Introduction
Resection of colorectal liver metastases (CRLMs) improves survival and may lead to cure. Resectability rates can be improved with conversion therapy1,2.
RAS and BRAF mutations are found in 50 and 5–20 per cent of tumours respectively in patients with metastatic colorectal cancer3,4. These mutations limit systemic therapy alternatives5 and have been associated with worse outcomes in patients with CRLMs6. Patients with the BRAF V600E mutation clearly have shorter median survival, but some may survive without recurrence7.
Multidisciplinary teams (MDTs) have emerged to facilitate cooperation between medical specialties to ensure optimal care for the patient8–11. The aim of this study was to evaluate how RAS and BRAF mutational status affected resectability and conversion assessments performed by local hospitals and by a centralized MDT, and how this information could be used to improve resection rates and survival in patients with CRLMs.
Methods
Study design
RAXO was a prospective, investigator-initiated, nationwide Finnish study (NCT01531621, EudraCT 2011-003158-24) that included 1086 patients with metastatic colorectal cancer between 2012 and 2018. The main protocol12, liver metastases group13, and RAS/BRAF mutations in studies of metastatic colorectal cancer14 have been published previously. This substudy included patients with known RAS/BRAF status and CRLMs. Further details are available in the supplementary material. Patients with non-V600E BRAF mutations were excluded. The patients were assessed as having liver-only metastatic disease or liver and extrahepatic disease at the time of inclusion in the study. The central MDT at Helsinki University Hospital tertiary centre evaluated each patient’s technical resectability as described previously12,13 and in the supplementary material. The mutational status was mostly known to the local team, but only occasionally to the central MDT. Patients were classified into the following resection outcome groups: R0–1, R2/local ablative therapy (LAT) or systemic therapy only. The study was approved by the Ethics Committee at Helsinki University Hospital and all patients provided written informed consent. Statistical methodology is presented in the supplementary material.
Results
Of 672 patients included, 226 (33.6 per cent) had RAS&BRAF wild-type (wt) tumours, 392 (58.3 per cent) RAS mutation (mt) tumours, and 54 (8.0 per cent) BRAFmt tumours. Median follow-up was 55 (95 per cent c.i. 50–59; minimum 18) months. Patient demographics are summarized in Table S1.
Upfront resectability and conversion rates in the central assessment of 354 patients with liver-only and 318 with liver and extrahepatic metastases are shown in Fig. 1. In the liver-only group, the central MDT considered the metastases to be upfront resectable in 48.0, 45.5, and 27.3 per cent of patients with RAS&BRAFwt, RASmt, and BRAFmt tumours respectively. Conversion rates for the borderline or unresectable liver-only group were 48.4, 39.5, and 25.0 per cent respectively. Conversion rates for patients with initially borderline liver-only CRLMs were 78.9 per cent for RAS&BRAFwt (reference), 81.5 per cent for RASmt (OR 1.17, 95 per cent c.i. 0.42 to 3.32), and 40.0 per cent for BRAFmt (OR 0.18, 0.04 to 0.79) subgroups. The overall R0–1 resection rates for patients with liver-only CRLMs were 67.5 per cent for those with RAS&BRAFwt tumours (reference), 51.2 per cent for patients with RASmt tumours (OR 0.51, 0.32 to 0.80), and 31.8 per cent for those with BRAFmt tumours (OR 0.22, 0.09 to 0.60). The influence of tumour location on conversion is shown in Table S2.
Fig. 1.
Resectability, conversion, and resection rates according to mutational status
a Resectability and b resection rates for patients with liver-only metastases, and c resectability and d resection rates for patients with liver and extrahepatic metastases. wt, Wild type; mt, mutation; LAT, local ablative therapy. *OR 0.31 (95% c.i. 0.12 to 0.77); †OR 0.74 (0.46 to 1.22); ‡OR 0.79 (0.44 to 1.44).
Patients with liver and extrahepatic RAS&BRAFwt and RASmt metastases had similar upfront resectability and conversion rates. There was, however, a difference in R0–1 resection rates between the RAS&BRAFwt (12.6 per cent; reference) and RASmt (4.9 per cent; OR 0.35, 0.15 to 0.87).
