Second-line Treatment Of mCRC Research Articles

Irinotecan plus raltitrexed as second-line treatment in locally advanced or metastatic colorectal cancer patients: a prospective open-label, single-arm, multi-center, phase II study

BackgroundColorectal cancer is the third most common cancer and the second leading cause of cancer death. There are limited therapeutic options for the treatment of locally advanced or metastatic colorectal cancers which fail first-line chemotherapy. Phase I/II studies showed that the combined application of the raltitrexed and irinotecan has significant synergistic effect and acceptable toxicity. However, most of these previous studies have relatively small sample size.MethodsThis is a prospective open-label, single-arm, multi-center, Phase II trial. Brief inclusion criteria: patients were aged 18 to 75 years with locally advanced or metastatic colorectal cancer after failure of 5-FU and oxaliplatin therapy. Enrolled patients received raltitrexed (3 mg/m2, d1) and irinotecan (180 mg/m2, d1) each 21-day cycle until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival, and the secondary endpoints were disease control rate, objective response rate, overall survival and safety.ResultsA total of 108 patients were enrolled between September 2016 and May 2020. The median age was 61 years, ECOG 1 score accounts for 67.6%, the rest were ECOG 0. A total of 502 cycles were completed, with an average of 4.6 cycles and a median of 4 cycles. 108 patients were evaluated, with an objective response rate of 17.6%, and disease control rate of 76.9%. The median follow-up time was 27 months (range:3.1–61.0 m) at data cut-off on March 2023. Median progression-free survival was 4.9 months (95% CI 4.1–5.7) and median overall survival was 13.1 months (95% CI 12.2–15.5). The most common adverse events that were elevated are alanine aminotransferase increased, aspartate aminotransferase increased, fatigue, diarrhoea, neutrocytopenia, thrombocytopenia, hypohemoglobin, and leukocytopenia. Most of the adverse events were Grade I/II, which were relieved after symptomatic treatment, and there were no treatment-related cardiotoxicities and deaths.ConclusionsThe combination of raltitrexed and irinotecan as second-line treatment for mCRC could be a reliable option after failure of standard 5-Fu-first-line chemotherapy in locally advanced or metastatic colorectal cancers, especially for patients with 5-FU intolerance (cardiac events or DPD deficiency patients).Trial registrationClinicalTrials.gov identifier: NCT03053167, registration date was 14/2/2017.

Prospective, Observational Study of Aflibercept Use in Combination with FOLFIRI in Patients with Metastatic Colorectal Cancer: A Real-World Effectiveness Study.

This was an observational study prospectively evaluating the effectiveness and safety of aflibercept/FOLFIRI administered in second-line mCRC per the reimbursement criteria in Poland. Consecutive mCRC patients who progressed with first-line oxaliplatin-based chemotherapy received aflibercept (4 mg/kg IV) followed by FOLFIRI every 2 weeks until progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS); overall survival (OS) and safety were the secondary endpoints. A total of 93 patients were treated at 17 Polish sites. A median of 10 cycles was administered. Over a median treatment duration of 5.3 months, median PFS and median OS were 8.4 months [95% CI, 6.9-9.9] and 27.0 months [95% CI, 23.9-30.1], respectively. There was no significant impact of primary tumor location, metastatic site, or KRAS status on PFS and OS. Main grade ≥ 3 adverse events were neutropenia (16%), hypertension (8%), diarrhea (4%), and stomatitis (4%). The benefits/risks of Aflibercept plus FOLFIRI administered per the Polish reimbursement criteria in second-line treatment of mCRC after failure of a prior oxaliplatin-based regimen is confirmed.

A decade of progress: advances in the third-line treatment of patients with metastatic colorectal cancer.

The treatment of metastatic colorectal cancer (mCRC) remains challenging. There has been substantial progress in understanding the molecular pathology of the disease that has led to meaningful advancements in treatment options with varying mechanisms of action, although treatment remains costly. Cytotoxic therapies, which are typically combined with targeted therapies, remain the mainstay of first- and second-line treatment for mCRC. While also relevant in earlier lines of therapy, molecular testing has become increasingly important to guide therapy across lines of therapy, for which treatment options are limited. A paucity of data exists in establishing clinical criteria for optimizing the sequencing of therapies in the third line and beyond. A customized approach should consider the efficacy of the therapy balanced with the patient's goals. Sequencing criteria should include a consideration for exposing patients to as many different modes of therapy as possible while preserving quality of life, avoiding serious toxicities, and accounting for the potential impact of cumulative toxicities from prior therapies.

