results There was no statistically significant difference in overall survival between patients who received chemotherapy and those who did not. Among the patients with diploid tumors (n=39), there was no significant difference in survival between the chemotherapy group (n=20, 5-year survival rate of 34.3%) and the no-chemotherapy group (n=19, 5-year survival rate of 27.1%). By contrast, among the aptients with aneuploid tumors (n=36), the survival rate was significantly better in the chemotherapy group (n=18, 5-year survival rate of 77.8%), than in the no-chemotherapy group (n=18, 5-year survival rate of 43.7%) (P=0.023). Conclusion These results suggest that aneuploid tumors are more sensitive to adjuvant chemotherapy, using 5-fluorouracil+leucovorin, than are diploid tumors.     

Five-day continuous infusion of 5-fluorouracil and pulsed folinic acid in patients with metastatic colorectal carcinoma: An effective second-line regimen

Objective: A previous phase I trial in 14 pretreated patients with progressive advanced colorectal cancer demonstrated 750 mg/m² to be the maximum tolerable dose of 5-fluorouracil (5-FU) administered as a 5-day continuous infusion modulated by short infusions of 100 mg/m² folinic acid twice daily. The dose-limiting toxicities were hand-foot syndrome and severe mucositis. A response rate of 21% and 50% stable disease could be achieved. In order to determine the effectiveness and tolerability, we initiated a multicenter phase II trial applying a 650 mg/m² recommended dose of 5-FU and 100 mg/m² folinic acid twice daily every three weeks.Patients and methods: From January 1994 to July 1996, 88 advanced and progressive colorectal cancer patients either previously treated with a bolus schedule of 5-FU and folinic acid (34 patients) or without (54 patients) previous chemotherapy were included in this trial.Results: In the group of previously treated patients, therapy led to 6% (2 of 34 patients) remissions while stable disease could be observed in 68% (23 of 34 patients) of the patients. The median survival time was 14 months. The main toxicity was mucositis grade 3 in 15% of the previously treated patients and 10% in the nonpretreated patients. In the population of nonpretreated patients, the overall response rate was 15% (eight of 54 patients) and stable disease could be induced in 67% (36 of 54 patients). The median survival time was 13.7 months.Conclusion: This regimen is an active second-line therapy in advanced colorectal cancer with minimal toxicity, thus preserving the quality of life during palliative chemotherapy. Antitumor activity in previously untreated patients does not seem superior to that obtained with weekly regimens applying 24- or 48-hour continuous infusions of 5-FU and folinic acid.     

Irinotecan plus gemcitabine vs irinotecan for the second-line treatment of patients with advanced non-small-cell lung cancer pretreated with docetaxel and cisplatin: a multicentre, randomised, phase II study

To compare irinotecan (CPT-11)+gemcitabine vs CPT-11 alone as second-line treatment for patients with advanced non-small cell lung cancer (NSCLC) progressing after docetaxel-cisplatinum-based therapy. A total of 147 evaluable, pretreated patients, with NSCLC, received either gemcitabine (1000 mg m(-2), days 1 and 8)+CPT-11 (300 mg m(-2), day 8) (Group A, n=76) or CPT-11 (300 mg m(-2), day 1) (Group B, n=71), every 3 weeks. All patients were evaluable for response and toxicity. The objective response rate was 18.4% (95% CI: 9.71-27.14%) and 4.2% (95% CI: 0-8.90%) (P=0.009) for groups A and B, respectively. No significant differences between the two groups in terms of the median duration of response, time to tumour progression, overall survival and 1-year survival were observed. The CPT-11/gemcitabine regimen significantly improved the patients' quality of life ('general mood today' (P=0.014), 'coughing' (P=0.003) and 'intensity of symptoms' (P=0.034)) compared with CPT-11. More cycles had to be delayed (P=0.001) and required prophylactic growth factor support (P=0.001) in Group A than B. Three (3.9%) patients in Group A and eight (11.3%) in Group B developed febrile neutropenia (P=0.09); one patient died of sepsis in each group. Three additional (Group A, n=1; Group B, n=2) treatment-related deaths were observed. Grade 3-4 haematologic toxicity was comparable in the two groups except anaemia (P=0.03 in favour of CPT-11). Other nonhaematologic toxicities were mild and similar in the two groups. CPT-11+gemcitabine resulted in a higher response rate and better control of disease-related symptoms than CPT-11 alone, but without any improvement in the overall survival.     

