Phase II trial of target-guided personalized chemotherapy in first-line metastatic colorectal cancer

Antonio Cubillo, Jesús Rodriguez-Pascual, Fernando López-Ríos, Carlos Plaza, Elena García, Rafael Álvarez, Emilio de Vicente, Yolanda Quijano, Ovidio Hernando, Carmen Rubio, Sofía Perea, Gema Sanchez, Manuel Hidalgo

Research output: Contribution to journalArticle

Abstract

PURPOSE: The aim of this study was to investigate the feasibility and efficacy of personalizing treatment of patients with advanced untreated colorectal cancer (CRC). PATIENTS AND METHODS: Patients with untreated metastatic CRC, performance status 0-1, and candidates for systemic chemotherapy were eligible. Tumor tissues were analyzed for KRAS, BRAF, and PI3K mutations and expression of topoisomerase-1 (Topo-1), excision repair cross-complementing gene 1 (ERCC1), thymidylate synthase (TS), and thymidine phosphorylase (TP). Patients with Topo-1 expression received irinotecan, whereas patients with negative Topo-1 and ERCC1 expression received oxaliplatin. Otherwise, patients received physician's choice of treatment. If TS was positive, no fluoropyrimidine was administered and if negative, 5-flurorouracil if TP was negative, or capecitabine if TP was positive. KRAS-mutated patients were treated with bevacizumab, whereas KRAS-native received cetuximab. The primary endpoint of the study was progression-free survival (PFS). RESULTS: A total of 74 patients were enrolled and 67 received personalized treatment including irinotecan (n=27), oxaliplatin (n=16), FOLFIRI (n=12), and FOLFOX (n=12). Thirty-eight patients received cetuximab and 29 bevacizumab. With a median follow-up time of 18.3 months (95% confidence interval [CI], 4-36), the overall median PFS was 8.3 months (95% CI, 6.9-9.7), representing a 12-month PFS rate of 36.5% (95% CI, 25-48). Overall clinical benefit, including response rate and disease stabilization, was 86% (95% CI, 73%-97%). The overall median survival was 21 months (95% CI, 11-40). CONCLUSIONS: Real-time target-guided personalized first-line treatment of patients with advanced CRC is feasible but, with the approached used, did not result in a clear improvement in PFS to warrant phase III testing.

Original languageEnglish (US)
JournalAmerican Journal of Clinical Oncology: Cancer Clinical Trials
DOIs
StateAccepted/In press - Feb 10 2014
Externally publishedYes

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Colorectal Neoplasms
Drug Therapy
oxaliplatin
irinotecan
Thymidine Phosphorylase
Disease-Free Survival
Confidence Intervals
Thymidylate Synthase
DNA Repair
Phosphatidylinositol 3-Kinases
Therapeutics
Survival Rate
Physicians
Gene Expression
Mutation
Survival
Genes
Neoplasms

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Phase II trial of target-guided personalized chemotherapy in first-line metastatic colorectal cancer. / Cubillo, Antonio; Rodriguez-Pascual, Jesús; López-Ríos, Fernando; Plaza, Carlos; García, Elena; Álvarez, Rafael; de Vicente, Emilio; Quijano, Yolanda; Hernando, Ovidio; Rubio, Carmen; Perea, Sofía; Sanchez, Gema; Hidalgo, Manuel.

In: American Journal of Clinical Oncology: Cancer Clinical Trials, 10.02.2014.

Research output: Contribution to journalArticle

Cubillo, A, Rodriguez-Pascual, J, López-Ríos, F, Plaza, C, García, E, Álvarez, R, de Vicente, E, Quijano, Y, Hernando, O, Rubio, C, Perea, S, Sanchez, G & Hidalgo, M 2014, 'Phase II trial of target-guided personalized chemotherapy in first-line metastatic colorectal cancer', American Journal of Clinical Oncology: Cancer Clinical Trials. https://doi.org/10.1097/COC.0000000000000045
Cubillo, Antonio ; Rodriguez-Pascual, Jesús ; López-Ríos, Fernando ; Plaza, Carlos ; García, Elena ; Álvarez, Rafael ; de Vicente, Emilio ; Quijano, Yolanda ; Hernando, Ovidio ; Rubio, Carmen ; Perea, Sofía ; Sanchez, Gema ; Hidalgo, Manuel. / Phase II trial of target-guided personalized chemotherapy in first-line metastatic colorectal cancer. In: American Journal of Clinical Oncology: Cancer Clinical Trials. 2014.
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abstract = "PURPOSE: The aim of this study was to investigate the feasibility and efficacy of personalizing treatment of patients with advanced untreated colorectal cancer (CRC). PATIENTS AND METHODS: Patients with untreated metastatic CRC, performance status 0-1, and candidates for systemic chemotherapy were eligible. Tumor tissues were analyzed for KRAS, BRAF, and PI3K mutations and expression of topoisomerase-1 (Topo-1), excision repair cross-complementing gene 1 (ERCC1), thymidylate synthase (TS), and thymidine phosphorylase (TP). Patients with Topo-1 expression received irinotecan, whereas patients with negative Topo-1 and ERCC1 expression received oxaliplatin. Otherwise, patients received physician's choice of treatment. If TS was positive, no fluoropyrimidine was administered and if negative, 5-flurorouracil if TP was negative, or capecitabine if TP was positive. KRAS-mutated patients were treated with bevacizumab, whereas KRAS-native received cetuximab. The primary endpoint of the study was progression-free survival (PFS). RESULTS: A total of 74 patients were enrolled and 67 received personalized treatment including irinotecan (n=27), oxaliplatin (n=16), FOLFIRI (n=12), and FOLFOX (n=12). Thirty-eight patients received cetuximab and 29 bevacizumab. With a median follow-up time of 18.3 months (95{\%} confidence interval [CI], 4-36), the overall median PFS was 8.3 months (95{\%} CI, 6.9-9.7), representing a 12-month PFS rate of 36.5{\%} (95{\%} CI, 25-48). Overall clinical benefit, including response rate and disease stabilization, was 86{\%} (95{\%} CI, 73{\%}-97{\%}). The overall median survival was 21 months (95{\%} CI, 11-40). CONCLUSIONS: Real-time target-guided personalized first-line treatment of patients with advanced CRC is feasible but, with the approached used, did not result in a clear improvement in PFS to warrant phase III testing.",
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AU - Cubillo, Antonio

