Pancreatic Cancer pp 1153-1171 | Cite as

Modern Japanese Approach to Pancreas Cancer

  • Masao Tanaka


Strong invasiveness, late appearance of clinical symptoms and a lack of efficient screening methods make the prognosis of pancreatic cancer dismal. Principal clues to early diagnosis of pancreatic cancer including pancreatic duct dilatation, diabetes, and intraductal papillary mucinous neoplasms are discussed, referring to many Japanese contributions. The Japan Pancreas Society (JPS) published Clinical Guidelines for Management of Pancreatic Cancer in 2006. The guidelines provide answers to 29 clinical questions with graded evidence-based recommendations. Diagnosis, chemotherapy, radiation therapy, surgical, and adjuvant treatments are addressed using two algorithms for the diagnosis and treatment. Treatment of the clinical stage IVa disease is still controversial, being resectable in some patients but not in others. Patients with no major arterial invasion should undergo resection rather than chemoradiation according to a prospective randomized study from Japan. The survival benefit of combined resection of the portal vein has not been proven yet. With regard to surgical treatments Japanese surgeons pursued cure by means of extended resection with complete dissection of retroperitoneal lymph nodes and neural plexus. However, several prospective randomized trials did not confirm the survival benefit of extended resection compared to standard resection with regional lymph node dissection only. One prospective randomized multi-institutional study from Japan yielded no significant difference in 1-year and 3-year survival rates after extended resection. The survival benefit of extended resection in those with lymph node metastasis demonstrated in one study may still justify D2 lymph node dissection. Current interest is focused on the significance of postoperative adjuvant chemotherapy. The analysis of the JPS Pancreatic Cancer Registry indicates that the 5-year survival rate of patients with resected pancreatic cancer has been significantly improved after the introduction of gemcitabine into Japan. A prospective randomized comparison of resection with and without postoperative administration of gemcitabine for 6 months conducted in Europe showed lengthened disease-free and overall 5-year survival rates. A Japanese group conducted a similar study with gemcitabine adjuvant treatment for 3 months after resection, which produced similarly prolonged disease free survival so far. If 5-year overall survival should not be improved, it may suggest the necessity of a longer period of adjuvant chemotherapy.


Pancreatic Cancer Chronic Pancreatitis Main Pancreatic Duct Intraductal Papillary Mucinous Neoplasm Resected Pancreatic Cancer 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Japan Pancreas Society: Pancreatic cancer registry report 2007. Survival rates after resection of ordinary-type pancreatic cancer. Suizou 2007;22:e39–e390. Google Scholar
  2. 2.
    Schnelldorfer T, Ware AL, Sarr MG, Smyrk TC, Zhang L, Qin R, Gullerud RE, Donohue JH, Nagorney DM, Farnell MB: Long-term survival after pancreatoduodenectomy for pancreatic adenocarcinoma: is cure possible? Ann Surg 2008;247:456–462.CrossRefPubMedGoogle Scholar
  3. 3.
    The Japan Pancreas Society: Evidence-based clinical guidelines for the management of pancreatic cancer. Tokyo, Japan: Kanehara, 2006 (in Japanese)Google Scholar
  4. 4.
    The Japan Pancreas Society: Classification of pancreatic carcinoma. 2nd English version. Tokyo, Japan: Kanehara, 2003.Google Scholar
  5. 5.
    Inoue K, Ohuchida J, Ohtsuka T, Nabae T, Yokohata K, Ogawa Y, Yamaguchi K, Tanaka M: Severe localized stenosis and marked dilatation of the main pancreatic duct are indicators of pancreatic cancer instead of chronic pancreatitis on endoscopic retrograde balloon pancreatography. Gastrointest Endosc 2003;58:510–515.CrossRefPubMedGoogle Scholar
  6. 6.
    Tada M, Omata M, Kawai S, Saisho H, Ohto M, Saiki RK, Sninsky JJ: Detection of ras gene mutations in pancreatic juice and peripheral blood of patients with pancreatic adenocarcinoma. Cancer Res 1993;53:2472–2474.PubMedGoogle Scholar
  7. 7.
    Suehara N, Mizumoto K, Muta T, Tominaga Y, Shimura H, Kitajima S, Hamasaki N, Tsuneyoshi M, Tanaka M: Telomerase elevation in pancreatic ductal carcinoma compared to nonmalignant pathological states. Clin Cancer Res 1997;3:993–998.PubMedGoogle Scholar
  8. 8.
    Suehara N, Mizumoto K, Tanaka M, Niiyama H, Yokohata K, Tominaga Y, Shimura H, Muta T, Hamasaki N: Telomerase activity in pancreatic juice differentiates ductal carcinoma from adenoma and pancreatitis. Clin Cancer Res 1997;3:2479–2483.PubMedGoogle Scholar
  9. 9.
