Use of the folinic acid/5-fluorouracil/irinotecan (FOLFIRI 1) regimen in elderly patients as a first-line treatment for metastatic colorectal cancer: a Phase II study

Background  The aim of this study was to evaluate the effects of a combination of folinic acid, 5-fluorouracil (5FU) and irinotecan (FOLFIRI 1) administered every 2 weeks in a population of elderly subjects with advanced colorectal cancer. Patients and methods  Patients with metastatic colorectal cancer included in this study were aged at least 70 years, with a performance status of 0/1, without geriatric syndrome and without previous palliative chemotherapy. They received irinotecan [180 mg/m² intravenous (iv) infusion over 90 min] followed by folinic acid (400 mg/m² iv over 2 h), then 5FU (400 mg/m² iv bolus) and 5FU (2,400 mg/m² continuous iv infusion for 46 h) every 2 weeks. Results  Forty eligible patients were included. The median age was 77.3 years (range 70–84.7). The objective response rate was 40% and the stabilisation rate was 45%. Median progression-free survival was 8 months, overall survival was 17.2 months and cancer-related specific survival was 20.2 months. In total, 300 cycles of chemotherapy were administered with a median number of eight cycles per patient (range 1–18). Tolerance was good; grade 3/4 toxicities included diarrhoea (15%), asthenia (15%), nausea/vomiting (7.5%) and neutropenia (7.5%). One toxic death was observed due to grade 4 diarrhoea. Conclusion  The FOLFIRI 1 regimen is a valid therapeutic option for elderly patients in good clinical condition. This study was partly sponsored by Pfizer, Paris, France.     

Combination chemotherapy of biweekly irinotecan (CPT-11) plus tegafur/uracil (UFT) and leucovorin (LV) for patients with metastatic colorectal cancer: phase I/II study in Japanese patients

Purpose  We aimed to evaluate the safety and efficacy of combination chemotherapy with biweekly irinotecan (CPT-11) plus oral tegafur/uracil (UFT) and leucovorin (LV) in patients with previously untreated metastatic colorectal adenocarcinoma in phase I/II setting. Patients and methods  We recruited 37 patients with histologically proven metastatic colorectal adenocarcinoma. UFT (300 mg/m² per day) and LV (75 mg/day) were administered orally on days 1–21. CPT-11 was administered intravenously on day 1 and 15, at an initial dose of 60 mg/m², stepping up to 150 mg/m² in a traditional phase I fashion. The treatment was repeated every 4 weeks. After patients enrolled into a phase II portion, the efficacy and toxicity of this regimen were also assessed. Results  The recommended dose of CPT-11 was determined to be 150 mg/m². Although one patient had a pulmonary embolism after 60 mg/m² of CPT-11, the treatment was well tolerated in general. The overall objective response rate was 37.8% (14/37; 95% CI, 22.5–55.2) in all patients. Median progression-free survival was 226 days (95% CI, 133–276). Conclusions  Biweekly CPT-11 plus UFT and LV had a reasonable safety profile with manageable toxicity, and had a promising activity in patients with metastatic colorectal cancer. Further trials are indicated based on the promising results observed in this study.     

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.     

A phase I/II study of oral uracil/tegafur (UFT), leucovorin and irinotecan in patients with advanced colorectal cancer.

BACKGROUND: The aim of this study was to determine the maximum tolerated dose (MTD), toxicity profile and response rate of the oral 5-fluorouracil prodrug UFT (tegafur/uracil) and leucovorin (LV) in combination with irinotecan in patients with advanced or metastatic colorectal cancer. PATIENTS AND METHODS: Patients with histologically proven advanced or metastatic colorectal adenocarcinoma received first-line chemotherapy comprising UFT 250 mg/m(2)/day and LV 90 mg/day given on days 1 to 14, with escalating doses of irinotecan (200-300 mg/m(2)) administered intravenously on day 1 of a three-weekly cycle. Eligibility criteria were standard. The MTD was defined as the dose at which >33% of six patients experienced a dose-limiting toxicity (DLT) during cycle 1. RESULTS: A total of 32 patients were studied. Initially, six patients were treated at each of the irinotecan dose levels (200, 250 and 300 mg/m(2)) combined with UFT 250 mg/m(2)/day and LV 90 mg/day. DLTs consisting of grade 3 or 4 diarrhoea and febrile neutropenia were observed in one of 20 patients at 250 mg/m(2) and three of six patients at the 300 mg/m(2) irinotecan dose level. Having defined the MTD, the 250 mg/m(2) dose level was established as the recommended dose (RD) and expanded to 20 patients in whom treatment was generally well tolerated. The overall response rate was 19%, with five patients having a partial response (PR) and 18 stable disease (SD) out of 32 response-evaluable patients. CONCLUSION: UFT and LV can be safely combined with irinotecan. The RDs for future studies are UFT 250 mg/m(2)/day and LV 90 mg/day given on days 1-14, with irinotecan 250 mg/m(2) administered on day 1, every 3 weeks. This combination is well tolerated and active. Further investigation of UFT and LV in combination with irinotecan is warranted in patients with colorectal cancer.     

