Abstract
Postoperative chemoradiotherapy (CRT) with concurrent 5-fluorouracil is the standard care for gastric cancer patients after curative surgery. The previous studies revealed that the subgroup of patients with high recurrence risk would benefit most from adjuvant CRT. S-1, a novel oral fluorouracil, has showed very effective in metastatic gastric cancer and became the standard option for gastric cancer with D2 dissection. The safety and dosage of S-1 combined with postoperative radiotherapy have not yet been evaluated. This study is to determine the maximum tolerate dose (MTD) and dose-limiting toxicity (DLT) of S-1 given concurrently with postoperative high-dose radiotherapy in gastric cancer. Patients with more advanced stage (pT4 and/or pN+) after R0 resection were recruited. Eligible patients received one cycle standard SOX (S-1 plus oxaliplatin) chemotherapy, then S-1 monotherapy with concurrent radiotherapy for 6 weeks, followed by additional three cycles of SOX. During the concurrent CRT, S-1 was administered on every radiotherapy treatment day according to a predefined dose-escalation schedule. Radiotherapy (3D-RT or IMRT) was given to a total dose of 50.4 Gy in 28 fractions. DLT was defined as grade 3 or 4 hematologic and non-hematologic toxicity. From March 2011 to October 2012, 21 patients were enrolled at five dose levels: 40 (n = 3), 50 (n = 3), 60 (n = 6), 70 (n = 6) and 80 mg/m2/day (n = 3). D2-dissection was performed in 18 patients (85.7 %) and 15 patients (71.4 %) had stage III disease. The most common dose-related toxicity was anorexia, nausea and vomiting, fatigue and leucopenia. DLT was occurred in one patient at 60 mg/m2/day (grade 3 fatigue), one patient at 70 mg/m2/day (grade 3 vomiting and anorexia), two patients at 80 mg/m2/day (one with grade 3 vomiting and anorexia; another with grade 3 febrile leucopenia). Four patients did not complete CRT as planned. Overall, this phase I study demonstrated that postoperative CRT with daily S-1 was feasible in gastric cancer and the MTD of S-1 concurrent with radiotherapy was 70 mg/m2/day. This S-1-based postoperative CRT will be investigated in a multicenter phase III study in West China.
Similar content being viewed by others
References
He J, Chen WQ. Chinese Cancer Registry Annual Report, 2012. Beijing: Military Medical Science Press; 2012. p. 28–30.
Hundahl SA, Phillips JL, Menck HR. The National Cancer Data Base Report on poor survival of U.S. gastric carcinoma patients treated with gastrectomy: Fifth Edition American Joint Committee on Cancer staging, proximal disease, and the “different disease” hypothesis. Cancer. 2000;88:921–32.
Macdonald JS, Smalley SR, Benedetti J, et al. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med. 2001;345:725–30.
Smalley SR, Benedetti JK, Haller DG, et al. 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.
NCCN Guideline Panel National Comprehensive Cancer Network Guidelines in Oncology (NCCN Guidelines) Gastric cancer 2013;Version 2.
Kozak KR, Moody JS. The survival impact of the intergroup 0116 trial on patients with gastric cancer. Int J Radiat Oncol Biol Phys. 2008;72:517–21.
Kajitani T. The general rules for the gastric cancer study in surgery and pathology. Part I. Clinical classification. Jpn J Surg. 1981;11:127–39.
Japanese gastric cancer treatment guidelines. ver. 3. Gastric Cancer. 2010;2011(14):113–23.
Hartgrink HH, van de Velde CJ, Putter H, et al. Extended lymph node dissection for gastric cancer: who may benefit? Final results of the randomized Dutch gastric cancer group trial. J Clin Oncol. 2004;22:2069–77.
Lee J, Lim do H, Kim S, et al. 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;30:268–73.
Koizumi W, Narahara H, Hara T, et al. 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;9:215–21.
Huang J, Cao Y, Wu L, Liao C, He Y, Gao F. S-1-based therapy versus 5-FU-based therapy in advanced gastric cancer: a meta-analysis. Med Oncol. 2011;28:1004–11.
Sakuramoto S, Sasako M, Yamaguchi T, et al. Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine. N Engl J Med. 2007;357:1810–20.
Sasako M, Sakuramoto S, Katai H, 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;29:4387–93.
Fukushima M, Satake H, Uchida J, et al. Preclinical antitumor efficacy of S-1: a new oral formulation of 5-fluorouracil on human tumor xenografts. Int J Oncol. 1998;13:693–8.
Harada K, Kawaguchi S. Supriatno, Onoue T, Yoshida H, Sato M. Combined effects of the oral fluoropyrimidine anticancer agent, S-1 and radiation on human oral cancer cells. Oral Oncol. 2004;40:713–9.
Jansen EP, Boot H, Dubbelman R, Verheij M, Cats A. Postoperative chemoradiotherapy in gastric cancer−a phase I–II study of radiotherapy with dose escalation of weekly cisplatin and daily capecitabine chemotherapy. Ann Oncol. 2010;21:530–4.
Jansen EP, Boot H, Saunders MP, et al. A phase I–II study of postoperative capecitabine-based chemoradiotherapy in gastric cancer. Int J Radiat Oncol Biol Phys. 2007;69:1424–8.
Wang X, Jin J, Li YX, et al. Phase I study of postoperative radiotherapy combined with capecitabine for gastric cancer. World J Gastroenterol. 2014;20:1067–73.
