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İmmünoterapi Alan Kanser Hastalarında İlaç Tedavisine İnancı Etkileyen Faktörlerin Belirlenmesi

Year 2021, , 251 - 259, 01.04.2021
https://doi.org/10.31067/acusaglik.850778

Abstract

Amaç:Bu çalışmanın amacı immünoterapi tedavisi alan kanser hastalarında ilaç inancı ve etkileyen faktörlerin belirlenmesiydi.
Hastalar ve Yöntem:Tanımlayıcı tipteki bu çalışmanın örneklemini Aralık 2018-Mayıs 2019 tarihleri arasında bir eğitim ve araştırma hastanesinin tıbbi onkoloji kliniğine ayaktan başvuran, immünoterapi tedavisi alan ve araştırmaya katılmayı kabul eden hastalar (N=85) oluşturdu. Verilerin toplanmasında hasta tanıtıcı bilgi formu ve İlaçlar Hakkında İnançlar Anketi kullanıldı. Veriler bilgisayar ortamında SPSS for Windows 22.00 paket programında değerlendirildi. Verilerin normal dağılıma uygunluğu Shapiro-Wilk Testi ile değerlendirildi. p ≤ 0.05 istatistiksel olarak anlamlı kabul edildi.
Bulgular:Katılımcıların yaş ortalaması 58.80±14.23 yıl, %50.6’sı kadın, %56.5’i evre IV kanser hastasıydı ve %74.1’inin metastazı vardı. İmmünoterapinin yan etkilerinden etkilenen hastalar katılımcıların %54.1’ini oluşturdu. Yaşa göre İlaç İnanç Anketinin alt ölçek puan ortalamaları karşılaştırıldığında 65 yaş üzeri hastaların “Spesifik Endişe” puan ortalamalarının genç hastalara göre daha düşük olduğu saptandı (t=2.175, p=0.032). Metastaz varlığına göre alt ölçek puan ortalamaları karşılaştırıldığında, metastazı olan hastaların “spesifik gereklilik” alt ölçeğinden aldıkları puan ortalamalarının metastazı olmayanlara göre daha yüksek olduğu bulundu (z=-2.185, p=0.029). İlaçların yan etki oluşturmasına göre ilaç yan etkisi olan hastaların “Genel Aşırı Kullanım” ve “Genel Zarar” alt ölçeklerinden aldıkları puan ortalamalarının yan etki yaşamayan hastalara göre daha yüksek olduğu saptandı (sırasıyla; z=-2.599, p=0.009; z=-1.966, p=0.049).
Sonuç:Sonuç olarak yaşlı kanser hastalarının immünoterapi ilaçları konusunda daha az endişe duyduğu, metastazı olan hastaların kullandıkları ilaçların gerekli olduğuna daha fazla inandığı, yan etki yaşayan hastaların yaşamayanlara göre genel zarar ve genel aşırı kullanım inançlarının daha yüksek olduğu değerlendirildi.