When patients with liver-only disease were considered to have upfront resectable tumours by the central MDT, the local hospital underestimated resectability in 39, 41, and 83 per cent for RAS&BRAFwt, RASmt, and BRAFmt tumours respectively (Fig. 2a). If the central MDT considered a patient to have borderline resectable disease, 16, 15, and 0 per cent respectively of the local assessments were scored as never resectable.
Fig. 2.
Centralized resectability assessment compared with local assessment according to mutational status for patients with liver-only metastases and those with liver and extrahepatic metastases
a Patients with liver-only metastases and b patients with liver and extrahepatic metastases. wt, Wild type; mt, mutation.
Among patients with liver and extrahepatic metastases considered upfront resectable by the central MDT, the local teams underestimated resectability in 69 and 53 per cent of those with RAS&BRAFwt and RASmt tumours respectively (Fig. 2b). The rate of underestimation for borderline liver and extrahepatic metastases was 31 per cent for RAS&BRAFwt and 50 per cent for RASmt tumours. Reasons for not resecting technically resectable metastases are listed in Table S3.
Forty-two patients (6.3 per cent) had CRLMs that the local team considered never resectable. These were considered upfront or borderline resectable in central assessment, and 28 became technically resectable. Nine of these patients underwent resection with curative intent, including six with RAS&BRAFwt tumours (5 with liver-limited and 1 with liver and extrahepatic metastases) and three with RASmt tumours (2 liver-limited, and 1 liver and extrahepatic metastases).
Median overall survival (OS) after the first resection of metastases for 197 patients with liver-only metastases who underwent R0–1 resection was 82, 73, and 28 months according to RAS&BRAFwt (reference), RASmt (HR 1.55, 0.91 to 2.65), and BRAFmt status (HR 7.24, 2.38 to 22.00) respectively (P < 0.001). Corresponding 5-year OS rates were 68, 60, and 0 per cent respectively (Fig. S1). For 22 patients with RAS&BRAFwt and RASmt status who underwent R0–1 resection of liver and extrahepatic metastases, median OS was 79 and 71 months respectively (P = 0.847). Corresponding 5-year OS rates were 79 and 88 per cent. Recurrence-free survival, survival according to resection status, mutational status, and extent of disease, and a 12-month conditional landmark analysis of OS are shown in Figs S2–S4.
In multivariable analysis of risk factors for OS, assessment as unresectable by the central MDT appeared to be a strong risk factor. The second most notable factor was mutational status (Table 1).
Table 1.
Multivariable analysis of risk factors for overall survival
| HR | ||
|---|---|---|
| Univariable analysis | Multivariable analysis | |
| Age > 70 years | 1.22 (1.01, 1.48) | 1.27 (1.04, 1.56) |
| Female sex | 1.04 (0.86, 1.26) | |
| ECOG score | ||
| PS 0 | 1.00 (reference) | 1.00 (reference) |
| PS 1 | 1.89 (1.50, 2.39) | 1.47 (1.16, 1.87) |
| PS 2–3 | 3.38 (2.54, 4.48) | 2.29 (1.70, 3.09) |
| Charlson Co-morbidity Index score | ||
| 0 | 1.00 (reference) | |
| 1–2 | 1.20 (0.96, 1.48) | |
| 3–5 | 1.25 (0.47, 3.36) | |
| BMI (kg/m2) | ||
| < 20 | 1.00 (reference) | |
| 20–30 | 0.96 (0.67, 1.36) | |
| > 30 | 0.85 (0.57, 1.27) | |
| Primary tumour in right colon | 1.76 (1.44, 2.14) | 1.76 (1.42, 2.18) |
| Primary tumour not operated at baseline (yes versus no) | 1.89 (1.53, 2.27) | 1.49 (1.20, 1.85) |
| Synchronous metastases* | 1.10 (1.20, 1.88) | 1.35 (1.04, 1.77) |
| ≥ 3 liver segments involved | 2.37 (1.91, 2.94) | 1.54 (1.21, 1.98) |
| Extrahepatic metastases | 2.41 (2.00, 2.91) | 1.21 (0.97, 1.50) |
| Mutational status | ||
| RAS and BRAF wild type | 1.00 (reference) | 1.00 (reference) |
| RAS mutation | 1.57 (1.27, 1.93) | 1.62 (1.30, 2.00) |
| BRAF mutation | 3.34 (3.09, 6.07) | 2.55 (1.78, 3.64) |
| Upfront resectability assessment by central MDT | ||
| Resectable | 1.00 (reference) | 1.00 (reference) |
| Borderline | 1.50 (1.09, 2.06) | 1.11 (0.79, 1.55) |
| Unresectable | 5.54 (4.28, 7.18) | 3.69 (2.68, 5.08) |
Values in parentheses are 95% confidence intervals. Co-variables significant in univariable analyses were entered into the multivariable analysis. *Within 2 months of diagnosis of primary tumour. ECOG, Eastern Cooperative Oncology Group; PS, performance status; MDT, multidisciplinary team.
