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Higher Tumor Burden Neutralizes Negative Margin Status in Hepatectomy for Colorectal Cancer Liver Metastasis

  • Hepatobiliary Tumors
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Objective

The aim of this study was to examine if the prognostic significance of margin status in hepatectomy for colorectal cancer liver metastasis (CRLM) varies for different levels of tumor burden because hepatectomy indications for CRLM have been recently expanded to include patients with a higher tumor burden in whom achieving an R0 resection is difficult.

Methods

Clinicopathological variables in an exploration cohort of 290 patients receiving hepatectomy in Japan for CRLM were investigated. R0 resection was defined as a margin width > 0 mm. Tumor burden was assessed using the recently introduced Tumor Burden Score (TBS), which was calculated as TBS2 = (maximum tumor diameter in cm)2 + (number of lesions)2. The principal findings were validated using a cohort from the United States.

Results

R1 resection rates significantly increased as TBS increased: 4/86 (4.7%) in patients with TBS < 3, 29/171 (17.0%) in patients with TBS ≥ 3 and < 9, and 9/33 (27.3%) in patients with TBS ≥ 9 (p < 0.001). R0 resection was significantly superior to R1 resection in patients with TBS ≥ 5; however, this was not the case for TBS ≥ 6, as confirmed by both univariate and multivariate analyses. Furthermore, prehepatectomy chemotherapy was associated with significantly improved survival for patients with TBS ≥ 8. Analysis of the validation cohort yielded similar results.

Conclusions

R0 resection appeared to have a positive impact on prognosis among patients with low tumor burden; however, this was not the case for patients with high tumor burden. As such, systemic treatment, in addition to surgery, may be central to achieving satisfactory outcomes in the latter patient population.

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References

  1. Ekberg H, Tranberg KG, Andersson R, Lundstedt C, Hagerstrand I, Ranstam J, et al. Determinants of survival in liver resection for colorectal secondaries. Br J Surg. 1986;73:727–731.

    Article  CAS  PubMed  Google Scholar 

  2. Shirabe K, Takenaka K, Gion T, Fujiwara Y, Shimada M, Yanaga K, et al. Analysis of prognostic risk factors in hepatic resection for metastatic colorectal carcinoma with special reference to the surgical margin. Br J Surg. 1997;84:1077–1080.

    Article  CAS  PubMed  Google Scholar 

  3. Kokudo N, Miki Y, Sugai S, Yanagisawa A, Kato Y, Sakamoto Y, et al. Genetic and histological assessment of surgical margins in resected liver metastases from colorectal carcinoma. Arch Surg. 2002;137:833–840.

    Article  PubMed  Google Scholar 

  4. Are C, Gonen M, Zazzali K, DeMatteo RP, Jarnagin WR, Fong Y, et al. The impact of margins on outcome after hepatic reseection for colorectal metastasis. Ann Surg. 2007;246:295–300.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Wakai T, Shirai Y, Sakata J, Valera VA, Korita PV, Akazawa K, et al. Appraisal of 1 cm hepatectomy margin for intrahepatic micrometastases in patients with colorectal carcinoma liver metastasis. Ann Surg Oncol. 2008;15:2472–2481.

    Article  PubMed  Google Scholar 

  6. Nuzzo G, Giulante F, Ardito F, Vellone M, Giovannini I, Federico B, et al. Influence of surgical margin on type or recurrence after liver resection for colorectal metastases: a single-center experience. Surgery. 2008;143:384–393.

    Article  PubMed  Google Scholar 

  7. Gomez D, Morris-Stiff G, Wyatt J, Toogood GJ, Lodge JPA, Prasad KR. Surgical technique and systemic inflammation influences long-term disease-free survival following hepatic resection for colorectal metastasis. J Surg Oncol. 2008;98:371–376.

    Article  PubMed  Google Scholar 

  8. Vandeweyer D, Neo EL, Chen JWC, Maddern GJ, Wilson TG, Padbury RTA. Influence of resection margin on survival in hepatic resection for colorectal liver metastases. HPB (Oxford). 2009;11:499–504.