References

  • 1. American Cancer Society, Cancer Immunotherapy, Copyright American Cancer Society. https://www.cancer.org/treatment/treatments-and-side-effects/treatment-types/ immunotherapy/what-is-immunotherapy.html (Erişim tarihi: 05/12/2018)
  • 2. Wayteck L, Breckpot K, Demeester J, De Smedt SC, Raemdonck KA. Personalized View on Cancer Immunotherapy. Cancer Letters 2014;352:113-125.
  • 3. Zugazagoitia J, Guedes C, Ponce S, Ferrer I, Molina- Pinelo S, Paz- Ares L. Current Challenges in Cancer Treatment. Clinical Therapeutics 2016;38(7):1551–1566.
  • 4. Rothschild, S. I., Thommen, D. S., Moersig, W., Müller, P., & Zippelius, A. Cancer immunology–development of novel anti-cancer therapies. Swiss Medical Weekly2015;145(0506).
  • 5. Gulley JL, Madan RA, Schlom J. Impact of tumour volume on the potential efficacy of therapeutic vaccines. Current Oncology, 2011; 18:e150 – 7.
  • 6. Maude, S. L., Frey, N., Shaw, P. A., Aplenc, R., Barrett, D. M., Bunin, N. J., ... & Mahnke, Y. D. (2014). Chimeric antigen receptor T cells for sustained remissions in leukemia. New England Journal of Medicine, 371(16), 1507-1517.
  • 7. Zorlu, M. Malign melanomda cerrahi sonrası adjuvan immunoterapi ve kemoterapi deneyimimiz. Çağdaş Tıp Dergisi 2018;8(4):299-303.
  • 8. Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF, et al, IMPACT Study Investigators. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. New England Journal Medicine 2010; 363:411 - 22;
  • 9. Zhang, Y., Kurupati, R., Liu, L., Zhou, X. Y., Zhang, G., Hudaihed, A., ... & Schuchter, L. M.Enhancing CD8+ T cell fatty acid catabolism within a metabolically challenging tumor microenvironment increases the efficacy of melanoma immunotherapy. Cancer Cell 2017;32(3): 377-391.
  • 10. Zhou J. Advances and Prospects in Cancer Immunotherapy. New Journal of Science 2014;1-13.
  • 11. Ventola CL. Cancer Immunotherapy, Part 1: Current Strategies and Agents. P&T 2017;42(6):375–383.
  • 12. Yang Y. Cancer Immunotherapy: Harnessing the Immune System to Battle Cancer. The Journal of Clinical Investigation 2015;125(9):3335–3337.
  • 13. Sanmamed MF, Chen L.A Paradigm Shift in Cancer Immunotherapy: From Enhancement to Normalization. Cell, 2018;4,175(2):313-326.
  • 14. Çalıkuşu Z. Kanserde İmmünoterapi Yan Etkileri ve Yönetimi ACU Sağlık Bilimleri Dergisi 2019; 10(2):142-147.
  • 15. Yılmaz F, Yavuz Çolak M. Kronik Hastalığı Olan Yaşlı Bireylerde İlaç İnancının ve Tedaviye Uyumun Değerlendirilmesi. Turkiye Klinikleri Journal of Health Sciences 2018;3(2):113-121.
  • 16. Drangsholt SH, Cappelen UW, Von Der Lippe N, Høıeggen A, Os I, Brekke FB. Beliefs About Medicines in Dialysis Patients and After Renal Transplantation. Hemodialysis International 2019; 23:117–125.
  • 17. Tsianou K, Giannakeas N, Tsipouras MG, Tzallas AT, Skamnelos A, Christodoulou DK, et al. Accessing Patient Views about Medication in Chronic Conditions Using the Beliefs about Medicine Questionnaire (BMQ): A Review Study. Journal of Drug Research and Development 2017;3(1):2470-1009.
  • 18. Jiang Y, Sereika SM, Bender CM, Brufsky AM, Rosenzweig MQ. Beliefs in Chemotherapy and Knowledge of Cancer and Treatment Among African American Women With Newly Diagnosed Breast Cancer Oncology Nursing Forum 2016;43(2):180-189.
  • 19. Marshall VK, Given BA. Factors Associated With Medication Beliefs in Patients With Cancer: An Integrative ReviewOncology Nursing Forum 2018;45(4):508–526.
  • 20. Alhewiti A.Adherence to Long-Term Therapies and Beliefs About Medications. International Journal of Family Medicine, 2014. doi: http://dx.doi.org/10.1155/2014/479596
  • 21. Brett J, Hulbert-Williams NJ, Fenlon D, Boulton M, Walter FM, Donnelly P, et al. Psychometric Properties of the Beliefs About Medicine Questionnaire–Adjuvant Endocrine Therapy (BMQ-AET) for Women Taking AETs Following Early-Stage Breast Cancer. Health Psychology Open July-December 2017:1–8.
  • 22. Niea B, Chapmanb SCE, Chenc Z, Wangd X, Weia L. Utilization of the Beliefs About Medicine Questionnaire and Prediction of Medication Adherence in China: A Systematic Review and Meta-analysis.Journal of Psychosomatic Research 2019;122:54-68.
