Surgical Treatment of Metastases and its Impact on Prognosis in Patients with Metastatic Colorectal Carcinoma

Czech version

Authors: K. Ševčíková ^1,2; V. Ušáková ¹; Z. Bartošová ³; M. Sabol ⁴; M. Ondrušová ^5,6; D. Ondruš ²; S. Špánik ^1,2
Authors‘ workplace: Interná onkologická klinika, Onkologický ústav sv. Alžbety, Bratislava ¹; I. onkologická klinika LF UK a Onkologický ústav sv. Alžbety, Bratislava ²; Oddelenie lekárskej genetiky, Onkologický ústav sv. Alžbety, Bratislava ³; Klinika onkologickej chirurgie LF UK a Onkologický ústav sv. Alžbety, Bratislava ⁴; Ústav experimentálnej onkológie, SAV, Bratislava ⁵; Vysoká škola zdravotníctva a sociálnej práce sv. Alžbety, Bratislava ⁶
Published in: Klin Onkol 2014; 27(1): 38-44
Category: Original Articles

Overview

Background:
Approximately one quarter of patients with colorectal carcinoma (CRC) have distant metastases at initial diagnosis and almost 50% will develop them during the disease course. Only radical surgical resection of metastases improves clinical outcome and offers a chance of long‑term survival. Initially unresectable metastases can become resectable after downsizing with systemic therapy.

Materials and Methods:
Retrospective analysis included 21 patients with metastatic colorectal carcinoma (mCRC) who were treated from 2006 to 2012 and underwent resection/ ablation of metastases. Fourteen patients had resection at initial diagnosis of metastatic disease and seven patients achieved operability of metastases after systemic treatment. The aim of the analysis was to evaluate surgical treatment of metastases and its impact on prognosis in patients with mCRC in correlation with clinical‑ pathological‑ genetic factors.

Results:
The median age of patients was 59 years. Fourteen patients had metastases in the liver, one patient had metastases in the lungs, two patients had combination of hepatic and extrahepatic metastases and four patients had metastases in other regions. During median follow‑up of 47 months, 17 patients experienced disease progression and 13 patients died. Median progression free survival (PFS) after surgical resection/ ablation of metastases was 17 months (95% CI 13.88−20.12), and median overall survival (OS) was 48 months (95% CI 38.77−57.23). KRAS mutation was detected in 47.6% of patients and BRAF mutation in 9.5% of patients. Patients with BRAF mutation had worse PFS (median = 10 months vs 17 months; p = 0.523) and OS (median = 22 months vs 51 months; p = 0.05) compared to patients with BRAF wild‑type. No difference was observed in PFS and OS between the patients with one or more metastatic lesions and between the patients who underwent resection/ ablation of metastases initially or after systemic treatment.

Conclusion:
These data suggest that resection/ ablation of metastases significantly improves prognosis of patients with mCRC and support the notion that mutated BRAF has a strong negative prognostic significance also in the group of patients, who undergo surgical resection/ ablation of metastatic lesions.

Key words:
colorectal cancer – liver metastases – metastasectomy – prognosis – survival

The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.

The Editorial Board declares that the manuscript met the ICMJE “uniform requirements” for biomedical papers.

Submitted:
2. 7. 2013

Accepted:
25. 7. 2013

Sources

1. Ferlay J, Shin HR, Bray F et al (eds). GLOBOCAN 2008 v2.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 10 [monograph on the Internet]. Lyon: International Agency for Research on Cancer; 2010 [cited 2013 Jun 6]. Available from: http:/ / globocan.iarc.fr.

2. Safaei Diba Ch, Pleško I, Hlava P (eds.). Incidencia zhubných nádorov v Slovenskej republike 2007. Národný onkologický register SR. Bratislava: NCZI 2012: 136.

3. Ondrušová M, Mužík J, Hrčka R et al. Do we know the cause of the highest colorectal cancer incidence, the changes in the mortality trends and the clinical stages in the Slovak and Czech Republic, the representatives of the Central European region? Neoplasma 2011; 58(4): 283– 290.

