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FIRST BRAZILIAN CONSENSUS ON MULTIMODAL TREATMENT OF COLORECTAL LIVER METASTASES. MODULE 1: PRE-TREATMENT EVALUATION

Abstracts

Background

: Liver metastases of colorectal cancer are frequent and potentially fatal event in the evolution of patients with these tumors.

Aim

: In this module, was contextualized the clinical situations and parameterized epidemiological data and results of the various treatment modalities established.

Method:

Was realized deep discussion on detecting and staging metastatic colorectal cancer, as well as employment of imaging methods in the evaluation of response to instituted systemic therapy.

Results

: The next step was based on the definition of which patients would have their metastases considered resectable and how to expand the amount of patients elegible for modalities with curative intent.

Conclusion

: Were presented clinical, pathological and molecular prognostic factors, validated to be taken into account in clinical practice.

Colorectal cancer; Liver metastases; Brazilian consensus; Pre-treatment workout


Racional

: As metástases hepáticas de câncer colorretal são evento frequente e potencialmente fatal na evolução de pacientes com estas neoplasias.

Objetivo

: Neste módulo procurou-se contextualizar esta situação clínica, bem como parametrizar dados epidemiológicos e de resultados das diversas modalidades de tratamento estabelecidas.

Método

: Foi realizada discussão sobre como detectar e estadiar o câncer colorretal metastático, bem como o emprego dos métodos de imagem na avaliação de resposta ao tratamento sistêmico instituído.

Resultado

: Fundamentou na definição de quais pacientes teriam suas metástases consideradas ressecáveis e de como se poderia ampliar a gama de pacientes submetidos às modalidades de tratamento ditas de intuito curativo.

Conclusão

: Foram apresentados os fatores prognósticos clínicos, patológicos e moleculares com validação para serem levados em consideração na prática clínica.

Câncer colorretal; Metástases hepáticas; Consenso Brasileiro; Avaliação pré-tratamento


INTRODUCTION

Liver metastases of colorectal cancer are frequent and potentially fatal event in the evolution of patients with these malignancies. In this module was contextualize its clinical situation, as well as parameterize epidemiological data and results of the various established treatment modalities.

METHOD

Discussion on detecting and staging metastatic colorectal cancer was performed, as well as the use of imaging methods in the evaluation of response to systemic treatment instituted.

RESULTS

Topic 1 - Epidemiology and results of treatment in colorectal liver metastases (CLM)

Colorectal cancer (CRC) ranks fourth in global statistics of cancer incidence, with approximately 1,360,000 cases/year. With regard to mortality, it is estimated that there are over 693,000 deaths related to the disease in the world and it is the third leading cause of death in women and the fourth in men11. GLOBOCAN 2012. Estimated cancer incidence, mortality and prevalence worldwide in 2012. International Agency for Research on Cancer, Lyon, France. http://globocan.iarc.fr/Pages/fact_sheets_population.aspx. acessado em 19/07/2014.
http://globocan.iarc.fr/Pages/fact_sheet...
. The number of new cases estimated for Brazil in 2014 was approximately 32,600 and it was the third most common cancer in men and the second among women, excluding non-melanoma skin cancers22. Instituto Nacional de Câncer José Alencar Gomes da Silva, Coordenação de Prevenção e Vigilância. Estimativa 2014: Incidência de Câncer no Brasil. Rio de Janeiro: INCA, 2014. http://www.inca.gov.br/estimativa/2014/estimativa-24042014.pdf.
http://www.inca.gov.br/estimativa/2014/e...
.

Approximately half of the patients with CRC develop metastases during their lives33. Abdalla EK, Adam R, Bilchik AJ, Jaeck D, Vauthey JN, Mahvi D. Improving resectability of hepatic colorectal metastases: expert consensus statement. Ann Surg Oncol 2006;13(10):1271-80.,44. Al-Asfoor A, Fedorowicz Z. Resection versus no intervention or other surgical interventions for colorectal cancer liver metastases. Cochrane Database Syst Rev 2008;16(2):CD006039.,55. Fong Y, Cohen AM, Fortner JG, Enker WE, Turnbull AD, Coit DG, et al. Liver resection for colorectal metastases. J Clin Oncol 1997;15(3):938-46.,66. Sheth KR, Clary BM. Management of hepatic metastases from colorrectal cancer. Clin Colon Rectal Surg 2005;18(3):215-23.,77. Pozzo C, Basso M, Cassano A, Quirino M, Schinzari G, Trigila N, et al. Neoadjuvant treatment of unresectable liver disease with irinotecan and 5-fluorouracil plus folinic acid in colorrectal cancer patients. Ann Oncol 2004;(15):933-9.,88. Manfredi S, Lepage C, Hatem C, Coatmeur O, Faivre J, Bouvier AM. Epidemiology and management of liver metastases from colorectal cancer. Ann Surg 2006;244(2):254-9.. The most common site of metastatic CRC is the liver, occurring in 80% of cases88. Manfredi S, Lepage C, Hatem C, Coatmeur O, Faivre J, Bouvier AM. Epidemiology and management of liver metastases from colorectal cancer. Ann Surg 2006;244(2):254-9.,99. Welch JP, Donaldson GA. The clinical correlation of an autopsy study of recurrent colorectal cancer. Ann Surg 1979;189(4):496-502.,1010. Shindo K. Recurrence of carcinoma of the large intestine. A statistical review. Am J Proctol 1974;25(3):80-90.,1111. Mantke R, Schmidt U, Wolff S, Kube R, Lippert H. Incidence of synchronous liver metastases in patients with colorectal cancer in relationship to clinico-pathologic characteristics. Results of a German prospective multicenter observational study. Eur J Surg Oncol 2012;38(3):259-65.,1212. Pawlik TM, Shulick R, Chot M. Expanding criteria for resectability of colorectal liver metastases. Oncologist 2008;13(1):51-64.,1313. Lupinacci RM, Coelho FF, Perini MV, Lobo EJ, Ferreira FG, Szutan LA, et al. Current management of liver metastases from colorectal cancer: recommendations of the São Paulo Liver Club. Rev Col Bras Cir 2013;40(3): 251-60., representing approximately half of all patients with CRC33. Abdalla EK, Adam R, Bilchik AJ, Jaeck D, Vauthey JN, Mahvi D. Improving resectability of hepatic colorectal metastases: expert consensus statement. Ann Surg Oncol 2006;13(10):1271-80.,44. Al-Asfoor A, Fedorowicz Z. Resection versus no intervention or other surgical interventions for colorectal cancer liver metastases. Cochrane Database Syst Rev 2008;16(2):CD006039.,55. Fong Y, Cohen AM, Fortner JG, Enker WE, Turnbull AD, Coit DG, et al. Liver resection for colorectal metastases. J Clin Oncol 1997;15(3):938-46.,66. Sheth KR, Clary BM. Management of hepatic metastases from colorrectal cancer. Clin Colon Rectal Surg 2005;18(3):215-23.,77. Pozzo C, Basso M, Cassano A, Quirino M, Schinzari G, Trigila N, et al. Neoadjuvant treatment of unresectable liver disease with irinotecan and 5-fluorouracil plus folinic acid in colorrectal cancer patients. Ann Oncol 2004;(15):933-9.,88. Manfredi S, Lepage C, Hatem C, Coatmeur O, Faivre J, Bouvier AM. Epidemiology and management of liver metastases from colorectal cancer. Ann Surg 2006;244(2):254-9. and as the single site of metastasis in 20 to 50%1414. Ghiringhelli F, Hennequin A, Drouillard A, Lepage C, Faivre J, Bouvier AM. Epidemiology and prognosis of synchronous and metachronous colon cancer metastases: A French population-based study. Dig Liver Dis 2014;46(9):854-8.,1515. Zavadsky KE, Lee YT. Liver metastases from colorectal carcinoma: incidence, resectability, and survival results. Am Surg 1994;60(12):929-33.,1616. Pugh S, Fuller A, Rose P, Perera-Salazar R, Mellor J, George S, et al. What is the true incidence of metachronous colorectal liver metástases? Evidence from the UK FACS (follow-up after colorectal surgery) trial. Gut (Medical Abstracts) 2012;61 Suppl 2:A24.; however, only 15 to 30% are candidates for resection1212. Pawlik TM, Shulick R, Chot M. Expanding criteria for resectability of colorectal liver metastases. Oncologist 2008;13(1):51-64.,1313. Lupinacci RM, Coelho FF, Perini MV, Lobo EJ, Ferreira FG, Szutan LA, et al. Current management of liver metastases from colorectal cancer: recommendations of the São Paulo Liver Club. Rev Col Bras Cir 2013;40(3): 251-60.,1717. Coimbra FJF, Pires TC, Costa Jr WL, Diniz AL, Ribeiro HSC. Avanços no tratamento cirúrgico das metástases hepáticas colorretais. Rev Assoc Med Bras 2011;57(2):220-7..

