Effect of the pringle maneuver on tumor recurrence of hepatocellular carcinoma after curative resection (EPTRH): a randomized, prospective, controlled multicenter trial

Feng Xiaobin, Zheng Shuguo, Zhou Jian, Qiu Yudong, Liang Lijian, Ma Kuansheng, Li Xiaowu, Xia Feng, Yi Dong, Wang Shuguang, Bie Ping, Dong Jiahong, Feng Xiaobin, Zheng Shuguo, Zhou Jian, Qiu Yudong, Liang Lijian, Ma Kuansheng, Li Xiaowu, Xia Feng, Yi Dong, Wang Shuguang, Bie Ping, Dong Jiahong

Abstract

Background: Hepatic resection is currently still the best choice of therapeutic strategies for liver cancer, but the long-term survival rate after surgery is unsatisfactory. Most patients develop intra- and/or extrahepatic recurrence. The reasons for this high recurrence rate are not entirely clear. Recent studies have indicated that ischemia-reperfusion injury to the liver may be a significant factor promoting tumor recurrence and metastasis in animal models. If this is also true in humans, the effects of the Pringle maneuver, which has been widely used in hepatectomy for the past century, should be examined. To date, there are no reported data or randomized controlled studies examining the relationship between use of the Pringle maneuver and local tumor recurrence. We hypothesize that the long-term prognosis of patients with liver cancer could be worsened by use of the Pringle maneuver due to an increase in the rate of tumor recurrence in the liver remnant. We designed a multicenter, prospective, randomized surgical trial to test this hypothesis.

Methods: At least 498 eligible patients from five participating centers will be enrolled and randomized into either the Pringle group or the non-Pringle group in a ratio of 1:1 using a permuted-blocks randomization protocol. After the completion of surgical intervention, patients will be included in a 3-year follow-up program.

Discussion: This multicenter surgical trial will examine whether the Pringle maneuver has a negative effect on the long-term outcome of hepatocellular carcinoma patients. The trial will also provide information about prognostic differences, safety, advantages and disadvantages between Pringle and non-Pringle surgical procedures. Ultimately, the results will increase the available information about the effects of ischemia-reperfusion injury on tumor recurrence, which will be of immense benefit to general surgery.

Trial registration: http://www.clinicaltrials.gov NCT00725335.

Figures

Figure 1
Figure 1
Detailed flow chart of the clinical trial. Eligible patients from five centers will be enrolled, and randomly divided into an experimental group and a control group by permuted-blocks randomization. Each patient will be followed up for 3 years after their primary operation.