4. Van Cutsem E, Nordlinger B, Cervantes A. ESMO Guidelines Working Group. Advanced colorectal cancer: ESMO Clinical Practice Guidelines for treatment. Ann Oncol 2010; 21 (Suppl 5): v93– v97. doi: 10.1093/ annonc/ mdq222.

5. O‘Conell JB, Maggard MA, Ko CY. Colon Cancer Survival Rates With the New American Joint Committee on Cancer Sixth Edition Staging. J Natl Cancer Inst 2004; 96(19): 1420– 1425.

6. Van Cutsem E, Nordlinger B, Adam R et al. Towards a pan‑ European consensus on the treatment of patients with colorectal liver metastases. Eur J Cancer 2006; 42(14): 2212– 2221.

7. Choti MA, Sitzmann JV, Tiburi MF et al. Trends in long‑term survival following liver resection for hepatic colorectal metastases. Ann Surg 2002; 235(6): 759– 766.

8. Berri RN, Abdalla EK. Curable metastatic colorectal cancer: recommended paradigms. Curr Oncol Rep 2009; 11(3): 200– 208.

9. Adam R, de Haas RJ, Wicherts DA et al. Is hepatic resection justified after chemotherapy in patients with colorectal liver metastases and lymph node involvement? J Clin Oncol 2008; 26(22): 3672– 3680. doi: 10.1200/ JCO.2007.15.7297.

10. nccn.org [homepage on the Internet]. National Comprehensive Cancer Network (NCCN) guidelines [cited 2013 Jun 26]. Available from: www.nccn.org.

11. Carpizo DR, Are C, Jarnagin W et al. Liver resection for metastatic colorectal cancer in patients with concurrent extrahepatic disease: results in 127 patients treated at a single center. Ann Surg Oncol 2009; 16(8): 2138– 2146. doi: 10.1245/ s10434– 009– 0521– 6.

12. Adam R, Delvart V, Pascal G et al. Rescue surgery for unresectable colorectal liver metastases downstaged by chemotherapy: a model to predict long‑term survival. Ann Surg 2004; 240(4): 644– 657.

13. Adam R, Avisar E, Ariche A et al. Five‑year survival following hepatic resection after neoadjuvant therapy for nonresectable colorectal. Ann Surg Oncol 2001; 8(4): 347– 353.

14. Blazer DG 3rd, Kishi Y, Maru DM 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– 5351. doi: 10.1200/ JCO.2008.17.5299.

15. Adam R, Aloia T, Lévi F et al. Hepatic resection after rescue cetuximab treatment for colorectal liver metastases previously refractory to conventional systemic therapy. J Clin Oncol 2007; 25(29): 4593– 4602.

16. Van Cutsem E, Köhne CH, Hitre E et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 2009; 360(14): 1408– 1417. doi: 10.1056/ NEJMoa0805019.

17. Saltz LB, Clarke S, Díaz‑ Rubio E et al. Bevacizumab in combination with oxaliplatin‑based chemotherapy as first‑line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol 2008; 26(12): 2013– 2019. doi: 10.1200/ JCO.2007.14.9930.

18. Folprecht G, Gruenberger T, Bechstein WO 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. doi: 10.1016/ S1470– 2045(09)70330– 4.

19. Bokemeyer C, Bondarenko I, Makhson A et al. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first‑line treatment of metastatic colorectal cancer. J Clin Oncol 2009; 27(5): 663– 671. doi: 10.1200/ JCO.2008.20.8397.

20. Rubbia‑ Brandt L, Audard V, Sartoretti P et al. Severe hepatic sinusoidal obstruction associated with oxaliplatin‑based chemotherapy in patients with metastatic colorectal cancer. Ann Oncol 2004; 15(3): 460– 466.

21. Vauthey JN, Pawlik TM, Ribero D et al. Chemotherapy regimen predicts steatohepatitis and an increase in 90- day mortality after surgery for hepatic colorectal metastases. J Clin Oncol 2006; 24(13): 2065– 2072.

