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Reappraisal of Peritoneal Washing Cytology in 984 Patients with Pancreatic Ductal Adenocarcinoma Who Underwent Margin-Negative Resection

Journal of Gastrointestinal Surgery volume 19, pages 6–14 (2015)Cite this article

Abstract

Objective

The objective of the present study was to reappraise the clinical value of peritoneal washing cytology (CY) in 984 pancreatic ductal adenocarcinoma patients who underwent margin-negative resection.

Methods

In a 2001–2011 database from seven high-volume surgical institutions in Japan, 69 patients (7 %) had positive CY (CY+ group) indicative of M1 disease and 915 patients had negative CY (CY− group). Clinicopathological data and survival were compared between groups.

Results

Significant correlations between CY+ and high CA19-9 level, pancreatic body and tail cancer, lymph node metastasis, and a lower frequency of R0 resection were observed. Overall survival (OS) of CY+ patients was significantly worse than that of CY− patients (median survival time [MST], 16 vs. 25 months; 3-year OS rate, 6 vs. 37 %; p < 0.001). CY+ patients had a significantly higher rate of post-operative peritoneal carcinomatosis than CY− patients (48 vs. 21 %; p < 0.001). Administration of adjuvant chemotherapy did not provide a favorable survival outcome to CY+ patients. The current study showed that patients with M1 disease had acceptable MST after margin-negative resection and a high incidence of peritoneal carcinomatosis within 3 years after surgery, resulting in decreased long-term survival. The development of a new strategy to control peritoneal carcinomatosis when surgical resection is performed in such patients is required.

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References

  1. Takai S, Satoi S, Toyokawa H, et al. Clinicopathologic evaluation after resection for ductal adenocarcinoma of the pancreas: a retrospective, single-institution experience. Pancreas. 2003;26:243–9.

    CAS  PubMed  Article  Google Scholar 

  2. Conlon KC, Klimstra DS, Brennan MF. Long term survival after curative resection for pancreatic ductal adenocarcinoma. Ann Surg. 1996;223:273–9.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  3. Adham M, Jaeck D, Le Borgne J, et al. Long-term survival (5–20 years) after pancreatectomy for pancreatic ductal adenocarcinoma: a series of 30 patients collected from 3 institutions. Pancreas. 2008;37:352–7.

    PubMed  Article  Google Scholar 

  4. Schnelldorfer T, Ware AL, Sarr MG, et al. Long-term survival after pancreatoduodenectomy for pancreatic adenocarcinoma: is cure possible? Ann Surg. 2008;247:456–62.

    PubMed  Article  Google Scholar 

  5. Han SS, Jang JY, Kim SW, et al. Analysis of long-term survivors after surgical resection for pancreatic cancer. Pancreas. 2006;32:271–5.

    PubMed  Article  Google Scholar 

  6. Edge SBB DR., Compton CC, Fritz AG, et al., Eds. AJCC Cancer Staging Manual (ed 7th edition). New York: Springer; 2010. Edge SB, Compton CC. The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol. (2010);17: 1471–4.

  7. Ferrone CR, Haas B, Tang L et al. The influence of positive peritoneal cytology on survival in patients with pancreatic adenocarcinoma. J Gastrointest Surg. 2006;10:1347–53.

    PubMed  Article  Google Scholar 

  8. Yoshioka R, Saiura A, Koga R et al. The implication of positive peritoneal cytology in potentially resectable pancreatic cancer. World J Surg. 2012;36:2187–91.

    PubMed  Article  Google Scholar 

  9. Yamada S, Takeda S, Fujii T et al. Clinical implications of peritoneal cytology in potentially resectable pancreatic cancer: positive peritoneal cytology may not confer an adverse prognosis. Ann Surg. 2007;246:254–8.

    PubMed Central  PubMed  Article  Google Scholar 

  10. Yachida S, Fukushima N, Sakamoto M et al. Implications of peritoneal washing cytology in patients with potentially resectable pancreatic cancer. Br J Surg. 2002;89:573–8.

    CAS  PubMed  Article  Google Scholar 

  11. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Pancreatic Adenocarcinoma. Version 1.2014. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp#site [Accessed 20 January 2014].

  12. Motoi F, Rikiyama T, Katayose Y, et al. Retrospective evaluation of the influence of postoperative tumor marker status on survival and patterns of recurrence after surgery for pancreatic cancer based on RECIST guidelines. Ann Surg Oncol. 2011; 18:371–9.

    PubMed  Article  Google Scholar 

  13. Edge SB, Compton CC. The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol. 2010; 17:1471–4.

    PubMed  Article  Google Scholar 

  14. Sobin L, Gospodarowicz M, Wittekind C e. TNM Classification of Malignant Tumours, 7th ed. New York: Wiley-Liss, 2009.

    Google Scholar 

  15. Burris HA 3rd, Moore MJ, Andersen J, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: A randomized trial. J Clin Oncol. 1997;15:2403–13.

