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Late side effects in the thyroid gland in association with transforming growth factor β1 (TGF-β1) levels in patients with head and neck cancers treated with radiation therapy

Katarzyna Wiśniowska-Kabara1, Dorota Kiprian2, Milena Niemiec2, Maria Kowalska3, Małgorzata Fuksiewicz3, Beata Kotowicz3, Marek Dedecjus4, Paulina Jakubczak1, Wojciech Michalski5, Andrzej Jarząbski2, Andrzej Kawecki6


Introduction. Radiotherapy and radiochemotherapy are, besides surgery, common treatments for head and neck cancers. Despite using advanced modern radiation techniques, the late side effects are a serious problem. From a multitude of cytokines and growth factors shown to contribute to the injury process after cancer therapy, transforming growth factor β1 (TGF-β1) is among the most fundamental ones. The study evaluated if a high level of TGF-β1 before, during, and after treatment can predict thyroid gland fibrosis, which causes hypothyroidism, one of the common late side effects of head and neck cancer irradiation. 

Material and methods. Fifty-six patients with head and neck cancer who underwent radiation alone or concomitant chemoradiotherapy were included in the study. Analyzed variables included thyroid stimulating hormone (TSH), volume and echogenicity of the thyroid gland, and the level of TGF-β1. 

Results. In comparison to the initial level, statistically significant increased levels of TSH and statistically significant decreased volume of the thyroid gland were observed 6 and 12 months after irradiation. Moreover, statistically significant decreased levels of TGF-β1 were observed one month after irradiation. High levels of TGF-β1 before treatment or changes in TGF-β1 levels during and after treatment influenced changes neither in TSH levels nor in volume and echogenicity of the thyroid gland one year after radiotherapy. 

Conclusions. Early evaluation of TSH after radiation is needed to predict hypothyroidism. High TGF-β1 levels before and changes during and after radiation cannot predict hypothyroidism one year after treatment.