22. Aloia T, Sebagh M, Plasse M et al. Liver histology and surgical outcomes after preoperative chemotherapy with fluorouracil plus oxaliplatin in colorectal cancer liver metastases. J Clin Oncol 2006; 24(31): 4983– 4990.

23. Ward J, Guthrie JA, Sheridan MB et al. Sinusoidal obstructive syndrome diagnosed with superparamagnetic iron oxide‑ enhanced magnetic resonance imaging in patients with chemotherapy‑treated colorectal liver metastases. J Clin Oncol 2008; 26(26): 4304– 4310. doi: 10.1200/ JCO.2008.16.1893.

24. Pawlik TM, Olino K, Gleisner AL et al. Preoperative chemotherapy for colorectal liver metastases: impact on hepatic histology and postoperative outcome. J Gastrointest Surg 2007; 11(7): 860– 868.

25. Hubert C, Fervaille C, Sempoux C et al. Prevalence and clinical relevance of pathological hepatic changes occurring after neoadjuvant chemotherapy for colorectal liver metastases. Surgery 2010; 147(2): 185– 194. doi: 10.1016/ j.surg.2009.01.004.

26. Karoui M, Penna C, Amin‑Hashem M et al. Influence of preoperative chemotherapy on the risk of major hepatectomy for colorectal liver metastases. Ann Surg 2006; 243(1): 1– 7.

27. Soubrane O, Brouquet A, Zalinski S et al. Predicting high grade lesions of sinusoidal obstruction syndrome related to oxaliplatin‑based chemotherapy for colorectal liver metastases: correlation with post‑hepatectomy outcome. Ann Surg 2010; 251(3): 454– 460. doi: 10.1097/ SLA.0b013e3181c79403.

28. Robinson SM, Wilson CH, Burt AD et al. Chemotherapy‑associated liver injury in patients with colorectal liver metastases: a systematic review and meta‑analysis. Ann Surg Oncol 2012; 19(13): 4287– 4299. doi: 10.1245/ s10434– 012– 2438– 8.

29. Kooby DA, Fong Y, Suriawinata A et al. Impact of steatosis on perioperative outcome following hepatic resection. J Gastrointest Surg 2003; 7(8): 1034– 1044.

30. Gruenberger B, Tamandl D, Schueller J et al. Bevacizumab, capecitabine, and oxaliplatin as neoadjuvant therapy for patients with potentially curable metastatic colorectal cancer. J Clin Oncol 2008; 26(11): 1830– 1835. doi: 10.1200/ JCO.2007.13.7679.

31. Okines A, Puerto OD, Cunningham D et al. Surgery with curative‑ intent in patients treated with first‑line chemotherapy plus bevacizumab for metastatic colorectal cancer First BEAT and the randomised phase‑ III NO16966 trial. Br J Cancer 2009; 101(7): 1033– 1038. doi: 10.1038/ sj.bjc.6605259.

32. D‘Angelica M, Kornprat P, Gonen M et al. Lack of evidence for increased operative morbidity after hepatectomy with perioperative use of bevacizumab: a matched case‑ control study. Ann Surg Oncol 2007; 14(2): 759– 765.

33. Reddy SK, Morse MA, Hurwitz HI et al. Addition of bevacizumab to irinotecan‑ and oxaliplatin‑based preoperative chemotherapy regimens does not increase morbidity after resection of colorectal liver metastases. J Am Coll Surg 2008; 206(1): 96– 106.

34. Kesmodel SB, Ellis LM, Lin E et al. Preoperative bevacizumab does not significantly increase postoperative complication rates in patients undergoing hepatic surgery for colorectal cancer liver metastases. J Clin Oncol 2008; 26(32): 5254– 5260. doi: 10.1200/ JCO.2008.17.7857.

35. Tamandl D, Gruenberger B, Klinger M et al. Liver resection remains a safe procedure after neoadjuvant chemotherapy including bevacizumab: a case‑ controlled study. Ann Surg 2010; 252(1): 124– 130. doi: 10.1097/ SLA.0b013e3181deb67f.

