Top

Published in:

01-12-2015 | Original Article

Evaluation of the safety and pathological effects of neoadjuvant full-dose gemcitabine combination radiation therapy in patients with biliary tract cancer

Authors: Shogo Kobayashi, Akira Tomokuni, Kunihito Gotoh, Hidenori Takahashi, Hirofumi Akita, Shigeru Marubashi, Terumasa Yamada, Teruki Teshima, Kinji Nishiyama, Masahiko Yano, Hiroaki Ohigashi, Osamu Ishikawa, Masato Sakon

Published in: Cancer Chemotherapy and Pharmacology | Issue 6/2015

Abstract

Purpose

This study aimed to evaluate the safety of neoadjuvant gemcitabine combination radiation therapy in the treatment of biliary tract cancer and to investigate the pathological effects of chemoradiation therapy and its impact on survival.

Methods

Chemoradiation therapy entailed three cycles of full dose of gemcitabine (1000 mg/m² at days 1, 8, and 15, every 4 weeks) with 50–60 Gy radiation (2 Gy/day) at the main tumor and the regional and para-aortic lymph nodes. The present study included 25 patients.

Results

All of the patients were pathologically diagnosed before treatment. The relative dose intensity of gemcitabine was 84 %. The average dose of radiation was 53.8 Gy. Sixty percent of the patients underwent pancreatoduodenectomy, and 32 % underwent hemi-hepatectomy due to bile duct cancer (n = 24) or gall bladder cancer (n = 1). During neoadjuvant therapy, 21 patients (84 %) suffered from adverse events. The common hematological adverse events were leukopenia (44 %) and thrombocytopenia (32 %). It was necessary to exchange the plastic biliary stent in 11 patients (44 %). An R0 resection was achieved in 96 % of the patients, with pathological lymph node metastasis noted in 16 %. Moderate or marked histological changes were noted in 32 % of the patients. The 3-year overall survival rate after the first treatment was 74.6 %, with a 3.2-year observation period.

Conclusions

Neoadjuvant therapy was feasible and is expected to improve survival by controlling regional extension.

Yamanaka K, Hatano E, Kanai M, Tanaka S, Yamamoto K, Narita M, Nagata H, Ishii T, Machimoto T, Taura K, Uemoto S (2014) A single-center analysis of the survival benefits of adjuvant gemcitabine chemotherapy for biliary tract cancer. Int J Clin Oncol 19:485–489CrossRefPubMed

Kobayashi S, Nagano H, Marubashi S, Wada H, Eguchi H, Takeda Y, Tanemura M, Umeshita K, Doki Y, Mori M (2011) Treatment of borderline cases for curative resection of biliary tract cancer. J Surg Oncol 104:499–503CrossRefPubMed

Miyakawa S, Ishihara S, Horiguchi A, Takada T, Miyazaki M, Nagakawa T (2009) Biliary tract cancer treatment: 5584 results from the Biliary Tract Cancer Statistics Registry from 1998 to 2004 in Japan. J Hepatobiliary Pancreat Surg 16:1–7CrossRefPubMed

Hasegawa S, Ikai I, Fujii H, Hatano E, Shimahara Y (2007) Surgical resection of hilar cholangiocarcinoma. Analysis of survival and postoperative complications. World J Surg 31:1256–1263CrossRefPubMed

Kobayashi S, Nagano H, Marubashi S, Takeda Y, Tanemura M, Konishi K, Yoshioka Y, Inoue T, Doki Y, Mori M (2009) Impact of postoperative irradiation after non-curative resection of hilar biliary cancer. J Surg Oncol 100:657–662CrossRefPubMed

Kobayashi S, Miyamoto A, Shimizu J, Kashiwazaki M, Takeda Y, Ueshima S, Kim Y, Kitagawa T, Dono K, Mori M, Doki Y, Nagano H (2011) Comparison of 4-weekly vs 3-weekly gemcitabine as adjuvant chemotherapy following curative resection for biliary tract cancer: a prospective randomized controlled trial. J Cancer Ther 2:703–709CrossRef

Kobayashi S, Nagano H, Sakai D, Eguchi H, Hatano E, Kanai M, Seo S, Taura K, Fujiwara Y, Ajiki T, Takemura S, Kubo S, Yanagimoto H, Toyokawa H, Tsuji A, Terajima H, Morita S, Ioka T (2014) Phase I study of adjuvant gemcitabine or S-1 in patients with biliary tract cancers undergoing major hepatectomy: KHBO1003 study. Cancer Chemother Pharmacol 74:699–709CrossRefPubMed