Discussion
With the help of centralized multidisciplinary assessment, high resectability, conversion, and resection rates are achievable for patients with RAS&BRAFwt and RASmt CRLMs. Selected patients with unfavourable BRAF mutation or with extrahepatic metastases may even undergo potentially curative resection.
Prospective studies of highly selected patients, often with RASwt tumours, have reported a conversion rate of 44–64 per cent and secondary resection/LAT rates of 44–61 per cent for patients with initially borderline or unresectable CRLMs2,15–17. In patients who also underwent hepatic artery infusion as induction therapy, conversion and secondary resection/LAT rates were 32 per cent for patients with RAS&BRAFwt tumours, 39 per cent for those with RASmt lesions, and 0 per cent for those with BRAFmt disease18. In a retrospective neoadjuvant therapy response assessment19, disease in up to 53 per cent of patients, mostly with RASwt tumours, was considered resectable upfront or after conversion, but only 29 per cent of these patients actually underwent resection. The present prospective study has shown comparable secondary resection/LAT rates for patients with liver-only RAS&BRAFwt and RASmt metastases, and a secondary resection/LAT rate as high as 25 per cent for patients with BRAFmt tumours.
In the literature, resectability and resection rates range from 18 to 71 per cent and from 16 to 54 per cent respectively for patients with liver-only metastases1,9,19,20. This study has shown that the chance of curative resection is highest for liver-only RAS&BRAFwt metastases, then RASmt metastases. Even for patients with tumours harbouring a BRAF mutation, a resectability rate of 45 per cent and corresponding resection rate of 32 per cent provided at least a chance of prolonged survival.
Other groups have reported up to 44 per cent resectability, but resection rates of only 5–11 per cent for patients with multiorgan metastases19,20. The present study has shown that such patients are indeed less likely to undergo resection. After conversion therapy, curative resection of all diseased organs could still be completed in 13 and 5 per cent of patients with RAS&BRAFwt and RASmt tumours respectively.
Reported disagreements between surgeons assessing resectability of 35–52 per cent, including 7–11 per cent major disagreements, have stressed the importance of a multidisciplinary team9,15. Disagreement between local teams and central MDT was considerable in the present study, with most major disagreements relating to borderline resectable or extrahepatic disease, suggesting that patients with more advanced disease could benefit even more from centralized MDT assessment. In multivariable survival analysis, central MDT assessment was associated with survival. This indicates that the central MDT is capable of including important clinical and radiological information in their decision, and underlines the potential additional value of multidisciplinary assessment of patients with liver-only or liver-dominant CRLMs.
