Intravenous Infusion Of Irinotecan Research Articles

Phase 2 randomized, active-controlled, multicenter trial to assess the safety and efficacy of RRx-001 + irinotecan vs. regorafenib + irinotecan in third/fourth-line colorectal cancer.

97 Background: RRx-001 is a novel cysteine-targeted alkylating agent that, upon binding, under severe hypoxia, which is primarily present in tumors, releases nitric oxide (NO) and other cytotoxic metabolites. The primary biological activities of this hybrid molecule include macrophage repolarization, CD47 downregulation, and vascular normalization. The purpose of this clinical trial (ROCKET) (NCT02096354) was to compare the safety and efficacy of the combination therapy RRx-001 + irinotecan vs. regorafenib + irinotecan in 3rd/4th line colorectal cancer that previously received treatment with irinotecan. Methods: A total of 34 patients were randomized (24 to RRx-001 + irinotecan (RxI) and 10 to regorafenib + irinotecan (RegI)) and were the basis for the intention-to-treat analysis (ITT, comprising all 34 patients). RRx-001 treatment was administered as an up-to-2-month induction therapy or “primer” followed by irinotecan for patients randomized to the RRx-001 arm (24). The efficacy and safety data are presented for the 34 patients in the ITT efficacy analysis. Therapy consisted of intravenous administration of RRx-001 at 4 mg once weekly for up to 2 months followed by intravenous infusion of irinotecan at 180 mg/m2 on day 1 in a 21-day cycle vs. 160 mg oral regorafenib daily for 3/4 weeks followed at progression, if applicable, by irinotecan 180 mg/m2 on day 1 in a 21-day cycle. Results: Median patient follow-up was approximately 14.5 months (SD 4.5 months). Median overall survival was 8.6 months for RxI and 4.7 months for RegI. Median progression free survival was 6.1 months for RxI vs. 1.7 months for RegI (a statistically significant result, two-sided log-rank test, p = 0.0030). Overall response rate was 20.8% for RxI vs. 0% for RegI. Moreover, the toxicity profile of RxI was substantially improved compared with RegI. Conclusions: The results of this trial demonstrate improved efficacy of RxI compared with RegI in patients with metastatic colorectal cancer after previous treatment with irinotecan, and late-stage clinical development in this indication is planned on the strength of the observed “signal” accompanied by a sufficient safety profile. Clinical trial information: NCT02096354 .

ROCKET: Phase II Randomized, Active-controlled, Multicenter Trial to Assess the Safety and Efficacy of RRx-001 + Irinotecan vs. Single-agent Regorafenib in Third/Fourth Line Colorectal Cancer

IntroductionRRx-001 is a novel cysteine-targeted alkylating agent that releases nitric oxide (NO). The primary biological activities of this hybrid molecule include macrophage repolarizing and vascular normalization. The purpose of this clinical trial (ROCKET) (NCT02096354) was to compare the safety and efficacy of the combination therapy RRx-001 + irinotecan vs. regorafenib in third/fourth line colorectal cancer that previously received treatment with irinotecan. Patients and MethodsA total of 34 patients were randomized (24 to RRx-001 + irinotecan (RxI) and 10 to single-agent regorafenib (RegI)) and were the basis for the intention-to-treat analysis (ITT, comprising all 34 patients). RRx-001 treatment was administered as an up-to-2-month “primer” followed by irinotecan for patients randomized to the RRx-001 arm (24). The efficacy and safety data are presented for the 34 patients in the (ITT) efficacy analysis. Therapy consisted of intravenous administration of RRx-001 at 4 mg once weekly for up to 2 months, at which point RRx-001 was discontinued, followed by intravenous infusion of irinotecan at 180 mg/m2 on day 1 in a 21-day cycle vs. 160 mg oral regorafenib daily for 3/4 weeks followed at progression, if applicable, by irinotecan 180 mg/m2 on day 1 in a 21-day cycle. There were 3 patients (3/24 = 12.5%) with prior single agent irinotecan on the RRx-001 randomized arm and 2 (2/10 = 20%) on the regorafenib randomized arm. Numerous patients had irinotecan combination therapies prior to randomized treatment. There were 15 patients on RRx-001 arm that received irinotecan post-RRx-001 in the randomized trial. There were 5 PRs on RRx-001 plus irinotecan leading to an overall response of 20.8% (5/24). There were 37.5% (9/24) of RRx-001 randomized patients with KRAS mutant type while 60% (6/10) regorafenib randomized patients were of KRAS type mutant. There were only 4 patients with available QOL and Edmonton Symptom Assessment System, an insufficient sample size to allow for any meaningful analysis. ResultsMedian patient follow-up was approximately 14.5 months (SD 4.5 months). Median overall survival was 8.6 months for RxI and 4.7 months for RegI. Median progression free survival was 6.1 months for RxI vs. 1.7 months for RegI (a statistically significant result, 2-sided log-rank test, P = .0030). The toxicity profile of RxI was substantially improved compared with RegI. ConclusionThe results of this trial demonstrate improved efficacy of RxI compared with RegI in patients with metastatic colorectal cancer after previous treatment with irinotecan, and late-stage clinical development in this indication is planned on the strength of the observed “signal” accompanied by a sufficient safety profile.

