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- Carlsson, Göran, 1951, et al.
(författare)
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A phase I/II study of arfolitixorin and 5-fluorouracil in combination with oxaliplatin (plus or minus bevacizumab) or irinotecan in metastatic colorectal cancer
- 2022
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Ingår i: ESMO Open. - : Elsevier BV. - 2059-7029. ; 7:5
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Tidskriftsartikel (refereegranskat)abstract
- Background: 5-fluorouracil (5-FU) combined with a folate remains an essential treatment component for metastatic colorectal cancer (mCRC). Leucovorin is the folate most often used, but requires intracellular conversion to a reduced folate, and has high pharmacokinetic variability and limited bioavailability in patients with low folate pathway gene expression. Arfolitixorin is an immediately active form of folate, [6R]-5,10-methylenetetrahydrofolate ([6R]-MTHF), and may improve outcomes.Patients and methods: This open-label, multicenter, phase I/II study in patients with mCRC (NCT02244632) assessed the tolerability and efficacy of first-or second-line arfolitixorin (30, 60, 120, or 240 mg/m2 intravenous) with 5-FU alone, or in combination with oxaliplatin (plus or minus bevacizumab) or irinotecan, every 14 days. Safety, efficacy, and pharmacokinetics were assessed before and after four cycles (8 weeks) of treatment.Results: In 105 treated patients, investigators reported 583 adverse events (AEs) in 86 patients (81.9%), and 256 AEs (43.9%) were potentially related to arfolitixorin and 5-FU. Dose adjustments were required in 16 patients (15.2%). At 8 weeks, 9 out of 57 patients assessed for efficacy achieved an objective response (15.8%), and all 9 achieved a partial response. Six of these nine patients had received arfolitixorin as a first-line treatment. A further 33 patients (57.9%) achieved stable disease. Pharmacokinetics were assessed in 35 patients. The average tmax was 10 min, and area under the plasma concentrationetime curve from time 0 to 1 h increased linearly between 30 and 240 mg/m2. No accumulation was observed for [6R]-MTHF following repeated administration, and there were no major pharmacokinetic differences between cycle 1 and cycle 4 at any dose.Conclusions: Arfolitixorin is a well-tolerated moderator of 5-FU activity. It is suitable for further investigation in mCRC and has the potential to improve treatment outcomes in patients with low folate pathway gene expression. Arfolitixorin can easily be incorporated into current standard of care, requiring minimal changes to chemotherapy regimens.
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| 2. |
- Emland, Frans, et al.
(författare)
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Prolonged postoperative length of stay may be a valuable marker for susceptibility to relapse beyond established risk factors in patients with stage III colon cancer
- 2022
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Ingår i: World Journal of Surgical Oncology. - : Springer Science and Business Media LLC. - 1477-7819. ; 20:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Delay from surgery to adjuvant chemotherapy causes impaired survival among patients undergoing radical resection for stage III colon cancer, and the underlying mechanism for this is incompletely clarified. It is established that prolonged postoperative hospital length of stay (LOS) is associated with delayed initiation of the adjuvant treatment driving the assumption that prolonged LOS is prognostically unfavorable due to this fact and case mix factors. We hypothesize that prolonged LOS after surgery is a valuable marker for susceptibility to relapse that is not detected in established prognostic factors and, alone, associated with a shorter disease-free survival (DFS). Materials and methods: A total of 690 consecutive patients undergoing elective radical resection for stage III colon cancer in 2000–2015 were identified in a prospective detailed facility database. Univariate and multivariate analyses were performed using Cox proportional hazards model in the evaluation of LOS as an independent prognostic factor. Results: Short postoperative LOS, low comorbidity, and few complications were associated with longer DFS (p < 0.01). Fewer patients in the short and intermediate LOS groups had a relapse in their disease (28% and 33%, respectively), compared to the patients with longer LOS (40%, p < 0.05). LOS was a prognostic factor for DFS in the unadjusted univariate model (HR 1.04 per unit change) and remained statistically significant in the adjusted multivariate analysis, with a HR of 1.03 per hospital day (p < 0.01). Conclusions: Postoperative LOS independently correlates with the risk of recurrence and DFS, regardless of if adjuvant chemotherapy is given, along with the factors such as age, comorbidity, complications, and tumor features. We propose a further investigation into the causal mechanisms based on tumor and host biology linking LOS to DFS beyond established risk factors.