Phase III trial of irinotecan plus infusional 5-fluorouracil/folinic acid versus irinotecan plus oxaliplatin as first-line treatment of advanced colorectal cancer

Purpose

To determine whether irinotecan plus oxaliplatin (mIROX) is superior to irinotecan plus infusional 5-fluorouracil, leucovorin (FUFIRI) as first-line therapy of patients with metastatic colorectal cancer (mCRC).

Patients and methods

A phase III, randomised, open-label multicentre study compared standard treatment with FUFIRI (irinotecan 80 mg/m², 5-fluorouracil 2000 mg/m², folinic acid 500 mg/m² weekly times 6) to mIROX using an identical schedule of irinotecan plus oxaliplatin 85 mg/m² applied on days 1, 15 and 29 of a 7-week cycle. The primary end-point was progression-free survival (PFS).

Results

A total of 479 eligible patients were randomly assigned. Progression-free survival was 7.2 months in the mIROX arm and 8.2 months in the FUFIRI arm [hazard ratio = 1.14; 95% confidence interval (CI) 0.94-1.37; P = 0.178]. Comparable results were also obtained for overall survival time with 19 months in the mIROX-arm and 22 months in the FUFIRI-arm (hazard ratio = 1.08, P = 0.276). Both regimens induced an identical objective response rate (ORR) of 41%, but disease control rate (ORR plus stable disease) was significantly greater in the FUFIRI group (81% versus 68%, P = 0.001). Most frequent grades 1-4 side-effects of mIROX and FUFIRI treatment were nausea (80% versus 73%) and delayed diarrhoea (79% versus 68%). Grades 3-4 toxicities were generally below 10%, except for diarrhoea which was more frequent in the mIROX-arm compared to the FUFIRI-arm (19% versus 30%, P = 0.006)

Conclusion

mIROX failed to show superior activity compared to high-dose 5-FU/folinic acid plus irinotecan. Due to better tolerability the combination of high-dose 5-FU/folinic acid and irinotecan remains a standard of care in first-line treatment of metastatic colorectal cancer.     

Cetuximab and irinotecan as third-line therapy in advanced colorectal cancer patients: a single centre phase II trial

The epidermal growth factor receptor (EGFR), which participates in signalling pathways that are deregulated in cancer cells, is frequently mutated in colorectal-cancer cells. Cetuximab is a monoclonal antibody that specifically blocks the EGFR. We evaluated the efficacy of cetuximab in weekly combination with irinotecan in metastatic colorectal cancer patients refractory to previous treatments based on oxaliplatin or irinotecan. We included 55 heavily pretreated patients (colon/rectum: 34/11, M/F: 16/29, median age 63 years, range: 27-79) whose disease had progressed during or within an oxaliplatin-based first-line chemotherapy and a irinotecan-based second-line regimen. Patients were followed for tumour response and were also evaluated for the time to tumour progression, and safety of treatment. Cetuximab was given at an initial dose of 400 mg m(-2), followed by weekly infusions of 250 mg m(-2). Irinotecan was administered weekly at the dose of 90 mg m(-2). All patients were assessable for treatment efficacy and safety response rate was 25.4% (95% CI: 21.7-39.6%); 38.2% (95 CI: 18.6-39.8%) of patients showed a disease stability as the best response. As a consequence, the overall tumour control rate was 63.6% (95% CI: 46.4-70.6%). The median time to progression was 4.7 months (95% CI: 2.5-7.1 months) and the median survival time was 9.8 months (95% CI: 3.9-10.1 months). The most common G3-4 noncutaneous side toxicities were: diarrhoea (16.4%), fatigue (12.7%) and stomatitis (7.3%). 89.1% of patients developed skin toxicity and 32.6% of cases was of grade 3-4. No allergic reactions were identified at any courses in any patients. Fever was documented in 27.3% of patients and was most commonly recorded after the first administration. Cetuximab has clinically significant activity even in heavily pretreated colorectal cancer patients progressed after both oxaliplatin and irinotecan-based chemotherapy regimens.     