A Comparison of Folinic Acid, Fluorouracil and Irinotecan (FOLFIRI) plus Bevacizumab and FOLFIRI plus Aflibercept as Second-line Treatment for Metastatic Colorectal Cancer

AimTo compare the efficacy and safety of folinic acid, fluorouracil and irinotecan (FOLFIRI) plus bevacizumab or aflibercept in metastatic colorectal cancer (mCRC) patients pretreated with oxaliplatin-based chemotherapy. Materials and methodsWe analysed the treatment outcomes of patients receiving FOLFIRI in combination with bevacizumab or aflibercept as second-line treatment for mCRC between October 2017 and March 2020. This analysis included 67 patients receiving FOLFIRI plus aflibercept and 83 receiving FOLFIRI plus bevacizumab. ResultsThe overall response rate (ORR) was 13.6% (95% confidence interval 4.85–22.34) in the FOLFIRI–aflibercept group and 14.7% (95% confidence interval 6.68–22.71) in the FOLFIRI–bevacizumab group. This difference in ORR was not statistically significant. The median progression-free survival was 8.6 months in the FOLFIRI–bevacizumab group and 8.5 months in the FOLFIRI–aflibercept group (P = 0.752). Patients in the FOLFIRI–bevacizumab group showed a median overall survival of 12.4 months, whereas patients in the FOLFIRI–aflibercept group had a median overall survival of 13.7 months (P = 0.276). There were no significant differences in survival between the two treatment groups. The adverse events were also largely similar between the two groups. However, hypertension of grade 3 or more was more frequent in the FOLFIRI–aflibercept group. ConclusionFOLFIRI plus bevacizumab and FOLFIRI plus aflibercept had similar anti-tumour activities and toxicity profiles when used as second-line therapy in mCRC patients. Based on these data, both aflibercept and bevacizumab are suitable anti-angiogenic agents when used in combination with FOLFIRI for mCRC.

P-81 HGCSG1901: A retrospective cohort study evaluating the safety and efficacy of S-1 and irinotecan plus bevacizumab in patients with metastatic colorectal cancer: Analysis of second-line treatment

The FIRIS trial, which is a phase III trial, showed non-inferiority of S-1 and irinotecan (IRIS) to FOLFIRI as second-line treatment for metastatic colorectal cancer (mCRC) patients. In addition, the ML18147 study showed the survival benefit of bevacizumab (Bev) combination treatment after progression to first-line treatment with Bev. Based on these results, IRIS/Bev is recommended as second-line treatment for mCRC patients in the Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines. However, there are few studies exploring the efficacy and safety of IRIS/Bev for the second-line setting in real-world practice. Therefore, we performed this retrospective analysis in order to investigate the real-world efficacy and safety of IRIS/Bev as second-line treatment in patients with mCRC (HGCSG1901). We retrospectively analyzed the clinical data of 284 patients who received IRIS/Bev as second-line treatment from August 2011 to March 2018 in 24 centers. IRIS/Bev regimen consisted of bevacizumab (5 mg/kg) given as an intravenous infusion, followed by an intravenous infusion of irinotecan (100 mg/m2) on day 1 and day 15 of each 4-week cycle. S-1 (40-60 mg) was taken orally twice daily, from the night on day 1 to the morning on day 15, followed by a 14-day rest. In this study, CTCAE ver.4.01 and RECIST criteria ver.1.1 were used for analysis of adverse events (AEs) and response rate (RR)/disease control rate (DCR). The time to treatment failure (TTF), progression-free survival (PFS), and overall survival (OS) were estimated with the Kaplan-Meier method. Patient characteristics were as follows; male/female 159/125, median age 65 (range 30-82), ECOG PS (0/1/2) 188/91/5, location of the primary site right/left 100/184, KRAS status wild/mutant/unknown 130/145/9, UGT1A1 status wild/single heterozygous/double heterozygous or homozygous/unknown 99/65/5/9/106. Median relative dose intensity of irinotecan, S-1 and bevacizumab were 0.752 (range 0.055-1.120), 0.799 (range 0.010-1.120), and 0.835 (range 0.021-1.120), respectively. The common AEs (≥5%) of grade 3 or 4 were decreased neutrophil count (23.5%), decreased white blood cells (16.6%), diarrhea (16.5%), anemia (12.0%), anorexia (9.5%), hypertension (9.2%), fatigue (6.0%), and febrile neutropenia (5.3%). RR and DCR were 14.7% and 76.6%, respectively. Median TTF was 5.9 months (95%C.I. 5.0-6.7). The common reason for treatment discontinuation were disease progression (72.4%) and AEs (16.0%). Subsequent treatment was given to 209 (76.0%) of the 275 patients who discontinued IRIS/Bev. Median PFS and OS were 7.2 (95%C.I. 6.3-8.0) and 16.3 months (95%C.I. 14.4-18.3), respectively. In this retrospective analysis, IRIS/Bev in real-world clinical practice showed efficacy comparable to other standard second-line treatments for mCRC. In this study, the incidence of diarrhea (≥ Grade 3) was 16.5%, which was lower than the incidence of diarrhea (≥ Grade 3) with IRIS (20.5%) in the FIRIS study. Diarrhea of IRIS/Bev as second-line treatment for mCRC was manageable with appropriate dose reduction and interruption.