In population studies, the frequency of synchronous liver metastases from colorectal cancer CLM varies from 14.5 to 24%88. Manfredi S, Lepage C, Hatem C, Coatmeur O, Faivre J, Bouvier AM. Epidemiology and management of liver metastases from colorectal cancer. Ann Surg 2006;244(2):254-9.,1212. Pawlik TM, Shulick R, Chot M. Expanding criteria for resectability of colorectal liver metastases. Oncologist 2008;13(1):51-64.,1414. Ghiringhelli F, Hennequin A, Drouillard A, Lepage C, Faivre J, Bouvier AM. Epidemiology and prognosis of synchronous and metachronous colon cancer metastases: A French population-based study. Dig Liver Dis 2014;46(9):854-8.,1818. Leporrier J, Maurel J, Chiche L, Bara S, Segol P, Launoy G. A population-based study of the incidence, management and prognosis of hepatic metastases from colorectal cancer. Br J Surg 2006;93(4):465-74.,1919. Hackl C, Gerken M, Loss M, Klinkhammer-Schalke M, Piso P, Schlitt HJ. A population-based analysis on the rate and surgical management of colorectal liver metastases in Southern Germany. Int J Colorectal Dis 2011;26(11):1475-81.,2020. Kune GA, Kune S, Field B, Wgite R, Brough W, Schellemberger R, et al. Survival in patients with large-bowel cancer. A population-based investigation from the Melbourne Colorectal Cancer Study. Dis Colon Rectum 1990;33(11):938-46.,2121. Alley PG, McNee RK. Colorectal cancer in Auckland 1981-1982: patients with liver metastases. N Z Med J 1985;98(785):697-9.. In a French population-based study with 24 years of follow-up of patients diagnosed with CRC, there was stability in the diagnosis of synchronous CLM during the period with crude incidence calculated at 11.3/100,000 for men and 6.9/100,000 for women, age-adjusted incidence at 7.6/100,000 and 3.7/100,000 respectively88. Manfredi S, Lepage C, Hatem C, Coatmeur O, Faivre J, Bouvier AM. Epidemiology and management of liver metastases from colorectal cancer. Ann Surg 2006;244(2):254-9..

The frequency of metachronous CLM is highly variable in the literature, arising from database differences and diversity of definitions. In prospective and retrospective studies of referral centers, this rate reaches 35%2222. Bengmark S, Hafströn L. The natural history of primary and secondary malignant tumor of the liver. The prognosis for patients with hepatic metastases from colonic and rectal carcinoma by laparotomy. Cancer 1969;23(1):198-202.,2323. Thomasset SC, Dennison AR, Metcalfe MS, Steward WP, Garcea G. Changing trends in the presentation of colorectal liver metastases in a single hepatobiliary tertiary referral centre over fourteen years. Eur J Surg Oncol 2013;39(11):1243-7.,2424. Taylor I, Mullee MA, Campbell MJ. Prognostic index for the development of liver metastases in patients with colorectal cancer. Br J Surg 1990;77(5):499-501.. In observational prospective studies and population studies, this frequency is lower, ranging from 5.7 to 16.3%88. Manfredi S, Lepage C, Hatem C, Coatmeur O, Faivre J, Bouvier AM. Epidemiology and management of liver metastases from colorectal cancer. Ann Surg 2006;244(2):254-9.,1414. Ghiringhelli F, Hennequin A, Drouillard A, Lepage C, Faivre J, Bouvier AM. Epidemiology and prognosis of synchronous and metachronous colon cancer metastases: A French population-based study. Dig Liver Dis 2014;46(9):854-8.,1818. Leporrier J, Maurel J, Chiche L, Bara S, Segol P, Launoy G. A population-based study of the incidence, management and prognosis of hepatic metastases from colorectal cancer. Br J Surg 2006;93(4):465-74.,1919. Hackl C, Gerken M, Loss M, Klinkhammer-Schalke M, Piso P, Schlitt HJ. A population-based analysis on the rate and surgical management of colorectal liver metastases in Southern Germany. Int J Colorectal Dis 2011;26(11):1475-81.,2323. Thomasset SC, Dennison AR, Metcalfe MS, Steward WP, Garcea G. Changing trends in the presentation of colorectal liver metastases in a single hepatobiliary tertiary referral centre over fourteen years. Eur J Surg Oncol 2013;39(11):1243-7.. A majority of CLM occurs in the first three years88. Manfredi S, Lepage C, Hatem C, Coatmeur O, Faivre J, Bouvier AM. Epidemiology and management of liver metastases from colorectal cancer. Ann Surg 2006;244(2):254-9.,1414. Ghiringhelli F, Hennequin A, Drouillard A, Lepage C, Faivre J, Bouvier AM. Epidemiology and prognosis of synchronous and metachronous colon cancer metastases: A French population-based study. Dig Liver Dis 2014;46(9):854-8.,1616. Pugh S, Fuller A, Rose P, Perera-Salazar R, Mellor J, George S, et al. What is the true incidence of metachronous colorectal liver metástases? Evidence from the UK FACS (follow-up after colorectal surgery) trial. Gut (Medical Abstracts) 2012;61 Suppl 2:A24.,1818. Leporrier J, Maurel J, Chiche L, Bara S, Segol P, Launoy G. A population-based study of the incidence, management and prognosis of hepatic metastases from colorectal cancer. Br J Surg 2006;93(4):465-74.,1919. Hackl C, Gerken M, Loss M, Klinkhammer-Schalke M, Piso P, Schlitt HJ. A population-based analysis on the rate and surgical management of colorectal liver metastases in Southern Germany. Int J Colorectal Dis 2011;26(11):1475-81.. The incidence of CLM is approximately 4.3% at one year, 8.7% at two years, 12% at three years and 16.5% at five years after resection88. Manfredi S, Lepage C, Hatem C, Coatmeur O, Faivre J, Bouvier AM. Epidemiology and management of liver metastases from colorectal cancer. Ann Surg 2006;244(2):254-9.,1818. Leporrier J, Maurel J, Chiche L, Bara S, Segol P, Launoy G. A population-based study of the incidence, management and prognosis of hepatic metastases from colorectal cancer. Br J Surg 2006;93(4):465-74..

An interesting point to note is that the incidence of CLM may be lower in patients with chronic liver disease such as steatosis2525. Murono K, Kitayama J, Tsuno NH, Nozawa H, Kawai K, Sunami E, et al. Hepatic steatosis is associated with lower incidence of liver metastasis from colorectal cancer. Int J Colorectal Dis 2013;28(8):1065-72., virus B hepatitis and virus C hepatitis 2626. Li Destri G, Castaing M, Ferlito F, Minutolo V, Di Cataldo A, Puleo S. Rare hepatic metastases of colorectal cancer in livers with symptomatic HBV and HCV hepatitis. Ann Ital Chir 2013;84(3):323-7.,2727. Wang FS, Shao ZG, Zhang JL, Liu YF. Colorectal liver metastases rarely occur in patients with chronic hepatitis virus infection. Hepatogastroenterology 2012;59(117):1390-2.,2828. Qiu HB, Zhang LY, Zeng ZL, Wang ZQ, Luo Hy, Keshari RP, et al. HBV infection decreases risk of liver metastasis in patients with colorectal cancer: A cohort study. World J Gastroenterol 2011;17(6):804-8.. In a meta-analysis of observational studies, there was a lower incidence of CLM (OR=0.26 [0.18 to 0.38]; p<0.0001) in patients with chronic liver disease2929. Augustin G, Bruketa T, Korolija D, Milosevic M. Lower incidence of hepatic metastases of colorectal cancer in patients with chronic liver diseases: meta-analysis. Hepatogastroenterology 2013;60(125):1164-8..

Attention must be paid to the fact that there are no specific Brazilian epidemiological studies to determine the proportion of patients with CRC who develop liver metastases. In addition, the Brazilian National Cancer Institute (INCA) estimates may be underestimated because of underreporting, besides the fact that data are collected only in some reference centers in Brazil, not representing the entire population.

Emphasizing the observation above, a tentative estimate made for the Brazilian population based on the incidence rates supplied by INCA for colorectal cancer in 2014, which is 32,600 new cases/year, one can suppose that around 16,300 (50%) patients have or will have CLM, of which 2,445 to 4,890 patients/year (15 to 30%) will be potential candidates for liver resections.