A phase II trial of weekly high dose continuous infusion 5-fluorouracil plus oral leucovorin in patients with advanced colorectal cancer

Background. In a previous Phase II trial, the authors showed that a weekly continuous infusion of 5-fluorouracil (5-FU) at a dose of 3.5 g/m² for 48 hours is an active treatment for advanced colorectal cancer. The overall response rate was 38.5%, and the median survival was 12 months. These data were comparable to those achieved by biochemical modulation of 5-FU with leucovorin. To study the modulation of this weekly, high dose, continuous infusion 5-FU with oral leucovorin, a new Phase II trial was planned. Methods. From December 1991 to July 1992, 43 previously untreated patients with measurable advanced colorectal cancer were included in a multicenter study. They received on an outpatient basis 5-FU at a weekly dose of 3 g/m² by continuous infusion for 48 hours until progression or toxicity. Oral leucovorin (60 mg every 6 hours) also was given during the infusion of 5-FU. Results. Patients received a median dose intensity of 5-FU of 2.2 g/m²/week (range, 0.76-3 g/m²/week). One complete response and 11 partial responses were observed. The overall response rate was 29% (95% confidence interval [CI], 16–45%). Median time to progression was 7 months, and the median survival was 15 months. World Health Organization Grades 3 and 4 diarrhea were observed in 19 (45%) and 6 (14%) patients, respectively. Grade 3 mucositis also was observed in 10 (24%) patients, and Grade 4 mucositis was observed in 1. Grade 3 nausea and vomiting were reported in seven (17%) patients. Grade 3 hand–foot syndrome was detected in only two (2.5%) patients. No leukopenia or thrombocytopenia was observed. Conclusions. Oral leucovorin modulation of a weekly 48-hour infusion of 5-FU at a dose of 3 g/m² of leucovorin is a toxic regimen, always requiring dose reduction, with diarrhea and mucositis as the main limiting toxicities. Its antitumor activity does not seem superior to that observed with a weekly 48-hour infusion of 5-FU alone at a dose of 3.5 g/m². Cancer 1995; 76:559–63.     

Randomised phase 2 trial of SIR-Spheres plus fluorouracil/leucovorin chemotherapy versus fluorouracil/leucovorin chemotherapy alone in advanced colorectal cancer

PURPOSE: Selective internal radiation therapy (SIRT) with SIR-Spheres(R) is a new technique for selectively targeting high doses of radiation to tumours within the liver. The primary objectives of this randomised trial were to compare the response rate, time to progressive disease (PD), and toxicity of a regimen of systemic fluorouracil/leucovorin chemotherapy versus the same chemotherapy plus a single administration of SIR-Spheres in patients with advanced colorectal liver metastases. The trial was designed to presage a larger trial that would have survival as the primary outcome. PATIENTS AND METHODS: Twenty-one patients with previously untreated advanced colorectal liver metastases, with or without extrahepatic metastases, were randomised into the study. RESULTS: Using RECIST criteria, the response rate for 11 patients receiving the combination treatment was significantly greater than for 10 patients receiving chemotherapy alone (First Integrated Response; 10 PR, 1 SD vs. 0 PR, 6 SD, 4 PD, P < 0.001 and Best Confirmed Response; 8 PR, 3 SD vs. 0 PR, 6 SD, 4 PD P < 0.001). The time to PD was greater for patients receiving the combination treatment (18.6 months vs. 3.6 months, P < 0.0005). Median survival was significantly longer for patients receiving the combination treatment (29.4 months vs. 12.8 months, P = 0.02). One patient in the combination arm died from chemotherapy induced neutropenic sepsis after the fourth chemotherapy cycle. There were more Grade 3 and 4 toxicity events in patients receiving the combination treatment. There was no difference in quality-of-life over a 3 month period between the two treatments when rated by patients (P = 0.96) or physicians (P = 0.98). CONCLUSIONS: This small phase 2 randomised trial demonstrated that the addition of a single administration of SIR-Spheres to a regimen of systemic fluorouracil/leucovorin chemotherapy significantly increased both treatment related response, time to PD, and survival with acceptable toxicity. The combination of SIR-Spheres plus systemic chemotherapy is now the subject of ongoing trials to further define patient benefit.     