AU - Rodriguez-Pascual, Jesús

AU - López-Ríos, Fernando

AU - Plaza, Carlos

AU - García, Elena

AU - Álvarez, Rafael

AU - de Vicente, Emilio

AU - Quijano, Yolanda

AU - Hernando, Ovidio

AU - Rubio, Carmen

AU - Perea, Sofía

AU - Sanchez, Gema

AU - Hidalgo, Manuel

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N2 - PURPOSE: The aim of this study was to investigate the feasibility and efficacy of personalizing treatment of patients with advanced untreated colorectal cancer (CRC). PATIENTS AND METHODS: Patients with untreated metastatic CRC, performance status 0-1, and candidates for systemic chemotherapy were eligible. Tumor tissues were analyzed for KRAS, BRAF, and PI3K mutations and expression of topoisomerase-1 (Topo-1), excision repair cross-complementing gene 1 (ERCC1), thymidylate synthase (TS), and thymidine phosphorylase (TP). Patients with Topo-1 expression received irinotecan, whereas patients with negative Topo-1 and ERCC1 expression received oxaliplatin. Otherwise, patients received physician's choice of treatment. If TS was positive, no fluoropyrimidine was administered and if negative, 5-flurorouracil if TP was negative, or capecitabine if TP was positive. KRAS-mutated patients were treated with bevacizumab, whereas KRAS-native received cetuximab. The primary endpoint of the study was progression-free survival (PFS). RESULTS: A total of 74 patients were enrolled and 67 received personalized treatment including irinotecan (n=27), oxaliplatin (n=16), FOLFIRI (n=12), and FOLFOX (n=12). Thirty-eight patients received cetuximab and 29 bevacizumab. With a median follow-up time of 18.3 months (95% confidence interval [CI], 4-36), the overall median PFS was 8.3 months (95% CI, 6.9-9.7), representing a 12-month PFS rate of 36.5% (95% CI, 25-48). Overall clinical benefit, including response rate and disease stabilization, was 86% (95% CI, 73%-97%). The overall median survival was 21 months (95% CI, 11-40). CONCLUSIONS: Real-time target-guided personalized first-line treatment of patients with advanced CRC is feasible but, with the approached used, did not result in a clear improvement in PFS to warrant phase III testing.

AB - PURPOSE: The aim of this study was to investigate the feasibility and efficacy of personalizing treatment of patients with advanced untreated colorectal cancer (CRC). PATIENTS AND METHODS: Patients with untreated metastatic CRC, performance status 0-1, and candidates for systemic chemotherapy were eligible. Tumor tissues were analyzed for KRAS, BRAF, and PI3K mutations and expression of topoisomerase-1 (Topo-1), excision repair cross-complementing gene 1 (ERCC1), thymidylate synthase (TS), and thymidine phosphorylase (TP). Patients with Topo-1 expression received irinotecan, whereas patients with negative Topo-1 and ERCC1 expression received oxaliplatin. Otherwise, patients received physician's choice of treatment. If TS was positive, no fluoropyrimidine was administered and if negative, 5-flurorouracil if TP was negative, or capecitabine if TP was positive. KRAS-mutated patients were treated with bevacizumab, whereas KRAS-native received cetuximab. The primary endpoint of the study was progression-free survival (PFS). RESULTS: A total of 74 patients were enrolled and 67 received personalized treatment including irinotecan (n=27), oxaliplatin (n=16), FOLFIRI (n=12), and FOLFOX (n=12). Thirty-eight patients received cetuximab and 29 bevacizumab. With a median follow-up time of 18.3 months (95% confidence interval [CI], 4-36), the overall median PFS was 8.3 months (95% CI, 6.9-9.7), representing a 12-month PFS rate of 36.5% (95% CI, 25-48). Overall clinical benefit, including response rate and disease stabilization, was 86% (95% CI, 73%-97%). The overall median survival was 21 months (95% CI, 11-40). CONCLUSIONS: Real-time target-guided personalized first-line treatment of patients with advanced CRC is feasible but, with the approached used, did not result in a clear improvement in PFS to warrant phase III testing.

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