Predictive value of VEGF gene polymorphisms in metastatic colorectal cancer patients treated with a bevacizumab-based chemotherapy.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e14512-e14512
Author(s):  
Paola Ulivi ◽  
Giorgia Marisi ◽  
Emanuela Scarpi ◽  
Alessandro Passardi ◽  
Angela Ragazzini ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Direct Sequencing ◽  
Statistical Significance ◽  
Objective Response ◽  
Case Series ◽  
Predictive Marker ◽  
Treated Group ◽  
Phase Iii ◽  
Nucleotide Polymorphisms

e14512 Background: Bevacizumab (B) + chemotherapy (CT) is a common choice for first-line treatment of metastatic colorectal cancer (mCRC). However, molecular predictors of B efficacy have still not been identified. In this study we verified the role of specific VEGF polymorphisms as predictive markers of the efficacy of B in mCRC patients. Methods: One hundred and forty-nine patients enrolled onto the phase III prospective multicentric randomized “Italian Trial in Advanced Colorectal Cancer (ITACa)” trial were considered for this study. Seventy-four patients received FOLFIRI or FOLFOX plus B and 75 patients received only CT. A peripheral blood sample was collected from each patients and submitted to genomic DNA extraction. Five single nucleotide polymorphisms (SNPs) were analyzed by direct sequencing: VEGF -2578 C/A, -1498 C/T, -1154 G/A, -634 G/C, +936 C/T. All candidate genotypes were evaluated for a potential correlation with objective response rate (ORR) (Chi-square test). Results: In the B-treated group, the presence of VEGF -2578 AA, -634 GG or -1498 CC polymorphisms was associated with a better ORR compared to the other genotypes. In particular, of the 17 patients carrying the VEGF -2578 AA genotype, 14 (82.4%) showed a response, whereas only 30 (54.6%) of the 55 patients carrying -2578 CC or CA responded to therapy (p=0.05). Similarly, of 30 patients with VEGF -634 GG, 23 (76.7%) responded to therapy, whereas only 21 (50%) of the 42 patients with VEGF -634 GC or CC were responders (p=0.03). Moreover, 13 (81.3%) of the 16 patients carrying VEGF -1498 CC were responders, whereas of the 56 patients with VEGF -1498 CT or TT, only 31 (55.4%) showed a response (p=0.07). No differences in terms of ORR were observed in patients receiving only chemotherapy. However, as a result of the low power of the interaction test, the relation between ORR and treatment was very close to statistical significance for VEGF -2578 only (p=0.07). Conclusions: VEGF -2578 C/A seems to be a potential predictive marker for B-based CT in mCRC patients. Further studies on larger case series are now needed to confirm this finding.

Association of TLR9 polymorphism with overall survival in metastatic colorectal cancer patients treated with FOLFIRI plus bevacizumab enrolled in FIRE3.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 498-498 ◽  
Author(s):  
Satoshi Okazaki ◽  
Sebastian Stintzing ◽  
Volker Heinemann ◽  
Shu Cao ◽  
Wu Zhang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Multivariate Analysis ◽  
Clinical Outcome ◽  
Metastatic Colorectal Cancer ◽  
Direct Sequencing ◽  
Statistical Significance ◽  
Nucleotide Polymorphisms ◽  
Mutant Type ◽  
Tlr9 Gene