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  1. Boomsma MJ, Bijl HP, Langendijk JA. Radiation-induced hypothyroidism in head and neck cancer patients: a systematic review. Radiother Oncol. 2011; 99(1): 1–5.
  2. Tell R, Lundell G, Nilsson Bo, et al. Long-term incidence of hypothyroidism after radiotherapy in patients with head-and-neck cancer. Int J Radiat Oncol Biol Phys. 2004; 60(2): 395–400.
  3. Osuch-Wójcikiewicz E, Bruzgielewicz A. Powikłania po radioterapii nowotworów głowy i szyi. Otolaryngologia Przegląd Kliniczny. 2010; 9(3).
  4. Martin D, Wells I, Goodwin C. Physics of ultrasound. Anaesthesia & Intensive Care Medicine. 2015; 16(3): 132–135.
  5. Diaz R, Jaboin JJ, Morales-Paliza M, et al. Hypothyroidism as a consequence of intensity-modulated radiotherapy with concurrent taxane-based chemotherapy for locally advanced head-and-neck cancer. Int J Radiat Oncol Biol Phys. 2010; 77(2): 468–476.
  6. Zhai RP, Kong FF, Du CR, et al. Radiation-induced hypothyroidism after IMRT for nasopharyngeal carcinoma: Clinical and dosimetric predictors in a prospective cohort study. Oral Oncol. 2017; 68: 44–49.
  7. Citrin DE, Mitchell JB. Mechanisms of Normal Tissue Injury From Irradiation. Semin Radiat Oncol. 2017; 27(4): 316–324.
  8. Anscher MS, Marks LB, Shafman TD, et al. Using plasma transforming growth factor beta-1 during radiotherapy to select patients for dose escalation. J Clin Oncol. 2001; 19(17): 3758–3765.
  9. Martin M, Lefaix J, Delanian S. TGF-beta1 and radiation fibrosis: a master switch and a specific therapeutic target? Int J Radiat Oncol Biol Phys. 2000; 47(2): 277–290.
  10. Farhood B, Khodamoradi E, Hoseini-Ghahfarokhi M, et al. TGF-β in radiotherapy: Mechanisms of tumor resistance and normal tissues injury. Pharmacol Res. 2020; 155: 104745.
  11. Anscher MS. Targeting the TGF-beta1 pathway to prevent normal tissue injury after cancer therapy. Oncologist. 2010; 15(4): 350–359.
  12. Border WA, Brees D, Noble NA. Transforming growth factor-beta and extracellular matrix deposition in the kidney. Contrib Nephrol. 1994; 107: 140–145.
  13. Bartram U, Speer CP. The role of transforming growth factor beta in lung development and disease. Chest. 2004; 125(2): 754–765.
  14. Monceau V, Pasinetti N, Schupp C, et al. Modulation of the Rho/ROCK pathway in heart and lung after thorax irradiation reveals targets to improve normal tissue toxicity. Curr Drug Targets. 2010; 11(11): 1395–1404.
  15. Oken M, Creech R, Tormey D, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982; 5(6): 649–656.
  16. Sommat K, Ong WS, Hussain A, et al. Thyroid V40 Predicts Primary Hypothyroidism After Intensity Modulated Radiation Therapy for Nasopharyngeal Carcinoma. Int J Radiat Oncol Biol Phys. 2017; 98(3): 574–580.
  17. Fujiwara M, Kamikonya N, Odawara S, et al. The threshold of hypothyroidism after radiation therapy for head and neck cancer: a retrospective analysis of 116 cases. J Radiat Res. 2015; 56(3): 577–582.
  18. Koc M, Capoglu I. Thyroid Dysfunction in Patients Treated With Radiotherapy for Neck. Am J Clin Oncol. 2009; 32(2): 150–153.
  19. Ihnatsenka B, Boezaart AP. Ultrasound: Basic understanding and learning the language. Int J Shoulder Surg. 2010; 4(3): 55–62.
  20. Vehmas T, Kaukiainen A, Luoma K, et al. Liver echogenicity: measurement or visual grading? Comput Med Imaging Graph. 2004; 28(5): 289–293.
  21. Vogelius IR, Bentzen SM, Maraldo MV, et al. Risk factors for radiation-induced hypothyroidism: a literature-based meta-analysis. Cancer. 2011; 117(23): 5250–5260.
  22. Anscher MS, Peters WP, Reisenbichler H, et al. Transforming growth factor beta as a predictor of liver and lung fibrosis after autologous bone marrow transplantation for advanced breast cancer. N Engl J Med. 1993; 328(22): 1592–1598.
  23. Anscher MS, Kong FM, Andrews K, et al. Plasma transforming growth factor beta1 as a predictor of radiation pneumonitis. Int J Radiat Oncol Biol Phys. 1998; 41(5): 1029–1035.
  24. Anscher MS, Murase T, Prescott DM, et al. Changes in plasma TGF beta levels during pulmonary radiotherapy as a predictor of the risk of developing radiation pneumonitis. Int J Radiat Oncol Biol Phys. 1994; 30(3): 671–676.
  25. Fu XL, Huang H, Bentel G, et al. Predicting the risk of symptomatic radiation-induced lung injury using both the physical and biologic parameters V(30) and transforming growth factor beta. Int J Radiat Oncol Biol Phys. 2001; 50(4): 899–908.
  26. Kong FM, Ao X, Wang Li, et al. The use of blood biomarkers to predict radiation lung toxicity: a potential strategy to individualize thoracic radiation therapy. Cancer Control. 2008; 15(2): 140–150.
  27. Palmer JD, Zaorsky NG, Witek M, et al. Molecular markers to predict clinical outcome and radiation induced toxicity in lung cancer. J Thorac Dis. 2014; 6(4): 387–398.