Various modalities, either isolated or associated, can be used in the treatment of liver metastases. Liver resection showed benefit compared to unresectable patients, with 5-year overall survival of 55.2% versus 19.5% and a median overall survival of 65.3 months versus 26.7 months, respectively3030. Kopetz S, Chang GJ, Overman MJ, Eng C, Sargent DJ, Larson DW, et al. Improved survival in metastatic colorectal cancer is associated with adotion of hepatic resection and improved chemotherapy. J Clin Oncol 2009;27(22):3677-83.. Unfortunately, recurrence rates after surgery can reach up to 70% of cases3131. Pedersen IK, Burcharth F, Roikjaer O, Baden H. Resection of liver metastases from colorectal cancer. Indications and results. Dis Colon Rectum 1994;37(11):1078-82.,3232. Nordlinger B, Sorbye H, Glimelius B, Poston GJ, Schlag PM, Rougier P, et al. Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial. Lancet 2008;371(9617):1007-16..

Looking at the same resectable metastases, a study by the European Organization for Research and Treatment of Cancer (EORTC) evaluated the role of chemotherapy with perioperative FOLFOX4 regimen. This study showed an absolute increase in progression-free survival of 8.1% (33.2% vs. 42.4%, HR: 0.77, p=0.041) in eligible patients, with a greater number of complications for the group submitted to chemotherapy3232. Nordlinger B, Sorbye H, Glimelius B, Poston GJ, Schlag PM, Rougier P, et al. Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial. Lancet 2008;371(9617):1007-16..

Other studies had the aim to show the benefit of adjuvant chemotherapy after resection. A meta-analysis encompassing three randomized clinical studies confirmed a gain in progression-free survival and disease-free survival, but benefit in overall survival was not reached3333. Ciliberto D, Prati U, Roveda L, Barbieri V, Staropoli N, Abbruzzese A, et al. Role of systemic chemotherapy in the management of resected or resectable colorectal liver metastases: a systematic review and meta-analysis of randomized controlled trials. Oncol Rep 2012;27(6):1849-56..

However, in the setting of unresectable metastatic disease, chemotherapy has an unquestionable role. Studies have evaluated its role (without monoclonal antibody) and found a conversion rate for resectable tumors of approximately 13.5%3434. Adam R, Avisar E, Ariche A, Giachetti S, Azoulay D, Castaing D, et al. Five-year survival following hepatic resection after neoadjuvant therapy for nonresectable colorectal. Ann Surg Oncol 2001;8(4):347-53.. Additionally, in tumors that became resectable, the 5-year survival was between 23% and 35%3434. Adam R, Avisar E, Ariche A, Giachetti S, Azoulay D, Castaing D, et al. Five-year survival following hepatic resection after neoadjuvant therapy for nonresectable colorectal. Ann Surg Oncol 2001;8(4):347-53.,3535. Adam R, Delvart V, Pascal G, Valeanu A, Castaing D, Azoulay D, et al. Rescue surgery for unresectable colorectal liver metastases downstaged by chemotherapy. Ann Surg 2004; 240(4):644-658.,3636. Ardito F, Vellone M, Cassano A, De Rose AM, Pozzo C, Coppola A, et al. Chance of cure following liver resection for initially unresectable colorectal metastases: analysis of actual 5-year survival. J Gastrointest Surg 2013;17(2):352-9., and 10-year survival around 27%3535. Adam R, Delvart V, Pascal G, Valeanu A, Castaing D, Azoulay D, et al. Rescue surgery for unresectable colorectal liver metastases downstaged by chemotherapy. Ann Surg 2004; 240(4):644-658.. When we add more drugs to the chemotherapy regimen, as in the FOLFOXIRI regimen, the conversion rate was increased to 36%, accompanied by median overall survival of 22.6 months3737. Falcone A, Ricci S, Brunetti I, Pfanner E, Allegrini G, Barbara C, et al. Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: the gruppo oncologico nord ovest. J Clin Oncol 2007;25(13):1670-6..

In this same scenario of unresectable metastatic disease, cetuximab was evaluated when associated with the FOLFIRI or FOLFOX regimen. The resectability of liver lesions was achieved in 38% of patients. In addition, in a retrospective analysis of KRAS status, the resection rate increased to 60% in patients with wild-type KRAS treated with cetuximab3838. Folprecht G, Gruenberger T, Bechstein WO, Raab HR, Lordick F, Hartmann JT, et 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(1):38-47.. In another study with only FOLFOX associated with or not with cetuximab, the overall and median 5-year survival was 30% and 24.4 months, respectively, with a complete resection rate of 25.7%. The median survival in patients undergoing complete resection was 46.4 months3939. Ye LC, Liu TS, Ren L, Wei Y, Zhu DX, Zai SY, et al. Randomized controlled trial of cetuximab plus chemotherapy for patients with Kras wild-type unresectable colorectal liver-limited metastases. J Clin Oncol 2013;31(16):1931-8.. Studies with panitumumab showed similar results with median overall survival not yet reached in patients with complete resection4040. Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, BarugelM, et al. Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME Study. J Clin Oncol 2010;28(31): 4697-705.. More recent Phase II studies evaluating the role of targeted therapy, without restricting metastasis sites, showed median overall survival of 25 to 29.9 months4141. Venook AP, Weiser MR, Tepper JE. Colorectal cancer: all hands on deck. Am Soc Clin Oncol Educ Book 2014:83-9,4242. Heinemann V, von Weikersthal LF, Decker T, Kiani A, Vehling-Kaiser U, Al-Batran SE, et al. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial. Lancet Oncol 2014;15(10):1065-75..

Another monoclonal antibody, not taking into account the RAS status, is bevacizumab, an antibody that binds to circulating VEGF-A increasing the efficacy of any cytotoxic active regimen4343. Moertel CG, Fleming TR, Macdonald JS, Haller DG, Laurie JA, Goodman PJ, et al. Levamisole and Fluorouracil for adjuvante therapy of resected colon carcinoma. N Engl J Med 1990;322(6):352-8.. First-line use showed an increase in overall and progression-free survival and response rate when combined with 5FU/leucovorin / irinotecan4444. Wolmark N, Rockette H, Mamounas E, Jones J, Wieand S, Wickerhm, et al. Clinical trial to assess the relative efficacy of fluorouracil and leucovorin, fluorouracil and levamisole, and fluorouracil, leucovorin, and levamisole in patients with Dukes' B and C carcinoma of the colon: results from National Surgical Adjuvant Breast and Bowel Project C-04. J Clin Oncol 1999;17(11):3553-9.,4545. André T, Boni C, Navarro M, Taberno J, Hickish T, Topham C, et al. Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol 2009;27(19):3109-16. or only 5FU/leucovorin4545. André T, Boni C, Navarro M, Taberno J, Hickish T, Topham C, et al. Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol 2009;27(19):3109-16. or capecitabine4646. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology. Colon Cancer (Version 1.2012). http://www.nccn.org/professionals/physician_gls/pdf/colon.pdf. April 2012.
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,4747. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology. Rectal Cancer (Version 1.2012). http://www.nccn.org/professionals/physician_gls/pdf/rectal.pdf. Jan 2012.
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. Combining oxaliplatin also showed an increase in progression-free survival4848. Konopke R, Kersting S, Bergert H, Bloomenthal A, Gastmeier J, Saeger, et al. Contrast-enhanced ultrasonography to detect liver metastases: a prospective trial to compare transcutaneous unenhanced and contrast-enhanced ultrasonography in patients undergoing laparotomy. Int J Colorectal Dis 2007;22(2):201-7.. The combination with FOLFOXIRI showed better progression-free survival and response rate, with one of the longest survival rates that has been reported so far in this scenario4949. Larsen LP, Rosenkilde M, Christensen H, Bang N, Bolvig L, Christiansen T, et al. The value of contrast enhanced ultrasonography in detection of liver metastases from colorectal cancer: a prospective double-blinded study. Eur J Radiol 2007;62(2):302-7..

To understand the impact of liver metastases in patient survival, we can make a non-ideal comparison between the above studies presented and those that evaluated the role of the same treatments in non-metastatic disease, especially in patients with stage III tumors. Survival rates vary from 47% at three years when only surgery is offered5050. Floriani I, Torri V, Rulli E, Garavaglia D, Compagnoni A, Salvolini L, et al. Performance of imaging modalities in diagnosis of liver metastases from colorectal cancer: a systematic review and meta-analysis. J Magn Reson Imaging 2010; 31(1):19-31., 57% at five years when adjuvant chemotherapy with a 5-fluorouracil and leucovorin regimen is added5151. Niekel MC, Bipat S, Stoker J. Diagnostic imaging of colorectal liver metastases with CT, MR imaging, FDG PET, and/or FDG PET/CT: a meta-analysis of prospective studies including patients who have not previously undergone treatment. Radiology 2010; 257(3):674-84., and 72.9% at six years when oxaliplatin is associated with the previous regimen5252. Kamel IR, Fishman EK. Recent advances in CT imaging of liver metastases. Cancer J. 2004; 10(2):104-20..