498 Background: Toll-like receptors (TLRs) play crucial roles in carcinogenesis and evolution of the tumor microenvironment. TLR9 dependent stimulation is known to cause antitumor activity not only by activating anti-tumor immunity but also by interfering with angiogenesis. We tested the hypothesis that genetic variations in TLR9 will be associated with clinical outcome in metastatic colorectal cancer (mCRC) patients treated with bevacizumab based chemotherapy. Methods: Genomic DNA was isolated from tissue samples from 301 mCRC patients enrolled in the FIRE3 trial and treated in first-line with FOLFIRI plus bevacizumab. Three single nucleotide polymorphisms (SNPs) in the TLR9 gene, rs187084 A/G, rs352140 C/T, and rs5743836 T/C, were analyzed by PCR-based direct sequencing. These SNPs were tested for the association with tumor response, progression free survival (PFS), and overall survival (OS). Subgroup analyses by gender, tumor location, and Kras status were also analyzed. Results: The patients carrying variant genotype (T/C or C/C) for rs5743836 showed a strong trend toward shorter OS compared to those with a wild-type T/T genotype (median: 21.2 vs. 24.8 months, HR: 1.35, P = 0.069). This difference remained statistically significant in the multivariate analysis (HR: 1.53, 95%CI: 1.09-2.15, P = 0.014). In the subgroup of Kras-mutant type, the variants (T/C and C/C) were significantly associated with worse PFS (8.1 vs. 11.3 months, HR 2.06, p = 0.043) and OS (16.4 vs. 25.1 months, HR: 2.44, p = 0.012), which retained statistical significance in the multivariate analysis. No association with clinical outcome was observed for rs187084 and rs352140. Conclusions: Our findings suggest that TLR9 polymorphism of rs5743836 is a prognostic marker of mCRC patients, especially of those with Kras-mutant type, who were treated with FOLFIRI plus bevacizumab.

Phase III Multicenter Randomized Trial of Oxaliplatin Added to Chronomodulated Fluorouracil–Leucovorin as First-Line Treatment of Metastatic Colorectal Cancer

2000 ◽  
Vol 18 (1) ◽  
pp. 136-136 ◽  
Author(s):  
S. Giacchetti ◽  
B. Perpoint ◽  
R. Zidani ◽  
N. Le Bail ◽  
R. Faggiuolo ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Objective Response ◽  
Sensory Neuropathy ◽  
Phase Iii ◽  
Line Treatment ◽  
Survival Times ◽  
First Line ◽  
Grade 3 ◽  
First Line Treatment

PURPOSE: To study how adding oxaliplatin (l-OHP) to chronomodulated fluorouracil (5-FU)–leucovorin (LV) affected the objective response rate, as first-line treatment of metastatic colorectal cancer. PATIENTS AND METHODS: Two hundred patients from 15 institutions in four countries were randomly assigned to receive a 5-day course of chronomodulated 5-FU and LV (700 and 300 mg/m2/d, respectively; peak delivery rate at 0400 hours) with or without l-OHP on the first day of each course (125 mg/m2, as a 6-hour infusion). Each course was repeated every 21 days. Response was assessed by extramural review of computed tomography scans. RESULTS: Grade 3 to 4 toxicity from 5-FU–LV occurred in ≤ 5% of the patients (≤ 1% of the courses). Grade 3 to 4 diarrhea occurred in 43% of the patients given l-OHP (10% of the courses), and less than 2% of the patients had severe hematotoxicity. Thirteen percent of the patients had moderate functional impairment from peripheral sensory neuropathy. Sixteen percent of the patients receiving 5-FU–LV had an objective response (95% confidence interval [CI], 9% to 24%), compared with 53% of those receiving additional l-OHP (95% CI, 42% to 63%) (P < .001). The median progression-free survival time was 6.1 months with 5-FU–LV (range, 4.1 to 7.4 months) and 8.7 months (7.4 to 9.2 months) with l-OHP and 5-FU–LV (P = .048). Median survival times were 19.9 and 19.4 months, respectively. CONCLUSION: By chronomodulating 5-FU–LV, we were able to add l-OHP without compromising dose-intensities. l-OHP significantly improved the antitumor efficacy of this regimen.