Collaborators
RAXO Study Group: Heikki Mäkisalo, Riikka Huuhtanen, Eila Lantto, Juhani Kosunen, Sirpa Leppä, Petri Bono, Johanna Mattson, Jari Räsänen, Anna Lepistö, Heidi Penttinen, Siru Mäkelä, Olli Carpén, Nina Lundbom, Antti Hakkarainen, Marjut Timonen (Helsinki University Hospital, Helsinki, Finland); Veera Salminen, Niina Paunu, Irina Rinta-Kiikka, Martine Vornanen (Tampere University Hospital, Tampere, Finland); Johanna Virtanen, Eija Korkeila, Eija Sutinen, Maija Lavonius, Jari Sundström, Roberto Blanco (Turku University Hospital, Turku, Finland); Eija Pääkkö (Oulu University Hospital, Oulu, Finland); Tiina Tuomisto-Huttunen, Päivi Auvinen, Vesa Kärjä, Sakari Kainulainen, Hannu-Pekka Kettunen (Kuopio University Hospital, Kuopio, Finland); Ilmo Kellokumpu, Markku Aarnio, Ville Väyrynen, Kaija Vasala, Sanna Ketola, Kyösti Nuorva (Central Finland Hospital Nova, Jyväskylä, Finland); Maija-Leena Murashev, Kalevi Pulkkanen, Venla Viitanen, Marko Nieppola, Elina Haalisto (Satakunta Central Hospital, Pori, Finland); Paul Nyandoto, Aino Aalto (Päijät-Häme Central Hospital, Lahti, Finland); Timo Ala-Luhtala, Jukka Tuominiemi (Seinäjöki Central Hospital, Seinäjoki, Finland), Anneli Sainast, Laura Pusa, Sanna Kosonen, Leena Helle (Kymenlaakso Central Hospital, Kotka, Finland); Terhi Hermansson (Kymenlaakso Central Hospital, Kotka, Finland and South Savo Central Hospital, Mikkeli, Finland); Riitta Kokko, Laura Aroviita, Petri Nokisalmi (Kanta-Häme Central Hospital, Hämeenlinna, Finland); Liisa Sailas, Heikki Tokola (North Karelia Central Hospital, Joensuu, Finland); Antti Jekunen, Teemu Pöytäkangas (Vaasa Central Hospital, Vaasa, Finland); Kari Möykkynen, Sanna Kosonen (South Karelia Central Hospital, Lappeenranta, Finland); Olli-Pekka Isokangas, Svea Vaarala (Lapland Central Hospital, Rovaniemi, Finland); Tuula Klaavuniemi, Rainer Kolle (South Savo Central Hospital, Mikkeli, Finland); Peeter Karihtala, Mirja Heikkinen (Kainuu Central Hospital, Kajaani, Finland); Kaisu Johansson, Anna Sjöstrand, Piia Kajasviita (Central Ostrobothnia Central Hospital, Kokkola, Finland); Jaana Kaleva-Kerola (Länsi-Pohja Central Hospital, Kemi, Finland); Esa Männistö (Savonlinna Central Hospital, Savonlinna, Finland); Reneé Lindvall-Andersson, Tom Kaunismaa, Pia Vihinen, Nina Cavalli-Björkman (Åland Central Hospital, Mariehamn, Finland).
Supplementary Material
Acknowledgements
A.N. and E.O. are joint second authors; P.O. and H.I. are joint last authors. The authors thank the patients and their families, investigators, study personnel, and hospitals that participated in this study. The authors acknowledge C. Österlund for preparation of figures and S. Field, medical writer at Meducom BV, for English language editing of the manuscript. C.Ö. and S.F. were compensated for their support by grants.
This paper reports subgroup study results of the preregistered RAXO study (NCT01531621, EudraCT 2011-003158-24). The preregistration can be accessed at https://clinicaltrials.gov/ct2/show/NCT01531621. Understanding of the significance of molecular pathology has increased greatly since the RAXO study was originally conceived. The analysis plan for molecular pathology has been developed partially during the course of the study, and can be found in the RAXO Protocol version 3.2, dated 7 May 201712.
Contributor Information
Aki Uutela, Department of Transplantation and Liver Surgery, Abdominal Centre, Helsinki University Hospital and University of Helsinki, Helsinki, Finland; Department of Transplant and Hepatopancreatobiliary Surgery, Royal Infirmary of Edinburgh, Edinburgh, UK.
Arno Nordin, Department of Transplantation and Liver Surgery, Abdominal Centre, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.
Emerik Osterlund, Department of Transplantation and Liver Surgery, Abdominal Centre, Helsinki University Hospital and University of Helsinki, Helsinki, Finland; Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
Päivi Halonen, Department of Oncology, Helsinki University Hospital Comprehensive Cancer Centre and University of Helsinki, Helsinki, Finland.
Raija Kallio, Department of Oncology, Oulu University Hospital, Oulu, Finland.