In a non-ideal comparison, it is concluded that patients with CLM may have their chance of being alive at five years reduced by at least 50%. Therefore, liver metastasis are considered the leading cause of morbimortality in these patients1212. Pawlik TM, Shulick R, Chot M. Expanding criteria for resectability of colorectal liver metastases. Oncologist 2008;13(1):51-64., accounting for at least two-thirds of disease-related deaths33. Abdalla EK, Adam R, Bilchik AJ, Jaeck D, Vauthey JN, Mahvi D. Improving resectability of hepatic colorectal metastases: expert consensus statement. Ann Surg Oncol 2006;13(10):1271-80..

Topic 2 - Diagnosis and staging of CLM

Imaging techniques that allow evaluation of liver metastases include ultrasound (US), computed tomography (CT), magnetic resonance (MRI) and positron emission tomography (FDG-PET)5353. Soyer P, Poccard M, Boudiaf M, Abitbol M, Hamzi L, Panis Y, et al. Detection of hypovascular hepatic metastases at triple-phase helical CT: sensitivity of phases and comparison with surgical and histopathologic findings. Radiology 2004;231(2):413-20.,5454. Schwartz LH, Gandras EJ, Colangelo SM, Ercolani MC, Panicek DM. Prevalence and importance of small hepatic lesions found at CT in patients with cancer. Radiology 1999;210(1):71-4.. The modality of choice is determined by local availability and service experience.

Transabdominal ultrasound

Despite being a method widely available and inexpensive, it exhibits low sensitivity rates and therefore has limited application in the evaluation of CLM.

The overall sensitivity ranges between 50-77%, but it does not exceed 20% in lesions smaller than 1 cm.

Its main disadvantages: 1) operator-dependent method; 2) limited evaluation in obese patients with bowel distension or non-collaborative subjects.

The use of intravenous contrast (microspheres) increases the sensitivity for detection of focal liver lesions in about 20%, with results similar to those of CT with multidetectors5555. Chen L, Zhang J, Zhang L, Bao J, Liu C, Xia Y, et al. Meta-Analysis of Gadoxetic Acid Disodium (Gd-EOB-DTPA)-Enhanced Magnetic Resonance Imaging for the Detection of Liver Metastases. PLoS One 2012;7(11):e48681,5656. Löwenthal D, Zeile M, Lim WY, Wybranski C, Fischbach F, Wieners G, et al. Detection and characterisation of focal liver lesions in colorectal carcinoma patients: comparison of diffusion-weighted and Gd-EOB-DTPA enhanced MR imaging. Eur Radiol 2011;21(4):832-40.. However, this is a recently used technique with limited availability in Brazil.

Computed tomography (CT)

It is a widely available and relatively low-cost method; currently considered a standard technique for tumor staging, response evaluation and follow-up.

The test should be performed in a multidetector-computed tomography (MDCT) with a dynamic study using intravenous iodinated contrast.

The limitations/disadvantages of the technique include exposure to ionizing radiation, risk of anaphylactic reactions to iodinated contrast and renal failure potential.

The main diagnostic limitations are identification and characterization of focal hepatic lesions in livers with fat deposition5757. Shimada K, Isoda H, Hirokawa Y, Arizono S, Shibata T, Togashi H. Comparison of gadolinium-EOB-DTPA-enhanced and diffusion-weighted liver MRI for detection of small hepatic metastases. Eur Radiol 2010;20(11):2690-8.,5858. Koh DM, Collins DJ, Wallace T, Chau I, Riddell AM. Combining diffusion-weighted MRI with Gd-EOB-DTPA-enhanced MRI improves the detection of colorectal liver metastases. Br J Radiol 2011;85(1015):980-9. and of sub-centimeter lesions5959. Gandhi SN, Brown MA, Wong JG, Aguirre DA, Sirlin CB. MR contrast agents for liver imaging: what, when, how. Radiographics 2006;26(6):1621-36.,6060. Hammerstingl R, Huppertz A, Breuer J, Balzer T, Blakeborough A, Carter R, et al. Diagnostic efficacy of gadoxetic acid (Primovist)-enhanced MRI and spiral CT for a therapeutic strategy: comparison with intraoperative and histopathologic findings in focal liver lesions. Eur Radiol 2008;18(3):457-67.,6161. Seo HJ, Kim MJ, Lee JD, Chung WS, Kim YE. Gadoxetate disodium-enhanced magnetic resonance imaging versus contrast-enhanced 18F-fluorodeoxyglucose positron emission tomography/computed tomography for the detection of colorectal liver metastases. Invest Radiol 2011;46(9):548-55..

Magnetic resonance imaging (MRI)

It is the most accurate imaging technique for the detection and characterization of focal liver lesions. However, costs are higher and it has restricted availability. Other limitations include magnetic field exposure and gadolinium use restrictions in patients with renal insufficiency.

The test may be performed using 1.5 or 3 Tesla equipment and the protocol should include sequences weighted in T1, T2, Diffusion (DWI) and volumetric T1 (3D) with dynamic study after contrast.

Dynamic study is usually performed with the administration of an extracellular distribution of gadolinium chelate, a hepatobiliary agent (disodium gadoxetato), that is available for use in Brazil. The hepatobiliary agent increases the detection rate of liver metastases6262. Zech CJ, Korpraphong P, Huppertz A, Denecke T, Kim MJ, Tanomkiat W, et al. Randomized multicentre trial of gadoxetic acid-enhanced MRI versus conventional MRI or CT in the staging of colorectal cancer liver metastases. Br J Sueg 2014;101(6):613-21..

Retrospective studies and recent meta-analyzes have demonstrated the superiority of MRI in the evaluation of liver metastases of colorectal carcinoma: 1) MRI showed superior sensitivity to TC both in analysis per patient (81.1 to 88.2% vs. 74.8 to 83.6%) and in analysis per lesion (80.3 to 86.3% vs. 74.4 to 82.6%); such superiority is related to higher detection of lesions smaller than 1 cm5757. Shimada K, Isoda H, Hirokawa Y, Arizono S, Shibata T, Togashi H. Comparison of gadolinium-EOB-DTPA-enhanced and diffusion-weighted liver MRI for detection of small hepatic metastases. Eur Radiol 2010;20(11):2690-8.,5858. Koh DM, Collins DJ, Wallace T, Chau I, Riddell AM. Combining diffusion-weighted MRI with Gd-EOB-DTPA-enhanced MRI improves the detection of colorectal liver metastases. Br J Radiol 2011;85(1015):980-9.; 2) MRI with conventional study + DWI + hepatobiliary contrast is the most sensitive and specific method for the characterization of LMCRC, especially in lesions smaller than 1 cm (sensitivity 94% and specificity 95%)6363. Erturk SM, Ichikawa T, Fujii H, Yasuda S, Ros PR. PET imaging for evaluation of metastatic colorectal cancer of the liver. Eur J Radiol 2006;58(2):229-35.,6464. Chua SC, Groves AM, Kayani I, Menezes L, Gacinovic S, Du Y, et al. The impact of 18F-FDG PET/CT in patients with liver metastases. Eur J Nucl Med Mol Imaging 2007;34(12):1906-14.,6565. Glazer ES, Beaty K, Abdalla EK, Vauthey JN, Curley SA. Effectiveness of positron emission tomography for predicting chemotherapy response in colorectal cancer liver metastases. Arch Surg 2010;145(4):340-45.; 3) combined use of DWI and dynamic study with disodium gadoxetato significantly increases the diagnostic performance of MRI, with a detection rate higher than the isolated techniques 6464. Chua SC, Groves AM, Kayani I, Menezes L, Gacinovic S, Du Y, et al. The impact of 18F-FDG PET/CT in patients with liver metastases. Eur J Nucl Med Mol Imaging 2007;34(12):1906-14.,6565. Glazer ES, Beaty K, Abdalla EK, Vauthey JN, Curley SA. Effectiveness of positron emission tomography for predicting chemotherapy response in colorectal cancer liver metastases. Arch Surg 2010;145(4):340-45.,6666. Moulton CA, Gu CS, Law CH, Tandan VR, Hart R, Quan D, et al. Effect of PET Before Liver Resection on Surgical Management for Colorectal Adenocarcinoma Metastases - A Randomized Clinical Trial. JAMA 2014;311(18):1863-9.,6767. Cervone A, Sardi A, Conaway GL. Intraoperative ultrasound (IOUS) is essential in the management of metastatic colorectal liver lesions. Am Surg 2000;66(7):611-5.; 4) MRI with hepatobiliary contrast has greater accuracy than FDG-PET/CT in detection of small liver metastases (92% vs. 60%)6868. Scaife CL, Ng CS, Ellis LM, Vauthey JN, Charnsangavej C, Curley SA. Accuracy of preoperative imaging of hepatic tumors with helical computed tomography. Ann Surg Oncol 2006;13(4):542-6..