Glazer ES, Liu P, Abdalla EK, Vauthey JN, Curley SA (2012) Neither neoadjuvant nor adjuvant therapy increases survival after biliary tract cancer resection with wide negative margins. J Gastrointest Surg 16:1666–1671CrossRefPubMed

Katayose Y, Rikiyama T, Motoi F, Yamamoto K, Yoshida H, Morikawa T, Hayashi H, Kanno A, Hirota M, Satoh K, Ariga H, Suzuki M, Ohyauchi M, Kondo Y, Ikeya S, Ogawa Y, Shimosegawa T, Egawa S, Unno M (2011) Phase I trial of neoadjuvant chemoradiation with gemcitabine and surgical resection for cholangiocarcinoma patients (NACRAC study). Hepatogastroenterology 58:1866–1872PubMed

10.

McMasters KM, Tuttle TM, Leach SD, Rich T, Cleary KR, Evans DB, Curley SA (1997) Neoadjuvant chemoradiation for extrahepatic cholangiocarcinoma. Am J Surg 174:605–608CrossRefPubMed

11.

Murad SD, Kim WR, Harnois DM, Douglas DD, Burton J, Kulik LM, Botha JF, Mezrich JD, Chapman WC, Schwartz JJ, Hong JC, Emond JC, Jeon H, Rosen CB, Gores GJ, Heimbach JK (2012) Efficacy of neoadjuvant chemoradiation, followed by liver transplantation, for perihilar cholangiocarcinoma at 12 US centers. Gastroenterology 143:88–98CrossRef

12.

Takahashi H, Ohigashi H, Gotoh K, Marubashi S, Yamada T, Murata M, Ioka T, Uehara H, Yano M, Ishikawa O (2013) Preoperative gemcitabine-based chemoradiation therapy for resectable and borderline resectable pancreatic cancer. Ann Surg 258:1040–1050CrossRefPubMed

13.

Ohigashi H, Ishikawa O, Eguchi H, Takahashi H, Gotoh K, Yamada T, Yano M, Nakaizumi A, Uehara H, Tomita Y, Nishiyama K (2009) Feasibility and efficacy of combination therapy with preoperative full-dose gemcitabine, concurrent three-dimensional conformal radiation, surgery, and postoperative liver perfusion chemotherapy for T3-pancreatic cancer. Ann Surg 250:88–95CrossRefPubMed

14.

Kobayashi S, Nagano H, Marubashi S, Wada H, Eguchi H, Takeda Y, Tanemura M, Doki Y, Mori M (2010) Multi-detector computed tomography for preoperative prediction of postsurgical prognosis of patients with extrahepatic biliary cancer. J Surg Oncol 101:376–383PubMed

15.

Kobayashi S, Nagano H, Hoshino H, Wada H, Marubashi S, Eguchi H, Takeda Y, Tanemura M, Kim T, Shimosegawa E, Hatazawa J, Doki Y, Mori M (2011) Diagnostic value of FDG-PET for lymph node metastasis and outcome of surgery for biliary cancer. J Surg Oncol 103:223–229CrossRefPubMed

16.

Makuuchi M, Thai BL, Takayasu K, Takayama T, Kosuge T, Gunvén P, Yamazaki S, Hasegawa H, Ozaki H (1990) Preoperative portal embolization to increase safety of major hepatectomy for hilar bile duct carcinoma: a preliminary report. Surgery 107:521–527PubMed

17.

Nagino M, Nimura Y, Kamiya J, Kondo S, Uesaka K, Kin Y, Hayakawa N, Yamamoto H (1995) Changes in hepatic lobe volume in biliary tract cancer patients after right portal vein embolization. Hepatology 21:434–439PubMed

18.

Sobin LH, Gospodarowicz M, Wittekind C (2010) International union against cancer, TNM classification of malignant tumors, 7th edn. Wiley, New York

19.

Shimosato Y, Oboshi S, Baba K (1971) Histological evaluation of effects of radiotherapy and chemotherapy for carcinomas. Jpn J Clin Oncol 1:19–35

20.

Dindo D, Demartines N, Clavien PA (2004) Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg 240:205–213PubMedCentralCrossRefPubMed

21.

