Very Late Effects of Radiotherapy – Limiting Factor of Current Radiotherapy Techniques

Česká verzia

Authors: J. Kubeš ^1,2; P. Vítek ^1,2; K. Dědečková ¹; B. Ondrová ¹
Authors place of work: Proton Therapy Center Czech s. r. o., Praha ¹; 1. LF UK v Praze ²
Published in the journal: Klin Onkol 2014; 27(3): 161-165
Category: Přehled

Summary

Background:
Very late effects of radiotherapy occur within decades after the initial exposure. Their development is induced by low doses of ionizing radiation (from 4 Gy per radiation series) and their clinical manifestations are difficult to distinguish from other independent diseases diagnosed in individuals not formerly treated with radiation. A long time period from the exposure confounds any causal relationships between radiation and adverse events. Still, these side effects not only reduce the patients‘ quality of life but also lead to an early morbidity and mortality, hence generating significant costs in health‑ care and social systems.

Purpose:
This article summarizes findings about the most common very late consequences of radiotherapy, which include cardiotoxicity, CNS toxicity, pneumotoxicity, renal toxicity and secondary malignancies. This issue is crucial in the group of children cancer patients, malignant lymphomas, testicular tumors and CNS tumors. Generally, the risk of very late effects of radiotherapy (RT) should be considered in all patients irradiated at a relatively early age with a high chance of long/ term survival. The risk of very late effects of RT is also one of the key limiting factors in the use of RT in the treatment of paients with benign lesions with long‑term survival expectation, e. g. in paients with glomus tumors, neurofibromas, desmoid tumors or hemangiomas or other benign lesions (arterio‑ venous malformations). Currently, the only known prevention of these very late adverse effects is to minimize the dose to critical structures to the lowest achievable level.

Key words:
radiotherapy – adverse effect – heart disease – brain injury

The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.

The Editorial Board declares that the manuscript met the ICMJE “uniform requirements” for biomedical papers.

Submitted:
5. 2. 2014

Accepted:
5. 3. 2014

Zdroje

1. Wang J, Boerma M, Fu Q et al. Significance of endothelial dysfunction in the pathogenesis of early and delayed radiation enteropathy. World J Gastroenterol 2007; 13(22): 3047– 3055.

2. Veinot JP, Edwards WD. Pathology of radiation‑induced heart disease: a surgical and autopsy study of 27 cases. Hum Pathol 1996, 27(8): 766– 773.

3. Keefe DL. Cardiovascular emergencies in the cancer patient. Semin Oncol 2000, 27(3): 244– 255.

4. Ozasa K, Shimizu Y, Suyama A et al. Studies of the mortality of atomic bomb survivors, report 14, 1950– 2003: an overview of cancer and noncancer diseases. Radiat Res 2012; 177(3): 229– 243.

5. Little MP, Tawn EJ, Tzoulaki I et al. A systematic review of epidemiological associations between low and moderate doses of ionizing radiation and late cardiovascular effects, and their possible mechanisms. Radiat Res 2008; 169: 99– 109.

6. Cuzick J, Stewart H, Rutqvist L et al. Cause‑ specific mortality in long‑term survivors of breast cancer who participated in trials of radiotherapy. J Clin Oncol 1994; 12(3): 447– 453.

7. Giordano SH, Kuo YF, Freeman JL et al. Risk of cardiac death after adjuvant radiotherapy for breast cancer. J Nant Cancer Inst 2005; 97(6): 419– 424.

8. Schellong G, Riepenhausen M, Bruch C et al. Late valvular and other cardiac diseases after different doses of mediastinal radiotherapy for Hodgkin disease in children and adolescents: report from the longitudinal GPOH follow‑up project of the German‑ Austrian DAL‑ HD studies. Pediatr Blood Cancer 2010; 55(6): 1145– 1152. doi: 10.1002/ pbc.22664.

9. Heidenreich PA, Hancock SL, Lee BK et al. Asymptomatic cardiac disease following mediastinal irradiation. J Am Coll Cardiol 2003; 42(4): 743– 749.

10. Hull MC, Morris CG, Pepine CJ et al. Valvular dysfunction and carotid, subclavian, and coronary artery disease in survivors of Hodgkin lymphoma treated with radiation therapy. JAMA 2003; 290(21): 2831– 2837.

11. Lam WW, Leung SF, So NM et al. Incidence of carotid stenosis in nasopharyngeal carcinoma patients after radiotherapy. Cancer 2001; 92(9): 2357– 2363.

12. Patel DA, Kochanski J, Suen AW et al. Clinical manifestations of non coronary atherosclerotic vascular disease after moderate dose irradiation. Cancer 2006; 106(3): 718– 725.

13. Campen CJ, Kranick SM, Kasner SE et al. Cranial irradiation increases risk of stroke in pediatric brain tumor survivors. Stroke 2012; 43(11): 3035– 3040. doi: 10.1161/ STROKEAHA.112.661561.

14. Mueller S, Sear K, Hills NK et al. Risk of first and recurrent stroke in childhood cancer survivors treated with cranial and cervical radiation therapy. Int J Radiat Oncol Biol Phys 2013; 86(4): 643– 648. doi: 10.1016/ j.ijrobp.2013.03.004.