An open-label, multicenter, randomized controlled study of mXELIRI versus FOLFIRI in combination with bevacizumab as the first-line treatment in metastatic colorectal cancer: A single-center report.

52 Background: The first-line treatments in metastatic colorectal cancer were FOLFOX, CAPOX, FOLFIRI and even FOLFOXIRI as basic chemotherapy regimen combined with targeted therapy. XELIRI regimen was not recommended because of the concerns about the toxicity, efficacy and controversy in optimal dosage. An increasing number of studies indicated promising efficacy with manageable safety profile of dosage and administration-adjusted XELIRI regimen. Therefore, the present study investigated the efficacy, safety and appropriate dosage of mXELIRI regimen in the first-line treatment of advanced colorectal cancer. Methods: The EXIST study was a multicenter, randomized controlled, non-inferiority study and we performed stratification based on the tumor location (left or right side). In the mXELIRI+Bev group, patients received intravenous infusion of irinotecan (a reduced dosage,150mg/m2) with bevacizumab (5mg/kg) on day 1 and oral administration of capecitabine (2000mg/m2/day) tablet on day 1-10/Q14 days. Patients in FOLFIRI+Bev group received intravenous infusion of irinotecan (180mg/m2), calcium folinate (400mg/m2) and 5-Fu (400mg/m2) bolus with bevacizumab (5mg/kg) on day 1 followed by a 46-hour continuous infusion of 5-Fu (2400mg/m2)/Q14 days. The primary endpoint was progression-free survival rate at 12 month(PFSR12m) and the secondary endpoints included ORR,OS and safety. Results: 142 patients were enrolled and randomly assigned to receive mXELIRI+Bev (n=76) or FOLIRI+Bev (n=66) in our center between May 2018 and April 2021. Baseline characteristics were well balanced between two groups. In the mXELIRI+Bev group, 70 patients were evaluable with an ORR of 60.0% (1 complete response, CR; 41 partial response, PR; 24 stable disease, SD; 4 progression disease PD). While 57 patients were evaluable in the FOLFIRI+Bev group, with an ORR of 63.2% (36 PR; 15 SD; 6 PD). The PFSR12m for two groups were 32.3% and 21.3%, the median PFS were 9.72 months and 8.77 months, respectively. For safety profiles, no statistical differences were observed in adverse events, such as nausea, vomiting, diarrhea, bone marrow suppression and abnormal liver function. While 10 serious adverse events were recorded in the mXELIRI+Bev group, including intestinal obstruction occurred in 8 patients, intestinal perforation occurred in 1 patients and venous thrombosis occurred in 1 patient. In the FOLIRI+Bev group, intestinal obstruction, venous thrombosis and pulmonary thrombosis was reported in one patient respectively. Conclusions: The modified biweekly XELIRI plus bevacizumab regimen demonstrated promising effect and could be well tolerated based on the data from a single center. Clinical trial information: NCT04247984.

