Chemotherapy-related Cognitive Impairment in Patients with Hodgkin Lymphoma – Pathophysiology and Risk Factors
Authors:
D. Fayette 1; Ľ. Gahérová 2; H. Mociková 2; J. Marková 2; T. Kozák 2; J. Horáček 1
Authors‘ workplace:
Národní ústav duševního zdraví, Klecany
1; Interní hematologická klinika 3. LF UK a FN Královské Vinohrady, Praha
2
Published in:
Klin Onkol 2017; 30(2): 93-99
Category:
Reviews
doi:
https://doi.org/10.14735/amko201793
Overview
Background:
Cognitive impairment (impairment of memory, attention, or concentration) is documented in 17–75% of patients with various malignancies treated with chemotherapeutic agents that worsen quality of life. CRCI affects patients of all ages. The impairment of cognitive function in connection with chemotherapy is usually mild, but an event. relationship with dementia remains to be confirmed. Chemotherapy in combination with radiotherapy in Hodgkin lymphoma can cure 80–90% of patients.
Aim:
This review summarizes the most frequently observed changes in cognitive function in patients suffering from CRCI. The article further describes the possible pathophysiological mechanisms behind these changes and the risk factors that can increase the likelihood of cognitive functional impairment after chemotherapy of malignant tumors. Special attention is given to how this relates to Hodgkin’s lymphoma. We also discuss the neuroprotective factors involved in chemotherapy-related cognitive impairment and its treatment options.
Conclusion:
Changes occur mainly in the ability to learn and remember, in the speed of reactions, and in attention and executive functions. Although CRCI pathophysiological mechanisms are complex and not yet fully understood, the involvement of neurotoxicity, such as that induced by treatment, anemia, higher levels of oxidative stress and inflammatory responses, genetic factors, and reduced brain connectivity is discussed. CRCI is further modified by comorbidities and patient age. Pharmacological and nonpharmacological treatment options for CRCI are outlined.
Key words:
Hodgkin lymphoma – chemotherapy – cognitive impairment – risk factors
The project was supported by the grant of the Agency for the Czech Republic Health Research of the Ministry of Health of the Czech Republic 16-29857A and by the project Sustainability for the National Institute of Mental Health No. LO1611 with a financial support of the Ministry of Education, Youth and Sports of the Czech Republic in the frame of the National Sustainability Programme I.
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 recommendation for biomedical papers.
Submitted:
29. 9. 2016
Accepted:
12. 2. 2017
Sources
1. Hess LM, Insel KC. Chemotherapy-related change in cognitive function: a conceptual model. Oncol Nurs Forum 2007; 34 (5): 981–994.
2. Correa DD, Ahles TA. Cognitive adverse effects of chemotherapy in breast cancer patients. Curr Opin Support Palliat Care 2007; 1 (1): 57–62. doi: 10.1097/SPC.0b013e32813a328f.
3. Hodgson KD, Hutchinson AD, Wilson CJ et al. A meta-analysis of the effects of chemotherapy on cognition in patients with cancer. Cancer Treat Rev 2013; 39 (3): 297–304. doi: 10.1016/j.ctrv.2012.11.001.
4. Gehring K, Roukema JA, Sitskoorn MM et al. Review of recent studies on interventions for cognitive deficits in patients with cancer. Expert Rev Anticancer Ther 2012; 12 (2): 255–269. doi: 10.1586/era.11.202.
5. Nelson CJ, Nandy N, Roth AJ. Chemotherapy and cognitive deficits: Mechanisms, findings, and potential interventions. Palliat Support Care 2007: 5 (3): 273–280. doi: 10.1017/S1478951507000442.
6. Raffa RB, Duong PV, Finney J et al. Is ‚chemo-fog‘/‘chemo-brain‘ caused by cancer chemotherapy? J Clin Pharm Ther 2006; 31 (2): 129–138.
7. Schmidt D, Anderson L, Bingen K et al. Late effects in adult survivors of childhood cancer: considerations for the general practitioner. WMJ 2010; 109 (2): 98–107.
8. Samson K. Chemobrain: large meta-analysis documents persistent mild cognitive deficits in breast cancer patients post-chemotherapy. Oncology Times 2012; 34 (22): 10–11.
