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1
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Zhou Y, Ding Y, Xu B, Fei H, Wang Z. Genetically druggable targets for MAPK-activated colorectal cancer by a two-sample mendelian randomization analysis. Sci Rep 2025; 15:12239. [PMID: 40210889 PMCID: PMC11986099 DOI: 10.1038/s41598-024-82567-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2024] [Accepted: 12/06/2024] [Indexed: 04/12/2025] Open
Abstract
Colorectal cancer (CRC) is a significant worldwide health issue, ranking second in women and third in men. Predictions estimate a rise to 2.5 million cases by 2035, with CRC being the fourth deadliest cancer due to delayed diagnosis and the scarcity of effective treatment options. Over 60% of CRC cases involve MAPK-activated signal pathways, particularly driven by RAS oncogene mutations, which hinder treatment responses, making them 'undruggable.' This study conducts a two-sample Mendelian randomization protein quantitative trait loci (pQTL) analysis to investigate the causal association between plasma proteins and MAPK-activated CRCs. The study indicates that four plasma proteins-MHC class I polypeptide-related sequence B (MICB), complement C4A, C4B, and interleukin-21 (IL-21) are associated with an increased risk of MAPK-activated CRCs. These findings highlight the possibility of utilizing plasma proteins as therapeutic targets and diagnostic markers to advance the fight against CRCs, indicating promising results for more effective interventions. To ascertain and expand upon these discoveries, further research is imperative to fully harness the potential of these discoveries.
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Affiliation(s)
- Yuxuan Zhou
- Department of Gastrointestinal Surgery/Hernia Surgery, Jilin Province People's Hospital, No. 1183 Gongnong Road, Changchun, Jilin, China
| | - Yunlong Ding
- Department of Emergency General Surgery, Weifang People's Hospital, Weifang, Shandong, China
| | - Bangyue Xu
- Jilin Central General Hospital, Changchun, Jilin, China
| | - Hongyang Fei
- Department of Hepatobiliary and Pancreatic Surgery, Jilin Province People's Hospital, No. 1183 Gongnong Road, Changchun, Jilin, China
| | - Zheng Wang
- Department of Gastrointestinal Surgery/Hernia Surgery, Jilin Province People's Hospital, No. 1183 Gongnong Road, Changchun, Jilin, China.
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2
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Avallone A, Giuliani F, De Stefano A, Santabarbara G, Nasti G, Montesarchio V, Rosati G, Cassata A, Leo S, Romano C, Tamburini E, Silvestro L, Lotesoriere C, Nappi A, Santini D, Petrillo A, Colombo A, Febbraro A, Leone A, Mannavola F, Laterza MM, Izzo F, Sobrero A, Delrio P, Giannarelli D, Budillon A. Intermittent or Continuous Panitumumab Plus Fluorouracil, Leucovorin, and Irinotecan for First-Line Treatment of RAS and BRAF Wild-Type Metastatic Colorectal Cancer: The IMPROVE Trial. J Clin Oncol 2025; 43:829-839. [PMID: 39576946 PMCID: PMC11856000 DOI: 10.1200/jco.24.00979] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2024] [Revised: 08/29/2024] [Accepted: 10/19/2024] [Indexed: 11/24/2024] Open
Abstract
PURPOSE To investigate whether intermittent treatment after an induction phase of first-line schedule of fluorouracil, leucovorin, and irinotecan (FOLFIRI) plus panitumumab (PAN) prevents or delays the onset of resistance and improves safety and compliance with treatment in patients with unresectable RAS/BRAF wild-type (wt) metastatic colorectal cancer (mCRC). PATIENTS AND METHODS IMPROVE (ClinicalTrials.gov identifier: NCT04425239) was an open-label, multicenter, randomized phase II noncomparative trial. Patients with unresectable RAS/BRAF wt mCRC were randomly assigned (1:1) to receive FOLFIRI plus PAN continuously until progression (arm A) or intermittently, with treatment-free intervals (arm B) until progression on treatment, toxicity, or death. The primary end point was progression-free survival on treatment (PFSot) at 12 months. Assuming a null hypothesis of median PFSot time ≤7 months and target PFSot ≥10 months, 65 patients per arm were needed to achieve 80% power and 10% type I error, according to the binomial test. RESULTS Between May 2018 and June 2021, 69 patients were randomly assigned to arm A and 68 to arm B. The median number of treatment cycles was 13 in arm A and 16 in arm B. At a median follow-up of 43.2 months (IQR, 35.0-50.5), median PFSot was 11.2 and 17.5 months with 12-month PFSot rates of 45.7% and 58.5%, for arms A and B, respectively. The overall response rates were 68.1% and 61.2%, and median overall survival rates were 36.3 and 35.1 months in arms A and B, respectively. The overall rate of grade >2 skin PAN-related adverse events was 30.3% in arm A and 17.9% in arm B. CONCLUSION Intermittent FOLFIRI plus PAN after the induction phase was feasible, and the primary end point was met with reduced toxicity while allowing patients more time off treatment.
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Affiliation(s)
- Antonio Avallone
- Experimental Clinical Abdominal Oncology Unit, Istituto Nazionale Tumori—IRCCS—Fondazione G. Pascale, Napoli, Italia
| | - Francesco Giuliani
- Medical Oncology Irccs Giovanni Paolo II Bari and Medical Oncology San Paolo Hospital ASL, Bari, Italy
| | - Alfonso De Stefano
- Experimental Clinical Abdominal Oncology Unit, Istituto Nazionale Tumori—IRCCS—Fondazione G. Pascale, Napoli, Italia
| | | | - Guglielmo Nasti
- Innovative Therapies Liver Metastases Unit, Istituto Nazionale Tumori—IRCCS—Fondazione G. Pascale, Napoli, Italia
| | | | - Gerardo Rosati
- Medical Oncology Unit, S. Carlo Hospital, Potenza, Italy
| | - Antonino Cassata
- Experimental Clinical Abdominal Oncology Unit, Istituto Nazionale Tumori—IRCCS—Fondazione G. Pascale, Napoli, Italia
| | - Silvana Leo
- Medical Oncology Unit, Ospedale Vito Fazzi, Lecce, Italy
| | - Carmela Romano
- Experimental Clinical Abdominal Oncology Unit, Istituto Nazionale Tumori—IRCCS—Fondazione G. Pascale, Napoli, Italia
| | | | - Lucrezia Silvestro
- Experimental Clinical Abdominal Oncology Unit, Istituto Nazionale Tumori—IRCCS—Fondazione G. Pascale, Napoli, Italia
| | - Claudio Lotesoriere
- Medical Oncology Unit, IRCCS Saverio de Bellis Hospital, Castellana Grotte, Italy
| | - Anna Nappi
- Experimental Clinical Abdominal Oncology Unit, Istituto Nazionale Tumori—IRCCS—Fondazione G. Pascale, Napoli, Italia
| | - Daniele Santini
- Medical Oncology Unit, Policlinico Umberto I, University of Rome, Sapienza, Rome, Italy
| | - Antonella Petrillo
- Radiology Unit, Istituto Nazionale Tumori-IRCCS—Fondazione G. Pascale, Napoli, Italia
| | - Alfredo Colombo
- Medical Oncology Unit, Casa di Cura Macchiarella, Palermo, Italy
| | - Antonio Febbraro
- Medical Oncology Unit, Ospedale Sacro Cuore di Gesù-Fatebenefratelli, Benevento, Italy
| | - Alessandra Leone
- Experimental Pharmacology Unit, Istituto Nazionale Tumori—IRCCS—Fondazione G. Pascale, Napoli, Italia
| | | | | | - Francesco Izzo
- Hepatobiliary Surgery Unit, Istituto Nazionale Tumori—IRCCS—Fondazione G. Pascale, Napoli, Italia
| | - Alberto Sobrero
- Medical Oncology Unit, IRCCS San Martino General Hospital, Genoa, Italy
| | - Paolo Delrio
- Colorectal Surgical Oncology Unit, Istituto Nazionale Tumori—IRCCS—Fondazione G. Pascale, Napoli, Italia
| | - Diana Giannarelli
- Statistics, Fondazione Policlinico Universitario A. Gemelli, IRCCS, Rome, Italy
| | - Alfredo Budillon
- Scientific Directorate Istituto Nazionale Tumori IRCCS—Fondazione G. Pascale, Napoli, Italia
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Azeem M, Ur Rehman A, Rasheed S, Shahzad A, Javed MH, Jamil QA, Karuniawati H, Al-Tamimi SK. The impact of combining cetuximab with the traditional chemotherapy regimens on clinical effectiveness in metastatic colorectal cancer: a systematic review and meta-analysis. BMC Cancer 2025; 25:331. [PMID: 39994602 PMCID: PMC11849154 DOI: 10.1186/s12885-025-13515-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Accepted: 01/14/2025] [Indexed: 02/26/2025] Open
Abstract
BACKGROUND Metastatic colorectal cancer (mCRC) poses a high rate of morbidity and mortality despite various treatment advances. Cetuximab, an anti-EGFR, has shown promising efficacy in improving outcomes when combined with chemotherapy. Understanding its efficacy is essential for optimizing treatment strategies in mCRC. This systematic review and meta-analysis aims to evaluate the effectiveness of combining cetuximab with chemotherapy in mCRC. METHODS PubMed and Google Scholar were systematically searched following the benchmarks indicated by PRISMA. The primary outcomes of the study were progression-free survival (PFS) and overall survival (OS). Statistical analyses were executed using Stata version 16. RESULTS The meta-analysis encompassed 25 studies involving 3788 mCRC patients. The median age spans from 18 to 77 years. The cetuximab plus chemotherapy exhibited a higher PFS and OS with a significant difference (PFS: HR = 0.79, 95% CI = 0.63-0.96, p < 0.01, I2 = 38% and OS: HR = 0.78, 95% CI = 0.60-0.91, p < 0.01, I2 = 47%) compared to the control group. Subgroup analysis based on randomized controlled trials demonstrated consistent treatment effects for PFS (HR = 0.77, 95% CI = 0.62-0.93) and OS (HR = 0.76, 95% CI = 0.61-0.88) in the cetuximab treatment group. CONCLUSIONS Combining cetuximab with chemotherapy offers a potential benefit in improving survival outcomes for metastatic colorectal cancer patients, as indicated by this study. These results suggest that cetuximab may be a valuable addition to mCRC treatment strategies, warranting further clinical investigation and integration into standard care.
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Affiliation(s)
- Marryam Azeem
- Department of Pharmacy Practice, Faculty of Pharmacy, Bahauddin Zakariya University, Multan, Pakistan
| | - Anees Ur Rehman
- Department of Pharmacy Practice, Faculty of Pharmacy, Bahauddin Zakariya University, Multan, Pakistan.
| | - Saba Rasheed
- Department of Pharmacy Practice, Faculty of Pharmacy, Bahauddin Zakariya University, Multan, Pakistan
| | - Aleena Shahzad
- Department of Pharmacy Practice, Faculty of Pharmacy, Bahauddin Zakariya University, Multan, Pakistan
| | - Muhammad Hamza Javed
- Department of Pharmacy Practice, Faculty of Pharmacy, Bahauddin Zakariya University, Multan, Pakistan
| | - Qurratul Ain Jamil
- Department of Pharmacy Practice, Faculty of Pharmacy, The Islamia University of Bahawalpur, Bahawalpur, Pakistan
| | - Hidayah Karuniawati
- Department of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Universitas Muhammadiyah Surakarta, Surakarta, Indonesia
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Wills C, Watts K, Houseman A, Maughan TS, Fisher D, Al-Tassan NA, Houlston RS, Escott-Price V, Cheadle JP. Relationship between inherited genetic variation and survival from colorectal cancer stratified by tumour location. Sci Rep 2025; 15:2423. [PMID: 39827162 PMCID: PMC11742712 DOI: 10.1038/s41598-024-77870-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Accepted: 10/25/2024] [Indexed: 01/22/2025] Open
Abstract
The location of a patient's colorectal cancer (CRC) influences their outcome but inherited factors may also be involved. We studied 1899 patients with advanced CRC (514 had proximal colonic, 493 distal colonic and 892 rectal tumours) and carried out genome-wide association studies for survival. Single nucleotide polymorphisms (SNPs) suggestive of association (P < 1.0 × 10-5) were tested for replication in 5078 CRC patients from the UK Biobank. We investigated the relationship between Phosphatidylinositol 4-Kinase Type 2 Beta (PI4K2B) expression in colorectal tumours and survival in 597 patients from The Human Protein Atlas (THPA). We also analysed 3 SNPs previously associated with survival by anatomical site. We found that SNPs at 54 independent loci were suggestive of an association with survival when stratified by tumour location. rs76011559 replicated in patients with proximal tumours (COIN, COIN-B and UK Biobank combined Hazard Ratio [HR] = 1.53, 95% Confidence Intervals [CI] = 1.19-1.86, P = 7.5 × 10-7) and rs12273047 replicated in patients with rectal tumours (combined HR = 1.27, 95% CI = 1.09-1.46, P = 4.1 × 10-7). In gene analyses, PI4K2B associated with survival in patients with distal cancers (P = 2.1 × 10-6) and increased PI4K2B expression in colorectal tumours was associated with improved survival (P = 9.6 × 10-5). No previously associated SNPs were replicated. Our data identify novel loci associated with survival when stratified by tumour location.
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Affiliation(s)
- Christopher Wills
- Division of Cancer and Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, CF14 4XN, UK
| | - Katie Watts
- Division of Cancer and Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, CF14 4XN, UK
| | - Amy Houseman
- Division of Cancer and Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, CF14 4XN, UK
| | - Timothy S Maughan
- CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Roosevelt Drive, Oxford, OX3 7DQ, UK
| | - David Fisher
- MRC Clinical Trials Unit, University College of London, 125 Kingsway, London, WC2B 6NH, UK
| | - Nada A Al-Tassan
- Department of Genetics, King Faisal Specialist Hospital and Research Center, P.O. Box 3354, 11211, Riyadh, Saudi Arabia
| | - Richard S Houlston
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London, SW7 3RP, UK
| | - Valentina Escott-Price
- Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff, CF24 4HQ, UK
| | - Jeremy P Cheadle
- Division of Cancer and Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, CF14 4XN, UK.
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Stahler A, Karthaus M, Fruehauf S, Graeven U, Müller L, Fischer von Weikersthal L, Caca K, Goekkurt E, Ballhausen A, Sommerhäuser G, Alig AH, Held S, Jarosch A, Horst D, Reinacher-Schick A, Kasper S, Heinemann V, Stintzing S, Trarbach T, Modest DP. Panitumumab plus 5-fluorouracil and folinic acid or 5-fluorouracil and folinic acid alone as maintenance therapy in RAS wild-type metastatic colorectal cancer (PanaMa, AIO KRK 0212): final efficacy analysis of a randomised, open-label, phase 2 trial. EClinicalMedicine 2025; 79:103004. [PMID: 39802302 PMCID: PMC11719858 DOI: 10.1016/j.eclinm.2024.103004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Revised: 11/26/2024] [Accepted: 11/27/2024] [Indexed: 01/16/2025] Open
Abstract
Background The PanaMa trial aimed to compare the efficacy of 5-fluorouracil and folinic acid (FU/FA) ± panitumumab maintenance in untreated RAS wild-type metastatic colorectal cancer (mCRC) patients. Methods In this final phase 2 trial analysis, adult mCRC patients responding to six cycles of FU/FA, oxaliplatin and panitumumab were randomized (1:1, open-label) to maintenance of either FU/FA + panitumumab or FU/FA alone. The primary endpoint was superiority of progression-free survival of maintenance (PFS; time from random assignment to progression/death) in favour of FU/FA + panitumumab. Secondary endpoints included PFS of re-induction (PFS re-ind.), time to failure of strategy (TFS) and overall survival (OS). The trial is registered with ClinicalTrials.gov (NCT01991873). Findings In 248 patients of the Full Analysis Set recruited between May 2014 and February 2021, with a median observation of 64.0 (range 12.5-86.3) months and 59.7 (range 3.7-97.3) months in the treatment arms, 230 events for PFS (92.7%) and 196 events for OS (79.0%) were recorded. Adding panitumumab to FU/FA resulted in significantly longer PFS (8.8 versus 5.8 months, HR = 0.73 (95% CI 0.56-0.94), P = 0.015), shorter PFS re-ind. (4.1 versus 7.4 months, HR = 1.93 (95% CI 1.33-2.82), P < 0.001), comparable TFS (17.1 versus 15.7 months, HR = 0.98 (95% CI 0.68-1.42), P = 0.92) and numerically longer OS (29.9 versus 24.7 months, HR = 0.85 (95% CI 0.64-1.12), P = 0.24). The most frequent adverse event (AE) grade ≥3 was rash (FU/FA + panitumumab: n = 15, 12.0%, FU/FA: n = 17, 6.9%). 141 patients (37.3%) experienced at least one serious AE One treatment-related death occurred (neutropenic sepsis, FU/FA). Interpretation Panitumumab plus FU/FA might be considered a standard of care maintenance regimen since a potential re-induction therapy with panitumumab cannot be guaranteed at the time of maintenance treatment decision. Funding Amgen.
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Affiliation(s)
- Arndt Stahler
- Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Hematology, Oncology and Cancer Immunology, Berlin, Germany
| | - Meinolf Karthaus
- Department of Hematology and Oncology, Munich Hospital Neuperlach, Munich, Germany
| | | | | | | | | | - Karel Caca
- Department of Gastroenterology, Hematology and Oncology, Hospital Ludwigsburg, Ludwigsburg, Germany
| | - Eray Goekkurt
- Practice of Hematology and Oncology (HOPE), Hamburg, Germany
- University Cancer Center Hamburg (UCCH), Hamburg, Germany
| | - Alexej Ballhausen
- Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Hematology, Oncology and Cancer Immunology, Berlin, Germany
| | - Greta Sommerhäuser
- Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Hematology, Oncology and Cancer Immunology, Berlin, Germany
| | - Annabel H.S. Alig
- Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Hematology, Oncology and Cancer Immunology, Berlin, Germany
| | | | - Armin Jarosch
- Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Pathology, Berlin, Germany
| | - David Horst
- Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Pathology, Berlin, Germany
- German Cancer Consortium (DKTK), German Cancer Research Centre (DKFZ), Heidelberg, Germany
| | | | - Stefan Kasper
- German Cancer Consortium (DKTK), German Cancer Research Centre (DKFZ), Heidelberg, Germany
- Department of Medical Oncology, West German Cancer Center, Westdeutsches Tumorzentrum, University Hospital of Essen, Essen, Germany
| | - Volker Heinemann
- German Cancer Consortium (DKTK), German Cancer Research Centre (DKFZ), Heidelberg, Germany
- Department of Medicine 2I and Comprehensive Cancer Center, University Hospital (LMU), Munich, Germany
| | - Sebastian Stintzing
- Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Hematology, Oncology and Cancer Immunology, Berlin, Germany
- German Cancer Consortium (DKTK), German Cancer Research Centre (DKFZ), Heidelberg, Germany
| | - Tanja Trarbach
- Department of Medical Oncology, West German Cancer Center, Westdeutsches Tumorzentrum, University Hospital of Essen, Essen, Germany
- Reha-Zentrum am Meer, Bad Zwischenahn, Niedersachsen, Germany
| | - Dominik P. Modest
- Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Hematology, Oncology and Cancer Immunology, Berlin, Germany
- German Cancer Consortium (DKTK), German Cancer Research Centre (DKFZ), Heidelberg, Germany
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6
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Cohen R, Raeisi M, Chibaudel B, Shi Q, Yoshino T, Zalcberg JR, Adams R, Cremolini C, Van Cutsem E, Heinemann V, Tabernero J, Punt CJA, Arnold D, Hurwitz HI, Douillard JY, Venook AP, Saltz LB, Maughan TS, Kabbinavar F, Bokemeyer C, Grothey A, Mayer RJ, Kaplan R, Tebbutt NC, Randolph Hecht J, Giantonio BJ, Díaz-Rubio E, Sobrero AF, Peeters M, Koopman M, Goldberg RM, Andre T, de Gramont A. Prognostic value of liver metastases in colorectal cancer treated by systemic therapy: An ARCAD pooled analysis. Eur J Cancer 2024; 207:114160. [PMID: 38896997 DOI: 10.1016/j.ejca.2024.114160] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2024] [Revised: 05/27/2024] [Accepted: 05/30/2024] [Indexed: 06/21/2024]
Abstract
BACKGROUND The liver is the most frequent site of metastases in colorectal cancer (CRC). This study aimed to assess the response rate and survival outcomes in metastatic CRC patients with non-liver metastases (NLM) compared to those with liver metastases (LM) across different lines of treatment. METHODS A total of 17,924 mCRC patients included in 26 trials from the ARCAD CRC database were analyzed. The analysis was conducted based on the presence or absence of LM across different treatment groups: chemotherapy (CT) alone, CT + anti-VEGF, CT + anti-EGFR in KRAS wild-type tumors, within the first-line (1 L) and second-line (2 L), and patients enrolled in third-line (≥3 L) trials treated with trifluridine/tipiracil or regorafenib or placebo. The endpoints were overall survival (OS), progression-free survival (PFS), and overall response rate (ORR). RESULTS Out of the 17,924 patients, 14,066 had LM (30.6 % with only liver involvement and 69.4 % with liver and other metastatic sites), while 3858 patients had NLM. In the CT alone and CT + anti-VEGF subgroups, NLM patients showed better OS and PFS in the 1 L and 2 L settings. However, in the CT + anti-EGFR 1 L and 2 L subgroups, there was no significant difference in OS and PFS between NLM and LM patients. In the ≥ 3 L subgroups, better OS and PFS were observed in NLM patients. ORRs were higher in LM patients than in NLM patients across all cohorts treated in the 1 L and only in the anti-EGFR cohort in the 2 L. CONCLUSION LM is a poor prognostic factor for mCRC increasing from 1 L to ≥ 3 L except for patients in 1 L and 2 L receiving CT+anti-EGFR. These data justify using LM as a stratification factor in future trials for patients with unresectable mCRC.