    Tada M, Teratani T, Komatsu Y, Kawabe T, Shiratori Y, Omata M: Quantitative analysis of ras gene mutation in pancreatic juice for diagnosis of pancreatic adenocarcinoma. Dig Dis Sci 1998;43:15–20.CrossRefPubMedGoogle Scholar
  10. 10.
    Tateishi K, Tada M, Yamagata M, Isayama H, Komatsu Y, Kawabe T, Shiratori Y, Omata M: High proportion of mutant K-ras gene in pancreatic juice of patients with pancreatic cystic lesions. Gut 1999;45:737–740.CrossRefPubMedGoogle Scholar
  11. 11.
    Uehara H, Nakaizumi A, Tatsuta M, Baba M, Takenaka A, Uedo N, Sakai N, Yano H, Iishi H, Ohigashi H, Ishikawa O, Okada S, Kakizoe T: Diagnosis of pancreatic cancer by detecting telomerase activity in pancreatic juice: comparison with K-ras mutations. Am J Gastroenterol 1999;94:2513–2518.CrossRefPubMedGoogle Scholar
  12. 12.
    Nakaizumi A, Uehara H, Takenaka A, Uedo N, Sakai N, Yano H, Ohigashi H, Ishikawa O, Ishiguro S, Sugano K, Tatsuta M: Diagnosis of pancreatic cancer by cytology and measurement of oncogene and tumor markers in pure pancreatic juice aspirated by endoscopy. Hepatogastroenterology 1999;46:31–37.PubMedGoogle Scholar
  13. 13.
    Sato N, Maehara N, Mizumoto K, Nagai E, Yasoshima T, Hirata K, Tanaka M: Telomerase activity correlates with aggressive behavior of human pancreatic cancer cells. Cancer 2000;91:496–504.CrossRefGoogle Scholar
  14. 14.
    Tada M, Tateishi K, Kawabe T, Sasahira N, Isayama H, Komatsu Y, Shiratori Y, Omata M: Quantity of mutant K-ras gene in pancreatic secretions for diagnosis of pancreatic carcinoma with different assays: analysis of 100 patients. Clin Chim Acta 2002;324:105–111.CrossRefPubMedGoogle Scholar
  15. 15.
    Ohuchida K, Mizumoto K, Ishikawa N, Sato N, Nagai E, Yamaguchi K, Takaishi H, Ide T, Tanaka M: A highly sensitive and quantitative telomerase activity assay with pancreatic juice is useful for diagnosis of pancreatic carcinoma without problems due to polymerase chain reaction inhibitors. Cancer 2004;101:2309–2317.CrossRefPubMedGoogle Scholar
  16. 16.
    Ohuchida K, Mizumoto K, Ogura Y, Ishikawa N, Nagai E, Yamaguchi K, Tanaka M: Quantitative assessment of telomerase activity and human telomerase reverse transcriptase messenger RNA levels in pancreatic juice samples for the diagnosis of pancreatic cancer. Clin Cancer Res 2005;11:2285–2292.CrossRefPubMedGoogle Scholar
  17. 17.
    Ohuchida K, Mizumoto K, Fujita H, Yamaguchi H, Konomi H, Nagai E, Yamaguchi K, Tsuneyoshi M, Tanaka M: Sonic hedgehog is an early developmental marker of intraductal papillary mucinous neoplasms: clinical implications of mRNA levels in pancreatic juice. J Pathol 2006;210:42–48.CrossRefPubMedGoogle Scholar
  18. 18.
    Ohuchida K, Mizumoto K, Yamada D, Fujii K, Ishikawa N, Konomi H, Nagai E, Yamaguchi K, Tsuneyoshi M, Tanaka M: Quantitative analysis of MUC1 and MUC5AC mRNA in pancreatic juice for preoperative diagnosis of pancreatic cancer. Int J Cancer 2006;1182:405–411.CrossRefGoogle Scholar
  19. 19.
    Ohuchida K, Mizumoto K, Ohhashi S, Yamaguchi H, Konomi H, Nagai E, Yamaguchi K, Tsuneyoshi M, Tanaka M: Twist, a novel oncogene, is upregulated in pancreatic cancer: Clinical implication of Twist expression in pancreatic juice. Int J Cancer 2007;120:1634–1640.CrossRefPubMedGoogle Scholar
  20. 20.
    Ohuchida K, Mizumoto K, Yu J, Yamaguchi H, Konomi H, Nagai E, Yamaguchi K, Tsuneyoshi M, Tanaka M: S100A6 is increased in a stepwise manner during pancreatic carcinogenesis: clinical value of expression analysis in 98 pancreatic juice samples. Cancer Epidemiol Biomarkers Prev 2007;16:649–654.CrossRefPubMedGoogle Scholar
  21. 21.
