Cancer Res Treat.  2017 Jul;49(3):824-833. 10.4143/crt.2016.336.

Impact of Resection Margin Distance on Survival of Pancreatic Cancer: A Systematic Review and Meta-Analysis

• Kim KS
• Kwon J
• Kim K
• Chie EK

• KMID: 2388328
• DOI: http://doi.org/10.4143/crt.2016.336

Abstract

PURPOSE
While curative resection is the only chance of cure in pancreatic cancer, controversies exist about the impact of surgical margin status on survival. Non-standardized pathologic report and different criteria on the R1 status made it difficult to implicate adjuvant therapy after resection based on the margin status. We evaluated the influence of resection margins on survival by meta-analysis.
MATERIALS AND METHODS
We thoroughly searched electronic databases of PubMed, EMBASE, and Cochrane Library. We included studies reporting survival outcomes with different margin status: involved margin (R0 mm), margin clearance with ≤ 1 mm (R0-1 mm), and margin with > 1 mm (R>1 mm). Hazard ratio (HR) for overall survival was extracted, and a random-effects model was used for pooled analysis.
RESULTS
A total of eight retrospective studies involving 1,932 patients were included. Pooled HR for overall survival showed that patients with R>1 mm had reduced risk of death than those with R0-1 mm (HR, 0.74; 95% confidence interval [CI], 0.61 to 0.88; p=0.001). In addition, patients with R0-1 mm had reduced risk of death than those with R0 mm (HR, 0.81; 95% CI, 0.72 to 0.91; p < 0.001). There was no heterogeneity between the included studies (I2 index, 42% and 0%; p=0.10 and p=0.82, respectively).
CONCLUSION
Our results suggest that stratification of the patients based on margin status is warranted in the clinical trials assessing the role of adjuvant treatment for pancreatic cancer.

Keyword

Meta-analysis; Pancreatic neoplasms; Resection margin; Systematic review

MeSH Terms

Humans
Pancreatic Neoplasms*
Population Characteristics
Retrospective Studies

Figure

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  Fig. 1. Study selection process.

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  Fig. 2. Forest plot for HR of the R>1 mm and R0-1 mm margin (A) or R0-1 mm and R0 mm margin (B). R0 mm, involved margin; R0-1 mm, margin clearance with ≤ 1 mm; R>1 mm, margin with > 1 mm; HR, hazard ratio; CI, confidence interval.

• 

  Fig. 3. Funnel plot of the included studies regarding R>1 mm and R0-1 mm margin (A) or R0-1 mm and R0 mm margin (B).

Reference

References

1. Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014; 64:9–29.

2. Bilimoria KY, Bentrem DJ, Ko CY, Stewart AK, Winchester DP, Talamonti MS. National failure to operate on early stage pancreatic cancer. Ann Surg. 2007; 246:173–80.

3. Neoptolemos JP, Stocken DD, Dunn JA, Almond J, Beger HG, Pederzoli P, et al. Influence of resection margins on survival for patients with pancreatic cancer treated by adjuvant chemoradiation and/or chemotherapy in the ESPAC-1 randomized controlled trial. Ann Surg. 2001; 234:758–68.

4. Menon KV, Gomez D, Smith AM, Anthoney A, Verbeke CS. Impact of margin status on survival following pancreatoduodenectomy for cancer: the Leeds Pathology Protocol (LEEPP). HPB (Oxford). 2009; 11:18–24.

5. Hartwig W, Hackert T, Hinz U, Gluth A, Bergmann F, Strobel O, et al. Pancreatic cancer surgery in the new millennium: better prediction of outcome. Ann Surg. 2011; 254:311–9.

6. Gnerlich JL, Luka SR, Deshpande AD, Dubray BJ, Weir JS, Carpenter DH, et al. Microscopic margins and patterns of treatment failure in resected pancreatic adenocarcinoma. Arch Surg. 2012; 147:753–60.

7. Raut CP, Tseng JF, Sun CC, Wang H, Wolff RA, Crane CH, et al. Impact of resection status on pattern of failure and survival after pancreaticoduodenectomy for pancreatic adenocarcinoma. Ann Surg. 2007; 246:52–60.