A phase II trial of the epothilone B analog, BMS-247550, in patients with previously treated advanced colorectal cancer.

BACKGROUND: The epothilone B analog, BMS-247550, is a non-taxane microtubulin-stabilizing agent with preclinical activity in taxane-resistant cell lines and phase I activity in colorectal cancer. We conducted a phase II study of single-agent BMS-247550 in advanced colorectal cancer patients who had disease progression following treatment with irinotecan-5-fluorouracil-leucovorin (IFL). PATIENTS AND METHODS: Patients were required to have histologically or cytologically confirmed advanced or metastatic colorectal cancer; progressed on or after chemotherapy with IFL; Eastern Cooperative Oncology Group performance status < or =1; peripheral neuropathy grade < or =1; and adequate laboratory parameters. BMS-247550 40 mg/m(2) was administered intravenously over 3 h every 3 weeks. Patients were evaluated for response every 6 weeks. RESULTS: Twenty-five patients were enrolled; all were evaluable for toxicity and 23 were evaluable for response. There were no complete or partial responses. Thirteen patients (56%) had stable disease after two cycles of therapy; five patients (20%) received six or more cycles. The median time to progression was 11 weeks; median overall survival was 36 weeks. There was considerable grade 3/4 hematological toxicity, including neutropenia (48%) and leukopenia (36%). Grade 3/4 non-hematological toxicities included grade 3 hypersensitivity reaction (12%) and peripheral neuropathy (20%). CONCLUSIONS: Single-agent BMS-247550 (40 mg/m(2)) administered every 21 days demonstrated no activity in advanced colorectal cancer. Peripheral neuropathy was treatment-limiting.     

Oxaliplatin, irinotecan, and fluorouracil/folinic acid in advanced gastric cancer: a multicenter phase II trial of the Southern Italy Cooperative Oncology Group

Purpose  This phase II trial assessed the tolerability and efficacy of a triplet of oxaliplatin, irinotecan, and fluorouracil/folinic acid in advanced gastric cancer. Methods  Patients with unresectable or metastatic gastric cancer, unexposed to palliative chemotherapy, received oxaliplatin 85 mg/m² iv and irinotecan 150 mg/m² iv on day 1, 6S-folinic acid 250 mg/m² iv and fluorouracil 750 mg/m² iv on day 2, every 2 weeks. Response rate (RR) was assessed after a minimum of four cycles, and treatment continued up to 12 cycles. Results  Sixty-three patients were treated, with a median of eight (range 1–12) cycles/patient. Two complete and 19 partial responses were registered (RR 33% [95% CI, 22–46%]). Median progression-free survival was 7.5 (95% CI, 5.6–9.4) months, and median overall survival was 12.1 (95% CI, 10.8–13.4) months. Most common grade ≥3 toxicities were neutropenia (59%), febrile neutropenia (7%), vomiting (20%), and diarrhoea (10%). All-grade neurotoxicity affected 33% of patients. Conclusions  Oxaliplatin, irinotecan, and fluorouracil/folinic acid administered every 2 weeks are safe and active in advanced gastric cancer. SICOG trial 0405, EudraCT number 2006-0066869-16.     

Oxaliplatin plus high-dose folinic acid and 5-fluorouracil i.v. bolus (OXAFAFU) versus irinotecan plus high-dose folinic acid and 5-fluorouracil i.v. bolus (IRIFAFU) in patients with metastatic colorectal carcinoma: a Southern Italy Cooperative Oncology Group phase III trial.

