Exploratory phase II trial in a multicenter setting to evaluate the clinical value of a chemosensitivity test in patients with gastric cancer (JACCRO-GC 04, Kubota memorial trial)

Nobuhiko Tanigawa, Hiroki Yamaue, Shigekazu Ohyama, Shinichi Sakuramoto, Takao Inada, Yasuhiro Kodera, Yuko Kitagawa, Kenji Omura, Masanori Terashima, Yuh Sakata, Atsushi Nashimoto, Toshiharu Yamaguchi, Keisho Chin, Eiji Nomura, San-Woong Lee, Masahiro Takeuchi, Masashi Fujii, Toshifusa Nakajima, Nobuhiko Tanigawa, Hiroki Yamaue, Shigekazu Ohyama, Shinichi Sakuramoto, Takao Inada, Yasuhiro Kodera, Yuko Kitagawa, Kenji Omura, Masanori Terashima, Yuh Sakata, Atsushi Nashimoto, Toshiharu Yamaguchi, Keisho Chin, Eiji Nomura, San-Woong Lee, Masahiro Takeuchi, Masashi Fujii, Toshifusa Nakajima

Abstract

Background: Although postoperative adjuvant chemotherapy with S-1, an oral fluoropyrimidine, has become a standard of care for gastric cancer in Japan, nonresponders may suffer from the cost and adverse reactions without clinical benefit. This multicenter exploratory phase II trial was conducted to see whether a chemosensitivity test, the collagen gel droplet embedded culture drug sensitivity test (CD-DST), can adequately select patients for chemotherapy.

Methods: The CD-DST using four different concentrations of 5-fluorouracil was conducted with resected specimens from preregistered patients who underwent gastrectomy with D2 or more extensive lymphadenectomy. Patients who were histopathologically confirmed to have stage II or greater disease without distant metastasis were eligible for final enrollment. All patients underwent protocol-specified adjuvant chemotherapy with S-1. Three-year relapse-free survival was compared between patients determined as sensitive by the CD-DST (responders) and those deemed insensitive (nonresponders). Appropriate cutoff values for in vitro growth inhibition were defined when the hazard ratio for relapse in responders and the log-rank P values were at their minimum.

Results: Of the 311 patients enrolled, 14 were ineligible and 27 failed to start the protocol treatment. The CD-DST failed in 64 other patients, and survival analyses were conducted with the remaining 206 patients (39 stage II disease, 155 stage III disease, and 12 stage IV disease). The outcome of patients who were determined to be responders was significantly superior to that of nonresponders regardless of the 5-fluorouracil concentrations, although no differences in clinicopathologic characteristics were observed between the two groups, except for age.

Conclusions: The CD-DST identified those who benefit from adjuvant chemotherapy. It deserves further evaluation in the setting of a prospective randomized trial. ClinicalTrials.gov identifier: NCT00287755.

Keywords: Appropriate cutoff values; Chemosensitivity test; Nonresponder; Relapse-free survival; Responder.

Figures

Fig. 1
Fig. 1
Study schema
Fig. 2
Fig. 2
CONSORT diagram
Fig. 3
Fig. 3
Forest plot to identify appropriate cutoff values for each of the four in vitro 5-fluorouracil concentrations for a total of 206 patients. CI confidence interval, HR hazard ratio, Non nonresponders, Res responders, RFS relapse-free survival
Fig. 4
Fig. 4
Relapse-free survival (RFS) of responder (Res) and nonresponder (Non) groups classified by a growth inhibition rate of 60 % at an in vitro 5-fluorouracil concentration of 1.0 µg/ml. CI confidence interval, HR hazard ratio