AGENT: An open-label phase III study of arfolitixorin versus leucovorin in modified FOLFOX-6 for first-line treatment of metastatic colorectal cancer.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. TPS268-TPS268
Author(s):  
Heinz-Josef Lenz ◽  
Peter Gibbs ◽  
Sebastian Stintzing ◽  
Gerald W. Prager ◽  
Peter Nygren ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Objective Response ◽  
Metabolic Activation ◽  
Phase Iii ◽  
First Line ◽  
Open Label ◽  
Eligibility Criteria ◽  
Number Of Patients ◽  
Secondary Endpoints

TPS268 Background: 5-fluorouracil (5FU), in combination with folates, is an established cornerstone of metastatic colorectal cancer (mCRC) treatment. All folates currently approved for mCRC need to be metabolically activated to [6R]-5,10-methylenetetrahydrofolic acid ([6R]-MTHF), the active thymidylate synthase co-substrate that potentiates the effect of 5FU. Arfolitixorin does not require multi-step metabolic activation, and may produce higher, and less inter- and intraindividually variable, concentrations of [6R]-MTHF than leucovorin. Methods: The phase III AGENT trial (NCT03750786) is a randomized, multicenter, parallel-group study comparing the efficacy of arfolitixorin versus leucovorin in mCRC patients treated with first-line 5FU, oxaliplatin, and bevacizumab. Patients are randomized (1:1) to the investigational arm (arfolitixorin + 5FU + oxaliplatin [ARFOX] + bevacizumab) or the comparator arm (leucovorin + 5FU + oxaliplatin [modified FOLFOX-6] + bevacizumab), and treated until disease progression based on RECIST 1.1 criteria. Recruitment is ongoing, and aims to randomize 440 patients in 18 months. Eligibility criteria include non-resectable mCRC; eligibility for 5FU, oxaliplatin, and bevacizumab therapy; ECOG PS 0 or 1. The study will be conducted across approximately 100 sites in Australia, Austria, Canada, France, Germany, Greece, Japan, Spain, Sweden, and USA. The primary endpoint is objective response rate. Key secondary endpoints are progression-free survival and duration of response. Additional secondary endpoints include overall survival, quality of life, safety and tolerability, and number of patients undergoing curative metastasis resection. A translational program will evaluate expression levels of several folate metabolism- and transportation-related genes in mCRC tumor biopsies to determine their relationship to treatment outcome. A broad array of genes will analyzed, including ATP-binding cassette C3 (ABCC3) transporter, methylenetetrahydrofolate dehydrogenase 2 (MTHFD2), proton-coupled folate transporter (PCFT), and serine hydroxymethyltransferase 1 (SHMT1). Interim data are expected in mid 2020. Clinical trial information: NCT03750786.

Gene polymorphisms of CCL3, CCL4, CCL5, and CCR5 network in metastatic colorectal cancer patients treated with regorafenib.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 199-199
Author(s):  
Mitsukuni Suenaga ◽  
Wu Zhang ◽  
Tetsuo Mashima ◽  
Marta Schirripa ◽  
Shu Cao ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Cancer Patients ◽  
Gene Polymorphisms ◽  
Direct Sequencing ◽  
Rank Test ◽  
Alternative Mechanism ◽  
Nucleotide Polymorphisms ◽  
Positive Correlation ◽  
Colorectal Cancer Patients