Effect of capecitabine combined with irinotecan on the safety of colon cancer treatment, patients’ adverse reactions and quality of life

Purpose: To study the impact of the combination of capecitabine and irinotecan on the safety of colon cancer treatment, adverse reactions and wellbeing of patients.Methods: Colon cancer subjects (n =120) admitted to Guangzhou First People’s Hospital, Guangzhou, China were assigned equally to two groups (A and B) according to their order of admission, and they received intravenous infusion of irinotecan. In addition, group A patients were administered capecitabine, but those in B group were given tegafur, gimeracil and oteracil porassium. The patients in groups A and B were compared with respect to the incidence of unwanted effects, quality of life (QoL), and overall clinical efficacy of the treatments.Results: Cases of nausea and vomiting, delayed diarrhea and sensory neuropathy of the patients were significantly reduced in group A, relative to group B. Moreover, QoL score after treatment was markedly higher in group A than in group B, while the objective response rate (ORR) of colon cancer patients in group A was also significantly higher than that in group B (p < 0.05). However, no obvious difference in disease control rate (DCR) was observed between groups A and B (p > 0.05).Conclusion: Combined capecitabine and irinotecan therapy effectively improves clinical prognosis, reduces the incidence of adverse reactions, and is safe in colon cancer patients. Therefore, the combined treatment may be beneficial in the management of colon cancer.

Correlation between nUGT1A1 gene polymorphisms and adverse events of irinotecan plus S-1 for patients with recurrent or metastatic esophageal squamous cell carcinoma: a prospective, open-label, randomized controlled trial (ESWN 01)

Objective: To investigate the correlation between UGT1A1 polymorphisms and the irinotecan plus S-1 regimen-induced toxicities in Chinese advanced esophageal squamous cell carcinoma (ESCC) patients. Methods: A total of 46 recurrent or metastatic ESCC patients selected from ESWN 01 trial were randomly assigned to irinotecan plus S-1 group [intravenous infusion of irinotecan (160 mg/m(2)) on day 1 and oral S-1 (80-120 mg) on days 1-10, repeated every 14 days]. Peripheral venous blood at baseline was collected and genomic DNA was extracted. The genetic polymorphisms of UGT1A1*6 and UGT1A1*28 were analyzed by polymerase chain reaction (PCR) amplification. Irinotecan plus S-1 regimen-induced toxicities of patients with different UGT1A1 polymorphisms were observed. The correlation between UGT1A1 polymorphisms and the adverse effects was analyzed. Results: Among the 46 patients, the numbers of UGT1A1*6 wild type genotype (GG), mutant heterozygote (GA) and mutant homozygote (AA) were 30, 15 and 1, while those with UGT1A1*28 wild type genotype (TA6/6), mutant heterozygote (TA6/7) and mutant homozygote (TA7/7) were 36, 8 and 2, respectively. Only one patient with UGT1A1*6 AA genotype occurred grade 3 diarrhea, while one of the 2 patients with UGT1A1*28 TA7/7 genotype occurred grade 4 diarrhea. No neutropenia was observed in the patient with UGT1A1*6 AA genotype, however, both of the two patients with UGT1A1*28 TA7/7 genotype occurred grade 3-4 neutropenia. Patients with UGT1A1*28 genetic polymorphism (TA 6/7 or TA7/7) had a higher response rate compared with wild-type TA6/6 carriers. (55.6% versus 26.5%). Conclusions: The homozygous genotype of UGT1A1*6 AA and UGT1A1*28 TA7/7 are rare (<5%) in Chinese ESCC population. Not all homozygous AA and TA7/7 carriers occur severe dose limited toxicities (DLT) when treated with irinotecan (160 mg/m(2)) plus S-1 regimen for 2 weeks. However, it's still necessary torigorously observe the occurrence of severe diarrhea and neutropenia in patients with UGT1A1*6 AA and UGT1A1*28 TA7/7 and adjust the dose timely.

P-81 HGCSG1901: A retrospective cohort study evaluating the safety and efficacy of S-1 and irinotecan plus bevacizumab in patients with metastatic colorectal cancer: Analysis of second-line treatment