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| 3. |
- Taflin, Helena, et al.
(författare)
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Increasing Dosage of Leucovorin Results in Pharmacokinetic and Gene Expression Differences When Administered as Two-Hour Infusion or Bolus Injection to Patients with Colon Cancer
- 2022
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Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 2023:15(1)
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Tidskriftsartikel (refereegranskat)abstract
- The combination of 5-fluorouracil (5-FU) and leucovorin (LV) forms the chemotherapy backbone for patients with colorectal cancer. However, the LV administration is often standardized and not based on robust scientific data. To address these issues, a randomized pharmacokinetics study was performed in patients with colon cancer. Thirty patients were enrolled, receiving 60, 200 or 500 mg/m2 LV as a single two-hour infusion. Blood, tumor, mucosa, and resection margin biopsies were collected. Folate concentrations were analyzed with LC-MS/MS and gene expression with qPCR. Data from a previous study where patients received LV as bolus injections were used as comparison. Saturation of methylenetetrahydrofolate (MeTHF) and tetrahydrofolate (THF) levels was seen after two-hour infusion and polyglutamated MeTHF + THF levels in tumors decreased with increasing LV dosage. The decrease was associated with decreased FPGS and increased GGH expression, which was not observed after LV bolus injection. In the bolus group, results indicate activation of a metabolic switch possibly promoting TYMS inhibition in response to 5-FU. Different metabolic mechanisms appear to be induced when LV is administered as infusion and bolus injection. Since maximal inhibition of TYMS by the 5-FU metabolite 5-fluoro-2′-deoxyuridine 5′-monophosphate (FdUMP) requires excess polyglutamated MeTHF, the results point in favor of the bolus regimen.
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| 4. |
- Taflin, Helena, et al.
(författare)
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Plasma deoxyuridine as a surrogate marker for toxicity and early clinical response in patients with metastatic colorectal cancer after 5-FU-based therapy in combination with arfolitixorin
- 2021
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Ingår i: Cancer Chemotherapy and Pharmacology. - : Springer Science and Business Media LLC. - 0344-5704 .- 1432-0843. ; 87, s. 31-41
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Tidskriftsartikel (refereegranskat)abstract
- Purpose The aim was to explore the correlation between increasing doses of [6R]-5,10-methylenetetrahydrofolate (arfolitixorin) and plasma concentrations of deoxyuridine (dUr) in patients with metastatic colorectal cancer (mCRC), subjected to 5-fluorouracil (5-FU)-based chemotherapy. The aim was further to investigate the possibility to predict toxicity and clinical response during treatment using gender, age, and plasma dUr as explanatory variables. Methods Thirty-three patients from the ISO-CC-005 phase I/IIa study, which investigated safety and tolerability of arfolitixorin at four dose levels, were included. Toxicity and clinical response were evaluated after 4 cycles of chemotherapy. Plasma dUr was quantified before (0 h) and 24 h after 5-FU administration at the first (C1) and fourth (C4) cycle using LC-MS/MS. Fit modelling was used to predict toxicity and clinical response. Results The dUr levels increased with increasing arfolitixorin dose. Females had higher total and haematological toxicity scores (p = 0.0004 and 0.0089, respectively), and needed dose reduction more often than males (p = 0.012). Fit modeling showed that gender and the dUr levels at C1-0 h and C4-24 h predicted total toxicity (p = 0.0011), whereas dUr C4-0 h alone was associated with gastrointestinal toxicity (p = 0.026). Haematological toxicity was predicted by gender and age (p = 0.0071). The haematological toxicity score in combination with the dUr levels at C1-24 h and C4-24 h predicted early clinical response (p = 0.018). Conclusion The dUr level before and during administration of 5-FU and arfolitixorin was predictive for toxicity and early clinical response and could be a potential surrogate marker for thymidylate synthase inhibition in patients with mCRC.
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