Fuchs CS, Moore MR, Harker G, Villa L, Rinaldi D, Hecht JRPhase III comparison of two irinotecan dosing regimens in second-line therapy of metastatic colorectal cancer. J Clin Oncol 21: 807-814

Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Journal of Clinical Oncology (Impact Factor: 18.43). 03/2003; 21(5):807-14. DOI: 10.1200/JCO.2003.08.058
Source: PubMed


Randomized trials in fluorouracil (FU)-refractory colorectal cancer demonstrate significant survival advantages for patients receiving irinotecan. We prospectively compared the efficacy and tolerability of two irinotecan regimens (once a week for 4 weeks followed by a 2-week rest period [weekly] v once every 3 weeks) in such patients.
This multicenter, open-label, phase III study randomly assigned patients in a 1:2 ratio to irinotecan given either weekly (125 mg/m(2)) or once every 3 weeks (350 mg/m(2), or 300 mg/m(2) in patients who were >/= 70 years of age, who had Eastern Cooperative Oncology Group performance status equal to 2, or who had prior pelvic irradiation).
With median follow-up of 15.8 months, there was no significant difference in 1-year survival (46% v 41%, respectively; P =.42), median survival (9.9 v 9.9 months, respectively; P =.43), or median time to progression (4.0 v 3.0 months, respectively; P =.54) between the two regimens. Grade 3/4 diarrhea occurred in 36% of patients treated weekly and in 19% of those treated once every 3 weeks (P =.002). Grade 3/4 neutropenia occurred in 29% of patients treated weekly and 34% of those treated once every 3 weeks (P =.35). Treatment-related mortality occurred in five patients (5.3%) receiving irinotecan weekly and three patients (1.6%) given therapy once every 3 weeks (P =.12). Global quality of life was not statistically different between treatment groups.
Irinotecan schedules of weekly and of once every 3 weeks demonstrated similar efficacy and quality of life in patients with FU-refractory, metastatic colorectal cancer. The regimen of once every 3 weeks was associated with a significantly lower incidence of severe diarrhea.

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    • "Second line irinotecan (CPT-11), in 5-fluorouracil (5-FU) refractory MCRC pts, achieved median PFS of 3–4 months and OS 9.9 months (12,13). Doublet FOLFOX6 or FOLFIRI showed similar efficacy (7), with <2% metastasectomies. "
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    ABSTRACT: Clinical outcome post-progression to first-line triplet chemotherapy (CT) plus bevacizumab (FIr-B/FOx) was evaluated in metastatic colorectal cancer (MCRC) patients (pts). Second-line treatment was selected according to fitness, KRAS genotype, previous efficacy and safety. Efficacy was evaluated and compared according to treatment or KRAS genotype, using log-rank analysis. Among 54 pts, median overall survival (OS) post-progression was 12 months, significantly better in 40 (74.1%) treated compared to 14 (25.9%) who died without further treatment. Second-line surgical treatment, 4 pts (7.4%), medical treatment, 36 pts (66.7%): triplet CT plus targeted agent, 10 (18.5%); triplet regimens, 19 (35.2%); doublet/monotherapy, 7 (13%). At follow-up of 14 months, objective response rate (ORR) was 38%, metastasectomies 12.5%, progression-free survival (PFS) 10 months, OS 14 months. According to treatment, ORR, metastasectomies, PFS and OS were significantly favourable in triplet CT plus targeted agent compared to triplet, respectively: 80%, 40%, 13 months, not reached; 28%, 6%, 8 months, 11 months. PFS and OS were significantly worse in c.35 G>A mutant compared to wild-type and/or other mutant patients. Prognosis after progression to first‑line FIr-B/FOx may be significantly favourable in MCRC pts re-challenged with intensive regimens, and unfavourable in c.35 G>A KRAS mutant patients.
    International Journal of Oncology 11/2013; 44(1). DOI:10.3892/ijo.2013.2179 · 3.03 Impact Factor
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    • "The most common grade 3 or 4 adverse events observed in a phase III trial of single-agent irinotecan administered every 3 weeks were neutropenia, diarrhoea, and vomiting (Fuchs et al, 2003). "
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    ABSTRACT: 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. 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. 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. 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.
    British Journal of Cancer 09/2010; 103(7):993-1000. DOI:10.1038/sj.bjc.6605852 · 4.84 Impact Factor
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    • "The results of our trial evaluating radioembolisation beyond 3 or 4 lines of chemotherapy match favourably with other trials of systemic chemotherapy. In this treatment setting, median survivals are 4.5 months for historical controls (Kennedy et al, 2006), and 6.4 – 10.0 months with irinotecan (Fuchs et al, 2003; Schoemaker et al, 2004; Van Cutsem et al, 2005; Seymour et al, 2007; Sobrero et al, 2008), 6.3 – 9.3 months for panitumumab (Van Cutsem et al, 2007, 2008), 8.6 – 10.7 months for irinotecan/ cetuximab (Cunningham et al, 2004; Sobrero et al, 2008; Wilke et al, 2008), 10.8 months for FOLFOX4, 10.2 months for bevacizumab and 9.5 – 12.9 months for FOLFOX4 or FOLFIRI and bevacizumab combined (Giantonio et al, 2007; Kang et al, 2009) as second, third or subsequent lines of systemic therapy in phase II/III studies. Recently, two small studies from the Paul Brousse Hospital in Paris have shown median survivals of 18.0 and 13.7 months with chronomodulated hepatic arterial infusion chemotherapy, and systemic circadian chronomodulated chemotherapy plus cetuximab, as a second or subsequent line of therapy (Bouchahda et al, 2009; Lévi et al, 2010). "
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    ABSTRACT: This multi-centre phase II clinical trial is the first prospective evaluation of radioembolisation of patients with colorectal liver metastases (mCRC) who failed previous oxaliplatin- and irinotecan-based systemic chemotherapy regimens. Eligible patients had adequate hepatic, haemopoietic and renal function, and an absence of major hepatic vascular anomalies and hepato-pulmonary shunting. Gastroduodenal and right gastric arteries were embolised before hepatic arterial administration of yttrium-90 resin microspheres (median activity, 1.7 GBq; range, 0.9-2.2). Of 50 eligible patients, 38 (76%) had received > or =4 lines of chemotherapy. Most presented with synchronous disease (72%), >4 hepatic metastases (58%), 25-50% replacement of total liver volume (60%) and bilateral spread (70%). Early and intermediate (>48 h) WHO G1-2 adverse events (mostly fever and pain) were observed in 16 and 22% of patients respectively. Two died due to renal failure at 40 days or liver failure at 60 days respectively. By intention-to-treat analysis using Response Evaluation Criteria in Solid Tumours, 1 patient (2%) had a complete response, 11 (22%) partial response, 12 (24%) stable disease, 22 (44%) progressive disease; 4 (8%) were non-evaluable. Median overall survival was 12.6 months (95% CI, 7.0-18.3); 2-year survival was 19.6%. Radioembolisation produced meaningful response and disease stabilisation in patients with advanced, unresectable and chemorefractory mCRC.
    British Journal of Cancer 07/2010; 103(3):324-31. DOI:10.1038/sj.bjc.6605770 · 4.84 Impact Factor
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