9. Nelson WL, Suls J. New approaches to understand cognitive changes associated with chemotherapy for non-central nervous system tumors. J Pain Symptom Manage 2013; 46 (5): 707–721. doi: 10.1016/j.jpainsymman.2012.11.005.
10. Yang M, Moon C. Neurotoxicity of cancer chemotherapy. Neural Regen Res 2013; 8 (17): 1606–1614. doi: 10.3969/j.issn.1673-5374.2013.17.009.
11. Koppelmans V, Breteler MM, Boogerd W et al. Late effects of adjuvant chemotherapy for adult onset non-CNS cancer; cognitive impairment, brain structure and risk of dementia. Crit Rev Oncol Hematol 2013; 88 (1): 87–101. doi: 10.1016/j.critrevonc.2013.04.002.
12. Katsumata R, Sagawa R, Akechi T et al. A case with Hodgkin lymphoma and fronto-temporal lobular degeneration (FTLD) -like dementia facilitated by chemotherapy. Jap J Clin Oncol 2010; 40 (4): 365–368. doi: 10.1093/jjco/hyp170.
13. Engert A, Plutschow A, Eich HT et al. Reduced treatment intensity in patients with early-stage Hodgkin‘s lymphoma. N Engl J Med 2010; 363 (7): 640–652. doi: 10.1056/NEJMoa1000067.
14. von Tresckow B, Plütschow A, Fuchs M et al. Dose-intensification in early unfavorable Hodgkin‘s lymphoma: final analysis of the German Hodgkin Study Group HD14 trial. J Clin Oncol 2012; 30 (9): 907–913. doi: 10.1200/JCO.2011.38.5807.
15. Engert A, Haverkamp H, Kobe C et al. Reduced-intensity chemotherapy and PET-guided radiotherapy in patients with advanced stage Hodgkin‘s lymphoma (HD15 trial): a randomised, open-label, phase 3 non-inferiority trial. Lancet 2012; 379 (9828): 1791–1799. doi: 10.1016/S0140-6736 (11) 61940-5.
16. van Nimwegen FA, Schaapveld M, Janus CP et al. Cardiovascular disease after Hodgkin lymphoma treatment: 40-year disease risk. JAMA Intern Med 2015; 175 (6): 1007–1017. doi: 10.1001/jamainternmed.2015. 1180.
17. van Eggermond AM, Schaapveld M, Lugtenburg PJ et al. Risk of multiple primary malignancies following treatment of Hodgkin lymphoma. Blood 2014; 124 (3): 319–327. doi: 10.1182/blood-2013-10-532184.
18. Bisiacchi P, Borella E, Bergamaschi S et al. Interplay between memory and executive functions in normal and pathological aging: A quantitative meta-analysis. J Clin Exp Neuropsychol 2008; 30 (6): 723–733. doi: 10.1080/13803390701689587.
19. Wefel JS, Vardy J, Ahles T et al. International cognition and cancer task force recommendations to harmonise studies of cognitive function in patients with cancer. Lancet Oncol 2011; 12 (7): 703–708. doi: 10.1016/S1470-2045 (10) 70294-1.
20. Inagaki M, Yoshikawa E, Matsuoka Y et al. Smaller regional volumes of brain gray and white matter demonstrated in breast cancer survivors exposed to adjuvant chemotherapy. Cancer 2007; 109 (1): 146–156.
21. Abraham J, Haut MW, Moran MT et al. Adjuvant chemotherapy for breast cancer: effects on cerebral white matter seen in diffusion tensor imaging. Clin Breast Cancer 2008; 8 (1): 88–91. doi: 10.3816/CBC.2008.n.007.
22. McDonald BC, Conroy SK, Ahles TA et al. Alterations in brain activation during working memory processing associated with breast cancer and treatment: a prospective functional magnetic resonance imaging study. J Clin Oncol 2012; 30 (20): 2500–2508. doi: 10.1200/JCO.2011.38.5674.
23. McDonald BC, Conroy SK, Ahles TA et al. Gray matter reduction associated with systemic chemotherapy for breast cancer: a prospective MRI study. Breast Cancer Res Treat 2010; 123 (3): 819–828. doi: 10.1007/s10549-010-1088-4.
24. Koppelmans V, de Ruiter MB, van der Lijn et al. Global and focal brain volume in long-term breast cancer survivors exposed to adjuvant chemotherapy. Breast Cancer Res Treat 2012; 132 (3): 1099–1106. doi: 10.1007/s10549-011-1888-1.
