Cancer Research and Treatment

Original Articles

Gastrointestinal cancer

A Phase 1b/2a Study of GC1118 with 5-Fluorouracil, Leucovorin and Irinotecan (FOLFIRI) in Patients with Recurrent or Metastatic Colorectal Cancer: Keun-Wook Lee, Sae-Won Han, Tae Won Kim, Joong Bae Ahn, Ji Yeon Baek, Sang Hee Cho, Howard Lee, Jin Won Kim, Ji-Won Kim, Tae-You Kim, Yong Sang Hong, Seung-Hoon Beom, Yongjun Cha, Yoonjung Choi, Seonhui Kim, Yung-Jue Bang; Cancer Res Treat. 2024;56(2):590-601. Published online December 7, 2023; DOI: https://doi.org/10.4143/crt.2023.1117

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Purpose
GC1118 is a novel antibody targeting epidermal growth factor receptor (EGFR) with enhanced blocking activity against both low- and high-affinity EGFR ligands. A phase 1b/2a study was conducted to determine a recommended phase 2 dose (RP2D) of GC1118 in combination with 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) (phase 1b) and to assess the safety and efficacy of GC1118 plus FOLFIRI as a second-line therapy for recurrent/metastatic colorectal cancer (CRC) (phase 2a).
Materials and Methods
Phase 1b was designed as a standard 3+3 dose-escalation study with a starting dose of GC1118 (3 mg/kg/week) in combination with biweekly FOLFIRI (irinotecan 180 mg/m²; leucovorin 400 mg/m²; 5-fluorouracil 400 mg/m² bolus and 2,400 mg/m² infusion over 46 hours) in patients with solid tumors refractory to standard treatments. The subsequent phase 2a part was conducted with objective response rate (ORR) as a primary endpoint. Patients with KRAS/NRAS/BRAF wild-type, EGFR-positive, recurrent/metastatic CRC resistant to the first-line treatment were enrolled in the phase 2a study.
Results
RP2D of GC1118 was determined to be 3 mg/kg/wk in the phase 1b study (n=7). Common adverse drug reactions (ADRs) observed in the phase 2a study (n=24) were acneiform rash (95.8%), dry skin (66.7%), paronychia (58.3%), and stomatitis (50.0%). The most common ADR of ≥ grade 3 was neutropenia (33.3%). ORR was 42.5% (95% confidence interval [CI], 23.5 to 62.0), and median progression-free survival was 6.7 months (95% CI, 4.0-8.0).
Conclusion
GC1118 administered weekly at 3 mg/kg in combination with FOLFIRI appears as an effective and safe treatment option in recurrent/metastatic CRC.

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Drug combinations of camptothecin derivatives promote the antitumor properties
Zhen Liu, Yajie Yuan, Ning Wang, Peng Yu, Yuou Teng
European Journal of Medicinal Chemistry.2024; 279: 116872. CrossRef

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Analysis of Plasma Circulating Tumor DNA in Borderline Resectable Pancreatic Cancer Treated with Neoadjuvant Modified FOLFIRINOX: Clinical Relevance of DNA Damage Repair Gene Alteration Detection: Dong-Hoon Lim, Hyunseok Yoon, Kyu-pyo Kim, Baek-Yeol Ryoo, Sang Soo Lee, Do Hyun Park, Tae Jun Song, Dae Wook Hwang, Jae Hoon Lee, Ki Byung Song, Song Cheol Kim, Seung-Mo Hong, Jaewon Hyung, Changhoon Yoo; Cancer Res Treat. 2023;55(4):1313-1320. Published online May 4, 2023; DOI: https://doi.org/10.4143/crt.2023.452

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Purpose
There are no reliable biomarkers to guide treatment for patients with borderline resectable pancreatic cancer (BRPC) in the neoadjuvant setting. We used plasma circulating tumor DNA (ctDNA) sequencing to search biomarkers for patients with BRPC receiving neoadjuvant mFOLFIRINOX in our phase 2 clinical trial (NCT02749136).
Materials and Methods
Among the 44 patients enrolled in the trial, patients with plasma ctDNA sequencing at baseline or post-operation were included in this analysis. Plasma cell-free DNA isolation and sequencing were performed using the Guardant 360 assay. Detection of genomic alterations, including DNA damage repair (DDR) genes, were examined for correlations with survival.
Results
Among the 44 patients, 28 patients had ctDNA sequencing data qualified for the analysis and were included in this study. Among the 25 patients with baseline plasma ctDNA data, 10 patients (40%) had alterations of DDR genes detected at baseline, inclu-ding ATM, BRCA1, BRCA2 and MLH1, and showed significantly better progression-free survival than those without such DDR gene alterations detected (median, 26.6 vs. 13.5 months; log-rank p=0.004). Patients with somatic KRAS mutations detected at baseline (n=6) had significantly worse overall survival (median, 8.5 months vs. not applicable; log-rank p=0.003) than those without. Among 13 patients with post-operative plasma ctDNA data, eight patients (61.5%) had detectable somatic alterations.
Conclusion
Detection of DDR gene mutations from plasma ctDNA at baseline was associated with better survival outcomes of pati-ents with borderline resectable pancreatic ductal adenocarcinoma treated with neoadjuvant mFOLFIRINOX and may be a prognostic biomarker.