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Affiliation(s)
- Romain Cohen
- Sorbonne University, Department of Medical Oncology, Hôpital Saint-Antoine, AP-HP, and INSERM UMRS 938, Équipe Instabilité des Microsatellites et Cancer, Équipe Labellisée par la Ligue Nationale Contre le Cancer, SIRIC CURAMUS, Centre de recherche Saint Antoine, Paris, France
| | | | - Benoist Chibaudel
- Department of Medical Oncology, Franco-British Hospital, Fondation Cognacq-Jay, Levallois-Perret, France
| | - Qian Shi
- Department of Quantitative Health Science, Mayo Clinic, Rochester, USA
| | - Takayuki Yoshino
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - John R Zalcberg
- Monash University School of Public Health and Preventive Medicine and Department of Medical Oncology, Alfred Health, Melbourne, VIC, Australia
| | - Richard Adams
- Cardiff University and Velindre Cancer Centre, Cardiff, United Kingdom
| | - Chiara Cremolini
- Department of Translational Research and New Technologies, University of Pisa, Pisa, Italy
| | - Eric Van Cutsem
- Department of Gastrointestinal and Liver Diseases, Digestive Oncology Unit, University Hospitals Leuven and KU Leuven, Leuven, Belgium
| | - Volker Heinemann
- Department of Medical Oncology, LMU Hospital, University of Munich, Munich, Germany
| | - Josep Tabernero
- Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology (VHIO), IOB-Quiron, Barcelona, Spain
| | | | - Dirk Arnold
- Asklepios Tumorzentrum Hamburg, Asklepios Klinik Altona, Hamburg, Germany
| | | | - Jean-Yves Douillard
- Medical Oncology Department, Integrated Centers for Oncology Nantes, Nantes, France
| | - Alan P Venook
- Department of Medicine, The University of California San Francisco, San Francisco, CA, USA
| | | | | | | | - Carsten Bokemeyer
- Department of Oncology and Hematology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | | | | | | | - Niall C Tebbutt
- Department of Medical Oncology, Olivia Newton-John Cancer, Wellness and Research Centre, Austin Health, Heidelberg, VIC, Australia
| | - J Randolph Hecht
- David Geffen School of Medicine at UCLA, University of California at Los Angeles, Los Angeles, USA
| | | | | | | | | | - Miriam Koopman
- University Medical Center Utrecht, Utrecht, the Netherlands
| | - Richard M Goldberg
- Department of Medicine, West Virginia University Cancer Institute, Morgantown, USA
| | - Thierry Andre
- Sorbonne University, Department of Medical Oncology, Hôpital Saint-Antoine, AP-HP, and INSERM UMRS 938, Équipe Instabilité des Microsatellites et Cancer, Équipe Labellisée par la Ligue Nationale Contre le Cancer, SIRIC CURAMUS, Centre de recherche Saint Antoine, Paris, France; ARCAD Foundation, Paris, France
| | - Aimery de Gramont
- ARCAD Foundation, Paris, France; Department of Medical Oncology, Franco-British Hospital, Levallois-Perret, France
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7
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Kieran R, Hennessy M, Coakley K, O'Sullivan H, Cronin T, Lynch D, Mulroe E, Cooke K, Collins D, O'Reilly S. Optimising oncology drug expenditure in Ireland. Ir J Med Sci 2024; 193:1735-1747. [PMID: 38568369 PMCID: PMC11294381 DOI: 10.1007/s11845-024-03672-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Accepted: 03/15/2024] [Indexed: 08/02/2024]
Abstract
A combination of improvements in patient survival, increasing treatment duration, and the development of more expensive agents has led to a doubling of per-capita spending on cancer medicines in Ireland (2008-2018). Despite this, access to new drugs is poor in comparison to other EU countries. We examine methods to optimise oncology drug spending to facilitate access to newer anticancer agents. Key targets for spending optimisation (biosimilar use, clinical trials and expanded access programs, waste reduction, avoidance of futile treatment, and altered drug scheduling) were identified through an exploratory analysis. A structured literature search was performed, with a focus on articles relevant to the Irish Healthcare system, supplemented by reports from statutory bodies. At the present time, EMA-approved agents are available once approved by the NCPE. Optimising drug costs occurs through guideline-based practice and biosimilar integration, the latter provides €80 million in cost savings annually. Access to novel therapies can occur via over 50 clinical trials and 28 currently available expanded access programmes. Additional strategies include reversion to weight-based immunotherapy dosing, potentially saving €400,000 per year in our centre alone, vial sharing, and optimisation of treatment schedules. A variety of techniques are being employed by oncologists to optimise costs and increase access to innovation for patients. Use of biosimilars, drug wastage, and prescribing at end of life should be audited as key performance indicators, which may lead to reflective practice on treatment planning. Such measures could further optimise oncology drug expenditure nationally facilitating approval of new agents.
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Affiliation(s)
- Ruth Kieran
- Department of Medical Oncology, Cork University Hospital, Cork, Ireland.
- Cancer Research@UCC, College of Medicine & Health, University College Cork, Cork, Ireland.
| | - Maeve Hennessy
- Department of Medical Oncology, Cork University Hospital, Cork, Ireland
- Cancer Research@UCC, College of Medicine & Health, University College Cork, Cork, Ireland
| | - Kate Coakley
- Department of Medical Oncology, Cork University Hospital, Cork, Ireland
| | - Hazel O'Sullivan
- Department of Medical Oncology, Cork University Hospital, Cork, Ireland
| | - Tim Cronin
- College of Medicine & Health, University College Cork, Cork, Ireland
| | - Daire Lynch
- Cancer Trials Ireland, RCSI House, 121 St Stephen's , Dublin 2, Green, Ireland
| | - Eibhlin Mulroe
- Cancer Trials Ireland, RCSI House, 121 St Stephen's , Dublin 2, Green, Ireland
| | - Katie Cooke
- Department of Pharmacy, Cork University Hospital, Cork, Ireland
| | - Dearbhaile Collins
- Department of Medical Oncology, Cork University Hospital, Cork, Ireland
- Cancer Research@UCC, College of Medicine & Health, University College Cork, Cork, Ireland
| | - Seamus O'Reilly
- Department of Medical Oncology, Cork University Hospital, Cork, Ireland
- Cancer Research@UCC, College of Medicine & Health, University College Cork, Cork, Ireland
- Cancer Trials Ireland, RCSI House, 121 St Stephen's , Dublin 2, Green, Ireland
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8
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Xiang Y, Zhang C, Wang J, Cheng Y, Wang K, Wang L, Tong Y, Yan D. Role of blood metabolites in mediating the effect of gut microbiome on the mutated-RAS/BRAF metastatic colorectal cancer-specific survival. Int J Colorectal Dis 2024; 39:116. [PMID: 39046546 PMCID: PMC11269474 DOI: 10.1007/s00384-024-04686-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/09/2024] [Indexed: 07/25/2024]
Abstract
BACKGROUND Recent studies have linked alterations in the gut microbiome and metabolic disruptions to the invasive behavior and metastasis of colorectal cancer (CRC), thus affecting patient prognosis. However, the specific relationship among gut microbiome, metabolite profiles, and mutated-RAS/BRAF metastatic colorectal cancer (M-mCRC) remains unclear. Furthermore, the potential mechanisms and prognostic implications of metabolic changes induced by gut microbiome alterations in patients with M-mCRC still need to be better understood. METHODS We conducted Mendelian randomization (MR) to evaluate the causal relationship of genetically predicted 196 gut microbiome features and 1400 plasma metabolites/metabolite ratios on M-mCRC-specific survival. Additionally, we identified significant gut microbiome-metabolites/metabolite ratio associations based on M-mCRC. Metabolite information was annotated, and functional annotation and pathway enrichment analyses were performed on shared proteins corresponding to significant metabolite ratios, aiming to reveal potential mechanisms by which gut microbiome influences M-mCRC prognosis via modulation of human metabolism. RESULTS We identified 11 gut microbiome features and 49 known metabolites/metabolite ratios correlated with M-mCRC-specific survival. Furthermore, we identified 17 gut microbiome-metabolite/metabolite ratio associations specific to M-mCRC, involving eight lipid metabolites and three bilirubin degradation products. The shared proteins corresponding to significant metabolite ratios were predominantly localized within the integral component of the membrane and exhibited enzymatic activities such as glucuronosyltransferase and UDP-glucuronosyltransferase, crucial in processes such as glucuronidation, bile secretion, and lipid metabolism. Moreover, these proteins were significantly enriched in pathways related to ascorbate and aldarate metabolism, pentose and glucuronate interconversions, steroid hormone biosynthesis, and bile secretion. CONCLUSION Our study offers novel insights into the potential mechanisms underlying the impact of the gut microbiome on the prognosis of M-mCRC. These findings serve as a meaningful reference for exploring potential therapeutic targets and strategies in the future.
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Affiliation(s)
- Yaoxian Xiang
- Department of Oncology, Beijing Luhe Hospital Affiliated to Capital Medical University, Beijing, 101149, China
| | - Chan Zhang
- Department of Oncology, Beijing Luhe Hospital Affiliated to Capital Medical University, Beijing, 101149, China
| | - Jing Wang
- Department of Oncology, Beijing Luhe Hospital Affiliated to Capital Medical University, Beijing, 101149, China
| | - Yurong Cheng
- Department of Oncology, Beijing Luhe Hospital Affiliated to Capital Medical University, Beijing, 101149, China
| | - Kangjie Wang
- Department of Oncology, Beijing Luhe Hospital Affiliated to Capital Medical University, Beijing, 101149, China
| | - Li Wang
- Department of Oncology, Beijing Luhe Hospital Affiliated to Capital Medical University, Beijing, 101149, China
| | - Yingying Tong
- Department of Oncology, Beijing Luhe Hospital Affiliated to Capital Medical University, Beijing, 101149, China
| | - Dong Yan
- Department of Oncology, Beijing Luhe Hospital Affiliated to Capital Medical University, Beijing, 101149, China.
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9
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Zhou Y, Wu S, Qu FJ. Therapeutic strategies targeting the epidermal growth factor receptor signaling pathway in metastatic colorectal cancer. World J Gastrointest Oncol 2024; 16:2362-2379. [PMID: 38994135 PMCID: PMC11236217 DOI: 10.4251/wjgo.v16.i6.2362] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Revised: 02/13/2024] [Accepted: 04/01/2024] [Indexed: 06/14/2024] Open
Abstract
More than 1.9 million new colorectal cancer (CRC) cases and 935000 deaths were estimated to occur worldwide in 2020, representing about one in ten cancer cases and deaths. Overall, colorectal ranks third in incidence, but second in mortality. More than half of the patients are in advanced stages at diagnosis. Treatment options are complex because of the heterogeneity of the patient population, including different molecular subtypes. Treatments have included conventional fluorouracil-based chemotherapy, targeted therapy, immunotherapy, etc. In recent years, with the development of genetic testing technology, more and more targeted drugs have been applied to the treatment of CRC, which has further prolonged the survival of metastatic CRC patients.
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Affiliation(s)
- Yi Zhou
- Department of Oncology, Affiliated Dalian Third People’s Hospital of Dalian Medical University, Dalian 116033, Liaoning Province, China
| | - Shuang Wu
- Department of Oncology, Affiliated Dalian Third People’s Hospital of Dalian Medical University, Dalian 116033, Liaoning Province, China
| | - Fan-Jie Qu
- Department of Oncology, Affiliated Dalian Third People’s Hospital of Dalian Medical University, Dalian 116033, Liaoning Province, China
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10
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Pinto C, Orlandi A, Normanno N, Maiello E, Calegari MA, Antonuzzo L, Bordonaro R, Zampino MG, Pini S, Bergamo F, Tonini G, Avallone A, Latiano TP, Rosati G, Cogoni AA, Ballestrero A, Zaniboni A, Roselli M, Tamberi S, Barone C. Fluorouracil, Leucovorin, and Irinotecan Plus Cetuximab Versus Cetuximab as Maintenance Therapy in First-Line Therapy for RAS and BRAF Wild-Type Metastatic Colorectal Cancer: Phase III ERMES Study. J Clin Oncol 2024; 42:1278-1287. [PMID: 38181312 PMCID: PMC11095858 DOI: 10.1200/jco.23.01021] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Revised: 08/12/2023] [Accepted: 09/25/2023] [Indexed: 01/07/2024] Open
Abstract
PURPOSE The intensity of anti-EGFR-based first-line therapy for RAS/BRAF wild-type (wt) metastatic colorectal cancer (mCRC), once disease control is achieved, is controversial. A de-escalation strategy with anti-EGFR monotherapy represents a potential option to maintain efficacy while reducing cytotoxicity. METHODS In this multicenter, open-label, phase III trial, patients with untreated RAS/BRAF wt mCRC were randomly assigned to receive either fluorouracil, leucovorin, and irinotecan/cetuximab (FOLFIRI/Cet) until disease progression (arm A) or FOLFIRI/Cet for eight cycles followed by Cet alone (arm B). The coprimary end points were a noninferior progression-free survival (PFS) in the modified per-protocol (mPP) population (>eight cycles) and a lower incidence of grade (G) 3-4 adverse events (AEs) for arm B compared with arm A. RESULTS Overall, 606 patients were randomly assigned, with 300 assigned to arm A and 306 to arm B. The median follow-up was 22.3 months. In the mPP population, 291 events occurred with a PFS of 10 versus 12.2 months for arms B and A, respectively (P of noninferiority = .43). In the intention-to-treatment (ITT, ≥one cycle) population, 503 events occurred with a PFS of 9 versus 10.7 months (P = .39). The overall survival was 35.7 versus 30.7 months (P = .119) and 31.0 versus 25.2 months (P = .32) in the mPP and ITT population, respectively. Arm B had lower G3-4 AEs during the maintenance period than arm A (20.2% v 35.1%). CONCLUSION The ERMES study did not demonstrate noninferiority of maintenance with Cet alone. Despite a more favorable safety profile, maintenance with single-agent Cet after induction with FOLFIRI/Cet cannot be recommended for all patients but could represent an option in selected cases.
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Affiliation(s)
- Carmine Pinto
- Medical Oncology, Comprehensive Cancer Centre Azienda USL—IRCCS di Reggio Emilia, Reggio Emilia, Italy
| | - Armando Orlandi
- Comprehensive Cancer Center, UOC Medical Oncology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, Italy
| | - Nicola Normanno
- Translational Research Departement, Istituto Nazionale Tumori IRCCS—Fondazione G. Pascale, Napoli, Italy
| | - Evaristo Maiello
- Oncology Unit, Foundation IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Maria A. Calegari
- Comprehensive Cancer Center, UOC Medical Oncology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, Italy
| | - Lorenzo Antonuzzo
- Department of Experimental and Clinical Medicine, University of Florence, Italy Clinical Oncology Unit, Careggi University Hospital, Firenze, Italy
| | - Roberto Bordonaro
- Medical Oncology, Azienda Ospedaliera ARNAS Garibaldi, Catania, Italy
| | - Maria G. Zampino
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IRCCS, Milan, Italy
| | - Sara Pini
- Ospedale Santa Maria delle Croci, Ravenna, Italy
| | - Francesca Bergamo
- Dipartimento Oncologia 1, IOV—Istituto Oncologico Veneto IRCCS, Padova, Italy
| | - Giuseppe Tonini
- Dipartimento di Oncologia, Fondazione Policlinico Campus Bio-Medico, Facoltà di Medicina Università Campus Bio-Medico, Rome, Italy
| | - Antonio Avallone
- Medical Oncology, Istituto Nazionale Tumori-IRCCS Fondazione G. Pascale, Naples, Italy
| | - Tiziana P. Latiano
- Oncology Unit, Foundation IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Gerardo Rosati
- Medical Oncology Unit, S. Carlo Hospital, Potenza, Italy
| | | | - Alberto Ballestrero
- DiMI Università degli Studi di Genova e Ospedale Policlinico San Martino IRCCS, Genova, Italy
| | | | - Mario Roselli
- Medical Oncology Unit, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Stefano Tamberi
- UO Medical Oncology, Area Vasta Romagna Ausl di Ravenna, Presidio Ospedaliero di Faenza, Ospedale Civile degli Infermi, Faenza, Italy
| | - Carlo Barone
- Comprehensive Cancer Center, UOC Medical Oncology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, Italy
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11
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Xuan T, Wang Z, Meng S, Li J, Li J, Cao F, Qu L. Efficacy and Safety of Maintenance Therapy Using Cetuximab in Patients with Metastatic Colorectal Cancer: Retrospective Study. Cancer Manag Res 2024; 16:185-197. [PMID: 38525371 PMCID: PMC10960546 DOI: 10.2147/cmar.s443666] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Accepted: 02/28/2024] [Indexed: 03/26/2024] Open
Abstract
Purpose Cetuximab (CET) combined with chemotherapy significantly improved the survival in RAS and RAF wild-type metastatic colorectal cancer (mCRC) patients, while clinical evidence was lacking on the use of maintenance therapy (MT). The study aimed to explore the role of maintenance therapy following Cetuximab + chemotherapy and the optimal Cetuximab-based maintenance therapy regimen. Patients and Methods We retrospectively reviewed data on the efficacy and safety of CET-based MT in patients with mCRC who achieved disease control after induction therapy. Results Eighty-one patients with mCRC who achieved disease control after CET + chemotherapy induction were enrolled. Overall median progression-free survival (PFS) was 10.5 (95% CI = 8.8-12.2) months and median maintenance/observation PFS (mnPFS) was 6.0 (95% CI = 5.0-7.0) months. Among these 81 patients, 61 patients were prescribed MT (CET alone for 21 patients and CET + chemotherapy for 40 patients). Median PFS and mnPFS in the MT group were significantly longer than those for the non-MT group. Different MT regimens did not affect PFS and mnPFS significantly. Univariate and multivariate analysis demonstrated MT, complete response/partial response during induction therapy, and absence of peritoneal metastasis to be positively associated with longer PFS and mnPFS. Treatment-related adverse events (AEs) were tolerable during MT, and AE-related deaths were not observed. Conclusion MT with CET or CET + chemotherapy was an appropriate option following initial induction chemotherapy for patients with RAS and RAF wild-type mCRC. This strategy endowed survival benefits and a tolerable safety profile.
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Affiliation(s)
- Tiantian Xuan
- Department of Medical Oncology, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, Shandong, People’s Republic of China
| | - Zhanmei Wang
- Department of Medical Oncology, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, Shandong, People’s Republic of China
| | - Sibo Meng
- Department of Medical Oncology, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, Shandong, People’s Republic of China
| | - Jiaxin Li
- Department of Medical Oncology, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, Shandong, People’s Republic of China
| | - Jisheng Li
- Department of Medical Oncology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, People’s Republic of China
| | - Fangli Cao
- Department of Medical Oncology, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, Shandong, People’s Republic of China
| | - Linli Qu
- Department of Medical Oncology, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, Shandong, People’s Republic of China
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12
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Petrelli F, Cherri S, Ghidini M, Tomasello G, Ghidini A, Zaniboni A. Efficacy of different maintenance strategies for RAS wild-type colorectal cancer: A network meta-analysis. Dig Liver Dis 2024; 56:242-247. [PMID: 37369616 DOI: 10.1016/j.dld.2023.06.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 06/05/2023] [Accepted: 06/06/2023] [Indexed: 06/29/2023]
Abstract
INTRODUCTION In metastatic RAS wild-type colorectal cancer (CRC), induction combination chemotherapy doublets (CT) with an anti-EGFR agent are considered the primary treatment. We performed a network meta-analysis (NMA) to compare the relative efficacy of different maintenance treatments for advanced RAS wild-type CRC. MATERIALS AND METHODS PubMed, EMBASE and Cochrane, from database inception until December 2021 were used. Randomized clinical trials enrolling adults with advanced RAS wild-type CRC and providing overall survival (OS) and/or progression-free survival (PFS) data PRISMA guidelines for NMA were followed. Between-group comparisons were estimated using hazard ratios (HRs) with 95% credible intervals (95% CrIs). Agents were ranked using surface under the cumulative ranking (SUCRA) probabilities. RESULTS A total of 7 randomized phase 2 trials were included (for a total of 1286 patients). Compared to depotentiation treatments, continuous CT + anti-EGFR was not significantly superior to other maintenance regimens for OS and was ranked as the best option for NMA (SUCRA p-score=0.69). Conversely, in the PFS analysis, single-agent fluoropyrimidines + anti-EGFR was ranked as the best treatment (SUCRA p-score=0.60). CONCLUSIONS Maintaining chemotherapy doublet + anti-EGFR until progression appears to be the best first-line strategy in terms of OS for advanced unresectable RAS wild-type mCRC treatment. However, fluoropyrimidines single-agent + cetuximab or panitumumab represent a reasonable choice regarding PFS.
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Affiliation(s)
| | - Sara Cherri
- Oncology Unit, Fondazione Poliambulanza, Brescia, Italy
| | - Michele Ghidini
- Oncology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy
| | - Gianluca Tomasello
- Oncology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy
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13
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Kasi PM, Afable MG, Herting C, Lukanowski M, Jin Z. Anti-EGFR Antibodies in the Management of Advanced Colorectal Cancer. Oncologist 2023; 28:1034-1048. [PMID: 37774394 PMCID: PMC11025386 DOI: 10.1093/oncolo/oyad262] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Accepted: 08/25/2023] [Indexed: 10/01/2023] Open
Abstract
Colorectal cancer is the third most common cancer worldwide, and incidence is rising in younger individuals. Anti-EGFR antibodies, including cetuximab and panitumumab, have been incorporated into standard-of-care practice for patients with advanced disease. Herein, we review the molecular characteristics of these agents and the trials that lead to their approvals. Further, we discuss clinical implications of data regarding biomarkers that dictate treatment selection, different dosing strategies, and side effect management. Finally, we look towards the future and describe contexts in which these agents are currently being investigated clinically with a focus on combinations with MAPK-targeted therapies and immunotherapy. Overall, this review provides historical context, current clinical usage, and future directions for anti-EGFR antibodies in advanced colorectal cancer.
