A phase I dose-finding clinical pharmacokinetic study of an oral formulation of irinotecan (CPT-11) administered for 5 days every 3 weeks in patients with advanced solid tumours.

BACKGROUND: Oral administration of irinotecan (CPT-11) should allow sustained exposure to the drug without the inconvenience of intravenous delivery and with fewer side-effects. PATIENTS AND METHODS: The present phase I trial of CPT-11, administered orally as a powder-filled capsule for 5 consecutive days every 3 weeks at doses ranging from 30 to 90 mg/m(2)/day, was conducted in 47 patients for whom a satisfactory standard treatment option was no longer available (24 males/23 females; median age 51 years, range 26-85). Tumour types included melanoma (11), colorectal (4), urinary tract (3), lung/pleura (4), thyroid (3), liver (3), gallbladder (2), cervix/uterus (3), breast (2), pancreas (2), carcinoma and other cancer types (10). RESULTS: A total of 171 cycles were administered (median 3, range 1-11). Dose limiting toxicities (DLTs) occurred during the first cycle in five of 31 patients in the dose-escalation part of the study: one patient at the 50 mg/m(2)/day dose level (diarrhoea grade 4); one patient at the 80 mg/m(2)/day dose level (prolonged neutropenia grade 4 and diarrhoea grade 3); and three patients at the 90 mg/m(2)/day dose level (diarrhoea, vomiting and neutropenia). The 80 mg/m(2)/day dose level was expanded, as a feasibility study, to include 16 additional patients, five of whom had received extensive prior pelvic irradiation. A further three patients in this cohort experienced DLTs, two of whom had received extensive prior pelvic irradiation. One patient died on study day 15 during the first cycle of oral CPT-11 following grade 3 diarrhoea, febrile neutropenia and a necrotic enterocolitis. Overall the grade 3/4 toxicities in 47 patients were asthenia (19%), anorexia (17%), neutropenia (14.9 %), diarrhoea (13%), nausea (12.7%), vomiting (8.5%) and thrombocytopenia (8.5%). Partial responses were observed in two melanoma patients and disease stabilisation was noted in 17 (36.1%) patients. Pharmacokinetic parameters were recorded for 46 patients. CONCLUSIONS: At the maximum tolerated dose, defined as 80 mg/m(2)/day for 5 days every 3 weeks, oral CPT-11 was shown to be well tolerated and safe with few of the haematological toxicities associated with the intravenous formulation.     

Phase I dose-finding and pharmacokinetic trial of irinotecan (CPT-11) administered every two weeks

Objectives:This trial was performed to determine themaximum tolerated dose (MTD), dose-limiting toxicity (DLT), andpharmacokinetic profile of irinotecan (CPT-11) when administered on aonce-every-2-week schedule. Patients and methods:CPT-11was administered to successive cohorts of patients at progressivelyincreasing starting doses ranging from 125 to 350 mg/m². TheMTD and DLTs were determined both for CPT-11 alone and for CPT-11followed by filgrastim (G-CSF). Plasma samples were obtained during thefirst 24 hours after initial dosing to determine the totalconcentrations (lactone + carboxylate forms) of CPT-11; of theactive metabolite SN-38; and of SN-38 glucuronide (SN-38G). Results:Neutropenic fever was the DLT for CPT-11 atthe 300 mg/m² dose level. When G-CSF was added, doseescalation beyond 350 mg/m² could not be achieved due tograde 2–3 toxicities that prevented on-time retreatment withCPT-11. Severe, late diarrhea was uncommon on this schedule. Peak plasmaconcentrations of SN-38 and SN-38G were approximately 2.5% and4.2% of the corresponding peak plasma concentration for CPT-11,respectively. The harmonic mean terminal half-lives for CPT-11, SN-38,and SN-38G were 7.1 hours, 13.4 hours, and 12.7 hours, respectively. Nopredictive correlation was observed between CPT-11 or SN-38 peakconcentration or AUC and first-cycle diarrhea, neutropenia, nausea, orvomiting. Across the range of doses studied, mean CPT-11 clearance was14.0 ± 4.0 l/h/m² and volume of distribution was 146± 45.9 l/m². Conclusions:Whenadministered every two weeks, the recommended phase II starting dose ofCPT-11 is 250 mg/m² when given alone and 300 mg/m²when supported by G-CSF. This every-two-week regimen offers a tolerableand active alternative to weekly or every-three-week single-agent CPT-11therapy.     