    CAS  PubMed  Google Scholar 

  16. Moore MJ, Goldstein D, Hamm J, et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: A phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007;25:1960–6.

    CAS  PubMed  Article  Google Scholar 

  17. Clark CJ, Traverso LW. Positive peritoneal lavage cytology is a predictor of worse survival in locally advanced pancreatic cancer. Am J Surg. 2010;199:657–62.

    PubMed  Article  Google Scholar 

  18. Yamada S, Fujii T, Kanda M, et al. Value of peritoneal cytology in potentially resectable pancreatic cancer. Brit J Surg. doi: 10.1002/bjs.9307.

  19. Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364:1817–25.

    CAS  PubMed  Article  Google Scholar 

  20. Ueno H, Ioka T, Ikeda M, et al. Randomized phase III study of gemcitabine plus S-1, S-1 alone, or gemcitabine alone in patients with locally advanced and metastatic pancreatic cancer in Japan and Taiwan: GEST study. J Clin Oncol. 2013;31:1640–8.

    CAS  PubMed  Article  Google Scholar 

  21. Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013; 369:1691–703.

    Article  Google Scholar 

  22. Shinchi H, Maemura K, Mataki Y et al. A phase II study of oral S-1 with concurrent radiotherapy followed by chemotherapy with S-1 alone for locally advanced pancreatic cancer. J Hepatobilliary Pancreat Sci. 2012; 19: 152–8.

    Article  Google Scholar 

  23. Sudo K, Yamaguchi T, Ishihara T et al. Phase II study of oral S-1 and concurrent radiotherapy in patients with unresectable locally advanced pancreatic cancer. Int J Radiat Oncol Bio Phys. 2011; 80: 119–25.

    Article  Google Scholar 

  24. Thomassen I, Lemmens VE, Nienhuijs SW, et al. Incidence, prognosis, and possible treatment strategies of peritoneal carcinomatosis of pancreatic origin: a population-based study. Pancreas. 2013;42:72–5.

    PubMed  Article  Google Scholar 

  25. Yamamoto K, Shimada S, Hirota M, et al. EIPL (extensive intraoperative peritoneal lavage) therapy significantly reduces peritoneal recurrence after pancreatectomy in patients with pancreatic cancer. Int J Oncol. 2005;27:1321–8.

    PubMed  Google Scholar 

  26. Verwaal VJ, Bruin S, Boot H, et al. 8-year follow-up of randomized trial: cytoreduction and hyperthermic intraperitoneal chemotherapy versus systemic chemotherapy in patients with peritoneal carcinomatosis of colorectal cancer. Ann Surg Oncol. 2008;15:2426–32.

    PubMed  Article  Google Scholar 

  27. Sugarbaker PH, Stuart OA, Bijelic L. Intraperitoneal gemcitabine chemotherapy treatment for patients with resected pancreatic cancer: rationale and report of early data. Int J Surg Oncol. 2011;2011;161862. doi: 10.1155/2011/161862. Epub 2011 Dec 12.

    PubMed Central  PubMed  Google Scholar 

  28. Ishigami H, Kitayama J, Kaisaki S, et al. Phase II study of weekly intravenous and intraperitoneal paclitaxel combined with S-1 for advanced gastric cancer with peritoneal metastasis. Ann Oncol. 2010;21:67–70.

    CAS  PubMed  Article  Google Scholar 

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Conflict of Interest

The authors have no conflicts of interest to disclose.

Author information

Affiliations

  1. Department of Surgery, Kansai Medical University, Osaka, Japan

    Sohei Satoi, Hiroaki Yanagimoto, Tomohisa Yamamoto & A-Hon Kwon

  2. Department of Surgery, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-4, Kasumi, Minami-ku, Hiroshima, 734-8551, Japan

    Yoshiaki Murakami, Kenichiro Uemura & Yasushi Hashimoto

  3. Division of Gastroenterological Surgery, Department of Surgery, Tohoku University, Sendai, Japan

    Fuyuhiko Motoi, Masamichi Mizuma & Michiaki Unno

  4. Second Department of Surgery, Wakayama Medical University, Wakayama, Japan

    Manabu Kawai, Seiko Hirono & Hiroki Yamaue

  5. Department of Surgery, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan

    Masanao Kurata & Goro Honda

  6. Department of Surgery, Nara Medical University, Nara, Japan

    Masayuki Sho, Minako Nagai & Yoshiyuki Nakajima

  7. Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, Kobe University Graduate School of Medicine, Kobe, Japan

    Ippei Matsumoto, Makoto Shinzeki & Takumi Fukumoto

Authors
  1. Sohei Satoi
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  2. Yoshiaki Murakami
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  3. Fuyuhiko Motoi
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  4. Kenichiro Uemura
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  5. Manabu Kawai
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  6. Masanao Kurata
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  7. Masayuki Sho
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  8. Ippei Matsumoto
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  9. Hiroaki Yanagimoto
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  10. Tomohisa Yamamoto
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  11. Masamichi Mizuma
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  12. Michiaki Unno
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  13. Yasushi Hashimoto
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  14. Seiko Hirono
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  15. Hiroki Yamaue
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  16. Goro Honda
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  17. Minako Nagai
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  18. Yoshiyuki Nakajima
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  19. Makoto Shinzeki
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  20. Takumi Fukumoto
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  21. A-Hon Kwon
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Corresponding author

Correspondence to Yoshiaki Murakami.