25. de Ruiter MB, Reneman L, Boogerd W et al. Late effects of high-dose adjuvant chemotherapy on white and gray matter in breast cancer survivors: converging results from multimodal magnetic resonance imaging. Hum Brain Mapp 2012; 33 (12): 2971–2983. doi: 10.1002/hbm.21422.
26. Janelsins MC, Kesler SR, Ahles TA et al. Prevalence, mechanisms, and management of cancer-related cognitive impairment. Int Rev Psychiatry 2014; 26 (1): 102–113. doi: 10.3109/09540261.2013.864260.
27. Conklin HM, Krull KR, Reddick WE et al. Cognitive outcomes following contemporary treatment without cranial irradiation for childhood acute lymphoblastic leukemia. J Natl Cancer Inst 2012; 104 (18): 1386–1395.
28. Daams M, Schuitema I, van Dijk BW et al. Long-term effects of cranial irradiation and intrathecal chemotherapy in treatment of childhood leukemia: a MEG study of powerspectrum and correlated cognitive dysfunction. BMC Neurology 2012; 12: 84. doi: 10.1186/1471-2377-12-84.
29. Armstrong GT, Reddick WE, Petersen RC et al. Evaluation of memory impairment in aging adult survivors of childhood acute lymphoblastic leukemia treated with cranial radiotherapy. J Natl Cancer Inst 2013; 105 (12): 899–907. doi: 10.1093/jnci/djt089.
30. Krull KR, Zhang N, Santucci A et al. Long-term decline in intelligence among adult survivors of childhood acute lymphoblastic leukemia treated with cranial radiation. Blood 2013; 122 (4): 550–553. doi: 10.1182/blood-2013-03-487744.
31. Zimmer P, Mierau A, Bloch W et al. Post-chemotherapy cognitive impairment in patients with B-cell non-Hodgkin lymphoma: a first comprehensive approach to determine cognitive impairments after treatment with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone or rituximab and bendamustine. Leuk Lymphoma 2015; 56 (2): 347–352. doi: 10.3109/10428194.2014.915546.
32. Móciková H. Epidemiologie a rizikové faktory spojené s Hodgkinovým lymfomem. Transfuze Hematol Dnes 2014; 20 (3): 81–86.
33. Mulrooney DA, Ness KK, Neglia JP et al. Fatigue and sleep disturbance in adult survivors of childhood cancer: a report from the childhood cancer survivor study (CCSS). Sleep 2008; 31 (2): 271–281.
34. Krull KR, Sabin ND, Reddick WE et al. Neurocognitive function and CNS integrity in adult survivors of childhood Hodgkin lymphoma. J Clin Oncol 2012; 30 (29): 3618–3624. doi: 10.1200/JCO.2012.42.6841.
35. Aluise CD, Sultana R, Tangpong J,et al. Chemo brain (chemo fog) as a potential side effect of doxorubicin administration: role of cytokine-induced, oxidative/nitrosative stress in cognitive dysfunction. Adv Exp Med Biol 2010; 678: 147–156.
36. Li J, O W, Li W et al. Oxidative stress and neurodegenerative disorders. Int J Mol Sci 2013; 14 (12): 24438–24475. doi: 10.3390/ijms141224438.
37. Butterfield DA. The 2013 SFRBM discovery award: selected discoveries from the butterfield laboratory of oxidative stress and its sequela in brain in cognitive disorders exemplified by Alzheimer disease and chemotherapy induced cognitive impairment. Free Radic Biol Med 2014; 74: 157–174. doi: 10.1016/j.freeradbiomed.2014.06. 006.
38. Wardill HR, Mander KA, Van Sebille YZ. Cytokine-mediated blood brain barrier disruption as a conduit for cancer/chemotherapy-associated neurotoxicity and cognitive dysfunction. Int J Cancer 2016; 139 (12): 2635–2645. doi: 10.1002/ijc.30252.
39. Walker CH, Drew BA, Antoon JW et al. Neurocognitive effects of chemotherapy and endocrine therapies in the treatment of breast cancer: recent perspectives. Cancer Invest 2012; 30 (2): 135–148. doi: 10.3109/07357907.2011.636116.
