ABSTRACT:

Introduction:

Hormonal therapy in breast cancer is essential to the transition from active treatment to care survival, because it improves long-term survival and provides a better quality of life. reducing hospital costs as well. However, adherence and persistence in the recommended treatment are important to achieve the desirable results.

Methodology:

This is a cohort retrospective study of 182 women on hormonal treatment identified at a high complexity oncology unit, in the southeastern region of Brazil, and followed-up until 2014. We performed a bivariate analysis to analyze the factors associated with adherence and we conducted the multivariate Cox regression to identify variables associated with discontinuity of treatment over time.

Results:

Overall adherence was 85.2% and persistence was 45.4% at the end of 5 years. No association was found between the studied independent variables and adherence. Women with advanced stage (HR = 2.24; 95% confidence interval 1.45 - 3.45), who did not undergo surgery (HR = 3.46; 95%CI 2.00 - 5.97), and with three or more hospitalizations (HR = 6.06; 95%CI 2.53 - 14.54) exhibited increased risk of discontinuity.

Discussion:

The variables associated with persistence reflect the relation between the highest disease severity and the discontinuity of adjuvant hormonal treatment.

Conclusion:

Despite the high adherence level, there is a progressive increase in non-persistence among women on hormonal therapy, influenced by characteristics related to disease severity, which contributes to an inadequate therapeutic response.

Keywords:
Breast neoplasms; Antineoplastic agents, Hormonal; Medication adherence; Patient dropouts; Risk factors; Drug therapy

INTRODUCTION

Use of the hormonal therapy to treat breast cancer has a main role in the transition from active treatment to survival care, because it significantly improves long-term survival results. Studies show that using such drugs to treat breast cancer at early stages may decrease the risk of recurrence and mortality to 15 years and, therefore, it is recommended as a preventive measurement in 75 to 80% of the disease cases¹1. Burstein HJ, Prestrud AA, Seidenfeld J, Anderson H, Buchholz TA, Davidson NE. American society of clinical oncology clinical practice guideline: update on adjuvant endocrine therapy for women with hormone receptor-positive breast cancer. J Clin Oncol 2010; 28(23): 3784-96. DOI. 10.1200/JCO.2009.26.3756
https://doi.org/10.1200/JCO.2009.26.3756... ^,22. Murphy CC, Bartholomew LK, Carpentier MY, Bluethmann SM, Vernon SW. Adherence to adjuvant hormonal therapy among breast cancer survivors in clinical practice: a systematic review. Breast Cancer Res Treat 2012; 134(2): 459-78. DOI: 10.1007/s10549-012-2114-5
https://doi.org/10.1007/s10549-012-2114-... . In addition, considering that oral medications are used, hormonal therapy may also provide better quality of life to ill subjects with more feeling of control on the therapeutics and less interference in social life³3. Oliveira AT, Queiroz AP. Perfil de uso da terapia antineoplásica oral: a importância da orientação farmacêutica. Rev Bras Farm Hosp Serv Saúde 2012; 3(4): 24-9.. Another benefit of the hormonal therapy in comparison with the conventional chemotherapy is its cost-effective strategy in hospitalization, equipment, and human resources⁴4. Timmers L, Boons CC, Kropff F, Ven PM, Swart EL, Smit EF, et al. Adherence and patients' experiences with the use of oral anticancer agents. Acta Oncol 2014; 53(2): 259-67. DOI: 10.3109/0284186X.2013.844353
https://doi.org/10.3109/0284186X.2013.84... ^,55. Benjamin L, Buthion V, Iskedjian M, Farah B, Rioufol C, Vidal-Trecan G. Budget impact analysis of the use of oral and intravenous anti-cancer drugs for the treatment of HER2-positive metastatic breast cancer. J Med Econ 2013; 16(1): 96-107. DOI: 10.3111/13696998.2012.729549
https://doi.org/10.3111/13696998.2012.72... .