Additional information

Discussant

Dr. Steven J Hughes (Gainesville, FL):

The peritoneum is a rich soil for cancerous seeds, and carcinomatosis is a devastating development for pancreatic cancer patients. The authors’ findings that CY+ is a profound indicator of poor prognosis are intuitive, and I rise to applaud your thoughtful study design and careful analysis of data from a truly impressive series of pancreas cancer patients. I would also like to thank the authors for providing me with a copy of the manuscript well in advance of the meeting. I have two questions.

Question #1: I am inclined to think that positive cytology should be indicative of subsequent carcinomatosis. I can understand why carcinomatosis was not subsequently identified in approximately half of the CY+ patients; cross-sectional imaging struggles to accurately diagnose this condition. Nonetheless, your data would suggest that current methods of cytology are not particularly specific for the development of clinically relevant carcinomatosis. More importantly in my mind, 21 % of CY− patients did subsequently develop carcinomatosis. Thus, this data suggests this particular assay may lack sensitivity. What are the authors’ opinions regarding the sensitivity and specificity of peritoneal washings and how should that impact our interpretation of the data.

Question #2: For pancreatic adenocarcinoma, the NCCN guidelines characterize positive cytology as M1 disease, yet some authors have advocated proceeding with curative resection in this setting based upon data that your study would suggest suffered from Type II error. In your series, 7 % of patients proved to have positive cytology. How would you suggest we apply your findings to current clinical practice? Specifically, do you advocate diagnostic laparoscopy with peritoneal washings as a separate procedure? Are there barriers to intraoperative cytology?

Closing Discussant

Dr. Satoi:

Answer #1. I greatly appreciate your very important suggestions. The current study was retrospectively performed in a multi-center setting, and cytology analysis was conducted using Papanicolou and May-Giemsa staining, not with molecular techniques. As Dr. Hughes indicated, I agree that current cytology methods may not be particularly specific. The current method of cytology for predicting subsequent peritoneal carcinomatosis as the primary site of recurrence showed sensitivity of 15 %, specificity of 95 %, a positive predictive value of 49 %, and a negative predictive value of 21 %. However, it is difficult to accurately evaluate the sensitivity and specificity of peritoneal washing because the second site of recurrence was not recorded in this database. Therefore, we could not evaluate the overall rate of peritoneal recurrence. We should conduct a prospective study to evaluate this issue.

We would like to share the data from a Korean multi-center randomized control trial that showed that extended lymph node dissection was significantly associated with a high rate (25 %) of peritoneal carcinomatosis relative to the 9 % rate in patients who underwent standard lymphadenectomy. In the current study, extended lymph node dissection had been routinely performed at the seven institutions. I therefore think that patients with CY− may have had a high frequency of peritoneal carcinomatosis due to extended lymph node dissection.

Answer #2. First, we strongly suggest that peritoneal washing cytology should be done in pancreatic cancer patients who undergo planned surgical resection in all centers to select patients with CY+. Although we recognize that CY+ can be a prognostic factor and a risk factor for the development of peritoneal carcinomatosis after surgical resection, margin-negative resection might not be a good surgical indication in patients with CY+ but should not be a contraindication. The important issue for such patients is to control the development of peritoneal carcinomatosis and malignant ascites. There are two potential approaches for treating such patients. The availability of diagnostic laparoscopy is limited and intraoperative cytology is not available in some centers. In such a situation, we advocate surgical resection followed by effective adjuvant chemotherapy such as hyperthermic intraperitoneal chemotherapy or intravenous and intraperitoneal chemotherapy in patients with CY+ in a clinical trial setting. We also advocate the selective use of diagnostic laparoscopy in patients at risk for occult distant organ metastasis. Chemotherapy for controlling the development of peritoneal carcinomatosis should be first administered in such patients, and surgical resection should be selectively performed in patients with long-term favorable responses to chemotherapy. These approaches should be appropriately used according to the availability of staging laparoscopy and intraoperative cytology in each institution.

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Satoi, S., Murakami, Y., Motoi, F. et al. Reappraisal of Peritoneal Washing Cytology in 984 Patients with Pancreatic Ductal Adenocarcinoma Who Underwent Margin-Negative Resection. J Gastrointest Surg 19, 6–14 (2015). https://doi.org/10.1007/s11605-014-2637-7

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  • DOI: https://doi.org/10.1007/s11605-014-2637-7

Keywords

  • Pancreatic ductal adenocarcinoma
  • Peritoneal washing cytology
  • Peritoneal carcinomatosis
  • Survival analysis
  • Adjuvant chemotherapy