The impact of postresection syndrome on tolerability and efficacy of immunotherapy in patients with metastatic gastric cancer: results of a prospective study

Aim of the study – to comprehensively evaluate the impact of postresection syndrome on the tolerability and efficacy of immunotherapy in patients with metastatic gastric cancer and to determine the role of personalized comprehensive rehabilitation in correcting metabolic-nutritional, electrolyte, and psychological impairments in this vulnerable subgroup.

Materials and methods. A prospective randomized study (2021–2025) included 168 patients with histologically confirmed stage IV gastric cancer receiving PD-1 inhibitor immunotherapy (pembrolizumab/nivolumab) in the 3rd-4th line. Patients were randomized into an experimental group (n=82): immunotherapy + comprehensive rehabilitation (nutritional support, H₂/O₂ inhalations, magnetic therapy, psychological correction, electrolyte balance correction); and a control group (n=86): immunotherapy only. Special focus was placed on the subgroup with prior total gastrectomy (n=84).

Results. Gastrectomized patients in the experimental group exhibited a pronounced postresection syndrome: baseline PNI 34.66±2.8 (vs. 38.15±3.5 in non-resected, p=0.0047), hypocalcemia (2.05±0.15 mmol/L), hypomagnesemia (0.61±0.09 mmol/L), and chronic pain (78.6 %). After 6 months, the experimental group demonstrated: maximal PNI increase (+21.54 to 56.20, p<0.001), nitrogen balance normalization (+5.2 g/day, p=0.03), Ca²⁺ elevation (to 2.31 mmol/L) and Mg²⁺ recovery (to 0.87 mmol/L) (p<0.05), and significant EORTC QLQ-C 30 improvement (global QoL +15.2 %, physical functioning +14.8 %, pain reduction –55.6 %, p<0.05). Psychological reasons for therapy discontinuation decreased 3.2-fold (OR=0.31). Confirmed progression (iCPD) among patients with unconfirmed progression (iUPD) at week 8 was significantly lower in the experimental group (45.0 % vs. 72.3 %, p=0.05).

Conclusions. Patients with a history of gastrectomy constitute a vulnerable subgroup with severe postresection malabsorption, electrolyte deficiency, and nutritional decompensation that impair immunotherapy tolerability and potentially reduce efficacy. Comprehensive rehabilitation integrating metabolic, nutritional, physical, and psychological support effectively restores homeostasis, improves quality of life, and promotes disease stabilization. These findings justify the early integration of personalized rehabilitation programs into clinical standards for this patient category.

1. Kaprin A. D., Starinsky V. V., Shakhzadova A. O. Malignant neoplasms in Russia in 2023. Medical alphabet. 2024; (1): 12–18. (In Russ.).

2. Uvarov I. B., Sidorov A. V., Kozlov N. A. Chronic pain in patients with metastatic gastric cancer: frequency and features of therapy // Innovative medicine of Kuban. 2024; (1): 34–42. (In Russ.).

3. Janjigian Y. Y., Shitara K., Moehler M. et al. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric cancer (CheckMate 649) // Lancet. 2021. Vol. 398, № 10294. P. 27–40. DOI: 10.1016/S0140–6736(21)00797-2

4. Clinical guidelines for oncology rehabilitation / Ministry of Health of the Russian Federation. Version 2023. URL: https://cr.minzdrav.gov.ru (date of access: 11.11.2025). (In Russ.).

5. Kang Y. K., Boku N., Satoh T. et al. Nivolumab in advanced gastric cancer refractory to chemotherapy (ATTRACTION-2) // Lancet. 2017. Vol. 390, № 10111. P. 2461–2471. DOI: 10.1016/S0140–6736(17)31827-5

6. Smyth E. C., Nilsson M., Grabsch H. I. et al. Gastric cancer: ESMO Clinical Practice Guideline // Ann Oncol. 2023. Vol. 34, № 5. P. 398–414. DOI: 10.1016/j.annonc.2023.02.004

7. Johannet P., Sawyers A., Qian Y. et al. Baseline prognostic nutritional index and changes in BMI predict immunotherapy response // J Immunother Cancer. 2020. Vol. 8, № 2. Art. e001674. DOI: 10.1136/jitc-2020–001674

8. Fearon K., Strasser F., Anker S. D. et al. Definition and classification of cancer cachexia // Lancet Oncol. 2011. Vol. 12, № 5. P. 489–495. DOI: 10.1016/S1470–2045(10)70293-8