PURPOSE: The primary end point of this phase III trial was to compare the response rate (RR) of oxaliplatin (OXA) plus levo-folinic acid (l-FA) and 5-fluorouracil (5-FU) bolus with that of irinotecan (IRI) plus l-FA and 5-FU bolus in advanced colorectal carcinoma. PATIENTS AND METHODS: Patients with measurable metastatic colorectal carcinoma were randomly allocated to receive: IRI 200 mg/m(2) on day 1, l-FA 250 mg/m(2) intravenously plus 5-FU 850 mg/m(2) on day 2 (IRIFAFU); or OXA 100 mg/m(2) on day 1, l-FA 250 mg/m(2) plus 5-FU 1050 mg/m(2) on day 2 [OXAFAFU high dose (hd)]. Cycles were given every 2 weeks. After a planned interim analysis, OXA was reduced to 85 mg/m(2) and 5-FU to 850 mg/m(2) [OXAFAFU low dose (ld)]. RESULTS: Two hundred and seventy-four patients (IRIFAFU, 135; OXAFAFUhd, 71; OXAFAFUld, 68) were treated. Forty-two confirmed responses were achieved with IRIFAFU, 29 with OXAFAFUhd and 32 with OXAFAFUld. The response rate with OXAFAFU [44%; 95% confidence interval (CI) 35% to 52%] was significantly higher (P=0.029) than that of IRIFAFU (31%; 95% CI 23% to 40%). Occurrence of grade > or =3 neutropenia with OXAFAFUld was similar to that for IRIFAFU (29% versus 31%), while severe diarrhoea was significantly lower (12% versus 24%). Median failure-free survival (7 versus 5.8 months; P=0.046) and overall survival of patients (18.9 versus 15.6 months; P=0.032) were significantly prolonged with OXAFAFU. CONCLUSIONS: OXAFAFU was more active and less toxic than IRIFAFU, and it should be preferred in the first-line treatment of advanced colorectal cancer patients.     

Randomised phase-II trial of CAPIRI (capecitabine, irinotecan) plus bevacizumab vs FOLFIRI (folinic acid, 5-fluorouracil, irinotecan) plus bevacizumab as first-line treatment of patients with unresectable/metastatic colorectal cancer (mCRC)

Background:

To compare the efficacy and safety of CAPIRI+bevacizumab (Bev) in comparison with FOLFIRI+Bev as first-line treatment for patients with metastatic colorectal cancer (mCRC).

Methods:

Patients were randomised to receive either FOLFIRI plus Bev 5 mg kg⁻¹ every 2 weeks (Arm-A) or CAPIRI plus Bev 7.5 mg kg⁻¹ every 3 weeks (Arm-B).

Results:

Three hundred thirty-three patients (Arm-A=167; Arm-B=166) were enrolled into the study. No difference was observed in median progression-free survival (PFS) (10.0 and 8.9 months; P=0.64), overall survival (25.7 and 27.5 months; P=0.55) or response rates (45.5 and 39.8.7% P=0.32) for FOLFIRI-Bev and CAPIRI-Bev, respectively. Patients treated with CAPIRI-Bev presented significantly higher incidence of diarrhoea (P=0.005), febrile neutropenia (P=0.003) and hand–foot skin reactions (P=0.02) compared with patients treated with FOLFIRI-Bev. Treatment delays (P=0.05), dose reduction (P<0.001) and treatment discontinuation owing to toxicity (P=0.01) occurred more frequently in the CAPIRI-Bev arm.

Conclusion:

The PFS of FOLFIRI-BEV is not superior to that observed with the CAPIRI-Bev regimen. CAPIRI-Bev has a less favourable toxicity profile, requiring dose reductions, in order to be considered as an option in first-line treatment of patients with mCRC.     

Safety of irinotecan and infusional fluorouracil/leucovorin (FOLFIRI) in Japan: a retrospective review of 48 patients with metastatic colorectal cancer