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。     

Weekly irinotecan (CPT-11) in 5-FU heavily pretreated and poor-performance-status patients with advanced colorectal cancer

Irinotecan (CPT-11) is an effective drug in patients with advanced colorectal cancer (CRC). Little is known about its efficacy and safety in previously treated patients with poor performance status. We prospectively evaluated the antitumor efficacy and safety of CPT-11 monotherapy in this setting. Thirty-four patients with poor performance status (Karnofsky score between 60 and 80) and/or progressing on one or more previous 5-FU-based chemotherapy lines for advanced colorectal adenocarcinoma were enrolled in this study. Treatment consisted of irinotecan (CPT-11) at 100 mg/m² administered as a 60-min iv infusion every week for four consecutive weeks followed by a 2-wk rest period until disease progression or unacceptable toxicity. The overall objective response rate (WHO criteria) for the 34 patients included was 20.6% [95% confidence interval (CI): 6.3%–34.9%]. Stable disease was obtained in 13 patients (38.2%) and 14 patients (41.2%) progressed. The median time to disease progression was 5.5 mo (range: 0.9–17.5) and the median survival was 8.3 mo (95% CI: 1.7–16.9). Overall, weekly CPT-11 was well tolerated with grade 3/4 neutropenia as the main hematological toxicity (11 patients: 32.4%; 14 infusions: 3.3%), and delayed diarrhea (10 patients: 29.4%; 16 infusions: 3.8%) as the main grade 3/4 non-hematological toxicity. In conclusion, weekly CPT-11 at 100 mg/m² for four consecutive weeks followed by a 2-wk rest period showed antitumor efficacy and may be safely administered to heavily pretreated patients with advanced colorectal cancer and a poor performance status. Weekly CPT-11 monotherapy may be considered as a therapeutic option for this population of patients.     

Phase I safety and pharmacokinetic study of SU-014813 in combination with docetaxel in patients with advanced solid tumours

Background

In pre-clinical models enhanced anti-tumour activity was observed when SU-014813, an oral multi-targeted tyrosine kinase inhibitor was combined with docetaxel. This synergy might be explained by improvement of the penetration of cytotoxic agents into tumours as a result of both VEGFR and PDGFR inhibition. We assessed the maximal tolerated dose (MTD), evaluated the pharmacokinetics and preliminary anti-tumour efficacy of oral SU-014813 administered continuously in combination with docetaxel to patients with advanced solid tumours.

Methods

In this phase I study successive patient cohorts received docetaxel 60 or 75 mg/m² every 3 weeks in combination with chronic daily dosing of SU-014813. Dose limiting toxicity was assessed both in the first and second treatment cycle.

Results

Twenty-five patients were entered on study of which 24 started treatment. Dose limiting toxicities were prolonged neutropenia, neutropenic fever, fatigue and diarrhoea. Other toxicities included fatigue, alopecia, nausea, vomiting, anorexia, rash, hypertension and hair discolouration. The recommended phase II dose was determined to be docetaxel 75 mg/m² in combination with SU-014813 50 mg/day. There was no clinically relevant pharmacokinetic drug-drug interaction. Two patients (8%) achieved a partial response (PR) and 7 patients (29%) had stabilisation of their disease (SD) >6 months, for a clinical benefit rate of 37.5%. The activity observed in patients with melanoma and sunitinib refractory gastrointestinal stromal tumours (GIST) was particularly noteworthy.