Cost-effectiveness of Capecitabine + Irinotecan Versus Leucovorin + Fluorouracil + Irinotecan in the Second-line Treatment of Metastatic Colorectal Cancer in China

PurposeThe AXEPT trial demonstrated that modified XELIRI (mXELIRI; capecitabine + irinotecan) was noninferior to standard treatment with FOLFIRI (fluorouracil + leucovorin + irinotecan), both ± bevacizumab, in the treatment of metastatic colorectal cancer (mCRC). The present study was designed to evaluate the cost-effectiveness of mXELIRI versus FOLFIRI as a second-line treatment of mCRC. MethodsWe developed a Markov model to estimate the costs and health outcomes of mXELIRI and FOLFIRI in patients with mCRC from the Chinese payer perspective. Survival data, transition probabilities, and health utility values were obtained from published studies. The costs of drugs were obtained from the West China Hospital. Life-years (LYs), quality-adjusted life-years (QALYs) gained, incremental cost-utility ratio (ICUR), and incremental cost-effectiveness ratio (ICER) values were regarded as the primary end points. One-way sensitivity analysis and probabilistic sensitivity analysis were performed to evaluate the impact of uncertainty of parameters in the analysis. FindingsThe effectiveness was found to be 0.48 QALYs (1.14 LYs) in the mXELIRI arm and 0.41 QALYs (1.05 LYs) in the FOLFIRI arm, with total costs of 29,896.41 US dollars (USD) in the mXELIRI arm and 28,894.68 USD in the FOLFIRI arm. The ICER and ICUR with mXELIRI versus FOLFIRI were 11,130.33 USD/LY and 14,310.43 USD/QALY gained, which were less than the willingness-to-pay threshold in China (25,840.88 USD/QALY). ImplicationsBased on the results of this study, mXELIRI was found to be a cost-effective alternative to FOLFIRI as a second-line treatment of mCRC in patients in China.

Comparative Cost-effectiveness of Aflibercept and Ramucirumab in Combination with Irinotecan and Fluorouracil-based Therapy for the Second-line Treatment of Metastatic Colorectal Cancer in Japan