The main hormonal agents used in breast cancer treatment include the selective estrogen receptor modulators - tamoxifen (TMX) - and the aromatase inhibitors (AIs), such as anastrozole. To update the guideline of clinical practice in adjuvant endocrine therapy, the American Society of Clinical Oncology (ASCO) conducted a systematic review on the optimal treatment duration throughout the years 2009-2013. They found survival, recurrent disease and occurrence of adverse events as the outcomes of interest. The earlier guidelines of ASCO recommended five years of treatment with TMX or AIs. However, current evidence suggests the treatment should last ten years¹1. Burstein HJ, Prestrud AA, Seidenfeld J, Anderson H, Buchholz TA, Davidson NE. American society of clinical oncology clinical practice guideline: update on adjuvant endocrine therapy for women with hormone receptor-positive breast cancer. J Clin Oncol 2010; 28(23): 3784-96. DOI. 10.1200/JCO.2009.26.3756
https://doi.org/10.1200/JCO.2009.26.3756... . The last protocol presented in 2011, by the Brazilian Medical Association [Associação Médica Brasileira (AMB)] and by the Supplementary Health Brazilian Agency [Agência Nacional de Saúde Suplementar (ANSS)], during the project “Diretrizes - Câncer de Mama: Terapia Endócrina e Terapia-Alvo”, recommends that hormonal therapy should also be used for all patients with a positive hormone receptor and during a 5-year period, without considering complementary benefits after treatment prolongation.

All benefits of hormonal therapy are well-known, including increase of survival. In addition, the medication is distributed by the Brazilian Unified Health System (SUS) for free. Nevertheless, the desirable results many times are not achieved due to problems such as low adherence and low persistence in the recommended treatment, whose associated factors should be carefully evaluated. Evidence ensures that benefits in the change from the mortality and disease recurrence rates only happen effectively if the treatment is completely followed⁶6. Brito C, Portela MC, Vasconcellos MT. Fatores associados à persistência à terapia hormonal em mulheres com câncer de mama. Rev Saúde Pública 2014; 48(2): 284-95. DOI. 10.1590/S0034-8910.2014048004799
https://doi.org/10.1590/S0034-8910.20140... ^,77. Makubate B, Donnan PT, Dewar JA, Thompson AM, McCowan C. Cohort study of adherence to adjuvant endocrine therapy, breast cancer recurrence and mortality. Br J Cancer 2013; 108(7): 1515-24. DOI: 10.1038/bjc.2013.116
https://doi.org/10.1038/bjc.2013.116... .

Attention has been given to adherence and persistence studies (A & P) due to the concept that clinical results of the treatment are not only affected by how patients take the drugs, but also by the period of uninterrupted use⁸8. Cramer JA, Roy A, Burrell A, Fairchild CJ, Fuldeore MJ, Ollendorf DA, et al. Medication compliance and persistence: terminology and definitions. Value Health 2008; 11(1): 44-7. DOI: 10.1111/j.1524-4733.2007.00213.x
https://doi.org/10.1111/j.1524-4733.2007... . Therefore, adherence and persistence should be separately defined and measured to characterize the medication intake in a broader manner, thus providing more understanding on this conduct⁸8. Cramer JA, Roy A, Burrell A, Fairchild CJ, Fuldeore MJ, Ollendorf DA, et al. Medication compliance and persistence: terminology and definitions. Value Health 2008; 11(1): 44-7. DOI: 10.1111/j.1524-4733.2007.00213.x
https://doi.org/10.1111/j.1524-4733.2007... ^,99. Peterson AM, Nau DP, Cramer JA, Benner J, Gwadry-Sridhar F, Nichol M. A checklist for medication compliance and persistence studies using retrospective databases. Value Health 2007; 10(1): 3-12. DOI: 10.1111/j.1524-4733.2006.00139.x
https://doi.org/10.1111/j.1524-4733.2006... .