199 Background: We previously reported that genetic variant in the CCL5/CCR5 pathway predict efficacy of regorafenib in metastatic colorectal cancer patients (mCRC). CCL5 rs2280789 G allele and CCL5 rs3817655 T allele were associated with longer overall survival (OS) and severe skin toxicity due to low VEGF-A production via endothelial progenitor cell (EPC). CCL4 rs1634517 G allele and CCL3 rs1130371 C allele correlated with longer Progression-free survival (PFS) and OS. We investigated the biological role of CCL4 and CCL3 gene polymorphisms. Methods: We analyzed genomic DNA extracted from 79 samples of a Japanese cohort receiving regorafenib. Single nucleotide polymorphisms (SNPs) of genes in CCL5/CCR5 pathway were analyzed by PCR-based direct sequencing. Blood samples were obtained from 57 patients at baseline (BL), day 21 and progressive disease (PD), and serum CCR5, CCR5 ligands (CCL3, CCL4, CCL5) and VEGF-A levels were measured using ELISA. PFS and OS were analyzed using Kaplan-Meier curves and log-rank test. Results: Increased CCL3 levels at PD were associated with longer OS than decreased (12.6 vs 4.8 mos, P = 0.003). Patients with decreased CCL4 levels at day 21 had a trend toward longer PFS and tumor shrinkage. Positive correlation was observed between CCL3 and CCR5 throughout the treatment independent of other ligands (change at day 21: r = 0.426, P = 0.009). There was no significant correlation of CCL3 and CCL4 levels with VEGF-A levels. Patients with the G/G variant in CCL3 rs1130371 had increased CCL3, CCR5 and CCL5 levels at day 21 than any A allele. Similarly, patients with the C/C variant had increased CCL3, CCR5 and CCL5 levels at day 21 compared with those with any A allele. In contrast, both CCL5 rs2280789 G allele and CCL5 rs3817655 T allele were associated with increased CCL3 levels and decreased CCL4 levels at day 21 (P = 0.006, P = 0.043; P = 0.006, P = 0.043). Conclusions: Positive correlation of CCL3, CCR5 and CCL5 impact similarly on CCL3 and CCL4 SNPs, while different manner between CCL3 and CCL4 was found in CCL5 SNPs. This suggests an alternative mechanism of action in the network of CCR5 and the ligands except CCL5-VEGF-A signaling via EPC in mCRC patients receiving regorafenib.

Response-Independent Survival Benefit in Metastatic Colorectal Cancer: A Comparative Analysis of N9741 and AVF2107

2008 ◽  
Vol 26 (2) ◽  
pp. 183-189 ◽  
Author(s):  
Axel Grothey ◽  
Eric E. Hedrick ◽  
Robert D. Mass ◽  
Somnath Sarkar ◽  
Sam Suzuki ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Survival Benefit ◽  
Tumor Response ◽  
Objective Response ◽  
Progression Free Survival ◽  
Phase Iii ◽  
First Line ◽  
First Line Therapy ◽  
Phase Iii Study

PurposeIn the phase III study AVF2107g, bevacizumab (BV) demonstrated a survival benefit when added to irinotecan, fluorouracil, and leucovorin (IFL) in first-line metastatic colorectal cancer (mCRC). In a parallel phase III study, Intergroup N9741, oxaliplatin plus fluorouracil and leucovorin (FOLFOX) also demonstrated a survival benefit compared with IFL. As these two superior therapies have differing mechanisms of action, we explored whether the improved survival associated with the superior therapy was dependent on tumor response.Patients and MethodsFor these retrospective, exploratory analyses, patients were defined as responders or nonresponders by whether complete or partial response was achieved with first-line therapy.ResultsCompared with IFL alone, BV plus IFL and FOLFOX each demonstrated statistically significant improvements in progression-free survival (PFS) and overall survival (OS) regardless of objective tumor response. BV-treated nonresponders had a hazard ratio (HR) of 0.63 (P = .0001) for PFS and 0.76 (P = .0188) for OS compared with IFL-treated nonresponders. FOLFOX-treated nonresponders had an HR of 0.75 (P = .0029) for PFS and 0.74 (P = .0030) for OS compared with IFL-treated nonresponders.ConclusionIn both AVF2107g and N9741, objective response did not predict the magnitude of PFS or OS benefit from the superior therapy; nonresponders, despite a poorer prognosis than responders, achieved extended PFS and OS from BV plus IFL or FOLFOX compared with IFL. On the basis of these data, tumor response in metastatic colorectal cancer is not a necessary factor for a therapy to provide benefit to an individual patient.