  • 23. Sirey JA, Greenfield A, Weinberger MI, Bruce ML. Medication Beliefs and Self-Reported Adherence Among Community-Dwelling Older Adults. Clinical Therapeutics 2013;35(2):153-60.
  • 24. Ceulemans M, Van Calsteren K, Allegaert K, Foulon V. Beliefs About Medicines and Information Needs Among Pregnant Women Visiting A Tertiary Hospital in Belgium. European Journal of Clinical Pharmacology 2019;75:995–1003.
  • 25. Mack JW, Walling A, Dy S, Antonio ALM, Adams J, Keating NL, Tisnado D. Patient Beliefs That Chemotherapy May Be Curative and Care Received at the End of Life Among Patients With Metastatic Lung and Colorectal Cancer. Cancer 2015;1:1891-1896.
  • 26. Horne R, Weinman J, Hankins M. The Beliefs about Medicines Questionnaire: The Development and Evaluation of ANew Method for Assessing the Cognitive Representation of Medication. Psychology& Health 1999;14(1):1–24.
  • 27. Çınar M, Çınar FI, Açıkel C, Yılmaz S, Çakar M, Horne R, et al. Reliability and Validity of the Turkish Translation of the Beliefs About Medicines Questionnaire (BMQ-T) in Patients With Behçet’s Disease. Clinicaland Experimental Rheumatology 2016;34(6 Suppl 102),46-51.
  • 28. Wan BK., Cheung WH, BallPA, JacksonDM, Maynard GJ.Beliefs About Medicines Among Hong Kong Hospital Outpatients. International Journal of Pharmacy Practice 2017;25(6),447-453.
  • 29. ArriolaJKR, Mason TA, Bannon KA, Holmes C, Powell CL, Horne K, O’Regan R. Modifiable Risk Factors for Adherence to Adjuvant Endocrine Therapy Among Breast Cancer Patients. Patient Education and Counseling 2014;95,98–103.
  • 30. Jorgensen ML, Young JM,Solomon MJ. Adjuvant Chemotherapy for Colorectal Cancer: Age Differences in Factors Influencing Patients’ Treatment Decisions. Patient Preference and Adherence 2013,7:827–834.
  • 31. SalgadoTM, Davis EJ, Farris KB, Fawaz S, Batra P, Henry NL.Identifying Socio-demographic and Clinical Characteristics Associated With Medication Beliefs About Aromatase Inhibitors Among Postmenopausal Women With Breast Cancer. Breast Cancer Research and Treatment 2017;163:311–319.
  • 32. Voogt E, van der Heide A, Rietjens JA, van Leeuwen AF, Visser AP, van der Rijt CC, et al. Attitudes of Patients With Incurable Cancer Toward Medical Treatment in the Last Phase of Life. Journal of Clinical Oncology 2005;23:2012–2019.
  • 33. Kaya H, Turan N, Çulha Y, Aydın GA. Yaşlı Bireylerde İlaç Yönetiminde Hemşirenin Rolü. JAREN/Hemşirelik Akademik Araştırma Dergisi 2018;4(2):120-126.
  • 34. Hammoudi BM, Ismaile S, Abu Yahya O. Factors Associated With Medication Administration Errors and Why Nurses Fail to Report Them. Scandinavian Journal of Caring Sciences 2017;32(3):1038-1046.
  • 35. IskandarsyahA, de Klerk C, Suardi DR, Soemitro MP, Sadarjoen SS, Passchier J. Psychosocial and Cultural Reasons For Delay in Seeking Help and Nonadherence to Treatment in Indonesian Women With Breast Cancer: A Qualitative Study. Health Psychology 2014;33:214–221.
  • 36. HeisigSR, Shedden‐Mora MC, von Blanckenburg P, Rief W, Witzel I, Albert US, NestoriucY. (2016). What Do Women With Breast Cancer Expect From Their Treatment? Correlates of Negative Treatment Expectations About Endocrine Therapy. Psycho‐Oncology, 25(12):1485-1492.
  • 37. Konstantis A, Exiara T. Family Caregiver Beliefs and Barriers to Effective Pain Management of Cancer Patients in Home Care Settings. JBUON 2018;23(7):144-152.
  • 38. BanningM. Adherence to Adjuvant Therapy inPost-Menopausal Breast Cancer Patients: A Review. European Journal of Cancer Care 2012;21:10–19.
  • 39. Hirose T, Yamaoka T, Ohnishi T, Sugiyama T, Kusumoto S, Shirai T, et al. Patient Willingness to Undergo Chemotherapy and Thoracic Radiotherapy for Locally AdvancedNon-small Cell Lung Cancer. Psycho-Oncology 2019;18:483–489.
  • 40. Marshall VK, Given CW, Sikorskii A, Given BA, Lehto RH. How Adverse Events and Permanent Medication Stoppages Affect Changes in Patients' Beliefs About Oral Antineoplastic Agents. Supportive Care in Cancer 2019;1-8.