PurposeThe addition of aflibercept (AFL) or ramucirumab (RAM) to folinic acid, fluorouracil, and irinotecan (FOLFIRI) prolongs overall survival and progression-free survival compared with FOLFIRI alone in patients with metastatic colorectal cancer (mCRC) as second-line therapy. Although these combination regimens are recommended among the standard therapies, significant additional cost is a concern. The comparative cost-effectiveness of AFL and RAM was examined from the perspective of the Japanese health care payer. MethodsA partitioned survival analysis was constructed. The data sources were the VELOUR (Aflibercept Versus Placebo in Combination With Irinotecan and 5-FU in the Treatment of Patients With Metastatic Colorectal Cancer After Failure of an Oxaliplatin Based Regimen) and RAISE (Ramucirumab Versus Placebo in Combination With Second-Line FOLFIRI in Patients With Metastatic Colorectal Carcinoma That Progressed During or After First-Line Therapy With Bevacizumab, Oxaliplatin, and a Fluoropyrimidine) trials, which compared FOLFIRI alone with AFL or RAM in second-line treatment for mCRC. The cost and effectiveness of the combination of AFL or RAM with FOLFIRI were compared with those of FOLFIRI alone and examined between both agents in a 10-year time horizon. The health outcomes were life-years (LYs) and quality-adjusted life-years (QALYs). The costs were 2019 revisions to the drug prices and medical fees. The robustness of the model was verified by 1-way sensitivity analyses and a probability sensitivity analysis. A 2% annual discount was applied to the expenses and QALYs. A willingness-to-pay threshold of ¥7.5 million was used. FindingsCompared with FOLFIRI alone, combination AFL or RAM with FOLFIRI had incremental effects of 0.173 QALYs (0.253 LYs) and 0.137 QALYs (0.197 LYs), incremental costs of ¥3,423,481 (US $31,010) and ¥5,766,106 (US $52,229), and incremental cost-effectiveness ratios of ¥19, 836, 504 (US $179,678) and ¥41, 947, 989 (US $379,964) per QALY, respectively. Results of 1-way sensitivity analyses and probability sensitivity analysis all exceeded a willingness-to-pay threshold of ¥7.5 million. In the comparison of the 2 agents, AFL was a dominant over RAM. ImplicationsAdding AFL or RAM to FOLFIRI in the second line of mCRC treatment was not cost-effective in the Japanese health care system. On the basis of the results of this study, in the treatment of mCRC, it will be necessary to adjust the prices of AFL and RAM with the improvement of clinical parameters, such as survival time and adverse events. Of the 2 agents, AFL was more cost-effective than RAM.

FOLFIRI versus irinotecan monodrug as second-line treatment in metastatic colorectal cancer patients: An open, multicenter, prospective, randomized controlled phase III clinical study.

4038 Background: The most commonly used treatment methods for metastatic colorectal cancer (mCRC)are systemic chemotherapy, molecular targeted therapy and local treatment. The main chemotherapy drugs for mCRC include Irinotecan, Oxaliplatin and 5-Fu. V308 Research shows that FOLFOX and FOLFIRI can be standard first or second-line of each other in the treatment of metastatic colorectal cancer. However if the first-line treatment regimen containing 5-FU fails, whether it is necessary to re-challenge 5-FU when Irinotecan is applied in the second line is unknown. There is no head-to-head comparative study to answer whether the FOLFIRI regimen is better than the Irinotecan monodrug. Therefore, it is necessary to carry out a comparative study of FOLFIRI Versus Irinotecan monodrug to observe whether adding 5-Fu on the basis of Irinotecan can improve the therapeutic effect. Methods: This was a randomized phase III trial. Patients from 5 centers in China with metastatic colorectal adenocarcinoma, for whom first-line of chemotherapy including oxaliplatin combined with fluorouracil drugs (combined or not combined with targeted therapy) had failed, were enrolled. 172 patients with mCRC were randomly treated with FOLFIRI or Irinotecan monodrug were included in this study. FOLFIRI group: Irinotecan 180mg/m2; Lecovorin 400mg/m2; 5-Fu 400mg/m2; 5-Fu 2400mg/m2 CIV 46h. Irinotecan monodrug group 180mg/m2, The regimen was repeated every 2 weeks. The primary endpoint is PFS, and this clinical trail is a superiority trial. Results: ITT (Intention-To-Treat) analysis: Among 172 patients, 10 had PR, 93 had SD, and 63 had PD, 6 patients have not received efficacy evaluation yet. The ORR was 5.68% VS. 5.95%, and the DCR was 61.36% and 54.76% in FOLFIRI group and Irinotecan monodrug group, respectively. Adverse reactions included neutropenia, stomatitis, diarrhea, fatigue, abnormal liver enzymes, pyrexia, arrhythmia, nausea and most of these were grade 1-2. The dose reduction rate induced by drug tocixity of was 13.64% and 7.14% in FOLFIRI group and Irinotecan monodrug group, respectively. Conclusions: These data show that Irinotecan monodrug has the similar ORR and DCR with FOLFIRI regimen in second-line treatment of mCRC. Irinotecan monodrug has lower adverse effect. Clinical trial information: NCT02935764 .

Efficacy and safety of regorafenib in combination with chemotherapy as second-line therapy in patients with metastatic colorectal cancer: A network meta-analysis.