Open-Label Phase III Trial of Panitumumab Plus Best Supportive Care Compared With Best Supportive Care Alone in Patients With Chemotherapy-Refractory Metastatic Colorectal Cancer

2007 ◽  
Vol 25 (13) ◽  
pp. 1658-1664 ◽  
Author(s):  
Eric Van Cutsem ◽  
Marc Peeters ◽  
Salvatore Siena ◽  
Yves Humblet ◽  
Alain Hendlisz ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Supportive Care ◽  
Metastatic Colorectal Cancer ◽  
Disease Progression ◽  
Human Monoclonal Antibody ◽  
Objective Response ◽  
Response Rates ◽  
Best Supportive Care ◽  
Phase Iii ◽  
Tumor Cell Membrane

PurposePanitumumab is a fully human monoclonal antibody directed against the epidermal growth factor receptor (EGFR). We compared the activity of panitumumab plus best supportive care (BSC) to that of BSC alone in patients with metastatic colorectal cancer who had progressed after standard chemotherapy.Patients and MethodsWe randomly assigned 463 patients with 1% or more EGFR tumor cell membrane staining, measurable disease, and radiologic documentation of disease progression during or within 6 months of most recent chemotherapy to panitumumab 6 mg/kg every 2 weeks plus BSC (n = 231) or BSC alone (n = 232). Tumor assessments by blinded central review were scheduled from week 8 until disease progression. The primary end point was progression-free survival (PFS). Secondary end points included objective response, overall survival (OS), and safety. BSC patients who progressed could receive panitumumab in a cross-over study.ResultsPanitumumab significantly prolonged PFS (hazard ratio [HR], 0.54; 95% CI, 0.44 to 0.66, [P < .0001]). Median PFS time was 8 weeks (95% CI, 7.9 to 8.4) for panitumumab and 7.3 weeks (95% CI, 7.1 to 7.7) for BSC. Mean (standard error) PFS time was 13.8 (0.8) weeks for panitumumab and 8.5 (0.5) weeks for BSC. Objective response rates also favored panitumumab over BSC; after a 12-month minimum follow-up, response rates were 10% for panitumumab and 0% for BSC (P < .0001). No difference was observed in OS (HR, 1.00; 95% CI, 0.82 to 1.22), which was confounded by similar activity of panitumumab after 76% of BSC patients entered the cross-over study. Panitumumab was well tolerated. Skin toxicities, hypomagnesaemia, and diarrhea were the most common toxicities observed. No patients had grade 3/4 infusion reactions.ConclusionPanitumumab significantly improved PFS with manageable toxicity in patients with chemorefractory colorectal cancer.

A randomized, double-blind, placebo-controlled, multi-centered phase 3 trial comparing fruquintinib versus placebo plus best supportive care in Chinese patients with metastatic colorectal cancer (FRESCO).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 3508-3508 ◽  
Author(s):  
Jin Li ◽  
Shukui Qin ◽  
Yuxian Bai ◽  
Yanhong Deng ◽  
Lei Yang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Kinase Inhibitor ◽  
Objective Response ◽  
Group Versus ◽  
Phase Iii ◽  
Chinese Patients ◽  
Double Blind ◽  
Double Blind Placebo ◽  
Third Line

3508 Background: Treatment options for third-line metastatic colorectal cancer (mCRC) patients remain limited in China. Fruquintinib, an oral kinase inhibitor selectively targeting vascular endothelial growth factor receptors, in a phase II study was found to significantly improve progression free survival (“PFS”) in patients with mCRC as compared to placebo (ESMO abs#2111). Based on these results, a Phase III registration trial, FRESCO, was carried out to confirm fruquintinib’s efficacy and safety in third-line mCRC patients (clinicaltrials.gov # NCT02314819). Methods: This is a randomized, double-blind, placebo-controlled, multi-center phase III trial. Patients with mCRC who have failed at least 2 lines of systemic chemotherapy were enrolled from 28 centers in China. Patients were stratified based on prior anti-VEGF therapy and K-ras status and randomized to a fruquintinib or placebo arm in a 2:1 ratio. The primary endpoint was overall survival (“OS”) which was analyzed in the intent-to-treat population. Results: Between December 12, 2014 and May 13, 2016, 416 patients were randomized. Protocol predefined number of OS events for final analysis was reached on January 17, 2017. Fruquintinib significantly improved OS comparing to placebo with a hazard ratio of 0.65 (95% CI: 0.51-0.83; two sided p<0.001). Median OS was 9.30 months [95% CI 8.18-10.45] in the fruquintinib group versus 6.57 months [95% CI 5.88-8.11] in the placebo group. Statistically significant benefits were also seen with fruquintinib in all secondary endpoints, such as PFS, objective response rate and disease control rate. The most frequent fruquintinib-related ≥ Grade 3 treatment emerged adverse events included hypertension (21.6%), hand-foot skin reaction (10.8%), proteinuria (3.2%) and diarrhea (3.2%). Conclusion: In this phase III confirmatory trial, fruquintinib demonstrated a statistically significant and clinically meaningful OS benefit as compared with placebo in mCRC patients in China. Fruquintinib was well tolerated with a safety profile that is consistent with what was reported previously. Clinical trial information: NCT02314819.