Determining the Factors Affecting the Beliefs of Patients with Cancer on Immunotherapy Medications

Year 2021, , 251 - 259, 01.04.2021
https://doi.org/10.31067/acusaglik.850778

Abstract

Purpose:The aim of this study was to determine the beliefs about medications and the affecting factors in patients with cancer having immunotherapy treatment.
Patients and Methods:The sample of this descriptive study consisted of patients (n = 85) who were admitted to the outpatient medical oncology clinic of an education and research hospital between December 2018-May 2019. Data were collected using the patient information form and the Beliefs about Medications Questionnaire. Data were analysed by SPSS for Windows 22.00 package program. p ≤ 0.05 was considered statistically significant.
Results:The mean age of the participants was 58.80±14.23 years, 50.6% were female, 56.5% had stage IV cancer and 74.1% had metastasis. More than half of the patients (54.1%) experienced adverse effects of immunotherapy. It was found that the “Specific Concern” subscale scores of the patients over 65 years were lower than the younger patients (t = 2.175, p = 0.032). The mean “Specific Necessity” subscale scores of the patients with metastasis were higher than those without metastasis (z = -2.185, p = 0.029). It was found that the mean “General Harm” and “General Overuse” subscale scores of the patients who had adverse effects were higher than the patients who did not experience adverse effects (z = -1.966, p = 0.049; z = -2.599, p = 0.009, respectively).
Conclusion:Elderly patients with cancer were less concerned about immunotherapy, patients with metastasis believed that immunotherapy medications were necessary, and patients who had adverse effects during immunotherapy treatment believed that medications were harmful and overused.

