First-line systemic treatment strategies in patients with initially unresectable colorectal cancer liver metastases (CAIRO5): an open-label, multicentre, randomised, controlled, phase 3 study from the Dutch Colorectal Cancer Group

Bond, Marinde J G; Bolhuis, Karen; Loosveld, Olaf; Groot, Jan Willem B. de; Droogendijk, Helga J.; Helgason, Helgi H.; Hendriks, Mathijs P.; Klaase, Joost M.; Kazemier, Geert; Liem, Mike S L; Rijken, Arjen M.; Verhoef, Cornelis; Wilt, Johannes H. W. de; Jong, Koert P. de; Gerhards, Michael F.; Amerongen, Martinus J. van; Engelbrecht, Marc R.; Lienden, Krijn P. van; Molenaar, I. Quintus; Valk, B. De; Haberkorn, Brigitte C M; Kerver, Emile D.; Erdkamp, Frans; Alphen, Robbert J. van; Stein, Daniëlle Mathijssen‐van; Komurcu, Aysun; López-Yurda, Marta; Swijnenburg, Rutger-Jan; Punt, Cornelis J.A.; Gulik, Thomas van; Huiskens, Joost; Dejong, Cornelis H. C.; Grünhagen, Dirk J.; Patijn, Gijs A.; Ruers, Theo J.M.; Chapelle, T.; Hermans, John J.; Leclercq, Wouter K G; Iersel, Liselot Valkenburg-van; Grootscholten, Cecile; Jong, Joyce M. van Dodewaard-de; Vincent, Jeroen; Houtsma, Danny; Los, Maartje; Boer, Marien den; Trajkovic-Vidakovic, Marija; Voorthuizen, Theo van; Koopman, Miriam; Vestjens, J.H.M.J.; Torrenga, Hans; Mekenkamp, L.; Veldhuis, G.J.; Polée, Marco B.; Dohmen, Serge E.; Schut, H.; Vulink, Annelie J.E.; Halteren, Henk K. van; Hadj, Jamal Oulad; Schiphorst, P. P.; Hoekstra, Ronald

doi:10.1016/s1470-2045(23)00219-x

Cited by 56 publications

(18 citation statements)

References 30 publications

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“…However, in the 2023 ESMO congress, the CAIRO5 study indicated that OS was not different between adding panitumumab versus bevacizumab to FOLFOX/FOLFIRI for initially unresectable left-sided RAS/BRAF V600E wild-type CRLM. Compared with chemotherapy plus bevacizumab, there was neither no improvement in PFS (10.8 months versus 10.4 months; p = 0.46)) or R0/R1 resection and/or ablation rate (58% versus 58%; p = 1.0) from chemotherapy plus anti-EGFR therapy in this population, but was associated with more toxicity ( 48 ). Further research needs to be conducted to identify the patients who may benefit most from this regimen.…”

Section: Discussionmentioning

confidence: 74%

FOLFOXIRI plus cetuximab as conversion therapy for unresectable RAS/BRAF wild-type left-sided colorectal cancer with liver-limited metastases: a prospective dual-center pilot study

Yang,

Chen,

Niu

et al. 2024

Front. Oncol.

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PurposeTo explore the efficacy and safety of FOLFOXIRI plus cetuximab regimen as conversion therapy for patients with unresectable RAS/BRAF wild-type colorectal liver-limited metastases (CLM).Patients and methodsThis was a dual-center, phase II trial with the rate of no evidence of disease (NED) achieved as the primary endpoint. All enrolled patients with initially unresectable left-sided RAS/BRAF wild-type colorectal liver-limited metastases received a modified FOLFOXIRI plus cetuximab regimen as conversion therapy.ResultsBetween October 2019 and October 2021, fifteen patients were enrolled. Nine patients (60%) achieved NED. The overall response rate (ORR) was 92.9%, and the disease control rate (DCR) was 100%. The median relapse‐free survival (RFS) was 9 (95% CI: 0–20.7) months. The median progression-free survival (PFS) was 13.0 months (95% CI: 5.7-20.5), and the median overall survival (OS) was not reached. The most frequently occurring grade 3-4 adverse events were neutropenia (20%), peripheral neurotoxicity (13.3%), diarrhea (6.7%), and rash acneiform (6.7%).ConclusionThe FOLFOXIRI plus cetuximab regimen displayed tolerable toxicity and promising anti-tumor activity in terms of the rate of NED achieved and response rate in patients with initially unresectable left-sided RAS/BRAF wild-type CLM. This regimen merits further investigation.

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Section: Discussionmentioning

confidence: 74%

FOLFOXIRI plus cetuximab as conversion therapy for unresectable RAS/BRAF wild-type left-sided colorectal cancer with liver-limited metastases: a prospective dual-center pilot study

Yang,

Chen,

Niu

et al. 2024

Front. Oncol.