40. O‘Shaughnessy JA. Chemotherapy-induced cognitive dysfunction: a clearer picture. Clin Breast Cancer 2003; 4 (Suppl 2): S89–S94.
41. Kesler SR, Kent JS, O‘Hara R. Prefrontal cortex and executive function impairments in primary breast cancer. Arch Neurol 2011; 68 (11): 1447–1453. doi: 10.1001/archneurol.2011.245.
42. Kesler SR, Wefel JS, Hosseini SM et al. Default mode network connectivity distinguishes chemotherapy-treated breast cancer survivors from controls. Proc Natl Acad Sci U S A 2013; 110 (28): 11600–11605. doi: 10.1073/pnas.1214551110.
43. Sleurs C, Deprez S, Emsell L et al. Chemotherapy-induced neurotoxicity in pediatric solid non-CNS tumor patients: an update on current state of research and recommended future directions. Crit Rev Oncol Hematol 2016; 103: 37–48. doi: 10.1016/j.critrevonc.2016.05.001.
44. Dietrich J, Han R, Yang Y et al. CNS progenitor cells and oligodendrocytes are targets of chemotherapeutic agents in vitro and in vivo. J Biol 2006; 5 (7): 22.
45. Nelson CJ, Nandy N, Roth AJ. Chemotherapy and cognitive deficits: mechanisms, findings, and potential interventions. Palliat Support Care 2007; 5 (3): 273–280.
46. Seigers R, Schagen SB, Van Tellingen O et al. Chemotherapy-related cognitive dysfunction: current animal studies and future directions. Brain Imaging Behav 2013; 7 (4): 453–459. doi: 10.1007/s11682-013-9250-3.
47. Kluck RM, Bossy-Wetzel E, Green DR et al. The release of cytochrome c from mitochondria: a primary site for Bcl-2 regulation of apoptosis. Science 1997; 275 (5303): 1132–1136.
48. Topinková E. Apoptóza – programovaná buněčná smrt a stárnutí. Sanquis 2002; 20: 14.
49. Aluise CD, Miriyala S, Noel T et al. 2-Mercaptoethane sulfonate prevents doxorubicin-induced plasma protein oxidation and TNF-α release: implications for the reactive oxygen species-mediated mechanisms of chemobrain. Free Radic Biol Med 2011; 50 (11): 1630–1638. doi: 10.1016/j.freeradbiomed.2011.03.009.
50. Kesler S, Janelsins M, Kooyakkattu D et al. Reduced hippocampal volume and verbal memory performance associated with interleukin-6 and tumor necrosis factor-alpha levels in chemotherapy-treated breast cancer survivors. Brain Behav Immun 2012; 30: S109–S116. doi: 10.1016/j.bbi.2012.05.017.
51. Ganz PA, Bower JE, Kwan L et al. Does tumor necrosis factor-alpha (TNF-a) play a role in post-chemotherapy cerebral dysfunction? Brain Behav Immun 2013; 30 (Suppl): S99–S108. doi: 10.1016/j.bbi.2012.07.015.
52. Gutierez EG, Banks WA, Kastin AJ. Murine tumor necrosis factor alpha is transported from blood to brain in the mouse. J Neuroimunol 1993; 47 (2): 169–176.
53. Felger JC, Lotrich FE. Inflammatory cytokines in depression: Neurobiological mechanism and therapeutic implications. Neuroscience 2013; 246: 199–229. doi: 10.1016/j.neuroscience.2013.04.060.
54. Johnston GR, Webster NR. Cytokines and the immunomodulatory function of the vagus nerve. Br J Anaesth 2009 (4); 102: 453–462. doi: 10.1093/bja/aep037.
55. Wang XM, Walitt B, Saligan L et al. Chemobrain: a critical review and causal hypothesis of link between cytokines and epigenetic reprogramming associated with chemotherapy. Cytokine 2015; 72 (1): 86–96. doi: 10.1016/j.cyto.2014.12.006.
56. Brichtová E, Mackerle Z. Vztah genotypu apolipoproteinu E ke klinickému průběhu a následkům poranění mozku u dětí a mladistvých. Cesk Slov Neurol N 2011; 74/107 (4): 437–442.
57. Ahles TA, Saykin AJ, Noll WW et al. The relationship of APOE genotype to neuropsychological performance in long-term cancer survivors treated with standard dose chemotherapy. Psychooncology 2003; 12 (6): 612–619.
