Phase I study of neoadjuvant chemoradiotherapy with S-1 plus biweekly cisplatin for advanced gastric cancer patients with lymph node metastasis: -KOGC04-

Radiation Oncology

Yuko Kitagawa²  Naoyuki Shigematsu¹  Hiroya Takeuchi²  Osamu Kawaguchi¹  Yoshiro Saikawa²  Hirofumi Kawakubo²  Kazumasa Fukuda²  Junichi Fukada¹  Tsunehiro Takahashi²  Satoru Matsuda² 

[1] Department of Radiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan;Department of Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan

关键词: Phase I;    Cisplatin;    S-1;    Chemoradiotherapy;    Neoadjuvant;    Gastric cancer;   

Others  :  815117
DOI  :  10.1186/1748-717X-9-9

 received in 2013-08-01, accepted in 2013-10-23,  发布年份 2014

【 摘 要 】

Background

In patients with highly advanced gastric cancer, the recurrence rate remains high and the prognosis disappointing. We previously reported a phase I study of a neoadjuvant chemoradiotherapy of S-1 plus weekly cisplatin. Although adequate safety and efficacy were reported, myelosuppression was frequently observed, leading to treatment delay in several cases. To decrease toxicity and improve efficacy, we planned a phase I study with a modified chemotherapy regimen with biweekly cisplatin.

Methods

Patients with advanced gastric cancer and lymph node metastasis who were treated by our institution between 2011 and 2012 were eligible for inclusion. The initial chemoradiotherapy schedule consisted of 6 weeks of S-1 orally administered on days 1–15 with an escalating dose of cisplatin administered on days 1 and 15. The starting dose (level 1) of cisplatin was 15 mg/m², the second dose (level 2) was 20 mg/m², and the third dose (level 3) was 25 mg/m². Radiation of 40 Gy was administered in 20 fractions. After initial chemoradiotherapy, one cycle of combination chemotherapy with S-1 plus cisplatin was delivered. The second cycle was 42 days in duration and included S-1 administered on days 1–29 plus biweekly cisplatin administered on days 1, 15, and 29. After neoadjuvant treatment, a curative gastrectomy with extended (D2) lymph node dissection was planned.

Results

Nine patients were enrolled. At level 3, one patient had dose-limiting grade 3 diarrhea. Another patient experienced grade 3 nausea and intended to discontinue the treatment. Overall, because 2 of 3 patients experienced dose-limiting toxicity at level 3, we confirmed level 3 (Cisplatin 25 mg/m²) as the maximum tolerated dose and level 2 (Cisplatin 20 mg/m²) as the recommended dose (RD). The response rate was 78%, and 8 patients underwent curative gastrectomy. Resected specimens showed a histological response in 6 patients (75%), including one with a pathological complete response.

Conclusions

In this phase I trial, RD of cisplatin was identified as 20 mg/m². Generally, S-1 plus biweekly cisplatin can be given safely with concurrent radiation. We have initiated a multicenter phase II trial to further confirm the efficacy and safety of this approach.