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Affiliation(s)
- Pashtoon Murtaza Kasi
- Department of Oncology/Hematology, Division of Internal Medicine, Weill Cornell Medicine, Meyer Cancer Center, Englander Institute of Precision Medicine, New York, NY, USA
| | | | - Cameron Herting
- Medical Affairs, Eli Lilly and Company, Indianapolis, IN, USA
| | | | - Zhaohui Jin
- Department of Oncology, Mayo Clinic, Rochester, MN, USA
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14
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Mastrantoni L, Beccia V, Caira G, Trovato G, Calegari MA, Basso M, Salvatore L, Pozzo C, Tortora G, Bria E, Orlandi A. Maintenance strategies after anti-EGFR-based induction in metastatic colorectal cancer: A systematic review and bayesian network meta-analysis. Crit Rev Oncol Hematol 2023; 191:104106. [PMID: 37659764 DOI: 10.1016/j.critrevonc.2023.104106] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Accepted: 08/20/2023] [Indexed: 09/04/2023] Open
Abstract
BACKGROUND In RAS wild type (wt) metastatic colorectal cancer (mCRC) maintenance therapy after induction with fluoropyrimidine (FP)-based cytotoxic therapy (CT) plus anti-EGFR agents is controversial. METHODS Phase II-III randomized trials were included. Maintenance strategies considered were: observation, anti-EGFR or FP monotherapy, FP + anti-EGFR, doublet CT + anti-EGFR. RESULTS Maintenance with FP + anti-EGFR (HR 0.56, 95% CrI 0.36-0.89) showed the greatest PFS benefit compared to observation, ranking first on SUCRA analysis (96.4%). Considering OS, doublet CT+ anti-EGFR, FP + anti-EGFR and anti-EGFR monotherapy yielded similar results. For PFS, FP + anti-EGFR confirmed to be valuable in BRAF wt patients and left sided tumors. In left sided tumors, the OS benefit of adding CT was limited. FP plus anti-EGFR showed a favourable safety profile compared to doublet CT + anti-EGFR. CONCLUSIONS FP + anti-EGFR can be considered a valuable maintenance option in RAS wt mCRC. EGFR monotherapy can be considered, especially in left-sided tumors.
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Affiliation(s)
- Luca Mastrantoni
- Medical Oncology, Università Cattolica del Sacro Cuore, Rome, Italy.
| | - Viria Beccia
- Medical Oncology, Università Cattolica del Sacro Cuore, Rome, Italy.
| | - Giulia Caira
- Medical Oncology, Università Cattolica del Sacro Cuore, Rome, Italy.
| | - Giovanni Trovato
- Medical Oncology, Università Cattolica del Sacro Cuore, Rome, Italy.
| | - Maria Alessandra Calegari
- Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS Rome, Italy.
| | - Michele Basso
- Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS Rome, Italy.
| | - Lisa Salvatore
- Medical Oncology, Università Cattolica del Sacro Cuore, Rome, Italy; Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS Rome, Italy.
| | - Carmelo Pozzo
- Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS Rome, Italy.
| | - Giampaolo Tortora
- Medical Oncology, Università Cattolica del Sacro Cuore, Rome, Italy; Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS Rome, Italy.
| | - Emilio Bria
- Medical Oncology, Università Cattolica del Sacro Cuore, Rome, Italy; Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS Rome, Italy.
| | - Armando Orlandi
- Medical Oncology, Università Cattolica del Sacro Cuore, Rome, Italy.
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15
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Li J, Zhang H, Guo X, Dong S, Li Y, Huang W, Yuan X. A Real-World Retrospective Study to Evaluate the Reliability of Cetuximab plus Capecitabine versus Capecitabine as Maintenance Therapy in Patients with RAS and BRAF Wild-Type Metastatic Colorectal Cancer. Med Princ Pract 2023; 33:31-40. [PMID: 37725905 PMCID: PMC10896611 DOI: 10.1159/000533528] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Accepted: 08/07/2023] [Indexed: 09/21/2023] Open
Abstract
BACKGROUND The optimal maintenance therapy for rat sarcoma (RAS) and v-raf murine sarcoma viral oncogene homolog B (BRAF) metastatic colorectal cancers (mCRCs) remains unclear. It is critical to evaluate the reliability of cetuximab-capecitabine (the observation group) relative to capecitabine alone (control group). PATIENTS AND METHODS In this retrospective analysis, patients with RAS and BRAF mCRC admitted to Huizhou Municipal Central Hospital, between January 2016 and October 2020 were enrolled and treated with cetuximab plus 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) as an initial therapy. Patients whose disease was controlled after at least six cycles of treatment were administered a maintenance therapy until disease progression. We also analyzed the prognosis of patients according to clinicopathological features. Altogether, 39 RAS and BRAF mCRC patients were recruited from January 2016 to October 2020, with 18 cases in the treatment group and 21 cases in the control group. The difference in baseline clinicopathological features between the two treatments is not obvious. RESULTS The median progression-free survival after maintenance treatment in observation group (9.5 months [95% confidence interval (CI) = 6.4-12.6]), was significantly better than the control group (7.3 months [95% CI = 5.8-8.8]). During maintenance treatment, there were no deaths caused by treatment-related adverse events, and the overall incidence of rash acne was different between the observation and control groups (p < 0.05). Most adverse events were mild and easily controlled. Primary tumor site, baseline carcinoembryonic antigen levels, and microsatellite instability status were independent prognostic factors. CONCLUSION Maintenance therapy using cetuximab plus capecitabine improved survival in patients with mCRC and was well tolerated by patients.
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Affiliation(s)
- Jun Li
- The Second Department of Medical Oncology, Huizhou First Hospital, Huizhou, China
| | - Hang Zhang
- The Second Department of Medical Oncology, Huizhou First Hospital, Huizhou, China
| | - Xuli Guo
- Department of Medical Oncology, The Central People’s Hospital of Huizhou, Huizhou, China
| | - Shaoting Dong
- Department of Medical Oncology, The Central People’s Hospital of Huizhou, Huizhou, China
| | - Yi Li
- The Second Department of Medical Oncology, Huizhou First Hospital, Huizhou, China
| | - Weizhen Huang
- The Second Department of Medical Oncology, Huizhou First Hospital, Huizhou, China
| | - Xia Yuan
- The Second Department of Medical Oncology, Huizhou First Hospital, Huizhou, China
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16
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Boige V, Blons H, François E, Ben Abdelghani M, Phelip JM, Le Brun-Ly V, Mineur L, Galais MP, Villing AL, Hautefeuille V, Miglianico L, De La Fouchardière C, Genet D, Levasseur N, Levaché CB, Penel N, Mitry E, Jacquot S, Aparicio T, Brument E, Gourgou S, Castan F, Bouché O. Maintenance Therapy With Cetuximab After FOLFIRI Plus Cetuximab for RAS Wild-Type Metastatic Colorectal Cancer: A Phase 2 Randomized Clinical Trial. JAMA Netw Open 2023; 6:e2333533. [PMID: 37721754 PMCID: PMC10507485 DOI: 10.1001/jamanetworkopen.2023.33533] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Accepted: 07/28/2023] [Indexed: 09/19/2023] Open
Abstract
Importance The optimal maintenance strategy after induction chemotherapy with anti-epidermal growth factor receptor antibody for patients with RAS wild-type metastatic colorectal cancer (mCRC) remains to be debated. Objective To evaluate the efficacy and safety of maintenance therapy with single-agent cetuximab after FOLFIRI (leucovorin [folinic acid], fluorouracil, and irinotecan) plus cetuximab induction therapy. Design, Setting, and Participants The TIME (Treatment After Irinotecan-Based Frontline Therapy: Maintenance With Erbitux]) (PRODIGE 28 [Partenariat de Recherche en Oncologie Digestive]-UCGI 27 [UniCancer GastroIntestinal Group]) phase 2 noncomparative, multicenter randomized clinical trial was conducted from January 15, 2014, to November 23, 2018, among 139 patients with unresectable RAS wild-type mCRC. The cutoff date for analysis was July 21, 2022. Interventions After first-line induction therapy with 8 cycles of FOLFIRI plus cetuximab, patients without disease progression were randomized (1:1) to biweekly maintenance with cetuximab or observation. On disease progression, the same induction regimen was recommended for 16 weeks followed by further maintenance with cetuximab or observation until disease progression under the full induction regimen. Main Outcomes and Measures The primary end point was the 6-month progression-free rate from randomization. Analysis was performed on an intention-to-treat basis. An exploratory biomolecular analysis, using next-generation sequencing, investigated the putative prognostic value of the tumor mutation profile. Results Of 214 patients enrolled (141 men [65.9%]; median age, 67 years [range, 23-85 years]), 139 were randomized to receive cetuximab (n = 67; 45 men [67.2%]; median age, 64 years [range, 34-85 years]) or to be observed (n = 72; 50 men [69.4%]; median age, 68 years [23-85 years]). The 6-month progression-free rate was 38.8% ([26 of 67] 95% CI, 27.1%-51.5%) in the cetuximab group and 5.6% ([4 of 72] 95% CI, 1.5%-13.6%) in the observation group. At a median follow-up of 40.5 months (95% CI, 33.6-47.5 months), median progression-free survival (PFS) from randomization was 5.3 months (95% CI, 3.7-7.4 months) in the cetuximab group and 2.0 months (95% CI, 1.8-2.7 months) in the observation group. Median overall survival (OS) was 24.8 months (95% CI, 18.7-30.4 months) in the cetuximab group and 19.7 months (95% CI, 13.3-24.4 months) in the observation group. In an exploratory multivariate analysis, any tumor-activating mutation in the mitogen-activated protein kinase (MAPK) pathway genes was associated with shorter PFS from randomization regardless of treatment group (hazard ratio, 1.63 [95% CI, 1.01-2.62]; P = .04). The most frequent grade 3 or 4 treatment-related toxic effect in the cetuximab group during maintenance therapy was rash (8 of 67 [11.9%]). Conclusion and Relevance The randomized clinical trial did not meet its primary end point but suggests clinically meaningful PFS and OS benefits associated with cetuximab maintenance therapy. However, maintenance cetuximab or treatment breaks after first-line combination FOLFIRI-cetuximab therapy seems inappropriate for patients with MAPK-mutated independently of the side of primary tumor. A more complete assessment of MAPK pathway mutations warrants further investigation to the refine treatment strategy for patients with RAS wild-type mCRC. Trial Registration ClinicalTrials.gov Identifier: NCT02404935.
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Affiliation(s)
- Valérie Boige
- Department of Cancer Medicine, Gustave Roussy, Villejuif, France
- INSERM UMR-S1138, Centre de Recherche des Cordeliers-Sorbonne Université- Université de Paris Cité, Paris, France
| | - Hélène Blons
- INSERM UMR-S1138, Centre de Recherche des Cordeliers-Sorbonne Université- Université de Paris Cité, Paris, France
- Department of Biochemistry, Molecular Oncology and Pharmacogenetics, European Georges Pompidou Hospital, APHP-Centre, Université Paris Cité, Paris Cancer Institute CARPEM, Paris, France
| | - Eric François
- Department of Medical Oncology, Antoine Lacassagne Centre, Nice, France
| | | | - Jean-Marc Phelip
- Departement of Hepato-gastroenterology, Saint Etienne Hospital, Saint Priest en Jarez, France
| | - Valerie Le Brun-Ly
- Departement of Medical Oncology and Radiotherapy, Dupuytren Hospital, Limoges, France
| | - Laurent Mineur
- Departement of Clinical Research, Sainte Catherine Institute, Avignon, France
| | | | | | | | - Laurent Miglianico
- Department of Radiotherapy, Saint Grégoire Hospital, Saint-Grégoire, France
| | | | - Dominique Genet
- Departement of Oncology and Radiotherapy, François Chénieux Clinic, Limoges, France
| | - Nadia Levasseur
- Department of Oncology, Jean Rougier Hospital, Cahors, France
| | - Charles-Briac Levaché
- Departement of Oncology and Radiotherapy, Francheville Polyclinic, Périgueux, France
| | - Nicolas Penel
- Pole of Oncology, Oscar Lambret Centre, Lille, France
| | - Emmanuel Mitry
- Department of Medical Oncology, Paoli Calmettes Institute, Marseille, France
| | - Stéphane Jacquot
- Department of Radiotherapy, Clementville Clinic, Montpellier, France
| | - Thomas Aparicio
- Department of Gastro-enterology, Saint Louis Hospital, APHP, Université Paris Cité, Paris, France
| | | | - Sophie Gourgou
- Biometry Unit, Montpellier Cancer Institute, Montpellier, France
| | - Florence Castan
- Biometry Unit, Montpellier Cancer Institute, Montpellier, France
| | - Olivier Bouché
- Department of Digestive Oncology, CHU Reims, Université Reims Champagne-Ardenne, Reims, France
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17
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Raimondi A, Nichetti F, Stahler A, Wasan HS, Aranda E, Randon G, Kurreck A, Meade AM, Díaz-Rubio E, Niger M, Stintzing S, Palermo F, Trarbach T, Prisciandaro M, Sommerhäuser G, Fisher D, Morano F, Pietrantonio F, Modest DP. Optimal maintenance strategy following FOLFOX plus anti-EGFR induction therapy in patients with RAS wild type metastatic colorectal cancer: An individual patient data pooled analysis of randomised clinical trials. Eur J Cancer 2023; 190:112945. [PMID: 37441940 DOI: 10.1016/j.ejca.2023.112945] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Revised: 06/04/2023] [Accepted: 06/11/2023] [Indexed: 07/15/2023]
Abstract
BACKGROUND Anti-EGFR antibodies plus doublet chemotherapy is the standard of care in RAS/BRAF wild-type metastatic colorectal cancer (mCRC). No phase-3 level of evidence is available to guide treatment de-escalation after anti-EGFR-based first-line. Several randomised clinical trials investigated de-intensification strategies with 5-fluorouracil/leucovorin (5-FU/LV) and/or anti-EGFR. METHODS We performed an individual patient data pooled analysis of Valentino, Panama, MACRO-2, COIN-B trials including RAS wild-type mCRC patients who received first-line therapy with FOLFOX plus panitumumab or cetuximab followed by pre-specified maintenance strategy. Only patients who started maintenance according to the assigned arm were included. Patients were categorised by type of maintenance (i.e. 5-FU/LV, anti-EGFR or 5-FU/LV + anti-EGFR). Progression-free survival (PFS) and overall survival (OS) were calculated from the start of maintenance; toxicity was evaluated for the maintenance treatment period. RESULTS A total of 518 patients were included in the pooled analysis. Overall, 123, 185 and 210 patients received maintenance with 5-FU/LV, anti-EGFR, 5-FU/LV + anti-EGFR, respectively. Median PFS was 5.6, 6.0 and 9.0 (P = 0.009) and OS was 25.7, 24.0 and 28.0 months (P = 0.134) in 5-FU/LV, anti-EGFR and 5-FU/LV + anti-EGFR arms, respectively. Monotherapy maintenance (either 5-FU/LV or anti-EGFR) was inferior to combination in terms of PFS (hazard ratios [HR] 1.26, P = 0.016) and non-significantly trending also in OS (HR 1.20, P = 0.111). An increase of overall any grade and grade ≥ 3 AEs and selected AEs was reported in combination compared to either 5-FU/LV or anti-EGFR arms. CONCLUSIONS This pooled analysis including four randomised phase II supports the use of 5-FU/LV plus anti-EGFR as the preferred maintenance regimen. Data provide rational for a more individualised maintenance treatment approach based on tumour and patients features.
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Affiliation(s)
- Alessandra Raimondi
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Federico Nichetti
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; Computational Oncology Group, Molecular Precision Oncology Program, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Arndt Stahler
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Hematology, Oncology and Tumor Immunology, Berlin, Germany
| | | | - Enrique Aranda
- IMIBIC, Universidad de Córdoba, CIBERONC, Instituto de Salud Carlos III, Hospital Universitario Reina Sofía, Córdoba, Spain
| | - Giovanni Randon
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Annika Kurreck
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Hematology, Oncology and Tumor Immunology, Berlin, Germany
| | - Angela M Meade
- MRC Clinical Trials Unit, University College London, Redhill, England, London, UK
| | - Eduardo Díaz-Rubio
- Department of Medical Oncology, Hospital Clinico San Carlos, Madrid, Spain
| | - Monica Niger
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Sebastian Stintzing
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Hematology, Oncology and Tumor Immunology, Berlin, Germany
| | - Federica Palermo
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Tanja Trarbach
- Department of Medical Oncology, Reha-Zentrum am Meer, Bad Zwischenahn, Niedersachsen, Germany
| | - Michele Prisciandaro
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Greta Sommerhäuser
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Hematology, Oncology and Tumor Immunology, Berlin, Germany
| | - David Fisher
- MRC Clinical Trials Unit, University College London, Redhill, England, London, UK
| | - Federica Morano
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Filippo Pietrantonio
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
| | - Dominik P Modest
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Hematology, Oncology and Tumor Immunology, Berlin, Germany
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18
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Doleschal B, Petzer A, Rumpold H. Current concepts of anti-EGFR targeting in metastatic colorectal cancer. Front Oncol 2022; 12:1048166. [PMID: 36465407 PMCID: PMC9714621 DOI: 10.3389/fonc.2022.1048166] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Accepted: 10/26/2022] [Indexed: 11/07/2023] Open
Abstract
Anti-EGFR targeting is one of the key strategies in the treatment of metastatic colorectal cancer (mCRC). For almost two decades oncologists have struggled to implement EGFR antibodies in the mCRC continuum of care. Both sidedness and RAS mutational status rank high among the predictive factors for the clinical efficacy of EGFR inhibitors. A prospective phase III trial has recently confirmed that anti-EGFR targeting confers an overall survival benefit only in left sided RAS-wildtype tumors when given in first line. It is a matter of discussion if more clinical benefit can be reached by considering putative primary resistance mechanisms (e.g., HER2, BRAF, PIK3CA, etc.) at this early stage of treatment. The value of this procedure in daily routine clinical utility has not yet been clearly delineated. Re-exposure to EGFR antibodies becomes increasingly crucial in the disease journey of mCRC. Yet re- induction or re-challenge strategies have been problematic as they relied on mathematical models that described the timely decay of EGFR antibody resistant clones. The advent of liquid biopsy and the implementation of more accurate next-generation sequencing (NGS) based high throughput methods allows for tracing of EGFR resistant clones in real time. These displays the spatiotemporal heterogeneity of metastatic disease compared to the former standard radiographic assessment and re-biopsy. These techniques may move EGFR inhibition in mCRC into the area of precision medicine in order to apply EGFR antibodies with the increase or decrease of EGFR resistant clones. This review critically discusses established concepts of tackling the EGFR pathway in mCRC and provides insight into the growing field of liquid biopsy guided personalized approaches of EGFR inhibition in mCRC.
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Affiliation(s)
- Bernhard Doleschal
- Department of Internal Medicine I for Hematology With Stem Cell Transplantation, Hemostaseology and Medical Oncology, Ordensklinikum Linz, Linz, Austria
| | - Andreas Petzer
- Department of Internal Medicine I for Hematology With Stem Cell Transplantation, Hemostaseology and Medical Oncology, Ordensklinikum Linz, Linz, Austria
| | - Holger Rumpold
- Gastrointestinal Cancer Center, Ordensklinikum Linz, Linz, Austria
- Johannes Kepler University Linz, Medical Faculty, Linz, Austria
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19
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Henderson RH, French D, McFerran E, Adams R, Wasan H, Glynne-Jones R, Fisher D, Richman S, Dunne PD, Wilde L, Maughan TS, Sullivan R, Lawler M. Spend less to achieve more: Economic analysis of intermittent versus continuous cetuximab in KRAS wild-type patients with metastatic colorectal cancer. J Cancer Policy 2022; 33:100342. [PMID: 35718327 DOI: 10.1016/j.jcpo.2022.100342] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 06/02/2022] [Accepted: 06/13/2022] [Indexed: 10/18/2022]
Abstract
BACKGROUND In 2014, the COIN-B clinical trial demonstrated that intermittent cetuximab (IC) was a safe alternative to continuous cetuximab (CC), with less cytotoxic chemotherapy, in first-line treatment for KRAS wild-type metastatic colorectal cancer (mCRC). Cetuximab has been available for this indication in England since 2015, but treatment breaks beyond 6 weeks were prohibited, despite real-world evidence that therapy de-escalation maintains equivalent disease control, but with superior Quality-of-Life (QoL). We performed health economic analyses of IC versus CC and used this evidence to help underpin policy change and guide clinical practice through reduction in unnecessary treatment for mCRC patients. METHODS Employing cost-minimization analysis, we conducted partitioned survival modelling (PSM) and Markov Chain Monte-Carlo (MCMC) simulation to determine costs and quality-adjusted-life-years for IC versus CC. RESULTS IC reduced costs by £ 35,763 (PSM; p < 0.001) or £ 30,189 (MCMC) per patient annually, while preserving treatment efficacy and enhancing QoL. Extrapolating to all mCRC patients eligible for cetuximab therapy would have generated cost savings of ~£ 1.2 billion over this cohort's lifetime. These data helped underpin a request to NHS England to remove treatment break restrictions in first-line mCRC therapy, which has been adopted as an interim treatment option policy in colorectal cancer during the Covid-19 pandemic. CONCLUSIONS Our results highlight substantial cost savings achievable by treatment de-escalation, while also reinforcing the importance of therapy breaks to potentially increase tumour responsiveness and reduce treatment toxicity. Our study also highlights how health economic evidence can influence health policy, championing reduced treatment intensity approaches without compromising patient outcomes, which is of particular relevance when addressing the reduced capacity and treatment backlogs experienced during the pandemic.
