Combined modality treatment of patients with stage IV gastric cancer with peritoneal carcinomatosis

Peritoneal carcinomatosis is associated with poor prognosis in gastric cancer patients. Stage IV gastric cancer (GC) is diagnosed in 39.8 % of patients; local metastases without evidence of distant metastases occur only in 18–20 % of stage IV gastric cancer patients.

The purpose of the study was to estimate the efficacy of personalized chemotherapy in the combined modality treatment of patients with stage IV GC with peritoneal carcinomatosis.

Material and Methods. Cytoreductive surgery was performed in 70 patients with GC with peritoneal dissemination. The control group patients (n=35) received postoperative chemotherapy with the FOLFOX regimen. The study group patients (n=35) received personalized systemic and intraperitoneal chemotherapy based on the expression of chemosensitivity and resistance genes.

Results. The median survival time (18.7 months) in the study group patients was higher than that in the control group and in studies described in the world literature (CRS + HIPEC). Personalized chemotherapy improved median progressionfree survival (PFS) by 4.6 months (29.1 %) and median overall survival (OS) by 6 months (32 %) compared to FOLFOX regimen chemotherapy. In the study group, the 1-, 2and 3-year survival rates were observed in 35 (100 %), 9 (27 %) and 1 (3 %) patients, respectively.

Conclusion. Personalized chemotherapy in the combined modality treatment can improve long-term treatment outcomes (longer median PFS and OS) in GC patients with peritoneal dissemination.

1. Bray F., Ferlay J., Soerjomataram I., Siegel R.L., Torre L.A., Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018; 68(6): 394–424. doi: 10.3322/caac.21492. Erratum in: CA Cancer J Clin. 2020; 70(4): 313.

2. Stepanov I.V., Paderov Yu.М., Afanasyev S.G. Peritoneal carcinomatosis. Siberian Journal of Oncology. 2014; 5: 45–53. (in Russian).

3. Malignant neoplasms in Russia in 2019 (incidence and mortality). Ed. by A.D. Kaprina, V.V. Starinsky, G.V. Petrova. Moscow: P.A. Herzen Moscow Research Institure – branch of the National Medical Research Radiological Center of the Ministry of Health of Russia, 2020. 252 p. (in Russian).

4. Ida S., Watanabe M. Conversion surgery for stage IV gastric cancer. J Cancer Metastasis Treat. 2018; 4: 22. doi: 10.20517/2394-4722.2017.75.

5. Boerner T., Piso P. A narrative review of intraperitoneal chemotherapy and cytoreductive surgery (CRS) for peritoneal metastases in gastric cancer. J Gastrointest Oncol. 2021; 12(Suppl 1): 59–67. doi: 10.21037/jgo-20-284.

6. Yonemura Y., Prabhu A., Sako S., Ishibashi H., Mizumoto A., Takao N., Ichinose M., Motoi S., Liu Y., Nishihara K., Brandl A., Fushida S. Long Term Survival after Cytoreductive Surgery Combined with Perioperative Chemotherapy in Gastric Cancer Patients with Peritoneal Metastasis. Cancers (Basel). 2020; 12(1): 116. doi: 10.3390/cancers12010116.

7. Fujitani K., Yang H.K., Mizusawa J., Kim Y.W., Terashima M., Han S.U., Iwasaki Y., Hyung W.J., Takagane A., Park D.J., Yoshikawa T., Hahn S., Nakamura K., Park C.H., Kurokawa Y., Bang Y.J., Park B.J., Sasako M., Tsujinaka T.; REGATTA study investigators. Gastrectomy plus chemotherapy versus chemotherapy alone for advanced gastric cancer with a single non-curable factor (REGATTA): a phase 3, randomised controlled trial. Lancet Oncol. 2016; 17(3): 309–18. doi: 10.1016/S14702045(15)00553-7.

8. Llueca A., Climent M.T., Escrig J., Carrasco P., Serra A.; MUAPOS working group (Multidisciplinary Unit of Abdominal Pelvic Oncology Surgery). Validation of three predictive models for suboptimal cytoreductive surgery in advanced ovarian cancer. Sci Rep. 2021; 11(1): 8111. doi: 10.1038/s41598-021-86928-2.