It is known that adherence and persistence may be influenced by several factors related to the patient, such as treatment, health services, beliefs, and life habits²2. Murphy CC, Bartholomew LK, Carpentier MY, Bluethmann SM, Vernon SW. Adherence to adjuvant hormonal therapy among breast cancer survivors in clinical practice: a systematic review. Breast Cancer Res Treat 2012; 134(2): 459-78. DOI: 10.1007/s10549-012-2114-5
https://doi.org/10.1007/s10549-012-2114-... ^,1010. Rolnick SJ, Pawloski PA, Hedblom BD, Asche SE, Bruzek RJ. Patient characteristics associated with medication adherence. Clin Med Res 2013; 11(2): 54-65. DOI: 10.3121/cmr.2013.1113
https://doi.org/10.3121/cmr.2013.1113... . The performance of researches able to measure such phenomena and to portray them in a defined context represents an important strategy for comparing, understanding and producing evidence for health services and professionals to promote the success of the employed therapy, the improvement of patient’s quality of life and, finally, the reduction of mortality²2. Murphy CC, Bartholomew LK, Carpentier MY, Bluethmann SM, Vernon SW. Adherence to adjuvant hormonal therapy among breast cancer survivors in clinical practice: a systematic review. Breast Cancer Res Treat 2012; 134(2): 459-78. DOI: 10.1007/s10549-012-2114-5
https://doi.org/10.1007/s10549-012-2114-... ^,1010. Rolnick SJ, Pawloski PA, Hedblom BD, Asche SE, Bruzek RJ. Patient characteristics associated with medication adherence. Clin Med Res 2013; 11(2): 54-65. DOI: 10.3121/cmr.2013.1113
https://doi.org/10.3121/cmr.2013.1113... ^,1111. Remondi FA, Cabrera MA, Souza RK. Não adesão ao tratamento medicamentoso contínuo: prevalência e determinantes em adultos de 40 anos e mais. Cad Saúde Pública 2014; 30(1): 126-36. DOI. 10.1590/0102-311X00092613
https://doi.org/10.1590/0102-311X0009261... .

Hence, this study aimed to determine the adherence, persistence, and associated factors among breast cancer patients that received adjuvant hormonal therapy in a reference hospital from the city of Muriaé, Minas Gerais State, Brazil.

METHODOLOGY

We performed an analytical and longitudinal study based on secondary data collection of breast cancer women who underwent adjuvant hormonal therapy, receiving treatment in a high-complexity oncology hospital that is known for its cancer treatment and that provides treatment for more than four million residents in Muriaé, Minas Gerais¹²12. Fundação Cristiano Varella. Hospital do Câncer de Muriaé. História. [Internet]. Disponível em:http://fcv.org.br/site/conteudo/conteudo.php?id=87 (Acessado em fevereiro de 2016).
http://fcv.org.br/site/conteudo/conteudo... .

The study population comprised a cohort of women diagnosed with breast cancer, older than 18 years and treated in the mentioned hospital, who had begun hormonal therapy in the year of 2009 and had their medications dismissed more than once until December 31^st, 2014, according to data from the hospital pharmacy department. The study removed patients without registration in such database with the record of at least two different dates.

We collected the following information available in registrations from different service departments:

This study adopted the recommendation of one daily tablet of hormonal therapy for 5 years¹³13. Instituto Nacional de Câncer José Alencar Gomes da Silva. Tratamento pelo Sistema Único de Saúde. [Internet]. Disponível em: http://www.inca.gov.br/wps/wcm/connect/cancer/site/tratamento/ondetratarsus/ (Acessado em fevereiro de 2016).
http://www.inca.gov.br/wps/wcm/connect/c... ^,1414. Sociedade Brasileira de Cancerologia, Sociedade Brasileira de Mastologia, Federação Brasileira das Associações de Ginecologia e Obstetrícia. Câncer de mama: terapia endócrina e terapia alvo. Agência Nacional de Saúde Suplementar; Associação Médica Brasileira: 2011. [Internet]. Disponível em: http://diretrizes.amb.org.br/ans/cancer_de_mamaterapia_endocrina_e_terapia_alvo.pdf (Acessado em: outubro de 2015).
http://diretrizes.amb.org.br/ans/cancer_... ^,1515. Sociedade Brasileira de Oncologia Clínica. Manual de Condutas 2011. [Internet]. Disponível em: http://www.sboc.org.br/downloads/MANUAL_CONDUTAS_2011.pdf (Acessado em 18 de outubro de 2015).
http://www.sboc.org.br/downloads/MANUAL_... . TMX and AIs, such as anastrozole, play the role of medications distributed for free by SUS in the study hospital for breast cancer treatment. All the cohort women began their hormone therapy between January 1^st and December 31^st in 2009, without censure on the left in the observations; the follow-up of women receiving hormonal therapy for more than 5 years was incomplete by the end of the period established for observation.

