Second-line Treatment Of Metastatic Colorectal Cancer Research Articles

Irinotecan plus raltitrexed as second‑line chemotherapy for metastatic colorectal cancer: A retrospective study.

The present study evaluated the efficiency, prognostic factors for and the safety of irinotecan combined with raltitrexed (TOMIRI) in patients with metastatic colorectal cancer (CRC). Outcome data of patients who received TOMIRI as first-, second- and third- or later-line treatment regimens were assessed to compare the efficacy of this regimen. Progression-free survival (PFS), overall survival (OS), objective response rate (ORR) and disease control rate (DCR) were evaluated for each group. Kaplan-Meier curves and univariate and multivariate analyses were performed to evaluate efficacy. From January 2017 to December 2019, TOMIRI was administered as a first-line treatment in 23 patients, second-line treatment in 164 patients and third- or later-line treatment in 18 patients. Irinotecan and 5-fluorouracil (FOLFIRI) was administered to another 50 patients, who served as the control group. The median PFS was 9, 7 and 6 months and the median OS was 37, 21 and 17 months for first-, second- and third- or later-line treatments, respectively. The ORRs of the included patients were 21.7, 13.4 and 11.1%, respectively, and the DCRs were 91.3, 81.7 and 66.7%, respectively. Compared with FOLFIRI, TOMIRI as a second-line chemotherapy treatment was associated with longer survival of the patients with CRC. Further analysis demonstrated that pathologic tumor-node-metastasis category, carcinoembryonic antigen, carbohydrate antigen 19-9, treatment cycles, targeted therapy, treatment of local metastases and first-line PFS were prognostic factors for second-line treatment. Among these, the number of treatment cycles was of vital importance. Hepatic dysfunction was the most commonly reported grade 1-2 (55.1%) and grade 3-4 (7.3%) adverse event. Neutropenia (12.2%), thrombocytopenia (10.2%), anemia (27.3%), proteinuria (38.1%) and hematuria (21.0%) were also common grade 1-2 adverse events. In conclusion, TOMIRI may be recommended as an effective and safe second-line treatment for metastatic CRC in the clinic.

Anti-angiogenic agents in second-line treatment for metastatic colorectal cancer: the optimization of pharmacological costs.

In western Countries, colorectal cancer (CRC) is the second most common cause of death from cancer. In particular, the introduction of active new anti-angiogenic agents for the second-line treatment of metastatic CRC (mCRC) is associated with a relevant increase of costs, and it is therefore important to make a balance between the costs of treatment and the added value represented by the improvement of the clinical parameters of interest such as progression-free survival (PFS). The analysis was conducted to assess the effect of second-line therapy with anti-angiogenic agents on the PFS and was restricted to pivotal phase III randomized controlled trials (RCTs). The present analysis evaluated four phase III RCTs, including 3938 patients. Dividing the costs of therapy by the measure of efficacy represented by PFS, we found out that the lowest cost per month of PFS gained (4581 €) was associated with the use of FOLFIRI plus aflibercept. Combining pharmacological costs of drugs with the measure of efficacy represented by the PFS, aflibercept in combination with FOLFIRI is a cost-effective second-line treatment for patients with mCRC.

Cost-effectiveness of anti-angiogenic agents in second-line treatment for metastatic colorectal cancer. Integrating the EUROPEAN Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS) with the costs of drugs

Background: In western Countries, colorectal cancer (CRC) is the second most common cause of death from cancer. In particular, the introduction of active new anti-angiogenic agents for the second-line treatment of metastatic CRC (mCRC) is associated with a relevant increase of costs and it is therefore important to make a balance between the costs of treatment and the added value represented by the improvement of the clinical parameters of interest such as progression free survival (PFS). Materials and methods: The analysis was conducted to assess the effect of second-line therapy with anti-angiogenic agents on the PFS and was restricted to pivotal phase III randomized controlled trials (RCTs). We calculated the pharmacological costs necessary to get the benefit in PFS, for each trial. Calculations were based on an “ideal patient” (BSA 1.8 sqm; weight 70 Kg). The costs of drugs are at the Pharmacy of our Hospital and are expressed in euros (€). We have subsequently applied the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS) to the above pivotal phase III RCTs. Results: The present analysis evaluated 4 phase III RCTs, including 3938 patients. PFS ranged from 2.7 months of bevacizumab alone in the E3200 trial to 7.3 months of the combination of FOLFOX and bevacizumab in the same trial. ESMO-MCBS reached medium score for VELOUR trial and low grade scores (grade 1 and 2) for RAISE, TML and E3200 trials, respectively. Dividing the costs of therapy by the measure of efficacy represented by PFS we found out that the lowest cost per month of PFS gained (4581 €) was associated with the use of FOLFIRI plus aflibercept; the highest cost per month of PFS gained (23 827 €) was associated with the use of FOLFIRI plus ramucirumab. Conclusions: Combining pharmacological costs of drugs with the measure of efficacy represented by the PFS, aflibercept in combination with FOLFIRI is a cost-effective second-line treatment for patients with mCRC. The lack of correlation between PFS and OS is a well known phenomenon with the clinical use of anti-angiogenic treatment and reinforces the importance of the evaluation of PFS as a strong end-point, even on a pharmaco-economic perspective.