9. Zhang C., Patel A., Hegeholz D., Brown K., Shostrom V., Pottebaum M., Foster J.M. Cytoreductive Surgery with HIPEC is a Safe and Effective Palliative Option in Chemorefractory Symptomatic Peritoneal Metastasis. Ann Surg Oncol. 2022; 29(5): 3337–46. doi: 10.1245/s10434022-11323-8.

10. Afanasyev S.G., Dobrodeev A.Yu. Cytoreductive surgery (Should the primary tumor be removed? Practical Oncology. 2014; 15(2): 93–100. (in Russian).

11. Yonemura Y., Fong Y., Gamblin T., Han E., Lee B., Zager J. Role of Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in the Treatment of Peritoneal Metastasis of Gastric Cancer. Cancer Reg Ther. 2020; 113–24. doi: 10.1007/978-3-030-28891-4_10.

12. Yonemura Y., Iahibashi H., Sako S., Mizumoto A., Takao N., Ichinose M., Motoi S., Liu Y., Wakama S., Kamada Y., Nishihara K. Advances with pharmacotherapy for peritoneal metastasis. Expert Opin Pharmacother. 2020; 21(16): 2057–66. doi: 10.1080/14656566.2020.1793957.

13. Chia C.S., You B., Decullier E., Vaudoyer D., Lorimier G., Abboud K., Bereder J.M., Arvieux C., Boschetti G., Glehen O.; BIG RENAPE Group. Patients with Peritoneal Carcinomatosis from Gastric Cancer Treated with Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy: Is Cure a Possibility? Ann Surg Oncol. 2016; 23(6): 1971–9. doi: 10.1245/s10434-015-5081-3.

14. Macedo F., Ladeira K., Longatto-Filho A., Martins S.F. Gastric cancer treated with pressurized intraperitoneal aerosol chemotherapy: revising an option for peritoneal carcinomatosis. J Cancer Metastasis Treat 2018; 4: 8. doi: 10.20517/2394-4722.2017.72.

15. Maeda H., Kobayashi M., Sakamoto J. Evaluation and treatment of malignant ascites secondary to gastric cancer. World J Gastroenterol. 2015; 21(39): 10936–47. doi: 10.3748/wjg.v21.i39.10936.

16. Sugarbaker P.H. Stomach cancer: prevention and treatment of metastases in the peritoneum. J Treatment of cancer metastases 2018, 4: 7. doi: 10.20517/2394-4722.2017.67.

17. Cisło M., Filip A.A., Arnold Offerhaus G.J., Ciseł B., RawiczPruszyński K., Skierucha M., Polkowski W.P. Distinct molecular subtypes of gastric cancer: from Laurén to molecular pathology. Oncotarget. 2018; 9(27): 19427–42. doi: 10.18632/oncotarget.24827.

18. Rodionov E.O., Miller S.V., Evteev L.A., Tuzikov S.A., Tsyganov M.M., Deryusheva I.V., Litvyakov N.V., Markovich V.A., Urmanov U.B. Combined treatment of patients with non-small cell lung cancer with personalized adjuvant chemotherapy. Avicenna’s Bulletin. 2019; 21(3): 420–5. (in Russian). doi: 10.25005/2074-0581-2019-21-3-420-425.

19. Kazantseva P., Slonimskaya E.M., Litvyakov N.V. Personalized neoadjuvant chemotherapy based on the molecular genetic characteristics of the tumor in patients with luminal B breast cancer. Malignant tumors. 2015; 4(s2): 354–5. (in Russian).

20. Tsyganov M.M., Rodionov E.O., Ibragimova M.K., Miller S.V., Cheremisina O.V., Frolova I.G., Tuzikov S.A., Litviakov N.V. Personalized Prescription of Chemotherapy Based on Assessment of mRNA Expression of BRCA1, RRM1, ERCC1, TOP1, TOP2α, TUBβ3, TYMS, and GSTP1 Genes in Tumors Compared to Standard Chemotherapy in the Treatment of Non-Small-Cell Lung Cancer. J Pers Med. 2022; 12(10): 1647. doi: 10.3390/jpm12101647.