Conclusions

Oral SU-014813 50 mg/day with docetaxel 75 mg/m² is a clinically feasible regimen with a manageable safety profile and anti-tumour activity. Further development is warranted in patients with melanoma and GIST.     

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.     

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.     

Two different schedules of irinotecan (CPT-11) in patients with advanced colorectal carcinoma relapsing after a 5-fluorouracil and leucovorin combination. A randomized study

Purpose To evaluate the efficacy and safety of irinotecan as second-line treatment in patients with advanced colorectal cancer (ACC) failing or relapsing after 5-fluorouracil (5-FU) plus leucovorin (LV) standard chemotherapy.Patients and methods Irinotecan was randomly administered in two different schedules (once every 3 weeks, and every 10 days) in patients failing prior 5-FU plus LV. Patients were randomized to two treatment groups: group A received irinotecan 350 mg/m² every 21 days and group B received irinotecan 175 mg/m² days 1 and 10 every 21 days.Results Group A comprised 60 patients: 34 male/26 female, median age 64 years (range 48–70 years), and median Karnofsky performance status (PS) 90. Their metastatic sites included liver (n=47), lymph nodes (n=27), lung (n=14), abdomen (n=14), pelvis (n=8), "other" (n=2), and local recurrence (n=12). Group B comprised 60 patients: 36 male/24 female, median age 62 years (46–70 years), and median PS 90. Their metastatic sites included liver (n=49), lymph nodes (n=29), lung (n=17), abdomen (n=16), pelvis (n=11), "other" (n=2), and local recurrence (n=13). Group A showed the following responses: complete response (CR) 2, partial response (PR) 12, stable disease (SD) 21, progressive disease (PD) 26, overall response rate (ORR) 23%, tumor growth control 58%. Group B showed the following responses: CR 1, PR 14, SD 22, PD 23; ORR 25%; tumor growth control 62%. Toxicities included acute cholinergic syndrome (group A 53%, group B 19%; P<0.0001), late-onset diarrhea grade 1/2 (group A 21%, group B 46%) and grade 3/4 (group A 41%, group B 66%; P<0.0001), nausea and vomiting grade 1/2 (group A 34%, group B 59%) and grade 3/4 (group A 30%, group B 12%; P<0.0001), neutropenia grade 3/4 (group A 27%, group B 28%; P<0.03), with febrile neutropenia seen in only four patients in group A, anemia grade more than 2 (group A 28%, group B 12%; P<0.05), asthenia grade more than 3 (group A 24%, group B 18%; P<0.001), and alopecia grade more than 3 (group A 40%, group B 34%; P<0.2).Conclusions The present study indicates that, in patients with ACC who have relapsed after 5-FU plus LV, the administration of irinotecan fractionated into two doses every 21 days yields a similar efficacy to, but a much lower incidence of toxicity than, the same total dose of irinotecan administered once every 21 days.     

A dose-escalation study of irinotecan (CPT-11) in combination with cisplatin in patients with advanced non-small cell lung cancer previously treated with a docetaxel-based front line chemotherapy

