A prospective phase I study of hypo-fractionated neoadjuvant radiotherapy for locally advanced gastric cancer

Ning Li, Xin Wang, Yuan Tang, Dongbing Zhao, Yihebali Chi, Lin Yang, Liming Jiang, Jun Jiang, Wenyang Liu, Yu Tang, Hui Fang, Yueping Liu, Yongwen Song, Shulian Wang, Jing Jin, Yexiong Li, Ning Li, Xin Wang, Yuan Tang, Dongbing Zhao, Yihebali Chi, Lin Yang, Liming Jiang, Jun Jiang, Wenyang Liu, Yu Tang, Hui Fang, Yueping Liu, Yongwen Song, Shulian Wang, Jing Jin, Yexiong Li

Abstract

Background: Previous studies have reported that neoadjuvant chemoradiotherapy can downstage the advanced gastric cancer. However, no studies are available on the application of hypo-radiotherapy to neoadjuvant radiotherapy. This study sought to assess the maximum tolerated dose (MTD) and dose-limited toxicity (DLT) of hypo-fractionated chemoradiotherapy for local advanced gastric cancer.

Method: Patients with cT3-4 and/or lymph node-positive locally advanced gastric cancer or Siewert II/III esophagogastric junction adenocarcinoma were enrolled. Preoperative chemoradiation was followed by 3 cycles of oxaliplatin + S-1 neoadjuvant chemotherapy with an interval duration of 3-4 weeks. D2 resection was performed 2-4 weeks after neoadjuvant therapy. Three cycles of adjuvant chemotherapy were planned after surgery. Intensity-modulated radiotherapy (IMRT) was used. The radiotherapy dose level was defined using three levels, namely, 40.0 Gy/2.5 Gy, 41.6 Gy/2.6 Gy, 43.2 Gy/2.7 Gy delivered concurrently with S-1 at 80 mg/m2.

Results: From May 2016 to Dec 2016, nine patients with a median age of 63 years were enrolled in this study. The most common grade I-III adverse events were leukopenia (88.9%), nausea (88.9%), vomiting (77.8%) and weight loss (66.7%). Grade III adverse events consisted of vomiting and weight loss.

Conclusion: The MTD of hypo-fractionated radiotherapy for locally advanced gastric cancer was 40.0 Gy/2.5 Gy, and the DLTs were vomiting and weight loss.

Trial registration: Clinicaltrials.gov ID: NCT03427684 (Retrospectively registered on February 9, 2018).

Keywords: Chemoradiotherapy; Gastric cancer; Hypo-fractionated radiotherapy; Phase I study.

Conflict of interest statement

This study was approved by the ethics committee of Cancer Institute and Hospital, Chinese Academy of Medical Sciences (CH-GI-100). All subjects signed a written informed consent form.

Not applicable.

The authors declare that they have no competing interests.

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Treatment schedule
Fig. 2
Fig. 2
Dose distributions of 250 cGy × 16 fractions radiotherapy plan with 6MV-X based volumetric-modulated arc radiotherapy (VMAT) on a top level, b GTV level, c center level, d bottom level, e sagittal view and f coronal view. Isodose line of 1000 cGy, 2000 cGy, 3000 cGy, 4000 cGy and 4400 cGy were colored in purple, rose red, gold, red and yellow, respectively