36. Wicherts DA, de Haas RJ, Sebagh M et al. Impact of bevacizumab on functional recovery and histology of the liver after resection of colorectal metastases. Br J Surg 2011; 98(3): 399– 407. doi: 10.1002/ bjs.7368.

37. van der Pool AE, Marsman HA, Verheij J et al. Effect of bevacizumab added preoperatively to oxaliplatin on liver injury and complications after resection of colorectal liver metastases. J Surg Oncol 2012; 106(7): 892– 897. doi: 10.1002/ jso.23142.

38. de Reyniès A, Boige V, Milano G et al. KRAS mutation signature in colorectal tumors significantly overlaps with the cetuximab response signature. J Clin Oncol 2008; 26(13): 2228– 2230. doi: 10.1200/ JCO.2007.15.9186.

39. Karapetis CS, Khambata‑ Ford S, Jonker DJ et al. K‑ ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med 2008; 359(17): 1757– 1765. doi: 10.1056/ NEJMoa0804385.

40. Khambata‑ Ford S, Garrett CR, Meropol NJ et al. Expression of epiregulin and amphiregulin and K‑ ras mutation status predict disease control in metastatic colorectal cancer patients treated with cetuximab. J Clin Oncol 2007; 25(22): 3230– 3237.

41. Lièvre A, Bachet JB, Boige V et al. KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J Clin Oncol 2008; 26(3): 374– 379. doi: 10.1200/ JCO.2007.12.5906.

42. Amado RG, Wolf M, Peeters M et al. Wild‑type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol 2008; 26(10): 1626– 1634. doi: 10.1200/ JCO.2007.14.7116.

43. Di Fiore F, Blanchard F, Charbonnier F et al. Clinical relevance of KRAS mutation detection in metastatic colorectal cancer treated by Cetuximab plus chemotherapy. Br J Cancer 2007; 96(8): 1166– 1169.

44. Loupakis F, Ruzzo A, Cremolini C et al. KRAS codon 61, 146 and BRAF mutations predict resistance to cetuximab plus irinotecan in KRAS codon 12 and 13 wild‑type metastatic colorectal cancer. Br J Cancer 2009; 101(4): 715– 721. doi: 10.1038/ sj.bjc.6605177.

45. Richman SD, Seymour MT, Chambers P et al. KRAS and BRAF mutations in advanced colorectal cancer are associated with poor prognosis but do not preclude benefit from oxaliplatin or irinotecan: results from the MRC FOCUS trial. J Clin Oncol 2009; 27(35): 5931– 5937. doi: 10.1200/ JCO.2009.22.4295.

46. Tabernero J, Cervantes A, Rivera F et al. Pharmacogenomic and pharmacoproteomic studies of cetuximab in metastatic colorectal cancer: biomarker analysis of a phase I dose‑escalation study. J Clin Oncol 2010; 28(7): 1181– 1189. doi: 10.1200/ JCO.2009.22.6043.

47. Dahabreh IJ, Terasawa T, Castaldi PJ et al. Systematic review: Anti‑epidermal growth factor receptor treatment effect modification by KRAS mutations in advanced colorectal cancer. Ann Intern Med 2011; 154(1): 37– 49. doi: 10.7326/ 0003– 4819– 154– 1– 201101040– 00006.

48. Tougeron D, Lecomte T, Pagès JC et al. Effect of low‑ frequency KRAS mutations on the response to anti‑EGFR therapy in metastatic colorectal cancer. Ann Oncol 2013; 24(5): 1267– 1273. doi: 10.1093/ annonc/ mds620.

49. Robešová B, Bajerová M, Vašíková A et al. Molecular biological diagnostics of KRAS and BRAF mutations in patients with colorectal cancer – laboratory experience. Klin Onkol 2013; 26(1): 25– 30.

50. Han CB, Li F, Ma JT et al. Concordant KRAS mutations in primary and metastatic colorectal cancer tissue specimens: a meta‑analysis and systematic review. Cancer Invest 2012; 30(10): 741– 747. doi: 10.3109/ 07357907.2012.732159.