Purpose: A phase I study was conducted to determine the maximum-tolerated dose (MTD) and the dose-limiting toxicities (DLTs) of a CPT-11 plus cisplatin combination as salvage treatment in patients with advanced non-small cell lung cancer (NSCLC). Patients and methods: Twenty-two patients with histologically confirmed NSCLC, who had failed taxotere-based front-line chemotherapy, were enrolled. The patients’ median age was 61 years, 19 (86%) were male, and 17 (77%) had a performance status (World Health Organization (WHO)) 0–1. CPT-11 was administered as a 60-min i.v. infusion at a fixed dose of 100 mg/m² on day 1 and at escalating doses on day 8, starting from 100 mg/m² with increments of 10 mg/m² ; cisplatin was administered at a fixed dose of 80 mg/m² on day 8, 2 h after CPT-11 administration. Treatment was repeated every 3 weeks. Results: At the dose of CPT-11 120 mg/m² , three out of four enrolled patients presented DLTs (grade 4 neutropenia, febrile neutropenia and delayed diarrhea); the addition of G-CSF at this level did not permit further dose-escalation. Grade 3/4 neutropenia was observed in 12 (18%) cycles, febrile neutropenia in four (6%), and grade 3/4 thrombocytopenia in four (6%). Grade 3/4 diarrhea was seen in six (29%) patients, and grade 2/3 nausea and vomiting in 12 (57%). Neurotoxicity grade 2 was observed in six (29%) patients and grade 3 in one (5%). Other toxicities were mild. The MTD was CPT-11 100 mg/m² on day 1 and 110 mg/m² on day 8 in combination with CDDP 80 mg/m² on day 8. Among 12 patients evaluable for response, partial response was achieved in two (16.7%) patients and stable disease in five (41.7%). Conclusion: The combination of CPT-11 and cisplatin has substantial but manageable toxicity and marginal activity as salvage treatment of patients with NSCLC who have failed taxotere-based front-line chemotherapy; further investigation is warranted to define its precise role in the second-line setting.     

CPT-11联合5-FU/CF(FOLFIRI)化疗方案治疗晚期结直肠癌

背景与目的:CPT-11联合5-FU/CF(FOLFIRI)化疗方案是治疗晚期结直肠癌的有效方案.但是,该方案作为一线方案治疗中国晚期结直肠癌患者的资料缺乏,其疗效和安全性仍需进一步确定.本文旨在探讨FOLFIRI方案作为一线治疗方案对中国晚期结直肠癌患者的疗效和安全性.方法:自2002年1月至2005年9月期间,共54例晚期结直肠癌患者采用FOLFIRI方案作为一线方案进行治疗,回顾性分析其治疗有效率(response rate,BR)、疾病进展时间(time to progression,TTP)、总生存时间(overall survival,OS)和不良反应.结果:54例患者中52例可评价疗效.其中RR为42.6%,TTP为6个月,OS为15.2个月.最常见的不良反应为中性粒细胞减少(38.9%)、腹泻(37.1%)和恶心呕吐(50.0%),Ⅲ/Ⅳ级的发生率分别为5.6%、9.3%和9.3%,总体耐受性好.结论:FOLFIRI方案治疗中国晚期结直肠癌患者疗效肯定,作为一线化疗方案有较高的有效性,不良反应可以耐受.     

A dose-finding study of irinotecan (CPT-11) plus a four-day continuous 5-fluorouracil infusion in advanced colorectal cancer

OBJECTIVE: Irinotecan (CPT-11) has shown considerable activity in colorectal cancer, and its combination with 5-fluorouracil (5-FU) represents an attractive approach. A phase I study was conducted to determine the maximum tolerated dose (MTD) and the dose-limiting toxicities (DLTs) of CPT-11 in combination with a continuous infusion of 5-FU for 4 days. METHODS: Forty-two patients with histologically confirmed metastatic colorectal cancer who had not received prior treatment for advanced disease were enrolled. The patients' median age was 64 years; 26 (62%) patients were men, and the performance status (WHO) was 0 in 26 (62%) patients, 1 in 15 (36%) and 2 in 1 (2%). Twenty-two (52%) patients had 2 or more metastatic sites. CPT-11 (starting dose 200 mg/m(2)) was administered as a 30-min intravenous infusion with increments of 50 mg/m(2) on day 4. 5-FU (starting dose 400 mg/m(2)) was administered as a 4-day continuous intravenous infusion with increments of 50 mg/m(2) on days 1-4. Treatment was repeated every 4 weeks. RESULTS: The MTD of the combination was found to be 600 mg/m(2) for 5-FU and 350 mg/m(2) for CPT-11. Neutropenia, febrile neutropenia and delayed diarrhea were the DLTs. Grade 3/4 neutropenia was observed in 22 (13%) out of 169 administered treatment cycles, febrile neutropenia in 7 (4%) and grade 3/4 diarrhea in 20 (12%). Other toxicities were mild. Among 36 patients evaluable for response, partial response was achieved in 8 (22%), stable disease in 12 (33%) and progressive disease in 16 (44%) patients. Responses were mostly seen at the higher dose levels. CONCLUSIONS: The combination of a 4-day continuous infusion of 5-FU followed by CPT-11 represents an active and well-tolerated regimen for patients with colorectal cancer. This regimen merits further evaluation in phase II studies.     

