PLANNING PHASE 2 MULTICENTER RANDOMIZED TRIAL OF NEOADJUVANT CHEMO-RADIOTHERAPY FOLLOWED BY D2 GASTRECTOMY AND ADJUVANT CHEMOTHERAPY FOR LOCALLY ADVANCED GASTRIC CANCER

Introduction. The prognosis for surgical treatment of locally advanced gastric cancer remains disappointing. Neoadjuvant chemo-radiation therapy is relatively new and the least researched method of treatment, it is attracting more and more attention, mainly abroad in recent years. The aims of neoadjuvant therapy is the earliest start of systemic therapy, damage of the primary tumor and regional metastases, an increase in the percentage of radical operations, improving treatment outcome. Material and methods. The planning study is a multicenter, randomized clinical phase II trial. Patients of the first (experimental) group will be treated as the followes: neoadjuvant chemo-radiotherapy (total tumor dose of 46 Gy in 23 fractions with the concurrent modified CapOX scheme) followed by D2 gastrectomy and adjuvant chemotherapy. Patients of the second (control) group will be treated with D2 gastrectomy and adjuvant chemotherapy. Adjuvant chemotherapy will be carried out under the following schemes (optional for the researchers): CapOX or FOLFOX. Toxicity evaluation of neoadjuvant chemo-radiotherapy and adjuvant chemotherapy will be conducted with NCI CTC Toxicity Scale Version 3.0. The main objectives of the trial are to assess the safety and immediate effectiveness of neoadjuvant chemo-radiotherapy according to the criteria of the frequency and severity of postoperative complications and mortality, and tumor response. We are planning to include 80 patients with morphologically confirmed gastric cancer сT2–4N1–3, сT3–4N0–3; М0. The proposed trial will be carried out in accordance with the principles of the Helsinki Declaration, it has been approved by local ethic committees of the participated institutions. Results. As a result of this multicenter randomized trial it is planned to show the reproducibility of obtained in MRRC and a number of foreign centers results – that is, the safety and high immediate effectiveness of neoadjuvant chemo-radiotherapy in patients with locally advanced gastric cancer. Conclusion. If we reach the goals of the planning trial, the results would allow to reasonably recommend the start of large international phase III trials for the final evaluation of the proposed neoadjuvant treatment as a standard one in patients with locally advanced gastric cancer.

1. Afanasyev S.G., Avgustinovich A.V., Tuzikov S.A., Pak A.V., Volkov M.Yu., Savel’ev I.N., Frolova I.G. Results of combined operations for locally advanced gastric cancer // Onkologija. Zhurnal im. P.A. Gercena. 2013. № 2. P. 12–15. [in Russian]

2. Malignancies in Russia in 2014 (morbidity and mortality) / Ed. by A.D. Kaprin, V.V. Starinskij, G.V. Petrova. М., 2016. 250 p. [in Russian]

3. Lushnikov Е.F., Abrosimov А.Yu., Berdov B.А., Neborak Yu.Т., Skoropad V.Yu. Pathological response of gastric cancerto neoadjuvantprolonged chemoradiotherapy followed by D2 gastrectomy // Sibirskiy onkologicheskiy zhurnal. 2011. № 5. P. 18–23. [in Russian]

4. Skoropad V.Yu., Berdov B.А., Evdokimov L.V., Neborak Yu.Т. Combined modality treatment in patients with gastric cancer (prolonged neoadjuvant chemoradiotherapy + D2 gastrectomy): short-term outcomes in clinical study Phase II // Onkokhirurgiya. 2012. № 3. P. 10–16. [in Russian]

5. Slugarev V.V., Gamayunov S.V., Denisenko A.N., Pakhomov S.R., Artifeksova A.A. Short term results of gastric cancer treatment using preoperative radiation therapy with radiomodification by capecitabine // Sibirskiy onkologicheskiy zhurnal. 2014. № 1. P. 5–10.

6. Ajani J.A., Winter K., Okawara G.S., Donohue J.H., Pisters P.W., Crane C.H., Greskovich J.F., Anne P.R., Bradley J.D., Willett C., Rich T.A. 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. Vol. 24 (24). Р. 3953–3958.

7. Becker K., Mueller J.D., Schulmacher C., Ott K., Fink U., Busch R., Böttcher K., Siewert J.R., Höfler H. Histomorphology and grading of regression in gastric carcinoma treated with neoadjuvant chemotherapy // Cancer. 2003. Vol. 98 (7). P.1521–1530.

8. Blank S., Stange A., Sisic L., Roth W., Grenacher L., Sterzing F., Burian M., Jäger D., Büchler M., Ott K. Preoperative therapy of esophagogastric cancer: the problem of nonresponding patients // Langenbecks Arch. Surg. 2013. Vol. 398 (2). P. 211–220. doi: 10.1007/s00423-012-1034-5

9. Chakravarty T., Crane C.H., Ajani J.A., Mansfield P.F., Briere T.M., Beddar A.S., Mok H., Reed V.K., Krishnan S., Delclos M.E., Das P. Intensity-modulated radiation therapy with concurrent chemotherapy as preoperative treatment for localized gastric adenocarcinoma // Int. J. Radiat. Oncol. Biol. Phys. 2012. Vol. 83 (2). P. 581–586. doi: 10.1016/j.ijrobp.2011.07.035.