    Hashimoto Y, Murakami Y, Uemura K, Hayashidani Y, Sudo T, Ohge H, Fukuda E, Sueda T, Hiyama E: Detection of human telomerase reverse transcriptase (hTERT) expression in tissue and pancreatic juice from pancreatic cancer. Surgery 2008;143:113–125.CrossRefPubMedGoogle Scholar
  22. 22.
    Uehara H, Nakaizumi A, Iishi H, Takenaka A, Eguchi H, Ohigashi H, Ishikawa O: In situ telomerase activity in pancreatic juice may discriminate pancreatic cancer from other pancreatic diseases. Pancreas 2008;36:236–240.CrossRefPubMedGoogle Scholar
  23. 23.
    Girelli CM, Reguzzoni G, Limido E, Savastano A, Rocca F: Pancreatic carcinoma: differences between patients with or without diabetes mellitus. Recent Prog Med 1995;86:143–146.Google Scholar
  24. 24.
    Hjalgrim H, Frisch M, Ekbom A, Kyvik KO, Melbye M, Green A: Cancer and diabetes--a follow-up study of two population-based cohorts of diabetic patients. J Intern Med 1997;241:471–475.CrossRefPubMedGoogle Scholar
  25. 25.
    Ogawa Y, Tanaka M, Inoue K, Yamaguchi K, Chijiiwa K, Mizumoto K, Tsutsu N, Nakamura Y: A prospective pancreatographic study of the prevalence of pancreatic carcinoma in patients with diabetes mellitus. Cancer 2002;94:2344–2349.CrossRefPubMedGoogle Scholar
  26. 26.
    Chari ST, Leibson CL, Rabe KG, Ransom J, de Andrade M, Petersen GM: Probability of pancreatic cancer following diabetes: a population-based study. Gastroenterology 2005;129:504–511.PubMedGoogle Scholar
  27. 27.
    Tanaka M, Chari S, Adsay V, Fernandez-del Castillo C, Falconi M, Shimizu M, Yamaguchi K, Yamao K, Matsuno S, International Association of Pancreatology: International consensus guidelines for management of intraductal papillary mucinous neoplasms and mucinous cystic neoplasms of the pancreas. Pancreatology 2006;6:17–32.CrossRefPubMedGoogle Scholar
  28. 28.
    Nakaizumi A, Tatsuta M, Uehara H, Takenaka A, Ohigashi H, Ishikawa O, Ishiguro S: Usefulness of simple endoscopic aspiration cytology of pancreatic juice for diagnosis of early pancreatic neoplasm. A prospective study. Dig Dis Sci 1997;42:1796–1803.CrossRefPubMedGoogle Scholar
  29. 29.
    Yamaguchi K, Nakamura K, Yokohata K, Shimizu S, Chijiiwa K, Tanaka M: Pancreatic cyst as a sentinel of in situ carcinoma of the pancreas. Report of two cases. Int J Pancreatol 1997;22:227–231.PubMedGoogle Scholar
  30. 30.
    Yamaguchi K, Ohuchida J, Ohtsuka T, Nakano K, Tanaka M: Intraductal papillary-mucinous tumor of the pancreas concomitant with ductal carcinoma of the pancreas. Pancreatology 2002;2:484–490.CrossRefPubMedGoogle Scholar
  31. 31.
    Tada M, Kawabe T, Arizumi M, Togawa O, Matsubara S, Yamamoto N, Nakai Y, Sasahira N, Hirano K, Tsujino T, Tateishi K, Isayama H, Toda N, Yoshida H, Omata M: Pancreatic cancer in patients with pancreatic cystic lesions: a prospective study in 197 patients. Clin Gastroenterol Hepatol 2006;4:1265–1270.CrossRefPubMedGoogle Scholar
  32. 32.
    Tanaka M, Yokohata K, Konomi H, Yamaguchi K, Chijiiwa K, Ohta M: Segmental balloon cytology for preoperative localization of in situ pancreatic cancer. Gastrointest Endosc 1997;46:447–449.CrossRefPubMedGoogle Scholar
  33. 33.
    Uehara H, Nakaizumi A, Ishikawa O, Iishi H, Tatsumi K, Takakura R, Ishida T, Takano Y, Tanaka S, Takenaka A: Development of ductal carcinoma of the pancreas during follow-up of branch duct intraductal papillary mucinous neoplasm of the pancreas. Gut 2008;57:1561–1565.CrossRefPubMedGoogle Scholar
  34. 34.