References

    1. Wu MC. Clinical research advances in primary liver cancer. World J Gastroenterol. 1998;4(6):471–474.
    1. Kiyosawa K, Sodeyama T. Global epidemiology of hepatocellular carcinoma. Nihon Rinsho. 2001;59(Suppl 6):13–19.
    1. Harada T, Shigemura T, Kodama S, Higuchi T, Ikeda S, Okazaki M. Hepatic resection is not enough forhepatocellular carcinoma. A follow-up study of 92 patients. J Clin Gastroenterol. 1992;14(3):245–250. doi: 10.1097/00004836-199204000-00011.
    1. Nagasue N, Uchida M, Makino Y, Takemoto Y, Yamanoi A, Hayashi T, Chang YC, Kohno H, Nakamura T, Yukaya H. Incidence and factors associated with intrahepatic recurrence following resection ofhepatocellular carcinoma. Gastroenterology. 1993;105(2):488–494.
    1. Jwo SC, Chiu JH, Chau GY, Loong CC, Lui WY. Risk factors linked to tumor recurrence of humanhepatocellular carcinoma after hepatic resection. Hepatology. 1992;16(6):1367–1371. doi: 10.1002/hep.1840160611.
    1. Yamamoto J, Kosuge T, Takayama T, Shimada K, Yamasaki S, Ozaki H, Yamaguchi N, Makuuchi M. Recurrence of hepatocellular carcinoma after surgery. Br J Surg. 1996;83(9):1219–1222. doi: 10.1002/bjs.1800830913.
    1. Poon RT, Fan ST, Ng IO, Lo CM, Liu CL, Wong J. Different risk factors and prognosis for early and lateintrahepatic recurrence after resection of hepatocellular carcinoma. Cancer. 2000;89(3):500–507. doi: 10.1002/1097-0142(20000801)89:3<500::AID-CNCR4>;2-O.
    1. Pringle JH. V. Notes on the Arrest of Hepatic Hemorrhage Due to Trauma. Ann Surg. 1908;48(4):541–549. doi: 10.1097/00000658-190810000-00005.
    1. Delva E, Camus Y, Nordlinger B, Hannoun L, Parc R, Deriaz H, Lienhart A, Huguet C. Vascular occlusionsfor liver resections. Operative management and tolerance to hepatic ischemia: 142 cases. Ann Surg. 1989;209(2):211–218. doi: 10.1097/00000658-198902000-00012.
    1. Stephenson KR, Steinberg SM, Hughes KS, Vetto JT, Sugarbaker PH, Chang AE. Perioperative bloodtransfusions are associated with decreased time to recurrence and decreased survival after resection ofcolorectal liver metastases. Ann Surg. 1988;208(6):679–687. doi: 10.1097/00000658-198812000-00002.
    1. Rudiger HA, Kang KJ, Sindram D, Riehle HM, Clavien PA. Comparison of ischemic preconditioning andintermittent and continuous inflow occlusion in the murine liver. Ann Surg. 2002;235(3):400–407. doi: 10.1097/00000658-200203000-00012.
    1. Torzilli G, Makuuchi M, Inoue K. The vascular control in liver resection: revisitation of a controversial issue. Hepatogastroenterology. 2002;49(43):28–31.
    1. Jaeschke H. Molecular mechanisms of hepatic ischemia-reperfusion injury and preconditioning. Am J Physiol Gastrointest Liver Physiol. 2003;284(1):G15–G26.
    1. Peralta C, Bartrons R, Riera L, Manzano A, Xaus C, Gelpi E, Rosello-Catafau J. Hepatic preconditioning preserves energy metabolism during sustained ischemia. Am J Physiol Gastrointest Liver Physiol. 2000;279(1):G163–G171.
    1. Serracino-Inglott F, Habib NA, Mathie RT. Hepatic ischemia-reperfusion injury. Am J Surg. 2001;181(2):160–166. doi: 10.1016/S0002-9610(00)00573-0.
    1. Glanemann M, Vollmar B, Nussler AK, Schaefer T, Neuhaus P, Menger MD. Ischemic preconditioning protects from hepatic ischemia/reperfusion-injury by preservation of microcirculation andmitochondrial redox-state. J Hepatol. 2003;38(1):59–66. doi: 10.1016/S0168-8278(02)00327-6.
    1. Pannen BH. New insights into the regulation of hepatic blood flow after ischemia and reperfusion. AnesthAnalg. 2002;94(6):1448–1457.
    1. Vollmar B, Glasz J, Leiderer R, Post S, Menger MD. Hepatic microcirculatory perfusion failure is adeterminant of liver dysfunction in warm ischemia-reperfusion. Am J Pathol. 1994;145(6):1421–1431.
    1. Clavien PA, Yadav S, Sindram D, Bentley RC. Protective effects of ischemic preconditioning for liver resection performed under inflow occlusion in humans. Ann Surg. 2000;232(2):155–162. doi: 10.1097/00000658-200008000-00001.