References

  • 1. American Cancer Society, Cancer Immunotherapy, Copyright American Cancer Society. https://www.cancer.org/treatment/treatments-and-side-effects/treatment-types/ immunotherapy/what-is-immunotherapy.html (Erişim tarihi: 05/12/2018)
  • 2. Wayteck L, Breckpot K, Demeester J, De Smedt SC, Raemdonck KA. Personalized View on Cancer Immunotherapy. Cancer Letters 2014;352:113-125.
  • 3. Zugazagoitia J, Guedes C, Ponce S, Ferrer I, Molina- Pinelo S, Paz- Ares L. Current Challenges in Cancer Treatment. Clinical Therapeutics 2016;38(7):1551–1566.
  • 4. Rothschild, S. I., Thommen, D. S., Moersig, W., Müller, P., & Zippelius, A. Cancer immunology–development of novel anti-cancer therapies. Swiss Medical Weekly2015;145(0506).
  • 5. Gulley JL, Madan RA, Schlom J. Impact of tumour volume on the potential efficacy of therapeutic vaccines. Current Oncology, 2011; 18:e150 – 7.
  • 6. Maude, S. L., Frey, N., Shaw, P. A., Aplenc, R., Barrett, D. M., Bunin, N. J., ... & Mahnke, Y. D. (2014). Chimeric antigen receptor T cells for sustained remissions in leukemia. New England Journal of Medicine, 371(16), 1507-1517.
  • 7. Zorlu, M. Malign melanomda cerrahi sonrası adjuvan immunoterapi ve kemoterapi deneyimimiz. Çağdaş Tıp Dergisi 2018;8(4):299-303.
  • 8. Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF, et al, IMPACT Study Investigators. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. New England Journal Medicine 2010; 363:411 - 22;
  • 9. Zhang, Y., Kurupati, R., Liu, L., Zhou, X. Y., Zhang, G., Hudaihed, A., ... & Schuchter, L. M.Enhancing CD8+ T cell fatty acid catabolism within a metabolically challenging tumor microenvironment increases the efficacy of melanoma immunotherapy. Cancer Cell 2017;32(3): 377-391.
  • 10. Zhou J. Advances and Prospects in Cancer Immunotherapy. New Journal of Science 2014;1-13.
  • 11. Ventola CL. Cancer Immunotherapy, Part 1: Current Strategies and Agents. P&T 2017;42(6):375–383.
  • 12. Yang Y. Cancer Immunotherapy: Harnessing the Immune System to Battle Cancer. The Journal of Clinical Investigation 2015;125(9):3335–3337.
  • 13. Sanmamed MF, Chen L.A Paradigm Shift in Cancer Immunotherapy: From Enhancement to Normalization. Cell, 2018;4,175(2):313-326.
  • 14. Çalıkuşu Z. Kanserde İmmünoterapi Yan Etkileri ve Yönetimi ACU Sağlık Bilimleri Dergisi 2019; 10(2):142-147.
  • 15. Yılmaz F, Yavuz Çolak M. Kronik Hastalığı Olan Yaşlı Bireylerde İlaç İnancının ve Tedaviye Uyumun Değerlendirilmesi. Turkiye Klinikleri Journal of Health Sciences 2018;3(2):113-121.
  • 16. Drangsholt SH, Cappelen UW, Von Der Lippe N, Høıeggen A, Os I, Brekke FB. Beliefs About Medicines in Dialysis Patients and After Renal Transplantation. Hemodialysis International 2019; 23:117–125.
  • 17. Tsianou K, Giannakeas N, Tsipouras MG, Tzallas AT, Skamnelos A, Christodoulou DK, et al. Accessing Patient Views about Medication in Chronic Conditions Using the Beliefs about Medicine Questionnaire (BMQ): A Review Study. Journal of Drug Research and Development 2017;3(1):2470-1009.
  • 18. Jiang Y, Sereika SM, Bender CM, Brufsky AM, Rosenzweig MQ. Beliefs in Chemotherapy and Knowledge of Cancer and Treatment Among African American Women With Newly Diagnosed Breast Cancer Oncology Nursing Forum 2016;43(2):180-189.
  • 19. Marshall VK, Given BA. Factors Associated With Medication Beliefs in Patients With Cancer: An Integrative ReviewOncology Nursing Forum 2018;45(4):508–526.
  • 20. Alhewiti A.Adherence to Long-Term Therapies and Beliefs About Medications. International Journal of Family Medicine, 2014. doi: http://dx.doi.org/10.1155/2014/479596
  • 21. Brett J, Hulbert-Williams NJ, Fenlon D, Boulton M, Walter FM, Donnelly P, et al. Psychometric Properties of the Beliefs About Medicine Questionnaire–Adjuvant Endocrine Therapy (BMQ-AET) for Women Taking AETs Following Early-Stage Breast Cancer. Health Psychology Open July-December 2017:1–8.
  • 22. Niea B, Chapmanb SCE, Chenc Z, Wangd X, Weia L. Utilization of the Beliefs About Medicine Questionnaire and Prediction of Medication Adherence in China: A Systematic Review and Meta-analysis.Journal of Psychosomatic Research 2019;122:54-68.
  • 23. Sirey JA, Greenfield A, Weinberger MI, Bruce ML. Medication Beliefs and Self-Reported Adherence Among Community-Dwelling Older Adults. Clinical Therapeutics 2013;35(2):153-60.