References

    1. Sakuramoto S, Sasako M, Yamaguchi T, Kinoshita T, Fujii M, Nashimoto A, et al. Adjuvant chemotherapy for gastric cancer with S-1, on oral fluoropyrimidine. N Engl J Med. 2007;357:1810–1820. doi: 10.1056/NEJMoa072252.
    1. Sasako M, Sakuramoto S, Takai H, Kinoshita T, Furukawa H, Yamaguchi T, et al. Five-year outcomes of a randomized phase III trial comparing adjuvant chemotherapy with S-1 versus surgery alone in stage II or III gastric cancer. J Clin Oncol. 2011;29:4387–4393. doi: 10.1200/JCO.2011.36.5908.
    1. Tanigawa N, Mizuno Y, Hashimura T, Honda K, Satomura K, Hikasa Y, et al. Comparison of drug sensitivity among tumor cells within a tumor, between primary and metastases, and between different metastases in the human tumor-colony forming assay. Cancer Res. 1984;44:2309–2312.
    1. Trope C, Hakansson L, Dencker H. Heterogeneity of human adenocarcinomas of the colon and the stomach as regards sensitivity to cytostatic drugs. Neoplasma. 1975;22:423–430.
    1. Blorklund A, Hakansson L, Stenstam B, Trope C, Akerman M. On heterogeneity of non-Hodgkin’s lymphomas as regards sensitivity to cytostatic drugs. An in vitro study. Eur J Cancer. 1980;16:647–654. doi: 10.1016/0014-2964(80)90205-4.
    1. Tsuruo T, Fidler IJ. Differences in drug sensitivity among tumor cells from parental tumors, selected varients, and spontaneous metastases. Cancer Res. 1981;41:3058–3064.
    1. Tanigawa N, Kern DH, Hikasa Y, Morton DL. Rapid assay for evaluating the chemosensitivity of human tumors in soft agar culture. Cancer Res. 1982;42:2159–2164.
    1. Sondak VK, Bertelsen CA, Tanigawa N, Hilderbrand-Zanki SU, Morton DL, Kern DH. Clinical correlation with chemosensitivities measured in a rapid thymidine incorporation assay. Cancer Res. 1984;44:1725–1732.
    1. Vescio RA, Connors KM, Kubota T, Hoffman RM. Correlation of histology and drug response of human tumors grown in native-state three-dimensional histoculture and in nude mice. Proc Natl Acad Sci U S A. 1991;88:5163–5166. doi: 10.1073/pnas.88.12.5163.
    1. Yamaue H, Tanimura H, Noguchi K, Hotta T, Tani M, Tsunoda T, et al. Chemosensitivity testing of fresh human gastric cancer with highly purified tumour cells using the MTT assay. Br J Cancer. 1992;66:794–799. doi: 10.1038/bjc.1992.362.
    1. Weisenthal LM. Clinical correlations for cell culture assays based on the concept of total cell kill. Contrib Gynecol Obstet. 1994;19:82–90.
    1. Yamaue H, Tanimura H, Nakamori M, Noguchi K, Iwahashi M, Tani M, et al. Clinical evaluation of chemosensitivity testing for patients with colorectal cancer using MTT assay. Dis Colon Rectum. 1996;39:416–422. doi: 10.1007/BF02054057.
    1. Kondo T, Yamauchi M, Tominaga S. Evaluation of usefulness of in vitro drug sensitivity testing for adjuvant chemotherapy of stomach cancer. Int J Clin Oncol. 2000;5:174–182. doi: 10.1007/PL00012034.
    1. Cortazar P, Johnson BE. Reviews of the efficacy of individualized chemotherapy selected by in vitro drug sensitivity testing for patients with cancer. J Clin Oncol. 1999;17:1625–1631.
    1. Samson DJ, Seidenfeld J, Ziegler K, Aronson N. Chemotherapy sensitivity and resistance assays: a systemic review. J Clin Oncol. 2004;22:3618–3630. doi: 10.1200/JCO.2004.04.077.
    1. Japanese Gastric Cancer Association: Gastric cancer treatment guidelines 2010. Tokyo: Kanehara; 2010.