51. Bokemeyer C, Kohne C, Rougier P et al. Cetuximab with chemotherapy (CT) as first‑line treatment for metastatic colorectal cancer (mCRC): Analysis of the CRYSTAL and OPUS studies according to KRAS and BRAF mutation status. J Clin Oncol 2010; 28 (Suppl): 3506.

52. Van Cutsem E, Köhne CH, Láng I 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– 2019. doi: 10.1200/ JCO.2010.33.5091.

53. Ogino S, Shima K, Meyerhardt JA et al. Predictive and prognostic roles of BRAF mutation in stage III colon cancer: results from intergroup trial CALGB 89803. Clin Cancer Res 2012; 18(3): 890– 900. doi: 10.1158/ 1078– 0432.CCR‑ 11– 2246.

54. Fernandez FG, Drebin JA, Linehan DC et al. Five‑year survival after resection of hepatic metastases from colorectal cancer in patients screened by positron emission tomography with F‑ 18 fluorodeoxyglucose (FDG‑ PET). Ann Surg 2004; 240(3): 438– 447.

55. Scheele J, Stang R, Altendorf‑ Hofmann A et al. Resection of colorectal liver metastases. World J Surg 1995; 19(1): 59– 71.

56. Steele G Jr, Bleday R, Mayer RJ et al. A prospective evaluation of hepatic resection for colorectal carcinoma metastases to the liver: Gastrointestinal Tumor Study Group Protocol 6584. J Clin Oncol 1991; 9(7): 1105– 1112.

57. Nordlinger B, Guiguet M, Vaillant JC 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– 1262.

58. Yoon SS, Tanabe KK. Multidisciplinary management of metastatic colorectal cancer. Surg Oncol 1998; 7(3– 4): 197– 207.

59. Hughes KS, Simon R, Songhorabodi S et al. Resection of the liver for colorectal carcinoma metastases: a multi‑institutional study of patterns of recurrence. Surgery 1986; 100(2): 278– 284.

60. Jamison RL, Donohue JH, Nagorney DM et al. Hepatic resection for metastatic colorectal cancer results in cure for some patients. Arch Surg 1997; 132(5): 505– 510.

61. Fong Y, Fortner J, Sun RL et al. Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: analysis of 1001 consecutive cases. Ann Surg 1999; 230(3): 309– 318.

62. Iwatsuki S, Dvorchik I, Madariaga JR et al. Hepatic resection for metastatic colorectal adenocarcinoma: a proposal of a prognostic scoring system. J Am Coll Surg 1999; 189(3): 291– 299.

63. Abdalla EK, Vauthey JN, Ellis LM et al. Recurrence and outcomes following hepatic resection, radiofrequency ablation, and combined resection/ ablation for colorectal liver metastases. Ann Surg 2004; 239(6): 818– 825.

64. Wei AC, Greig PD, Grant D et al. Survival after hepatic resection for colorectal metastases: a 10‑year experience. Ann Surg Oncol 2006; 13(5): 668– 676.

65. Simmonds PC, Primrose JN, Colquitt JL et al. Surgical resection of hepatic metastases from colorectal cancer: a systematic review of published studies. Br J Cancer 2006; 94(7): 982– 999.

66. Cummings LC, Payes JD, Cooper GS. Survival after hepatic resection in metastatic colorectal cancer: a population‑based study. Cancer 2007; 109(4): 718– 726.

67. Rees M, Tekkis PP, Welsh FK et al. Evaluation of long‑term survival after hepatic resection for metastatic colorectal cancer: a multifactorial model of 929 patients. Ann Surg 2008; 247(1): 125– 135.

68. Morris EJ, Forman D, Thomas JD et al. Surgical management and outcomes of colorectal cancer liver metastases. Br J Surg 2010; 97(7): 1110– 1118. doi: 10.1002/ bjs.7032.

69. Ablorsu E, Kothaj P. Current role of surgery in treatment of liver metastases from colorectal cancer. Klin Onkol 2006; 19(2): 121– 123.