In a multicenter randomized prospective study, the performance of MRI with hepatobiliary contrast was superior to CT with iodinated contrast and MRI with extracellular gadolinium as first-line method in the initial evaluation of LMCRC6969. Ellsmere J, Kane R, Grinbaum R, Edwards M, Schneider B, Jones D. Intraoperative ultrasonography during planned liver resections: why are we still performing it? Surg Endosc 2007;21(8):1280-3..

Positron emission tomography with fluorine-18 deoxyglucose (FDG-PET)

It displays a very high sensitivity and specificity in the detection of liver metastases, with rates near 95%. Furthermore, it is useful to identify extra-hepatic metastases and local recurrence. However, its application is restricted due to low availability and high cost.

The main diagnostic limitations are in the detection of small pulmonary nodules and small liver metastases after chemotherapy 5757. Shimada K, Isoda H, Hirokawa Y, Arizono S, Shibata T, Togashi H. Comparison of gadolinium-EOB-DTPA-enhanced and diffusion-weighted liver MRI for detection of small hepatic metastases. Eur Radiol 2010;20(11):2690-8.,5858. Koh DM, Collins DJ, Wallace T, Chau I, Riddell AM. Combining diffusion-weighted MRI with Gd-EOB-DTPA-enhanced MRI improves the detection of colorectal liver metastases. Br J Radiol 2011;85(1015):980-9.,6868. Scaife CL, Ng CS, Ellis LM, Vauthey JN, Charnsangavej C, Curley SA. Accuracy of preoperative imaging of hepatic tumors with helical computed tomography. Ann Surg Oncol 2006;13(4):542-6..

Some studies have shown that in patients eligible for surgical resection of MHCR, FDG-PET/CT can identify extra-hepatic sites of metastases undetected by other methods, altering the therapeutic plan7070. Sahani DV, Kalva SP, Tanabe KK, Hayat SM, O`Neill MJ, Halpern EF, et al. Intraoperative US in patients undergoing surgery for liver neoplasms: comparison with MR imaging. Radiology 2004;232(3):810-4.,7171. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000;92(3):205-16.,7272. Chun YS, Vauthey JN, Boonsirikamchai P, Maru DM, Kopetz S, Palavecino M, et al. Association of computed tomography morphologic criteria with pathologic response and survival in patients treated with bevacizumab for colorectal liver metastases. JAMA 2009;302(21):2338-44.. However, in a recent randomized clinical trial there was no significant change observed in surgical intent with the use of FDG-PE /CT compared to isolated MDCT7373. Figueiras RG, Goh V, Padhani AR, Naveira AB, Caamaño AG, Martin CV. The role of functional imaging in colorectal cancer. AJR Am J Roentgenol 2010;195(1):54-66..

Intraoperative ultrasound (IOUS)

IOUS combined with surgical exploration is the gold standard method for detection of liver metastases and often alters the initial surgical plan7474. D'Onofrio M, De Robertis R, Demozzi E, Crosara S, Canestrini S, Pozzi Mucelli R. Liver volumetry: Is imaging reliable?Personal experience and review of the literature. World J Radiol 2014;6(4):62-71..

It is an operator-dependent method and should be performed by a radiologist or surgeon experienced in the technique, using an intraoperative probe (5-12 MHz). In a study of 250 patients with preoperative evaluation performed with helical CT, IOUS detected additional hepatic lesions in 27% of patients7575. Karlo C, Reiner CS, Stolzmann P, Breitenstein S, Marincek B, Weishaupt D, Frauenfelder T. CT- and MRI-based volumetry of resected liver specimen: comparison to intraoperative volume and weight measurements and calculation of conversion factors. Eur J Radiol 2010;75(1): e107-11.. Currently, even with the routine use of MDCT, benefits of IOUS are still observed, with changes to surgery in up to 20% of cases7676. Niehues SM, Unger JK, Malinowski M, Neymeyer J, Hamm B, Stockmann M. Liver volume measurement: reason of the difference between in vivo CT-volumetry and intraoperative ex vivo determination and how to cope it. Eur J Med Res 2010;15(8): 345-50.,7777. Luciani A, Rusko L, Pichon E, Loze B, Deux JF, Laurent A, et al. Automated liver volumetry in orthotopic liver transplantation using multiphase acquisitions on MDCT. Am J Roentgenol 2012;198(6): w568-74..

Evaluation of systemic treatment response

The evaluation of response by imaging methods can be performed based on the following perspectives:

Dimensional criteria

The RECIST guideline criteria (version 1.1) is the most commonly used model for the evaluation of solid tumor response7878. Dello SA, Stoot JH, Van Stiphout RS, Bloemen JG, Wigmore SJ, Dejong CH, et al. Prospective volumetric assessment of the liver on a personal computer by nonradiologists prior to partial hepatectomy. World J Surg 2011;35(2):386-92.

Morphologic criteria

It was proven to be valid in cases of targeted therapy with bevacizumab. However, it was described in a study with high quality MDCT performed in a specialized center, and has yet to be validated in independent studies7979. Ribero D, Chun YS, Vauthey JN. Standardized liver volumetry for portal vein embolization. Semin Intervent Radiol 2008;25(2):104-9.

Functional methods

There is not enough evidence to support the routine use of FDG-PET and other functional techniques such as MRI with diffusion in CLM response evaluation8080. Jones RP, Vauthey JN, Adam R, Rees M, Berry D, Jackson R, et al. Effect of specialist decision-making on treatment strategies for colorectal liver metastases. Br J Surg. 2012;99(11):1263-9..

Topic 3 - Definition of respectability

How to estimate the mass/function of the future liver remnant

Liver volumetry

The literature shows overlapping results in terms of residual liver mass estimate when compared to tomography and magnetic resonance. Ultrasonography has limitations inherented to the method, such as the interobserver variability. CT and MRI have shown similar results, but there are many more studies with CT, with further validated results8181. Shah A, Alberts S, Adam R. Accomplishments in 2007 in the Management of Curable Metastatic Colorectal Cancer. Gastrointestinal Cancer Research 2008;2(3):S13-8.. Emphasis should be made to the correlation with volume measured in imaging and surgical weight of the resected liver, as it appears that both methods underestimate this result. The calculation of hepatic volume by CT and MRI is accurate and recommended for surgical planning, with similar results, using different correction factors8282. Pawlik TM, Scoggins CR, Zorzi D, Abdalla EK, Adres A, Eng C, et al. Effect of surgical margin status on survival and site of recurrence after hepatic resection for colorectal metastases. Ann Surg 2005;241(5):715-24.. CT - correction factor: 0.85; MRI - correction factor: 0.78. The main cause of discrepancy between liver volume calculated by CT and ex-vivo volume is blood perfusion and should be considered an overestimation in the order of 13%8383. Are C, Gonen M, Zazzali K, Dematteo RP, Jarnagin WR, Fong Y, et al. The impact of margins on outcome after hepatic resection for colorectal metastasis. Ann Surg 2007;246(2):295-300.. Hepatic volume by CT performed manually or automatically correlates strongly with actual liver volume. The automated way is faster8484. De Haas RJ, Wicherts DA, Flores E, Azoulay D,Castaing D, Adam R. Resection by necessity for colorectal lier metastases. Is it still a contraindication to surgery? Ann Surg 2008;248(4):626-37.. Open and free software programs can be used by the surgeon to calculate the hepatic volume by CT with similar results to those obtained by the radiologist using dedicated software at workstations8585. Cook EJ, Welsh FK, Chandrakumaran K, John TG, Rees M. Resection of colorectal liver metastases in the elderly: does age matter? Colorectal Dis 2012;14(10):1210-6..

Importantly, the estimates are only based on percentage of liver volume and are subject to limitation and should be viewed critically, especially in patients with hepatic steatosis/obesity and long courses of chemotherapy in the past. Some formulas have been developed and validated in search of greater security and should be used with caution especially in patients after portal vein embolization with modest growth8686. Frankel TL, D'Angelica TL. Hepatic resection for colorectal metastases. J Surg Oncol 2014;109(1):2-7..