References

    1. Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, Jemal A, Yu XQ, He J. Cancer statistics in China, 2015. CA Cancer J Clin. 2016;66(2):115–132. doi: 10.3322/caac.21338.
    1. Ajani JA, Winter K, Okawara GS, Donohue JH, Pisters PW, Crane CH, Greskovich JF, Anne PR, Bradley JD, Willett C, et al. Phase II trial of preoperative chemoradiation in patients with localized gastric adenocarcinoma (RTOG 9904): quality of combined modality therapy and pathologic response. J Clin Oncol. 2006;24(24):3953–3958. doi: 10.1200/JCO.2006.06.4840.
    1. Stahl M, Walz MK, Riera-Knorrenschild J, Stuschke M, Sandermann A, Bitzer M, Wilke H, Budach W. Preoperative chemotherapy versus chemoradiotherapy in locally advanced adenocarcinomas of the oesophagogastric junction (POET): long-term results of a controlled randomised trial. Eur J Cancer. 2017;81:183–190. doi: 10.1016/j.ejca.2017.04.027.
    1. Kim MS, Lim JS, Hyung WJ, Lee YC, Rha SY, Keum KC, Koom WS. Neoadjuvant chemoradiotherapy followed by D2 gastrectomy in locally advanced gastric cancer. World J Gastroenterol. 2015;21(9):2711–2718. doi: 10.3748/wjg.v21.i9.2711.
    1. Shapiro J, van Lanschot JJ, Hulshof MC, van Hagen P, van Berge Henegouwen MI, Wijnhoven BP, van Laarhoven HW, Nieuwenhuijzen GA, Hospers GA, Bonenkamp JJ, et al. Neoadjuvant chemoradiotherapy plus surgery versus surgery alone for oesophageal or junctional cancer (CROSS): long-term results of a randomised controlled trial. Lancet Oncol. 2015;16(9):1090–1098. doi: 10.1016/S1470-2045(15)00040-6.
    1. Mandard AM, Dalibard F, Mandard JC, Marnay J, Henry-Amar M, Petiot JF, Roussel A, Jacob JH, Segol P, Samama G, et al. Pathologic assessment of tumor regression after preoperative chemoradiotherapy of esophageal carcinoma. Clinicopathologic correlations. Cancer. 1994;73(11):2680–2686. doi: 10.1002/1097-0142(19940601)73:11<2680::AID-CNCR2820731105>;2-C.
    1. Cunningham D, Allum WH, Stenning SP, Thompson JN, Van de Velde CJ, Nicolson M, Scarffe JH, Lofts FJ, Falk SJ, Iveson TJ, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med. 2006;355(1):11–20. doi: 10.1056/NEJMoa055531.
    1. Ychou M, Boige V, Pignon JP, Conroy T, Bouche O, Lebreton G, Ducourtieux M, Bedenne L, Fabre JM, Saint-Aubert B, et al. Perioperative chemotherapy compared with surgery alone for resectable gastroesophageal adenocarcinoma: an FNCLCC and FFCD multicenter phase III trial. J Clin Oncol. 2011;29(13):1715–1721. doi: 10.1200/JCO.2010.33.0597.
    1. Zhang ZX, Gu XZ, Yin WB, Huang GJ, Zhang DW, Zhang RG. Randomized clinical trial on the combination of preoperative irradiation and surgery in the treatment of adenocarcinoma of gastric cardia (AGC)--report on 370 patients. Int J Radiat Oncol Biol Phys. 1998;42(5):929–934. doi: 10.1016/S0360-3016(98)00280-6.
    1. Pera M, Gallego R, Montagut C, Martin-Richard M, Iglesias M, Conill C, Reig A, Balague C, Petriz L, Momblan D, et al. Phase II trial of preoperative chemoradiotherapy with oxaliplatin, cisplatin, and 5-FU in locally advanced esophageal and gastric cancer. Ann Oncol. 2012;23(3):664–670. doi: 10.1093/annonc/mdr291.
    1. Kim MM, Rana V, Janjan NA, Das P, Phan AT, Delclos ME, Mansfield PF, Ajani JA, Crane CH, Krishnan S. Clinical benefit of palliative radiation therapy in advanced gastric cancer. Acta Oncol. 2008;47(3):421–427. doi: 10.1080/02841860701621233.