Leena-Maija Soveri, Home Care Geriatric Clinic and Palliative Care, Joint Municipal Authority for Health Care and Social Services in Keski-Uusimaa, Hyvinkää, Finland; Faculty of Medicine, University of Helsinki, Helsinki, Finland.
Tapio Salminen, Department of Oncology, Tampere University Hospital and University of Tampere, Tampere, Finland.
Annika Ålgars, Department of Oncology, Turku University Hospital and University of Turku, Turku, Finland.
Ari Ristimäki, Department of Pathology, HUS Diagnostic Centre and Applied Tumour Genomics, Research Programmes Unit, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.
Ali Ovissi, Department of Radiology, HUS Medical Imaging Centre, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.
Annamarja Lamminmäki, Department of Oncology, Kuopio University Hospital and University of Eastern Finland, Kuopio, Finland.
Timo Muhonen, Faculty of Medicine, University of Helsinki, Helsinki, Finland; Department of Oncology, South Carelia Central Hospital, Lappeenranta, Finland.
Juha Kononen, Department of Oncology, Central Finland Hospital Nova, Jyväskylä, Finland; Docrates Cancer Center, Helsinki, Finland.
Raija Ristamäki, Department of Oncology, Turku University Hospital and University of Turku, Turku, Finland.
Eetu Heervä, Department of Oncology, Turku University Hospital and University of Turku, Turku, Finland.
Hanna Stedt, Department of Oncology, Kuopio University Hospital and University of Eastern Finland, Kuopio, Finland.
Kaisa Lehtomäki, Department of Oncology, Tampere University Hospital and University of Tampere, Tampere, Finland.
Soili Kytölä, Department of Genetics, HUSLAB, HUS Diagnostic Centre, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.
Jari Sundström, Department of Pathology, Turku University Hospital and University of Turku, Turku, Finland.
Markus J Mäkinen, Department of Pathology, Oulu University Hospital and University of Oulu, Oulu, Finland.
Lasse Nieminen, Department of Pathology, Tampere University Hospital and University of Tampere, Tampere, Finland.
Teijo Kuopio, Department of Pathology, Central Finland Central Hospital, Jyväskylä, Finland.
Mauri Keinänen, Department of Genetics, FIMLAB laboratories, Tampere University Hospital, Tampere, Finland.
Pia Osterlund, Department of Oncology, Helsinki University Hospital Comprehensive Cancer Centre and University of Helsinki, Helsinki, Finland; Department of Oncology, Tampere University Hospital and University of Tampere, Tampere, Finland; Department of Oncology/Pathology, Karolinska Institutet and Karolinska Sjukhuset, Cancer Centre of Excellence, Stockholm, Sweden.
Helena Isoniemi, Department of Transplantation and Liver Surgery, Abdominal Centre, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.
the RAXO Study Group:
Heikki Mäkisalo, Riikka Huuhtanen, Eila Lantto, Juhani Kosunen, Sirpa Leppä, Petri Bono, Johanna Mattson, Jari Räsänen, Anna Lepistö, Heidi Penttinen, Siru Mäkelä, Olli Carpén, Nina Lundbom, Antti Hakkarainen, Marjut Timonen, Veera Salminen, Niina Paunu, Irina Rinta-Kiikka, Martine Vornanen, Johanna Virtanen, Eija Korkeila, Eija Sutinen, Maija Lavonius, Jari Sundström, Roberto Blanco, Eija Pääkkö, Tiina Tuomisto-Huttunen, Päivi Auvinen, Vesa Kärjä, Sakari Kainulainen, Hannu-Pekka Kettunen, Ilmo Kellokumpu, Markku Aarnio, Ville Väyrynen, Kaija Vasala, Sanna Ketola, Kyösti Nuorva, Maija-Leena Murashev, Kalevi Pulkkanen, Venla Viitanen, Marko Nieppola, Elina Haalisto, Paul Nyandoto, Aino Aalto, Timo Ala-Luhtala, Jukka Tuominiemi, Anneli Sainast, Laura Pusa, Sanna Kosonen, Leena Helle, Terhi Hermansson, Riitta Kokko, Laura Aroviita, Petri Nokisalmi, Liisa Sailas, Heikki Tokola, Antti Jekunen, Teemu Pöytäkangas, Kari Möykkynen, Sanna Kosonen, Olli-Pekka Isokangas, Svea Vaarala, Tuula Klaavuniemi, Rainer Kolle, Peeter Karihtala, Mirja Heikkinen, Kaisu Johansson, Anna Sjöstrand, Piia Kajasviita, Jaana Kaleva-Kerola, Esa Männistö, Reneé Lindvall-Andersson, Tom Kaunismaa, Pia Vihinen, and Nina Cavalli-Björkman