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A Review of Circulating Tumor DNA (ctDNA) in Pancreatic Cancer: Ready for the Clinic?
Purvi Jonnalagadda, Virginia Arnold, Benjamin A. Weinberg
Journal of Gastrointestinal Cancer.2025;[Epub] CrossRef
A Practical Approach to Interpreting Circulating Tumor DNA in the Management of Gastrointestinal Cancers
Zexi Allan, David S Liu, Margaret M Lee, Jeanne Tie, Nicholas J Clemons
Clinical Chemistry.2024; 70(1): 49. CrossRef
High somatic mutations in circulating tumor DNA predict response of metastatic pancreatic ductal adenocarcinoma to first-line nab-paclitaxel plus S-1: prospective study
Lei Huang, Yao Lv, Shasha Guan, Huan Yan, Lu Han, Zhikuan Wang, Quanli Han, Guanghai Dai, Yan Shi
Journal of Translational Medicine.2024;[Epub] CrossRef
Decoding the Dynamics of Circulating Tumor DNA in Liquid Biopsies
Khadija Turabi, Kelsey Klute, Prakash Radhakrishnan
Cancers.2024; 16(13): 2432. CrossRef
Building on the clinical applicability of ctDNA analysis in non-metastatic pancreatic ductal adenocarcinoma
Ibone Labiano, Ana E. Huerta, Maria Alsina, Hugo Arasanz, Natalia Castro, Saioa Mendaza, Arturo Lecumberri, Iranzu Gonzalez-Borja, David Guerrero-Setas, Ana Patiño-Garcia, Gorka Alkorta-Aranburu, Irene Hernández-Garcia, Virginia Arrazubi, Elena Mata, Davi
Scientific Reports.2024;[Epub] CrossRef
Liquid biopsy analysis of lipometabolic exosomes in pancreatic cancer
Wei Guo, Peiyao Ying, Ruiyang Ma, Zuoqian Jing, Gang Ma, Jin Long, Guichen Li, Zhe Liu
Cytokine & Growth Factor Reviews.2023; 73: 69. CrossRef

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Survival Benefit of Adjuvant Chemotherapy in Patients with Pancreatic Ductal Adenocarcinoma Who Underwent Surgery Following Neoadjuvant FOLFIRINOX: So Heun Lee, Dae Wook Hwang, Changhoon Yoo, Kyu-pyo Kim, Sora Kang, Jae Ho Jeong, Dongwook Oh, Tae Jun Song, Sang Soo Lee, Do Hyun Park, Dong Wan Seo, Jin-hong Park, Ki Byung Song, Jae Hoon Lee, Woohyung Lee, Yejong Park, Bong Jun Kwak, Heung-Moon Chang, Baek-Yeol Ryoo, Song Cheol Kim; Cancer Res Treat. 2023;55(3):956-968. Published online February 27, 2023; DOI: https://doi.org/10.4143/crt.2022.409

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Purpose
The benefit of adjuvant chemotherapy following curative-intent surgery in pancreatic ductal adenocarcinoma (PDAC) patients who had received neoadjuvant FOLFIRINOX is unclear. This study aimed to assess the survival benefit of adjuvant chemotherapy in this patient population.
Materials and Methods
This retrospective study included 218 patients with localized non-metastatic PDAC who received neoadjuvant FOLFIRINOX and underwent curative-intent surgery (R0 or R1) between January 2017 and December 2020. The association of adjuvant chemotherapy with disease-free survival (DFS) and overall survival (OS) was evaluated in overall patients and in the propensity score matched (PSM) cohort. Subgroup analysis was conducted according to the pathology-proven lymph node status.
Results
Adjuvant chemotherapy was administered to 149 patients (68.3%). In the overall cohort, the adjuvant chemotherapy group had significantly improved DFS and OS compared to the observation group (DFS: median, 13.8 months [95% confidence interval (CI), 11.0 to 19.1] vs. 8.2 months [95% CI, 6.5 to 12.0]; p < 0.001; and OS: median, 38.0 months [95% CI, 32.2 to not assessable] vs. 25.7 months [95% CI, 18.3 to not assessable]; p=0.005). In the PSM cohort of 57 matched pairs of patients, DFS and OS were better in the adjuvant chemotherapy group than in the observation group (p < 0.001 and p=0.038, respectively). In the multivariate analysis, adjuvant chemotherapy was a significant favorable prognostic factor (vs. observation; DFS: hazard ratio [HR], 0.51 [95% CI, 0.36 to 0.71; p < 0.001]; OS: HR, 0.45 [95% CI, 0.29 to 0.71; p < 0.001]).
Conclusion
Among PDAC patients who underwent surgery following neoadjuvant FOLFIRINOX, adjuvant chemotherapy may be associated with improved survival. Randomized studies should be conducted to validate this finding.