The FIRIS trial, which is a phase III trial, showed non-inferiority of S-1 and irinotecan (IRIS) to FOLFIRI as second-line treatment for metastatic colorectal cancer (mCRC) patients. In addition, the ML18147 study showed the survival benefit of bevacizumab (Bev) combination treatment after progression to first-line treatment with Bev. Based on these results, IRIS/Bev is recommended as second-line treatment for mCRC patients in the Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines. However, there are few studies exploring the efficacy and safety of IRIS/Bev for the second-line setting in real-world practice. Therefore, we performed this retrospective analysis in order to investigate the real-world efficacy and safety of IRIS/Bev as second-line treatment in patients with mCRC (HGCSG1901). We retrospectively analyzed the clinical data of 284 patients who received IRIS/Bev as second-line treatment from August 2011 to March 2018 in 24 centers. IRIS/Bev regimen consisted of bevacizumab (5 mg/kg) given as an intravenous infusion, followed by an intravenous infusion of irinotecan (100 mg/m2) on day 1 and day 15 of each 4-week cycle. S-1 (40-60 mg) was taken orally twice daily, from the night on day 1 to the morning on day 15, followed by a 14-day rest. In this study, CTCAE ver.4.01 and RECIST criteria ver.1.1 were used for analysis of adverse events (AEs) and response rate (RR)/disease control rate (DCR). The time to treatment failure (TTF), progression-free survival (PFS), and overall survival (OS) were estimated with the Kaplan-Meier method. Patient characteristics were as follows; male/female 159/125, median age 65 (range 30-82), ECOG PS (0/1/2) 188/91/5, location of the primary site right/left 100/184, KRAS status wild/mutant/unknown 130/145/9, UGT1A1 status wild/single heterozygous/double heterozygous or homozygous/unknown 99/65/5/9/106. Median relative dose intensity of irinotecan, S-1 and bevacizumab were 0.752 (range 0.055-1.120), 0.799 (range 0.010-1.120), and 0.835 (range 0.021-1.120), respectively. The common AEs (≥5%) of grade 3 or 4 were decreased neutrophil count (23.5%), decreased white blood cells (16.6%), diarrhea (16.5%), anemia (12.0%), anorexia (9.5%), hypertension (9.2%), fatigue (6.0%), and febrile neutropenia (5.3%). RR and DCR were 14.7% and 76.6%, respectively. Median TTF was 5.9 months (95%C.I. 5.0-6.7). The common reason for treatment discontinuation were disease progression (72.4%) and AEs (16.0%). Subsequent treatment was given to 209 (76.0%) of the 275 patients who discontinued IRIS/Bev. Median PFS and OS were 7.2 (95%C.I. 6.3-8.0) and 16.3 months (95%C.I. 14.4-18.3), respectively. In this retrospective analysis, IRIS/Bev in real-world clinical practice showed efficacy comparable to other standard second-line treatments for mCRC. In this study, the incidence of diarrhea (≥ Grade 3) was 16.5%, which was lower than the incidence of diarrhea (≥ Grade 3) with IRIS (20.5%) in the FIRIS study. Diarrhea of IRIS/Bev as second-line treatment for mCRC was manageable with appropriate dose reduction and interruption.

Phase II expansion cohort in colorectal cancer to evaluate the safety and tolerability of RRx-001 blood mix.

e16144 Background: In a 34 patient randomized Phase 2 trial in 3rd/4th line colorectal cancer called ROCKET (NCT02096354) of RRx-001 + irinotecan versus regorafenib + irinotecan, RRx-001 + irinotecan demonstrated improved overall survival (OS) (8.6 vs 4.7 months) and progression free survival 2 (PFS2) (7.5 vs. 1.7 months) compared to the regorafenib control arm. The main adverse event attributed to RRx-001 treatment, which involved once weekly peripheral or central infusion, was a painful infusion-related superficial phlebitis in 80% of patients. Following the randomized portion of the ROCKET trial, another 18 colorectal patients were enrolled in an expansion cohort to evaluate the safety and tolerability of an RRx-001 “blood mix”, the objective of which was mitigation of the phlebitic complications of direct RRx-001 infusion. Methods: Therapy consisted of intravenous administration of RRx-001 at 4 mg once weekly via blood mix until progression followed by intravenous infusion of irinotecan at 180 mg/m2 on day 1 in a 21-day cycle. Results: The median OS and PFS2 were 6.3 and 5.2 months, respectively, which was similar to that of RRx-001 administered by direct infusion in the randomized part of the trial. No patients experienced phlebitis. The adverse event profile was otherwise unchanged compared with direct IV infusion of RRx-001. Conclusions: The results of this expansion cohort demonstrate similar activity of RRx-001 given by blood mix followed by irinotecan to RRx-001 given by direct IV infusion followed by irinotecan.RRx-001 alleviated the pain that had been observed in the direct IV infusion and therefore allowed for a shorter infusion time without any apparent compromise in activity (based on OS/PFS2 comparability to earlier results). Finally, since phlebitis in theory may progress to deep venous thrombosis or suppurative thrombophlebitis in hypercoagulable and immunosuppressed cancer patients, blood mix RRx-001 is the preferred method of infusion. Clinical trial information: NCT02096354 .