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Affiliation(s)
- Raymond H Henderson
- Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, UK; Queen's Management School, Queen's University Belfast, UK; Salutem Insights Ltd, Garryduff, Clough, Portlaoise R32 V653, Ireland.
| | - Declan French
- Queen's Management School, Queen's University Belfast, UK
| | - Ethna McFerran
- Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, UK
| | | | - Harpreet Wasan
- Oncology Hammersmith Hospital, Imperial College Healthcare Trust & Imperial College, London, UK
| | | | - David Fisher
- MRC Clinical Trials Unit at UCL, Institute of Clinical Trials & Methodology, Aviation House, 125 Kingsway, London WC2B 6NH, UK
| | - Susan Richman
- Department of Pathology and Data Analytics, Leeds Institute of Medical Research, St James' University Hospital, Leeds LS9 7TF, UK
| | - Philip D Dunne
- Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, UK
| | - Lisa Wilde
- Bowel Cancer UK, Edinburgh House, 170 Kennington Lane, London, UK
| | - Timothy S Maughan
- Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK
| | - Richard Sullivan
- Institute of Cancer Policy, School of Cancer Sciences, King's College London, UK
| | - Mark Lawler
- Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, UK
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20
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Parisi A, Ghidini M, Giampieri R, Tomasello G, Luciani A, Ferri C, Berardi R, Petrelli F. Post-induction Strategies in Metastatic Colorectal Cancer Patients Treated With First-Line Anti-EGFR-Based Treatment: A Systematic Review and Meta-Analysis. Clin Colorectal Cancer 2022; 21:e162-e170. [PMID: 35184993 DOI: 10.1016/j.clcc.2021.12.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 12/25/2021] [Accepted: 12/27/2021] [Indexed: 11/03/2022]
Abstract
Few data from randomized clinical trials (RCTs) investigating the efficacy of post-induction strategies after the first-line treatment with anti-Epidermal Growth Factor Receptor (EGFR) in patients with metastatic colorectal cancer (mCRC) are available. A systematic review and metanalysis might therefore be useful to highlight and even strengthen these data. A literature search in Pubmed, Embase, American Society of Clinical Oncology (ASCO) Annual Meetings, ASCO Gastrointestinal Symposia, and European Society for Medical Oncology (ESMO) Congresses was performed. The search included RCTs of patients with mCRC treated with an initial period of cytotoxic chemotherapy (CT) in association with anti-EGFR (ie, panitumumab or cetuximab) as first-line regimen, and then switched to one of the following strategies: observation; maintenance with anti-EGFR, fluoropyrimidine (FP), or both; or continuing the induction regimen until disease progression or unacceptable toxicity. Outcomes of interest included overall survival (OS) and progression-free survival (PFS). The overall effect was pooled using the Mantel-Haenszel method fixed-effect model or the DerSimonian-Laird method random-effect model according to heterogeneity (I2). Analysis was performed on June 9, 2021. 7 studies (all phase II trials), including 1038 patients, were considered eligible for the meta-analysis. In all studies, CT (induction or maintenance with FP) + anti-EGFR until disease progression or unacceptable toxicity prolonged OS (HR = 0.72 [95%CI 0.61-0.86]; P < .01) and PFS (HR = 0.76, 95%CI 0.68-0.85; P < .01) compared to other agents (FP ± bevacizumab) or observation. Subgroup analyses for OS and PFS were performed according to type of maintenance therapy (containing or not containing single-agent anti-EGFR). Within patients evaluable for OS, CT + anti-EGFR combinations continued until disease progression were able to decrease the risk of death by 32% (HR 0.68; 95% CI 0.56-0.84; P < .01) and the risk of progression by 25% (HR 0.75; 95% CI 0.65-0.85; P < .01) over no maintenance or maintenance with anti-EGFR alone. Conversely, combination of CT + anti-EGFR were no better over anti-EGFR with FP in term of OS (HR = 0.81 [95%CI 0.60-1.09]; P = .17) and PFS (HR = 0.81 [95% 0.64, 1.01]; P = .06). Maintenance treatment with anti-EGFR + FP might be regarded as the better option following anti-EGFR based induction treatment in RAS wild-type mCRC, in terms of efficacy. This effect might be particularly amplified in left-sided BRAF wild-type mCRC patients. A higher level of evidence coming from phase III trials is auspicable.
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Affiliation(s)
- Alessandro Parisi
- Medical Oncology, St. Salvatore Hospital, L'Aquila, Italy; Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy.
| | - Michele Ghidini
- Medical Oncology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Riccardo Giampieri
- Clinica Oncologica e Centro Regionale di Genetica Oncologica, Università Politecnica delle Marche, AOU Ospedali Riuniti-Ancona, Italy
| | - Gianluca Tomasello
- Medical Oncology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | | | - Claudio Ferri
- Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy
| | - Rossana Berardi
- Clinica Oncologica e Centro Regionale di Genetica Oncologica, Università Politecnica delle Marche, AOU Ospedali Riuniti-Ancona, Italy
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21
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Raimondi A, Randon G, Prisciandaro M, Pagani F, Lonardi S, Antoniotti C, Bozzarelli S, Sartore-Bianchi A, Tampellini M, Fanchini L, Murialdo R, Clavarezza M, Zaniboni A, Berenato R, Ratti M, Petrelli F, Antonuzzo L, Giordano M, Rossi A, Di Bartolomeo M, Di Maio M, Pietrantonio F, Morano F. Early onset metastatic colorectal cancer in patients receiving panitumumab-based upfront strategy: Overall and sex-specific outcomes in the Valentino trial. Int J Cancer 2022; 151:1760-1769. [PMID: 35678328 DOI: 10.1002/ijc.34156] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Revised: 05/24/2022] [Accepted: 05/25/2022] [Indexed: 11/12/2022]
Abstract
Anti-EGFRs plus doublet chemotherapy is considered the optimal upfront option for RAS/BRAF wild-type left-sided metastatic colorectal cancer (mCRC). Early-onset (EO) mCRC has an increasing incidence and its prognostic/predictive role and management is debatable. We performed a post hoc analysis of Valentino study, that randomized RAS wild-type mCRC patients to two panitumumab-based maintenance regimens after FOLFOX/panitumumab induction. We assessed the safety and efficacy outcomes in patients stratified for age (<50/≥50 years old). We assessed progression-free survival (PFS), overall survival (OS), response rate (ORR), rate of treatment-related and panitumumab-related adverse events (AEs) and quality of life (QoL). In 229 patients enrolled, 35 (15%) had EO mCRC, with a higher rate of female sex (P = .020) and lower rate of primary tumor resection (P = .001). Median PFS and OS were 10.9 vs 10.8 months (P = .593) and 28.1 vs 27.5 months (P = .865) in patients <50 and ≥50 years old, respectively, with no significant impact of maintenance arm. ORR and disease control rate were 74% vs 65% (P = .337) and 97% vs 81% (P = .013) in patients <50 or ≥50 years old. In younger patients, a trend for increased chemotherapy-related AEs (peculiarly anemia) was shown, while significantly decreased EGFR-related hypomagnesemia and increased skin rash were reported. No significant differences in treatment intensity or QoL were observed. In patients with EO mCRC and RAS wild-type status, we found no differences in terms of survival outcomes based on age when selecting maintenance strategies. Management of treatment-related AEs should consider the differential toxicity profile of age and sex.
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Affiliation(s)
- Alessandra Raimondi
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Giovanni Randon
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Michele Prisciandaro
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.,Oncology and Hemato-oncology Department, University of Milan, Milan, Italy
| | - Filippo Pagani
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Sara Lonardi
- Department of Oncology, Veneto Institute of Oncology IRCCS, Padua, Italy
| | - Carlotta Antoniotti
- Unit of Medical Oncology, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
| | - Silvia Bozzarelli
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano, Italy
| | - Andrea Sartore-Bianchi
- Oncology and Hemato-oncology Department, University of Milan, Milan, Italy.,Division of Oncology, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Marco Tampellini
- Department of Oncology, AOU San Luigi di Orbassano, University of Torino, Orbassano, Italy
| | - Laura Fanchini
- SSD ColoRectal Cancer Unit-Dipartimento di Oncologia, AOU Città della Salute e della Scienza di Torino, Torino, Italy
| | - Roberto Murialdo
- Department of Internal Medicine, University of Genoa and IRCCS AOU San Martino-IST, Genoa, Italy
| | - Matteo Clavarezza
- Medical Oncology Unit, Ente Ospedaliero Ospedali Galliera, Genoa, Italy
| | | | | | | | - Fausto Petrelli
- Medical Oncology Unit, Oncology Department, ASST Bergamo Ovest, Treviglio, Italy
| | - Lorenzo Antonuzzo
- Clinical Oncology Unit, AOU Careggi, Florence, Italy.,Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Monica Giordano
- Medical Oncology Unit, Azienda Socio Sanitaria Territoriale Lariana, Como, Italy
| | - Alessandro Rossi
- Department of Clinical and Molecular Medicine, Oncology Unit, "La Sapienza" University of Rome, Azienda Ospedaliera Sant'Andrea, Rome, Italy
| | - Maria Di Bartolomeo
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Massimo Di Maio
- Department of Oncology, University of Turin, Division of Medical Oncology, Ordine Mauriziano Hospital, Turin, Italy
| | - Filippo Pietrantonio
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Federica Morano
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
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22
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Yuan M, Wang Z, Lv W, Pan H. The Role of Anti-EGFR Monoclonal Antibody in mCRC Maintenance Therapy. Front Mol Biosci 2022; 9:870395. [PMID: 35433839 PMCID: PMC9006990 DOI: 10.3389/fmolb.2022.870395] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2022] [Accepted: 02/24/2022] [Indexed: 12/22/2022] Open
Abstract
Background: Epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs) combined with chemotherapy in patients with RAS (rat sarcoma viral oncogene homolog) wild-type metastatic colorectal cancer (mCRC) can alleviate and stabilize the disease, effectively prolong the progression-free survival (PFS) and overall survival (OS), and improve the overall response rate (ORR), which is the first-line treatment standard scheme for RAS wild-type mCRC currently. However, whether anti-EGFR mAb can be used for the maintenance treatment after the first-line treatment of mCRC remains controversial. We reviewed the recent studies on anti-EGFR mAb. The contents include five parts, introduction, anti-EGFR mAb in mCRC and its status in first-line therapy, establishment of the maintenance treatment pattern after the standard first-line treatment for mCRC, research progress of anti-EGFR mAb in mCRC maintenance therapy, and conclusion. More studies support the maintenance treatment of anti-EGFR mAb, but some researchers raise the problems about high cost and drug resistance. Despite lack of the maintenance evidence of anti-EGFR mAb, especially lack of large-scale phase III prospective clinical trials, with the emergence of new evidence and more accurate screening of treatment-dominant groups, maintenance therapy with anti-EGFR mAb monotherapy or anti-EGFR mAb combined with fluorouracil-based schemes after first-line chemotherapy combined with anti-EGFR mAb therapy might strive for more treatment opportunities, optimize treatment strategies and prolong treatment continuity, and finally, lead to more survival benefit for suitable patients.
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Affiliation(s)
- Meiqin Yuan
- The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
- Zhejiang University School of Medicine, Hangzhou, China
| | - Zeng Wang
- The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
| | - Wangxia Lv
- The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
| | - Hongming Pan
- Zhejiang University School of Medicine, Sir Run Run Shaw Hospital, Hangzhou, China
- *Correspondence: Hongming Pan,
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23
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Fucà G, Raimondi A, Prisciandaro M, Lonardi S, Cremolini C, Ratti M, Clavarezza M, Murialdo R, Sartore-Bianchi A, Smiroldo V, Berenato R, Racca P, Bergamo F, Corallo S, Di Bartolomeo M, de Braud F, Morano F, Pietrantonio F. Reinduction of an Anti-EGFR-based First-line Regimen in Patients with RAS Wild-type Metastatic Colorectal Cancer Enrolled in the Valentino Study. Oncologist 2022; 27:e29-e36. [PMID: 35305093 PMCID: PMC8842305 DOI: 10.1093/oncolo/oyab012] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Accepted: 11/17/2021] [Indexed: 11/14/2022] Open
Abstract
Abstract
Background
In patients with RAS/BRAF wild-type metastatic colorectal cancer (mCRC), growing evidence supports anti-epidermal growth factor receptor (EGFR) retreatment, whereas little is known on the outcomes of anti-EGFR-based reinduction therapy during the upfront strategy.
Methods
We included patients enrolled in the Valentino study who had disease progression and received at least one dose of post-progression therapy. The Kaplan–Meier method and Cox proportional hazards regression were used for the survival analysis. When comparing the outcomes of anti-EGFR-based reinduction versus any second line, a propensity score–based matching was used.
Results
Liver-limited/single site of disease (P < .001 and P = .002), left-sidedness (P = .029), surgery of metastases (P = .003), early tumor shrinkage, and deeper responses (P = .018 and P = .036) were associated with the use of anti-EGFR-based reinduction versus any other second line. All patients treated with reinduction had an anti-EGFR-free interval of at least 3 months. In the propensity score–matched population, progression-free survival (PFS) was similar in the 2 treatment groups, the overall survival (OS) was significantly longer for patients treated with reinduction (P = .029), and the response rate was higher in patients treated with reinduction (P = .033). An oxaliplatin-free interval ≥12 months, left-sidedness, and molecular hyperselection beyond RAS/BRAF were associated with significantly better outcomes after anti-EGFR-based reinduction.
Conclusions
Reinduction strategies with anti-EGFR-based regimens are commonly used in clinical practice. Our data highlight the importance of clinical–molecular selection for re-treatments and the need for prospective strategy trials in selected populations.
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Affiliation(s)
- Giovanni Fucà
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Alessandra Raimondi
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Michele Prisciandaro
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Sara Lonardi
- Department of Oncology, Veneto Institute of Oncology IOV - IRCCS, Padua, Italy
| | - Chiara Cremolini
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
- Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
| | - Margherita Ratti
- Oncology Unit, Oncology Department, ASST of Cremona, Cremona, Italy
| | - Matteo Clavarezza
- Medical Oncology Unit, Ente Ospedaliero Ospedali Galliera, Genoa, Italy
| | - Roberto Murialdo
- Department of Internal Medicine (Di.M.I.), University of Genoa and IRCCS AOU San Martino-IST, Genoa, Italy
| | - Andrea Sartore-Bianchi
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
- Oncology and Hemato-oncology Department, University of Milan, Milan, Italy
| | - Valeria Smiroldo
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano, Italy
| | - Rosa Berenato
- Medical Oncology Unit A.O. Papardo and Department of Human Pathology, University of Messina, Messina, Italy
| | - Patrizia Racca
- Colorectal Cancer Unit, Oncology Department, AOU Città della Salute e della Scienza di Torino, Turin, Italy
| | - Francesca Bergamo
- Department of Oncology, Veneto Institute of Oncology IOV - IRCCS, Padua, Italy
| | - Salvatore Corallo
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Maria Di Bartolomeo
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Filippo de Braud
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
- Oncology and Hemato-oncology Department, University of Milan, Milan, Italy
| | - Federica Morano
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Filippo Pietrantonio
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
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Modest DP, Karthaus M, Fruehauf S, Graeven U, Müller L, König AO, Fischer von Weikersthal L, Caca K, Kretzschmar A, Goekkurt E, Haas S, Kurreck A, Stahler A, Held S, Jarosch A, Horst D, Reinacher-Schick A, Kasper S, Heinemann V, Stintzing S, Trarbach T. Panitumumab Plus Fluorouracil and Folinic Acid Versus Fluorouracil and Folinic Acid Alone as Maintenance Therapy in RAS Wild-Type Metastatic Colorectal Cancer: The Randomized PANAMA Trial (AIO KRK 0212). J Clin Oncol 2022; 40:72-82. [PMID: 34533973 PMCID: PMC8683209 DOI: 10.1200/jco.21.01332] [Citation(s) in RCA: 55] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
PURPOSE The randomized PANAMA trial investigated the efficacy of panitumumab (Pmab) when added to maintenance therapy with fluorouracil and folinic acid (FU/FA) in patients with RAS wild-type metastatic colorectal cancer. METHODS Following first-line induction therapy with six cycles of FU/FA and oxaliplatin plus Pmab, responding patients (stable disease or partial or complete remission) were randomly assigned (1:1, open-label) to maintenance treatment with either FU/FA plus Pmab or FU/FA alone. The primary objective was to demonstrate superiority of progression-free survival (PFS, time from random assignment until progression or death) in favor of FU/FA plus Pmab with a hazard ratio (HR) of 0.75, a power of 80%, and a significance level of 10%. Secondary end points included overall survival, objective response rate of maintenance therapy, and toxicity. Survival end points were analyzed by the Kaplan-Meier method and compared by log-rank test and Cox regressions. Dichotomous variables were compared by Fisher's exact test; odds ratios were indicated when appropriate. The trial is registered with ClinicalTrials.gov (NCT01991873). RESULTS Overall, 248 patients were randomly assigned and received maintenance therapy with either FU/FA plus Pmab (125 patients) or FU/FA alone (123 patients). At data cutoff, with 218 events (of 218 needed), PFS of maintenance therapy was significantly improved with FU/FA plus Pmab (8.8 months v 5.7 months; HR, 0.72; 80% CI, 0.60 to 0.85; P = .014). Overall survival (event rate 54%) numerically favored the FU/FA plus Pmab arm (28.7 months v 25.7 months; HR, 0.84; 95% CI, 0.60 to 1.18; P = .32). Objective response rates were 40.8% in patients receiving FU/FA plus Pmab versus 26.0% in patients receiving FU/FA alone (odds ratio, 1.96; 95% CI, 1.14 to 3.36; P = .02). The most frequent Common Terminology Criteria for Adverse Event grade ≥ 3 event during maintenance therapy was skin rash (7.2%). CONCLUSION In RAS wild-type metastatic colorectal cancer, maintenance therapy with FU/FA plus Pmab induced a significantly superior PFS compared with FU/FA alone. If active maintenance therapy is aspired following induction therapy with FU/FA and oxaliplatin plus Pmab, FU/FA plus Pmab appears to be the most favorable option.
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Affiliation(s)
- Dominik Paul Modest
- Department of Hematology, Oncology and Tumorimmunology, Charité-Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany,German Cancer Consortium (DKTK), German Cancer Research Centre (DKFZ), Heidelberg, Germany,Dominik Paul Modest, Department of Hematology, Oncology, and Tumorimmunology (CVK), Charité-Universitätsmedizin Berlin, Augustenburgerplatz 1, 13353 Berlin, Germany; e-mail:
| | - Meinolf Karthaus
- Department of Hematology and Oncology, Munich Hospital Neuperlach, Munich, Germany
| | | | | | | | - Alexander Otto König
- Department of Gastroenterology, University Medicine Göttingen, Göttingen, Germany
| | | | - Karel Caca
- Department of Gastroenterology, Hematology and Oncology, Hospital Ludwigsburg, Ludwigsburg, Germany
| | | | - Eray Goekkurt
- Practice of Hematology and Oncology (HOPE), Hamburg, Germany,University Cancer Center Hamburg (UCCH), Hamburg, Germany
| | - Siegfried Haas
- Department of Hematology and Oncology, Friedrich-Ebert-Hospital, Neumünster, Germany
| | - Annika Kurreck
- Department of Hematology, Oncology and Tumorimmunology, Charité-Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Arndt Stahler
- Department of Hematology, Oncology and Tumorimmunology, Charité-Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Swantje Held
- Charité Universitätsmedizin, Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Pathology, Berlin, Germany
| | - Armin Jarosch
- Charité Universitätsmedizin, Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Pathology, Berlin, Germany
| | - David Horst
- German Cancer Consortium (DKTK), German Cancer Research Centre (DKFZ), Heidelberg, Germany,Charité Universitätsmedizin, Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Pathology, Berlin, Germany
| | | | - Stefan Kasper
- German Cancer Consortium (DKTK), German Cancer Research Centre (DKFZ), Heidelberg, Germany,Department of Medical Oncology, West German Cancer Center, Westdeutsches Tumorzentrum, University Hospital of Essen, Essen, Germany
| | - Volker Heinemann
- German Cancer Consortium (DKTK), German Cancer Research Centre (DKFZ), Heidelberg, Germany,Department of Medicine III and Comprehensive Cancer Center, University Hospital (LMU), Munich, Germany
| | - Sebastian Stintzing
- Department of Hematology, Oncology and Tumorimmunology, Charité-Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany,German Cancer Consortium (DKTK), German Cancer Research Centre (DKFZ), Heidelberg, Germany
| | - Tanja Trarbach
- Zentrum für Tumorbiologie und Integrative Medizin, Klinikum Wilhelmshaven, Wilhelmshaven, Germany
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25
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Wills C, He Y, Summers MG, Lin Y, Phipps AI, Watts K, Law PJ, Al-Tassan NA, Maughan TS, Kaplan R, Houlston RS, Peters U, Newcomb PA, Chan AT, Buchanan DD, Gallinger S, Marchand LL, Pai RK, Shi Q, Alberts SR, Gray V, West HD, Escott-Price V, Dunlop MG, Cheadle JP. A genome-wide search for determinants of survival in 1926 patients with advanced colorectal cancer with follow-up in over 22,000 patients. Eur J Cancer 2021; 159:247-258. [PMID: 34794066 PMCID: PMC9132154 DOI: 10.1016/j.ejca.2021.09.047] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 09/22/2021] [Accepted: 09/26/2021] [Indexed: 01/03/2023]
Abstract
BACKGROUND While genome-wide association studies (GWAS) have identified germline variants influencing the risk of developing colorectal cancer (CRC), there has been limited examination of the possible role of inherited variation as a determinant of patient outcome. PATIENTS AND METHODS We performed a GWAS for overall survival (OS) in 1926 patients with advanced CRC from the COIN and COIN-B clinical trials. For single nucleotide polymorphisms (SNPs) showing an association with OS (P < 1.0 × 10-5), we conducted sensitivity analyses based on the time from diagnosis to death and sought independent replications in 5675 patients from the Study of Colorectal Cancer in Scotland (SOCCS) and 16,964 patients from the International Survival Analysis in Colorectal cancer Consortium (ISACC). We analysed the Human Protein Atlas to determine if ERBB4 expression was associated with survival in 438 patients with colon adenocarcinomas. RESULTS The most significant SNP associated with OS was rs79612564 in ERBB4 (hazard ratio [HR] = 1.24, 95% confidence interval [CI] = 1.16-1.32, P = 1.9 × 10-7). SNPs at 17 loci had suggestive associations for OS and all had similar effects on the time from diagnosis to death. No lead SNPs were independently replicated in the meta-analysis of all patients from SOCCS and ISACC. However, rs79612564 was significant in stage-IV patients from SOCCS (P = 2.1 × 10-2) but not ISACC (P = 0.89) and SOCCS combined with COIN and COIN-B attained genome-wide significance (P = 1.7 × 10-8). Patients with high ERBB4 expression in their colon adenocarcinomas had worse survival (HR = 1.50, 95% CI = 1.1-1.9, P = 4.6 × 10-2). CONCLUSIONS Genetic and expression data support a potential role for rs79612564 in the receptor tyrosine kinase ERBB4 as a predictive biomarker of survival.
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Affiliation(s)
- Christopher Wills
- Division of Cancer and Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, CF14 4XN, UK
| | - Yazhou He
- Colon Cancer Genetics Group, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK; Department of Oncology, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, 610000, China
| | - Matthew G Summers
- Division of Cancer and Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, CF14 4XN, UK
| | - Yi Lin
- Epidemiology Department, University of Washington, Seattle, WA, USA; Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Amanda I Phipps
- Epidemiology Department, University of Washington, Seattle, WA, USA; Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Katie Watts
- Division of Cancer and Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, CF14 4XN, UK
| | - Philip J Law
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London, SW7 3RP, UK
| | - Nada A Al-Tassan
- Department of Genetics, King Faisal Specialist Hospital and Research Center, P.O. Box 3354, Riyadh 11211, Saudi Arabia
| | - Timothy S Maughan
- CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Roosevelt Drive, Oxford OX3 7DQ, UK
| | - Richard Kaplan
- MRC Clinical Trials Unit, University College of London, 125 Kingsway, London, WC2B 6NH, UK
| | - Richard S Houlston
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London, SW7 3RP, UK
| | - Ulrike Peters
- Epidemiology Department, University of Washington, Seattle, WA, USA; Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Polly A Newcomb
- Epidemiology Department, University of Washington, Seattle, WA, USA; Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Andrew T Chan
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Daniel D Buchanan
- Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Victoria, Australia; Centre for Cancer Research, Victorian Comprehensive Cancer Centre, The University of Melbourne, Parkville, Victoria, Australia; Genomic Medicine and Family Cancer Clinic, The Royal Melbourne Hospital, Parkville, Victoria, Australia
| | - Steve Gallinger
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada; Ontario Institute for Cancer Research, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
| | - Loic L Marchand
- Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA
| | - Rish K Pai
- Department of Laboratory Medicine and Pathology, Mayo Clinic Arizona, Scottsdale, AZ, USA
| | - Qian Shi
- Department of Quantitative Science, Mayo Clinic, Rochester, MN, USA
| | | | - Victoria Gray
- Division of Cancer and Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, CF14 4XN, UK
| | - Hannah D West
- Division of Cancer and Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, CF14 4XN, UK
| | - Valentina Escott-Price
- Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff, CF24 4HQ, UK
| | - Malcolm G Dunlop
- Colon Cancer Genetics Group, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK
| | - Jeremy P Cheadle
- Division of Cancer and Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, CF14 4XN, UK.