Citations

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The survival effect of neoadjuvant therapy and neoadjuvant plus adjuvant therapy on pancreatic ductal adenocarcinoma patients with different TNM stages: a propensity score matching analysis based on the SEER database
Hao Hu, Yang Xu, Qiang Zhang, Yuan Gao, Zhenyu Wu
Expert Review of Anticancer Therapy.2024; 24(6): 467. CrossRef
Neoadjuvant treatment of pancreatic ductal adenocarcinoma: Whom, when and how
Nebojsa Manojlovic, Goran Savic, Stevan Manojlovic
World Journal of Gastrointestinal Surgery.2024; 16(5): 1223. CrossRef
Case Study on Analysing the Early Disease Detection of Pancreatic Ductal Adenocarcinoma in Korean Association for Clinical Oncology
Sijithra Ponnarassery Chandran, N. Santhi
American Journal of Clinical Oncology.2024; 47(10): 475. CrossRef
Evaluating the benefits of adjuvant chemotherapy in patients with pancreatic cancer undergoing radical pancreatectomy after neoadjuvant therapy—a systematic review and meta-analysis
Jiahao Wu, Yike Zhang, Haodong Wang, Wenyi Guo, Chengqing Li, Yichen Yu, Han Liu, Feng Li, Lei Wang, Jianwei Xu
Frontiers in Oncology.2024;[Epub] CrossRef
Prognostic factors in localized pancreatic ductal adenocarcinoma after neoadjuvant therapy and resection: a systematic review and meta-analysis
Ammar A Javed, Alyssar Habib, Omar Mahmud, Asad Saulat Fatimi, Mahip Grewal, Nabiha Mughal, Jin He, Christopher L Wolfgang, Lois Daamen, Marc G Besselink
JNCI: Journal of the National Cancer Institute.2024;[Epub] CrossRef

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Modified FOLFIRI as Second-Line Chemotherapy after Failure of Modified FOLFOX-4 in Advanced Gastric Cancer: Eun Kyoung Jeon, Sook Hee Hong, Tae Hee Kim, Seung Eun Jung, Ji Chan Park, Hye-Sung Won, Yoon-Ho Ko, Sang Young Rho, Young Seon Hong; Cancer Res Treat. 2011;43(3):148-153. Published online September 30, 2011; DOI: https://doi.org/10.4143/crt.2011.43.3.148

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PURPOSE
The purpose of this study was to evaluate efficacy and toxicity of irinotecan, leucovorin and 5-fluorouracil (FOLFIRI) as second-line treatment after failure of oxaliplatin, leucovorin and 5-fluorouracil (FOLFOX) for advanced gastric cancer.
MATERIALS AND METHODS
Patients who received modified FOLFOX-4 as first-line treatment and then received sequential modified FOLFIRI for disease progression were included in this study. The modified FOLFIRI regimen consisted of irinotecan 150 mg/m2 in a 90-minute intravenous infusion on day 1, leucovorin (LV) 20 mg/m2 and 5-fluorouracil (5-FU) 400 mg/m2 as a bolus followed by 600 mg/m2 as a 22-hour infusion on days 1 and 2 with the same dose of 5-FU/LV of modified FOLFOX-4 every 2 weeks.
RESULTS
A total of 32 patients received 126 courses of FOLFIRI chemotherapy. No complete response was achieved. Three patients (9.4%; 95% confidence interval [CI], 0 to 20.1%) achieved partial response, whereas 11 (34.4%; 95% CI, 17.0 to 51.8%) patients showed stable disease. Disease control rate (complete response, partial responses and stable diseases) was 43.8% (95% CI, 25.6 to 61.9%) and median follow up duration was 11.3 months (range, 2.23 to 37.9 months). Median time to progression was 2 months (95% CI, 1.49 to 2.51 months), and median overall survival from the start of FOLFIRI was 5.84 months (95% CI, 4.34 to 7.34 months). Toxicities were tolerable.
CONCLUSION
Modified FOLFIRI as second-line chemotherapy after failure of the modified FOLFOX-4 in advanced gastric cancer was tolerable but showed a lower response rate. Further study about retrying 5-FU/LV with irinotecan after failure of the 5-FU/LV combined regimen is necessary in advanced gastric cancer.