K-Ras Mutation Status as a Predictive Biomarker in Metastatic Colorectal Cancer

Colorectal cancer (CRC) is the third most common cancer worldwide, with approximately 1 million new cases diagnosed every year. It is estimated that approximately half of the patients with CRC will develop metastasis. Current use of irinotecan, oxaliplatin and bevacizumab, combined with the long-time standards 5-fluourouracil and leucovorin as firstor second-line treatment for metastatic CRC (mCRC), has resulted in median overall survival (mOS) figures of greater than 20 months. However, most patients develop resistance to these therapies and finally die owing to progression of their disease. Additional improvements in treatment are likely to be facilitated by the use of rationally selected therapeutic agents that target functionally important proteins in tumor cells, such as the EGF receptor (EGFR), expressed in 75–90% of mCRC specimens [1]. The activation of EGFR leads to the activation of intracellular effectors involved in intracellular signaling pathways such as the G-protein K-Ras. K-Ras is a self-inactivating signal transducer, cycling from a GDP-bound ‘off ’ state to GTP-bound ‘on’ state in response to receptor activation [2]. This response is transient owing to the intrinsic GTPase activity. Interestingly, K-Ras oncogene may harbor activating mutations yielding proteins with reduced GTPase activity. These activating K-Ras mutations are among the most common oncogenic alterations in cancer [3]. Monoclonal antibodies designed to bind to the ectodomain of the EGFR have shown activity in chemorefractory mCRC. Several Phase II studies have demonstrated the activity of cetuximab (a chimeric monoclonal IgG1 antibody) and panitumumab (a fully human monoclonal IgG2 antibody) in refractory mCRC. In a randomized Phase II study, increased activity with cetuximab plus irinotecan, compared with

A phase I study of vorinostat (suberoylanilide hydroxamic acid, SAHA) in combination with 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) in patients with advanced colorectal cancer (CRC)

3592 Background: Vorinostat is a novel histone deacetylase (HDAC) inhibitor that potentiates 5-FU and platinum antitumor activity. This potentiation is associated with ∼ 40 fold decrease in thymidilate synthase (TS) expression, the main target of 5-FU, in preclinical models. We conducted a phase I study of vorinostat plus FOLFOX in patients with CRC to determine the recommended dose of this combination. Methods: Vorinostat was escalated in a standard 3+3 design. FOLFOX was administered at a fixed dose every 2 weeks: leucovorin 400mg/m2 and oxaliplatin 85mg/m2 over 2 hours followed by 5-FU bolus 400mg/m2 and 5-FU infusion 2400mg/m2 over 46 hours. Vorinostat started 3 days prior to FOLFOX and was given twice daily for 1 week followed by 1 week break. Investigated dose levels of vorinostat (twice daily) include 100, 200, and 300 mg. Tumor biopsies were obtained from patients with accessible liver metastases before and on the 4th day of vorinostat (prior to FOLFOX) to assess TS expression. Results: 9 patients (pts) enrolled (M/F: 8/1; median age: 57, ECOG 0/1: 5/4). All pts had failed prior FOLFOX, irinotecan, and cetuximab therapy. One pt at dose level (DL) 1 was not evaluable due to rapid clinical progression. No dose-limiting toxicities were noted among the 8 evaluable pts. No grade (G) 3 toxicities were noted on the first cycle of treatment (within 2 weeks after 1st FOLFOX) and accrual continues on DL3. Cycle 1 toxicities were attributed to FOLFOX and consisted of 1 G2 neutropenia, 1 G2 mucositis, and 2 G2 nausea/vomiting. Responses were evaluable in 6 pts: 1 pt with peritoneal carcinomatosis on DL 1 has stable disease 5 months + along with a stable CEA; 3 patients at DL2 have stable disease at 2 months along with declining CEA in 2/3 pts. Two pts (DL1) with liver metastases biopsies had a major decrease in TS expression by IHC after 4 days of vorinostat. Conclusions: Vorinostat at 100–200mg PO BID × 1 week every 2 weeks in combination with FOLFOX is well tolerated. The lowest DL of 100 mg PO BID is associated with down-regulation of TS. Disease stabilization in highly refractory patients is promising. The investigation of this regimen in the first or second-line treatment of metastatic CRC is warranted. No significant financial relationships to disclose.

Targeted therapies for patients with advanced colorectal cancer: focus on cetuximab

Colorectal cancer (CRC) is the fourth most common cancer in men and the third in women worldwide. Combinations of 5-fluorouracil (5-FU)/folinic acid (FA) with irinotecan or oxaliplatin form the standard treatment approaches for metastatic disease. The introduction of targeted agents has presented the opportunity to improve on the efficacy of current treatments without exacerbating the associated toxicity. Cetuximab (Erbitux®) is an IgG1 monoclonal antibody (MAb) that specifically targets the epidermal growth factor receptor (EGFR) with high affinity and competitively inhibits endogenous ligand binding. Cetuximab has shown good efficacy in combination with irinotecan in CRC that had previously progressed on irinotecan-based therapy. Cetuximab plus irinotecan and various schedules of 5-FU/FA have shown efficacy in a first-line setting. The activity of cetuximab and oxaliplatin-based regimens is being investigated in both first- and subsequent-line settings. Cetuximab is well tolerated and does not increase the side effect profile of agents it is combined with. Other EGFR inhibitors, including the tyrosine kinase inhibitors, gefitinib and erlotinib, and the MAbs, panitumumab and matuzumab, are also being investigated in a number of solid tumors. The vascular endothelial growth factor (VEGF) inhibitor, bevacizumab, although apparently inactive as a single agent, has demonstrated survival benefits when combined with bolus 5-FU/FA and irinotecan in a first-line setting and with 5-FU/FA and oxaliplatin in the second-line treatment of metastatic CRC. In this paper we discuss the use of targeted therapies in the treatment of metastatic CRC, with a focus on cetuximab.