The study dependent variables included adherence and persistence. According to the International Society for Pharmacoeconomics and Outcomes Research (ISPOR), adherence is the level in which the patient works accordingly to the prescribed daily treatment regarding the time, dose and frequency; and persistence is understood as the time since the beginning until the interruption of the drug therapy⁸8. Cramer JA, Roy A, Burrell A, Fairchild CJ, Fuldeore MJ, Ollendorf DA, et al. Medication compliance and persistence: terminology and definitions. Value Health 2008; 11(1): 44-7. DOI: 10.1111/j.1524-4733.2007.00213.x
https://doi.org/10.1111/j.1524-4733.2007... .

The method used for adherence calculation was the medication possession rate (MPR), based on the group of individual prescriptions in the following way: (total of days with the required medication)/(last date of drug dismissal - date of beginning + amount of medication delivered in the last dismissal). The result of this equation was converted into percentage and patients that obtained a value equal or higher than 80%¹⁶16. Raebel MA, Schmittdiel J, Karter AJ, Konieczny JL, Steiner JF. Standardizing terminology and definitions of medication adherence and persistence in research employing electronic databases. Med Care 2013; 51(8 Suppl 3): S11-21. DOI: 10.1097/MLR.0b013e31829b1d2a
https://doi.org/10.1097/MLR.0b013e31829b... were considered adherents.

We calculated the persistence measurement through the estimated level of persistence with therapy (ELPT) method, which considers the time between the beginning of the hormonal therapy and its abandonment or discontinuity for 60 days or longer by doing the accounting of the last supply of the obtained medication⁶6. Brito C, Portela MC, Vasconcellos MT. Fatores associados à persistência à terapia hormonal em mulheres com câncer de mama. Rev Saúde Pública 2014; 48(2): 284-95. DOI. 10.1590/S0034-8910.2014048004799
https://doi.org/10.1590/S0034-8910.20140... ^,1717. Dezii CM. Persistence with drug therapy: a practical approach using administrative claims data. Manag Care 2001; 10(2): 42-5.. Non-persistent was the patient that discontinued treatment during the mentioned term and without death confirmation. We considered therefore women who changed medications during the treatment by medical recommendation and satisfied the principles of A & P proportionally to the time of use of each medication.

The independent variables of interest were divided into three subgroups and, then, they were categorized to facilitate comparison with other studies:

To analyze the factors associated with adherence, we performed bivariate analyses using the chi-square test. To verify the factors associated with persistence, we used the methodology of survival analysis. The beginning of persistence counting time was considered as the date of hormonal therapy beginning. To analyze survival, we considered the discontinuity (loss of persistence) occurred until the end of the study follow-up. The follow-up time was censored in 60 months for women who persisted until the end of the follow-up or for those who died. The cases confirmed as follow-up loss were censored in the date of the last follow-up in the pharmaceutical department.

The persistence probabilities were calculated according to the method proposed by Kaplan-Meier and then compared, regarding the variables through the log-rank test. To evaluate the prognostic factors, we used the model of Cox proportional risks by computing the hazard ratio (HR) and their corresponding values of 95% confidence interval (95%CI). We chose the variables through the significance obtained in the univariate Cox model (p ≤ 0.2) and its clinical relevance. The variables included in the multiple analysis were removed according to the backward elimination process. The final model included women who remained statistically significant (p < 0.05). We used the likelihood-ratio test to verify the significance of the parameters of the reduced models and Schoenfeld’s residual diagnosis test to assess the proportionality of Cox models²²22. Bustamante-Teixeira MT, Faerstein E, Latorre MR. Técnicas de análise de sobrevida. Cad Saúde Pública 2002; 18(3): 579-94. DOI. 10.1590/S0102-311X2002000300003
https://doi.org/10.1590/S0102-311X200200... . Input and descriptive analysis of data were conducted in the Statistical Package for the Social Sciences (SPSS) program, version 15.0, and we used the STATA program, version 12.0, to analyze survival and prognostic factors.

We submitted the study for the Research Ethics Committee from Universidade Federal de Juiz de Fora (UFJF) that approved the project under protocol number 844.852.