115 Background: Recent studies have shown efficacy of chemotherapy (CTX) in combination with different biological agents including regorafenib (REG) in second-line treatment of metastatic colorectal cancer (mCRC). As there is no evidence on the relative efficacy and safety of REG as compared to other biological agents in combination with CTX, we evaluated the same in this network meta-analysis (NMA). Methods: Randomized controlled trials (RCTs) comparing efficacy and safety of biological agents + CTX against CTX alone as second-line treatment of mCRC were retrieved from PubMed, EMBASE and Cochrane databases. Progression free survival (PFS) was the primary outcome, while objective response rate (ORR), overall survival (OS) and safety were secondary outcomes. Outcomes were compared by random/mixed-effects NMA using Bayesian (R software, Gemtc package) and frequentist (R software, netmeta package) approaches. Results: Twelve RCTs comparing 9 different treatment regimens with a total of 6805 patients were included for analysis. Hazard ratios (HR)/ odds ratio (OR)/ relative risk (RR) and 95% confidence intervals (CI) for PFS, ORR and grade> 3 adverse events (AE) of selected comparisons from the results of the NMA are shown in table. Conclusions: REG combined with CTX might be a potential alternative to conventional therapeutic options and could be considered as the best option for treating KRAS and BRAF mutated mCRC patients. Future RCTs are needed to confirm our results. [Table: see text]

Association of consensus molecular subtypes (CMS) with time to progression (TTP), progression free survival (PFS), and overall survival (OS) with second-line FOLFIRI ± regorafenib in metastatic colorectal cancer (mCRC).

597 Background: LCCC1029 was a 2:1 randomized phase II trial of second-line FOLFIRI plus either regorafenib or placebo in mCRC that showed no statistically significant difference in PFS or OS. CMS, defined using gene expression, is prognostic for PFS and OS in previously untreated mCRC, but the impact of CMS in second-line treatment is unclear, as well as its impact on regorafenib efficacy. Methods: RNAseq on archival tumor tissue was successfully performed in 68 LCCC1029 patients (49 on regorafenib, 19 on placebo). A multinomial elastic net CMS classifier was trained using 6 CRC gene expression data sets with known CMS classification. We built our model with only CMS1-4 classified samples and then applied it to normalized and median adjusted RNASeq from LCCC1029 to classify all samples into CMS1-4. TTP, PFS, and OS were compared using Kaplan-Meier method and log-rank tests, and hazard ratios were estimated using Cox proportional hazards method. Results: Our model had > 93% sensitivity and specificity for CMS1-4 in the training data set; the 17% of non-consensus samples in the training data were predominantly labeled CMS2. We classified the LCCC1029 samples as CMS1 (12%), CMS2 (63%), CMS3 (4%), and CMS4 (21%). CMS was prognostic for TTP (log-rank p=0.03), with median for CMS1 of 2.0 months (95% CI 0.0-4.8) versus 5.6 months (5.3-5.9) for CMS2 and 7.8 months (5.5-10.1) for CMS4. There was a trend toward association between CMS and either PFS (log-rank p = 0.11) or OS (log-rank p = 0.085). CMS2 had superior OS compared to CMS1 (HR 0.39, 95% CI 0.17-0.87, p = 0.02). With our limited sample size, we found no significant interaction between CMS and treatment arm for TTP, PFS, or OS. Conclusions: CMS is associated with significant differences in TTP in second-line treatment of mCRC in LCCC1029, and specific CMS types also have differences in OS. Thus, the prognostic impact of CMS extends to second-line treatment in mCRC, meriting further study of CMS classification in additional non-first-line studies.

Cetuximab in treatment of metastatic colorectal cancer: background and clinical observation

Today, the researchers continue the search for the most optimal regimens of drug therapy for metastatic colorectal cancer (mCRC) which are supposed to increase progression-free survival (PFS) and overall survival (OS), improve patient quality of life. Due to significant progress in chemotherapy (CT) and surgical treatment of mCRC, and the multidisciplinary approach, the treatment algorithms have changed. The increase in life expectancy of patients is observed when all three of the most active chemotherapy drugs in this disease: oxaliplatin (Oxa), irinotecan (Iri), fluoropyrimidines are administered. The inclusion of the targeted drug cetuximab in modern mCRC treatment regimens led to a statistically significant increase in the objective response rate (ORR), median PFS and OS. The article presents the results of the most significant clinical studies of the eficacy of the antiEGFR drug cetuximab in combination with standard CT regimens for the first- and second-line treatment of mCRC, and describes a clinical case of the successful use of cetuximab in mCRC therapy.

