Abstract
Purpose
To improve the efficacy of adjuvant chemotherapy with mitomycin-C and fluoropyrimidine (Mf) in gastric cancer, we designed a new regimen (iceMFP) and investigated in a phase III study.
Methods
We randomly assigned 640 patients with resectable and macroscopically recognizable serosa-invading gastric cancer to Mf or iceMFP group during operation. The Mf consisted of intravenous mitomycin-C (20 mg/m2) at 3–6 weeks after surgery and oral doxifluridine (460–600 mg/m2/day) starting 4 weeks after the administration of mitomycin-C and continuing for 3 months. The iceMFP consisted of intraoperative intraperitoneal cisplatin (100 mg), intravenous mitomycin-C (15 mg/m2) on postoperative day 1, followed by oral doxifluridine for 12 months, and six monthly intravenous cisplatin (60 mg/m2). The primary endpoint was 3-year recurrence-free survival (RFS).
Results
A total of 521 patients (258 in Mf, 263 in iceMFP) were eligible for analysis after excluding patients with stage I disease, distant metastasis, or R1 resection. With a median follow-up of 3.5 years, the iceMFP group had a higher RFS (hazard ratio [HR] 0.70; 95 % confidence interval [CI] 0.54–0.90; p = 0.006; 3-year RFS 60 % vs. 50 %) and overall survival (HR 0.71; 95 % CI 0.53–0.95; p = 0.02; 3-year overall survival, 71 vs. 60 %) compared with the Mf group. This was confirmed at extension analysis after a median 6.6 years of follow-up. Both regimens were well tolerated with no differences in surgical complications.
Conclusion
The efficacy of adjuvant Mf was significantly improved by the additional therapeutic strategies of iceMFP. Considering negative results of AMC0201, these suggest that early initiation of chemotherapy and/or intraperitoneal cisplatin played a distinct role in the improved efficacy.
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References
Macdonald JS, Smalley SR, Benedetti J, Hundahl SA, Estes NC, Stemmermann GN, Haller DG, Ajani JA, Gunderson LL, Jessup JM, Martenson JA (2001) Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med 345(10):725–730
Cunningham D, Allum WH, Stenning SP, Thompson JN, Van de Velde CJ, Nicolson M, Scarffe JH, Lofts FJ, Falk SJ, Iveson TJ, Smith DB, Langley RE, Verma M, Weeden S, Chua YJ, MAGIC Trial Participants (2006) Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med 355(1):11–20
Sakuramoto S, Sasako M, Yamaguchi T, Kinoshita T, Fujii M, Nashimoto A, Furukawa H, Nakajima T, Ohashi Y, Imamura H, Higashino M, Yamamura Y, Kurita A, Arai K (2007) Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine. N Engl J Med 357(18):1810–1820
Bang YJ, Kim YW, Yang HK, Chung HC, Park YK, Lee KH, Lee KW, Kim YH, Noh SI, Cho JY, Mok YJ, Ji J, Yeh TS, Button P, Sirzen F, Noh SH (2012) Adjuvant capecitabine and oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): a phase 3 open-label, randomised controlled trial. Lancet 379(9813):315–321
Koo DH, Lee JL, Kim TW, Chang HM, Ryu MH, Yook JH, Oh ST, Kim BS, Lee JS, Kang YK (2007) Adjuvant chemotherapy with 5-fluorouracil, doxorubicin and mitomycin-C (FAM) for 6 months after curative resection of gastric carcinoma. Eur J Surg Oncol 33(7):843–848
Chang HM, Jung KH, Kim TY, Kim WS, Yang HK, Lee KU, Choe KJ, Heo DS, Bang YJ, Kim NK (2002) A phase III randomized trial of 5-fluorouracil, doxorubicin, and mitomycin C versus 5-fluorouracil and mitomycin C versus 5-fluorouracil alone in curatively resected gastric cancer. Ann Oncol 13(11):1779–1785
Earle CC, Maroun JA (1999) Adjuvant chemotherapy after curative resection for gastric cancer in non-Asian patients: revisiting a meta-analysis of randomised trials. Eur J Cancer 35(7):1059–1064