58. Small BJ, Rawson KS, Walsh E et al. Catechol-O-methyl-transferase genotype modulates cancer treatment-related cognitive deficits in breast cancer survivors. Cancer 2011; 117 (7): 1369–1376. doi: 10.1002/cncr.25685.
59. Jacobsen PB, Garland LL, Booth-Jones M et al. Relationship of hemoglobin levels to fatigue and cognitive functioning among cancer patients receiving chemotherapy. J Pain Symptom Manage 2004; 28 (1): 7–18.
60. Vearncombe KJ, Rolfe M, Wright M et al. Predictors of cognitive decline after chemotherapy in breast cancer patients. J Int Neuropsychol Soc 2009; 15 (6): 951–962. doi: 10.1017/S1355617709990567.
61. Iconomou G, Koutras A, Karaivazoglou K et al. Effect of epoetin alfa therapy on cognitive function in anaemic patients with solid tumours undergoing chemotherapy. Eur J Cancer Care 2008; 17 (6): 535–541. doi: 10.1111/j.1365-2354.2007.00857.x.
62. Kesler SR, Kent JS, O‘Hara R. Prefrontal cortex and executive function impairments in primary breast cancer. Arch Neurol 2011; 68 (11): 1447–1453. doi: 10.1001/archneurol.2011.245.
63. Kesler SR, Wefel JS, Hosseini SM et al. Default mode network connectivity distinguishes chemotherapy-treated breast cancer survivors from controls. Proc Natl Acad Sci USA 2013; 110 (28): 11600–11605. doi: 10.1073/pnas.1214551110.
64. Ahles TA. Brain vulnerability to chemotherapy toxicities. Psychooncology 2012; 21 (11): 1141–1148. doi: 10.1002/pon.3196.
65. Sambataro F, Murty VP, Callicott JH et al. Age-related alterations in default mode network: Impact on working memory performance. Neurobiol Aging 2010; 31 (5): 839–852. doi: 10.1016/j.neurobiolaging.2008.05.022.
66. Hafkemeijer A, Van der Grond J, Rombouts SA. Imaging the default mode network in aging and dementia. Biochim Biophys Acta 2012; 1822 (3): 431–441. doi: 10.1016/j.bbadis.2011.07.008.
67. Bender CM, Thelen BD. Cancer and cognitive changes: the complexity of the problem. Semin Oncol Nurs 2013; 29 (4): 232–237. doi: 10.1016/j.soncn.2013.08.003.
68. Li J, Yu L, Long Z et al. Perceived cognitive impairment in Chinese patients with breast cancer and its relationship with post-traumatic stress disorder symptoms and fatigue. Psychoncology 2015; 24 (6): 676–682. doi: 10.1002/pon.3710.
69. Walker CH, Drew BA, Antoon JW et al. Neurocognitive effects of chemotherapy and endocrine therapies in the treatment of breast cancer: recent perspectives. Cancer Invest 2012; 30 (2): 135–148. doi: 10.3109/07357907.2011.636116.
70. Bury M, Borkowska AR, Daniluk B. Impact of chemotherapy on memory, attention and executive functions depending on the stages of treatment and the level of depression in female patients with cancer. Acta Neuropsychologica 2014; 12 (4): 417–427.
71. Collins B, Mackenzie J, Stewart A et al. Cognitive effects of chemotherapy in post-menopausal breast cancer patients 1 year after treatment. Psychooncology 2009; 18 (2): 134–143. doi: 10.1002/pon.1379.
72. Ng T, Teo SM, Yeo HL et al. Brain-derived neurotrophic factor genetic polymorphism (rs6265) is protective against chemotherapy-associated cognitive impairment in patients with early-stage breast cancer. Neuro Oncol 2016; 18 (2): 244–251. doi: 10.1093/neuonc/nov162.
73. Cheung YT, Ng T, Shwe M et al. Association of proinflammatory cytokines and chemotherapy-associated cognitive impairment in breast cancer patients: a multi-centered, prospective, cohort study. Ann Oncol 2015; 26 (7): 1446–1451. doi: 10.1093/annonc/mdv206.
74. Stern J. What is cognitive reserve? Theory and research application of the reserve concept. J Int Neuropsychol Soc 2012; 8 (3): 448–460.