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26
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Parisi A, Cortellini A, Venditti O, Filippi R, Salvatore L, Tortora G, Ghidini M, Nigro O, Gelsomino F, Zurlo IV, Fulgenzi C, Lombardi P, Roselló Keränen S, Depetris I, Giampieri R, Morelli C, Di Marino P, Di Pietro FR, Zanaletti N, Vitale P, Garajova I, Spinelli GP, Zoratto F, Roberto M, Petrillo A, Aimar G, Patruno L, D'Orazio C, Ficorella C, Ferri C, Porzio G. Post-Induction Management in Patients With Left-Sided RAS and BRAF Wild-Type Metastatic Colorectal Cancer Treated With First-Line Anti-EGFR-Based Doublet Regimens: A Multicentre Study. Front Oncol 2021; 11:712053. [PMID: 34778029 PMCID: PMC8579084 DOI: 10.3389/fonc.2021.712053] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Accepted: 09/28/2021] [Indexed: 01/09/2023] Open
Abstract
Background Few data regarding post-induction management following first-line anti-epidermal growth factor receptor (EGFR)-based doublet regimens in patients with left-sided RAS/BRAF wild-type metastatic colorectal cancer (mCRC) are available. Methods This multicenter, retrospective study aimed at evaluating clinicians’ attitude, and the safety and effectiveness of post-induction strategies in consecutive patients affected by left-sided RAS/BRAF wild-type mCRC treated with doublet chemotherapy plus anti-EGFR as first-line regimen, who did not experience disease progression within 6 months from induction initiation, at 21 Italian and 1 Spanish Institutions. The measured clinical outcomes were: progression-free survival (PFS), overall survival (OS), adverse events, and objective response rate (ORR). Results At the data cutoff, among 686 consecutive patients with left-sided RAS/BRAF wild-type mCRC treated with doublet plus anti-EGFR as first-line regimen from March 2012 to October 2020, 355 eligible patients have been included in the present analysis. Among these, 118 (33.2%), 66 (18.6%), and 11 (3.1%) received a maintenance with 5-fluorouracil/leucovorin (5FU/LV)+anti-EGFR, anti-EGFR, and 5FU/LV, respectively, while 160 (45.1%) patients continued induction treatment (non-maintenance) until disease progression, unacceptable toxicity, patient decision, or completion of planned treatment. The median period of follow-up for the overall population was 33.7 months (95%CI = 28.9–35.6). The median PFS values of the 5FU/LV+anti-EGFR, anti-EGFR, 5FU/LV, and non-maintenance cohorts were 16.0 (95%CI = 14.3–17.7, 86 events), 13.0 (95%CI = 11.4–14.5, 56 events), 14.0 (95%CI = 8.1–20.0, 8 events), and 10.1 months (95%CI = 9.0–11.2, 136 events), respectively (p < 0.001). The median OS values were 39.6 (95%CI = 31.5–47.7, 43 events), 36.1 (95%CI = 31.6–40.7, 36 events), 39.5 (95%CI = 28.2–50.8, 4 events), and 25.1 months (95%CI = 22.6–27.6, 99 events), respectively (p < 0.001). After adjusting for key covariates, a statistically significant improvement in PFS in favor of 5FU/LV+anti-EGFR (HR = 0.59, 95%CI = 0.44–0.77, p < 0.001) and anti-EGFR (HR = 0.71, 95%CI = 0.51–0.98, p = 0.039) compared to the non-maintenance cohort was found. Compared to the non-maintenance cohort, OS was improved by 5FU/LV+anti-EGFR (HR = 0.55, 95%CI = 0.38–0.81, p = 0.002) and, with marginal significance, by anti-EGFR (HR = 0.67, 95%CI = 0.51–0.98, p = 0.051). No difference was found in ORR. Any grade non-hematological and hematological events were generally higher in the non-maintenance compared to the maintenance cohorts. Conclusion Among the treatment strategies following an anti-EGFR-based doublet first-line induction regimen in patients affected by left-sided RAS/BRAF wild-type mCRC treated in a “real-life” setting, 5FU/LV+anti-EGFR resulted the most adopted, effective, and relatively safe regimen.
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Affiliation(s)
- Alessandro Parisi
- Medical Oncology, St. Salvatore Hospital, L'Aquila, Italy.,Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy
| | - Alessio Cortellini
- Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy.,Department of Surgery and Cancer, Imperial College London, London, United Kingdom
| | - Olga Venditti
- Medical Oncology, St. Salvatore Hospital, L'Aquila, Italy
| | - Roberto Filippi
- Department of Oncology, University of Turin, Turin, Italy.,Division of Medical Oncology, Candiolo Cancer Institute, Fondazione Del Piemonte Per L'oncologia-Istiruto di Ricerca e Cura a Carattere Scientifico (FPO-IRCCS), Candiolo, Italy.,Centro Oncologico Ematologico Subalpino, Azienda Universitaria Ospedaliera Città della Salute e della Scienza di Torino, Turin, Italy
| | - Lisa Salvatore
- Università Cattolica del Sacro Cuore, Rome, Italy.,Medical Oncology, Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, Rome, Italy
| | - Giampaolo Tortora
- Università Cattolica del Sacro Cuore, Rome, Italy.,Medical Oncology, Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, Rome, Italy
| | - Michele Ghidini
- Medical Oncology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Olga Nigro
- Medical Oncology, ASST Sette Laghi, Ospedale di Circolo e Fondazione Macchi, Varese, Italy
| | - Fabio Gelsomino
- Department of Oncology and Hematology, Division of Oncology, University Hospital of Modena, Modena, Italy
| | | | - Claudia Fulgenzi
- Medical Oncology, Campus Bio-Medico, University of Rome, Rome, Italy
| | - Pasquale Lombardi
- Division of Medical Oncology, Candiolo Cancer Institute, Fondazione Del Piemonte Per L'oncologia-Istiruto di Ricerca e Cura a Carattere Scientifico (FPO-IRCCS), Candiolo, Italy
| | - Susana Roselló Keränen
- Department of Medical Oncology, Hospital Clínico Universitario de Valencia, INCLIVA Biomedical Research Institute, University of Valencia, Valencia, Spain.,CIBERONC, Instituto de Salud Carlos III, Madrid, Spain
| | - Ilaria Depetris
- Medical Oncology, ASL TO4, Ospedale Civile di Ivrea, Turin, Italy
| | - Riccardo Giampieri
- Clinica Oncologica e Centro Regionale di Genetica Oncologica, Università Politecnica delle Marche, AOU Ospedali Riuniti-Ancona, Ancona, Italy
| | - Cristina Morelli
- Medical Oncology Unit and PhD Program in Systems and Experimental Medicine (XXXV cycle), Tor Vergata University Hospital, Rome, Italy
| | - Pietro Di Marino
- Department of Medical, Oral and Biotechnological Sciences and Center for Advance Studies and Technology (CAST), G. D'Annunzio University, Chieti, Italy.,Clinical Oncology Unit, S.S. Annunziata Hospital, Chieti, Italy
| | | | - Nicoletta Zanaletti
- Experimental Clinical Abdominal Oncology Unit, Istituto Nazionale Tumori-IRCCS-Fondazione G.Pascale, Naples, Italy
| | - Pasquale Vitale
- Department of Precision Medicine, Università della Campania "Luigi Vanvitelli", Naples, Italy
| | - Ingrid Garajova
- Medical Oncology Unit, University Hospital of Parma, Parma, Italy
| | - Gian Paolo Spinelli
- UOC Territorial Oncology-AUSL Latina-CdS Aprilia-University of Rome "Sapienza", Rome, Italy
| | | | - Michela Roberto
- Department of Clinical and Molecular Medicine, Sapienza University of Rome, Oncology Unit, Sant'Andrea Hospital, Rome, Italy
| | | | - Giacomo Aimar
- Department of Oncology, University of Turin, Turin, Italy.,Division of Medical Oncology, Candiolo Cancer Institute, Fondazione Del Piemonte Per L'oncologia-Istiruto di Ricerca e Cura a Carattere Scientifico (FPO-IRCCS), Candiolo, Italy
| | - Leonardo Patruno
- Medical Oncology, St. Salvatore Hospital, L'Aquila, Italy.,Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy
| | - Carla D'Orazio
- Medical Oncology, St. Salvatore Hospital, L'Aquila, Italy.,Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy
| | - Corrado Ficorella
- Medical Oncology, St. Salvatore Hospital, L'Aquila, Italy.,Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy
| | - Claudio Ferri
- Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy
| | - Giampiero Porzio
- Medical Oncology, St. Salvatore Hospital, L'Aquila, Italy.,Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy
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27
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Wang X, Wu W, Zheng Z, Chi P. Exploring Better Strategies for RAS Mutation-Associated EGFR-Targeted Resistance in Colorectal Cancer: From the Perspective of Cancer Community Ecology. Front Oncol 2021; 11:754220. [PMID: 34745987 PMCID: PMC8568953 DOI: 10.3389/fonc.2021.754220] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Accepted: 09/29/2021] [Indexed: 12/25/2022] Open
Abstract
RAS is the most common mutated gene in colorectal cancer (CRC), and its occurrence is associated with primary and acquired resistance to anti-epidermal growth factor receptor (EGFR) blockade. Cancer community ecology, such as the competitive exclusion principle, is a valuable focus and would contribute to the understanding of drug resistance. We have presented several articles on RAS mutant clonal evolution monitoring during anti-EGFR treatment in CRC. In these articles, the availability of serially collected samples provided a unique opportunity to model the tumor evolutionary process from the perspective of cancer community ecology in those patients upon treatment. In this perspective article, we presented a theoretical basis and evidence from several experimental or phase II clinical trials for the contemporary application of ecological mechanisms in CRC treatment. In general, a reduction in targetable RAS wild-type cells to a maximum tolerated extent, such as continuous treatment, might lead to the competitive release of inextirpable RAS mutant cells and cancer progression. A full understanding of subclonal competition might be beneficial in managing CRC. Several ecological strategies, including anti-EGFR treatment reintroduced at an appropriate point of time for RAS mutant patients, intermittent treatment instead of continuous treatment, the appropriate sequence of nonselective targeted therapy, and combination therapy, were proposed.
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Affiliation(s)
- Xiaojie Wang
- Department of Colorectal Surgery, Union Hospital, Fujian Medical University, Fuzhou, China
| | - Wenchuan Wu
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Zhifang Zheng
- Department of Colorectal Surgery, Union Hospital, Fujian Medical University, Fuzhou, China
| | - Pan Chi
- Department of Colorectal Surgery, Union Hospital, Fujian Medical University, Fuzhou, China
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28
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Watts K, Wills C, Madi A, Palles C, Maughan TS, Kaplan R, Al-Tassan NA, Kerr R, Kerr D, Gray V, West H, Houlston RS, Escott-Price V, Cheadle JP. Genome-wide association studies of toxicity to oxaliplatin and fluoropyrimidine chemotherapy with or without cetuximab in 1800 patients with advanced colorectal cancer. Int J Cancer 2021; 149:1713-1722. [PMID: 34270794 PMCID: PMC7616640 DOI: 10.1002/ijc.33739] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Revised: 05/12/2021] [Accepted: 06/08/2021] [Indexed: 01/03/2023]
Abstract
Chemotherapies administered at normal therapeutic dosages can cause significant side-effects and may result in early treatment discontinuation. Inter-individual variation in toxicity highlights the need for biomarkers to personalise treatment. We sought to identify such biomarkers by conducting 40 genome-wide association studies, together with gene and gene set analyses, for any toxicity and 10 individual toxicities in 1800 patients with advanced colorectal cancer treated with oxaliplatin and fluoropyrimidine chemotherapy ± cetuximab from the MRC COIN and COIN-B trials (385 patients received FOLFOX, 360 FOLFOX + cetuximab, 707 XELOX and 348 XELOX + cetuximab). Single nucleotide polymorphisms (SNPs), genes and gene sets that reached genome-wide or suggestive significance were validated in independent patient groups. We found that MROH5 was significantly associated with neutropenia in MAGMA gene analyses in patients treated with XELOX (P = 6.6 × 10-7 ) and was independently validated in those receiving XELOX + cetuximab; pooled P = 3.7 × 10-7 . rs13260246 at 8q21.13 was significantly associated with vomiting in patients treated with XELOX (odds ratio = 5.0, 95% confidence interval = 3.0-8.3, P = 9.8 × 10-10 ) but was not independently replicated. SNPs at 139 loci had suggestive associations for toxicities and lead SNPs at five of these were independently validated (rs6030266 with diarrhoea, rs1546161 with hand-foot syndrome, rs9601722 with neutropenia, rs13413764 with lethargy and rs4600090 with nausea; all with pooled P's < 5.0 × 10-6 ). In conclusion, the association of MROH5 with neutropenia and five other putative biomarkers warrant further investigation for their potential clinical utility. Despite our comprehensive genome-wide analyses of large, well-characterised, clinical trials, we found a lack of common variants with modest effect sizes associated with toxicities.
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Affiliation(s)
- Katie Watts
- Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, UK
| | - Christopher Wills
- Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, UK
| | - Ayman Madi
- The Clatterbridge Cancer Centre NHS Foundation Trust, Bebington, UK
| | - Claire Palles
- Institute of Cancer and Genomic Sciences, Institute of Biomedical Research, University of Birmingham, Birmingham, UK
| | - Timothy S Maughan
- CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, UK
| | - Richard Kaplan
- MRC Clinical Trials Unit, University College of London, London, UK
| | - Nada A Al-Tassan
- Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Rachel Kerr
- Department of Oncology, University of Oxford, Oxford, UK
| | - David Kerr
- Nuffield Department of Clinical Laboratory Sciences, University of Oxford, John Radcliffe Hospital, Oxford, UK
| | - Victoria Gray
- Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, UK
| | - Hannah West
- Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, UK
| | - Richard S Houlston
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK
| | - Valentina Escott-Price
- Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK
| | - Jeremy P Cheadle
- Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, UK
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Raimondi A, Fucà G, Leone AG, Lonardi S, Antoniotti C, Smiroldo V, Amatu A, Tampellini M, Ritorto G, Murialdo R, Clavarezza M, Zaniboni A, Berenato R, Ratti M, Corallo S, Morano F, Di Bartolomeo M, Di Maio M, Pietrantonio F. Impact of age and gender on the efficacy and safety of upfront therapy with panitumumab plus FOLFOX followed by panitumumab-based maintenance: a pre-specified subgroup analysis of the Valentino study. ESMO Open 2021; 6:100246. [PMID: 34416469 PMCID: PMC8379288 DOI: 10.1016/j.esmoop.2021.100246] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Revised: 07/23/2021] [Accepted: 07/28/2021] [Indexed: 11/20/2022] Open
Abstract
BACKGROUND The safety and efficacy outcome of elderly metastatic colorectal cancer (mCRC) patients fit enough to receive combination chemotherapy plus biological agents is an issue of growing interest. Also, gender-specific differential toxicity and efficacy of anti-epidermal growth factor receptor (EGFR)-based upfront treatments need to be explored. PATIENTS AND METHODS Valentino was a multicenter, randomized, phase II trial, investigating two panitumumab-based maintenance strategies following first-line panitumumab plus FOLFOX in RAS wild-type mCRC patients. We carried out a subgroup analysis, aimed at assessing the differences in efficacy, safety and quality of life (QoL) according to age (<70 versus ≥70 years) and gender (male versus female). Efficacy endpoints were progression-free survival (PFS), overall survival (OS) and overall response rate (ORR); safety endpoints were rates of any grade and grade 3/4 adverse events (AEs). RESULTS No significant differences in terms of PFS, OS and ORR were observed between patients aged <70 or ≥70 years and the effect of the maintenance treatment arm on survival outcomes was similar in the two subgroups. The safety profile of both induction and maintenance treatment and the impact on QoL were similar in elderly and younger patients. No significant differences in PFS, OS, ORR or clinical benefit rate were observed according to gender. A significantly higher rate of overall grade 3/4 AEs (P = 0.008) and of grade 3/4 thrombocytopenia (P = 0.017), any grade and grade 3/4 neutropenia (P < 0.0001) and any grade conjunctivitis (P = 0.033) was reported in female as compared to male patients. Conversely, we reported a significantly higher incidence of any grade skin rash (P = 0.0007) and hypomagnesemia (P = 0.029) in male patients. CONCLUSIONS The upfront choice of an anti-EGFR-based doublet chemotherapy followed by a maintenance strategy represents a valuable option in RAS wild-type mCRC irrespective of gender and age, though a careful evaluation of patients to maximize the risk/benefit ratio is warranted.
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Affiliation(s)
- A Raimondi
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - G Fucà
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - A G Leone
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - S Lonardi
- Medical Oncology Unit 3, Department of Oncology, Istituto Oncologico Veneto-IRCCS, Padua, Italy
| | - C Antoniotti
- Unit of Medical Oncology, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
| | - V Smiroldo
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano, Italy
| | - A Amatu
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - M Tampellini
- Department of Oncology, AOU San Luigi di Orbassano, University of Torino, Orbassano, Italy
| | - G Ritorto
- SSD ColoRectal Cancer Unit, Oncology Department, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza, Torino, Italy
| | - R Murialdo
- Department of Internal Medicine, University of Genoa and IRCCS AOU San Martino-IST, Genoa, Italy
| | - M Clavarezza
- Medical Oncology Unit, Ente Ospedaliero Ospedali Galliera, Genoa, Italy
| | - A Zaniboni
- Medical Oncology Unit, Fondazione Poliambulanza, Brescia, Italy
| | - R Berenato
- Medical Oncology Unit, A.O. Papardo, Messina, Italy
| | - M Ratti
- Medical Oncology Unit, ASST Ospedale di Cremona, Cremona, Italy
| | - S Corallo
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - F Morano
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - M Di Bartolomeo
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - M Di Maio
- Department of Oncology, University of Turin, Ordine Mauriziano Hospital, Torino, Italy
| | - F Pietrantonio
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
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Cohen R, Liu H, Fiskum J, Adams R, Chibaudel B, Maughan TS, Van Cutsem E, Venook A, Douillard JY, Heinemann V, Punt CJ, Falcone A, Bokemeyer C, Kaplan R, Lenz HJ, Koopman M, Yoshino T, Zalcberg J, Grothey A, de Gramont A, Shi Q, André T. BRAF V600E Mutation in First-Line Metastatic Colorectal Cancer: An Analysis of Individual Patient Data From the ARCAD Database. J Natl Cancer Inst 2021; 113:1386-1395. [PMID: 33734401 PMCID: PMC7617278 DOI: 10.1093/jnci/djab042] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Revised: 01/06/2021] [Accepted: 03/15/2021] [Indexed: 01/09/2023] Open
Abstract
BACKGROUND First-line therapeutic strategies for patients with BRAFV600E-mutated (BRAFmt) metastatic colorectal cancer (mCRC) mainly rely on subgroup analyses from randomized controlled trials (RCTs). We aimed to assess the prognostic and predictive impact of BRAFmt on the efficacy of targeted therapies with first-line chemotherapy. METHODS Individual patient data from first-line RCTs with BRAF and KRAS status data in the ARCAD database were pooled. Progression-free survival and overall survival (OS) were assessed using Kaplan-Meier and Cox models. Outcomes were compared between treatment groups that were concurrently randomly assigned whenever possible. RESULTS A total of 6391 patients from 10 RCTs were included: 573 BRAFmt (9.0%), 2059 KRASmt (32.2%), and 3759 double wild type (58.8%). BRAFmt mCRC patients experienced statistically significantly poorer OS than those with KRASmt (adjusted hazard ratio [HRadj] = 1.46, 95% confidence interval [CI] = 1.30 to 1.64) and patients with double wild-type tumors (HRadj = 2.14, 95% CI = 1.94 to 2.36). Anti-EGFR agents did not improve progression-free survival or OS of BRAFmt mCRC patients, based on 4 RCTs testing chemotherapy with or without anti-epidermal growth factor receptor (anti-EGFR) (HRadj = 0.96, 95% CI = 0.71 to 1.30; and HRadj = 0.85, 95% CI = 0.66 to 1.14, respectively). CONCLUSIONS Our data suggest that the addition of anti-EGFR agents to chemotherapy is ineffective as first-line treatment for BRAFmt mCRC patients.