Mari E, Floriani I, Tinazzi A, Buda A, Belfiglio M, Valentini M, Cascinu S, Barni S, Labianca R, Torri V (2000) Efficacy of adjuvant chemotherapy after curative resection for gastric cancer: a meta-analysis of published randomised trials. A study of the GISCAD (Gruppo Italiano per lo Studio dei Carcinomi dell’Apparato Digerente). Ann Oncol 11(7):837–843
Sakamoto J, Morita S, Kodera Y, Rahman M, Nakao A (2004) Adjuvant chemotherapy for gastric cancer in Japan: global and Japanese perspectives. Cancer Chemother Pharmacol 54(Suppl 1):S25–S31
Paoletti X, Oba K, Burzykowski T, Michiels S, Ohashi Y, Pignon JP, Rougier P, Sakamoto J, Sargent D, Sasako M, Van Cutsem E, Buyse M (2010) Benefit of adjuvant chemotherapy for resectable gastric cancer: a meta-analysis. JAMA 303(17):1729–1737
Cirera L, Balil A, Batiste-Alentorn E, Tusquets I, Cardona T, Arcusa A, Jolis L, Saigi E, Guasch I, Badia A, Boleda M (1999) Randomized clinical trial of adjuvant mitomycin plus tegafur in patients with resected stage III gastric cancer. J Clin Oncol 17(12):3810–3815
Kang Y-K, Chang H-M, Yook JH, Ryu M-H, Park I, Min YJ, Zang DY, Kim GY, Yang DH, Jang SJ, Park YS, Lee J-L, Kim TW, Oh ST, Park BK, Jung H-Y, Kim BS (2013) Adjuvant chemotherapy for gastric cancer: a randomized phase 3 trial of mitomycin-C plus either short-term doxifluridine or long-term doxifluridine plus cisplatin after curative D2 gastrectomy (AMC0201). Br J Cancer 108(6):1245–1251
Kang Y-K, Change H-M, Zang DY, Lee J-L, Kim T-W, Yang DH, Jang SJ, Yook JH, Oh ST, Kim BS (2008) Postoperative adjuvant chemotherapy for grossly serosa-positive advanced gastric cancer: A randomized phase III trial of intraperitoneal cisplatin and early mitomycin-C plus long-term doxifluridine puls cisplatin (iceMFP) versus mitomycin-C plus short-term doxifluridine (Mf) (AMC0101) (NCT00296322). J Clin Oncol 28(May 20 suppl; abstr LBA4511)
Takiguchi N, Nakajima N, Saitoh N, Fujimoto S, Nakazato H (2000) A phase III randomized study comparing oral doxifluridine and oral 5-fluorouracil after curative resection of gastric cancer. Int J Oncol 16(5):1021–1027
Bouche O, Ychou M, Burtin P, Bedenne L, Ducreux M, Lebreton G, Baulieux J, Nordlinger B, Martin C, Seitz JF, Tigaud JM, Echinard E, Stremsdoerfer N, Milan C, Rougier P (2005) Adjuvant chemotherapy with 5-fluorouracil and cisplatin compared with surgery alone for gastric cancer: 7-year results of the FFCD randomized phase III trial (8801). Ann Oncol 16(9):1488–1497
Cascinu S, Labianca R, Barone C, Santoro A, Carnaghi C, Cassano A, Beretta GD, Catalano V, Bertetto O, Barni S, Frontini L, Aitini E, Rota S, Torri V, Floriani I, Pozzo C, Rimassa L, Mosconi S, Giordani P, Ardizzoia A, Foa P, Rabbi C, Chiara S, Gasparini G, Nardi M, Mansutti M, Arnoldi E, Piazza E, Cortesi E, Pucci F, Silva RR, Sobrero A, Ravaioli A (2007) Adjuvant treatment of high-risk, radically resected gastric cancer patients with 5-fluorouracil, leucovorin, cisplatin, and epidoxorubicin in a randomized controlled trial. J Natl Cancer Inst 99(8):601–607
Lee SE, Ryu KW, Nam BH, Lee JH, Choi IJ, Kook MC, Park SR, Kim YW (2009) Prognostic significance of intraoperatively estimated surgical stage in curatively resected gastric cancer patients. J Am Coll Surg 209(4):461–467
Kim JM, Jung H, Lee JS, Lee HH, Song KY, Park CH, Jeon MH (2012) Clinical implication of serosal change in pathologic subserosa-limited gastric cancer. World J Surg 36(2):355–361. doi:10.1007/s00268-011-1334-x
Fuchs CS, Tepper JE, Niedzwiecki D, Hollis D, Mamon HJ, Swanson R, Haller DG, Dragovich T, Alberts SR, Bjarnason GA, Willett CG, Enzinger PC, Goldberg RM, Venook AP, Mayer RJ (2011) Postoperative adjuvant chemoradiation for gastric or gastroesophageal junction (GEJ) adenocarcinoma using epirubicin, cisplatin, and infusional (CI) 5-FU (ECF) before and after CI 5-FU and radiotherapy (CRT) compared with bolus 5-FU/LV before and after CRT: Intergroup trial CALGB 80101. J Clin Oncol 29(suppl; abstr 4003)
