Role of nitric oxide in predicting radiotherapy-related side effects in patients with cervical cancer

Abstract

Objective: To assess whether serum nitric oxide (NO) levels can predict radiation-induced side effects in cervical cancer patients undergoing pelvic radiotherapy (RT). Patients and Methods: Twenty participants diagnosed with locally advanced-stage cervical cancer were included. Weekly blood samples were analyzed for NO levels. Genitourinary (GU), lower gastrointestinal (LGI), and upper gastrointestinal (UGI) toxicities were graded weekly. Two separate analyses were conducted based on initial NO levels either categorized as NO-low and NO-high or the mean NO ratios (NOR) recorded before and after RT. Lastly, the mean clinical symptoms (grade < 2 versus grade ≥ 2) at the end of RT were correlated with the mean NO values. Results: Serum NO levels increased significantly from baseline (p = 0.001). No significant differences in toxicity were found when comparing mean NOR values before and after RT. Symptomatic patients (grade ≥ 2) exhibited higher NO levels at week 5 for GU and LGI toxicities. Baseline NO levels did not consistently predict the severity of side effects. Conclusion: Serum NO levels increased significantly during RT. No definitive correlation with toxicity severity and NO levels were observed. Further studies require to clarify the potential of NO as a biomarker for predicting RT-induced side effects.

Keywords

• Cervical cancer
• Nitric oxide
• Predictive
• Radiotherapy
• Side effects

References

1. Hunsberger KS, Tewari KS, Monk BJ, Chase DM. Standard of care treatment for stage IVB cervical cancer: A systematic review and meta-analysis. Gynecol Oncol 2024 191: 259-64. doi: 10.1016/j.ygyno.2024.10.023.
2. Franco I, Viswanathan AN. Radiation oncology management of stage III and IVA cervical carcinoma. Int J Gynecol Cancer 2022 32:231-8. doi: 10.1136/ijgc-2021-002491.
3. Maduro JH, Pras E, Willemse PH, de Vries EG. Acute and long-term toxicity following radiotherapy alone or in combination with chemotherapy for locally advanced cervical cancer. Cancer Treat Rev 2003 29:471-88. doi: 10.1016/s0305- 7372(03)00117-8.
4. Damast S, Jeffery DD, Son CH, et al. Literature review of vaginal stenosis and dilator use in radiation oncology. Pract Radiat Oncol 2019 9:479-91. doi: 10.1016/j.prro.2019.07.001.
5. Lawrie TA, Green JT, Beresford M, et al. Interventions to reduce acute and late adverse gastrointestinal effects of pelvic radiotherapy for primary pelvic cancers. Cochrane Database Syst Rev 2018 1:CD012529. doi: 10.1002/14651858. CD012529.pub2.
6. Gandhi AK, Sharma DN, Rath GK, et al. Early clinical outcomes and toxicity of intensity modulated versus conventional pelvic radiation therapy for locally advanced cervix carcinoma: a prospective randomized study. Int J Radiat Oncol Biol Phys 2013 87:542-8. doi: 10.1016/j.ijrobp.2013.06.2059.
7. Aryankalayil M, Bylicky MA, Chopra S, et al. Biomarkers for biodosimetry and their role in predicting radiation injury. Cytogenet Genome Res 2023 163:103-9. doi: 10.1159/000531444.
8. Vorotnikova E, Rosenthal RA, Tries M, Doctrow SR, Braunhut SJ. Novel synthetic SOD/catalase mimetics can mitigate capillary endothelial cell apoptosis caused by ionizing radiation. Radiat Res 2010 173:748-59.

9. Aktan F. iNOS-mediated nitric oxide production and its regulation. Life Sci 2004 75: 639-53, 2004.
10. Guerrero T, Martinez J, McCurdy MR, Wolski M, McAleer MF. Elevation in exhaled nitric oxide predicts for radiation pneumonitis. Int J Radiat Oncol Biol Phys 2012;82:981-8. doi: 10.1016/j.ijrobp.2010.08.041.
11. Chen GG, Lee TW, Xu H, et al. Increased inducible nitric oxide synthase in lung carcinoma of smokers. Cancer 2008; 11: 372–81. doi: 10.1002/cncr.23166.
12. Basudhar D, Somasundaram V, de Oliveira GA, et al. Nitric oxide synthase-2-derived nitric oxide drives multiple pathways of breast cancer progression. Antioxid Redox Signal 2017; 26: 1044-58.
13. Naidu MS, Suryakar AN, Swami SC, Katkam RV, Kumbar KM. Oxidative stress and antioxidant status in cervical cancer patients. Indian J Clin Biochem 2007;22:140-4. doi: 10.1007/ BF02913333.
14. McCurdy MR, Wazni MW, Martinez J, McAleer MF, Guerrero T. Exhaled nitric oxide predicts radiation pneumonitis in esophageal and lung cancer patients receiving thoracic radiation. Radiother Oncol 2011;101:443-8. doi: 10.1016/j. radonc.2011.08.035.
15. Corbeau A, Heemsbergen WD, Kuipers SC, et al. Predictive factors for toxicity after primary chemoradiation for locally advanced cervical cancer: A systematic review. Int J Radiat Oncol Biol Phys 2024 119:127-42. doi: 10.1016/j. ijrobp.2023.11.010.
16. Moore DH. Cervical cancer. Obstet Gynecol 2006 107:1152- 61. doi: 10.1097/01.AOG.000.021.5986.48590.79.
17. Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982 5:649-55.
18. Trotti A, Byhardt R, Stetz J, et al. Common toxicity criteria: version 2.0. an improved reference for grading the acute effects of cancer treatment: impact on radiotherapy. Int J Radiat Oncol Biol Phys 2000 47:13-47. doi: 10.1016/s0360- 3016(99)00559-3.
19. Gao Y, Luo T, Huang D, et al. Construction of a checkpoint inhibitor-related pneumonia diagnostic model based on exhaled nitric oxide: a prospective observational study. Transl Lung Cancer Res 2025;14:1740-55. doi: 10.21037/tlcr-2024- 1085.
20. Ho YT, Lee TJ, Chang PH, Fu CH. Post-irradiation nasal nitric oxide in patients with nasopharyngeal carcinoma. Int Forum Allergy Rhinol 2023;13:1982-1986. doi: 10.1002/alr.23161.