  28. Śliwińska-Mossoń M, Wadowska K, Trembecki Ł, et al. Markers Useful in Monitoring Radiation-Induced Lung Injury in Lung Cancer Patients: A Review. J Pers Med. 2020; 10(3).
  29. Boothe D, Coplowitz S, Greenwood E, et al. Transforming Growth Factor β-1 (TGF-β1) Is a Serum Biomarker of Radiation Induced Fibrosis in Patients Treated With Intracavitary Accelerated Partial Breast Irradiation: Preliminary Results of a Prospective Study. Int J Radiat Oncol Biol Phys. 2013; 87(5): 1030–1036.
  30. Li C, Wilson PB, Levine E, et al. TGF-beta1 levels in pre-treatment plasma identify breast cancer patients at risk of developing post-radiotherapy fibrosis. Int J Cancer. 1999; 84(2): 155–159, doi: 10.1002/(sici)1097-0215(19990420)84:2<155::aid-ijc11>;2-s.
  31. Teicher BA. Malignant cells, directors of the malignant process: role of transforming growth factor-beta. Cancer Metastasis Rev. 2001; 20(1-2): 133–143.
  32. Kong FM, Anscher MS, Murase T, et al. Elevated plasma transforming growth factor-beta 1 levels in breast cancer patients decrease after surgical removal of the tumor. Ann Surg. 1995; 222(2): 155–162.
  33. Shariat SF, Kattan MW, Traxel E, et al. Association of pre- and postoperative plasma levels of transforming growth factor beta(1) and interleukin 6 and its soluble receptor with prostate cancer progression. Clin Cancer Res. 2004; 10(6): 1992–1999.
  34. Shariat SF, Walz J, Roehrborn CG, et al. Early postoperative plasma transforming growth factor-β1 is a strong predictor of biochemical progression after radical prostatectomy. J Urol. 2008; 179(4): 1593–1597.
  35. Wikström P, Damber J, Bergh A. Role of transforming growth factor-beta1 in prostate cancer. Microsc Res Tech. 2001; 52(4): 411–419, doi: 10.1002/1097-0029(20010215)52:4<411::AID-JEMT1026>3.0.CO;2-8.
  36. Zhang M, Kleber S, Röhrich M, et al. Blockade of TGF-β signaling by the TGFβR-I kinase inhibitor LY2109761 enhances radiation response and prolongs survival in glioblastoma. Cancer Res. 2011; 71(23): 7155–7167.
  37. Bierie B, Moses HL. Tumour microenvironment: TGFbeta: the molecular Jekyll and Hyde of cancer. Nat Rev Cancer. 2006; 6(7): 506–520.
  38. Beck C, Schreiber H, Rowley D. Role of TGF-beta in immune-evasion of cancer. Microsc Res Tech. 2001; 52(4): 387–395, doi: 10.1002/1097-0029(20010215)52:4<387::AID-JEMT1023>3.0.CO;2-W.
  39. Colak S, Ten Dijke P. Targeting TGF-β Signaling in Cancer. Trends Cancer. 2017; 3(1): 56–71.
  40. Ivanović V, Todorović-Raković N, Demajo M, et al. Elevated plasma levels of transforming growth factor-beta 1 (TGF-beta 1) in patients with advanced breast cancer: association with disease progression. Eur J Cancer. 2003; 39(4): 454–461.
  41. Maehara Y, Kakeji Y, Kabashima A, et al. Role of transforming growth factor-beta 1 in invasion and metastasis in gastric carcinoma. J Clin Oncol. 1999; 17(2): 607–614.
  42. Song BC, Chung YH, Kim JA, et al. Transforming growth factor-beta1 as a useful serologic marker of small hepatocellular carcinoma. Cancer. 2002; 94(1): 175–180.
  43. Tsushima H, Ito N, Tamura S, et al. Circulating transforming growth factor beta 1 as a predictor of liver metastasis after resection in colorectal cancer. Clin Cancer Res. 2001; 7(5): 1258–1262.
  44. Wunderlich H, Steiner T, Kosmehl H, et al. Increased transforming growth factor beta1 plasma level in patients with renal cell carcinoma: a tumor-specific marker? Urol Int. 1998; 60(4): 205–207.
  45. Kattan MW, Shariat SF, Andrews B, et al. The addition of interleukin-6 soluble receptor and transforming growth factor b1 improves a preoperative nomogram for predicting biochemical progression in patients with clinically localized prostate cancer. J Clin Oncol. 2003; 21(19): 3573–3579.
  46. Shariat SF, Shalev M, Menesses-Diaz A, et al. Preoperative plasma levels of transforming growth factor b(l) (TGF-b(l)) strongly predict progression in patients undergoing radical prostatectomy. J Clin Oncol. 2001; 19(11): 2856–2864.
  47. Lange I, Hammerer P, Knabbe C, et al. [Plasma TGF-beta1 concentrations in patients with prostate carcinoma or benign prostatic hyperplasia]. Urologe A. 1998; 37(2): 199–202.
  48. Feltl D, Zavadova E, Pala M, et al. The dynamics of plasma transforming growth factor beta 1 (TGF-beta1) level during radiotherapy with or without simultaneous chemotherapy in advanced head and neck cancer. Oral Oncol. 2005; 41(2): 208–213.
  49. Liu P, Menon K, Alvarez E, et al. Transforming growth factor-beta and response to anticancer therapies in human liver and gastric tumors in vitro and in vivo. Int J Oncol. 2000; 16(3): 599–610.
  50. Pang X, Tang YL, Liang XH. Transforming growth factor-β signaling in head and neck squamous cell carcinoma: Insights into cellular responses. Oncol Lett. 2018; 16(4): 4799–4806.