    1. Association Japanese Gastric Cancer. Japanese classification of gastric carcinoma – 2nd English edition –. Gastric Cancer. 1998;1:10–24. doi: 10.1007/PL00011681.
    1. Maejima K, Tokunaga A, Kiyama T, Kanno H, Bou H, Watanabe M, et al. Chemosensitivity test for 5-fluorouracil and 5-chloro-2,4-dihydroxypyridine predicts outcome of gastric cancer patients receiving S-1 postoperatively. Gastric Cancer. 2010;13:231–237. doi: 10.1007/s10120-010-0564-1.
    1. Naitoh H, Yamamoto H, Murata S, Kobayashi H, Inoue K, Tani T. Stratified phase II trial to establish the usefulness of the collagen gel droplet embedded culture-drug sensitivity test (CD-DST) for advanced gastric cancer. Gastric Cancer. 2014;7:630–637. doi: 10.1007/s10120-013-0320-4.
    1. Gu F, Ma Y, Zhang Z, Zhao J, Kobayashi H, Zhang L, et al. Expression of Stat3 and Notch1 is associated with cisplatin resistance in head and neck squamous cell carcinoma. Oncol Rep. 2010;23:671–676.
    1. Higashiyama M, Oda K, Okami J, Maeda J, Kodama K, Takami K, et al. In vitro chemosensitivity test using the collagen gel droplet-embedded drug sensitivity test (CD-DST) for malignant pleural mesothelioma: possibility of clinical application. Ann Thorac Cardiovasc Surg. 2008;14:355–362.
    1. Higashiyama M, Oda K, Okami J, Maeda J, Kodama K, Imamura F, et al. Predication of chemosetherapeutic effect on postoperative small cell lung cancer patients. Lung Cancer. 2010;68:472–477. doi: 10.1016/j.lungcan.2009.07.005.
    1. Kawamura M, Gika M, Abiko T, Inoue Y, Oyama T, Izumi Y, et al. Clinical evaluation of chemosensitivity test for patients with unresectable non-small cell lung cancer (NSCLC) using collagen gel droplet embedded culture-drug sensitivity test (CD-DST) Cancer Chemother Pharmacol. 2007;59:507–513. doi: 10.1007/s00280-006-0292-8.
    1. Takamura Y, Kobayashi H, Taguchi T, Motoyama K, Inaji H, Noguchi S. Prediction of chemotherapeutic response by collagen gel droplet embedded culture drug sensitivity test in human breast cancers. Int J Cancer. 2002;98:450–455. doi: 10.1002/ijc.10208.
    1. Kobayashi H, Higashiyama M, Minamigawa K, Tanisaka K, Takano T, Yokouchi H, et al. Examination of in vitro chemosensitivity test using collagen gel droplet culture method with colorimetric endpoint quantification. Jpn J Cancer Res. 2001;92:203–210. doi: 10.1111/j.1349-7006.2001.tb01083.x.
    1. Kobayashi H. Development of a new in vitro chemosensitivity test using collagen gel droplet embedded culture and image analysis for clinical usefulness. Recent Results Cancer Res. 2003;161:48–61. doi: 10.1007/978-3-642-19022-3_5.
    1. Heggie GD, Sommadossi JP, Cross DS, Huster WJ, Diasio RB. Clinical pharmacokineticsof 5-fluorouracil and its metabolites in plasma, urine, and bile. Cancer Res. 1987;47:2203–2206.
    1. Danenberg PV. Thymidilate synthase––a target enzyme in cancer chemotherapy. Biochem Biophys Acta. 1977;473:73–92.
    1. Peters GJ, Laurensse E, Leyva A, Lankelma J, Pnedo HM. Sensivity of human, murine, and rat cells drug metabolizing enzymes. Cancer Res. 1986;46:20–28. doi: 10.1016/S0065-230X(08)60036-6.
    1. Kodera Y, Ito S, Fujiwara M, Mochizuki Y, Nakayama G, Ohashi N, et al. Gene expression of 5-fluorouracil metabolic enzymes in primary gastric cancer: correlation with drug sensitivity against 5-fluorouracil. Cancer Lett. 2007;252:307–313. doi: 10.1016/j.canlet.2007.01.006.