ROCKET: A randomized, multicenter phase 2 study of RRx-001 + irinotecan versus regorafenib in 3rd/4th line colorectal cancer.

3526 Background: The purpose of this study was to assess the efficacy of combination therapy with RRx-001, an aerospace-derived macrophage repolarizing agent with epigenetic and vascular normalization properties, plus irinotecan vs. regorafenib plus irinotecan in 3rd/4th line metastatic colorectal cancer that previously received treatment with irinotecan. Methods: Between June 2014 and August 2015, 34 patients were enrolled. Therapy consisted of intravenous administration of RRx-001 at 4 mg once weekly until progression followed by intravenous infusion of irinotecan at 180 mg/m2 on day 1 in a 21-day cycle vs. 160 mg oral regorafenib daily for 3/4 weeks followed at progression, if applicable, by irinotecan 180 mg/m2 on day 1 in a 21-day cycle. Results: The survival follow up for RRx-001 + irinotecan range was approximately 14.5 months (mean 6.0 months, median 5.0 months, standard deviation 4.5 months). The survival follow up for regorafenib range was approximately 10.8 months (mean 4.5 months, median 4.0 months, standard deviation 3.9 months). The median survival time was 8.6 months for RRx-001 + irinotecan and 4.7 months for regorafenib. The median progression free survival was 7.5 months for RRx-001 + irinotecan vs. 1.7 months for regorafenib. In addition, the toxicity profile of RRx-001 + irinotecan was dramatically improved compared with regorafenib. The regorafenib arm was terminated for futility at interim analysis, after which any enrolled patients only received RRx-001 co-infused with an aliquot of autologous blood to evaluate the safety of that method of administration. Conclusions: The results of this trial demonstrate improved efficacy and efficacy of RRx-001 + irinotecan compared with regorafenib in patients with metastatic colorectal cancer. Clinical trial information: NCT02096354.

Irinotecan plus S-1 versus S-1 in patients with previously treated recurrent or metastatic esophageal cancer (ESWN 01): a prospective randomized, multicenter, open-labeled phase 3 trial

BackgroundThe benefit of systemic treatments in esophageal squamous cell carcinoma (ESCC) which has progressed after chemotherapy is still uncertain and optimal regimens based on randomized trials have not yet been established. We aimed to compare the efficacy of irinotecan plus S-1 with S-1 monotherapy in recurrent or metastatic ESCC patients who had resistance to platinum- or taxane-based chemotherapy.MethodsWe conducted a prospective randomized, multicenter, open-label, phase 3 trial in 15 centers across China. Eligible patients were adults with histologically confirmed recurrent or metastatic ESCC, and were randomly assigned (ratio, 1:1) to receive either irinotecan plus S-1 (intravenous infusion of irinotecan [160 mg/m2] on day 1 and oral S-1 [80–120 mg] on days 1–10, repeated every 14 days) or oral S-1 monotherapy (80–120 mg/day on days 1–14, repeated every 21 days) using a central computerized minimization procedure. The primary endpoint was progression-free survival (PFS).ResultsBetween December 23, 2014 and July 25, 2016, we screened 148 patients and randomly assigned 123 patients to receive either irinotecan plus S-1 regimen (n = 61) or S-1 monotherapy (n = 62). After a median follow-up of 29.2 months (95% confidence interval [CI] 17.5–40.9 months), the median PFS was significantly longer in the irinotecan plus S-1 group than in the S-1 monotherapy group (3.8 months [95% CI 2.9–4.3 months] vs. 1.7 months [95% CI 1.4–2.7 months], hazard ratio = 0.58, 95% CI 0.38–0.86, P = 0.006). The objective response rates were 24.6% in the irinotecan plus S-1 group and 9.7% in the S-1 monotherapy group (P = 0.002). The patients in the irinotecan plus S-1 group presented with increased rates of grade 3–4 leukopenia (16.4% vs. 0%), neutropenia (14.8% vs. 1.6%), and nausea (4.9% vs. 0%). No significant difference in grade 3–4 diarrhea and no treatment-related deaths were observed in both groups.ConclusionsThe combination of irinotecan with S-1 was similarly tolerable but significantly prolonged PFS compared to S-1 monotherapy as a second- or third-line treatment in patients with recurrent or metastatic ESCC.Clinical Trial Registration NCT02319187. Registered on December 9, 2014

A phase II trial of trastuzumab combined with irinotecan in patients with advanced HER2-positive chemo-refractory gastric cancer: OGSG1203 (HERBIS-5).