  • 24. Ceulemans M, Van Calsteren K, Allegaert K, Foulon V. Beliefs About Medicines and Information Needs Among Pregnant Women Visiting A Tertiary Hospital in Belgium. European Journal of Clinical Pharmacology 2019;75:995–1003.
  • 25. Mack JW, Walling A, Dy S, Antonio ALM, Adams J, Keating NL, Tisnado D. Patient Beliefs That Chemotherapy May Be Curative and Care Received at the End of Life Among Patients With Metastatic Lung and Colorectal Cancer. Cancer 2015;1:1891-1896.
  • 26. Horne R, Weinman J, Hankins M. The Beliefs about Medicines Questionnaire: The Development and Evaluation of ANew Method for Assessing the Cognitive Representation of Medication. Psychology& Health 1999;14(1):1–24.
  • 27. Çınar M, Çınar FI, Açıkel C, Yılmaz S, Çakar M, Horne R, et al. Reliability and Validity of the Turkish Translation of the Beliefs About Medicines Questionnaire (BMQ-T) in Patients With Behçet’s Disease. Clinicaland Experimental Rheumatology 2016;34(6 Suppl 102),46-51.
  • 28. Wan BK., Cheung WH, BallPA, JacksonDM, Maynard GJ.Beliefs About Medicines Among Hong Kong Hospital Outpatients. International Journal of Pharmacy Practice 2017;25(6),447-453.
  • 29. ArriolaJKR, Mason TA, Bannon KA, Holmes C, Powell CL, Horne K, O’Regan R. Modifiable Risk Factors for Adherence to Adjuvant Endocrine Therapy Among Breast Cancer Patients. Patient Education and Counseling 2014;95,98–103.
  • 30. Jorgensen ML, Young JM,Solomon MJ. Adjuvant Chemotherapy for Colorectal Cancer: Age Differences in Factors Influencing Patients’ Treatment Decisions. Patient Preference and Adherence 2013,7:827–834.
  • 31. SalgadoTM, Davis EJ, Farris KB, Fawaz S, Batra P, Henry NL.Identifying Socio-demographic and Clinical Characteristics Associated With Medication Beliefs About Aromatase Inhibitors Among Postmenopausal Women With Breast Cancer. Breast Cancer Research and Treatment 2017;163:311–319.
  • 32. Voogt E, van der Heide A, Rietjens JA, van Leeuwen AF, Visser AP, van der Rijt CC, et al. Attitudes of Patients With Incurable Cancer Toward Medical Treatment in the Last Phase of Life. Journal of Clinical Oncology 2005;23:2012–2019.
  • 33. Kaya H, Turan N, Çulha Y, Aydın GA. Yaşlı Bireylerde İlaç Yönetiminde Hemşirenin Rolü. JAREN/Hemşirelik Akademik Araştırma Dergisi 2018;4(2):120-126.
  • 34. Hammoudi BM, Ismaile S, Abu Yahya O. Factors Associated With Medication Administration Errors and Why Nurses Fail to Report Them. Scandinavian Journal of Caring Sciences 2017;32(3):1038-1046.
  • 35. IskandarsyahA, de Klerk C, Suardi DR, Soemitro MP, Sadarjoen SS, Passchier J. Psychosocial and Cultural Reasons For Delay in Seeking Help and Nonadherence to Treatment in Indonesian Women With Breast Cancer: A Qualitative Study. Health Psychology 2014;33:214–221.
  • 36. HeisigSR, Shedden‐Mora MC, von Blanckenburg P, Rief W, Witzel I, Albert US, NestoriucY. (2016). What Do Women With Breast Cancer Expect From Their Treatment? Correlates of Negative Treatment Expectations About Endocrine Therapy. Psycho‐Oncology, 25(12):1485-1492.
  • 37. Konstantis A, Exiara T. Family Caregiver Beliefs and Barriers to Effective Pain Management of Cancer Patients in Home Care Settings. JBUON 2018;23(7):144-152.
  • 38. BanningM. Adherence to Adjuvant Therapy inPost-Menopausal Breast Cancer Patients: A Review. European Journal of Cancer Care 2012;21:10–19.
  • 39. Hirose T, Yamaoka T, Ohnishi T, Sugiyama T, Kusumoto S, Shirai T, et al. Patient Willingness to Undergo Chemotherapy and Thoracic Radiotherapy for Locally AdvancedNon-small Cell Lung Cancer. Psycho-Oncology 2019;18:483–489.
  • 40. Marshall VK, Given CW, Sikorskii A, Given BA, Lehto RH. How Adverse Events and Permanent Medication Stoppages Affect Changes in Patients' Beliefs About Oral Antineoplastic Agents. Supportive Care in Cancer 2019;1-8.
There are 40 citations in total.

Details

Primary Language Turkish
Subjects Oncology and Carcinogenesis
Journal Section Research Articles
Authors

Betül Tosun

Canan Pörücü

Nuri Karadurmuş

Nursemin Ünal

Publication Date April 1, 2021
Submission Date January 18, 2020
Published in Issue Year 2021

Cite

EndNote Tosun B, Pörücü C, Karadurmuş N, Ünal N (April 1, 2021) İmmünoterapi Alan Kanser Hastalarında İlaç Tedavisine İnancı Etkileyen Faktörlerin Belirlenmesi. Acıbadem Üniversitesi Sağlık Bilimleri Dergisi 12 2 251–259.