Observational Cohort Study of Patients With Metastatic Colorectal Cancer Initiating Chemotherapy in Combination With Bevacizumab (CONCERT)

BackgroundThe CONCERT study (observational cohort study of patients with metastatic colorectal cancer initiating chemotherapy in combination with bevacizumab) aimed to describe patient characteristics, bevacizumab use, its efficacy in terms of progression-free survival (PFS) and overall survival (OS), and its safety in patients with metastatic colorectal cancer (mCRC) treated in daily medical practice. Patients and MethodsCONCERT was an observational, prospective, multicenter, cohort study conducted in France. Patients with mCRC initiating bevacizumab combined with chemotherapy were included and followed up for ≤ 36 months. ResultsOverall, 737 evaluable patients were assessed, and 71%, 21%, and 8% initiated bevacizumab as first-, second-, or third-line therapy or more, respectively. Their mean age was 64.5 years (range, 25-88 years), and 60% were men. Bevacizumab was mainly started at 5 mg/kg every 2 weeks (95%) and mostly combined with FOLFIRI (leucovorin, 5-fluorouracil, irinotecan; 68.0%) or FOLFOX (leucovorin, 5-fluorouracil, oxaliplatin; 22.0%). The median PFS was 10.4 months (95% confidence interval [CI], 9.6-11.3) in first-line, 8.5 months (95% CI, 7.0-9.2) in second-line, and 6.3 months (95% CI, 4.5-8.9) in third-line or beyond. The corresponding median OS was 25.3 months (95% CI, 21.5-28.6), 19.1 months (95% CI, 15.7-22.6), and 14.9 months (95% CI, 11.6-20.4). In first-line treatment, primary tumor resection and oxaliplatin-based chemotherapy were prognostic of a longer PFS. Eastern Cooperative Oncology Group performance status ≥ 2, > 1 metastatic sites, and intermediate or high risk using the Köhne prognostic index were associated with shorter PFS. The safety profile of bevacizumab combined with chemotherapy was comparable to that found by other observational studies of mCRC. ConclusionThe efficacy and safety results of bevacizumab plus chemotherapy as first- and second-line treatment of mCRC in daily practice in the CONCERT observational, prospective study were in line with those from randomized clinical studies.

Randomized phase II study of dual epidermal growth factor receptor inhibition with erlotinib and panitumumab with or without irinotecan as second-line therapy in patients with metastatic colorectal cancer.

e15037Background: Median PFS for second line treatment of mCRC with anti-EGFR ranges from 4.5-5.5 months. Preclinical data support the hypothesis that dual blockade of the EGFR with a monoclonal an...

Current controversies in the management of metastatic colorectal cancer.

The factors affecting the decisions for the treatment for patients with metastatic colorectal cancer (mCRC) are related to the patient, the tumor, and the treatment itself. Both cetuximab and panitumumab are anti-EGFR monoclonal antibody options for patients with RAS wild-type tumors. Several trials comparing these agents with bevacizumab are analyzed in this paper. The liver is the most common site of metastases in patients with CRC, and perioperative chemotherapy has been shown to yield benefits in this setting. In the second-line treatment for mCRC, maintenance with bevacizumab after progression following first-line treatment is convenient in some groups of patients with mCRC. Also, aflibercept has demonstrated benefits in response rate, progression-free survival, and overall survival in second-line treatment, whereas regorafenib provides benefits to patients progressing on all standard therapies. Several novel therapeutic options for patients with mCRC are under development, and these are discussed.

A Phase I/II Study of XELIRI Plus Bevacizumab as Second-Line Chemotherapy for Japanese Patients With Metastatic Colorectal Cancer (BIX Study)