Funding
This investigator-initiated RAXO study was supported by Finska Läkaresällskapet (2016, 2018–2022); Cancer Foundation Finland (2019–2020, 2021, 2022–2023); Relander Foundation (2020–2022); the Competitive State Research Financing of the Expert Responsibility Area of Tampere (2016–2022); the Competitive State Research Financing of the Expert Responsibility Area of Helsinki (2016–2022); the Competitive State Research Financing of the Expert Responsibility Area of Turku (2016–2022); Tampere University Hospital Funds (Tukisäätiö 2019, 2020; OOO 2020, 2022); and the Research Fund of Helsinki University Hospital (2019–2022). The infrastructure with database and study nurses were supported partly by pharmaceutical companies: Amgen unrestricted grant (2012–2020), Eli Lilly (2012–2017), Merck KGaA (2012–2020), Roche Oy (2012–2020), Sanofi (2012–2017), and Servier unrestricted grant (2016–2022).
Disclosure
The authors declare no conflict of interest. The funders had no role in the study design, analysis, interpretation of the data, decision to publish, or writing of this report.
Supplementary material
Supplementary material is available at BJS online.
Data availability
The original study database is not publicly available, but an anonymized version of the original data can be requested from the authors.
References
- 1. Folprecht G, Grothey A, Alberts S, Raab HR, Kohne CH. Neoadjuvant treatment of unresectable colorectal liver metastases: correlation between tumour response and resection rates. Ann Oncol 2005;16:1311–1319 [DOI] [PubMed] [Google Scholar]
- 2. Gruenberger T, Bridgewater J, Chau I, Garcia Alfonso P, Rivoire M, Mudan Set al. Bevacizumab plus mFOLFOX-6 or FOLFOXIRI in patients with initially unresectable liver metastases from colorectal cancer: the OLIVIA multinational randomised phase II trial. Ann Oncol 2015;26:702–708 [DOI] [PubMed] [Google Scholar]
- 3. Modest DP, Ricard I, Heinemann V, Hegewisch-Becker S, Schmiegel W, Porschen Ret al. Outcome according to KRAS-, NRAS- and BRAF-mutation as well as KRAS mutation variants: pooled analysis of five randomized trials in metastatic colorectal cancer by the AIO colorectal cancer study group. Ann Oncol 2016;27:1746–1753 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4. Sorbye H, Dragomir A, Sundstrom M, Pfeiffer P, Thunberg U, Bergfors Met al. High BRAF mutation frequency and marked survival differences in subgroups according to KRAS/BRAF mutation status and tumor tissue availability in a prospective population-based metastatic colorectal cancer cohort. PLoS One 2015;10:e0131046 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Cervantes A, Adam R, Rosello S, Arnold D, Normanno N, Taieb Jet al. Metastatic colorectal cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol 2022; DOI: 10.1016/j.annonc.2022.10.003 [Epub ahead of print] [DOI] [PubMed] [Google Scholar]
- 6. Tsilimigras DI, Ntanasis-Stathopoulos I, Bagante F, Moris D, Cloyd J, Spartalis Eet al. Clinical significance and prognostic relevance of KRAS, BRAF, PI3K and TP53 genetic mutation analysis for resectable and unresectable colorectal liver metastases: a systematic review of the current evidence. Surg Oncol 2018;27:280–288 [DOI] [PubMed] [Google Scholar]
- 7. Gau L, Ribeiro M, Pereira B, Poirot K, Dupre A, Pezet Det al. Impact of BRAF mutations on clinical outcomes following liver surgery for colorectal liver metastases: an updated meta-analysis. Eur J Surg Oncol 2021;47:2722–2733 [DOI] [PubMed] [Google Scholar]
- 8. Stelzner S, Radulova-Mauersberger O, Zschuppe E, Kittner T, Abolmaali N, Puffer Eet al. Prognosis in patients with synchronous colorectal cancer metastases after complete resection of the primary tumor and the metastases. J Surg Oncol 2019;120:438–445 [DOI] [PubMed] [Google Scholar]