    1. Hashimoto K, Mayahara H, Takashima A, Nakajima TE, Kato K, Hamaguchi T, Ito Y, Yamada Y, Kagami Y, Itami J, et al. Palliative radiation therapy for hemorrhage of unresectable gastric cancer: a single institute experience. J Cancer Res Clin Oncol. 2009;135(8):1117–1123. doi: 10.1007/s00432-009-0553-0.
    1. Asakura H, Hashimoto T, Harada H, Mizumoto M, Furutani K, Hasuike N, Matsuoka M, Ono H, Boku N, Nishimura T. Palliative radiotherapy for bleeding from advanced gastric cancer: is a schedule of 30 Gy in 10 fractions adequate? J Cancer Res Clin Oncol. 2011;137(1):125–130. doi: 10.1007/s00432-010-0866-z.
    1. Chaw CL, Niblock PG, Chaw CS, Adamson DJ. The role of palliative radiotherapy for haemostasis in unresectable gastric cancer: a single-institution experience. Ecancermedicalscience. 2014;8:384.
    1. Tey J, Choo BA, Leong CN, Loy EY, Wong LC, Lim K, Lu JJ, Koh WY. Clinical outcome of palliative radiotherapy for locally advanced symptomatic gastric cancer in the modern era. Medicine (Baltimore) 2014;93(22):e118. doi: 10.1097/MD.0000000000000118.
    1. Bang YJ, Kim YW, Yang HK, Chung HC, Park YK, Lee KH, Lee KW, Kim YH, Noh SI, Cho JY, et al. Adjuvant capecitabine and oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): a phase 3 open-label, randomised controlled trial. Lancet. 2012;379(9813):315–321. doi: 10.1016/S0140-6736(11)61873-4.
    1. Sakuramoto S, Sasako M, Yamaguchi T, Kinoshita T, Fujii M, Nashimoto A, Furukawa H, Nakajima T, Ohashi Y, Imamura H, et al. Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine. N Engl J Med. 2007;357(18):1810–1820. doi: 10.1056/NEJMoa072252.
    1. Wang X, Zhao DB, Yang L, Chi Y, Tang Y, Li N, Wang SL, Song YW, Liu YP, Liu WY, et al. S-1 chemotherapy and intensity-modulated radiotherapy after D1/D2 lymph node dissection in patients with node-positive gastric cancer: a phase I/II study. Br J Cancer. 2018;118(3):338–43. doi: 10.1038/bjc.2017.424.
    1. Wang X, Zhao DB, Jin J, Chi Y, Yang L, Tang Y, Che X, Zhao H, Jiang LM, Ren H. A randomized phase II trial of neoadjuvant chemotherapy compared with Chemoradiation therapy in locally advanced gastroesophageal and gastric adenocarcinoma: preliminary results. Int J Radiat Oncol. 2016;96(2S):S32. doi: 10.1016/j.ijrobp.2016.06.090.
    1. Ajani JA, Faust J, Ikeda K, Yao JC, Anbe H, Carr KL, Houghton M, Urrea P. Phase I pharmacokinetic study of S-1 plus cisplatin in patients with advanced gastric carcinoma. J Clin Oncol. 2005;23(28):6957–6965. doi: 10.1200/JCO.2005.01.917.
    1. Ajani JA, Rodriguez W, Bodoky G, Moiseyenko V, Lichinitser M, Gorbunova V, Vynnychenko I, Garin A, Lang I, Falcon S. Multicenter phase III comparison of cisplatin/S-1 with cisplatin/infusional fluorouracil in advanced gastric or gastroesophageal adenocarcinoma study: the FLAGS trial. J Clin Oncol. 2010;28(9):1547–1553. doi: 10.1200/JCO.2009.25.4706.
    1. Spolverato G, Ejaz A, Kim Y, Squires MH, Poultsides GA, Fields RC, Schmidt C, Weber SM, Votanopoulos K, Maithel SK, et al. Rates and patterns of recurrence after curative intent resection for gastric cancer: a United States multi-institutional analysis. J Am Coll Surg. 2014;219(4):664–675. doi: 10.1016/j.jamcollsurg.2014.03.062.
    1. Wang X, Jin J, Li Y, Wang W, Liu Y, Song Y, Liu X, Yu Z. Prognostic factor for locally advanced gastric or gastroesophageal cancer patients after curative gastrectomy and indications for adjuvant therapy. Chin J Radiat Oncol. 2011;20(4):306–311.

Source: PubMed

Sponsors en medewerkers

Medische omstandigheden

Geneesmiddelinterventies

3
Abonneren