RESULTS

182 women began hormonal therapy in the study period. The average age at diagnosis was 58.2 years old (± 13.5), varying from 31 to 88 years old. Most of the women were not white (54.4%), had educational level from 1 to 8 years (62.1%) and were married (47.3%). Regarding the menopause condition, 121 (66.5%) were in the post-menopausal period. Infiltrating ductal carcinoma was the most frequent histological type (n = 136; 74.7%). All cases were positive for estrogen (ER) and/or progesterone receptor (PgR), distributed into: 120 positive cases only for the ER (66%), 11 positive cases only for the PgR (6%) and 51 cases positive for both receptors (28%). Most of the women were diagnosed with the disease in the initial stage (EC 0, I and II) (67.5%). Exclusive treatment with TMX was described in 72.0% of the sample. All women received chemotherapy (except for hormonal therapy); most of them performed radiotherapy (77.5%) and surgery (78.0%). The mean of appointments with an oncologist was equal to 9.00 (IIQ 3.62), whereas the mean of hospitalizations during the study period was 2.00 hospitalizations (IIQ 2.00) (Table 1).

Adherence between the participants was 85.2% (95%CI 79.2 - 89.8); of whom 47.7% (95%CI 39.8 - 55.7) remained under treatment. Treatment persistence after 5 years was 49.5% (95%CI 42.2 - 56.7); however, such behavior changed throughout time and presented rates of 83.5% in the end of the first year, 66.5% in two years; 53.4% in three years, 51.6% in 4 years, and 45.2% in the last year (Figure 1).

We did not observe any statistically significant association between adherence to hormone therapy and the independent variables studied (Table 2). The factors associated with more probability of persistence include: initial stage of the disease at diagnosis; use of TMX; undergoing radiotherapy and surgery; number of appointments with oncologist based on recommendations (n ≥ 14). and lower frequency of hospitalizations (Table 3). None of the variables related to socioeconomic characteristics seemed to be associated with higher probability of persistence.

Table 4 shows crude and adjusted HR values of the variables chosen for the multivariate model. Advanced stage at diagnosis, non-performance of surgery and larger number of hospitalizations showed higher risk of hormonal therapy discontinuity. Such variables did not violate the risk proportionality principle, with a non-significant p-value of Schoenfeld residual tests for the overall result (0.56) and for each variable.

DISCUSSION

We observed, in the studied population, that most of the patients (85.2%) adhered to hormonal therapy, but only 49.5% finished their treatment without significant interruptions. Such results, similarly to those found by other authors²2. Murphy CC, Bartholomew LK, Carpentier MY, Bluethmann SM, Vernon SW. Adherence to adjuvant hormonal therapy among breast cancer survivors in clinical practice: a systematic review. Breast Cancer Res Treat 2012; 134(2): 459-78. DOI: 10.1007/s10549-012-2114-5
https://doi.org/10.1007/s10549-012-2114-... ^,2323. Hershman DL, Kushi LH, Shao T, Buono D, Kershenbaum A, Tsai WY, et al. Early discontinuation and nonadherence to adjuvant hormonal therapy in a cohort of 8,769 early-stage breast cancer patients. J Clin Oncol 2010; 28(27): 4120-8. DOI. 10.1200/JCO.2009.25.9655
https://doi.org/10.1200/JCO.2009.25.9655... ^,2424. Huiart L, Ferdynus C, Dell'Aniello S, Bakiri N, Giorgi R, Suissa S. Measuring persistence to hormonal therapy in patients with breast cancer: accounting for temporary treatment discontinuation. Pharmacoepidemiol Drug Saf 2014; 23: 882-889., confirm that even though adherence to adjuvant hormonal therapy is, in general, high (70 - 80%), there is a progressive increase of the non-persistent patients in the treatment throughout time.