Oxaliplatin, 5-fluorouracil/leucovorin and epirubicin as first-line treatment in advanced gastric carcinoma: a phase II study

The association between oxaliplatin and 5-fluorouracil (5-FU) has been extensively reported to improve prognosis of gastric cancer patients. The present study is aimed at evaluating response rate and the toxicity profile of the association with oxaliplatin, 5-FU/lecovorin and epirubicin in gastric cancer patients with locally advanced or metastatic disease. Thirty-six patients have been enrolled and 35 evaluated. The treatment schedule was oxaliplatin (100 mg m(-2)), 5-FU (400 mg m(-2)), leucovorin (40 mg m(-2)) and epirubicin (60 mg m(-2)) intravenously. administered every 3 weeks for 6 months, for a total of 185 therapy cycles . Response rate and toxicity were assessed according to the international WHO criteria. Every patient received a mean of 5.3 therapy cycles in a day-hospital setting. Sixteen of 35 patients (46%) showed an objective response, two complete response and 14 partial response. Median time to progression was 33 weeks with an overall median survival of 49 weeks. During the study, anaemia grade 3 and neutropenia grade 3 were observed in 9 and 11% of patients respectively. A grade 3 periferic sensorial neuropathy was observed in 6% of patients. No life threatening or cardiac toxicity was recorded. The regimen used showed anticancer activity against gastric carcinoma, a tolerable toxicity profile and excellent patient compliance.     

HCPT联合FOLFOX4方案治疗晚期胃癌、大肠癌疗效观察

目的评价羟基喜树碱(HCPT)联合FOLFOX4方案治疗晚期胃癌、大肠癌的近期疗效和毒副反应。方法28例晚期消化道癌患者,先给予草酸铂(L-OHP)85mg/m2静脉点滴2h d1,亚叶酸钙(CF)200mg/m2静脉点滴2h d1~d2,随后5-氟尿嘧啶(5-FU)400mg/m2静脉推注,5-FU600mg/m2静脉点滴22h d1~d2,同时给予HCPT6 mg/m2静脉点滴3h d1~d3。2周重复,4周期后评价疗效。结果全组28例,其中完全缓解(CR)2例(7.1%),部分缓解(PR)16例(57.1%),稳定(SD)4例(14.3%),进展(PD)6例(21.4%)。总有效率(CR PR)64.3%。胃癌16例,11例有效,有效率68.8%。大肠癌12例,7例有效,有效率58.3%。毒副反应主要是恶心呕吐,白细胞减少,神经感觉毒性,无化疗相关死亡。结论HCPT联合FOLFOX4方案治疗晚期消化道癌疗效肯定,毒副反应能耐受。     

A phase II study of FOLFIRI-3 (double infusion of irinotecan combined with LV5FU) after FOLFOX in advanced colorectal cancer patients