    Article  PubMed Central  Google Scholar 

  9. Nanashima A, Araki M, Tobinaga S, Kunizaki M, Hidaka S, Shibata K, et al. Relationship between period of survival and clinicopathological characteristics in patients with colorectal liver metastasis. Eur J Surg Oncol. 2009;35:504–509.

    Article  CAS  PubMed  Google Scholar 

  10. 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;254:234–242.

    Article  PubMed  Google Scholar 

  11. Tranchart H, Chirica M, Faron M, Balladur P, Lefevre LB, Svrcek M, et al. Prognostic impact of positive surgical margins after resection of colorectal cancer liver metastasis: reappraisal in the era of modern chemotherapy. World J Surg. 2013;37:2647–2654.

    Article  PubMed  Google Scholar 

  12. Andreou A, Aloia TA, Brouquet A, Dickson PV, Zimmitti G, Maru DM, et al. Margin status remains an important determinant of survival after surgical resection of colorectal liver metastases in the era of modern chemotherapy. Ann Surg. 2013;257:1079–1088.

    Article  PubMed  PubMed Central  Google Scholar 

  13. John SKP, Robinson SM, Rehman S, Harrison B, Vallace A, French JJ, et al. Prognostic factors and survival after resection of colorectal liver metastasis in the era of preoperative chemotherapy: an 11-year single-centre study. Dig Surg. 2013;30:293–301.

    Article  CAS  PubMed  Google Scholar 

  14. Liu W, Sun Y, Xing BC. Negative surgical margin improved long-term survival of colorectal cancer liver metastases after hepatic resection: a systematic review and meta-analysis. Int J Colorectal Dis. 2015;30:1365–1373.

    Article  PubMed  Google Scholar 

  15. de Haas RJ, Wicherts DA, Flores E, Azoulay D, Casting D, Adam R. R1 resection by necessity for colorectal liver metastases: is it still a contraindication to surgery? Ann Surg. 2008;248:626–637.

    PubMed  Google Scholar 

  16. Poultsides GA, Schulick RD, Pawlik TM. Hepatic resection for colorectal metastases: the impact of surgical margin status on outcome. HPB (Oxford). 2010;12:43–49.

    Article  Google Scholar 

  17. Truant S, Sequier C, Leteurtre E, Boleslawski E, Elamrani M, Huet G, et al. Tumor biology of colorectal liver metastasis is a more important factor in survival than surgical margin clearance in the era of modern chemotherapy regimens. HPB (Oxford) 2015;17:176–184.

    Article  Google Scholar 

  18. Margonis GA, Sasaki K, Kim Y, Samaha M, Buettner S, Amini N, et al. Tumor biology rather than surgical technique dictates prognosis in colorectal cancer liver metastases. J Gastrointest Surg. 2016;20:1821–1829.

    Article  PubMed  Google Scholar 

  19. Margonis GA, Sasaki K, Andreatos N, Kim Y, Merath K, Wagner D, et al. KRAS mutation status dictates optimal surgical margin width in patients undergoing resection of colorectal liver metastases. Ann Surg Oncol. 2017;24:264–271.

    Article  PubMed  Google Scholar 

  20. Pawlik TM, Scoggins CR, Zorzi D, Abdalla EK, Andres 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;241:715–724.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Bodingbauer M, Tamandl D, Schmid K, Plamk C, Schima W, Gruenberger T. Size of surgical margin does not influence recurrence rates after curative liver resection for colorectal cancer liver metastases. Br J Surg. 2007;94:1133–1138.

    Article  CAS  PubMed  Google Scholar 

  22. Muratore A, Ribero D, Zimmitti G, Mellano A, Lamgella S, Capussotti L. Resection margin and recurrence-free survival after liver resection of colorectal metastases. Ann Surg Oncol. 2010;17:1324–1329.

    Article  PubMed  Google Scholar 

  23. Eveno C, Karoui M, Gayet E, Luciani A, Auriault ML, Kluger MD, et al. Liver resection for colorectal livermetastases with peri-operative chemotherapy: oncological results of R1 resection. HPB (Oxford). 2013;15:359–364.

