Oxaliplatin, irinotecan and 5-fluorouracil in combination with or without targeted therapies are well-documented treatment options for first- and second-line treatments of metastatic colorectal cancer. However, there are much less data on the beneficial effect on systemic therapy in the third-line setting. We therefore performed a systematic review of the current literature on third or later lines of treatment to patients with metastatic colorectal cancer after the use of approved drugs or combinations.
A computer-based literature search was carried out using Pubmed and data reported at international meetings. Original studies reporting ≥15 patients who had previously received 5-fluorouracil, oxaliplatin and irinotecan were included. Furthermore, patients with KRAS wild type tumours should had received EGFR-directed therapy.
Conventional chemotherapeutic agents as capecitabine, mitomycin C, and gemcitabine have limited or no activity. Retreatment with oxaliplatin might be an option in selected patients. In addition, rechallenge with EGFR-directed therapy might be a valuable strategy. Data also suggest that angiogenetic drugs may postpone further progression and prolong survival. Lately, regorafinib has been approved. In conclusion, our current knowledge is based on many retrospective studies, some phase II studies and very few randomized clinical trials. Further prospective phase III trials comparing an investigational drug or combination with best supportive care in third- or later lines of treatment in metastatic colorectal cancer are highly warranted. Identification of predictive biomarkers and improvement of our understanding of molecular mechanisms is crucial.
[Show abstract][Hide abstract] ABSTRACT: Recent evidence showed that a variety of DNA damaging agents including 5-FU and L-OHP impairs ribosomal biogenesis activating a ribosomal stress pathway. Here, we demonstrate that in lung and colon cancer cell lines devoid of p53, the efficacy of 5-FU and L-OHP chemotherapy depends on rpL3 status. Specifically, we demonstrate that ribosomal stress induced by 5-FU and L-OHP is associated to up-regulation of rpL3 and its accumulation as ribosome-free form. We show that rpL3 participates in the cell response to chemotherapy acting as a critical regulator of cell cycle, apoptosis and DNA repair, by modulating p21 expression. Moreover, we demonstrate that rpL3 is able to control DNA repair also independently from p21 status of cell. It is noteworthy that silencing of rpL3 abolishes the cytotoxic effects of 5-FU and L-OH indicating that the loss of rpL3 makes chemotherapy drugs ineffective. Taking together our results shed light on 5-FU and L-OHP mechanism of action and contribute to more effective clinical use of these drugs in cancer therapy.
[Show abstract][Hide abstract] ABSTRACT: The purpose of this study is to evaluate the influence of germline polymorphisms of cytochrome P450 (CYP450) on objective response, progression-free survival (PFS) and overall suruvival (OS) in metastatic colorectal cancer (mCRC) receiving the combination chemotherapy of irinotecan, 5-fluorouracil, and leucovorin (FOLFIRI). All SNPs in CYP450, whose minor allele frequency were more than 10 %, were genotyped in 82 patients with mCRC who received first-line FOLFIRI regimen. χ (2) test or Fisher's exact test was used to assess the correlation between SNPs and objective response as appropriate and log-rank test between SNPs and PFS or OS. Cox proportional hazards models were used to analyze the association of CYP450 gene polymorphisms and clinical factors for PFS and OS. No SNP showed predictive or prognostic value for clinical outcomes, except for CYP3A5 rs776746 A>G, which was significantly associated with PFS (P = 0.0002). Multivariate analysis confirmed its prognostic value for PFS (P = 0.002). CYP3A5 rs776746 A>G polymorphisms have a prognostic contribution toward FOLFIRI regimen in mCRC. This could represent a further step toward personalized therapy.
[Show abstract][Hide abstract] ABSTRACT: Background:
Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is an experimental drug delivery method that applies chemotherapy into the abdominal cavity as an aerosol under pressure. The first results obtained with PIPAC in colorectal peritoneal metastasis (CPM) are presented.
Retrospective analysis. PIPAC was applied in 17 consecutive patients with pretreated CPM. All patients had previously undergone surgery, and 16 previous had undergone previous lines of systemic chemotherapy (median: 2 lines). The mean peritoneal metastasis index (PCI) was 16 ± 10. Forty-eight applications of PIPAC with oxaliplatin (92 mg/m(2) ) were given every 6 weeks at 37°C and 12 mmHg for 30 min. The outcome criteria were microscopic pathological response, survival and adverse events according to CTCAE v. 4.0.
Forty-eight PIPAC administrations were performed with no intraoperative complications. The mean number of PIPACs was 2.8/patient (min = 1, max =6). Postoperative adverse events (CTCAE 3) were observed in 4 patients (23%), no CTCAE 4 level adverse events were reported. The hospital mortality was zero. Objective tumour responses were observed in 12/17 patients (71%), and the overall responses were as follows: complete pathological response (7 patients), major response (4 patients), partial response (1 patient), no response (2 patients), and not eligible (3 patients). The mean follow-up time was 37 ± 12 months, and the median survival was 15.7 months.
Repeated PIPAC with oxaliplatin can induce the regression of pretreated CPM. The toxicity appears to be low. These preliminary results are encouraging and justify prospective clinical studies. This article is protected by copyright. All rights reserved.
Andrea Bertotti, Eniko Papp, Siân Jones, Vilmos Adleff, Valsamo Anagnostou, Barbara Lupo, Mark Sausen, Jillian Phallen, Carolyn A Hruban, Collin Tokheim, [...], Johan Lantto, Andrea Cassingena, Qing Kay Li, Rachel Karchin, Robert Scharpf, Andrea Sartore-Bianchi, Salvatore Siena, Luis A Diaz, Livio Trusolino, Victor E Velculescu
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