8. Butturini G, Stocken DD, Wente MN, Jeekel H, Klinkenbijl JH, Bakkevold KE, et al. Influence of resection margins and treatment on survival in patients with pancreatic cancer: meta-analysis of randomized controlled trials. Arch Surg. 2008; 143:75–83.

9. Verbeke CS, Menon KV. Redefining resection margin status in pancreatic cancer. HPB (Oxford). 2009; 11:282–9.

10. Schlitter AM, Esposito I. Definition of microscopic tumor clearance (r0) in pancreatic cancer resections. Cancers (Basel). 2010; 2:2001–10.

11. Wagner M, Redaelli C, Lietz M, Seiler CA, Friess H, Buchler MW. Curative resection is the single most important factor determining outcome in patients with pancreatic adenocarcinoma. Br J Surg. 2004; 91:586–94.

12. Kuhlmann K, de Castro S, van Heek T, Busch O, van Gulik T, Obertop H, et al. Microscopically incomplete resection offers acceptable palliation in pancreatic cancer. Surgery. 2006; 139:188–96.

13. Westgaard A, Tafjord S, Farstad IN, Cvancarova M, Eide TJ, Mathisen O, et al. Resectable adenocarcinomas in the pancreatic head: the retroperitoneal resection margin is an independent prognostic factor. BMC Cancer. 2008; 8:5.

14. Verbeke CS, Leitch D, Menon KV, McMahon MJ, Guillou PJ, Anthoney A. Redefining the R1 resection in pancreatic cancer. Br J Surg. 2006; 93:1232–7.

15. Esposito I, Kleeff J, Bergmann F, Reiser C, Herpel E, Friess H, et al. Most pancreatic cancer resections are R1 resections. Ann Surg Oncol. 2008; 15:1651–60.

16. Campbell F, Smith RA, Whelan P, Sutton R, Raraty M, Neoptolemos JP, et al. Classification of R1 resections for pancreatic cancer: the prognostic relevance of tumour involvement within 1 mm of a resection margin. Histopathology. 2009; 55:277–83.

17. Jamieson NB, Chan NI, Foulis AK, Dickson EJ, McKay CJ, Carter CR. The prognostic influence of resection margin clearance following pancreaticoduodenectomy for pancreatic ductal adenocarcinoma. J Gastrointest Surg. 2013; 17:511–21.

18. Sobin LH, Gospodarowicz MK, Wittekind C. International Union Against Cancer. TNM classification of malignant tumours. 7th ed. Oxford: Wiley-Blackwell;2009.

19. College of American Pathologists. Protocol for the examination of specimens from patients with carcinoma of the exocrine pancreas [Internet]. Northfield, IL: College of American Pathologists;[cited 2015 Jun 1]. Available from: http://www.cap.org/web/home/resources/cancer-reporting-tools/cancer-protocol-templates.

20. The Royal College of Pathologists. Standards and minimum datasets for reporting cancers: dataset for the histopathological reporting of carcinomas of the pancreas, ampulla of Vater and common bile duct. London: The Royal College of Pathologists;2010.

21. Kim SY, Park JE, Lee YJ, Seo HJ, Sheen SS, Hahn S, et al. Testing a tool for assessing the risk of bias for nonrandomized studies showed moderate reliability and promising validity. J Clin Epidemiol. 2013; 66:408–14.

22. Tierney JF, Stewart LA, Ghersi D, Burdett S, Sydes MR. Practical methods for incorporating summary time-to-event data into meta-analysis. Trials. 2007; 8:16.

23. Chang DK, Johns AL, Merrett ND, Gill AJ, Colvin EK, Scarlett CJ, et al. Margin clearance and outcome in resected pancreatic cancer. J Clin Oncol. 2009; 27:2855–62.

24. Janot MS, Kersting S, Belyaev O, Matuschek A, Chromik AM, Suelberg D, et al. Can the new RCP R0/R1 classification predict the clinical outcome in ductal adenocarcinoma of the pancreatic head? Langenbecks Arch Surg. 2012; 397:917–25.

25. Thomay AA, Hoffman JP, Chun YS. Defining resection margins in pancreatic cancer after neoadjuvant chemoradiotherapy. Gastroenterology. 2012; 142(Suppl 1):S1062–3.