    1. Nagasue N, Yukaya H, Suehiro S, Ogawa Y. Tolerance of the cirrhotic liver to normothermic ischemia. A clinical study of 15 patients. Am J Surg. 1984;147(6):772–775. doi: 10.1016/0002-9610(84)90198-3.
    1. Matsumata T, Kanematsu T, Shirabe K, Yamagata M, Utsunomiya T, Furuta T, Sugimachi K. Modified16technique of Pringle’s maneuver in resection of the liver. Surg Gynecol Obstet. 1991;172(3):245–246.
    1. Isozaki H, Adam R, Gigou M, Szekely AM, Shen M, Bismuth H. Experimental study of the protective effect of intermittent hepatic pedicle clamping in the rat. Br J Surg. 1992;79(4):310–313. doi: 10.1002/bjs.1800790409.
    1. Man K, Fan ST, Ng IO, Lo CM, Liu CL, Wong J. Prospective evaluation of Pringle maneuver in hepatectomy for liver tumors by a randomized study. Ann Surg. 1997;226(6):704–711. doi: 10.1097/00000658-199712000-00007. discussion 711–703.
    1. Chau GY, Lui WY, Tsay SH, Chao Y, King KL, Wu CW. Postresectional adjuvant intraportal chemotherapy in patients with hepatocellular carcinoma: a case–control study. Ann Surg Oncol. 2006;13(10):1329–1337. doi: 10.1245/s10434-006-9004-1.
    1. Buell JF, Koffron A, Yoshida A, Hanaway M, Lo A, Layman R, Cronin DC, Posner MC, Millis JM. Is any method of vascular control superior in hepatic resection of metastatic cancers? Longmire clamping, pringle maneuver, and total vascular isolation. Arch Surg. 2001;136(5):569–575. doi: 10.1001/archsurg.136.5.569.
    1. Smyrniotis VE, Kostopanagiotou GG, Contis JC, Farantos CI, Voros DC, Kannas DC, Koskinas JS. Selective hepatic vascular exclusion versus Pringle maneuver in major liver resections: prospective study. World J Surg. 2003;27(7):765–769. doi: 10.1007/s00268-003-6978-8.
    1. Figueras J, Llado L, Ruiz D, Ramos E, Busquets J, Rafecas A, Torras J, Fabregat J. Complete versus selective portal triad clamping for minor liver resections: a prospective randomized trial. Ann Surg. 2005;241(4):582–590. doi: 10.1097/01.sla.0000157168.26021.b8.
    1. Chinnakotla S, Pande GK, Sahni P, Gupta SD, Maulik M, Kumari R, Nundy S, Chattopadhyay TK. Evaluation of Pringle maneuver during liver resection in a rat model of surgical obstructive jaundice. J Invest Surg. 2005;18(3):107–113. doi: 10.1080/08941930590956129.
    1. Popescu I, Vasile S, Sgarbura O. The Pringle maneuver in laparoscopic hepatic surgery: is it useful? Analysis of a series of 38 cases. Chirurgia (Bucur) 2007;102(5):521–525.
    1. Kim YI, Fujita S, Hwang YJ, Chun JM, Song KE, Chun BY. Successful intermittent application of the Pringle maneuver for 30 minutes during human hepatectomy: a clinical randomized study with use of aprotease inhibitor. Hepatogastroenterology. 2007;54(79):2055–2060.
    1. Shimoda M, Iwasaki Y, Sawada T, Kubota K. Protective effect of ischemic preconditioning against liver injury after major hepatectomy using the intermittent pringle maneuver in swine. Pathobiology. 2007;74(1):42–49. doi: 10.1159/000101050.
    1. Zhou W, Li A, Pan Z, Fu S, Yang Y, Tang L, Hou Z, Wu M. Selective hepatic vascular exclusion and Pringle maneuver: a comparative study in liver resection. Eur J Surg Oncol. 2008;34(1):49–54. doi: 10.1016/j.ejso.2007.07.001.
    1. Man K, Ng KT, Lo CM, Ho JW, Sun BS, Sun CK, Lee TK, Poon RT, Fan ST. Ischemia-reperfusion of small liver remnant promotes liver tumor growth and metastases–activation of cell invasion and migration pathways. Liver Transpl. 2007;13(12):1669–1677. doi: 10.1002/lt.21193.
    1. Man K, Lo CM, Xiao JW, Ng KT, Sun BS, Ng IO, Cheng Q, Sun CK, Fan ST. The significance of acute phase small-for-size graft injury on tumor growth and invasiveness after liver transplantation. Ann Surg. 2008;247(6):1049–1057. doi: 10.1097/SLA.0b013e31816ffab6XXX.
    1. Ozaki M, Todo S. Surgical stress and tumor behavior: impact of ischemia-reperfusion and hepatic resection on tumor progression. Liver Transpl. 2007;13(12):1623–1626. doi: 10.1002/lt.21230.