Although these results were closer to those observed in previous studies, slight differences are seen regarding the eligibility criteria of the studied population (some studies include only patients with initial tumors; others analyze prospective or retrospective cohorts of young or aged women, among other aspects) and regarding the methodology used to define and calculate the A & P (such as the use of the proportion of days covered for the adherence analysis, among other methods, and serum dosage or concentration in the urine of the drug under use for persistence evaluation), which many times make comparisons with other findings more difficult²⁵25. Font R, Espinas JA, Gil-Gil M, Barnadas A, Ojeda B, Tusquets I, et al. Prescription refill, patient self-report and physician report in assessing adherence to oral endocrine therapy in early breast cancer patients: a retrospective cohort study in Catalonia, Spain. Br J Cancer 2012; 107(8): 1249-56. DOI: 10.1038/bjc.2012.389
https://doi.org/10.1038/bjc.2012.389... ^,2626. Oberguggenberger AS, Sztankay M, Beer B, Schubert B, Meraner V, Oberacher H, et al. Adherence evaluation of endocrine treatment in breast cancer: methodological aspects. BMC Cancer 2012; 12: 474. DOI: 10.1186/1471-2407-12-474
https://doi.org/10.1186/1471-2407-12-474... ^,2727. Burstein HJ, Temin S, Anderson H, Buchholz TA, Davidson NE, Gelmon KE, et al. Adjuvant endocrine therapy for women with hormone receptor-positive breast cancer: american society of clinical oncology clinical practice guideline focused update. J Clin Oncol 2014; 32(21): 2255-69. DOI: 10.1200/JCO.2013.54.2258
https://doi.org/10.1200/JCO.2013.54.2258... . Among the variety of methods to estimate the A & P, those based on retrospective data are still more used due to their easiness of calculation and low cost, besides presenting closer rates to the real ones, when compared with studies that use direct methods to determine such behaviors¹⁴14. Sociedade Brasileira de Cancerologia, Sociedade Brasileira de Mastologia, Federação Brasileira das Associações de Ginecologia e Obstetrícia. Câncer de mama: terapia endócrina e terapia alvo. Agência Nacional de Saúde Suplementar; Associação Médica Brasileira: 2011. [Internet]. Disponível em: http://diretrizes.amb.org.br/ans/cancer_de_mamaterapia_endocrina_e_terapia_alvo.pdf (Acessado em: outubro de 2015).
http://diretrizes.amb.org.br/ans/cancer_... ^,2828. Neugut AI, Subar M, Wilde ET, Stratton S, Brouse CH, Hillyer GC, et al. Association between prescription co-payment amount and compliance with adjuvant hormonal therapy in women with early-stage breast cancer. J Clin Oncol 2011; 29(18): 2534-42. DOI: 10.1200/JCO.2010.33.3179
https://doi.org/10.1200/JCO.2010.33.3179... ^,2929. Chen JY, Diamant AL, Thind A, Maly RC. Determinants of breast cancer knowledge among newly diagnosed, low-income, medically underserved women with breast cancer. Cancer 2008; 112(5): 1153-61. DOI: 10.1002/cncr.23262
https://doi.org/10.1002/cncr.23262... . Regarding persistence estimates, we need to relativize the results, given the adopted concept considers the interruption of treatment for more than or 60 days. Women considered non-persistent may have returned to complete the treatment during the recommended period and, therefore, they can be considered adherent according to the used method. Nevertheless, women who experience larger lacks in the endocrine treatment for breast cancer will not probably enjoy the benefits regarding disease recurrence and survival³⁰30. Barron TI, Cahir C, Sharp L, Bennett K. A nested case-control study of adjuvant hormonal therapy persistence and compliance, and early breast cancer recurrence in women with stage I-III breast cancer. Br J Cancer 2013; 109(6): 1513-21. DOI: 10.1038/bjc.2013.518
https://doi.org/10.1038/bjc.2013.518... ^,3131. Pagani O, Gelber S, Colleoni M, Price KN, Simoncini E. Impact of SERM adherence on treatment effect: international breast cancer study group trials 13-93 and 14-93. Breast Cancer Res Treat 2013; 142(2): 455-9. DOI: 10.1007/s10549-013-2757-x
https://doi.org/10.1007/s10549-013-2757-... .

The association between independent variables and adherence based on the bivariate analysis was more difficult due to the high index of adherent women in the study. We assume that calculation, based on the medication possession ratio (MPR), might overestimate such behavior when considering only the time with medication on hands in the denominator, instead of the entire period of treatment³²32. Hess LM, Raebel MA, Conner DA, Malone DC. Measurement of adherence in pharmacy administrative databases: a proposal for standard definitions and preferred measures. Ann Pharmacother 2006; 40(7-8): 1280-88. DOI: 10.1345/aph.1H018
https://doi.org/10.1345/aph.1H018... . This is a limitation, but we believe this bias may be understated when such estimates are made from the secondary database of great populations³³33. Güth U, Myrick ME, Kilic N, Eppenberger-Castori S, Schmid SM. Compliance and persistence of endocrine adjuvant breast cancer therapy. Breast Cancer Res Treat 2012; 131(2): 491-9. DOI: 10.1007/s10549-011-1801-y
https://doi.org/10.1007/s10549-011-1801-... .