Bejetta E, Floriani I, Bartolomeo MD, Labianca R, Landi L, Santoro A, Casaretti R, Pasquini E, Fabio FD, Rondini E, Pinotti G, Bidoli P, Rosati G, Mambrini A, Ciarlo A, Cordio SS, Ricci S, Frassineti L, Costanzo FD, Bochicchio AM (2012) Intergroup trial of adjuvant chemotherapy in adenocarcinoma of the stomach (ITACA-S) trial: comparison of a sequential treatment with irinotecan (CPT-11) plus 5-fluorouracil (5-FU)/folinic acid (LV) followed by docetaxel and cisplatin versus a 5-FU/LV regimen as postoperative treatment for radically resected gastric cancer. J Clin Oncol 30(suppl; abstr LBA4001)
Eggermont AM, Steller EP, Sugarbaker PH (1987) Laparotomy enhances intraperitoneal tumor growth and abrogates the antitumor effects of interleukin-2 and lymphokine-activated killer cells. Surgery 102(1):71–78
Fisher B, Gunduz N, Coyle J, Rudock C, Saffer E (1989) Presence of a growth-stimulating factor in serum following primary tumor removal in mice. Cancer Res 49(8):1996–2001
Fisher B, Gunduz N, Saffer EA (1983) Influence of the interval between primary tumor removal and chemotherapy on kinetics and growth of metastases. Cancer Res 43(4):1488–1492
Biagi JJ, Raphael MJ, Mackillop WJ, Kong W, King WD, Booth CM (2011) Association between time to initiation of adjuvant chemotherapy and survival in colorectal cancer: a systematic review and meta-analysis. JAMA 305(22):2335–2342
Dedrick RL (1985) Theoretical and experimental bases of intraperitoneal chemotherapy. Semin Oncol 12(3 Suppl 4):1–6
Shimada T, Nomura M, Yokogawa K, Endo Y, Sasaki T, Miyamoto K, Yonemura Y (2005) Pharmacokinetic advantage of intraperitoneal injection of docetaxel in the treatment for peritoneal dissemination of cancer in mice. J Pharm Pharmacol 57(2):177–181. doi:10.1211/0022357055380
D’Angelica M, Gonen M, Brennan MF, Turnbull AD, Bains M, Karpeh MS (2004) Patterns of initial recurrence in completely resected gastric adenocarcinoma. Ann Surg 240(5):808–816
Yoo CH, Noh SH, Shin DW, Choi SH, Min JS (2000) Recurrence following curative resection for gastric carcinoma. Br J Surg 87(2):236–242
Matharu G, Tucker O, Alderson D (2011) Systematic review of intraperitoneal chemotherapy for gastric cancer. Br J Surg 98(9):1225–1235. doi:10.1002/bjs.7586
Yan TD, Black D, Sugarbaker PH, Zhu J, Yonemura Y, Petrou G, Morris DL (2007) A systematic review and meta-analysis of the randomized controlled trials on adjuvant intraperitoneal chemotherapy for resectable gastric cancer. Ann Surg Oncol 14(10):2702–2713. doi:10.1245/s10434-007-9487-4
Yu W, Whang I, Chung HY, Averbach A, Sugarbaker PH (2001) Indications for early postoperative intraperitoneal chemotherapy of advanced gastric cancer: results of a prospective randomized trial. World J Surg 25(8):985–990
Miyashiro I, Furukawa H, Sasako M, Yamamoto S, Nashimoto A, Nakajima T, Kinoshita T, Kobayashi O, Arai K (2011) Randomized clinical trial of adjuvant chemotherapy with intraperitoneal and intravenous cisplatin followed by oral fluorouracil (UFT) in serosa-positive gastric cancer versus curative resection alone: final results of the Japan Clinical Oncology Group trial JCOG9206-2. Gastric Cancer 14(3):212–218. doi:10.1007/s10120-011-0027-3
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The authors are indebted to Prof. J. Patrick Barron, Chairman of the Department of International Medical Communications of Tokyo Medical University, for his pro bono review of this manuscript.
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Kang, YK., Yook, J.H., Chang, HM. et al. Enhanced efficacy of postoperative adjuvant chemotherapy in advanced gastric cancer: results from a phase 3 randomized trial (AMC0101). Cancer Chemother Pharmacol 73, 139–149 (2014). https://doi.org/10.1007/s00280-013-2332-5
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DOI: https://doi.org/10.1007/s00280-013-2332-5