    Article  Google Scholar 

  24. Tanaka K, Nojiri K, Kumamoto T, Takeda K, Endo I. R1 resection for aggressive or advanced colorectal liver metastases is justified in combination with effective prehepatectomy chemotherapy. Eur J Surg Oncol. 2011;37:336–343.

    Article  CAS  PubMed  Google Scholar 

  25. Sasaki K, Margonis GA, Andreatos N, Wilson A, Weiss M, Wolfgang C, et al. Prognostic impact of margin status in liver resections for colorectal metastases after bevacizumab. Br J Surg. 2017;104:926–935.

    Article  CAS  PubMed  Google Scholar 

  26. Sasaki K, Morioka D, Conci S, Margonis GA, Sawada Y, Ruzzenente A, et al. The Tumor Burden Score: a new “metro-ticket” prognostic tool for colorectal liver metastases based on tumor size and number of tumors. Ann Surg. 2018;267:132–141.

    Article  PubMed  Google Scholar 

  27. Tanaka K, Hiroshima Y, Nakagawa K, Kumamoto T, Nojiri K, Takeda K, et al. Two-stage hepatectomy with effective perioperative chemotherapy does not induce tumor growth or growth factor expression in liver metastases from colorectal cancer. Surgery 2013;153:179–188.

    Article  PubMed  Google Scholar 

  28. Compton CC. Key issue in reporting common cancer specimens: problems in pathologic staging of colon cancer. Arch Pathol Lab Med. 2006;130:318–324.

    PubMed  Google Scholar 

  29. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228–247.

    Article  CAS  PubMed  Google Scholar 

  30. Strasberg SM, Belghiti J, Clavien PA, Gadzijev E, Garden JO, Lau WY, et al. The Brisbane 2000 terminology of liver anatomy and resections. HPB. 2000;2:333–339.

    Article  Google Scholar 

  31. Sasaki K, Margonis GA, Andreatos N, Wilson A, Gani F, Amini N, et al. Pre-hepatectomy carcinoembryonic antigen (CEA) levels among patients undergoing resection of colorectal liver metastases: do CEA levels still have prognostic implications? HPB (Oxford). 2016;18:1000–1009.

    Article  Google Scholar 

  32. Sasaki K, Margonis GA, Wilson A, Kim Y, Buettner S, Andreatos N, et al. Prognostic implication of KRAS status after hepatectomy for colorectal liver metastases varies according to primary colorectal tumor location. Ann Surg Oncol. 2016;23:3736–3743.

    Article  PubMed  Google Scholar 

  33. Sasaki K, Margonis GA, Andreatos N, Zhang XF, Buettner S, Wang J, et al. The prognostic utility of the “Tumor Burden Score” based on preoperative radiographic features of colorectal liver metastases. J Surg Oncol. 2017;116:515–523.

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan

    Masanori Oshi MD, Yu Sawada MD, PhD, Takafumi Kumamoto MD, PhD, Daisuke Morioka MD, PhD, Kuniya Tanaka MD, PhD & Itaru Endo MD, PhD

  2. Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Georgios Antonios Margonis MD, PhD, Nikolaos Andreatos MD, Jin He MD, PhD, Christopher Lee Wolfgang MD, PhD & Matthew John Weiss MD

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  1. Masanori Oshi MD
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  2. Georgios Antonios Margonis MD, PhD
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  6. Takafumi Kumamoto MD, PhD
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Corresponding author

Correspondence to Itaru Endo MD, PhD.