Fruquintinib in patients with metastatic colorectal cancer failed in previously bevacizumab-based therapy: A monocentric retrospective study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e15555-e15555
Author(s):  
Xiaoqiang Gu
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Safety Profile ◽  
Randomized Study ◽  
Objective Response ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Forest Plot ◽  
Lasso Regression ◽  
Standard Regimen

e15555 Background: Fruquintinib, a vascular endothelial growth factor receptor (VEGFR) inhibitor, is a new targeting anti-cancer agent for refractory metastatic colorectal cancer (mCRC). Promising antitumor effect of fruquintinib monotherapy was verified in a phase III FRESCO randomized study of mCRC patients, and only 30% patients were prior bevacizumab-treated. However, comprehensive effect evaluation of fruquintinib in mCRC patients who have previously failed in bevacizumab therapy were scarce. Methods: Forty patients with metastatic CRC who had previously failed at least 2 lines of standard regimen containing bevacizumab in Longhua Hospital affiliated to Shanghai University of Traditional Chinese Medicine from March 2019 to February 2020 were enrolled. These patients were administrated with fruquintinib (5mg orally, once daily) in cycles of 3 weeks on/ 1 week off. Furthermore, the primary endpoint was overall survival (OS). Secondary endpoints mainly included progression-free survival (PFS), disease control rate (DCR), objective response rate (ORR), and safety profile. Statistical analyses were performed using IBM SPSS statistics software and ‘R’ statistical software with the ‘forest plot’ package. Subsequently, the variables were screened and verified through LASSO regression with the R software “glmnet” package. Results: The mOS was 8.1months (95%CI, 5.6667-12.8667), mPFS was 4.1833 months (95% CI, 3.5333-5.0667), and DCR was 65% (26 SD in 40 patients). Particularly, gender (HR: 7.11, 95%CI:1.86-27.16,P = 0.005), age (HR:0.91, 95%CI:0.85-0.98,P = 0.012), ECOG(HR:3.75, 95%CI:1.13-12.42,P = 0.03), medication duration (HR:0.62, 95%CI:0.48-0.81,P＜0.001),and the number of metastases(HR:2.95,95%CI:1.21-7.18,P = 0.017) identified the statistically significant association with OS. Eliminating the influence of time factor, ECOG and medication cycle obtained by Lasso regression were the risk factors for OS. The most frequently reported adverse events were mainly hypertension, proteinuria, hand-foot skin reaction, fatigue and diarrhea, and any new safety signals were not observed. Conclusions: Fruquintinib showed an acceptable safety profile and promising efficacy in patients with metastatic colorectal cancer failed in previously bevacizumab-based therapy. Future studies of fruquintinib should focus on identifying the patients most likely to benefit and on minimizing toxicity.

scholarly journals How to Deal with Second Line Dilemma in Metastatic Colorectal Cancer? A Systematic Review and Meta-Analysis

Cancers ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 1189 ◽  
Author(s):  
Galvano ◽  
Incorvaia ◽  
Badalamenti ◽  
Rizzo ◽  
Guarini ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Growth Factor ◽  
Metastatic Colorectal Cancer ◽  
Objective Response ◽  
Phase Iii ◽  
Second Line ◽  
Anti Vegf ◽  
Significant Difference ◽  
Line Setting ◽  
The Impact