    Imamura M, Doi R, Imaizumi T, Funakoshi A, Wakasugi H, Sunamura M, Ogata Y, Hishinuma S, Asano T, Aikou T, Hosotani R, Maetani S: A randomized multicenter trial comparing resection and radiochemotherapy for resectable locally invasive pancreatic cancer. Surgery 2004;136:1003–1011.CrossRefPubMedGoogle Scholar
  35. 35.
    Doi R, Imamura M, Hosotani R, Imaizumi T, Hatori T, Takasaki K, Funakoshi A, Wakasugi H, Asano T, Hishinuma S, Ogata Y, Sunamura M, Yamaguchi K, Tanaka M, Takao S, Aikou T, Hirata K, Maguchi H, Aiura K, Aoki T, Kakita A, Sasaki M, Ozaki M, Matsusue S, Higashide S, Noda H, Ikeda S, Maetani S, Yoshida S: The Japan Pancreatic Cancer Study Group: Surgery versus radiochemotherapy for resectable locally invasive pancreatic cancer: Final results of a randomized multi-institutional trial. Surg Today 2008;38:1021–1028.CrossRefPubMedGoogle Scholar
  36. 36.
    Pedrazzoli S, DiCarlo V, Dionigi R, Mosca F, Pedersoli P, Pasquali C, Kleoppel G, Dhaene K, Michelassi F: Standard versus extended lymphadenectomy associated with pancreatoduodenectomy in the surgical treatment of adenocarcinoma of the head of the pancreas: a multicenter, prospective, randomized study. Lymphadenectomy Study Group. Ann Surg 1998;228:508–517.CrossRefPubMedGoogle Scholar
  37. 37.
    Yeo CJ, Cameron JL, Lillemoe KD, Sohn TA, Campbell KA, Sauter PK, Coleman J, Abrams RA, Hruban RH: Pancreaticoduodenectomy with or without distal gastrectomy and extended retroperitoneal lymphadenectomy for periampullary adenocarcinoma, part 2: randomized controlled trial evaluating survival, morbidity, and mortality. Ann Surg 2002;236:355–366.CrossRefPubMedGoogle Scholar
  38. 38.
    Nguyen TC, Sohn TA, Cameron JL, Lillemoe KD, Campbell KA, Coleman J, Sauter PK, Abrams RA, Hruban RH, Yeo CJ: Standard vs. radical pancreaticoduodenectomy for periampullary adenocarcinoma: a prospective, randomized trial evaluating quality of life in pancreaticoduodenectomy survivors. J Gastrointest Surg 2003;7:1–9.CrossRefPubMedGoogle Scholar
  39. 39.
    Farnell MB, Pearson RK, Sarr MG, DiMagno EP, Burgart LJ, Dahl TR, Foster N, Sargent DJ: Pancreas Cancer Working Group. A prospective randomized trial comparing standard pancreatoduodenectomy with pancreatoduodenectomy with extended lymphadenectomy in resectable pancreatic head adenocarcinoma. Surgery 2005;138:618–630.CrossRefPubMedGoogle Scholar
  40. 40.
    Nagino M, Yuji N: Does “extended” surgery for pancreatic head adenocarcinoma have survival impact? Nippon Geka Gakkai Zasshi 2006;107:173–176 (Review in Japanese).PubMedGoogle Scholar
  41. 41.
    Boeck S, Ankerst DP, Heinemann V: The role of adjuvant chemotherapy for patients with resected pancreatic cancer: systematic review of randomized controlled trials and meta-analysis. Oncology 2007;72:314–321.CrossRefPubMedGoogle Scholar
  42. 42.
    Japan Pancreas Society: Report of the Pancreatic Cancer Registry 2007. Trend of survival of the patients with histologically confirmed unresectable invasive pancreatic cancer of JPS Stage IVa, IVb and unknown Stage. Suizou 2007;22:e45.
  43. 43.
    Oettle H, Post S, Neuhaus P, Gellert K, Langrehr J, Ridwelski K, Schramm H, Fahlke J, Zuelke C, Burkart C, Gutberlet K, Kettner E, Schmalenberg H, Weigang-Koehler K, Bechstein WO, Niedergethmann M, Schmidt-Wolf I, Roll L, Doerken B, Riess H: Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial. JAMA 2007;297:267–277.CrossRefPubMedGoogle Scholar
  44. 44.
    Neuhaus P, Riess H, Post S, Gellert K, Ridwelski K, Schramm H, Zuelke C, Fahlke J, Langrehr J, Oettle H, Deutsche Krebsgesellschaft (CAO/AIO): CONKO-001: Final results of the randomized, prospective, multicenter phase III trial of adjuvant chemotherapy with gemcitabine versus observation in patients with resected pancreatic cancer. Chicago: ASCO, 2008.Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Masao Tanaka
    • 1
  1. 1.Department of Surgery and Oncology, Graduate School of Medical SciencesKyushu UniversityFukuokaJapan

Personalised recommendations