Combined radiotherapy, 5-fluorouracil continuous infusion and weekly oxaliplatin in advanced rectal cancer: a phase I study

The aim of this study was to determine the maximum-tolerated dose (MTD) of weekly oxaliplatin combined with 5-fluorouracil (5FU) continuous infusion administered concomitantly with fractionated radiotherapy in patients presenting advanced rectal cancer. Forty-three patients with rectal cancer (stage T3/T4 (n = 24), metastatic (n = 17) and 2 with local recurrence), were included. The radiotherapy dose delivered was 45 Gy over 5 weeks (1.8 Gy/fraction/day, 5 days per week). The initial weekly oxaliplatin dosage was 30 mg/m² and the 5FU dosage 150 mg/m²/d. The oxaliplatin and 5FU doses were escalated. Eight dose levels were tested. At dose level 8 (oxaliplatin 80 mg/m², 5FU 225 mg/m²/d), 2 patients out of 4 presented dose-limiting toxicity (severe diarrhoea with dehydration and fatal shock, rectovesical fistula). At dose level 7, 2 further patients presented with grade 3 diarrhoea. The main toxicity of the combination was diarrhoea. The hematological and neurological toxicities were not severe and were not dose-limiting. Out of the 30 patients undergoing surgery, 4 (13.3%) presented with pathological complete response and 4 (13.3%) only presented with microscopic residual disease. The results from this study enabled determination of the recommended weekly oxaliplatin dose (60 mg/m²) combined with 5FU continuous infusion (225 mg/m²) and fractionated radiotherapy (45 Gy) in the pre-operative treatment of advanced rectal cancer. The good safety profile of the regimen, associated with promising results in terms of histological response, suggest that the regimen could be developed in future phase II/III studies.     

A phase I,dose-finding study of sunitinib in combination with irinotecan in patients with advanced solid tumours

Background:

Sunitinib is a multitargeted, oral tyrosine kinase inhibitor with antitumour and antiangiogenic activity. We investigated the safety and pharmacokinetics of sunitinib in combination with irinotecan in patients with advanced, refractory solid tumours.

Methods:

Sunitinib was initially administered once daily at 37.5 mg per day on days 1–14 of a 21-day cycle, in which irinotecan 250 mg m⁻² was given on day 1. In a second cohort, the sunitinib dose was reduced to 25 mg per day. Blood samples were collected for pharmacokinetic studies.

Results:

In the sunitinib 37.5 mg per day cohort, 3 out of 10 evaluable patients had objective responses, but dose-limiting toxicities (DLTs) of neutropenia, pneumococcal sepsis, and fatigue were observed. There were no DLTs in the sunitinib 25 mg per day cohort. Paired observations of pharmacokinetic parameter values of sunitinib and irinotecan alone vs the combination did not reveal significant drug–drug interactions. The maximum tolerated dose was defined as sunitinib 25 mg per day (days 1–14) with irinotecan 250 mg m⁻² (day 1), but no activity was observed at this dose.

Conclusion:

Although a higher sunitinib dose of 37.5 mg per day (days 1–14) with irinotecan showed preliminary evidence of antitumour activity, this dose was poorly tolerated. Therefore, this particular combination will not be pursued for further studies.     

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.     