75. Massa E, Madeddu C, Lusso MR et al. Evaluation of the effectiveness of treatment with erythropoietin on anemia, cognitive functioning and functions studied by comprehensive geriatric assessment in elderly cancer patients with anemia related to cancer chemotherapy. Crit Rev Oncol Hematol 2006; 57 (2): 175–182.
76. O‘Shaughnessy JA, Vukelja SJ, Holmes FA et al. Feasibility of quantifying the effects of epoetin alfa therapy on cognitive function in women with breast cancer undergoing adjuvant or neoadjuvant chemotherapy. Clin Breast Cancer 2005; 5 (6): 439–446.
77. Fan HG, Park A, Xu W et al. The influence of erythropoietin on cognitive function in women following chemotherapy for breast cancer. Psychooncology 2009; 18 (2): 156–161. doi: 10.1002/pon.1372.
78. El Beltagy M, Mustafa S, Umka J et al. Fluoxetine improves the memory deficits caused by the chemotherapy agent 5-fluorouracil. Behav Brain Res 2010; 208 (1): 112–117. doi: 10.1016/j.bbr.2009.11.017.
79. Lyons L, El Beltagy M, Bennett G et al. Fluoxetine counteracts the cognitive and cellular effects of 5-fluorouracil in the rat hippocampus by a mechanism of prevention rather than recovery. PLoS One 2012; 7 (1): e30010. doi: 10.1371/journal.pone.0030010.
80. Shapovalov Y, Zettel M, Spielman SC et al. Fluoxetine modulates breast cancer metastasis to the brain in a murine model. BMC Cancer 2014; 14: 598–612. doi: 10.1186/1471-2407-14-598.
81. Kohli S, Fisher SG, Tra Y et al. The effect of modafinil on cognitive function in breast cancer survivors. Cancer 2009; 115 (15): 2605–2616. doi: 10.1002/cncr.24287.
82. Lundorff L, Jonsson B, Sjogren P. Modafinil for attentional and psychomotor dysfunction in advanced cancer: a double-blind, randomised, cross-over trial. Palliat Med 2009; 23 (8): 731–738. doi: 10.1177/0269216309106872.
83. Lower EE, Fleishman S, Cooper A et al. Efficacy of dexmethylphenidate for the treatment of fatigue after cancer chemotherapy: a randomized clinical trial. J Pain Symptom Manage 2009; 38 (5): 650–662. doi: 10.1016/j.jpainsymman.2009.03.011.
84. Winocur G, Binns MA, Tannock I. Donepezil reduces cognitive impairment associated with anti-cancer drugs in a mouse model. Neuropharmacology 2011; 61 (8): 1222–1228. doi: 10.1016/j.neuropharm.2011.07.013.
85. Lawrence JA, Griffin L, Balcueva EP et al. A study of donepezil in female breast cancer survivors with self-reported cognitive dysfunction 1 to 5 years following adjuvant chemotherapy. J Cancer Surviv 2016; 10 (1): 176–184. doi: 10.1007/s11764-015-0463-x.
86. Zimmer P, Baumann FT, Oberste M et al. Effects of exercise interventions and physical activity behavior on cancer related cognitive impairments: a systematic review. Biomed Res Int 2016; 2016: 1820954. doi: 10.1155/2016/1820954.
88. Szuhany KL, Bugatti M, Otto MW. A meta-analytic review of the effects of exercise on brain-derived neurotrophic factor. J Psychiatr Res 2015; 60: 56–64. doi: 10.1016/j.jpsychires.2014.10.003.
89. Acharya MM, Martirosian V, Chmielewski NN et al. Stem cell transplantation reverses chemotherapy-induced cognitive dysfunction. Cancer Res 2015; 75 (4): 676–686. doi: 10.1158/0008-5472.CAN-14-2237.
Labels
Paediatric clinical oncology Surgery Clinical oncologyArticle was published in
Clinical Oncology
2017 Issue 2
Most read in this issue
- Chemotherapy-related Cognitive Impairment in Patients with Hodgkin Lymphoma – Pathophysiology and Risk Factors
- Coffee in Cancer Chemoprevention
- Trends in Prostate Cancer Epidemiology in Slovakia – an International Comparison
- Stereotactic Body Radiotherapy of Prostate Cancer – Effectiveness and Toxicity