26. Sugiura T, Uesaka K, Mihara K, Sasaki K, Kanemoto H, Mizuno T, et al. Margin status, recurrence pattern, and prognosis after resection of pancreatic cancer. Surgery. 2013; 154:1078–86.

27. Konstantinidis IT, Warshaw AL, Allen JN, Blaszkowsky LS, Castillo CF, Deshpande V, et al. Pancreatic ductal adenocarcinoma: is there a survival difference for R1 resections versus locally advanced unresectable tumors? What is a "true" R0 resection? Ann Surg. 2013; 257:731–6.

28. Hashimoto Y, Murakami Y, Uemura K, Sudo T, Kondo N, Sueda T. Impact of margin clearance on survival after pancreaticoduodenectomy for pancreatic ductal adenocarcinoma: what is a “true” negative margin? Gastroenterology. 2013; 144(Suppl 1):S1128.

29. Staley CA, Cleary KR, Abbruzzese JL, Lee JE, Ames FC, Fenoglio CJ, et al. The need for standardized pathologic staging of pancreaticoduodenectomy specimens. Pancreas. 1996; 12:373–80.

30. Van den Broeck A, Sergeant G, Ectors N, Van Steenbergen W, Aerts R, Topal B. Patterns of recurrence after curative resection of pancreatic ductal adenocarcinoma. Eur J Surg Oncol. 2009; 35:600–4.

31. Kayahara M, Nagakawa T, Ueno K, Ohta T, Takeda T, Miyazaki I. An evaluation of radical resection for pancreatic cancer based on the mode of recurrence as determined by autopsy and diagnostic imaging. Cancer. 1993; 72:2118–23.

32. Nagakawa T, Nagamori M, Futakami F, Tsukioka Y, Kayahara M, Ohta T, et al. Results of extensive surgery for pancreatic carcinoma. Cancer. 1996; 77:640–5.

33. Japan Pancreas Society. General rules for the study of pancreatic cancer. 2nd ed. Tokyo: Kanehara;2003.

34. Verbeke CS. Resection margins and R1 rates in pancreatic cancer: are we there yet? Histopathology. 2008; 52:787–96.

35. Jamieson NB, Foulis AK, Oien KA, Going JJ, Glen P, Dickson EJ, et al. Positive mobilization margins alone do not influence survival following pancreatico-duodenectomy for pancreatic ductal adenocarcinoma. Ann Surg. 2010; 251:1003–10.

36. Verbeke CS, Knapp J, Gladhaug IP. Tumour growth is more dispersed in pancreatic head cancers than in rectal cancer: implications for resection margin assessment. Histopathology. 2011; 59:1111–21.

37. Gebauer F, Tachezy M, Vashist YK, Marx AH, Yekebas E, Izbicki JR, et al. Resection margin clearance in pancreatic cancer after implementation of the Leeds Pathology Protocol (LEEPP): clinically relevant or just academic? World J Surg. 2015; 39:493–9.

38. Stocken DD, Buchler MW, Dervenis C, Bassi C, Jeekel H, Klinkenbijl JH, et al. Meta-analysis of randomised adjuvant therapy trials for pancreatic cancer. Br J Cancer. 2005; 92:1372–81.

39. Pingpank JF, Hoffman JP, Ross EA, Cooper HS, Meropol NJ, Freedman G, et al. Effect of preoperative chemoradiotherapy on surgical margin status of resected adenocarcinoma of the head of the pancreas. J Gastrointest Surg. 2001; 5:121–30.

40. Katz MH, Wang H, Balachandran A, Bhosale P, Crane CH, Wang X, et al. Effect of neoadjuvant chemoradiation and surgical technique on recurrence of localized pancreatic cancer. J Gastrointest Surg. 2012; 16:68–78.

41. Barbier L, Turrini O, Gregoire E, Viret F, Le Treut YP, Delpero JR. Pancreatic head resectable adenocarcinoma: preoperative chemoradiation improves local control but does not affect survival. HPB (Oxford). 2011; 13:64–9.

42. Delpero JR, Bachellier P, Regenet N, Le Treut YP, Paye F, Carrere N, et al. Pancreaticoduodenectomy for pancreatic ductal adenocarcinoma: a French multicentre prospective evaluation of resection margins in 150 evaluable specimens. HPB (Oxford). 2014; 16:20–33.