Trial registration

UMIN000008941

【 授权许可】

   
2014 Matsuda et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

【 参考文献 】

• [1]Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM: Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 2010, 127:2893-917.
• [2]Songun I, Putter H, Kranenbarg EM, Sasako M, van de Velde CJ: Surgical treatment of gastric cancer: 15-year follow-up results of the randomised nationwide Dutch D1D2 trial. Lancet Oncol 2010, 11:439-49.
• [3]Wu CW, Hsiung CA, Lo SS, Hsieh MC, Chen JH, Li AF, Lui WY, Whang-Peng J: Nodal dissection for patients with gastric cancer: a randomised controlled trial. Lancet Oncol 2006, 7:309-15.
• [4]Maruyama K, Kaminishi M, Hayashi K, Isobe Y, Honda I, Katai H, Arai K, Kodera Y, Nashimoto A, Japanese Gastric Cancer Association Registration Committee: Gastric cancer treated in 1991 in Japan: data analysis of nationwide registry. Gastric Cancer 2006, 9:51-66.
• [5]Sano T, Sasako M, Kinoshita T, Maruyama K: Recurrence of early gastric cancer. Follow-up of 1475 patients and review of the Japanese literature. Cancer 1993, 72:3174-8.
• [6]Sasako M, Sakuramoto S, Katai H, Kinoshita T, Furukawa H, Yamaguchi T, Nashimoto A, Fujii M, Nakajima T, Ohashi Y: 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 Clinical Oncol 2011, 29:4387-93.
• [7]Yoo CH, Noh SH, Shin DW, Choi SH, Min JS: Recurrence following curative resection for gastric carcinoma. Br J Surg 2000, 87:236-42.
• [8]Japanese Gastric Cancer Association: Japanese classification of gastric carcinoma: 3rd English edition. Gastric Cancer 2011, 14:101-12.
• [9]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, ACTS-GC Group: Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine. New Engl J Med 2007, 357:1810-20.
• [10]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: Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. New Engl J Med 2006, 355:11-20.
• [11]Macdonald JS, Smalley SR, Benedetti J, Hundahl SA, Estes NC, Stemmermann GN, Haller DG, Ajani JA, Gunderson LL, Jessup JM, Martenson JA: Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. New Engl J Med 2001, 345:725-30.
• [12]Smalley SR, Benedetti JK, Haller DG, Hundahl SA, Estes NC, Ajani JA, Gunderson LL, Goldman B, Martenson JA, Jessup JM, Stemmermann GN, Blanke CD, Macdonald JS: Updated analysis of SWOG-directed intergroup study 0116: a phase III trial of adjuvant radiochemotherapy versus observation after curative gastric cancer resection. J Clin Oncol 2012, 30:2327-33.
• [13]Japanese Gastric Cancer Association: Japanese gastric cancer treatment guidelines 2010 (ver. 3). Gastric Cancer 2011, 14:113-123.
• [14]Kassam Z, Mackay H, Buckley CA, Fung S, Pintile M, Oza A, Brierley J, Swallow C, Cummings B, Knox JJ, Kim J, Wong R, Siu L, Feld R, Ringash J: Adjuvant chemoradiation for gastric cancer with infusional 5-fluorouracil and cisplatin: a phase I study. Curr Oncol 2010, 17:34-41.
• [15]Lee J, Lim do H, Kim S, Park SH, Park JO, Park YS, Lim HY, Choi MG, Sohn TS, Noh JH, Bae JM, Ahn YC, Sohn I, Jung SH, Park CK, Kim KM, Kang WK: Phase III trial comparing capecitabine plus cisplatin versus capecitabine plus cisplatin with concurrent capecitabine radiotherapy in completely resected gastric cancer with D2 lymph node dissection: the ARTIST trial. J Clin Oncol 2012, 30:268-273.
• [16]Yoshikawa T, Sasako M, Yamamoto S, Sano T, Imamura H, Fujitani K, Oshita H, Ito S, Kawashima Y, Fukushima N: Phase II study of neoadjuvant chemotherapy and extended surgery for locally advanced gastric cancer. Br J Surg 2009, 96:1015-22.
• [17]Nashimoto A, Yabusaki H, Nakagawa S, Takii Y, Tsuchiya Y, Otsuo T: Preoperative chemotherapy with S-1 and cisplatin for highly advanced gastric cancer. Anticancer Res 2009, 29:4689-96.
• [18]Inoue T, Yachida S, Usuki H, Kimura T, Hagiike M, Okano K, Suzuki Y: Pilot feasibility study of neoadjuvant chemoradiotherapy with S-1 in patients with locally advanced gastric cancer featuring adjacent tissue invasion or JGCA bulky N2 lymph node metastases. Ann Surg Oncol 2012, 19:2937-45.
• [19]Ajani JA, Mansfield PF, Janjan N, Morris J, Pisters PW, Lynch PM, Feig B, Myerson R, Nivers R, Cohen DS, Gunderson LL: Multi-institutional trial of preoperative chemoradiotherapy in patients with potentially resectable gastric carcinoma. J Clin Oncol 2004, 22:2774-80.
• [20]Saikawa Y, Kubota T, Kumagai K, Nakamura R, Kumai K, Shigematsu N, Kubo A, Kitajima M, Kitagawa Y: Phase II study of chemoradiotherapy with S-1 and low-dose cisplatin for inoperable advanced gastric cancer. Int J Radiat Oncol Biol Phys 2008, 71:173-9.
• [21]Takahashi T, Saikawa Y, Takaishi H, Takeuchi H, Wada N, Oyama T, Fukuda K, Fukada J, Kawaguchi O, Shigematsu N, Kitagawa Y: Phase I study of neoadjuvant chemoradiotherapy consisting of S-1 and cisplatin for patients with resectable advanced gastric cancer (KOGC-01). Anticancer Res 2011, 31:3079-83.
• [22]Takahashi T, Saikawa Y, Takaishi H, Takeuchi H, Wada N, Oyama T, Nakamura R, Kitagawa Y: Feasibility and efficacy of combination chemotherapy with S-1 and fractional Cisplatin for advanced gastric cancer. Anticancer Res 2010, 30:3759-62.
• [23]Koizumi Y, Nakahara H, Hara T, Takagane A, Akiya T, Takagi M, Miyashita K, Nishizaki T, Kobayashi O, Takitama W, Toh Y, Nagaie T, Takagi S, Yamamura Y, Yanaoka K, Orita H, Takeuchi M: S-1 plus cisplatin versus S-1 alone for first-line treatment of advanced gastric cancer (SPIRITS trial): a phase III trial. Lancet Oncol 2008, 9:215-221.
• [24]Wysocka B, Kassam Z, Lockwood G, Brierley J, Dawson LA, Buckley CA, Jaffray D, Cummings B, Kim J, Wong R, Ringash J: Interfraction and respiratory organ motion during conformal radiotherapy in gastric cancer. Int J Rad Oncol Bio Phys 2010, 77:53-59.
• [25]Chakravarty T, Crane CH, Ajani JA, Mansfield PF, Briere TM, Beddar AS, Mok H, Reed VK, Krishnan S, Delclos ME, Das P: Intensity-modulated radiation therapy with concurrent chemotherapy as preoperative treatment for localized gastric adenocarcinoma. Int J Rad Oncol Bio Phys 2012, 83:581-586.