21. Litviakov N.V., Ibragimova M.K., Tsyganov M.M., Kazantseva P.V., Doroshenko A.V., Garbukov E.Y., Frolova I.G., Slonimskaya E.M. Amplifications of Stemness Gene Loci-New Markers for the Determination of the Need for Neoadjuvant Chemotherapy for Patients with Breast Cancer. A Prospective Study. J Pers Med. 2021; 11(5): 397. doi: 10.3390/jpm11050397.

22. Tsyganov M.M., Rodionov E.O., Deryusheva I.V., Miller S.V., Ibragimova M.K., Pisareva L.F., Kzhyshkowska Ju.G., Tuzikov S.А., Cherdyntseva N.V., Litviakov N.V. Prognostic significance of monoresistance gene expression in the tumors of patients with small cell lung cancer after preoperative chemotherapy. Problems in Oncology. 2017; 63(1): 122–7. (in Russian).

23. Markovich V.A., Tuzikov S.A., Popova N.O., Rodionov E.O., Miller S.V., Levonyan L.V., Tsydenova I.A., Ibragimova M.K., Tsyganov M.M., Litvyakov N.V., Podolko D.V. Method of combined treatment of resectable locally advanced gastric cancer with peritoneal carcinomatosis using personalized systemic and intraperitoneal chemotherapy. RF patent No. 2773100. Publ. 05/30/2022. (in Russian).

24. Besova N.S., Bolotina L.V., Gamayunov S.V., Kalinin A.E., Kozlov N.A., Malikhova O.A., Nered S.N., Pirogov S.S., Protsenko S.A., Stilidi I.S., Ter-Ovanesov M.D., Tryakin A.A., Khomyakov V.M., Chernykh M.V. Practical recommendations for drug treatment of gastric cancer. Malignant Tumors: RUSSCO Practice Guidelines. 2022; 12(3s2): 382–400. (in Russian).

25. Kono K., Yong V.P., Okayama H., Shabbir A., Momma T., Ohki S., Takenoshita S., So J. Intraperitoneal chemotherapy for stomach cancer with peritoneal disease: the experience of Singapore and Japan. Gastric Cancer. 2016; 122–7. doi: 10.1007/s10120-016-0660-y.

26. Takahashi N., Kanda M., Yoshikawa T., Takiguchi N., Fujitani K., Miyamoto K., Ito Y., Takayama O., Imano M., Mitsumori N., Sakamoto J., Morita S., Kodera Y. A randomized phase II multicenter trial to explore efficacy of weekly intraperitoneal in comparison with intravenous paclitaxel administered immediately after gastrectomy to the patients with high risk of peritoneal recurrence: final results of the INPACT trial. Gastric Cancer. 2018; 21(6): 1014–23. doi: 10.1007/s10120-018-0817-y.

27. Chia D.K.A., So J.B.Y. Recent Advances in Intra-peritoneal Chemotherapy for Gastric Cancer. J Gastric Cancer. 2020; 20(2): 115–26. doi: 10.5230/jgc.2020.20.e15.

28. Gamboa A.C., Winer J.H. Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Gastric Cancer. Cancers. 2019; 11(11): 1662. doi: 10.3390/cancers11111662.

29. Bouché O., Raoul J.L., Bonnetain F., Giovannini M., Etienne P.L., Lledo G., Arsène D., Paitel J.F., Guérin-Meyer V., Mitry E., Buecher B., Kaminsky M.C., Seitz J.F., Rougier P., Bedenne L., Milan C.; Fédération Francophone de Cancérologie Digestive Group. Randomized multicenter phase II trial of a biweekly regimen of fluorouracil and leucovorin (LV5FU2), LV5FU2 plus cisplatin, or LV5FU2 plus irinotecan in patients with previously untreated metastatic gastric cancer: a Federation Francophone de Cancerologie Digestive Group Study--FFCD 9803. J Clin Oncol. 2004; 22(21): 4319–28. doi: 10.1200/JCO.2004.01.140.

30. Wen F., Zheng H., Zhang P., Zhou J., Chen H., Zhou K., Li Q., Bi F. Patient-based cost-effectiveness analysis of FOLFIRI versus FOLFOX7 for advanced gastric adenocarcinoma in China: A 4-year prospective randomised phase II study. Eur J Cancer Care (Engl). 2020; 29(1). doi: 10.1111/ecc.13196.