TY - JOUR
T1 - First-line systemic treatment strategies in patients with initially unresectable colorectal cancer liver metastases (CAIRO5)
T2 - an open-label, multicentre, randomised, controlled, phase 3 study from the Dutch Colorectal Cancer Group
AU - Bond, Marinde J G
AU - Bolhuis, Karen
AU - Loosveld, Olaf J L
AU - de Groot, Jan Willem B
AU - Droogendijk, Helga
AU - Helgason, Helgi H
AU - Hendriks, Mathijs P
AU - Klaase, Joost M
AU - Kazemier, Geert
AU - Liem, Mike S L
AU - Rijken, Arjen M
AU - Verhoef, Cornelis
AU - de Wilt, Johannes H W
AU - de Jong, Koert P
AU - Gerhards, Michael F
AU - van Amerongen, Martinus J
AU - Engelbrecht, Marc R W
AU - van Lienden, Krijn P
AU - Molenaar, I Quintus
AU - de Valk, Bart
AU - Haberkorn, Brigitte C M
AU - Kerver, Emile D
AU - Erdkamp, Frans
AU - van Alphen, Robbert J
AU - Mathijssen-van Stein, Daniëlle
AU - Komurcu, Aysun
AU - Lopez-Yurda, Marta
AU - Swijnenburg, Rutger-Jan
AU - Punt, Cornelis J A
N1 - Funding Information:
The CAIRO5 study was supported by unrestricted scientific grants from Roche and Amgen, The Netherlands. We would like to thank all patients and their families, and hospitals and their research teams for participating in the CAIRO5 study. We would like to acknowledge The Netherlands Comprehensive Cancer Organisation for the collaboration.
Funding Information:
The CAIRO5 study was supported by unrestricted scientific grants from Roche and Amgen, The Netherlands. We would like to thank all patients and their families, and hospitals and their research teams for participating in the CAIRO5 study. We would like to acknowledge The Netherlands Comprehensive Cancer Organisation for the collaboration.
Publisher Copyright:
© 2023 Elsevier Ltd
PY - 2023/7
Y1 - 2023/7
N2 - Background: Patients with initially unresectable colorectal cancer liver metastases might qualify for local treatment with curative intent after reducing the tumour size by induction systemic treatment. We aimed to compare the currently most active induction regimens. Methods: In this open-label, multicentre, randomised, phase 3 study (CAIRO5), patients aged 18 years or older with histologically confirmed colorectal cancer, known RAS/BRAF
V600E mutation status, WHO performance status of 0–1, and initially unresectable colorectal cancer liver metastases were enrolled at 46 Dutch and one Belgian secondary and tertiary centres. Resectability or unresectability of colorectal cancer liver metastases was assessed centrally by an expert panel of liver surgeons and radiologists, at baseline and every 2 months thereafter by predefined criteria. Randomisation was done centrally with the minimisation technique via a masked web-based allocation procedure. Patients with right-sided primary tumour site or RAS or BRAF
V600E mutated tumours were randomly assigned (1:1) to receive FOLFOX or FOLFIRI plus bevacizumab (group A) or FOLFOXIRI plus bevacizumab (group B). Patients with left-sided and RAS and BRAF
V600E wild-type tumours were randomly assigned (1:1) to receive FOLFOX or FOLFIRI plus bevacizumab (group C) or FOLFOX or FOLFIRI plus panitumumab (group D), every 14 days for up to 12 cycles. Patients were stratified by resectability of colorectal cancer liver metastases, serum lactate dehydrogenase concentration, choice of irinotecan versus oxaliplatin, and BRAF
V600E mutation status (for groups A and B). Bevacizumab was administered intravenously at 5 mg/kg. Panitumumab was administered intravenously at 6 mg/kg. FOLFIRI consisted of intravenous infusion of irinotecan at 180 mg/m
2 with folinic acid at 400 mg/m
2, followed by bolus fluorouracil at 400 mg/m
2 intravenously, followed by continuous infusion of fluorouracil at 2400 mg/m
2. FOLFOX consisted of oxaliplatin at 85 mg/m
2 intravenously together with the same schedule of folinic acid and fluorouracil as in FOLFIRI. FOLFOXIRI consisted of irinotecan at 165 mg/m
2 intravenously, followed by intravenous infusion of oxaliplatin at 85 mg/m
2 with folinic acid at 400 mg/m
2, followed by continuous infusion of fluorouracil at 3200 mg/m