We observed that variables associated with persistence, which were maintained in the final model of the multivariate analysis, reflect the relation between the highest disease severity and the interruption of the adjuvant hormonal treatment. Women with advanced stage are more susceptible to discontinuing the treatment. This relation has also been observed in previous studies⁶6. Brito C, Portela MC, Vasconcellos MT. Fatores associados à persistência à terapia hormonal em mulheres com câncer de mama. Rev Saúde Pública 2014; 48(2): 284-95. DOI. 10.1590/S0034-8910.2014048004799
https://doi.org/10.1590/S0034-8910.20140... ^,2323. Hershman DL, Kushi LH, Shao T, Buono D, Kershenbaum A, Tsai WY, et al. Early discontinuation and nonadherence to adjuvant hormonal therapy in a cohort of 8,769 early-stage breast cancer patients. J Clin Oncol 2010; 28(27): 4120-8. DOI. 10.1200/JCO.2009.25.9655
https://doi.org/10.1200/JCO.2009.25.9655... , in which women with more involved lymph nodes presented a higher rate of discontinuity and, as a consequence, lower success in the employed therapy, which also reaffirms the known inverse relation between the survival rate and the cancer stage at the moment of diagnosis⁷7. Makubate B, Donnan PT, Dewar JA, Thompson AM, McCowan C. Cohort study of adherence to adjuvant endocrine therapy, breast cancer recurrence and mortality. Br J Cancer 2013; 108(7): 1515-24. DOI: 10.1038/bjc.2013.116
https://doi.org/10.1038/bjc.2013.116... .

Non-performance of surgery was also related to a higher probability of non-persistence to treatment, which is in agreement with other studies³²32. Hess LM, Raebel MA, Conner DA, Malone DC. Measurement of adherence in pharmacy administrative databases: a proposal for standard definitions and preferred measures. Ann Pharmacother 2006; 40(7-8): 1280-88. DOI: 10.1345/aph.1H018
https://doi.org/10.1345/aph.1H018... ^,3434. Kemp A, Preen DB, Saunders C, Boyle F, Bulsara M, Malacova E, et al. Early discontinuation of endocrine therapy for breast cancer: who is at risk in clinical practice? Springerplus 2014; 3: 282. DOI: 10.1186/2193-1801-3-282
https://doi.org/10.1186/2193-1801-3-282... . A possible explanation for this relation is that the surgical procedure is many times indicated for patients with earlier stage, whereas in women with advanced disease, this therapeutic modality is often forgotten, considering the systemic treatment is prioritized⁶6. Brito C, Portela MC, Vasconcellos MT. Fatores associados à persistência à terapia hormonal em mulheres com câncer de mama. Rev Saúde Pública 2014; 48(2): 284-95. DOI. 10.1590/S0034-8910.2014048004799
https://doi.org/10.1590/S0034-8910.20140... ^,2525. Font R, Espinas JA, Gil-Gil M, Barnadas A, Ojeda B, Tusquets I, et al. Prescription refill, patient self-report and physician report in assessing adherence to oral endocrine therapy in early breast cancer patients: a retrospective cohort study in Catalonia, Spain. Br J Cancer 2012; 107(8): 1249-56. DOI: 10.1038/bjc.2012.389
https://doi.org/10.1038/bjc.2012.389... . According to Kemp, women undergoing more aggressive treatment may notice their condition as more severe and recognize their increased need of endocrine therapy. Risk of non-persistence increased with the number of hospitalizations. For Brito et al., although many studies do not associate this variable directly, such relation may be explained by the disease severity and the presence of other comorbidities and side effects, producing different responses to treatment⁶6. Brito C, Portela MC, Vasconcellos MT. Fatores associados à persistência à terapia hormonal em mulheres com câncer de mama. Rev Saúde Pública 2014; 48(2): 284-95. DOI. 10.1590/S0034-8910.2014048004799
https://doi.org/10.1590/S0034-8910.20140... . Presence and severity of disease symptoms are factors that might interfere in the treatment follow-up³⁵35. Bender CM, Gentry AL, Brufsky AM, Casillo FE, Cohen SM, Dailey MM, et al. Influence of patient and treatment factors on adherence to adjuvant endocrine therapy in breast cancer. Oncol Nurs Forum 2014; 41(3): 274-85. DOI: 10.1188/14
https://doi.org/10.1188/14... .