Phase I dose-escalation trial of irinotecan with continuous infusion 5-FU first line, in metastatic colorectal cancer

This single-centre phase I trial was designed to determine the maximum tolerated dose of irinotecan and the recommended dose to use in combination with a fixed dose of 5-fluorouracil (5-FU) administered as a protracted venous infusion, for the first-line treatment of metastatic colorectal cancer (CRC). Tolerability and efficacy were secondary end points. In all, 22 patients, median age 57 years, were treated with escalating, weekly doses of irinotecan (50, 75, 100 and 85 mg m(-2)) in combination with 250 mg m(-2) 5-FU administered as a continuous infusion. All patients had measurable disease. The combination was well tolerated up to an irinotecan dose of 75 mg m(-2). However, three out of five patients at the 100 mg m(-2) irinotecan dose level had their dose reduced due to multiple grade 2 toxicities, and eventually one patient stopped treatment due to grade 3 diarrhoea and multiple grade 2 toxicities. Subsequent patients were recruited at an irinotecan dose level of 85 mg m(-2). The overall response rate was 55%, comprising one complete and 11 partial responses (PRs). Six patients also achieved sustained stable disease (SD), giving a clinical benefit (complete response/PR/SD) response of 82%. The median duration of response was 238 days (8.5 months) and median time to progression was 224 days (8.0 months). Two patients who achieved PRs underwent partial hepatectomies. Thus, irinotecan (85 mg m(-2)) combined with a continuous infusion of 5-FU (250 mg m(-2)) is an active and well-tolerated regimen for the treatment of metastatic CRC. It represents an effective treatment for patients who require close supervision and support, throughout their initial exposure to chemotherapy for this disease, and this dose combination was recommended for an ongoing phase II study.     

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.     

Use of a topoisomerase I inhibitor (irinotecan, CPT-11) in metastatic adrenocortical carcinoma.

BACKGROUND: Complete responses are rare after medical treatment of adrenocortical tumors. We performed a single center prospective study of the antitumor effect of irinotecan (CPT-11) in patients with metastatic adrenocortical cancer. PATIENTS AND METHODS: Since 1999, all patients with advanced progressive adrenocortical carcinoma, referred to the Institut Gustave-Roussy, have been enrolled prospectively in this study. CPT-11 (250 mg/m(2)) was administered intravenously on day 1 in a 2-h infusion, every 14 days. World Health Organization (WHO) criteria were used to evaluate tumor response and toxicity. RESULTS: During treatment, no dose or schedule modifications were made. A median of three courses were given (range 1-8), and all but two patients received at least three complete chemotherapy courses. No objective or complete responses were observed. The best response achieved was stabilization in three patients, lasting from 1.5 to 4 months. Significant toxicity occurred in two patients. CONCLUSIONS: Our results do not support a major role of CPT-11 in adrenocortical carcinoma.     

Cisplatin plus weekly CPT-11/docetaxel in advanced esophagogastric cancer: a phase I study with pharmacogenetic assessment of XPD, XRCC3 and UGT1A1 polymorphisms

Purpose  A multicenter phase I trial to establish the recommended dose of CPT-11/docetaxel plus cisplatin in advanced esophagogastric cancer patients and to correlate the efficacy and toxicity with genetic polymorphisms in DNA repair genes (XPD and XRCC3) and the UGT1A1 gene. Methods  Four dose levels with a fixed dose of cisplatin (60 mg/m²), day 1, and dose-escalation of CPT-11 (50–70 mg/m²) and docetaxel (25–30 mg/m²), days 1 and 8, every 3 weeks were planned. Polymorphisms of XPD (Asp312Asn and Lys751Gln), XRCC3 (Thr241Met) and UGT1A1*28 were examined in baseline peripheral blood. Results  Twenty-eight patients were included at three different dose levels. Dose-limiting toxicities were febrile neutropenia and diarrhea; the recommended dose was established at CPT-11 60 mg/m² and docetaxel 25 mg/m² plus cisplatin 60 mg/m². Objective response was observed in 13 patients (50%). Median time to progression was 6.6 months, and median survival was 11.3 months. Median time to progression was 9.7 months for patients harboring the XRCC3 Met241Met genotype versus 8.4 months for patients with Thr241Met and 3.1 months for those with Thr241Thr (P = .04). Conclusions  CPT-11/docetaxel plus cisplatin is active in patients with advanced esophagogastric cancer. XRCC3 Met241Thr polymorphisms could be a useful marker to predict prognosis in patients treated with a cisplatin-based chemotherapy. However, these results are required to be confirmed with a great number of patients.     