Capecitabine is used mainly with oxaliplatin to treat metastatic colorectal cancer (mCRC). Results from capecitabine plus irinotecan (XELIRI) with or without bevacizumab (BV) have been reported in Europe but not in Japan. Consequently, the safety and efficacy of XELIRI plus BV in Japanese patients with mCRC were assessed in a single-arm phase II study. Eligible patients had had prior chemotherapy containing BV for mCRC and wild-type or heterozygous UGT1A1. Therapy in each 21-day treatment cycle consisted of capecitabine (800 mg/m(2) twice daily on days 1-15), irinotecan (200 mg/m(2) on day 1), and BV (7.5 mg/kg on day 1). The primary endpoint was dose-limiting toxicity in phase I and progression-free survival (PFS) in phase II. A total of 34 patients (6 in phase I, 28 in phase II) were enrolled from May 2010 to June 2011. Baseline characteristics included a median age of 60 years (range: 22-74 years) for 24 men and 10 women. No dose-limiting toxicities appeared in phase I. Median PFS was 240 days (95% confidence interval: 179-311 days). Overall response rate was 18.1%, and the disease-control rate was 90.9%. The incidence of adverse events frequently associated with irinotecan and capecitabine were neutropenia (any grade, 55.9%; grade 3 or 4, 11.8%), diarrhea (any grade, 50%; grade 3 or 4, 5.9%), and hand-foot syndrome (any grade, 61.8%; grade 3 or 4, 5.9%). Our results suggest that XELIRI plus BV is well tolerated and effective as a second-line treatment for mCRC in Japanese patients. This regimen could be especially appropriate for patients resistant to oxaliplatin-based regimens.

Surrogate endpoints in second-line treatment for mCRC: A systematic literature-based analysis from 23 randomised trials

Purpose. To evaluate progression-free survival (PFS), overall response rate (ORR) and disease control rate (DCR) as potential surrogate endpoints (SEP) for overall survival (OS) in second-line treatment for metastatic colorectal cancer (mCRC).Methods. A systematic literature search of randomised trials of second-line chemotherapy for mCRC reported from January 2000 to July 2013 was performed. Correlation coefficients weighted by number of patients in the treatment arms between median PFS, ORR and DCR with median OS were estimated.Results. Twenty-three trials reflecting 10 800 patients met the inclusion criteria. Median PFS and OS across all trials were 4.5 months and 11.5 months and median ORR and DCR were 11.4% and 65%, respectively. PFS showed moderate correlation with OS [RPFS = 0.73; 95% confidence interval (CI) 0.61–0.82]. In contrast, ORR only weakly correlated with OS (RORR = 0.58; 95% CI 0.38–0.72, n = 22). Despite a small number of studies (n = 10) reporting on DCR, moderate correlation with OS was observed (RDCR = 0.74; 95% CI 0.56–0.86).Conclusion. Based on the available trial-level data, PFS may serve as an appropriate SEP in second-line chemotherapy for mCRC. A small number of studies revealed moderate correlation of DCR with OS that justifies further investigation.

Treatment patterns and costs in second-line (2L) metastatic colorectal cancer (mCRC).

544 Background: Administrative claims databases are an important data source to examine treatment (tx) patterns, costs and outcomes, but are subject to limitations. This study included a chart review to assess a claims-based algorithm for identifying 2L mCRC patients (pts). Tx patterns and costs were compared between mCRC pts treated with bevacizumab (BEV) or cetuximab (CET). Methods: 2LmCRC pts were identified from a US commercial insurance claims database (1/2008-6/2011). Initial identification required pts to have ≥2 claims ≥30 d apart for colon or rectal cancer and metastatic (met) disease. Continuous enrollment for ≥6 mo before and after the date of 1st met claim, ≥2 lines of therapy (LOT), and 2L tx with BEV or anti-EGFR was required. 2L was defined as addition of any new agent ≥28 d after start of 1st LOT. Charts from 92 pts were abstracted and used to refine and corroborate the algorithm. Generalized Linear Models (GLM) were used to assess differences in healthcare costs between patients on BEV or CET during 2L. Results: The match rate of claims identified mCRC pts treated with multiple lines of therapy confirmed by chart abstraction ranged from 85% to 97%. Applying the final algorithm to the overall claims data resulted in the identification of 569 pts: 450 pts receiving BEV and 119 pts receiving CET. A total of 38 panitumumab patients were excluded from analysis due to small sample size. Pt characteristics were similar; mean age was 61 years and 58% were males. In 2L, BEV was commonly used with 5FU or capecitabine-based regimens (81%) and CET with irinotecan-based regimens (73%). BEV pts had significantly lower all-cause healthcare costs (adjusted difference: –$12,239, p=0.02), and medical costs (–$13,672, p=0.01) during 2L. While on second-line therapy, BEV pts also had lower average monthly all-cause and medical costs than CET pts. Sensitivity analysis using variations of the case finding algorithm yield similar results. Conclusions: The use of BEV during second line treatment of mCRC was found to be associated with significantly lower healthcare costs relative to the use of CET from a large US healthcare claims database.