10. Cho H., Nakamura J., Asaumi Y., Yabusaki H., Sakon M., Takasu N., Kobayashi T., Aoki T., Shiraishi O., Kishimoto H., Nunobe S., Yanagisawa S., Suda T., Ueshima S., Matono S., Maruyama H., Tatsumi M., Seya T., Tanizawa Y., Yoshikawa T. Long-term survival outcomes of advanced gastric cancer patients who achieved a pathological complete response with neoadjuvant chemotherapy: a systematic review of the literature // Ann. Surg. Oncol. 2015. Vol. 22 (3). P.787–792. doi: 10.1245/s10434-014-4084-9.

11. 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. Vol. 19 (9). P. 2937–2945. doi: 10.1245/s10434-012-2332-4. 12. Klautke G., Foitzik T., Ludwig K., Ketterer P., Klar E., Fietkau R. Neoadjuvant radiochemotherapy in locally advanced gastric carcinoma // Strahlenther. Onkol. 2004. Vol. 180 (11). P. 695–700.

12. Lee D.J., Sohn T.S., Lim do H., Ahn H.K., Park S.H., Lee J., Park J.O., Park Y.S., Lim H.Y., Choi D.I., Kim K.M., Choi M.G., Noh J.H., Bae J.M., Kim S., Min B.H., Kang W.K. Phase I study of neoadjuvant chemoradiotherapy with S-1 and oxaliplatin in patients with locally advanced gastric cancer // Cancer Chemother. Pharmacol. 2012. Vol. 69 (5). P. 1333–1338. doi: 10.1007/s00280-012-1836-8.

13. Lee J., Lim do H., Kim S., Park S.H., Park J.O., Park Y.S., Lim H.Y., Choi M.G., Sohn T.S., Noh J.H., Bae J.M., Ahn Y.C., Sohn I., Jung S.H., Park C.K., Kim K.M., Kang W.K. 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. Vol. 30 (3). P. 268–273. doi: 10.1200/JCO.2011.39.1953

14. Lowy A.M., Feig B.W., Janjan N., Rich T.A., Pisters P.W., Ajani J.A., Mansfield P.F. A pilot study of preoperative chemoradiotherapy for respectable gastric cancer // Ann. Surg. Oncol. 2001. Vol. 8 (6). P. 519–524.

15. Noh S.H., Park Y.K., Yang H.K., Chung H.C., Chung I.G., Kim S.W., Kim H.H., Choi J.H., Kim H.K., Wansik Y., Lee J.I., Shin D.B., Ji J., CLASSIC trial investigators. Adjuvant capecitabine plus oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): 5-year follow-up of an open-label, randomised phase 3 trial // Lancet Oncol. 2014. Vol. 15 (12). P. 1389–1396. doi: 10.1016/S1470-2045(14)70473-5.

16. Roth A.D., Allal A.S., Bründler M.A., de Peyer R., Mermillod B., Morel P., Huber O. Neoadjuvant radiochemotherapy for locally advanced gastric cancer: a phase 1-2 study // Ann. Oncol. 2003. Vol. 14 (1). P. 110–115.

17. 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. Clin. Oncol. 2011. Vol. 29 (33). P. 4387–4393. doi: 10.1200/JCO.2011.36.5908.

18. Shapiro J., van Lanschot J.J., Hulshof M.C., van Hagen P., van Berge Henegouwen M.I., Wijnhoven B.P., van Laarhoven H.W., Nieuwenhuijzen G.A., Hospers G.A., Bonenkamp J.J., Cuesta M.A., Blaisse R.J., Busch O.R., Ten Kate F.J., Creemers G.J., Punt C.J., Plukker J.T., Verheul H.M., Bilgen E.J., van Dekken H., van der Sangen M.J., Rozema T., Biermann K., Beukema J.C., Piet A.H., van Rij C.M., Reinders J.G., Tilanus H.W., Steyerberg E.W., van der Gaast A.; CROSS study group. Neoadjuvant chemoradiotherapy plus surgery versus surgery alone for oesophageal or junctional cancer (CROSS): long-term results of a randomised controlled trial // Lancet Oncol. 2015. Vol. 16 (9). P. 1090–1098. doi: 10.1016/S1470-2045(15)00040-6.

19. Trip A.K., Poppema B.J., van Berge Henegouwen M.I., Siemerink E., Beukema J.C., Verheij M., Plukker J.T., Richel D.J., Hulshof M.C., van Sandick J.W., Cats A., Jansen E.P., Hospers G.A. Preoperative chemoradiotherapy in locally advanced gastric cancer, a phase I/II feasibility and efficacy study // Radiother. Oncol. 2014. Vol. 112 (2). P. 284–288. doi: 10.1016/j.radonc.2014.05.003.

20. Wydmański J., Suwinski R., Poltorak S., Maka B., Miszczyk L., Wolny E., Bielaczyc G., Zajusz A. The tolerance and efficacy of preoperative chemoradiotherapy followed by gastrectomy in operable gastric cancer, a phase II study // Radiother. Oncol. 2007. Vol. 82 (2). Р. 132–136.