15. Gage FH, Kempermann G, Palmer TD et al. Multipotent progenitor cells in the adult dentate gyrus. J Neurobiol 1998; 36(2): 249– 266.

16. Bellinzona M, Gobbel GT, Shinohara C et al. Apoptosis is induced in the subependyma of young adult rats by ionizing irradiation. Neurosci Lett 1996; 208(3): 163– 166.

17. Mizumatsu S, Monje ML, Morhardt DR et al. Extreme sensitivity of adult neurogenesis to low doses of X‑ irradiation. Cancer Res 2003; 63(14): 4021– 4027.

18. Gondi V, Hermann BP, Mehta MP et al. Hippocampal dosimetry predicts neurocognitive function impairment after fractionated stereotactic radiotherapy for benign or low‑ grade adult brain tumors. Int J Radiat Oncol Biol Phys 2013; 85(2): 348– 354. doi: 10.1016/ j.ijrobp.2012.11.031.

19. Mulhern RK, Merchant TE, Gajjar A et al. Late neurocognitive sequelae in survivors of brain tumours in childhood. Lancet Oncol 2004; 5(7): 399– 408.

20. Redmond KJ, Mahone EM, Terezakis S et al. Association between radiation dose to neuronal progenitor cell niches and temporal lobes and performance on neuropsychological testing in children: a prospective study. Neuro Oncol 2013; 15(3): 360– 369. doi: 10.1093/ neuonc/ nos303.

21. Hsiao KY, Yeh SA, Chang CC et al. Cognitive function before and after intensity‑ modulated radiation therapy in patients with nasopharyngeal carcinoma: a prospective study. Int J Radiat Oncol Biol Phys 2010; 77(3): 722– 726. doi: 10.1016/ j.ijrobp.2009.06.080.

22. Awad R, Fogarty G, Hong A et al. Hippocampal avoidance with volumetric modulated arc therapy in melanoma brain metastases – the first Australian experience. Radiat Oncol 2013; 8: 62.

23. Kazda T, Pospíšil P, Doleželová H et al. Whole brain radiotherapy: consequences for personalized medicine. Rep Pract Oncol Radiother 2013; 18(3): 133– 138.

24. Armstrong GT, Stovall M, Robison LL. Long‑term effects of radiation exposure among adult survivors of childhood cancer: results from the childhood cancer survivor study. Radiat Res 2010; 174(6): 840– 850. doi: 10.1667/ RR1903.1.

25. Brusamolino E, Baio A, Orlandi E et al. Long‑term events in adult patients with clinical stage IA– IIA nonbulky Hodgkin‘s lymphoma treated with four cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine and adjuvant radiotherapy: a single‑institution 15‑year follow‑up. Clin Cancer Res 2006; 12(21): 6487– 6493.

26. Busia A, Laffranchi A, Viviani S et al. Cardiopulmonary toxicity of different chemoradiotherapy combined regimens for Hodgkin‘s disease Anticancer Res 2010; 30(10): 4381– 4387.

27. Fossa SD, Aass N, Winderen M et al. Long‑term renal function after treatment for malignant germ‑ cell tumours. Ann Oncol 2002; 13(2): 222– 228.

28. Kal HB, VAN Kempen‑ Harteveld ML. Induction of severe cataract and late renal dysfunction following total body irradiation: dose‑effect relationships. Anticancer Res 2009; 29(8): 3305– 3309.

29. Adams MJ, Grant EJ, Kodama K et al. Radiation dose associated with renal failure mortality: a potential pathway to partially explain increased cardiovascular disease mortality observed after whole‑ body irradiation. Radiat Res 2012; 177(2): 220– 228.

30. Valentová M, Mladosievicová B. Coronary heart disease and hypertension as late effects of testicular cancer treatment – a minireview. Klin Onkol 2011; 24(1): 18– 22.

31. Hemminki K, Liu H, Sundquist J. Second cancers after testicular cancer diagnosed after 1980 in Sweden. Ann Oncol 2010; 21(7): 1546– 1551. doi: 10.1093/ annonc/ mdp562.

32. Harbron RW, Feltbower RG, Glaser A et al. Secondary malignant neoplasms following radiotherapy for primary cancer in children and young adults. Pediatr Hematol Oncol 2013; 31(3): 259– 267. doi: 10.3109/ 08880018.2013.838723.

33. Cellai E, Magrini SM, Masala G et al. The risk of second malignant tumors and its consequences for the overall survivalof Hodgkin‘s disease patients and for the choice of their treatment at presentation: analysis of a series of 1524 cases consecutively treated at the Florence University Hospital. Int J Radiat Oncol Biol Phys 2001; 49(5): 1327– 1337.

34. Chung CS, Yock TI, Nelson K et al. Incidence of second malignancies among patients treated with proton versus photon radiation. Int J Radiat Oncol Biol Phys 2013; 87(1): 46– 52. doi: 10.1016/ j.ijrobp.2013.04.030.

35. Oeffinger KC, Mertens AC, Sklar CA et al. Chronic health conditions in adult survivors of childhood cancer. N Engl J Med 2006; 355(15): 1572– 1582.

36. Mailhot Vega RB, Kim J, Bussière M et al. Cost effectiveness of proton therapy compared with photon therapy in the management of pediatric medulloblastoma. Cancer 2013; 119(24): 4299– 4307. doi: 10.1002/ cncr.28322.