Phase I dose-escalating study of 24-h continuous infusion of 5-fluorouracil in combination with weekly docetaxel and cisplatin in patients with advanced gastric cancer

Purpose

To determine the maximum-tolerated dose (MTD) of a 24-h continuous infusion of 5-fluorouracil (5-FU) when administered in combination with a fixed weekly dose of docetaxel and cisplatin in patients with advanced gastric cancer.

Methods

Patients with advanced gastric adenocarcinoma (n = 21) received a weekly regimen of docetaxel, cisplatin and 5-FU (DCF) for 3 consecutive weeks every 4 weeks. The doses of docetaxel and cisplatin were fixed at 33.3 and 30 mg/m², respectively. The dose of 5-FU was increased from a starting dose of 1,000 mg/m² to the MTD.

Results

A total of 53 cycles of chemotherapy were administered (median = 3 cycles/patient). The MTD of 5-FU was 1,750 mg/m². All 21 patients were assessed for toxicity and 19 patients (90%) were evaluated for response. Both grade 3–4 hematologic and non-hematologic toxicities occurred in less than 10% of patients and there were no treatment-related deaths. Among the 19 patients, we observed 1 complete and 4 partial responses for an overall response rate of 26% (95% CI: 6–46%). This rate increased to 39% (95% CI: 12–66%) in 13 chemotherapy-naïve patients.

Conclusions

A consecutive weekly DCF regimen at 4-week intervals appears feasible for advanced gastric cancer with a favorable toxicity profile. The recommended doses are 33.3 mg/m² of docetaxel, 30 mg/m² of cisplatin and 1,500 mg/m² of a 24-h continuous intravenous infusion of 5-FU. The response of this weekly regimen in our study was favorable and deserved further investigation in a phase II trial.     

Concurrent chemoradiotherapy with protracted infusion of 5-fluorouracil (5-FU) and cisplatin for locally advanced resectable esophageal cancer

Background

Neoadjuvant concurrent chemoradiotherapy (CCRT) has become the standard treatment for esophageal cancer (EC) in North America. The cisplatin/5-flurouracil (5-FU) combination has been the most commonly used regimen. For the last 15 years we incorporated a daily continuous infusion of 5-FU and 2 doses of cisplatin into our neoadjuvant CCRT for potentially resectable EC.

Patients and methods

Between July 1997 and June 2012, 129 patients with locally advanced EC (T3 or N1 and higher), received neoadjuvant CCRT with cisplatin 75 mg/m² on day 1 and day 29 and continuous infusion of 5-FU (225 mg/m²/day) on the days of radiation.

Results

The median age of patients was 63 years, 85% had adenocarcinoma, 29, 74 and 26 patients had stage II, III and IVa disease respectively, 110 patients had N1 disease based on the American Joint Committee on Cancer (AJCC) 6^th edition, 118 patients experienced weight loss during treatment. All patients completed treatment. Treatment was well tolerated with 14% of patients having ≥ grade 3 toxicity and 18 patients requiring hospital admission. Sixty-four percent of patients had surgical resection following CCRT, with disease progression and patient refusal being the most common reasons for not proceeding with surgery. An R0 resection was achieved in 96% of patients. A pathological complete response (pCR) was achieved in 45% of patients. With a median follow up of 26 months (1.2-144 months), 48/129 patients recurred and 60/129 died of their disease.

Conclusions

Our study has its limitation, however, and compared to the conventional chemotherapy regimens containing the cisplatin/5-FU doublet, our treatment strategy for locally advanced EC CCRT seems to be feasible and well tolerated.