128 Background: Irinotecan is a key drug in second- or further-line chemotherapy for patients with advanced gastric cancer. Continuous administration of trastuzumab beyond first progression is expected to contribute to the benefit of chemotherapy for HER2-positive gastric cancer. We assessed the efficacy and safety of combination chemotherapy with trastuzumab and irinotecan in Japanese patients with advanced HER2-positive chemo-refractory gastric cancer. Methods: Intravenous infusion of irinotecan every 2 weeks at a dose of 150 mg/m2; intravenous infusion of trastuzumab at a dose of 8 mg/kg on day 1 of the first cycle, followed by 6 mg/kg every 3 weeks. Administration of irinotecan and trastuzumab were repeated in independent schedules. The primary endpoint was disease control rate. The secondary endpoints were adverse events, response rate, time-to-treatment failure, progression-free survival, overall survival, and response rate stratified by prior trastuzumab use. This study was conducted by the Osaka Gastrointestinal Cancer Chemotherapy Study Group (OGSG). Results: From October 2012 to Augst 2014, 30 patients were enrolled and one patient withdrew before study treatment. Accordingly, 29 patients were assessable for efficacy and safety. The disease control rate was 65.5% [95% C.I. 45.7 - 82.1%], and the response rate was 20.7% [95% C.I. 8.0 - 39.7%]. The median progression free survival and the median overall survival were 3.7 and 7.5 months, respectively. The major grade 3/4 toxic effects were neutropenia (24%); anemia (24%); leucopenia (21%); anorexia (11%); fatigue (14%); hypoalbuminemia (24%); and hypokalemia (14%). One death (NOS) was considered to be related to the study. Conclusions: The results of combination Trastuzumab with irinotecan showed feasible and promising efficacy against advanced HER2-positive chemo-refractory gastric cancer. These findings indicated that trastuzumab continuation use might be beneficial. Clinical trial information: 000008626.

Phase II study of FOLFIRI regimen in patients with advanced colorectal cancer refractory to fluoropyrimidine and oxaliplatin

To evaluate the efficacy and safety of FOLFIRI regimen in patients with advanced colorectal cancer refractory to fluoropyrimidine and oxaliplatin. The FOLFIRI regimen consisted of intravenous infusion of irinotecan 180 mg/m(2) on day 1 plus leucovorin (LV) 400 mg/m(2) on day 1 plus 5-fluorouracil (5-FU) 400 mg/m(2) bolus on day 1 plus 46-hour intravenous infusion of 5-FU 2,400 mg/m(2), every 2 weeks as one cycle. The main selection criterion for this study was the advanced colorectal cancer refractory to fluoropyrimidine and oxaliplatin. Of the 57 evaluable patients for efficacy, 4 (7.5%) had a partial response, 36 (67.9%) had stable disease, and 13 (24.5%) had progressive disease. Median progression-free survival was 4.8 months (95% CI 3.9-5.7 months), and median overall survival was 7.8 months (95% CI 13.1-16.5 months). Safety analysis was based on the data of 57 evaluable patients. The most frequently observed grade 3 or 4 toxicities were neutropenia 16 (27.8%), nausea/vomiting 7 (12.3%), and diarrhea 1 (1.8%). FOLFIRI regimen is effective and well tolerated in patients with advanced colorectal cancer refractory to fluoropyrimidine and oxaliplatin in Chinese population.