Evaluation of panitumumab (pmab) plus fluorouracil, leucovorin, and irinotecan (FOLFIRI) after first-line bevacizumab (bev) in patients (pts) with metastatic colorectal cancer (mCRC): A subgroup analysis of study 181.

3574^ Background: Pmab, a fully human monoclonal antibody targeting EGFR, has demonstrated activity in combination with FOLFIRI for second-line treatment of mCRC (study 181). Here, we describe the ...

Axitinib or bevacizumab (bev) plus FOLFOX or FOLFIRI as second-line therapy in patients (pts) with metastatic colorectal cancer (mCRC).

478 Background: Axitinib (AG-013736,AG), an oral selective inhibitor of vascular endothelial growth factor (VEGF) receptors 1, 2, and 3, shows activity in multiple tumor types including those refractory to front-line chemotherapy. Methods: This multicenter, open-label, randomized phase II trial compared AG and bev in combination with FOLFOX or FOLFIRI in second-line mCRC. Pts previously treated with irinotecan were randomized to mFOLFOX6 plus AG 5 mg BID or bev 5 mg/kg q2wk; pts who received oxaliplatin were randomized to FOLFIRI with AG or bev at the same doses, with stratification by performance status and prior bev therapy. Primary endpoint was progression-free survival (PFS). Results: 171 pts were randomized from March 2008 to July 2009. There were no significant differences in PFS or median overall survival (mOS) between the AG and bev arms with FOLFOX or FOLFIRI. However, there was a trend towards reduced mOS in the FOLFIRI arms with AG compared to bev, and a trend towards improved mOS with AG+FOLFOX vs bev+FOLFOX. There were more treatment discontinuations (DCs) and a higher incidence of grade ≥3 adverse events (AEs) in the AG arms (diarrhea, asthenia, fatigue; Table). Conclusions: This study did not meet the primary endpoint, showing similar PFS with AG compared to bev when added to second-line chemotherapy. A potential factor in these results was earlier DCs in the AG versus bev arms, likely secondary to increased AEs. While VEGF inhibitors may have a role in second-line treatment of mCRC, at current dosing regimens AG-based chemotherapy shows no improvement in outcome compared to bev. [Table: see text] [Table: see text]

State of the art: radiolabeled microspheres treatment for liver malignancies

Importance of the field: Metastatic tumours of the liver are responsible for significant morbidity and mortality, and only a small percentage is resectable with curative intent. Hepatic artery radioembolization (RE) with yttrium-90 (90Y)-loaded microspheres is an alternative treatment for patients with unresectable primary or secondary liver tumours, especially in cases of metastatic colorectal cancer (mCRC) and hepatocellular carcinoma (HCC).Areas covered in this review: Data from recent relevant clinical trials with 90Y-RE are discussed, focusing on response rate assessments and treatment outcome.What the reader will gain: Current data show that 90Y-RE combined with radiosensitizing chemotherapy is a safe and efficient modality that extends the time to progression in liver mCRC and unresectable HCC, although no survival benefits have been demonstrated. The treatment response after 90Y-RE seems to be better assessed using metabolic response assessments with serial fluorodeoxyglucose positron emission tomography (FDG-PET) in cases of FDG-avid tumours than with morphological criteria measured on computed tomography or magnetic resonance imaging (RECIST or WHO trials). Predictive models using multimodality imaging approaches (PET-SPECT-CT image fusion algorithms) have been proposed to better select patients for 90Y-RE. The optimal routine role of radioembolization remains to be defined; the complexity and wide availability of available therapeutic alternatives confuses the role of a locoregional treatment in a generalized disease.Take home message: 90Y-RE is a safe and efficient treatment modality in salvage therapy of colorectal cancer metastatic to the liver and in unresectable HCC. However, it has still to find its place as a first- or second-line treatment of mCRC in combination with or as an alternative to available biological agents. The role of 90Y-RE in other solid tumour types metastatic to the liver is much more uncertain and investigations in clinical situations in which disease is strictly limited to the liver are required. Pretherapeutic work-up, initially developed to explore hepatic vasculature and to assess lung shunting, might be able to predict treatment outcome, allowing a better patient selection.