Bassi C, Dervenis C, Butturini G, Fingerhut A, Yeo C, Izbicki J, Neoptolemos J, Sarr M, Traverso W, Buchler M, International Study Group on Pancreatic Fistula Definition (2005) Postoperative pancreatic fistula: an international study group (ISGPF) definition. Surgery 138(1):8–13CrossRefPubMed

22.

Rahbari NN, Garden OJ, Padbury R, Brooke-Smith M, Crawford M, Adam R, Koch M, Makuuchi M, Dematteo RP, Christophi C, Banting S, Usatoff V, Nagino M, Maddern G, Hugh TJ, Vauthey JN, Greig P, Rees M, Yokoyama Y, Fan ST, Nimura Y, Figueras J, Capussotti L, Büchler MW, Weitz J (2011) Posthepatectomy liver failure: a definition and grading by the International Study Group of Liver Surgery (ISGLS). Surgery 149(5):713–724CrossRefPubMed

23.

Valle J, Wasan H, Palmer DH, Cunningham D, Anthoney A, Maraveyas A, Madhusudan S, Iveson T, Hughes S, Pereira SP, Roughton M, Bridgewater J, ABC-02 Trial Investigators (2010) Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med 362:1273–1281CrossRefPubMed

24.

Nakashima S, Kobayashi S, Sakai D, Tomokuni A, Tomimaru Y, Hama N, Wada H, Kawamoto K, Marubashi S, Eguchi H, Matsuura N, Doki Y, Mori M, Nagano H (2014) Prognostic impact of tumoral and/or peri-tumoral stromal SPARC expressions after surgery in patients with biliary tract cancer. J Surg Oncol 110:1016–1022CrossRefPubMed

25.

Aoba T, Ebata T, Yokoyama Y, Igami T, Sugawara G, Takahashi Y, Nimura Y, Nagino M (2013) Assessment of nodal status for perihilar cholangiocarcinoma: location, number, or ratio of involved nodes. Ann Surg 257:718–725CrossRefPubMed

26.

Yamada D, Kobayashi S, Wada H, Kawamoto K, Marubashi S, Eguchi H, Ishii H, Nagano H, Doki Y, Mori M (2013) Role of crosstalk between interleukin-6 and transforming growth factor-beta 1 in epithelial-mesenchymal transition and chemoresistance in biliary tract cancer. Eur J Cancer 49:1725–1740CrossRefPubMed

27.

Nakashima S, Kobayashi S, Nagano H, Tomokuni A, Tomimaru Y, Asaoka T, Hama N, Wada H, Kawamoto K, Marubashi S, Eguchi H, Doki Y, Mori M (2015) BRCA/Fanconi anemia pathway implicates chemoresistance to gemcitabine in biliary tract cancer. Cancer Sci 106:584–591PubMedCentralCrossRefPubMed

Title: Evaluation of the safety and pathological effects of neoadjuvant full-dose gemcitabine combination radiation therapy in patients with biliary tract cancer
Authors: Shogo Kobayashi
Akira Tomokuni
Kunihito Gotoh
Hidenori Takahashi
Hirofumi Akita
Shigeru Marubashi
Terumasa Yamada
Teruki Teshima
Kinji Nishiyama
Masahiko Yano
Hiroaki Ohigashi
Osamu Ishikawa
Masato Sakon
Publication date: 01-12-2015
Publisher: Springer Berlin Heidelberg
Published in: Cancer Chemotherapy and Pharmacology / Issue 6/2015
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-015-2908-3

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 6/2015

A study to explore the correlation of ABCB1, ABCG2, OCT1 genetic polymorphisms and trough level concentration with imatinib mesylate-induced thrombocytopenia in chronic myeloid leukemia patients

Phase 1a/1b and pharmacogenetic study of docetaxel, oxaliplatin and capecitabine in patients with advanced cancer of the stomach or the gastroesophageal junction

Chemotherapy-induced neutropenia as a prognostic factor in patients with unresectable pancreatic cancer

Phase II study of lapatinib and capecitabine in second-line treatment for metastatic pancreatic cancer

Elevated preoperative plasma D-dimer level is a useful predictor of chemoresistance and poor disease outcome for serous ovarian cancer patients

Phase I study of nintedanib in combination with pemetrexed as second-line treatment of Japanese patients with advanced non-small cell lung cancer

Keynote webinar | Spotlight on antibody–drug conjugates in cancer