2. Patients and investigators were not masked to treatment allocation. The primary outcome was progression-free survival, analysed on a modified intention-to-treat basis, excluding patients who withdrew consent before starting study treatment or violated major entry criteria (no metastatic colorectal cancer, or previous liver surgery for colorectal cancer liver metastases). The study is registered with ClinicalTrials.gov, NCT02162563, and accrual is complete. Findings: Between Nov 13, 2014, and Jan 31, 2022, 530 patients (327 [62%] male and 203 [38%] female; median age 62 years [IQR 54–69]) were randomly assigned: 148 (28%) patients to group A, 146 (28%) patients to group B, 118 (22%) patients to group C, and 118 (22%) patients to group D. Groups C and D were prematurely closed for futility. 521 patients were included in the modified intention-to-treat population (147 in group A, 144 in group B, 114 in group C, and 116 in group D). The median follow-up at the time of this analysis was 51·1 months (95% CI 47·7–53·1) in groups A and B and 49·9 months (44·5–52·5) in in groups C and D. Median progression-free survival was 9·0 months (95% CI 7·7–10·5) in group A versus 10·6 months (9·9–12·1) in group B (stratified hazard ratio [HR] 0·76 [95% CI 0·60–0·98]; p=0·032), and 10·8 months (95% CI 9·9–12·6) in group C versus 10·4 months (9·8–13·0) in group D (stratified HR 1·11 [95% CI 0·84–1·48]; p=0·46). The most frequent grade 3–4 events in groups A and B were neutropenia (19 [13%] patients in group A vs 57 [40%] in group B; p<0·0001), hypertension (21 [14%] vs 20 [14%]; p=1·00), and diarrhoea (five [3%] vs 28 [19%]; p<0·0001), and in groups C and D were neutropenia (29 [25%] vs 24 [21%]; p=0·44), skin toxicity (one [1%] vs 29 [25%]; p<0·0001), hypertension (20 [18%] vs eight [7%]; p=0·016), and diarrhoea (five [4%] vs 18 [16%]; p=0·0072). Serious adverse events occurred in 46 (31%) patients in group A, 75 (52%) patients in group B, 41 (36%) patients in group C, and 49 (42%) patients in group D. Seven treatment-related deaths were reported in group B (two due to multiorgan failure, and one each due to sepsis, pneumonia, portal vein thrombosis, septic shock and liver failure, and sudden death), one in group C (multiorgan failure), and three in group D (cardiac arrest, pulmonary embolism, and abdominal sepsis). Interpretation: In patients with initially unresectable colorectal cancer liver metastases, FOLFOXIRI-bevacizumab was the preferred treatment in patients with a right-sided or RAS or BRAF
V600E mutated primary tumour. In patients with a left-sided and RAS and BRAF
V600E wild-type tumour, the addition of panitumumab to FOLFOX or FOLFIRI showed no clinical benefit over bevacizumab, but was associated with more toxicity. Funding: Roche and Amgen.
AB - Background: Patients with initially unresectable colorectal cancer liver metastases might qualify for local treatment with curative intent after reducing the tumour size by induction systemic treatment. We aimed to compare the currently most active induction regimens. Methods: In this open-label, multicentre, randomised, phase 3 study (CAIRO5), patients aged 18 years or older with histologically confirmed colorectal cancer, known RAS/BRAF
V600E mutation status, WHO performance status of 0–1, and initially unresectable colorectal cancer liver metastases were enrolled at 46 Dutch and one Belgian secondary and tertiary centres. Resectability or unresectability of colorectal cancer liver metastases was assessed centrally by an expert panel of liver surgeons and radiologists, at baseline and every 2 months thereafter by predefined criteria. Randomisation was done centrally with the minimisation technique via a masked web-based allocation procedure. Patients with right-sided primary tumour site or RAS or BRAF
V600E mutated tumours were randomly assigned (1:1) to receive FOLFOX or FOLFIRI plus bevacizumab (group A) or FOLFOXIRI plus bevacizumab (group B). Patients with left-sided and RAS and BRAF
V600E wild-type tumours were randomly assigned (1:1) to receive FOLFOX or FOLFIRI plus bevacizumab (group C) or FOLFOX or FOLFIRI plus panitumumab (group D), every 14 days for up to 12 cycles. Patients were stratified by resectability of colorectal cancer liver metastases, serum lactate dehydrogenase concentration, choice of irinotecan versus oxaliplatin, and BRAF