Anatomic, biological and clinical criteria of resectability

Resectability should be defined by an experienced surgeon in liver surgery8787. Evrard S. Limits of colorectal liver metastases resectability: how and why to overcome them? Recent Results Cancer Res 2014;203:213-29.. The anatomical resection criteria include: complete resection of the tumor, absence of residual tumor, preserving at least one hepatic vein, homolateral maintenance to the portal pedicle and future live remnant >20%8888. Abulkhir A, Limongelli P, Healey AJ, Damrah O, Tait P, Jackson J, et al. Preoperative portal vein embolization for major liver resection: a meta-analysis. Ann Surg 2008;247(1):49-57.. The recommended minimum margin at the time of resection is the macroscopic free margin. Positive microscopic margin can be accepted as an adverse finding in the postoperative period, but should not be offered as an option if imaging exams suggest that result8989. May BJ, Talenfeld AD, Madoff DC. Update on portal vein embolization: evidence-based outcomes, controversies, and novel strategies. J Vasc Interv Radiol 2013;24(2):241-54.,9090. Zorzi D, Chun YS, Madoff DC, Abdalla EK, Vauthey JN. Chemotherapy with bevacizumab does not affect liver regeneration after portal vein embolization in the treatment of colorectal liver metastases. Ann Surg Oncol 2008;15(10): 2765-72.. R1 surgery offers survival similar to R0 resection in selected studies but it is still controversial9191. Chua TC, Liauw W, Chu F, Morris DL. Summary outcomes of two-stage resection for advanced colorectal liver metastases. J Surg Oncol. 2013;107(2):211-6..

A careful clinical evaluation should precede any liver surgery, particularly in patients with many comorbidities or the elderly. Note that resections in elderly patients over 70 years had similar results to those under 70 years old, with higher morbimortality in the first 90 days9292. Lam VW, Laurence JM, Johnston E, Hollands MJ, Pleass HC, Richardson AJ. A systematic review of two-stage hepatectomy in patients with initially unresectable colorectal liver metastases. HPB (Oxford) 2013;15(7):483-91.. There are no studies that define the biological and clinical factors that represent criteria for resectability, but they are important prognostic factors and should be taken into consideration. They are: KRAS, NRAS, BRAF, CA 19-9, CEA, response to chemotherapy, number, size and location of metastases, synchronous or metachronous disease, presence of extrahepatic lesions, neutrophil-to-lymphocyte ratio, hypoechoic lesion on ultrasound, hTERT expression, disease-free interval, surgical margins, repeated resections9393. Jaeck D, Pessaux P. Bilobar colorectal liver metastases: treatment options. Surg Oncol Clin N Am 2008;17(3):553-68.,9494. Karoui M, Vigano L, Goyer P, Ferrero A, Luciani A, Aglietta M, et al. Combined first-stage hepatectomy and colorectal resection in a two-stage hepatectomy strategy for bilobar synchronous liver metastases. Br J Surg 2010;97(9):1354-62.

Strategies to increase respectability

Preoperative portal vein embolization (PPVE)

Percutaneous PPVE increases the contralateral lobe with low complication rate and virtually no mortality for the procedure. The hepatectomy should be performed within three to four weeks after the embolization procedure9595. Muratore A, Zimmitti G, Ribero D, Mellano A, Viganò L, Capussotti L. Chemotherapy between the first and second stages of a two-stage hepatectomy for colorectal liver metastases: should we routinely recommend it? Ann Surg Oncol 2012;19(4):1310-5.. Percutaneous PPVE should be indicated before hepatectomy when the surgical plan entails the removal of more than four liver segments and when future liver remnant (FLR) is: <20% in patients with normal liver; <30% in post-chemotherapy patients and <40% in cirrhotic patients1313. Lupinacci RM, Coelho FF, Perini MV, Lobo EJ, Ferreira FG, Szutan LA, et al. Current management of liver metastases from colorectal cancer: recommendations of the São Paulo Liver Club. Rev Col Bras Cir 2013;40(3): 251-60.,9696. Nadalin S, Capobianco I, Li J, Girotti P, Königsrainer I, Königsrainer A. Indications and limits for associating liver partition and portal vein ligation for staged hepatectomy (ALPPS). Lessons Learned from 15 cases at a single centre. Z Gastroenterol 2014;52(1):35-42.. Chemotherapy and anti-angiogenic inhibitors do not affect liver regeneration after portal vein embolization, but should be discontinued six weeks before the embolization procedure9797. Alvarez FA, Ardilles V, Sanchez Claria R, Pekolj J, De Santibañes E. Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS): tips and tricks. J Gastrointest Surg 2013 Apr;17(4):814-21.. Even after PPVE, there is the occurrence of transient liver failure in about 2.5% of cases and acute liver failure in 1% of cases of major hepatectomies for colorectal cancer metastases. PPVE does not guarantee resectability, as 15% of patients fail to be operated on, in most cases due to the progression of neoplastic disease or inappropriate FLR growth9595. Muratore A, Zimmitti G, Ribero D, Mellano A, Viganò L, Capussotti L. Chemotherapy between the first and second stages of a two-stage hepatectomy for colorectal liver metastases: should we routinely recommend it? Ann Surg Oncol 2012;19(4):1310-5..

Two-stage hepatectomy

The indication of hepatectomy in two stages is uncommon and should be considered in initially unresectable patients with bilobar metastases, in whom resection at one time was not feasible because of insufficient FLR, even with the use of PPVE and ablative therapies. After the first stage of resection, 25% of patients will fail to reach the second stage due to disease progression in most cases. The second stage has twice the morbimortality of the first stage. Patients who complete the two stages may have similar survival to those who undergo just a single resection in their treatment9898. Donatti M, Stavrou GA, Oldhafer KJ. Current position of ALPPS in the surgical landscape of CRLM treatment proposals. World J Gastroenterol 2013;19(39):6548-54.,9999. Aloia T, Vauthey JN. Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS): what is gained and what is lost? Ann Surg 2012;256(3): e9.. Some recommendations on the surgical technique should be highlighted as: avoid leaving viable metastasis in FLR after the first stage, using radiofrequency ablation if necessary; avoid dissection of the pedicle in the first stage and mobilization of the lobe to be resected in the second stage100100. Tschuor Ch, Croome KP, Sergeant G, Cano V, Schadde E, Ardiles V, et al. Salvage parenchymal liver transection for patients with insufficient volume increase after portal vein occlusion - an extension of the ALPPS approach. Eur J Surg Oncol 2013;39(11):1230-5; resection of the primary tumor in the first stage in patients with synchronous metastases decreases the number of surgical procedures and facilitates chemotherapy101101. Gauzolino R, Castagnet M, Blanieuil ML, Richer JP. The ALPPS technique for bilateral colorectal metastases: three "variations on a theme". Updat Surg 2013;65(2):141-8.. Chemotherapy in the interval between the first and second stage does not guarantee lower rate of disease progression or a greater chance to complete the second stage102102. Björnsson B, Gasslander T, Sandström P. In situ split of the liver when portal venous embolization fails to induce hypertrophy: a report of two cases. Case Rep Surg 2013;2012:238675..

Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS)