    1. Kubota T, Sasano N, Abe O, Nakao I, Kawamura E, Saito T, et al. Potential of the histoculture drug-response assay to contribute to cancer patient survival. Clin Cancer Res. 1995;1:1537–1543.
    1. Furukawa T, Kubota T, Hoffman RM. Clinical applications of the histoculture drug response assay. Clin Cancer Res. 1995;1:305–311.
    1. Xu JM, Song ST, Tang ZM, Jiang ZF, Liu XQ, Zhou L, et al. Predictive chemotherapy of advanced breast cancer directed by MTT assay in vitro. Breast Cancer Res Treat. 1999;53:77–85. doi: 10.1023/A:1006122912146.
    1. Kurbacher CM, Cree IA, Bruckner HW, Brenne U, Kurbacher JA, Muller K, et al. Use of an ex vivo ATP luminescence assay to direct chemotherapy for recurrent ovarian cancer. Anticancer Drugs. 1998;9:51–57. doi: 10.1097/00001813-199801000-00006.
    1. Kobayashi H, Tanisaka K, Doi O, Kodama K, Higashiyama M, Nakagawa H, et al. An in vitro chemosensitivity test for solid human tumors using collagen gel droplet embedded cultures. Int J Oncol. 1997;11:449–455.
    1. Schrag D, Garewal HS, Burstein HJ, Samson DJ, Von Hoff DD, Somerfield ASCO working group on chemotherapy sensitivity and resistance assays. American Society of Clinical Oncology technology assessment: chemotherapy sensitivity and resistance assays. J Clin Oncol. 2004;12:3631–3638. doi: 10.1200/JCO.2004.05.065.
    1. Fruehauf JP, Alberts DS. In vitro drug resistance versus chemosensitivity: two sides of different coins. J Clin Oncol. 2005;23:3646–3648. doi: 10.1200/JCO.2005.05.281.
    1. Ugurel S, Schadendorf D, Pfohler C, Neuber K, Thoelke A, Ulrich J, et al. In vitro drug sensitivity predicts response and survival after individualized sensitivity-directed chemotherapy in metastatic melanoma: a multicenter phase II trial of the Dermotologic Cooperative Oncology Group. Clin Cancer Res. 2006;12:5454–5463. doi: 10.1158/1078-0432.CCR-05-2763.
    1. Kodera Y, Ito S, Fujiwara M, Mochizuki Y, Ohashi N, Ito Y, et al. In vitro chemosensitivity test to predict chemosensitivity for paclitaxel, using human gastric carcinoma tissues. In J Clin Oncol. 2006;11:449–453. doi: 10.1007/s10147-006-0618-x.
    1. Mi Z, Holmes FA, Hellerstedt B, Pippen J, Collea R, Backner A, et al. Feasibility assessment of a chemoresponse assay to predict pathologic response in neoadjuvant chemotherapy for breast cancer patients. Anticancer Res. 2008;28:1733–1740.
    1. Wu B, Zhu JS, Zhang Y, Shen WM, Zhang Q. Predictive value of MTT assay as an in vitro chemosensitivity testing for gastric cancer: one institution’s experience. World J Gastroenterol. 2008;14:3064–3068. doi: 10.3748/wjg.14.3064.
    1. Burstein HJ, Mangu PB, Somerfield MR, Schrag D, Samson D, Holt L, et al. American Society of Clinical Oncology clinical practice guideline update on the use of chemotherapy sensitivity and resistance assays. J Clin Oncol. 2011;29:3328–3330. doi: 10.1200/JCO.2011.36.0354.
    1. Bang YJ, Kim YW, Yang HK, Chung HC, Park YK, Lee KH, Lee KW, Kim YH, Noh SH. Adjuvant capecitabine and oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): a phase 3 open-label, randomised controlled trial. Lancet. 2012;379:315–321. doi: 10.1016/S0140-6736(11)61873-4.

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