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Affiliation(s)
- Romain Cohen
- Department of Health Science Research, Mayo Clinic, Rochester, MN, USA
- Department of Medical Oncology, Sorbonne University, Saint-Antoine Hospital, Paris, France
| | - Heshan Liu
- Department of Health Science Research, Mayo Clinic, Rochester, MN, USA
| | - Jack Fiskum
- Department of Health Science Research, Mayo Clinic, Rochester, MN, USA
| | - Richard Adams
- Cardiff University and Velindre Cancer Centre, Cardiff, UK
| | - Benoist Chibaudel
- Department of Medical Oncology, Franco-British Institute, Levallois-Perret, France
| | - Timothy S. Maughan
- Cancer Research UK and the Medical Research Council Oxford Institute for Radiation Oncology, Oxford, UK
| | - Eric Van Cutsem
- Digestive Oncology, University Hospitals Gasthuisberg Leuven and University of Leuven, Belgium
| | - Alan Venook
- Department of Medicine, The University of California San Francisco, San Francisco, CA, USA
| | | | - Volker Heinemann
- Department of Medical Oncology and Comprehensive Cancer Center, University of Munich, Munich, Germany
| | - Cornelis Ja Punt
- Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands
| | | | - Carsten Bokemeyer
- Department of Oncology, Haematology and Bone Marrow Transplantation with Section of Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Richard Kaplan
- Medical Research Council Clinical Trials Unit, University College London, London, UK
| | - Heinz-Josef Lenz
- Department of Gastrointestinal Oncology, Keck School of Medicine at USC, Los Angeles, CA, USA
| | - Miriam Koopman
- Department of Medical Oncology, University Medical Center Utrecht, University of Utrecht, Utrecht, the Netherlands
| | - Takayuki Yoshino
- Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Chiba, Japan
| | | | | | - Aimery de Gramont
- Department of Medical Oncology, Franco-British Institute, Levallois-Perret, France
| | - Qian Shi
- Department of Health Science Research, Mayo Clinic, Rochester, MN, USA
| | - Thierry André
- Department of Medical Oncology, Sorbonne University, Saint-Antoine Hospital, Paris, France
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31
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Adams R, Goey K, Chibaudel B, Koopman M, Punt C, Arnold D, Hinke A, Hegewisch-Becker S, de Gramont A, Labianca R, Diaz Rubio E, Magne Tveit K, Wasan H, Kaplan R, Brown L, Maughan T, Fisher D. Treatment breaks in first line treatment of advanced colorectal cancer: An individual patient data meta-analysis. Cancer Treat Rev 2021; 99:102226. [PMID: 34130171 DOI: 10.1016/j.ctrv.2021.102226] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Revised: 05/11/2021] [Accepted: 05/15/2021] [Indexed: 12/16/2022]
Abstract
BACKGROUND Intermittent systemic anti-cancer therapy in patients with advanced colorectal cancer (aCRC) may improve quality of life without compromising overall survival (OS). We aimed to use individual patient data meta-analysis (IPDMA) from multiple randomised controlled trials evaluating intermittent strategies to inform clinical practice. We also aimed to validate whether thrombocytosis as a predictive biomarker identified patients with significantly reduced OS receiving a complete treatment break. PATIENTS AND METHODS An IPDMA of intermittent strategy impact on survival was undertaken, including all relevant trials in which data were available. Intermittent strategies were classified into two groups: a planned stopping of all therapy ("treatment break strategy"; 6 trials; 2,907 patients) or to the same treatment omitting oxaliplatin ("maintenance strategy"; 3 trials; 1,271 patients). The primary analysis sample was of patients successfully completing induction therapy. Additionally, a pre-planned analysis of the predictive value of thrombocytosis on survival under a continuous versus an intermittent strategy was undertaken. RESULTS All trials had comparable inclusion criteria. The overall IPDMA of intermittent therapy versus continuous therapy demonstrated no detriment in OS (HR = 1.03 [95% CI 0.93-1.14]), whether from complete break (HR 1.04 [95% CI 0.87-1.26]) or maintenance strategies (HR 0.99 [95% CI 0.87-1.13]). Thrombocytosis was confirmed as a marker of poor prognosis in aCRC, but did not predict for OS detriment from treatment break strategies (interaction HR = 0.97 [95% CI 0.66-1.40] compared to continuous therapy). CONCLUSION The highest levels of evidence from this IPDMA indicate no detriment in survival for patients receiving an intermittent therapy strategy, either for maintenance or complete break strategies. Although, thrombocytosis is confirmed as a marker of poor prognosis, it is not predictive of poor outcome for patients treated with intermittent therapy. An intermittent chemotherapy strategy can therefore be applied irrespective of baseline platelet count and does not result in inferior OS compared to continuous chemotherapy.
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Affiliation(s)
- Richard Adams
- Cardiff University and Velindre Cancer Centre, United Kingdom.
| | - Kaitlyn Goey
- University Medical Center, Utrecht, the Netherlands.
| | | | | | - Cornelis Punt
- Julius Center for Health Sciences and Primary Care, University Medical Center, Utrecht University, the Netherlands.
| | - Dirk Arnold
- Asklepios Tumorzentrum Hamburg, Germany and Instituto CUF de Oncologia, Lisbon, Portugal.
| | | | | | | | | | | | | | | | | | - Louise Brown
- MRC Clinical Trials Unit at UCL, United Kingdom.
| | | | - David Fisher
- MRC Clinical Trials Unit at UCL, United Kingdom.
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Drug Holidays and Overall Survival of Patients with Metastatic Colorectal Cancer. Cancers (Basel) 2021; 13:cancers13143504. [PMID: 34298718 PMCID: PMC8304309 DOI: 10.3390/cancers13143504] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Revised: 07/05/2021] [Accepted: 07/12/2021] [Indexed: 12/24/2022] Open
Abstract
Different de-escalation strategies have been proposed to limit the risk of cumulative toxicity and guarantee quality of life during the treatment trajectory of patients with metastatic colorectal cancer (mCRC). Programmed treatment interruptions, defined as drug holidays (DHs), have been implemented in clinical practice. We evaluated the association between DHs and overall survival (OS). This was a retrospective study, conducted at the University Hospital of Udine and the IRCCS CRO of Aviano. We retrieved records of 608 consecutive patients treated for mCRC from 1 January 2005 to 15 March 2017 and evaluated the impact of different de-escalation strategies (maintenance, DHs, or both) on OS through uni- and multivariate Cox regression analyses. We also looked at attrition rates across treatment lines according to the chosen strategy. In our study, 19.24% of patients received maintenance therapy, 16.12% DHs, and 9.87% both, while 32.07% continued full-intensity first-line treatment up to progression or death. In uni- and multivariate analyses first-line continuous treatment and early discontinuation (treatment for less than 3 months) were associated to worse OS compared to non-continuous strategies (HR, 1.68; 95% CI, 1.22-2.32; p = 0.002 and HR,4.89; 95% CI, 3.33-7.19; p < 0.001, respectively). Attrition rates were 22.8%, 20.61%, and 19.64% for maintenance, DHs, or both, respectively. For continuous therapy and for treatment of less than 3 months it was 21.57% and 49%. De-escalation strategies are safe and effective options. DHs after initial induction chemotherapy may be considered in clinically selected patients with metastatic colorectal cancer.
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33
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Martín-Richard M, Tobeña M. First-Line Maintenance Treatment in Metastatic Colorectal Cancer (mCRC): Quality and Clinical Benefit Overview. J Clin Med 2021; 10:jcm10030470. [PMID: 33530547 PMCID: PMC7865515 DOI: 10.3390/jcm10030470] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Revised: 12/22/2020] [Accepted: 01/21/2021] [Indexed: 01/02/2023] Open
Abstract
Different strategies of maintenance therapy (sequential CT, intermittent CT, intermittent CT and MAbs, or de-escalation MAbs monotherapy) after first-line treatment are undertaken. Many randomized clinical trials (RCT), which evaluated these approaches, suffer from incorrect design, heterogenous primary endpoints, inadequate size, and other methodology flaws. Drawing any conclusions becomes challenging and recommendations are mainly vague. We evaluated those studies from another perspective, focusing on the design quality and the clinical benefit measure with a more objective and accurate methodology. These data allowed a clearer and more exact overview of the statement in maintenance treatment.
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Affiliation(s)
- Marta Martín-Richard
- Medical Oncology Department, Sant Pau Hospital, 08043 Barcelona, Spain
- Correspondence:
| | - Maria Tobeña
- Medical Oncology Department, Quironsalud Hospital, 50006 Zaragoza, Spain;
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34
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Yang G, Huang L, Jia H, Aikemu B, Zhang S, Shao Y, Hong H, Yesseyeva G, Wang C, Li S, Sun J, Zheng M, Ma J. NDRG1 enhances the sensitivity of cetuximab by modulating EGFR trafficking in colorectal cancer. Oncogene 2021; 40:5993-6006. [PMID: 34385595 PMCID: PMC8516652 DOI: 10.1038/s41388-021-01962-8] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Revised: 07/07/2021] [Accepted: 07/13/2021] [Indexed: 02/07/2023]
Abstract
N-myc downstream-regulated gene 1 (NDRG1) is a key regulator that interacts with many classic tumor signaling pathways, including some molecules downstream of the epidermal growth factor receptor (EGFR). However, whether NDRG1 is involved in the mechanism of resistance to cetuximab (CTX), the first monoclonal antibody targeting the EGFR has not been reported. Here, we found that NDRG1 enhanced the sensitivity of CTX in colorectal cancer (CRC) cell lines. Afterwards, we determined the underlying mechanism of this phenomenon. We demonstrated that NDRG1 inhibited the expression of EGFR; blocked EGFR phosphorylation and reduced the EGFR distribution in the cell membrane, cytoplasm and nucleus. And then, NDRG1 suppressed the EGFR downstream signaling: RAS/RAF/ERK and PI3k/AKT/mTOR pathways. Moreover, we discovered that NDRG1 attenuated the endocytosis and degradation of EGFR induced by caveolin-1 (Cav1). Additionally, our findings were further observed in an animal model and human tissues. Our results represent a potentially significant discovery that explains the mechanisms of NDRG1 in CTX resistance. NDRG1 could be a promising biomarker to predict optimum responses to CTX, and a key target to enhance CTX activity in the treatment of metastatic CRC (mCRC).
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Affiliation(s)
- Guang Yang
- grid.16821.3c0000 0004 0368 8293Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China ,grid.16821.3c0000 0004 0368 8293Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ling Huang
- grid.16821.3c0000 0004 0368 8293Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China ,grid.16821.3c0000 0004 0368 8293Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hongtao Jia
- grid.16821.3c0000 0004 0368 8293Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China ,grid.16821.3c0000 0004 0368 8293Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Batuer Aikemu
- grid.16821.3c0000 0004 0368 8293Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China ,grid.16821.3c0000 0004 0368 8293Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Sen Zhang
- grid.16821.3c0000 0004 0368 8293Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China ,grid.16821.3c0000 0004 0368 8293Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yanfei Shao
- grid.16821.3c0000 0004 0368 8293Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China ,grid.16821.3c0000 0004 0368 8293Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hiju Hong
- grid.16821.3c0000 0004 0368 8293Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China ,grid.16821.3c0000 0004 0368 8293Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Galiya Yesseyeva
- grid.16821.3c0000 0004 0368 8293Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China ,grid.16821.3c0000 0004 0368 8293Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chenxing Wang
- grid.16821.3c0000 0004 0368 8293Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China ,grid.16821.3c0000 0004 0368 8293Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shuchun Li
- grid.16821.3c0000 0004 0368 8293Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China ,grid.16821.3c0000 0004 0368 8293Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jing Sun
- grid.16821.3c0000 0004 0368 8293Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China ,grid.16821.3c0000 0004 0368 8293Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Minhua Zheng
- grid.16821.3c0000 0004 0368 8293Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China ,grid.16821.3c0000 0004 0368 8293Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Junjun Ma
- grid.16821.3c0000 0004 0368 8293Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China ,grid.16821.3c0000 0004 0368 8293Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Treatments after first progression in metastatic colorectal cancer. A literature review and evidence-based algorithm. Cancer Treat Rev 2020; 92:102135. [PMID: 33307331 DOI: 10.1016/j.ctrv.2020.102135] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Revised: 11/17/2020] [Accepted: 11/18/2020] [Indexed: 12/23/2022]
Abstract
Prolonging survival, achieving symptoms palliation and preserving quality of life are the primary therapeutic goals of treatments administered after disease progression in mCRC. Even if the impact of these therapies on the prognosis of affected patients is less relevant than the impact of the upfront treatment, tailoring the optimal second-line therapy is increasingly important. Several therapeutic options are available, and different factors including not only patient- and disease-related characteristics, but also the first-line treatment received (i.e., type, timing of disease progression, observed outcome and reported toxicities) may drive this choice. Herein, we describe the current state of the art in the landscape of treatments after progression in mCRC. Based on a critical review of the literature, we built a patient-oriented therapeutic algorithm, aiming to guide clinicians in their daily decision-making.
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Oxaliplatin retreatment in metastatic colorectal cancer: Systematic review and future research opportunities. Cancer Treat Rev 2020; 91:102112. [PMID: 33091698 DOI: 10.1016/j.ctrv.2020.102112] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Revised: 09/28/2020] [Accepted: 10/02/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Oxaliplatin represents a main component of cytotoxic treatment regimens in colorectal cancer (CRC). Given its efficacy, oxaliplatin is frequently re-administered in the context of the continuum of care in metastatic CRC (mCRC). However, efficacy and tolerability of this therapeutic strategy has not been comprehensively assessed. METHODS We performed a systematic review of the literature on September 19th 2020, according to PRISMA criteria 2009. The research was performed on PubMed, ASCO Meeting Library, ESMO library and ClinicalTrials.gov for citations or ongoing trials. RESULTS 64 records were retrieved and 13 included in the systematic review: 8 full-text articles, 4 abstracts and 1 ongoing clinical trial. According to readministration timing, studies were classified as rechallenge/reintroduction (n = 8) or stop & go/intermittent therapeutic strategies (n = 4). The studies presented wide heterogeneity in terms of efficacy (Response Rate 6-31%; Disease Control Rate 39-79%; median Progression-Free Survival 3.1-7 months). Those patients who received retreatment after prior adjuvant oxaliplatin or exploiting a stop-&-go strategy appeared to achieve better outcomes. However, no formal comparisons on treatment outcomes were feasible. The most frequent grade 3 or higher adverse events were hematologic toxicities (5-27%), peripheral neuropathy (5-14%) and hypersensitivity reactions (5-20%). CONCLUSIONS Retreatment with oxaliplatin for mCRC is practiced based on scarce and heterogeneous data indicating efficacy and manageable toxicity. The best strategy to exploit this approach remains to be defined, and the most promising research avenue to improve therapeutic index of oxaliplatin is represented by selection of responder patients whose tumors harbor molecular defects in the DNA damage repair pathway.
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Tsongalis GJ, Al Turkmani MR, Suriawinata M, Babcock MJ, Mitchell K, Ding Y, Scicchitano L, Tira A, Buckingham L, Atkinson S, Lax A, Aisner DL, Davies KD, Wood HN, O’Neill SS, Levine EA, Sequeira J, Harada S, DeFrank G, Paluri R, Tan BA, Colabella H, Snead C, Cruz-Correa M, Ramirez V, Rojas A, Huang H, Mackinnon AC, Garcia FU, Cavone SM, Elfahal M, Abel G, Vasef MA, Judd A, Linder MW, Alkhateeb K, Skinner WL, Boccia R, Patel K. Comparison of Tissue Molecular Biomarker Testing Turnaround Times and Concordance Between Standard of Care and the Biocartis Idylla Platform in Patients With Colorectal Cancer. Am J Clin Pathol 2020; 154:266-276. [PMID: 32525522 PMCID: PMC10893851 DOI: 10.1093/ajcp/aqaa044] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
OBJECTIVES Management of colorectal cancer warrants mutational analysis of KRAS/NRAS when considering anti-epidermal growth factor receptor therapy and BRAF testing for prognostic stratification. In this multicenter study, we compared a fully integrated, cartridge-based system to standard-of-care assays used by participating laboratories. METHODS Twenty laboratories enrolled 874 colorectal cancer cases between November 2017 and December 2018. Testing was performed on the Idylla automated system (Biocartis) using the KRAS and NRAS-BRAF cartridges (research use only) and results compared with in-house standard-of-care testing methods. RESULTS There were sufficient data on 780 cases to measure turnaround time compared with standard assays. In-house polymerase chain reaction (PCR) had an average testing turnaround time of 5.6 days, send-out PCR of 22.5 days, in-house Sanger sequencing of 14.7 days, send-out Sanger of 17.8 days, in-house next-generation sequencing (NGS) of 12.5 days, and send-out NGS of 20.0 days. Standard testing had an average turnaround time of 11 days. Idylla average time to results was 4.9 days with a range of 0.4 to 13.5 days. CONCLUSIONS The described cartridge-based system offers rapid and reliable testing of clinically actionable mutation in colorectal cancer specimens directly from formalin-fixed, paraffin-embedded tissue sections. Its simplicity and ease of use compared with other molecular techniques make it suitable for routine clinical laboratory testing.
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Affiliation(s)
- Gregory J Tsongalis
- Clinical Genomics and Advanced Technology (CGAT) Laboratory, Department of Pathology and Laboratory Medicine, Dartmouth Hitchcock Health System, Lebanon, NH
- Geisel School of Medicine at Dartmouth, Hanover, NH
| | - M Rabie Al Turkmani
- Clinical Genomics and Advanced Technology (CGAT) Laboratory, Department of Pathology and Laboratory Medicine, Dartmouth Hitchcock Health System, Lebanon, NH
- Geisel School of Medicine at Dartmouth, Hanover, NH
| | - Michael Suriawinata
- Clinical Genomics and Advanced Technology (CGAT) Laboratory, Department of Pathology and Laboratory Medicine, Dartmouth Hitchcock Health System, Lebanon, NH
- Geisel School of Medicine at Dartmouth, Hanover, NH
| | - Michael J Babcock
- Bioinformatics & Molecular Pathology, Dahl-Chase Diagnostic Services & Pathology Associates, Bangor, ME
| | - Kristi Mitchell
- Bioinformatics & Molecular Pathology, Dahl-Chase Diagnostic Services & Pathology Associates, Bangor, ME
| | - Yi Ding
- Diagnostic Medicine Institute, Geisinger Medical Center, Danville, PA
| | - Lisa Scicchitano
- Diagnostic Medicine Institute, Geisinger Medical Center, Danville, PA
| | - Adrian Tira
- Department of Pathology, Rush University Medical Center, Chicago, IL
| | - Lela Buckingham
- Department of Pathology, Rush University Medical Center, Chicago, IL
| | - Sara Atkinson
- Department of Cytology, Cone Health Moses Cone Hospital, Greensboro, NC
| | - Amy Lax
- Department of Cytology, Cone Health Moses Cone Hospital, Greensboro, NC
| | - Dara L Aisner
- Colorado Molecular Correlates Laboratory (CMOCO), Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora
| | - Kurtis D Davies
- Colorado Molecular Correlates Laboratory (CMOCO), Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora
| | - Holly N Wood
- Colorado Molecular Correlates Laboratory (CMOCO), Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora
| | - Stacey S O’Neill
- Department of Pathology, Wake Forest School of Medicine, Winston-Salem, NC
| | - Edward A Levine
- Division of Surgical Oncology, Department of Surgery, Wake Forest School of Medicine, Winston-Salem, NC
| | - Judy Sequeira
- Department of Pathology and Laboratory Medicine, Comprehensive Care and Research Center, Cancer Treatment Centers of America Atlanta, Newnan, GA
| | - Shuko Harada
- Molecular Diagnostics Laboratory, Department of Pathology, University of Alabama Birmingham School of Medicine, Birmingham
| | - Gina DeFrank
- Molecular Diagnostics Laboratory, Department of Pathology, University of Alabama Birmingham School of Medicine, Birmingham
| | - Ravikumar Paluri
- Department of Medicine, Division of Hematology/Oncology, University of Alabama Birmingham School of Medicine, Birmingham
| | - Bradford A Tan
- Department of Pathology and Laboratory Medicine, Comprehensive Care and Research Center, Cancer Treatment Centers of America Chicago, Zion, IL
| | - Heather Colabella
- Department of Pathology and Laboratory Medicine, Comprehensive Care and Research Center, Cancer Treatment Centers of America Chicago, Zion, IL
| | | | - Marcia Cruz-Correa
- Pan American Center for Oncology Trials, Oncologic Hospital, Puerto Rico Medical Center, Rio Piedras, Puerto Rico
| | - Virginia Ramirez
- Pan American Center for Oncology Trials, Oncologic Hospital, Puerto Rico Medical Center, Rio Piedras, Puerto Rico
| | - Arnaldo Rojas
- Pan American Center for Oncology Trials, Oncologic Hospital, Puerto Rico Medical Center, Rio Piedras, Puerto Rico
| | - Huiya Huang
- Department of Pathology, Medical College of Wisconsin, Milwaukee
| | | | - Fernando U Garcia
- Department of Pathology and Laboratory Medicine, Comprehensive Care and Research Center, Cancer Treatment Centers of America Philadelphia, Philadelphia, PA
| | - Sharon M Cavone
- Department of Pathology and Laboratory Medicine, Comprehensive Care and Research Center, Cancer Treatment Centers of America Philadelphia, Philadelphia, PA
| | - Mutasim Elfahal
- Department of Pathology and Laboratory Medicine, Lahey Hospital and Medical Center, Beth Israel Lahey Health, Burlington, MA
| | - Gyorgy Abel
- Department of Pathology and Laboratory Medicine, Lahey Hospital and Medical Center, Beth Israel Lahey Health, Burlington, MA
| | - Mohammad A Vasef
- Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque
| | - Andrew Judd
- Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque
| | - Mark W Linder
- Department of Pathology and Laboratory Medicine, University of Louisville Hospital, Louisville, KY
| | - Khaled Alkhateeb
- Department of Pathology and Laboratory Medicine, University of Louisville Hospital, Louisville, KY
| | | | - Ralph Boccia
- The Center for Cancer and Blood Disorders, Bethesda, MD
| | - Kashyap Patel
- Carolina Blood and Cancer Care Associates, PA, Rock Hill, SC
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Raimondi A, Di Maio M, Morano F, Corallo S, Lonardi S, Antoniotti C, Rimassa L, Sartore-Bianchi A, Tampellini M, Ritorto G, Murialdo R, Clavarezza M, Zaniboni A, Adamo V, Tomasello G, Petrelli F, Antonuzzo L, Giordano M, Cinieri S, Longarini R, Bergamo F, Niger M, Antista M, Peverelli G, de Braud F, Di Bartolomeo M, Pietrantonio F. Health-related quality of life in patients with RAS wild-type metastatic colorectal cancer treated with panitumumab-based first-line treatment strategy: A pre-specified secondary analysis of the Valentino study. Eur J Cancer 2020; 135:230-239. [PMID: 32623288 DOI: 10.1016/j.ejca.2020.04.048] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Revised: 04/22/2020] [Accepted: 04/30/2020] [Indexed: 12/21/2022]
Abstract
BACKGROUND Quality of life (QoL) patient-reported outcomes (PROs) data from pivotal first-line trials in metastatic colorectal cancer (mCRC) are poor. The Valentino study showed that de-escalation to single-agent panitumumab after 4-month induction with panitumumab-FOLFOX is inferior to panitumumab-5-FU/LV in patients with RAS wild-type mCRC, although slightly reducing toxicity. We report QoL, a secondary end-point. METHODS PROs were assessed by European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire - Core 30 (QLQ-C30), EORTC QLQ-CR29, EuroQol EQ-5D questionnaires, at baseline and every 8 weeks until disease progression. First two evaluations correspond to induction treatment (identical in both arms), while subsequent to maintenance. To describe QoL changes over time, mean changes from baseline at each time point were calculated in overall population. To compare maintenance between two arms, mean changes and proportion of improved/stable/worse patients versus baseline were compared for each item. RESULTS In arm A/B, 91.5%/92.0% of enrolled patients completed questionnaires at baseline. No significant differences in the two arms were reported in compliance, baseline scores and mean changes versus baseline for the three questionnaires during maintenance (24/32/40 weeks). Overall, mean changes versus baseline showed an early deterioration during induction with partial recovering during maintenance for global QoL, functional scales and several symptoms/items of QLQ-C30 (fatigue, nausea/vomiting, appetite loss, diarrhoea) and QLQ-CR29 (body image, dry mouth, hair loss, taste, faecal incontinence, sore skin), and EQ-5D Visual Analogue Scale (VAS) score. CONCLUSION In patients with RAS wild-type mCRC, induction with oxaliplatin-containing chemotherapy plus anti-EGFRs induces a transient significant QoL deterioration. After induction phase, treatment deintensification determines an overall recovery of health-related QoL, besides the expected prevention of oxaliplatin-related neurotoxicity.