The ALPPS strategy must be performed by teams with experience in complex liver surgery103103. Cavaness KM, Doyle MB, Lin Y, Maynard E, Chapman WC. Using ALPPS to induce rapid liver hypertrophy in a patient with hepatic fibrosis and portal vein thrombosis. J Gastrointest Surg 2013;17(1):207-12.,104104. Oldhafer KJ, Donati M, Jenner RM, Stang A, Stavrou GA. ALPPS for patients with colorectal liver metastases: effective liver hypertrophy, but early tumor recurrence. World J Surg 2014;38(6):1504-9.,105105. Fukami Y, Kurumiya Y, Kobayashi S. Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS): an analysis of tumor activity. Updates Surg 2014;66(3):223-5.,106106. Andriani OC. Long-term results with associating liver partition and portal vein ligation for staged hepatectomy (ALPPS). Ann Surg 2012;256(3):e5.. During the stages of ALPPS, the association with major abdominal surgeries should be avoided104104. Oldhafer KJ, Donati M, Jenner RM, Stang A, Stavrou GA. ALPPS for patients with colorectal liver metastases: effective liver hypertrophy, but early tumor recurrence. World J Surg 2014;38(6):1504-9.. The indication for ALPPS is resection with curative intent of large liver tumors with inadequate FLR volume and as an alternative to the classic strategy in two stages, especially as salvage surgery in patients undergoing portal embolization/ligation with insufficient gain of residual liver mass107107. Schadde E, Ardiles V, Slankamenac K, Tschor C, Sergeant G, Amacker N, et al. ALPPS offers a better chance of complete resection in patients with primarily unresectable liver tumors compared with conventional-staged hepatectomies: results of a multicenter analysis.World J Surg 2014;38(6):1510-9.,108108. Shindoh J, Vauthey JN, Zimmitti G, Curley SA, Huang SY, Mahvash A, et al. Analysis of the Efficacy of Portal Vein Embolization for Patients with Extensive Liver Malignancy and Very Low Future Liver Remnant Volume, Including a Comparison with the Associating Liver Partition with Portal Vein Ligation for Staged Hepatectomy Approach. J Am Coll Surg 2013;217(1):126-34.,109109. Stang A, Fischbach R, Teichmann W, Bokemeyer C, Braumann D. A systematic review on the clinical benefit and role of radiofrequency ablation as treatment of colorectal liver metastases. Eur J Cancer 2009;45(10):1748-56.. ALPPS is a technical option in patients with portal branch thrombosis that precludes percutaneous embolization103103. Cavaness KM, Doyle MB, Lin Y, Maynard E, Chapman WC. Using ALPPS to induce rapid liver hypertrophy in a patient with hepatic fibrosis and portal vein thrombosis. J Gastrointest Surg 2013;17(1):207-12.,110110. Gleisner AL, Choti MA, Assumpcao L, Nathan H, Schulick RD, Pawlik TM. Colorectal liver metastases: recurrence and survival following hepatic resection, radiofrequency ablation, and combined resection-radiofrequency ablation. Arch Surg 2008;143(12): 1204-12.. The potential for tumor progression in the ALPPS strategy is at least the same as portal embolization111111. Eltawil KM, Boame N, Mimeault R, Shabana W, Balaa FK, Jonker DJ, et al. Patterns of recurrence following selective intraoperative radiofrequency ablation as an adjunct to hepatic resection for colorectal liver metastases. J Surg Oncol. 2014;110(6):734-8.,112112. Lieu CH, Renfro LA, de Gramont A, Meyers JP, Maughan TS, Seymour MT, et al. Association of Age With Survival in Patients With Metastatic Colorectal Cancer: Analysis From the ARCAD Clinical Trials Program. J Clin Oncol 2014;32(27):2975-82.,113113. de Haas RJ, Wicherts DA, Salloum C, Andreani P, Sotirov D, Adam R, et al. Long-term outcomes after hepatic resection for colorectal metastases in young patients. Cancer 2010;116(3):647-58.. However, ALPPS results in higher morbimortality rates as well as more severe postoperative complications in both surgical stages103103. Cavaness KM, Doyle MB, Lin Y, Maynard E, Chapman WC. Using ALPPS to induce rapid liver hypertrophy in a patient with hepatic fibrosis and portal vein thrombosis. J Gastrointest Surg 2013;17(1):207-12.,114114. Adam R, Frilling A, Elias D, Laurent C, Ramos E, Capussotti L, et al. Liver resection of colorectal metastases in elderly patients. Br J Surg 2010;97(3):366-76.,115115. Matsuda A, Matsumoto S, Seya T, Matsutani T, Kishi T, Yokoi K, et al. Does postoperative complication have a negative impact on long-term outcomes following hepatic resection for colorectal liver metastasis?: a meta-analysis. Ann Surg Oncol 2013;20(8):2485-92.. Hypertrophy of the residual liver provided by ALPPS (±75%) is similar to percutaneous portal embolization that extends to segment IV, and is significantly superior to isolated right portal embolization/ligation115115. Matsuda A, Matsumoto S, Seya T, Matsutani T, Kishi T, Yokoi K, et al. Does postoperative complication have a negative impact on long-term outcomes following hepatic resection for colorectal liver metastasis?: a meta-analysis. Ann Surg Oncol 2013;20(8):2485-92..

Radiofrequency associated with resection

Radiofrequency ablation (RFA) is no substitute for liver resection in the treatment of colorectal liver metastases, even in tumors smaller than 3 cm116116. Kornprat P, Jarnagin WR, Gonen M, DeMatteo RP, Fong Y, Blumgart LH, et al. Outcome after hepatectomy for multiple (four or more) colorectal metastases in the era of effective chemotherapy. Ann Surg Oncol 2007;14(3):1151-60.. The indication of RFA associated with hepatic resection is rare, but its use occurs in 25% of patients who require repeated hepatectomy in the course of their treatment, and is associated with increased intrahepatic recurrence117117. Saiura A, Yamamoto J, Hasegawa K, Koga R, Sakamoto Y, Hata S, et al. Liver resection for multiple colorectal liver metastases with surgery up-front approach: bi-institutional analysis of 736 consecutive cases. World J Surg 2012;36(9):2171-8.. In patients with bilobar metastases where resection was indicated in combination with RFA, recurrence was similar in the ablation site, in wedge resection margin and segmental resection margin. Resection associated with RFA of more than 10 lesions is associated with shorter time to recurrence118118. Kanas GP, Taylor A, Primrose JN, Langeberg WJ, Kelsh MA, Mowat FS, et al. Survival after liver resection in metastatic colorectal cancer: review and meta-analysis of prognostic factors. Clin Epediomol 2012;4:283-301.. One should always seek an ablation area that provides a minimum margin of 1 cm beyond the tumor. Its ideal use is for tumors up to 3 cm in surgery, where resection is not viable and/or patients without performance status for surgery and when percutaneous portal vein is preferable.

Topic 4 - Clinical, pathological and molecular prognostic factors in treatment definition

There are clinical, pathological and molecular factors that can help estimate the prognosis of patients with LMCRC who undergo hepatectomy. These factors can be considered individually or in association with clinical risk scores. They are useful to understand the potential benefits and risks of recurrence, but should not be used to contraindicate surgical resection. Some prognostic factors such as margin, postoperative complications and pathological response to chemotherapy can only help estimate the benefit or risk after surgery.

Age and postoperative complications

A study of 20,023 stage IV patients recruited in a randomized clinical trial (RCT) carried out by the ARCAD Clinical Trials Program database showed that younger and elderly patients had worse overall survival (OS) and progression-free survival (PFS)119119. Viganò L, Capussotti L, Lapointe R, Barroso E, Hubert C, Giuliante F, et al. Early recurrence after liver resection for colorectal metastases: risk factors, prognosis, and treatment. A LiverMetSurvey-based study of 6,025 patients. Ann Surg Oncol 2014;21(40):1276-86.. However, this study only analyzed patients treated with first-line palliative chemotherapy without analyzing the subgroup of patients undergoing resection of liver metastases.

In a retrospective study involving 806 patients undergoing hepatectomy in a single French center, 7% of patients had ≤40 years. Multivariate analysis showed that age ≤40 years was an independent prognostic factor associated with worse PFS120120. Fong Y, Fortner J, Sun RL, Brennan MF, Blumgart LH. Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: analysis of 1001 consecutive cases. Ann Surg 1999;230(30):309-18..

In the Livermet Survey study with 7,764 patients, 20.9% were aged ≥70 years. Mortality at 60 days for patients ≥70 years was 3.8% vs. 1.6% for younger patients (p<0.001) and 3-year OS was 57.1% vs. 60.2% (p<0.001) respectively121121. Iwatsuki S, Dvorchik I, Madariaga JR, Marsh JW, Dodson F, Bonham AC, et al. Hepatic resection for metastatic colorectal adenocarcinoma: a proposal of a prognostic scoring system. J Am Coll Surg 1999;189(3):291-9.. Therefore, resection of liver metastases in older patients has similar results to younger patients, with acceptable mortality.

A meta-analysis of four studies with 2,280 patients showed decreased 5-year DFS (OR 1.98) and OS (OR 1.68) for patients who had postoperative complications122122. Nordlinger B, Guiguet M, Vaillant JC, Balladur P, Boudjema K, Bachellier P, et al. Surgical resection of colorectal carcinoma metastases to the liver. A prognostic scoring system to improve case selection, based on 1568 patients. Association Française de Chirurgie. Cancer 1996;77(7):1254-62..

Multiple liver metastases

The Memorial Sloan Kettering Cancer Center analyzed its database of patients who underwent resection of liver metastases between 1998 and 2002, and from a total of 584 patients, 98 (17%) had four or more liver metastases123123. Reissfelder C, Rahbari NN, Koch M, Ulrich A, Pfeilschifter I, Waltert A, et al. Validation of prognostic scoring systems for patients undergoing resection of colorectal cancer liver metastases. Ann Surg Oncol. 2009;16(12):3279-88.. In this group of patients, median OS was 41 months and 5-year OS was 33%. However, median DFS was 14 months, 3-year and 5 year DFS were 12% and 0%, confirming the high risk of recurrence for patients with four or more liver metastases.

A retrospective Japanese study with 736 patients divided the patients into three groups: group A with 1-3 metastases (n = 493 patients), group B with 4-7 metastases (n=141) and group C with eight or more metastases (n=102)124124. Zakaria S, Donohue JH, Que FG, Farnell MB, Schleck CD, Ilstrup DM, et al. Hepatic resection for colorectal metastases: value for risk scoring systems? Ann Surg 2007;246(2):183-91.. OS at five years was 56% in group A, 41% in group B and 33% in group C. However, 5-year RFS was 29% for group A, 12% for group B and 1.7% for group C.