    1. Doi K, Horiuchi T, Uchinami M, Tabo T, Kimura N, Yokomachi J, Yoshida M, Tanaka K. Hepatic ischemia-reperfusion promotes liver metastasis of colon cancer. J Surg Res. 2002;105(2):243–247. doi: 10.1006/jsre.2002.6356.
    1. van der Bilt JD, Kranenburg O, Nijkamp MW, Smakman N, Veenendaal LM, Te Velde EA, Voest EE, vanDiest PJ, Borel Rinkes IH. Ischemia/reperfusion accelerates the outgrowth of hepatic micrometastases in a highly standardized murine model. Hepatology. 2005;42(1):165–175. doi: 10.1002/hep.20739.
    1. Yoshida M, Horiuchi T, Uchinami M, Tabo T, Kimura N, Yokomachi J, Doi K, Nakamura T, Tamagawa K, Tanaka K. Intermittent hepatic ischemia-reperfusion minimizes liver metastasis in rats. J Surg Res. 2003;111(2):255–260. doi: 10.1016/S0022-4804(03)00082-9.
    1. Picardo A, Karpoff HM, Ng B, Lee J, Brennan MF, Fong Y. Partial hepatectomy accelerates local tumor growth: potential roles of local cytokine activation. Surgery. 1998;124(1):57–64. doi: 10.1016/S0039-6060(98)70075-3.
    1. Ikeda Y, Matsumata T, Takenaka K, Sasaki O, Soejima K, Sugimachi K. Preliminary report of tumor metastasis during liver regeneration after hepatic resection in rats. Eur J Surg Oncol. 1995;21(2):188–190. doi: 10.1016/S0748-7983(95)90468-9.
    1. Lo CM, Fan ST, Liu CL, Chan SC, Ng IO, Wong J. Living donor versus deceased donor liver transplantation for early irresectable hepatocellular carcinoma. Br J Surg. 2007;94(1):78–86. doi: 10.1002/bjs.5528.
    1. Kulik L, Abecassis M. Living donor liver transplantation for hepatocellular carcinoma. Gastroenterology. 2004;127(5 Suppl 1):S277–S282.
    1. Xiaobin F, Zipei L, Shuguo Z, Jiahong D, Xiaowu L. The Pringle manoeuvre should be avoided in hepatectomy for cancer patients due to its side effects on tumor recurrence and worse prognosis. Med Hypotheses. 2009;72(4):398–401. doi: 10.1016/j.mehy.2008.11.029.
    1. Hanazaki K, Kajikawa S, Shimozawa N, Shimada K, Hiraguri M, Koide N, Adachi W, Amano J. Hepatic resection for hepatocellular carcinoma in diameter of > or = 10 cm. Hepatogastroenterology. 2002;49(44):518–523.
    1. Laurent C, Blanc JF, Nobili S, Sa Cunha A, le Bail B, Bioulac-Sage P, Balabaud C, Capdepont M, Saric J. Prognostic factors and long term survival after hepatic resection for hepatocellular carcinoma originating from noncirrhotic liver. J Am Coll Surg. 2005;201(5):656–662. doi: 10.1016/j.jamcollsurg.2005.05.027.
    1. Liau KH, Ruo L, Shia J, Padela A, Gonen M, Jarnagin WR, Fong Y, D’Angelica MI, Blumgart LH, DeMatteo RP. Outcome of partial hepatectomy for large (> 10 cm) hepatocellular carcinoma. Cancer. 2005;104(9):1948–1955. doi: 10.1002/cncr.21415.
    1. Wakai T, Shirai Y, Sakata J, Kaneko K, Cruz PV, Akazawa K, Hatakeyama K. Anatomic resection independently improves long-term survival in patients with T1-T2 hepatocellular carcinoma. Ann Surg Oncol. 2007;14(4):1356–1365. doi: 10.1245/s10434-006-9318-z.
    1. Tanaka K, Shimada H, Matsumoto C, Matsuo K, Nagano Y, Endo I, Togo S. Anatomic versus limited nonanatomic resection for solitary hepatocellular carcinoma. Surgery. 2008;143(5):607–615. doi: 10.1016/j.surg.2008.01.006.
    1. Shimada K, Sakamoto Y, Esaki M, Kosuge T, Morizane C, Ikeda M, Ueno H, Okusaka T, Arai Y, Takayasu K. Analysis of prognostic factors affecting survival after initial recurrence and treatment efficacy for recurrence in patients undergoing potentially curative hepatectomy for hepatocellular carcinoma. Ann Surg Oncol. 2007;14(8):2337–2347. doi: 10.1245/s10434-007-9415-7.
    1. Cho CS, Gonen M, Shia J, Kattan MW, Klimstra DS, Jarnagin WR, D’Angelica MI, Blumgart LH, De Matteo RP. A novel prognostic nomogram is more accurate than conventional staging systems for predicting survival after resection of hepatocellular carcinoma. J Am Coll Surg. 2008;206(2):281–291. doi: 10.1016/j.jamcollsurg.2007.07.031.

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