Background A combination of irinotecan and infusional fluorouracil/leucovorin (FOLFIRI) has become one of the global standard chemotherapy regimens for metastatic colorectal cancer. The aim of this study was to evaluate the feasibility of FOLFIRI in a Japanese population with metastatic colorectal cancer. Methods This retrospective analysis included 48 patients with unresectable metastatic colorectal cancer who received FOLFIRI between May 2004 and June 2005. Evaluation points included adverse events, dose intensity, response rate, progression-free survival, and overall survival. Results Thirty-eight (79%) patients received FOLFIRI as first-line chemotherapy. Eighteen patients received original full-dose FOLFIRI and 30 patients received reduced FOLFIRI with irinotecan at 150mg/m². Eighteen (38%) of the 48 patients experienced grade 3 or 4 neutropenia, 5 (10%) had grade 3 vomiting and 5 (10%) had grade 3 diarrhea. Toxicity was tolerable, with appropriate dose reduction if necessary. There were no treatment-related deaths or early deaths within the first 60 days of treatment. Median dose intensities (with relative dose intensities in parentheses) in all patients and in patients who received full-dose FOLFIRI were 129mg/m² per 2 weeks (71%) and 144mg/m² per 2 weeks (80%) for irinotecan and 2349mg/m² per 2 weeks (84%) and 2376mg/m² per 2 weeks (85%) for fluorouracil, respectively. The response rate in patients with measurable lesions was 37% (13/35; 95% confidence interval [CI], 21.1%–53.2%), and median progression-free survival was 8.4 months (95% CI, 6.4–10.3). Conclusion The dose intensity of irinotecan was relatively low, and toxicity was tolerable with appropriate dose reduction; efficacy was comparable to that previously reported. FOLFIRI is feasible and can be one of the standard treatment options for Japanese patients with metastatic colorectal cancer.     

Tritherapy with fluorouracil/leucovorin, irinotecan and oxaliplatin (FOLFIRINOX): a phase II study in colorectal cancer patients with non-resectable liver metastases

PURPOSE: To assess the rate of R(0) resection of liver metastases achieved after chemotherapy with FOLFIRINOX. PATIENTS AND METHODS: Patients with histologically proven primary colorectal cancer and bidimensionally measurable liver metastasis, not fully resectable based on technical inability to achieve R(0) resection, but potentially resectable after tumor reduction, were given FOLFIRINOX: oxaliplatin 85 mg/m(2), irinotecan 180 mg/m(2), leucovorin 400 mg/m(2), bolus fluorouracil 400 mg/m(2) and fluorouracil 46-h continuous IV infusion 2,400 mg/m(2), every 2 weeks for a maximum of 12 cycles. RESULTS: Thirty-four patients were enrolled. Response rate before surgery was 70.6% (95%CI: 52.5-84.9). Twenty-eight patients (82.4%) underwent hepatic resection and nine achieved R(0) resection [26.5% (95% CI: 12.9-44.4%)]. The rate of clinical complete remission after surgery was 79.4%. Two-year overall survival was 83%. The most frequent grade 3 or 4 toxicities were neutropenia (64.8%), diarrhea (29.4%), fatigue (23.5%), abdominal cramps (14.7%), neuropathy and nausea (11.8% each), and AST/ALT elevation (14.7/11.8%). Only one patient experienced febrile neutropenia, four patients withdrew due to toxicity and no toxic death was observed. CONCLUSION: FOLFIRINOX, with an acceptable toxicity profile, shows a high response rate in liver metastases from colorectal cancer. The rate of hepatic resection in patients initially not resectable, is attractive and warrants further assessment of this regimen in randomized studies compared to standard regimens.     

First-line treatment of metastatic colorectal cancer with irinotecan, oxaliplatin and 5-fluorouracil/leucovorin (FOLFOXIRI): results of a phase II study with a simplified biweekly schedule.