A phase II study of irinotecan, high-dose 24-h continuous intravenous infusion of floxuridine and leucovorin (IFLUX) for advanced, previously untreated colorectal cancer

Our objectives were to determine response rate, time to progression, overall survival and tolerability of novel combination chemotherapy, consisting of irinotecan, high-dose 24-h continuous intravenous infusion of floxuridine and leucovorin in advanced previously untreated colorectal cancer. Thirty-eight patients with advanced colorectal cancer were treated at Sylvester Comprehensive Cancer Center, University of Miami, from 2000 to 2004, and received weekly intravenous infusion of irinotecan at 110 mg/m with a combination of 120 mg/kg floxuridine and 500 mg/m leucovorin administered as a 24-h continuous intravenous infusion. The treatment cycle consisted of 4 weeks of consecutive therapy followed by 2 weeks of rest. Five (13%) patients achieved complete response, 10 (26%) patients achieved partial response, 17 (45%) patients attained stable disease and six (16%) patients progressed. The overall response rate was 39% in this study. This chemotherapy regiment was well tolerated; the most common grade 3 toxicities were neutropenia (16%), anemia (16%), vomiting (24%), diarrhea (16%), and hand-and-foot syndrome (26%). The median time to progression was 11.5 months (347.5 days) with 95% confidence intervals of 6.8-12.9 months (206-389 days). The time to progression ranged from 1.8 to 34 months. The median survival of the patients in this trial was 31.28 months (952 days) with a confidence interval of 20.9-38.0 months (629-1141 days). Intravenous infusion of floxuridine and leucovorin is beneficial as first-line therapy in advanced colorectal cancer, demonstrating a prolonged time to progression and overall survival with acceptable tolerability and manageable toxicity profile.

Phase II study of irinotecan plus doxorubicin for early recurrent or platinum-refractory ovarian cancer: interim analysis

The aim of this study was to evaluate the efficacy and toxicity of irinotecan and doxorubicin in the treatment of patients with early recurrent or platinum-refractory ovarian cancer. Nineteen woman from five different institutions were treated. Two patients had platinum-refractory cancer, 11 had platinum-resistant disease, and 6 had platinum-sensitive tumors. An intravenous infusion of Irinotecan (50 mg/m(2)) was given on days 1, 8, and 15, while doxorubicin (40 mg/m(2)) was administered as an intravenous bolus on day 3. This treatment schedule was repeated every 4 weeks. Among the 13 patients defined as having platinum-refractory/platinum-resistant disease, 4 patients achieved a clinical response (30.8%, 95% CI: 9.1-61.4), while only one of 6 patients defined as having platinum-sensitive disease achieved a clinical response (16.7%, 95% CI: 0.4-64.1). Leukopenia and neutropenia were the major dose-limiting toxicities. Grade 3 or 4 leukopenia and neutropenia were noted in 24 (48%) and 33 (66%) of the courses, while febrile neutropenia occurred in 2 courses. Five patients (26%) had grade 2 or worse diarrhea during 7 courses. Our data demonstrated that this regimen might be comparable to standard approved agents in patients with early recurrent or platinum refractory ovarian cancer.

Gene expression profiles of colorectal carcinoma in response to neo-adjuvant chemotherapy

The combination of irinotecan and a fluoropyrimidine has been widely accepted as a treatment for advanced colorectal carcinoma. However, there have been no evaluable data on the feasibility of these combinations. To assess the significance of such combinations, we attempted to identify gene expression patterns in response to irinotecan and two different types of fluoropyrimidines. In 12 patients dispositioned to receive preoperative chemotherapy for colorectal carcinoma, pre-therapy tumor biopsies and final resected specimens were available for analysis. Patients were randomly assigned to receive one of the following four regimens: (I), oral doxifluridine; (II), intravenous infusion of 5-FU; (III), intravenous infusion of irinotecan; (IV), combination of doxifluridine and irinotecan (I+III). To identify genes whose expressions changed, we analyzed the gene expression profiles prior to and after these therapies using an oligonucleotide microarray consisting of 12,000 genes. Next, we focused on the genes that demonstrated similar kinetics of altered expression in all patients in each of the regimens. We identified two proto-oncogenes, nuclear receptor of T-cells (NOT) and c-fos, that were up-regulated in doxifluridine- and irinotecan-related regimens but unchanged in the 5-FU-related regimen. Moreover, group IV tumors showed the highest apoptotic rate and lowest proliferation activity following the combined chemotherapy. These results suggest that doxifluridine has a synergistic impact on the therapeutic effect of irinotecan by up-regulating proto-oncogenes such as NOT and c-fos, and thus justify the use of one of the irinotecan and fluoropyrimidine combinations.