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“…The value of adjuvant therapy after recovery from surgery is an issue that requires further investigation in the future. Although the long-term overall survival benefit of adding therapy after surgery has not been reported in the recently published CAIRO 5 study [ 34 ], these data are eagerly awaited, as up to 64% of patients in this study were not subjected to adjuvant therapy after surgery.…”

Section: Discussionmentioning

confidence: 91%

Perioperative Chemotherapy Including Bevacizumab in Potentially Curable Metastatic Colorectal Cancer: Long-Term Follow-Up of the ASSO-LM1 Trial

Dong,

Santol,

Gruenberger

et al. 2024

Cancers

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In 2007, the ASSO-LM1 trial, a multicenter prospective study, was initiated to investigate the resectability (R0) rate following preoperative combination therapy with XELOX and bevacizumab in patients with potentially resectable colorectal liver metastases. Six cycles of systemic therapy were administered preoperatively, although the sixth cycle did not include bevacizumab, resulting in 5 weeks between the last bevacizumab dose and surgery. Treatment with bevacizumab plus XELOX was restarted for another six cycles postoperatively. In total, 43 patients were enrolled in the ASSO-LM1 trial. Eight patients were ineligible for resection due to protocol violation and progression in two patients. The resectability of operated patients was 97% with 34 R0 resections and one R1 resection. Postoperative morbidity occurred in 22% of patients, of which three operative revisions were related to the primary tumor resection. Efficacy results for response in 38 eligible patients confirmed an ORR of 66%, 31% SD and 3% PD according to RECIST. Preoperative grade 3/4 adverse events were 17% diarrhea, 5% HFS and 5% thromboembolic events. Overall survival significantly differed depending upon the fulfillment of adjuvant treatment in curative resected patients (59.1 mo vs. 30.8 mo). In conclusion, the ASSO-LM1 trial is a hypothesis-generating study confirming the prognostic benefits of perioperative therapy with XELOX and bevacizumab in patients with metastatic colorectal cancer confined to the liver.

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“…Colorectal cancer, a prevalent malignancy, is categorized into left-sided and right-sided types, each differing significantly in molecular characteristics, clinical manifestations, and prognosis ( Choi and Kim, 2023 ; Sustic et al, 2023 ; Talhouni et al, 2023 ). For instance, left-sided colorectal cancers are commonly associated with KRAS and BRAF mutations, whereas right-sided cancers are more linked to microsatellite instability and CpG island methylation anomalies ( Bond et al, 2023 ; Kajiwara et al, 2023 ). Mendelian randomization analysis, a statistical tool, utilizes these genetic variations as natural experiments to establish causative links between specific genetic markers and cancer risk, providing crucial insights into the molecular mechanisms of colorectal cancer and the development of new therapeutic strategies.…”

Section: Discussionmentioning

confidence: 99%

Single-cell transcriptomics and Mendelian randomization reveal LUCAT1’s role in right-sided colorectal cancer risk

Shang,

Xi,

Lai

et al. 2024

Front. Genet.

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Background: Colorectal cancer (CRC) is a malignancy with high incidence and mortality rates globally, categorized into left-sided and right-sided CRC, each exhibiting significant differences in molecular characteristics, clinical manifestations, and prognosis.Methods: This study employed single-cell transcriptomic data and various bioinformatics approaches, such as two-sample Mendelian randomization, reverse Mendelian randomization, colocalization analysis, directed filtering, pseudotime analysis, and intercellular communication analysis. It analyzed cellular-level disparities between left-sided and right-sided CRC, identifying distinct subpopulations with characteristic variations. For these cells, two-sample Mendelian randomization was utilized to explore gene-to-one-sided CRC causality.Results: LUCAT1 was enriched in high-abundance monocyte subpopulations in right-sided CRC and demonstrated potential risk factor status through Mendelian randomization analysis. The specific single-nucleotide polymorphism (SNP) rs10774624 was associated with an increased risk of CRC. Moreover, metabolic pathway analysis revealed that LUCAT1+ monocytes exhibit lower communication activity in the tumor microenvironment and heightened activity in metabolic functions like glycosaminoglycan degradation. Its biological functions are related to the positive regulation of interleukin-6 production and NF-kappa B signaling, among others.Conclusion: This study confirmed a potential causal relationship between LUCAT1 and right-sided CRC risk through Mendelian randomization analysis. These findings provide novel insights into the pathogenesis of right-sided CRC and may aid in developing early detection and treatment strategies for right-sided CRC.

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First-line systemic treatment strategies in patients with initially unresectable colorectal cancer liver metastases (CAIRO5): an open-label, multicentre, randomised, controlled, phase 3 study from the Dutch Colorectal Cancer Group

Cited by 56 publications

References 30 publications

FOLFOXIRI plus cetuximab as conversion therapy for unresectable RAS/BRAF wild-type left-sided colorectal cancer with liver-limited metastases: a prospective dual-center pilot study

FOLFOXIRI plus cetuximab as conversion therapy for unresectable RAS/BRAF wild-type left-sided colorectal cancer with liver-limited metastases: a prospective dual-center pilot study

Perioperative Chemotherapy Including Bevacizumab in Potentially Curable Metastatic Colorectal Cancer: Long-Term Follow-Up of the ASSO-LM1 Trial

Single-cell transcriptomics and Mendelian randomization reveal LUCAT1’s role in right-sided colorectal cancer risk

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