BACKGROUND: In a previous phase I-II study we demonstrated that the FOLFOXIRI regimen [irinotecan 125-175 mg/m2 day 1, oxaliplatin 100 mg/m2 day 1, l-leucovorin (l-LV) 200 mg/m2 day 1, 5-fluorouracil (5-FU) 3800 mg/m2 as a 48-h chronomodulated continuous infusion starting on day 1, repeated every 2 weeks] has promising activity and efficacy in metastatic colorectal cancer. However, this regimen required a chronomodulated infusion of 5-FU, and because neutropenia occurred in 32% of cycles, granulocyte colony-stimulating factor (G-CSF) was used and the delivered dose intensity was only approximately 78% of planned. Therefore, we conducted the present phase II study in order to develop a simplified FOLFOXIRI regimen that could be more easily administered in clinical practice as well as in multicenter settings. PATIENTS AND METHODS: A total of 32 patients with unresectable metastatic colorectal cancer received irinotecan 165 mg/m2 day 1, oxaliplatin 85 mg/m2 day 1, l-LV 200 mg/m2 day 1 and 5-FU 3200 mg/m2 as a 48-h continuous (not chronomodulated) infusion starting on day 1, repeated every 2 weeks. RESULTS: All 32 patients were evaluated for safety and the incidence of grade 3-4 toxic effects, and the use of G-CSF seemed to be lower than with the previous FOLFOXIRI regimen: grade 4 neutropenia (34%), grade 3 diarrhea (16%), grade 3 stomatitis (6%) and grade 2-3 peripheral neurotoxicity (37%) were reported, and G-CSF was used in 23% of cycles. Delivered dose intensity was 88% of that planned, and no toxic deaths occurred. The intention-to-treat analysis for activity showed four complete responses, 19 partial responses, seven stable disease and two progressive disease, for an overall response rate of 72% (95% confidence interval 53% to 86%). Eight (25%) patients with residual liver or lung metastases were radically resected after chemotherapy. After a median follow-up of 18.1 months, the median progression-free survival is 10.8 months and median survival is 28.4 months. CONCLUSIONS: This simplified FOLFOXIRI combination can be delivered easily in outpatient settings, with manageable toxic effects, and has very promising antitumor activity. While the safety profile seems to be improved in comparison with our previous FOLFOXIRI regimen, antitumor activity and efficacy appear to be maintained.     

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.     

Phase II study of UFT with leucovorin and irinotecan (TEGAFIRI): first-line therapy for metastatic colorectal cancer

This phase II trial was performed to evaluate the efficacy and tolerability of oral tegafur-uracil (UFT) with leucovorin (LV) combined with intravenous (i.v.) irinotecan every 3 weeks (TEGAFIRI) as first-line treatment for patients with metastatic colorectal cancer (mCRC). Patients received oral UFT 250 mg m(-2) day(-1) and LV 90 mg day(-1) in three divided daily doses for 14 days followed by a 1-week rest and i.v. irinotecan 250 mg m(-2) as a 90-min infusion every 3 weeks. Tumour responses, assessed every two cycles using RECIST criteria, were reviewed by an independent review committee. In 52 evaluable patients, the best overall response rate was 33% (95% confidence intervals (CI) 20-47%; 1 complete and 16 partial responses). The median time to progression was 5.4 months (95% CI 3.02-7.52 months) and median overall survival was 14.9 months (11.73-17.97 months). A total of 307 cycles were administered, with a median number of five cycles per patient (range: 1-10). The most common grade 3/4 toxicities were neutropenia (25% of patients), diarrhoea (22%), vomiting (11%) and anaemia (11%). The TEGAFIRI regimen is a feasible, well-tolerated and convenient treatment option for patients with non-resectable mCRC.     

Second-line chemotherapy with weekly oxaliplatin and high-dose 5-fluorouracil with folinic acid in metastatic colorectal carcinoma: A Hellenic Cooperative Oncology Group (HeCOG) phase II feasibility study

Backround:Oxaliplatin is a novel platinum derivative, which,combined with 5-fluorouracil (5-FU), and folinic acid (FA), demonstratessynergistic activity in metastatic colorectal cancer (MCC). The HeCOGperformed a multicenter phase II study of a weekly oxaliplatin administrationschedule in patients with previously treated MCC to evaluate the antitumorefficacy and toxicity of this combination. Patients and methods:Eligible patients included those whorelapsed after or during chemotherapy with 5-FU and FA and/or irinotecan.Prior radiotherapy was accepted provided that measurable disease was outsidethe radiation fields. Other eligibility criteria included written informedconsent, a WHO performance status 2 and adequate bone marrow, liver andrenal function. Treatment consisted of Oxaliplatin 50 mg/m² bytwo-hour intravenous (i.v.) infusion followed by FA 500 mg/m²(two-hour i.v. infusion) and 5-FU 2500 mg/m² (24-hour continuousi.v. infusion) on days 1, 8, 15, 22, 29, 36. The regimen was repeated every50 days. Results:Thirty-two patients (Median age 61 years, range25–76) entered the trial. The majority (75%) had progressed afterreceiving first-line chemotherapy.Diarrhea was the main non-hematologic toxicity. More than half of thepatients (53%) developed grades 3 or 4 diarrhea. Due to this sideeffect only 29% of cycles were given with at least 90% of theplanned dose of 5-FU. Hematologic toxicity included grade 3 neutropenia andthrombocytopenia (10% for each), and grade 4 thrombocytopenia(3%). Two patients (6%) died of sepsis, one related toneutropenia and one due to urinary tract sepsis. Sixteen patients (50%)developed grades 1 and 2 neurotoxicity in the form of sensory neuropathy,which was mild and transient. The objective response rate was 13%(95% CI: 3%–29%). All four responses were partial.Twelve patients (38%) had stable disease and 8 (25%) progressivedisease. The median time to progression was three months and the mediansurvival was nine months from the start of therapy. The Kaplan–Meierestimated probability of one-year survival for the group as a whole was32%. Conclusions:The weekly administration of oxaliplatin with 5-FUand FA was associated with considerably less neurotoxicity than otherschedules. However, the high percentage of diarrhea suggests that a dosereduction of 5-FU in this regimen may result in better therapeutic synergy.     

