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CPT-11 plus raltitrexed is active in patients with 5-FU-refractory ACC, at the expense of moderate toxicity.

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Objectives: The combination of irinotecan and raltitrexed is safe and active in 5-fluorouracil-refractory, metastatic colorectal cancer (CRC), with the advantage of its convenient three-weekly schedule. The aim of this multicenter phase II study was to assess its efficacy and toxicity in first-line treatment. Methods: Between May 2000 and March 2001, 62 previously untreated patients received irinotecan (350 mg/m²) plus raltitrexed (3 mg/m²), with courses repeated every 21 days. Objective response was assessed every three courses, and treatment maintained until tumor progression or unacceptable toxicity. Results: A total of 331 cycles were administered, with a median of five cycles per patient (range, 1–16). Seventeen patients achieved a partial response and 2 a complete response, for an overall intention-to-treat response rate of 30% (95% confidence interval, 18–44%). The incidence of grade 3–4 toxicity per patient was diarrhea (27%), emesis (13%), anemia (12%), neutropenia (9%), and asthenia (7%). Three patients (5%) died from treatment-related adverse events (diarrhea plus neutropenia). The median potential follow-up is now 37 months. Median survival was 12.2 months, and median time to progression was 6.3 months. Conclusions: The combination of irinotecan plus raltitrexed is an easy comfortable schedule for patients with metastatic CRC, but both efficacy and toxicity results seem suboptimal for first-line treatment.

The serial analysis of cell-free DNA (cfDNA) enables minimally invasive monitoring of tumor evolution, providing continuous genetic information. PERSEIDA was an observational, prospective study assessing the cfDNA RAS (KRAS/NRAS) mutational status evolution in first-line, metastatic CRC, RAS wild-type (according to baseline tumor tissue biopsy) patients. Plasma samples were collected before first-line treatment, after 20 ± 2 weeks, and at disease progression. One hundred and nineteen patients were included (102 received panitumumab and chemotherapy as first-line treatment—panitumumab subpopulation). Fifteen (12.6%) patients presented baseline cfDNA RAS mutations (n = 14 [13.7%], panitumumab subpopulation) (mutant allele fraction ≥0.02 for all results). No patients presented emergent mutations (cfDNA RAS mutations not present at baseline) at 20 weeks. At disease progression, 11 patients (n = 9; panitumumab subpopulation) presented emergent mutations (RAS conversion rate: 19.0% [11/58]; 17.7% [9/51], panitumumab subpopulation). In contrast, three (5.2%) patients presenting baseline cfDNA RAS mutations were RAS wild-type at disease progression. No significant associations were observed between overall response rate or progression-free survival and cfDNA RAS mutational status in the total panitumumab subpopulation. Although, in patients with left-sided tumors, a significantly longer progression-free survival was observed in cfDNA RAS wild-type patients compared to those presenting cfDNA RAS mutations at any time. Continuous evaluation of RAS mutations may provide valuable insights on tumor molecular dynamics that can help clinical practice.