Wang X, Wang Y, Qiu M, et al. Postoperative chemoradiotherapy in gastric cancer: a phase I study of radiotherapy with dose escalation of oxaliplatin, 5-fluorouracil, and leucovorin (FOLFOX regimen). Med Oncol. 2011;28(Suppl 1):S274–9.
Lee DJ, Sohn TS, Lim do H, et al. Phase I study of neoadjuvant chemoradiotherapy with S-1 and oxaliplatin in patients with locally advanced gastric cancer. Cancer Chemother Pharmacol. 2012;69:1333–8.
Eguchi H, Nagano H, Kobayashi S, et al. A phase I trial of combination therapy using gemcitabine and S-1 concurrent with full-dose radiation for resectable pancreatic cancer. Cancer Chemother Pharmacol. 2014;73:309–15.
Ohnishi K, Shioyama Y, Nakamura K, et al. Concurrent chemoradiotherapy with S-1 as first-line treatment for patients with oropharyngeal cancer. J Radiat Res. 2011;52:47–53.
Wada H, Nemoto K, Nomiya T, et al. A phase I trial of S-1 with concurrent radiotherapy in patients with locally recurrent rectal cancer. Int J Clin Oncol. 2013;18:273–8.
Cenitagoya GF, Bergh CK, Klinger-Roitman J. A prospective study of gastric cancer. ‘Real’ 5-year survival rates and mortality rates in a country with high incidence. Dig Surg. 1998;15:317–22.
Gunderson LL. Gastric cancer–patterns of relapse after surgical resection. Semin Radiat Oncol. 2002;12:150–61.
Ashraf N, Hoffe S, Kim R. Adjuvant treatment for gastric cancer: chemotherapy versus radiation. Oncologist. 2013;18:1013–21.
Bang YJ, Kim YW, Yang HK, et al. Adjuvant capecitabine and oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): a phase 3 open-label, randomised controlled trial. Lancet. 2012;379:315–21.
Yoo CH, Noh SH, Shin DW, Choi SH, Min JS. Recurrence following curative resection for gastric carcinoma. Br J Surg. 2000;87:236–42.
Kim S, Lim DH, Lee J, et al. An observational study suggesting clinical benefit for adjuvant postoperative chemoradiation in a population of over 500 cases after gastric resection with D2 nodal dissection for adenocarcinoma of the stomach. Int J Radiat Oncol Biol Phys. 2005;63:1279–85.
Kim TH, Park SR, Ryu KW, et al. Phase 3 trial of postoperative chemotherapy alone versus chemoradiation therapy in stage III-IV gastric cancer treated with R0 gastrectomy and D2 lymph node dissection. Int J Radiat Oncol Biol Phys. 2012;84:e585–92.
Park SH, Sohn TS, Lee J, et al. Phase III Trial to Compare Adjuvant Chemotherapy With Capecitabine and Cisplatin Versus Concurrent Chemoradiotherapy in Gastric Cancer: Final Report of the Adjuvant Chemoradiotherapy in Stomach Tumors Trial, Including Survival and Subset Analyses. J Clin Oncol. 2015.
Zhu WG, Xua DF, Pu J, et al. A randomized, controlled, multicenter study comparing intensity-modulated radiotherapy plus concurrent chemotherapy with chemotherapy alone in gastric cancer patients with D2 resection. Radiother Oncol. 2012;104:361–6.
Li Q, Li G, Palmer JD, Zhang Z. Lymph node burden as a predictive factor for selective chemoradiotherapy in patients With locally advanced gastric cancer after a D2 dissection: a retrospective study. Am J Clin Oncol. 2014.
Milano MT, Garofalo MC, Chmura SJ, et al. Intensity-modulated radiation therapy in the treatment of gastric cancer: early clinical outcome and dosimetric comparison with conventional techniques. Br J Radiol. 2006;79:497–503.
Leong T, Willis D, Joon DL, Condron S, Hui A, Ngan SY. 3D conformal radiotherapy for gastric cancer−results of a comparative planning study. Radiother Oncol. 2005;74:301–6.
Soyfer V, Corn BW, Melamud A, et al. Three-dimensional non-coplanar conformal radiotherapy yields better results than traditional beam arrangements for adjuvant treatment of gastric cancer. Int J Radiat Oncol Biol Phys. 2007;69:364–9.
El-Hossiny HA, Diab NA, El-Taher MM. A Comparative Dosimetric Study of Adjuvant 3D Conformal Radiotherapy for Operable Stomach Cancer Versus AP-PA Conventional Radiotherapy in NCI-Cairo. J Egypt Natl Canc Inst. 2009;21:197–202.
Minn AY, Hsu A, La T, et al. Comparison of intensity-modulated radiotherapy and 3-dimensional conformal radiotherapy as adjuvant therapy for gastric cancer. Cancer. 2010;116:3943–52.
Conflict of interest
None.
Author information
Authors and Affiliations
Corresponding author
Additional information
Meng Qiu and Xing-chen Peng have contributed equally to this work.
Rights and permissions
About this article
Cite this article
Qiu, M., Peng, Xc., Bi, F. et al. Phase I study of postoperative radiotherapy concurrent with S-1 in patients with gastric cancer. Med Oncol 32, 191 (2015). https://doi.org/10.1007/s12032-015-0635-6
Received:
Accepted:
Published:
DOI: https://doi.org/10.1007/s12032-015-0635-6