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Affiliation(s)
- Alessandra Raimondi
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale Dei Tumori, Milan, Italy
| | - Massimo Di Maio
- Department of Oncology, University of Turin, Ordine Mauriziano Hospital, Torino, Italy
| | - Federica Morano
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale Dei Tumori, Milan, Italy
| | - Salvatore Corallo
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale Dei Tumori, Milan, Italy
| | - Sara Lonardi
- Medical Oncology Unit 1, Department of Oncology, Istituto Oncologico Veneto - IRCCS, Padua, Italy
| | - Carlotta Antoniotti
- Unit of Medical Oncology, Azienda Ospedaliero-Universitaria Pisana, Department of Translational Research and New Technologies in Medicine, University of Pisa, Pisa, Italy
| | - Lorenza Rimassa
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, Humanitas Clinical and Research Center - IRCCS, Rozzano, Italy
| | - Andrea Sartore-Bianchi
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy; Oncology and Hemato-oncology Department, University of Milan, Milan, Italy
| | - Marco Tampellini
- Department of Oncology, AOU San Luigi di Orbassano, University of Torino, Orbassano, Italy
| | - Giuliana Ritorto
- Colorectal Cancer Unit, Medical Oncology Division 1, Azienda Ospedaliero-Universitaria Città Della Salute e Della Scienza, Torino, Italy
| | - Roberto Murialdo
- Department of Internal Medicine, University of Genoa and IRCCS AOU San Martino-IST, Genoa, Italy
| | - Matteo Clavarezza
- Medical Oncology Unit, Ente Ospedaliero Ospedali Galliera, Genoa, Italy
| | | | - Vincenzo Adamo
- Medical Oncology Unit A.O. Papardo & Department of Human Pathology, University of Messina, Messina, Italy
| | | | - Fausto Petrelli
- Medical Oncology Unit, Oncology Department, ASST Bergamo Ovest, Treviglio, Italy
| | - Lorenzo Antonuzzo
- Department of Medical Oncology, Oncology Unit, AOU Careggi, Florence, Italy
| | - Monica Giordano
- Medical Oncology Unit, Azienda Socio Sanitaria Territoriale Lariana, Como, Italy
| | - Saverio Cinieri
- Medical Oncology Unit, Ospedale Antonio Perrino, Brindisi, Italy
| | | | - Francesca Bergamo
- Medical Oncology Unit 1, Department of Oncology, Istituto Oncologico Veneto - IRCCS, Padua, Italy
| | - Monica Niger
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale Dei Tumori, Milan, Italy
| | - Maria Antista
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale Dei Tumori, Milan, Italy
| | - Giorgia Peverelli
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale Dei Tumori, Milan, Italy
| | - Filippo de Braud
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale Dei Tumori, Milan, Italy; Oncology and Hemato-oncology Department, University of Milan, Milan, Italy
| | - Maria Di Bartolomeo
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale Dei Tumori, Milan, Italy
| | - Filippo Pietrantonio
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale Dei Tumori, Milan, Italy; Oncology and Hemato-oncology Department, University of Milan, Milan, Italy.
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Wang L, Liu Y, Yin X, Fang W, Xiong J, Zhao B, Zhang M, Zou Y, Qiu H, Yuan X. Effect of Reduced-Dose Capecitabine Plus Cetuximab as Maintenance Therapy for RAS Wild-Type Metastatic Colorectal Cancer: A Phase 2 Clinical Trial. JAMA Netw Open 2020; 3:e2011036. [PMID: 32687588 PMCID: PMC7372324 DOI: 10.1001/jamanetworkopen.2020.11036] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
IMPORTANCE Fluorouracil-based chemotherapy combined with anti-epidermal growth factor receptor/vascular endothelial growth factor therapy is the standard first-line treatment for metastatic colorectal cancer followed by low-intensity maintenance therapy to balance the clinical efficacy and adverse effects (AEs). However, there have been concerns about the AEs of capecitabine plus cetuximab as a maintenance therapy in patients with RAS wild-type metastatic colorectal cancer. OBJECTIVE To evaluate the biological activity and safety of capecitabine plus cetuximab as a novel maintenance therapy for RAS wild-type metastatic colorectal cancer. DESIGN, SETTING, AND PARTICIPANTS This phase 2 prospective clinical trial was conducted from April 29, 2016, to April 29, 2019, at 5 centers in China. Patients diagnosed as having RAS wild-type metastatic colorectal cancer were recruited to receive fluorouracil-based cytotoxic agents combined with cetuximab followed by capecitabine plus cetuximab for maintenance therapy. Forty-seven patients with histologically confirmed metastatic colorectal cancer and genetic test results showing a wild-type RAS were enrolled in maintenance therapy. INTERVENTIONS Induction therapy for patients with RAS wild-type metastatic colorectal cancer was 8 to 12 cycles of fluorouracil-based chemotherapy combined with cetuximab. After stable disease status or better was achieved, reduced-dose capecitabine plus cetuximab was administered for maintenance therapy. MAIN OUTCOMES AND MEASURES The primary end point was progression-free survival during maintenance therapy. The secondary end points were total progression-free survival, overall survival, quality of life, safety, and toxic effects of treatment. RESULTS Forty-seven patients were enrolled in maintenance therapy, with a median age of 52 years (range, 25-81 years) and 32 (68%) of them being men. The median maintenance progression-free survival was 7.2 (95% CI, 5.8-8.6) months. The median progression-free survival was 12.7 (95% CI, 11.8-15.4) months. The median overall survival was 27.4 (95% CI, 21.4-35.5) months. Grade 3 to 4 AEs during induction therapy included neutropenia (4 patients [9%]), diarrhea (4 patients [9%]), nausea or vomiting (3 patients [6%]), rash acneiform (10 patients [21%]), and hand-foot syndrome (8 patients [17%]). Grade 3 to 4 AEs during maintenance therapy included diarrhea (2 patients [4%]), rash acneiform (8 patients [17%]), and hand-foot syndrome (5 patients [11%]). CONCLUSIONS AND RELEVANCE Reduced-dose capecitabine plus cetuximab after initial chemotherapy is a novel maintenance therapy for patients with RAS wild-type metastatic colorectal cancer that achieved good outcomes and tolerable nonserious AEs. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02717923.
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Affiliation(s)
- Lu Wang
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Ying Liu
- Department of Medical Oncology of Zhengzhou University Affiliated Cancer Hospital, Henan Cancer Hospital, Zhengzhou, Henan, China
| | - Xianli Yin
- Gastroenterology and Urology Department, Hunan Cancer Hospital & The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Weijia Fang
- Department of Medical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Jianping Xiong
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Ben Zhao
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Mingsheng Zhang
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yanmei Zou
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Hong Qiu
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Xianglin Yuan
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
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Cetuximab Maintenance Therapy in Patients with Unresectable Wild-Type RAS and BRAF Metastatic Colorectal Cancer: A Single-Institute Prospective Study. Adv Ther 2020; 37:2829-2840. [PMID: 32378072 DOI: 10.1007/s12325-020-01360-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Indexed: 10/24/2022]
Abstract
INTRODUCTION Cetuximab plus FOLFIRI (leucovorin, fluorouracil, and irinotecan) is the preferred first-line therapy for RAS and BRAF wild-type (RBWT) metastatic colorectal cancer (mCRC). To counter chemotherapy-induced side effects, use of maintenance therapy is suggested. Therefore, we evaluated the efficacy and safety of cetuximab maintenance therapy in patients after effective completion of first-line induction therapy. METHODS This prospective study enrolled untreated patients with mCRC RBWT who received first-line cetuximab plus FOLFIRI therapy. Following this, patients with treatment response either entered observation (stop treatment) or maintenance treatment 1 (cetuximab plus irinotecan) groups. After 6-12 cycles of maintenance treatment 1, patients entered maintenance treatment 2 (cetuximab only). If a patient progressed on maintenance 2, cetuximab plus FOLFIRI was reintroduced. The primary end point was failure-free survival (FFS), whereas the secondary end points included disease control rate (DCR), objective remission rate (ORR), and progression-free survival (PFS). Safety events were also evaluated. RESULTS Among 79 enrolled patients, 72 completed first-line treatment effectively (DCR 91.1%, ORR 63.9%) and 44 entered maintenance 1 [median PFS 1 (mPFS, maintenance 1) 6.1 months, 95% confidence interval (CI) 6.0-6.2; DCR 56.8%; ORR 22.7%]. Of them, 21 entered maintenance treatment 2 (mPFS2 8.7 months, 95% CI 3.3-14.1; DCR 28.6%; ORR 4.8%). Median FFS (mFFS) was significantly longer in the maintenance 1 group compared with the observation group [12.7 vs. 3.0 months; hazard ratio (HR) 0.202, 95% CI 0.111-0.369; P < 0.001]. Overall, mFFS was 19.0 and 9.3 months in maintenance and observation groups, respectively (HR 0.211, 95% CI 0.117-0.380; P < 0.001). Rash acneiform, mucositis, and asthenia were commonly observed adverse events during maintenance treatment. CONCLUSION Maintenance treatment with cetuximab after first-line therapy significantly improved FFS, with an acceptable safety profile in untreated patients with mCRC RBWT. TRIAL REGISTRATION Retrospectively registered, 2019/10/02, Chinese Clinical Trial Registry, ChiCTR number 1900026360.
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Hu H, Liu X, Cai W, Wu D, Xu J, Yuan Y. A Retrospective Exploration of Targeted Maintenance Therapy in Advanced Colorectal Cancer: Based on the Background of Chinese Patient Assistance Program. Front Oncol 2020; 10:522. [PMID: 32391263 PMCID: PMC7190810 DOI: 10.3389/fonc.2020.00522] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2019] [Accepted: 03/23/2020] [Indexed: 01/04/2023] Open
Abstract
Background: Maintenance therapy with bevacizumab (Bev) in patients with colorectal cancer (CRC) provides progression-free survival (PFS) benefits. However, the role of maintenance therapy with an anti-EGFR monoclonal antibody has not been established. Methods: Eligible CRC patients were assigned to maintenance therapy with cetuximab (Cet; Cet group) or Bev (Bev group). PFS, the duration of maintenance therapy, and safety were analyzed. Cox multivariate regression analyses were performed to determine independent prognostic factors. Results: A total of 143 eligible patients were assigned to the Cet (n = 79) or Bev (n = 64) groups. In the Cet group, all patients had KRAS wild-type. The baseline characteristics were well-balanced between the two groups, except for a higher percentage of patients with a left-sided primary tumor in the Cet group than in the Bev group (86.1 vs. 62.5%, P < 0.0001). The median PFS was not significantly different between the Cet group and the Bev group: 5.9 months (95% CI 2.30–9.50) vs. 7.0 months (95% CI 3.69–10.31) (HR 1.17, 95% CI 0.77–1.79, P = 0.45). The median duration of maintenance therapy in the Cet group was shorter than that in the Bev group: 4.0 months (95% CI 1.94–5.99) vs. 4.8 months (95% CI 2.68–6.98) (HR 0.90, 95% CI 0.61–1.33; P = 0.59). The subgroup analyses showed that the median PFS for the first maintenance therapy and the second maintenance therapy were 3.2 months (95% CI 1.69–4.78) and 5.2 months (95% CI 1.58–8.83), respectively (HR 0.89, 95% CI 0.44–1.81; P = 0.75). Conclusions: This study suggests that maintenance therapy with Cet or Bev can be considered an appropriate option following induction chemotherapy for selected patients with advanced CRC. Multiple maintenance therapy seems to confer survival benefits in advanced CRC. Maintenance therapy with Cet after first-line induction chemotherapy seems to be associated with greater survival benefits.
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Affiliation(s)
- Hanguang Hu
- Departments of Medical Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xue Liu
- Departments of Medical Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Wen Cai
- Departments of Medical Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Dehao Wu
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Junxi Xu
- Departments of Medical Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Ying Yuan
- Departments of Medical Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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Maintenance treatment in metastatic colorectal cancer: in search of the best strategy. Clin Transl Oncol 2020; 22:1205-1215. [PMID: 31898053 DOI: 10.1007/s12094-019-02267-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Accepted: 12/08/2019] [Indexed: 12/22/2022]
Abstract
Over the last 2 decades, the standard fluoropyrimidine-based chemotherapy backbone for metastatic colorectal cancer has been complemented by the addition of novel biological agents, achieving impressive increases in 5-year survival rates. Nonetheless, these new combinations have also entailed increases in toxicity, leading to evaluation of de-escalated chemotherapy regimens and "drug holiday" periods in attempts to reduce side effects and optimise quality of life without impairing efficacy. Here, we review the current and emerging evidence for maintenance schedules with chemotherapy and targeted agents, versus continuous treatment after induction treatment, in metastatic colorectal cancer patients.
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Summers MG, Maughan TS, Kaplan R, Law PJ, Houlston RS, Escott-Price V, Cheadle JP. Comprehensive analysis of colorectal cancer-risk loci and survival outcome: A prognostic role for CDH1 variants. Eur J Cancer 2020; 124:56-63. [PMID: 31734605 DOI: 10.1016/j.ejca.2019.09.024] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2019] [Revised: 09/20/2019] [Accepted: 09/28/2019] [Indexed: 12/29/2022]
Abstract
PURPOSE Genome-wide association studies have identified common single nucleotide polymorphisms (SNPs) at 83 loci associated with colorectal cancer (CRC) risk in European populations. Because germline variation can also influence patient outcome, we studied the relationship between these SNPs and CRC survivorship. EXPERIMENTAL DESIGN For the 83 risk loci, 10 lead SNPs were directly genotyped, 72 were imputed and 1 was not genotyped nor imputed, in 1948 unrelated patients with advanced CRC from the clinical trials COIN and COIN-B (oxaliplatin and fluoropyrimidine chemotherapy ± cetuximab). A Cox survival model was used for each variant, and variants classified by pathway, adjusting for known prognostic factors. We imposed a Bonferroni threshold of P = 6.6 × 10-4 for multiple testing. We carried out meta-analyses of published risk SNPs associated with survival. RESULTS Univariate analysis identified six SNPs associated with overall survival (OS) (P < 0.05); however, only rs9939049 in CDH1 remained significant beyond the Bonferroni threshold (Hazard Ratio [HR] 1.44, 95% Confidence Intervals [CI]: 1.21-1.71, P = 5.0 × 10-5). Fine mapping showed that rs12597188 was the most significant SNP at this locus and remained significant after adjustment for known prognostic factors beyond multiple testing thresholds (HR 1.23, 95% CI: 1.13-1.34, P = 1.9 × 10-6). rs12597188 was also associated with poor response to therapy (OR 0.61, 95% CI: 0.42-0.87, P = 6.6 × 10-3). No combinations of SNPs within pathways were more significantly associated with survival compared with single variants alone, and no other risk SNPs were associated with survival in meta-analyses. CONCLUSIONS The CRC susceptibility SNP rs9939049 in CDH1 influences patient survival and warrants further evaluation as a prognostic biomarker.
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Affiliation(s)
- Matthew G Summers
- Division of Cancer and Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, CF14 4XN, UK
| | - Timothy S Maughan
- CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Roosevelt Drive, Oxford OX3 7DQ, UK
| | - Richard Kaplan
- MRC Clinical Trials Unit, Aviation House, 125 Kingsway, London, WC2B 6NH, UK
| | - Philip J Law
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London, SW7 3RP, UK
| | - Richard S Houlston
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London, SW7 3RP, UK
| | - Valentina Escott-Price
- Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff, CF24 4HQ, UK
| | - Jeremy P Cheadle
- Division of Cancer and Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, CF14 4XN, UK.
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Parseghian CM, Napolitano S, Loree JM, Kopetz S. Mechanisms of Innate and Acquired Resistance to Anti-EGFR Therapy: A Review of Current Knowledge with a Focus on Rechallenge Therapies. Clin Cancer Res 2019; 25:6899-6908. [PMID: 31263029 PMCID: PMC6891150 DOI: 10.1158/1078-0432.ccr-19-0823] [Citation(s) in RCA: 84] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2019] [Revised: 05/16/2019] [Accepted: 06/26/2019] [Indexed: 02/06/2023]
Abstract
Innate and acquired resistance to anti-EGFR therapy (EGFRi) is a major limitation in the treatment of metastatic colorectal cancer (mCRC). Although RAS genes are the most commonly mutated innate and acquired oncogenes in cancer, there are a number of other mechanisms that limit the effectiveness of EGFRi. Patients with innate resistance have been found to contain BRAFV600E mutations, and possibly MET, MEK, PIK3CA, PTEN, and HER2 alterations. Meanwhile, BRAFV600E mutations may also be involved in acquired resistance to EGFRi, in addition to EGFR ectodomain mutations, MET alterations, and possibly HER2 amplification. In addition, paracrine effects and cell-fate mechanisms of resistance are being increasingly described as contributing to acquired resistance. Utilization of circulating tumor DNA has been paramount in monitoring the dynamic nature of acquired resistance and has helped to guide treatment decisions, particularly in the EGFRi rechallenge setting. Herein, we provide an in-depth review of EGFRi-resistance mechanisms and describe the current therapeutic landscape in the hopes of identifying effective rechallenge strategies.
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Affiliation(s)
- Christine M Parseghian
- Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
| | - Stefania Napolitano
- Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | | | - Scott Kopetz
- Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
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Sun H, Li Y, Su Y, Wu X, Zhou X, Han J, Li J. Efficacy and safety of anti-EGFR monoclonal antibodies combined with different chemotherapy regimens in patients with RAS wild-type metastatic colorectal cancer: A meta-analysis. J Evid Based Med 2019; 12:300-312. [PMID: 31596544 DOI: 10.1111/jebm.12360] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2019] [Accepted: 05/27/2019] [Indexed: 02/05/2023]
Abstract
OBJECTIVES To investigate the efficacy and safety of adding anti-epidermal growth factor receptor [EGFR] MoAbs to various chemotherapy regimens in patients with RAS wild-type metastasized colorectal cancer (RAS WT metastatic colorectal cancer [mCRC]) and to identify the optimal combination regimens. METHODS We searched MEDLINE, EMBASE, and CENTRAL from the inception date to 20th May 2019. Randomized clinical trials investigating chemotherapy with or without anti-EGFR MoAbs in treatment of patients with RAS WT mCRC were included. RESULTS Eighteen studies involving 8848 participants were eligible. Comparing with oxaliplatin-based chemotherapy, adding anti-EGFR MoAbs benefited only in progression-free survival (PFS) (hazard ratio [HR] = 0.80, 95% confidence interval [CI]: 0.67 to 0.94), but not in overall survival (OS) (HR = 0.89, 95% CI: 0.78 to 1.02). Further sensitivity analysis indicated that adding anti-EGFR MoAbs to FOLFOLX regimen as a first-line treatment showed benefits in both PFS and OS (PFS: HR = 0.74, 95% CI: 0.64 to 0.84; OS: HR = 0.83, 95% CI: 0.73 to 0.95, respectively). Comparing with irinotecan-based chemotherapy or best supportive care, adding anti-EGFR MoAbs revealed an improvement in both PFS (HR = 0.77, 95% CI: 0.69 to 0.86; HR = 0.46, 95% CI: 0.40 to 0.54, respectively) and OS (HR = 0.89, 95% CI: 0.80 to 0.98; HR = 0.65, 95% CI: 0.54 to 0.78, respectively). CONCLUSION Anti-EGFR MoAbs as a monotherapy or in combination with either irinotecan-based chemotherapy or FOLFOX in patients with RAS wild-type mCRC have better response and survival outcome, whereas OS does not benefit from adding anti-EGFR MoAbs to another oxaliplatin-based regimen. Anti-EGFR MoAbs have increased the risk of adverse effects than chemotherapy alone. More high-quality randomized controlled trials for RAS wild type are necessary.