We must emphasize that although there has been significance only in the non-adjusted survival analysis, the number of specialized appointments is considered relevant. The direct relation between a higher number of appointments and the higher probability in persisting to treatment reflects the importance of the doctor-patient relationship, both in the provision of information regarding the treatment and also in the appearance of side effects and their handling, as well as in the emotional support even after the disease active treatment. Evidence shows that most of the patients, after completing the “initial” phase of treatment (i.e. surgery, chemotherapy and radiotherapy), do not continue using the oncologist figure as his/her main care provider, which makes the maintenance of hormonal therapy more difficult²2. Murphy CC, Bartholomew LK, Carpentier MY, Bluethmann SM, Vernon SW. Adherence to adjuvant hormonal therapy among breast cancer survivors in clinical practice: a systematic review. Breast Cancer Res Treat 2012; 134(2): 459-78. DOI: 10.1007/s10549-012-2114-5
https://doi.org/10.1007/s10549-012-2114-... ^,3636. Cluze C, Rey D, Huiart L, BenDiane MK, Bouhnik AD, Berenger C, et al. Adjuvant endocrine therapy with tamoxifen in young women with breast cancer: determinants of interruptions vary over time. Ann Oncol 2012; 23(4): 882-90. DOI: 10.1093/annonc/mdr330
https://doi.org/10.1093/annonc/mdr330... ^,3737. Ziller V, Kyvernitakis I, Knöll D, Storch A, Hars O, Hadji P. Influence of a patient information program on adherence and persistence with an aromatase inhibitor in breast cancer treatment - the COMPAS study. BMC Cancer 2013; 13: 407. DOI: 10.1186/1471-2407-13-407
https://doi.org/10.1186/1471-2407-13-407... . Reasons for therapy discontinuation may change throughout the treatment; therefore, the professional must understand them to overcome them, by emphasizing the importance of its follow-up to patients³⁸38. Kuba S, Ishida M, Nakamura Y, Taguchi K, Ohno S. Persistence and discontinuation of adjuvant endocrine therapy in women with breast cancer. Breast Cancer 2016; 23(1): 128-33. DOI: 10.1007/s12282-014-0540-4
https://doi.org/10.1007/s12282-014-0540-... .

CONCLUSION

Although adherence is higher in this cohort (85.2%), we found an important decrease in the persistence rates year by year that reached a percentage value below 50% in the last year of treatment, which reinforces the importance of measuring such behaviors together. We must adopt such measurement not only to better understand the related factors and identify patients requiring more intervention in a more effective way, but also to assess the clinical and economic results, considering that low rates have been associated with side results and with high health care costs.

Increase in the discontinuity risk to hormonal therapy has been associated with characteristics related to the disease severity, which also reflects a high number of breast cancer diagnoses in advanced stages. Considering that the use of adjuvant hormonal therapy in these cases significantly reduces the appearance of secondary tumors and, consequently, improves the survival rates, strategies should be thought so that women may experience the benefits of this therapeutic modality.

Due to the retrospective character and secondary base of this study, we could not assess important questions regarding the patients, such as appearance and handling of side effects, as well as their beliefs and habits, which are described in literature as potentially associated with treatment discontinuation. Therefore, identifying such determiners that may be modifiable is an important factor for the development of interventions that aim to improve such behaviors.

This study aimed to contribute with information that enable the discussion on questions related to the operationalization of A & P studies for chronic pathologies, especially considering Brazilian results. Thus, it provides important reflections on the joined approach of A & P with hormonal therapy and collaborates for the analysis of the Brazilian Policy of Oncological Attention.

ACKNOWLEDGMENTS

To Hospital do Câncer de Muriaé - Fundação Cristiano Varella (FCV) for their cooperation, comprehension and social responsibility in authorizing the performance of this paper.

References

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