V600E mutation status (for groups A and B). Bevacizumab was administered intravenously at 5 mg/kg. Panitumumab was administered intravenously at 6 mg/kg. FOLFIRI consisted of intravenous infusion of irinotecan at 180 mg/m
2 with folinic acid at 400 mg/m
2, followed by bolus fluorouracil at 400 mg/m
2 intravenously, followed by continuous infusion of fluorouracil at 2400 mg/m
2. FOLFOX consisted of oxaliplatin at 85 mg/m
2 intravenously together with the same schedule of folinic acid and fluorouracil as in FOLFIRI. FOLFOXIRI consisted of irinotecan at 165 mg/m
2 intravenously, followed by intravenous infusion of oxaliplatin at 85 mg/m
2 with folinic acid at 400 mg/m
2, followed by continuous infusion of fluorouracil at 3200 mg/m
2. Patients and investigators were not masked to treatment allocation. The primary outcome was progression-free survival, analysed on a modified intention-to-treat basis, excluding patients who withdrew consent before starting study treatment or violated major entry criteria (no metastatic colorectal cancer, or previous liver surgery for colorectal cancer liver metastases). The study is registered with ClinicalTrials.gov, NCT02162563, and accrual is complete. Findings: Between Nov 13, 2014, and Jan 31, 2022, 530 patients (327 [62%] male and 203 [38%] female; median age 62 years [IQR 54–69]) were randomly assigned: 148 (28%) patients to group A, 146 (28%) patients to group B, 118 (22%) patients to group C, and 118 (22%) patients to group D. Groups C and D were prematurely closed for futility. 521 patients were included in the modified intention-to-treat population (147 in group A, 144 in group B, 114 in group C, and 116 in group D). The median follow-up at the time of this analysis was 51·1 months (95% CI 47·7–53·1) in groups A and B and 49·9 months (44·5–52·5) in in groups C and D. Median progression-free survival was 9·0 months (95% CI 7·7–10·5) in group A versus 10·6 months (9·9–12·1) in group B (stratified hazard ratio [HR] 0·76 [95% CI 0·60–0·98]; p=0·032), and 10·8 months (95% CI 9·9–12·6) in group C versus 10·4 months (9·8–13·0) in group D (stratified HR 1·11 [95% CI 0·84–1·48]; p=0·46). The most frequent grade 3–4 events in groups A and B were neutropenia (19 [13%] patients in group A vs 57 [40%] in group B; p<0·0001), hypertension (21 [14%] vs 20 [14%]; p=1·00), and diarrhoea (five [3%] vs 28 [19%]; p<0·0001), and in groups C and D were neutropenia (29 [25%] vs 24 [21%]; p=0·44), skin toxicity (one [1%] vs 29 [25%]; p<0·0001), hypertension (20 [18%] vs eight [7%]; p=0·016), and diarrhoea (five [4%] vs 18 [16%]; p=0·0072). Serious adverse events occurred in 46 (31%) patients in group A, 75 (52%) patients in group B, 41 (36%) patients in group C, and 49 (42%) patients in group D. Seven treatment-related deaths were reported in group B (two due to multiorgan failure, and one each due to sepsis, pneumonia, portal vein thrombosis, septic shock and liver failure, and sudden death), one in group C (multiorgan failure), and three in group D (cardiac arrest, pulmonary embolism, and abdominal sepsis). Interpretation: In patients with initially unresectable colorectal cancer liver metastases, FOLFOXIRI-bevacizumab was the preferred treatment in patients with a right-sided or RAS or BRAF
V600E mutated primary tumour. In patients with a left-sided and RAS and BRAF
V600E wild-type tumour, the addition of panitumumab to FOLFOX or FOLFIRI showed no clinical benefit over bevacizumab, but was associated with more toxicity. Funding: Roche and Amgen.
KW - Antineoplastic Combined Chemotherapy Protocols/adverse effects
KW - Bevacizumab
KW - Camptothecin/therapeutic use
KW - Colorectal Neoplasms/drug therapy
KW - Female
KW - Fluorouracil
KW - Humans
KW - Hypertension/chemically induced
KW - Irinotecan/therapeutic use
KW - Leucovorin
KW - Liver Neoplasms/drug therapy
KW - Male
KW - Middle Aged
KW - Neutropenia/chemically induced
KW - Oxaliplatin/therapeutic use
KW - Panitumumab/therapeutic use
KW - Proto-Oncogene Proteins B-raf/genetics
UR - http://www.scopus.com/inward/record.url?scp=85163525764&partnerID=8YFLogxK
U2 - 10.1016/S1470-2045(23)00219-X
DO - 10.1016/S1470-2045(23)00219-X
M3 - Article
C2 - 37329889
SN - 1470-2045
VL - 24
SP - 757
EP - 771
JO - LANCET ONCOLOGY
JF - LANCET ONCOLOGY
IS - 7
ER -