9. Arts N., Conchillo J. M., Masclee A. A. M. et al. Pathophysiology and management of dumping syndrome // Nat Rev Gastroenterol Hepatol. 2022. Vol. 19, № 9. P. 601–615. DOI: 10.1038/s41575-022-00641-2

10. Bosetti F., Mariani L., Lo Vullo S. et al. The effect of gastrectomy on the nutrition of cancer patients // Clin Nutr. 2019. Vol. 38, № 5. P. 2208–2214. DOI: 10.1016/j.clnu.2018.10.005

11. Van Cauwenberge H., Verhelst D., Van Biesen W. et al. Electrolyte disorders with immune checkpoint inhibitors // Kidney Int. 2021. Vol. 100, № 4. P. 945–947. DOI: 10.1016/j.kint.2021.05.033

12. Löcher J., Weis S., Schlicker L. et al. Magnesium sensing via LFA-1 regulates CD 8 + T cell effector function // Cell. 2022. Vol. 185, № 4. P. 585–602.e29. DOI: 10.1016/j.cell.2022.01.009

13. Zhang L., Wang F., Wang C. et al. Multidisciplinary supportive care in advanced gastric cancer // Support Care Cancer. 2022. Vol. 30, № 10. P. 7895–7907. DOI: 10.1007/s00520–022–07235-y

14. Argilés J. M., Busquets S., Stemmler B., López-Soriano F. J. The role of inflammation in cancer cachexia // Curr Opin Clin Nutr Metab Care. 2020. Vol. 23, № 1. P. 4–9. DOI: 10.1097/MCO.0000000000000604

15. Seymour L., Bogaerts J., Perrone A. et al. iRECIST: guidelines for immune checkpoint inhibitors // Lancet Oncol. 2017. Vol. 18, № 3. P. e143–e152. DOI: 10.1016/S1470–2045(17)30074-8

16. Fuchs C. S., Özgüroğlu M., Bang Y. J. et al. Pembrolizumab versus paclitaxel for previously treated PD-L1+ gastric cancer (KEYNOTE-061) // Gastric Cancer. 2022. Vol. 25, № 1. P. 197–206. DOI: 10.1007/s10120–021–01227-z

17. Xia C., Wang Y., Liu X. et al. Hydrogen inhalation improves fatigue and quality of life in head and neck cancer (H 2 -REHAB) // Front Oncol. 2023. Vol. 13. Art. 1125876. DOI: 10.3389/fonc.2023.1125876

18. Zhang Y., Liu D., Wang L. et al. Effects of H2/O2 inhalation on acid-base balance in advanced lung cancer // Respir Med. 2023. Vol. 215. Art. 107812. DOI: 10.1016/j.rmed.2023.107812

19. Tanaka Y., Sato K., Nakao A. et al. Hydrogen/oxygen inhalation for chemotherapy-related cognitive impairment (HYDRO-COG) // J Neuro-Oncol. 2024. Vol. 167, № 2. P. 301–310. DOI: 10.1007/s11060-024-04575-1

20. Wang Z., Liu M., Zhao Y. et al. Prevention of paclitaxel-induced neuropathy by H 2 /O 2 inhalation // Support Care Cancer. 2023. Vol. 31, № 9. Art. 542. DOI: 10.1007/s00520-023-08007-6

21. Ohsawa I., Ishikawa M., Takahashi K. et al. Hydrogen acts as a therapeutic antioxidant // Nat Med. 2007. Vol. 13, № 6. P. 688–694. DOI: 10.1038/nm1577

22. ESPEN practical guideline: Clinical Nutrition in cancer // Clin Nutr. 2021. Vol. 40, № 5. P. 2898–2913. DOI: 10.1016/j.clnu.2021.02.009

23. Arends J., Strasser F., Gonella S. et al. Cancer cachexia: ESMO Guidelines // ESMO Open. 2021. Vol. 6, № 3. Art. 100092. DOI: 10.1016/j.esmoop.2021.100092

24. Baldwin C., Spiro A., Ahern R. et al. Oral nutritional interventions for people with cancer // Cochrane Database Syst Rev. 2022. Vol. 8. Art. CD 013463. DOI: 10.1002/14651858.CD013463.pub2

25. Lu Z., Fang Y., Liu C. et al. Early interdisciplinary supportive care in metastatic esophagogastric cancer // J Clin Oncol. 2021. Vol. 39, № 7. P. 748–756. DOI: 10.1200/JCO.20.02084