A randomized phase II trial of capecitabine and two different schedules of irinotecan in first-line treatment of metastatic colorectal cancer: efficacy, quality-of-life and toxicity.

BACKGROUND: To determine the efficacy, impact on quality-of-life (QoL) and tolerability of two different irinotecan administration schedules in combination with capecitabine as first-line treatment of metastatic colorectal cancer. PATIENTS AND METHODS: We carried out a randomized phase II trial to select one of the following treatment regimens for further investigation: weekly irinotecan at a dose of 70 mg/m(2) days 1, 8, 15, 22, 29 (arm A) or 3-weekly irinotecan at a dose of 300/240 mg/m(2) day 1 and days 22 (arm B) in combination with capecitabine 1000 mg/m(2) twice daily days 1-14 and days 22-35 every 6 weeks. RESULTS: Seventy-five patients with good performance status entered the trial. The two arms were well balanced for relevant patient and disease characteristics. The most frequent toxic effects were grade 3/4 diarrhea (arm A: 34%, B: 19%), grade 3/4 neutropenia (A: 5%, B: 19%) and grade 2/3 alopecia (A: 26%, B: 65%). Other grade 3/4 toxic effects were rare (<5%). Response rates were 34% [95% confidence interval (CI) 20% to 51%] in arm A and 35% (95% CI: 20% to 53%) in arm B. Median time to progression was 6.9 (4.6-10.1) and 9.2 (7.9-11.5) months and median overall survival was 17.4 (12.6-23.0+) and 24.7 (16.3-26.4+) months. Patients with an objective tumor response reported better physical well-being (P < 0.01), mood (P < 0.05), functional performance (P < 0.05) and less effort to cope (P < 0.05) compared with the non-responders and stable disease patients. CONCLUSIONS: The primary end point of this study was the objective response rate and based on the statistical design of the trial, the 3-weekly irinotecan schedule was selected over weekly irinotecan administration. The 3-weekly irinotecan schedule also seemed advantageous in terms of grade 3/4 diarrhea, time to progression, overall survival and patient convenience, but the study was not designed to detect differences in these parameters. In addition, tumor response was shown to have a beneficial effect on QoL indicators.     

A phase II trial of irinotecan (CPT-11) for unresectable biliary tree carcinoma

Background:Unresectable adenocarcinomas of the biliary tree have a very poor prognosis. No good chemotherapeutic regimen is available. Irinotecan has not yet been fully tested in this disease. We evaluated its activity in unresectable bile duct cancers. Patients and methods:Twenty-five consecutive eligible patients at our two institutions were treated with irinotecan at a starting dose of 125 mg/m². A cycle consisted of once-a-week treatments for four consecutive weeks, followed by two weeks of rest. All patients were required to have histologically confirmed diagnosis, clinically documented metastatic or unresectable carcinoma and measurable disease. Patients were evaluated for response, toxicity, and survival. Results:A total of 83 cycles of therapy were delivered. Two patients had a partial response (8%; 95% confidence interval (CI): 0%–18%) and ten additional patients had stable disease for at least two months (40%; 95% CI: 20.8%–59.2%). The therapy was well tolerated, with moderate myelosuppression and diarrhea as the main toxicities. The overall median survival was 10 months. Conclusions:Irinotecan has minimal activity in biliary tree carcinomas, but is well tolerated with appropriate supportive care, and produces occasional objective responses.