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Affiliation(s)
- Huan Sun
- Department of Evidence-Based Medicine and Clinical Epidemiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yonghong Li
- Department of Evidence-Based Medicine and Clinical Epidemiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yana Su
- Department of Evidence-Based Medicine and Clinical Epidemiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Xinyu Wu
- Chengdu Fifth People's Hospital, Chengdu, Sichuan, China
| | - Xiaoqin Zhou
- Department of Clinical Research Management, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Jin Han
- School of Life Science and Technology, Shanghai Jiaotong University, Shanghai, China
| | - Jing Li
- Department of Evidence-Based Medicine and Clinical Epidemiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
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Cremolini C, Antoniotti C, Lonardi S, Aprile G, Bergamo F, Masi G, Grande R, Tonini G, Mescoli C, Cardellino GG, Coltelli L, Salvatore L, Corsi DC, Lupi C, Gemma D, Ronzoni M, Dell'Aquila E, Marmorino F, Di Fabio F, Mancini ML, Marcucci L, Fontanini G, Zagonel V, Boni L, Falcone A. Activity and Safety of Cetuximab Plus Modified FOLFOXIRI Followed by Maintenance With Cetuximab or Bevacizumab for RAS and BRAF Wild-type Metastatic Colorectal Cancer: A Randomized Phase 2 Clinical Trial. JAMA Oncol 2019; 4:529-536. [PMID: 29450468 DOI: 10.1001/jamaoncol.2017.5314] [Citation(s) in RCA: 81] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Importance The combination of a triple-drug chemotherapy regimen with an anti-epidermal growth factor receptor (EGFR) agent as a first-line treatment of metastatic colorectal cancer (mCRC) showed promising activity along with safety concerns in single-arm phase 2 trials. The role of maintenance following chemotherapy and anti-EGFR and the optimal regimen to be adopted are not established. Objectives To evaluate the activity and safety of cetuximab plus modified FOLFOXIRI (mFOLFOXIRI) and explore the role of maintenance with cetuximab or bevacizumab in RAS and BRAF wild-type mCRC. Design, Setting, and Participants In a prospective, noncomparative, open-label, multicenter, randomized phase 2 trial, patients aged 18 to 75 years with unresectable, previously untreated RAS and BRAF wild-type (before amendment, KRAS wild-type) mCRC were recruited from 21 oncology units in Italy from October 19, 2011, to March 1, 2015 (followed up through May 31, 2017). In total, 323 patients were screened and 143 were randomized to 2 treatment arms to receive as a first-line induction a regimen of mFOLFOXIRI plus cetuximab followed by cetuximab (arm A) or bevacizumab (arm B) until disease progression. Primary analyses were conducted in a modified intention-to-treat population. Interventions mFOLFOXIRI plus cetuximab repeated every 2 weeks for up to 8 cycles, followed by maintenance with cetuximab or bevacizumab until disease progression. Main Outcomes and Measures The primary end point was the 10-month progression-free rate (PFR); secondary end points included progression-free and overall survival, response rate, rate of metastases resection, and adverse events. Results Of 143 patients randomized, 116 (81.1%) (median [interquartile range (IQR)] age, 59.5 [53-67] years; 34 [29.3%] women) had RAS and BRAF wild-type mCRC. At a median (IQR) follow-up of 44.0 (30.5-52.1) months, 10-month PFRs were 50.8% (90% CI, 39.5%-62.2%) in arm A and 40.4% (90% CI, 29.4%-52.1%) in arm B. The overall response rate was 71.6% (95% CI, 62.4%-79.5%). Main grade 3/4 adverse events were neutropenia (occurring in 36 patients [31%]), diarrhea (in 21 patients [18%]), skin toxic effects (in 18 patients [16%]), asthenia (in 11 patients [9%]), stomatitis (in 7 patients [6%]), and febrile neutropenia (in 3 patients [3%]). Conclusions and Relevance Although neither of the 2 arms met the primary end point, the findings indicate that a 4-month induction regimen of mFOLFOXIRI plus cetuximab is feasible and provides relevant activity results, leading to a high surgical resection rate. Trial Registration clinicaltrials.gov Identifier: NCT02295930.
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Affiliation(s)
- Chiara Cremolini
- Unit of Medical Oncology 2, Department of Translational Research and New Technologies in Medicine and Surgery, Azienda Ospedaliera-Universitaria Pisana, University of Pisa, Pisa, Italy
| | - Carlotta Antoniotti
- Unit of Medical Oncology 2, Department of Translational Research and New Technologies in Medicine and Surgery, Azienda Ospedaliera-Universitaria Pisana, University of Pisa, Pisa, Italy
| | - Sara Lonardi
- Medical Oncology Unit 1, Department of Clinical and Experimental Oncology, Istituto Oncologico Veneto-IRCCS, Padova, Italy
| | - Giuseppe Aprile
- Department of Oncology, University and General Hospital, Udine, Italy.,Department of Oncology, San Bortolo General Hospital, ULSS8 Berica, East District, Vicenza, Italy
| | - Francesca Bergamo
- Medical Oncology Unit 1, Department of Clinical and Experimental Oncology, Istituto Oncologico Veneto-IRCCS, Padova, Italy
| | - Gianluca Masi
- Unit of Medical Oncology 2, Department of Translational Research and New Technologies in Medicine and Surgery, Azienda Ospedaliera-Universitaria Pisana, University of Pisa, Pisa, Italy
| | - Roberta Grande
- Department of Medical Oncology, Hospital of Frosinone, Frosinone, Italy
| | - Giuseppe Tonini
- Dipartimento di Oncologia Università Campus Bio-Medico di Roma, Rome, Italy
| | - Claudia Mescoli
- Surgical Pathology and Cytopathology Unit, Department of Medicine, University of Padua, Padova, Italy
| | | | - Luigi Coltelli
- Unit of Medical Oncology, Hospital Felice Lotti, Azienda Toscana Nord Ovest, Pontedera, Italy
| | - Lisa Salvatore
- Unit of Medical Oncology 2, Department of Translational Research and New Technologies in Medicine and Surgery, Azienda Ospedaliera-Universitaria Pisana, University of Pisa, Pisa, Italy.,Unit of Medical Oncology, Policlinico G. B. Rossi, Azienda Ospedaliera Integrata di Verona, Verona, Italy
| | | | - Cristiana Lupi
- Department of Surgical, Medical, Molecular Pathology and Critical Area, University of Pisa, Pisa, Italy
| | - Donatello Gemma
- Department of Medical Oncology, Hospital of Frosinone, Frosinone, Italy
| | - Monica Ronzoni
- Department of Oncology, Hospital San Raffaele IRCSS, Milan, Italy
| | | | - Federica Marmorino
- Unit of Medical Oncology 2, Department of Translational Research and New Technologies in Medicine and Surgery, Azienda Ospedaliera-Universitaria Pisana, University of Pisa, Pisa, Italy
| | - Francesca Di Fabio
- Unit of Medical Oncology, Policlinico Sant'Orsola-Malpighi, Bologna, Italy
| | - Maria Laura Mancini
- Department of Medical Oncology, Policlinico Umberto I Sapienza, University of Rome, Rome, Italy
| | - Lorenzo Marcucci
- Unit of Medical Oncology, Hospital Felice Lotti, Azienda Toscana Nord Ovest, Pontedera, Italy
| | - Gabriella Fontanini
- Department of Surgical, Medical, Molecular Pathology and Critical Area, University of Pisa, Pisa, Italy
| | - Vittorina Zagonel
- Medical Oncology Unit 1, Department of Clinical and Experimental Oncology, Istituto Oncologico Veneto-IRCCS, Padova, Italy
| | - Luca Boni
- Clinical Trials Coordinating Center, Toscano Cancer Institute, University Hospital Careggi, Florence, Italy
| | - Alfredo Falcone
- Unit of Medical Oncology 2, Department of Translational Research and New Technologies in Medicine and Surgery, Azienda Ospedaliera-Universitaria Pisana, University of Pisa, Pisa, Italy
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Pietrantonio F, Morano F, Corallo S, Miceli R, Lonardi S, Raimondi A, Cremolini C, Rimassa L, Bergamo F, Sartore-Bianchi A, Tampellini M, Racca P, Clavarezza M, Berenato R, Caporale M, Antista M, Niger M, Smiroldo V, Murialdo R, Zaniboni A, Adamo V, Tomasello G, Giordano M, Petrelli F, Longarini R, Cinieri S, Falcone A, Zagonel V, Di Bartolomeo M, de Braud F. Maintenance Therapy With Panitumumab Alone vs Panitumumab Plus Fluorouracil-Leucovorin in Patients With RAS Wild-Type Metastatic Colorectal Cancer: A Phase 2 Randomized Clinical Trial. JAMA Oncol 2019; 5:1268-1275. [PMID: 31268481 DOI: 10.1001/jamaoncol.2019.1467] [Citation(s) in RCA: 81] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Importance Few studies are available on the role of maintenance strategies after induction treatment regimens based on anti-epidermal growth factor receptors, and the optimal regimen for an anti-epidermal growth factor receptors-based maintenance treatment in patients with RAS wild-type metastatic colorectal cancer is still to be defined. Objective To determine whether maintenance therapy with single-agent panitumumab was noninferior to panitumumab plus fluorouracil and leucovorin after a 4-month induction treatment regimen. Design, Setting, and Participants This open-label, randomized phase 2 noninferiority trial was conducted from July 7, 2015, through October 27, 2017, at multiple Italian centers. Patients with RAS wild-type, unresectable metastatic colorectal adenocarcinoma who had not received previous treatment for metastatic disease were eligible. Induction therapy consisted of panitumumab plus FOLFOX-4 (panitumumab, 6 mg/kg, oxaliplatin, 85 mg/m2 at day 1, leucovorin calcium, 200 mg/m2, and fluorouracil, 400-mg/m2 bolus, followed by 600-mg/m2 continuous 24-hour infusion at days 1 and 2, every 2 weeks). Cutoff date for analyses was July 30, 2018. Interventions Patients were randomized (1:1) to first-line panitumumab plus FOLFOX-4 for 8 cycles followed by maintenance therapy with panitumumab plus fluorouracil-leucovorin (arm A) or panitumumab (arm B) until progressive disease, unacceptable toxic effects, or consent withdrawal. The minimization method was used to stratify randomization by previous adjuvant treatment and number of metastatic sites. Main Outcomes and Measures The prespecified primary end point was 10-month progression-free survival (PFS) analyzed on an intention-to-treat basis with a noninferiority margin of 1.515 for the upper limit of the 1-sided 90% CI of the hazard ratio (HR) of arm B vs A. Results Overall, 229 patients (153 male [66.8%]; median age, 64 years [interquartile range (IQR), 56-70 years]) were randomly assigned to arm A (n = 117) or arm B (n = 112). At a median follow-up of 18.0 months (IQR, 13.1-23.3 months]), a total of 169 disease progression or death events occurred. Arm B was inferior (upper limit of 1-sided 90% CI of the HR, 1.857). Ten-month PFS was 59.9% (95% CI, 51.5%-69.8%) in arm A vs 49.0% (95% CI, 40.5%-59.4%) in arm B (HR, 1.51; 95% CI, 1.11-2.07; P = .01). During maintenance, arm A had a higher incidence of grade 3 or greater treatment-related adverse events (36 [42.4%] vs 16 [20.3%]) and panitumumab-related adverse events (27 [31.8%] vs 13 [16.4%]), compared with arm B. Conclusions and Relevance In patients with RAS wild-type metastatic colorectal cancer, maintenance therapy with single-agent panitumumab was inferior in terms of PFS compared with panitumumab plus fluorouracil-leucovorin, which slightly increased the treatment toxic effects. Trial Registration ClinicalTrials.gov identifier: NCT02476045.
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Affiliation(s)
- Filippo Pietrantonio
- Oncology and Hemato-oncology Department, University of Milan, Milan, Italy.,Department of Medical Oncology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale dei Tumori, Milan, Italy
| | - Federica Morano
- Department of Medical Oncology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale dei Tumori, Milan, Italy
| | - Salvatore Corallo
- Department of Medical Oncology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale dei Tumori, Milan, Italy
| | - Rosalba Miceli
- Clinical Epidemiology and Trial Organization, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Sara Lonardi
- Unit of Medical Oncology 1, Department of Clinical and Experimental Oncology, Istituto Oncologico Veneto, IRCCS, Padua, Italy
| | - Alessandra Raimondi
- Department of Medical Oncology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale dei Tumori, Milan, Italy
| | - Chiara Cremolini
- Unit of Medical Oncology, Azienda Ospedaliero-Universitaria (AOU) Pisana, Department of Translational Research and New Technologies in Medicine, University of Pisa, Pisa, Italy
| | - Lorenza Rimassa
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, Humanitas Clinical and Research Center, Rozzano, Italy
| | - Francesca Bergamo
- Unit of Medical Oncology 1, Department of Clinical and Experimental Oncology, Istituto Oncologico Veneto, IRCCS, Padua, Italy
| | - Andrea Sartore-Bianchi
- Oncology and Hemato-oncology Department, University of Milan, Milan, Italy.,Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Marco Tampellini
- Department of Oncology, AOU San Luigi di Orbassano, University of Torino, Orbassano, Italy
| | - Patrizia Racca
- Colorectal Cancer Unit, Medical Oncology Division 1, AOU Città della Salute e della Scienza, Torino, Italy
| | - Matteo Clavarezza
- Medical Oncology Unit, Ente Ospedaliero Ospedali Galliera, Genoa, Italy
| | - Rosa Berenato
- Medical Oncology Unit A.O. Papardo and Department of Human Pathology, University of Messina, Messina, Italy
| | - Marta Caporale
- Department of Medical Oncology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale dei Tumori, Milan, Italy
| | - Maria Antista
- Department of Medical Oncology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale dei Tumori, Milan, Italy
| | - Monica Niger
- Department of Medical Oncology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale dei Tumori, Milan, Italy
| | - Valeria Smiroldo
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, Humanitas Clinical and Research Center, Rozzano, Italy
| | - Roberto Murialdo
- Department of Internal Medicine, University of Genoa and IRCCS AOU San Martino-IST, Genoa, Italy
| | | | - Vincenzo Adamo
- Medical Oncology Unit A.O. Papardo and Department of Human Pathology, University of Messina, Messina, Italy
| | - Gianluca Tomasello
- Medical Oncology Unit, Azienda Socio-Sanitaria Territoriale (ASST) Ospedale di Cremona, Cremona, Italy
| | - Monica Giordano
- Medical Oncology Unit, Azienda Socio Sanitaria Territoriale Lariana, Como, Italy
| | - Fausto Petrelli
- Medical Oncology Unit, Oncology Department, ASST Bergamo Ovest, Treviglio, Italy
| | | | - Saverio Cinieri
- Medical Oncology Unit, Ospedale Antonio Perrino, Brindisi, Italy
| | - Alfredo Falcone
- Unit of Medical Oncology, Azienda Ospedaliero-Universitaria (AOU) Pisana, Department of Translational Research and New Technologies in Medicine, University of Pisa, Pisa, Italy
| | - Vittorina Zagonel
- Unit of Medical Oncology 1, Department of Clinical and Experimental Oncology, Istituto Oncologico Veneto, IRCCS, Padua, Italy
| | - Maria Di Bartolomeo
- Department of Medical Oncology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale dei Tumori, Milan, Italy
| | - Filippo de Braud
- Oncology and Hemato-oncology Department, University of Milan, Milan, Italy.,Department of Medical Oncology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale dei Tumori, Milan, Italy
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Cardone C, Martinelli E, Troiani T, Sforza V, Avallone A, Nappi A, Montesarchio V, Andreozzi F, Biglietto M, Calabrese F, Bordonaro R, Cordio S, Bregni G, Febbraro A, Garcia-Carbonero R, Feliu J, Cervantes A, Ciardiello F. Exploratory findings from a prematurely closed international, multicentre, academic trial: RAVELLO, a phase III study of regorafenib versus placebo as maintenance therapy after first-line treatment in RAS wild-type metastatic colorectal cancer. ESMO Open 2019; 4:e000519. [PMID: 31555481 PMCID: PMC6735666 DOI: 10.1136/esmoopen-2019-000519] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2019] [Revised: 05/20/2019] [Accepted: 05/22/2019] [Indexed: 01/07/2023] Open
Abstract
Background In patients with RAS wild-type (WT) metastatic colorectal cancer (mCRC), the role of maintenance therapy after first-line treatment with chemotherapy plus antiepidermal growth factor receptor (EGFR) monoclonal antibodies (MoAb) is still an object of debate. Methods We assessed the efficacy and safety of regorafenib as a switch maintenance strategy after upfront 5-fluorouracil-based chemotherapy plus an anti-EGFR MoAb in patients with RAS WT mCRC. RAVELLO was a phase III, international, double-blind, placebo-controlled, academic trial. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival and toxicity. Regorafenib or placebo were administered daily for 3 weeks of 4-week cycle until disease progression or unacceptable toxicity, up to 24 months. Results The study was stopped prematurely due to slow accrual and lack of funding after the randomisation of 21 patients: 11 in the regorafenib arm and 10 in the placebo arm. The small sample size precludes any statistical analysis. Toxicity was acceptable and consistent with the known regorafenib safety profile. Median PFS was similar in the two arms. However, a subgroup of patients treated with regorafenib experienced a remarkably long PFS. Three patients were progression free at 9 months in the regorafenib arm versus one patient in the placebo arm, whereas at 12 months two regorafenib-treated patients were still progression free versus none in the placebo arm. Conclusion RAVELLO trial demonstrated that growing financial and bureaucratic hurdles affect the feasibility of independent academic research. Although stopped prematurely and within the limited sample size, RAVELLO suggests that regorafenib has not a major activity in maintenance setting after upfront chemotherapy and anti-EGFR MoAb. However, a subgroup of patients experienced a remarkable long PFS, indicating that a better refinement of the patient population would help to identify subjects that might benefit from a regorafenib personalised approach in the switch maintenance setting.
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Affiliation(s)
- Claudia Cardone
- Department of Precision Medicine, Università degli Studi della Campania Luigi Vanvitelli, Napoli, Campania, Italy
| | - Erika Martinelli
- Department of Precision Medicine, Università degli Studi della Campania Luigi Vanvitelli, Napoli, Campania, Italy
| | - Teresa Troiani
- Department of Precision Medicine, Università degli Studi della Campania Luigi Vanvitelli, Napoli, Campania, Italy
| | - Vincenzo Sforza
- Department of Precision Medicine, Università degli Studi della Campania Luigi Vanvitelli, Napoli, Campania, Italy
| | - Antonio Avallone
- Department of Experimental Medicine, Istituto Nazionale Tumori IRCCS Fondazione Pascale, Napoli, Italy
| | - Anna Nappi
- Department of Experimental Medicine, Istituto Nazionale Tumori IRCCS Fondazione Pascale, Napoli, Italy
| | | | - Francesca Andreozzi
- Azienda Ospedaliera dei Colli, Medical Oncology, Monaldi Hospital, Napoli, Italy
| | - Maria Biglietto
- Medical Oncology, Antonio Cardarelli Hospital, Napoli, Italy
| | | | - Roberto Bordonaro
- Medical Oncology, National Specialist Hospital Garibaldi, Catania, Italy
| | - Stefano Cordio
- Medical Oncology, National Specialist Hospital Garibaldi, Catania, Italy
| | | | - Antonio Febbraro
- Medical Oncology, Hospital Sacro Cuore di Gesù, Fatebenefratelli, Benevento, Italy
| | - Rocio Garcia-Carbonero
- Medical Oncology, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), UCM, CNIO, CIBERONC, Hospital Universitario 12 de Octubre, Madrid, Spain
| | - Jaime Feliu
- CIBERONC, Medical Oncology, Hospital Universitario La Paz, Madrid, Spain
| | - Andrés Cervantes
- CIBERONC, Medical Oncology, Biomedical Research Institute INCLIVA, University of Valencia, Valencia, Spain
| | - Fortunato Ciardiello
- Department of Precision Medicine, Università degli Studi della Campania Luigi Vanvitelli, Napoli, Campania, Italy
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50
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Gray V, Briggs S, Palles C, Jaeger E, Iveson T, Kerr R, Saunders MP, Paul J, Harkin A, McQueen J, Summers MG, Johnstone E, Wang H, Gatcombe L, Maughan TS, Kaplan R, Escott-Price V, Al-Tassan NA, Meyer BF, Wakil SM, Houlston RS, Cheadle JP, Tomlinson I, Church DN. Pattern Recognition Receptor Polymorphisms as Predictors of Oxaliplatin Benefit in Colorectal Cancer. J Natl Cancer Inst 2019; 111:828-836. [PMID: 30649440 PMCID: PMC6695319 DOI: 10.1093/jnci/djy215] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2018] [Revised: 08/22/2018] [Accepted: 11/19/2018] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Constitutional loss of function (LOF) single nucleotide polymorphisms (SNPs) in pattern recognition receptors FPR1, TLR3, and TLR4 have previously been reported to predict oxaliplatin benefit in colorectal cancer. Confirmation of this association could substantially improve patient stratification. METHODS We performed a retrospective biomarker analysis of the Short Course in Oncology Therapy (SCOT) and COIN/COIN-B trials. Participant status for LOF variants in FPR1 (rs867228), TLR3 (rs3775291), and TLR4 (rs4986790/rs4986791) was determined by genotyping array or genotype imputation. Associations between LOF variants and disease-free survival (DFS) and overall survival (OS) were analyzed by Cox regression, adjusted for confounders, using additive, dominant, and recessive genetic models. All statistical tests were two-sided. RESULTS Our validation study populations included 2929 and 1948 patients in the SCOT and COIN/COIN-B cohorts, respectively, of whom 2728 and 1672 patients had functional status of all three SNPs determined. We found no evidence of an association between any SNP and DFS in the SCOT cohort, or with OS in either cohort, irrespective of the type of model used. This included models for which an association was previously reported for rs867228 (recessive model, multivariable-adjusted hazard ratio [HR] for DFS in SCOT = 1.19, 95% confidence interval [CI] = 0.99 to 1.45, P = .07; HR for OS in COIN/COIN-B = 0.92, 95% CI = 0.63 to 1.34, P = .66), and rs4986790 (dominant model, multivariable-adjusted HR for DFS in SCOT = 0.86, 95% CI = 0.65 to 1.13, P = .27; HR for OS in COIN/COIN-B = 1.08, 95% CI = 0.90 to 1.31, P = .40). CONCLUSION In this prespecified analysis of two large clinical trials, we found no evidence that constitutional LOF SNPs in FPR1, TLR3, or TLR4 are associated with differential benefit from oxaliplatin. Our results suggest these SNPs are unlikely to be clinically useful biomarkers.
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Affiliation(s)
- Victoria Gray
- See the Notes section for the full list of authors’ affiliations
| | - Sarah Briggs
- See the Notes section for the full list of authors’ affiliations
| | - Claire Palles
- See the Notes section for the full list of authors’ affiliations
| | - Emma Jaeger
- See the Notes section for the full list of authors’ affiliations
| | - Timothy Iveson
- See the Notes section for the full list of authors’ affiliations
| | - Rachel Kerr
- See the Notes section for the full list of authors’ affiliations
| | - Mark P Saunders
- See the Notes section for the full list of authors’ affiliations
| | - James Paul
- See the Notes section for the full list of authors’ affiliations
| | - Andrea Harkin
- See the Notes section for the full list of authors’ affiliations
| | - John McQueen
- See the Notes section for the full list of authors’ affiliations
| | | | - Elaine Johnstone
- See the Notes section for the full list of authors’ affiliations
| | - Haitao Wang
- See the Notes section for the full list of authors’ affiliations
| | - Laura Gatcombe
- See the Notes section for the full list of authors’ affiliations
| | | | - Richard Kaplan
- See the Notes section for the full list of authors’ affiliations
| | | | - Nada A Al-Tassan
- See the Notes section for the full list of authors’ affiliations
| | - Brian F Meyer
- See the Notes section for the full list of authors’ affiliations
| | - Salma M Wakil
- See the Notes section for the full list of authors’ affiliations
| | | | - Jeremy P Cheadle
- See the Notes section for the full list of authors’ affiliations
| | - Ian Tomlinson
- See the Notes section for the full list of authors’ affiliations
| | - David N Church
- See the Notes section for the full list of authors’ affiliations
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