Meta-analysis of prognostic factors

A meta-analysis of survival after liver resection for metastatic colorectal cancer demonstrated a modest predictive relationship with survival; however, seven prognostic factors were significant: positive lymph node in the primary tumor, CEA level, extrahepatic disease, tumor grade, positive margins, more than one liver metastasis and tumor diameter greater than three centimeters125125. Kattan MW, Gönen M, Jarnagin WR, DeMatteo R, D'Angelica M, Weiser M, et al. A nomogram for predicting disease-specific survival after hepatic resection for metastatic colorectal cancer. Ann Surg 2008;247(2):282-7.. Pooled effect calculated for these seven prognostic factors ranged from 1.52 to 2.02.

Early relapse in less than six months

In a retrospective series of the Livermet Survey with 6,025 patients, 2,734 (45.4%) had recurrence, of which 639 (10.6%) had early recurrence126126. Reddy SK, Kattan MW, Yu C, Ceppa EP, de la Fuente SG, Fong Y, et al. Evaluation of peri-operative chemotherapy using a prognostic nomogram for survival after resection of colorectal liver metastases. HPB 2009;11(7):592-9.. OS at five years was 26.9% for patients with early recurrence vs. 49.4% (p<0.0001) for those who did not have it. Multivariate analysis demonstrated that the prognostic factors associated with early recurrence were: T3-4 tumors, synchronous metastases, more than three metastases, positive microscopic margin (R1 resection) and the use of radiofrequency ablation (RFA).

Clinical risk scores

Clinical risk scores and nomograms are intended to estimate the benefit of liver resection correlated with prognostic factors of survival 127127. Adam R, Wicherts DA, de Haas RJ, Aloia T, Lévi F, Paule B, et al. Complete pathologic response after preoperative chemotherapy for colorectal liver metastases: myth or reality? J Clin Oncol 2008;26(10):1635-41.,128128. Blazer DG 3rd, Kishi Y, Maru DM, Kopetz S, Chun YS, Overman MJ, et al. Pathologic response to preoperative chemotherapy: a new outcome end point after resection of hepatic colorectal metastases. J Clin Oncol 2008;26(33):5344-51.,129129. Figueras J, Burdio F, Ramos E, Torras J, Llado L, Lopez-Ben S, et al. Effect of subcentimeter nonpositive resection margin on hepatic recurrence in patients undergoing hepatectomy for colorectal liver metastases. Evidences from 663 liver resections. Ann Oncol 2007;18(7):1190-5.,130130. Herman P, Pinheiro RS, Mello ES, Lai Q, Lupinacci RM, Perini MV, et al. Surgical margin size in hepatic resections for colorectal metastasis: impact on recurrence and survival. Arq Bras Cir Dig 2013;26(4):309-14.,131131. Dhir M, Lyden ER, Wang A, Smith LM, Ullrich F, Are C. Influence of margins on overall survival after hepatic resection for colorectal metastasis: a meta-analysis. Ann Surg 2011;254(2):234-42.,132132. Hamady ZZ, Lodge JP, Welsh FK, Toogood GJ, White A, John T, et al. One-millimeter cancer-free margin is curative for colorectal liver metastases: a propensity score case-match approach. Ann Surg 2014;259(3):543-8.,133133. Douillard JY, Oliner KS, Siena S, Tabernero J, Burkes R, Barugel M, et al. Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med 2013;369(11):1023-34.. For example, Fong´s liver score criteria are node-positive primary tumors, DFS less than 12 months, more than one node, metastasis larger than five centimeters and CEA above 200 ng/mL127127. Adam R, Wicherts DA, de Haas RJ, Aloia T, Lévi F, Paule B, et al. Complete pathologic response after preoperative chemotherapy for colorectal liver metastases: myth or reality? J Clin Oncol 2008;26(10):1635-41.. The presence or absence of each of these factors leads to a score from 0 to 5, which correlated with with 5-year OS. Most clinical risk scores are rarely used and the lack of external validation of these risk calculations prevent their use in selecting patients eligible for liver resection.

Pathological response to preoperative chemotherapy

Retrospective studies demonstrate that pathological response to preoperative chemotherapy, with variable definitions of response from one study to another, correlate with improved OS134134. Douillard JY, Tabernero J, Siena S, Peeters M, Koukakis R, Terwey JH, et al. Survival outcomes in patients (pts) with KRAS/NRAS (RAS) wild-type (WT) metastatic colorectal cancer (mCRC) and non-liver-limited disease (non-LLD): Data from the PRIME study. J Clin Oncol (Meeting Abstracts) 2014;32 Suppl 15:3550.,135135. Ciardiello F, Lenz HJ, Kohne CH, Heinemann V, Tejpar S, Melezinek I, et al. Treatment outcome according to tumor RAS mutation status in CRYSTAL study patients with metastatic colorectal cancer (mCRC) randomized to FOLFIRI with/without cetuximab. J Clin Oncol (Meeting Abstracts) 2014;32: Suppl 15:3506..

Resection margins

Several retrospective studies demonstrate that positive margins are associated with increased risk of recurrence in the surgical margin, but that complete resection and not the millimeter size of the margin is what is more important 8989. May BJ, Talenfeld AD, Madoff DC. Update on portal vein embolization: evidence-based outcomes, controversies, and novel strategies. J Vasc Interv Radiol 2013;24(2):241-54.,9191. Chua TC, Liauw W, Chu F, Morris DL. Summary outcomes of two-stage resection for advanced colorectal liver metastases. J Surg Oncol. 2013;107(2):211-6.,136136. Van Cutsem E, Köhne CH, Láng I, Folprecht G, Nowacki MP, Cascinu S, et al. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol 2011;29(15):2011-9.,137137. Yaeger R, Cercek A, Chou JF, Sylvester BE, Kemeny NE, Hechtman JF, et al. BRAF mutation predicts for poor outcomes after metastasectomy in patients with metastatic colorectal cancer. Cancer 2014;120(15):2316-24.. A meta-analysis of 18 studies with 4,821 patients showed that negative margins ≥1 cm are superior to negative margins <1 cm in 5-year OS (46% vs. 38%, p=0.009)138138. Baas JM, Krens LL, Guchelaar HJ, Morreau H, Gelderblom H. Concordance of predictive markers for EGFR inhibitors in primary tumors and metastases in colorectal cancer: a review. Oncologist 2011;16(9):1239-49..

In a prospective observational study of 2,715 patients, positive margin was defined as the distance between metastasis and the border of resection less than one millimeter and negative margin as margin more than 1 mm. In this study, DFS at three years in patients with margin greater than 1 mm was significantly superior to that of cases with a shorter margin and there was no additional gain in DFS with margins greater than 1 mm139139. Vakiani E, Janakiraman M, Shen R, Sinha R, Zeng Z, Shia J, et al. Comparative genomic analysis of primary versus metastatic colorectal carcinomas. J Clin Oncol 2012;30(24):2956-62..

KRAS, NRAS and BRAF

KRAS and NRAS are predictors of therapy results with anti-EGFR, but they have a less established role as a prognostic factor in metastatic colorectal cancer 140 , 141 , 142. A retrospective analysis of a study with 202 patients suggests KRAS as a possible prognostic factor after surgery for liver metastases (HR 1.99)134134. Douillard JY, Tabernero J, Siena S, Peeters M, Koukakis R, Terwey JH, et al. Survival outcomes in patients (pts) with KRAS/NRAS (RAS) wild-type (WT) metastatic colorectal cancer (mCRC) and non-liver-limited disease (non-LLD): Data from the PRIME study. J Clin Oncol (Meeting Abstracts) 2014;32 Suppl 15:3550.. However, BRAF is a strong adverse prognostic factor in metastatic colorectal cancer and also post-metastectomy143 , 144.

There is a strong agreement (>90%) in RAS/BRAF results between primary tumor and metastasis and therefore the test can be done in both biopsies of the primary tumor and in metastases biopsies145 ,146.

It is recommended that the report should contain: 1) type of test performed and sensitivity; 2) type of material tested (primary tumor or metastases); 3) type of extraction (macro or laser) and the percentage of tumor represented; 4 ) mutated codon and the type of mutation; 5) cut-off used in the laboratory for the interpretation of the results.

CONCLUSION

Clinical, pathological and molecular prognostic factors with validation were presented to be taken into account in clinical practice.

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  • Financial source: none

Publication Dates

  • Publication in this collection
    Nov-Dec 2015

History

  • Received
    12 May 2015
  • Accepted
    11 Aug 2015
Colégio Brasileiro de Cirurgia Digestiva Av. Brigadeiro Luiz Antonio, 278 - 6° - Salas 10 e 11, 01318-901 São Paulo/SP Brasil, Tel.: (11) 3288-8174/3289-0741 - São Paulo - SP - Brazil
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