In advanced colorectal cancer previously treated with oxaliplatin, efficacy of irinotecan-based chemotherapy is poor and the best regimen is not defined. We designed FOLFIRI-3 and conducted a phase II study to establish its efficacy and safety in advanced colorectal cancer patients previously treated with FOLFOX. FOLFIRI-3 consisted of irinotecan 100 mg m-2 as a 60-min infusion on day 1, running concurrently with leucovorin 200 mg m-2 as a 2-h infusion on day 1, followed by 46-h continuous infusion of 5-fluorouracil (5FU) 2000 mg m-2, and irinotecan 100 mg m-2 repeated on day 3, at the end of the 5FU infusion, every 2 weeks. Sixty-five patients entered the study. The intent-to-treat objective response rate was 23% (95% CI 13-33%). Disease was stable in 37% of patients, progressed in 26% and was not assessable in 14%. From the start of FOLFIRI-3, median progression-free survival was 4.7 months and median survival 10.5 months. Main toxicities (% of patients) were grade 3-4 diarrhoea 23% and grade 4 neutropenia 11%. FOLFIRI-3 is a promising regimen achieving high response rate and progression-free survival in patients previously treated with FOLFOX with a moderate toxicity.     

A multicenter phase II study of a five-day regimen of oral 5-fluorouracil plus eniluracil with or without leucovorin in patients with metastatic colorectal cancer

Purpose:To evaluate the safety and efficacy of a five-day regimenof oral 5-fluorouracil (5-FU) plus eniluracil (776C85) in patients withmetastatic colorectal cancer (CRC). Patients and methods:Seventy-five patients with metastatic CRCthat was previously untreated or refractory to 5-FU–leucovorin (LV) wereenrolled and divided into two strata based upon their treatment history.Twenty-four had not previously received chemotherapy or had received adjuvantchemotherapy that ended >6 months prior to enrollment on study (previouslyuntreated stratum). Fifty-one patients had disease refractory to intravenous(i.v.) 5-FU–LV (previously treated stratum). All patients received sevenconsecutive daily doses of eniluracil (20 mg/day) with once daily oral 5-FUgiven on days 2–6, repeated every four weeks. One-half of the patientsin each stratum also received 50 mg/day oral LV on days 2–6. The 5-FUdose was 25 mg/m² when administered without LV and 20mg/m² when administered with LV. Results:Partial response (PR) was noted in 2 of 12 patientsreceiving eniluracil–5-FU and in 3 of 12 patients receivingeniluracil–5-FU–LV in the previously untreated stratum. Noresponses were observed in the refractory disease stratum, however, 15patients (30%) demonstrated stable disease over 2–18+ courses oftherapy. Non-hematologic toxicities were mild; only 7% of patientsexperienced grade 3 diarrhea. Myelosuppression was frequent and dose limiting.Neutropenic sepsis was reported in 13.5% of patients. Conclusions:Eniluracil with 5-FU administered orally with orwithout LV on a five-day schedule is active and well tolerated when given asprimary therapy to patients with metastatic CRC.     

Substantial activity of budesonide in patients with irinotecan (CPT-11) and 5-fluorouracil induced diarrhea and failure of loperamide treatment

Background: Diarrhea is one of the most disturbing effects of chemotherapy, affecting quality of life on the one hand and limiting applicable doses on the other. Irinotecan (CPT-11) and 5-fluorouracil (5-FU) are associated with an elevated risk of developing severe diarrhea. Standard therapy consists of high-dose loperamide, but is associated with frequent failure. Other therapeutic regimens are still experimental. Endoscopic examination of a patient with severe loperamide-resistant diarrhea after CPT-11 chemotherapy revealed an inflammation of the ileo-coecal region. Oral therapy with the topical corticosteroid budesonide was immediately effective. This led to a phase I study of budesonide in CPT-11- and 5-FU-induced and loperamide-refractory diarrhea.Patients and methods: Fourteen patients with CPT-11- and seven patients with 5-FU-induced grade 3–4 (NCI/WHO) diarrhea and loperamide failure were enrolled in this study. All patients had metastatic colorectal cancer.Results: In 86% of the CPT-11- and 57% of the 5-FU-treated patients with grade 3–4 diarrhea and loperamide failure, treatment with budesonide resulted in a reduction of diarrhea severity by at least two grades.Conclusions: The orally administered topical active steroid budesonide is highly effective in the therapy of loperamide-refractory chemotherapy (CPT-11 or 5-FU) -induced diarrhea.     

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.