Monoclonal antibodies targeting epidermal growth factor receptor (EGFR) or vascular endothelial growth factor (VEGF) have demonstrated efficacy with chemotherapy (CT) as second line treatment for metastatic colorectal cancer (mCRC). The right sequence of the treatments in all RAS (KRAS/NRAS) wild type (wt) patients has not precisely defined. We evaluated the impact of aforementioned targeted therapies in second line setting, analyzing efficacy and safety data from phase III clinical trials. We performed both direct and indirect comparisons between anti-EGFR and anti-VEGF. Outcomes included disease control rate (DCR), objective response rate (ORR), progression-free survival (PFS), overall survival (OS) and G3-G5 toxicities. Our results showed significantly improved OS (HR 0.83, 95% CI 0.72–0.94) and DCR (HR 1.27, 95% CI 1.04–1.54) favouring anti-VEGF combinations in overall population; no statistically significant differences in all RAS wt patients was observed (HR 0.87, 95% CI 0.70–1.09). Anti-EGFR combinations significantly increased ORR in all patients (RR 0.54, 95% CI 0.31–0.96), showing a trend also in all RAS wt patients (RR 0.63, 95% CI 0.48–0.83). No significant difference in PFS and DCR all RAS was registered. Our results provided for the first time a strong rationale to manage both targeted agents in second line setting.

Superiority of Oxaliplatin and Fluorouracil-Leucovorin Compared With Either Therapy Alone in Patients With Progressive Colorectal Cancer After Irinotecan and Fluorouracil-Leucovorin: Interim Results of a Phase III Trial

2003 ◽  
Vol 21 (11) ◽  
pp. 2059-2069 ◽  
Author(s):  
Mace L. Rothenberg ◽  
Amit M. Oza ◽  
Robert H. Bigelow ◽  
Jordan D. Berlin ◽  
John L. Marshall ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
North America ◽  
Metastatic Colorectal Cancer ◽  
Single Agent ◽  
Objective Response ◽  
Phase Iii ◽  
Rank Test ◽  
Line Treatment ◽  
Exact Test ◽  
Clinically Significant

Purpose: In North America, no effective therapy has been available for patients with progressive metastatic colorectal cancer after front-line treatment with irinotecan, bolus fluorouracil (FU), and leucovorin (IFL). Patients and Methods: Patients with metastatic colorectal cancer who progressed after IFL therapy were randomly assigned to bolus and infusional FU and leucovorin (LV5FU2), single-agent oxaliplatin, or the combination (FOLFOX4). This planned interim analysis evaluated objective response rate (RR), time to tumor progression (TTP), and alleviation of tumor-related symptoms (TRS) in an initial cohort of patients. Results: Between November 2000 and September 2001, 463 patients from 120 sites in North America were randomly assigned to treatment. FOLFOX4 proved superior to LV5FU2 in all measures of clinical efficacy. Objective RRs determined by an independent radiology panel were 9.9% for FOLFOX4 versus 0% for LV5FU2 (Fisher’s exact test, P < .0001). Median TTP was 4.6 months for FOLFOX4 versus 2.7 months for LV5FU2 (two-sided, stratified log-rank test, P < .0001). Relief of TRS occurred in 33% of patients treated with FOLFOX4 versus 12% of patients treated with LVFU2 (χ2 test, P < .001). Single-agent oxaliplatin was not superior to LV5FU2 in any measure of efficacy. Patients treated with FOLFOX4 experienced a higher incidence of clinically significant toxicities than patients treated with LV5FU2, but these toxicities were predictable and did not result in a higher rate of treatment discontinuation or 60-day mortality rate. Conclusion: For patients with metastatic colorectal cancer, second-line treatment with FOLFOX4 is superior to treatment with LVFU2 in terms of RR, TTP, and relief of TRS.

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