- 9. Huiskens J, Bolhuis K, Engelbrecht MR, De Jong KP, Kazemier G, Liem MSet al. Outcomes of resectability assessment of the Dutch Colorectal Cancer Group Liver Metastases Expert Panel. J Am Coll Surg 2019;229:523–532.e2 [DOI] [PubMed] [Google Scholar]
- 10. Germani MM, Borelli B, Boraschi P, Antoniotti C, Ugolini C, Urbani Let al. The management of colorectal liver metastases amenable of surgical resection: how to shape treatment strategies according to clinical, radiological, pathological and molecular features. Cancer Treat Rev 2022;106:102382. [DOI] [PubMed] [Google Scholar]
- 11. Adam R, Kitano Y. Multidisciplinary approach of liver metastases from colorectal cancer. Ann Gastroenterol Surg 2019;3:50–56 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12. Osterlund P, Salminen T, Soveri LM, Kallio R, Kellokumpu I, Lamminmaki Aet al. Repeated centralized multidisciplinary team assessment of resectability, clinical behavior, and outcomes in 1086 Finnish metastatic colorectal cancer patients (RAXO): a nationwide prospective intervention study. Lancet Reg Health Eur 2021;3:100049. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13. Isoniemi H, Uutela A, Nordin A, Lantto E, Kellokumpu I, Ovissi Aet al. Centralized repeated resectability assessment of patients with colorectal liver metastases during first-line treatment: prospective study. Br J Surg 2021;108:817–825 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14. Uutela A, Osterlund E, Halonen P, Kallio R, Algars A, Salminen Tet al. Resectability, conversion, metastasectomy and outcome according to RAS and BRAF status for metastatic colorectal cancer in the prospective RAXO study. Br J Cancer 2022;127:686–694 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15. Folprecht G, Gruenberger T, Bechstein WO, Raab HR, Lordick F, Hartmann JTet al. Tumour response and secondary resectability of colorectal liver metastases following neoadjuvant chemotherapy with cetuximab: the CELIM randomised phase 2 trial. Lancet Oncol 2010;11:38–47 [DOI] [PubMed] [Google Scholar]
- 16. Bolhuis K, Grosheide L, Wesdorp NJ, Komurcu A, Chapelle T, Dejong CHCet al. Short-term outcomes of secondary liver surgery for initially unresectable colorectal liver metastases following modern induction systemic therapy in the Dutch CAIRO5 trial. Ann Surg Open 2021;2:e081. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17. Cremolini C, Casagrande M, Loupakis F, Aprile G, Bergamo F, Masi Get al. Efficacy of FOLFOXIRI plus bevacizumab in liver-limited metastatic colorectal cancer: a pooled analysis of clinical studies by Gruppo Oncologico del Nord Ovest. Eur J Cancer 2017;73:74–84 [DOI] [PubMed] [Google Scholar]
- 18. Datta J, Narayan RR, Goldman DA, Chatila WK, Gonen M, Strong Jet al. Distinct genomic profiles are associated with conversion to resection and survival in patients with initially unresectable colorectal liver metastases treated with systemic and hepatic artery chemotherapy. Ann Surg 2022;276:e474–e482 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19. Modest DP, Denecke T, Pratschke J, Ricard I, Lang H, Bemelmans Met al. Surgical treatment options following chemotherapy plus cetuximab or bevacizumab in metastatic colorectal cancer—central evaluation of FIRE-3. Eur J Cancer 2018;88:77–86 [DOI] [PubMed] [Google Scholar]
- 20. van der Geest LG, Lam-Boer J, Koopman M, Verhoef C, Elferink MA, de Wilt JH. Nationwide trends in incidence, treatment and survival of colorectal cancer patients with synchronous metastases. Clin Exp Metastasis 2015;32:457–465 [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The original study database is not publicly available, but an anonymized version of the original data can be requested from the authors.