Citations

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Current therapeutic options for gastric adenocarcinoma
C.R. Akshatha, Smitha Bhat, R. Sindhu, Dharini Shashank, Sarana Rose Sommano, Wanaporn Tapingkae, Ratchadawan Cheewangkoon, Shashanka K. Prasad
Saudi Journal of Biological Sciences.2021; 28(9): 5371. CrossRef
Prognostic Nomogram and Patterns of Use of FOLFIRI-Aflibercept in Advanced Colorectal Cancer: A Real-World Data Analysis
Ana Fernández Montes, Carlos López López, Guillem Argilés Martínez, David Páez López, Ana María López Muñoz, Beatriz García Paredes, David Gutiérrez Abad, Carmen Castañón López, Paula Jiménez Fonseca, Javier Gallego Plazas, María Carmen López Doldán, Eva
The Oncologist.2019; 24(8): e687. CrossRef
Thymineless Death by the Fluoropyrimidine Polymer F10 Involves Replication Fork Collapse and Is Enhanced by Chk1 Inhibition
Chinnadurai Mani, Sachin Pai, Cinta Maria Papke, Komaraiah Palle, William H. Gmeiner
Neoplasia.2018; 20(12): 1236. CrossRef
Effect of FOLFOX4 combined with Brucea javanica emulsion on VEGF in patients with gastric cancer
Zheng Chen, Zhenyu Zhou, Zhigang Hu, Qiaodong Xu, Jie Wang
Oncology Letters.2017;[Epub] CrossRef
Sunitinib added to FOLFIRI versus FOLFIRI in patients with chemorefractory advanced adenocarcinoma of the stomach or lower esophagus: a randomized, placebo-controlled phase II AIO trial with serum biomarker program
Markus Moehler, Irina Gepfner-Tuma, Annett Maderer, Peter C. Thuss-Patience, Joern Ruessel, Susanna Hegewisch-Becker, Hansjochen Wilke, Salah-Eddin Al-Batran, Mohammad-Reza Rafiyan, Florian Weißinger, Hans-Joachim Schmoll, Frank Kullmann, Ludwig Fischer v
BMC Cancer.2016;[Epub] CrossRef
5-Fluorouracil derivatives: a patent review (2012 – 2014)
Esmeralda Carrillo, Saúl Abenhamar Navarro, Alberto Ramírez, María Ángel García, Carmen Griñán-Lisón, Macarena Perán, Juan Antonio Marchal
Expert Opinion on Therapeutic Patents.2015; 25(10): 1131. CrossRef
Efficacy and Safety of FOLFIRI as Second-line Chemotherapy in Advanced Gastric Cancer
Sung Chul Park, Hoon Jai Chun
The Korean Journal of Gastroenterology.2015; 66(1): 1. CrossRef
Efficacy and Safety of FOLFIRI after Failure of FOLFOX-4 in Advanced Gastric Cancer
Hye Jung Kwon, Moo In Park, Seun Ja Park, Won Moon, Sung Eun Kim, Hae Won Lee, Youn Jung Choi, Jae Hyun Kim
The Korean Journal of Gastroenterology.2015; 66(1): 10. CrossRef
FOLFIRI as Second-line Chemotherapy after Failure of FOLFOX4 in Advanced Colorectal Cancer: A Korean Single-center Experience
Jae Hyun Kim, Seun Ja Park, Moo In Park, Won Moon, Sung Eun Kim, Ki Hwan Ku, Sung Eun Song, Je Hun Kim
The Korean Journal of Gastroenterology.2014; 63(1): 18. CrossRef
5-Fluorouracil derivatives: a patent review
Pablo Álvarez, Juan Antonio Marchal, Houria Boulaiz, Esmeralda Carrillo, Celia Vélez, Fernando Rodríguez-Serrano, Consolación Melguizo, Jose Prados, Roberto Madeddu, Antonia Aranega
Expert Opinion on Therapeutic Patents.2012; 22(2): 107. CrossRef
Outcomes of Third-Line Docetaxel-Based Chemotherapy in Advanced Gastric Cancer Who Failed Previous Oxaliplatin-Based and Irinotecan-Based Chemotherapies
Min Jeong Lee, In Gyu Hwang, Joung-Soon Jang, Jin Hwa Choi, Byeong-Bae Park, Myung Hee Chang, Seung Tae Kim, Se Hoon Park, Myoung Hee Kang, Jung Hun Kang
Cancer Research and Treatment.2012; 44(4): 235. CrossRef
Irinotecan, leucovorin and 5-fluorouracil (modified FOLFIRI) as salvage chemotherapy for frail or elderly patients with advanced gastric cancer
JUNG HAN KIM, HYEONG SU KIM, A RUM HAN, IN HO MOH, DOO CHEOL CHUNG, DAE RO CHOI, HYUN JOO JANG, JIN BAE KIM, DAE HYUN YANG, SOON IL LEE, DAE YOUNG ZANG
Oncology Letters.2012; 4(4): 751. CrossRef

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