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Electronic supplementary material

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10434_2018_6830_MOESM1_ESM.tif

Supplementary material Fig. 1 Distribution of Tumor Burden Score (TBS). In the exploration (Yokohama) cohort, TBS ranged from 1.1 to 38.0, with a median of 4.4. Values of the 25th, 75th, and 90th percentiles were 2.7, 6.7, and 9.0, respectively. In the validation (Baltimore) cohort, TBS ranged from 1.0 to 21.4, with a median of 3.6. Values of the 25th, 75th, and 90th percentiles were 1.9, 5.1, and 7.3, respectively. Tumor burden was less for this cohort compared with the Yokohama cohort (p < 0.001), probably because it had a larger fraction of patients receiving prehepatectomy chemotherapy. (TIFF 84 kb)

10434_2018_6830_MOESM2_ESM.tif

Supplementary material Fig. 2 Prognostic impact of Tumor Burden Score (TBS) and margin status in Yokohama cohort. TBS clearly stratified long-term survival outcomes with the cut-off values of 3 and 9 in the entire cohort (a). Furthermore, either the disease-free or overall survival rate of patients receiving an R0 resection was significantly superior to that of patients receiving an R1 resection (b). (TIFF 122 kb)

10434_2018_6830_MOESM3_ESM.tif

Supplementary material Fig. 3 Varying impact of margin status in patients with different ranges of Tumor Burden Score (TBS) in the Yokohama cohort. Because the 75th percentile value of TBS was approximately 6, the cohort was repeatedly dichotomized by the TBS value of 6, 7, 8, or 9, respectively. When the cohort was dichotomized by using a TBS cut-off value of 6, 7, 8, or 9, disease-free survival (DFS) and overall survival (OS) were significantly worse in the R1 resection group than the R0 group in patients with TBS less than the cut-off value. By contrast, neither DFS nor OS were different between R1 and R0 groups in patients with TBS greater than the cut-ff. As the TBS cut-off value is increased from 6 to 9, the prognostic benefit of R0 resection gets eradicated (results for TBS cut-off values 8 and 9 are reported in Fig. 1). (TIFF 151 kb)

10434_2018_6830_MOESM4_ESM.tif

Supplementary material Fig. 4 Efficacy of prehepatectomy chemotherapy evaluated in cohorts with different levels of Tumor Burden Score (TBS) in the Yokohama cohort. Regarding the impact of prehepatectomy chemotherapy (PHC), disease-free survival (DFS) was not different between patients who received PHC and those who did not, among patients with a TBS beyond 6, 7, or 8. However, in patients with TBS ≥ 9, DFS was significantly better in patients who received PHC than in those who did not. Furthermore, overall (OS) was similar between patients who received PHC and those who did not in patients with TBS ≥ 6 or ≥ 7. However, in patients with TBS ≥ 8 or ≥ 9, OS was significantly better in patients who received PHC than in those who did not. Of note, there were no long-term survivors among patients with TBS ≥ 9 who did not receive PHC. (TIFF 144 kb)

10434_2018_6830_MOESM5_ESM.tif

Supplementary material Fig. 5 Varying impact of margin status in patients with different ranges of Tumor Burden Score (TBS) in the Baltimore cohort. When the cohort was dichotomized by using a TBS cut-off value of 4, 5, 6, or 7, disease-free survival (DFS) and overall survival (OS) were significantly worse for the R1 resection group than the R0 group for patients with TBS less than the cut-off. By contrast, neither DFS nor OS were different between the R1 and R0 groups for patients with TBS more than the cut-off. (TIFF 268 kb)

10434_2018_6830_MOESM6_ESM.tif

Supplementary material Fig. 6 Varying impact of margin status and prehepatectomy chemotherapy in patients with different ranges of Tumor Burden Score (TBS) in the Yokohama cohort. The negative impact of R1 resection on overall survival (OS) was eradicated in patients with TBS ≥ 8 or ≥ 9 who exhibited partial response to pre-hepatectomy chemotherapy (PHC), irrespective of regimen used or number of administered courses. In contrast, the disadvantageous effect of an R1 resection remained in patients exhibiting stable disease or progressive disease in response to PHC, although prognostic difference between modern and other regimens was not observed in this cohort. (TIFF 140 kb)

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Oshi, M., Margonis, G.A., Sawada, Y. et al. Higher Tumor Burden Neutralizes Negative Margin Status in Hepatectomy for Colorectal Cancer Liver Metastasis. Ann Surg Oncol 26, 593–603 (2019). https://doi.org/10.1245/s10434-018-6830-x

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