Abstract

Delays in treating breast cancer have been associated with a more advanced stage of the disease and a decrease in patient survival rates. The scope of this integrative review was to analyze the main causal factors and types of patient and system delays. The underlying causal factors of delays were compared among studies conducted in developing and developed countries. Of the 53 studies selected, 24 were carried out in developing countries and 29 in developed countries, respectively. Non-attribution of symptoms to cancer, fear of the disease and treatment and low educational level were the most frequent causes of patient delay. Less comprehensive health insurance coverage, older/younger age and false negative diagnosis tests were the three most common causal factors of system delay. The effects of factors such as age were not decisive per se and depended mainly on the social and cultural context. Some factors caused both patient delay and system delay. Studies conducted in developing countries identified more causal factors of patient delay and had a stronger focus on patient delay or the combination of both. Studies conducted in developed countries had a stronger focus on aspects of system delay during treatment and guidance of breast cancer patients in the health care system.

Key words
Breast cancer; Delay; Treatment; Developing countries; Developed countries

Resumo

O atraso no tratamento de câncer de mama foi associado com o aumento do palco da doença e a diminuição da sobrevida do paciente. O objetivo desta revisão integrativa foi a analise dos principais fatores causais e dos tipos de atraso. Sendo estes comparados entre estudos de países em desenvolvimento e desenvolvidos. Dos 53 estudos selecionados, 24 eram de países em desenvolvimento e 29 de países desenvolvidos, respectivamente. A não atribuição dos sintomas ao câncer, o medo e a menor escolaridade foram as causas mais citadas do atraso de paciente ao tratamento. Seguro menos abrangente, idade e testes diagnósticos falsos negativos foram às causas mais comuns identificadas do atraso do sistema. O efeito de vários fatores como o fator idade, dependeu principalmente do contexto social e cultural. Alguns fatores causaram tanto atraso relacionado ao paciente quanto ao sistema. Os estudos dos países em desenvolvimento identificaram mais fatores causais do atraso relacionado ao paciente, focando mais forte neste referido fator ou na combinação com o de sistema. Enquanto estudos de países desenvolvidos enfocaram com maior frequência aspectos do atraso de sistema durante o tratamento e a orientação de pacientes no sistema de saúde.

Palavras chave
Câncer de mama; Atraso; Tratamento; Países em desenvolvimento; Países desenvolvidos

Introduction

Breast cancer is the most common type of cancer among women worldwide, with about 1.67 million new cases diagnosed in the year 2012¹1. Benson JR, Jatoi I. The global breast cancer burden. Future Oncol 2012; 8(6):697-702.,²2. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 2014; 136(5):E359-386. The incidence of breast cancer is still high in developed countries, but the global burden of the disease is progressively shifting to developing countries¹1. Benson JR, Jatoi I. The global breast cancer burden. Future Oncol 2012; 8(6):697-702.,²2. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 2014; 136(5):E359-386. More than 70% of breast cancer patients in developed countries are diagnosed at stages I and II, whereas in low and middle-income countries, only 20-60% of patients are diagnosed in early stages of the disease³3. Unger-Saldaña K. Challenges to the early diagnosis and treatment of breast cancer in developing countries. World J Clin Oncol 2014; 5(3):465-477.. Breast cancer stage represents an important prognostic factor and advanced stage is associated with decreased time of disease-free survival and increased mortality rates⁴4. Arndt V, Stürmer T, Stegmaier C, Ziegler H, Dhom G, Brenner H. Patient delay and stage of diagnosis among breast cancer patients in Germany - a population based study. Br J Cancer 2002; 86(7):1034-1040.,⁵5. Howlader N, Noone A, Krapcho M, Neyman N, Aminou R, Altekruse S, Kosary C, Ruhl J, Tatalovich Z, Cho H, Mariotto A, Eisner M, Lewis D, Chen H, Feuer E, Cronin Ke. SEER Cancer Statistics Review, 1975-2009 (vintage 2009 populations). Bethesda: National Cancer Institute; 2012.. The mortality-to-incidence ratio of developing countries tended to be lower, compared to that of developed countries, largely due to the fact that patients have the disease at more advanced stages⁶6. Asadzadeh Vostakolaei F, Karim-Kos HE, Janssen- Heijnen ML, Visser O, Verbeek AL, Kiemeney LA. The validity of the mortality to incidence ratio as a proxy for sitespecific cancer survival. Eur J Public Health 2011; 21(5):573-577.,⁷7. Porter PL. Global trends in breast cancer incidence and mortality. Salud Publica Mex 2009; 51(Supl. 2):s141-146.. Furthermore, previous studies have shown that care delay associated with increased stage had a negative effect on the survival of breast cancer patients and were more common among patients in developing countries³3. Unger-Saldaña K. Challenges to the early diagnosis and treatment of breast cancer in developing countries. World J Clin Oncol 2014; 5(3):465-477.,⁴4. Arndt V, Stürmer T, Stegmaier C, Ziegler H, Dhom G, Brenner H. Patient delay and stage of diagnosis among breast cancer patients in Germany - a population based study. Br J Cancer 2002; 86(7):1034-1040.,⁸8. Sharma K, Costas A, Shulman LN, Meara JG. A systematic review of barriers to breast cancer care in developing countries resulting in delayed patient presentation. J Oncol 2012; 2012:121873.,⁹9. Richards MA, Smith P, Ramirez AJ, Fentiman IS, Rubens RD. The influence on survival of delay in the presentation and treatment of symptomatic breast cancer. Br J Cancer 1999; 79(5-6):858-864..

In literature, care delay has been subdivided in patient delay (PD) and health care system (SD) delay³3. Unger-Saldaña K. Challenges to the early diagnosis and treatment of breast cancer in developing countries. World J Clin Oncol 2014; 5(3):465-477.,¹⁰10. Caplan L. Delay in Breast Cancer: Implications for stage at diagnosis and survival. Front Public Health 2014; 2:87.. According to Lee Caplan (2014), PD is a delay in seeking medical attention after self-discovering a potential breast cancer symptom, whereas SD is a delay within the health care system¹⁰10. Caplan L. Delay in Breast Cancer: Implications for stage at diagnosis and survival. Front Public Health 2014; 2:87.. PD was mainly defined as a time gap >3 month between symptom detection and first medical consultation³3. Unger-Saldaña K. Challenges to the early diagnosis and treatment of breast cancer in developing countries. World J Clin Oncol 2014; 5(3):465-477.. The socio-economic and cultural background of patients can contribute to PD³3. Unger-Saldaña K. Challenges to the early diagnosis and treatment of breast cancer in developing countries. World J Clin Oncol 2014; 5(3):465-477.,¹⁰10. Caplan L. Delay in Breast Cancer: Implications for stage at diagnosis and survival. Front Public Health 2014; 2:87.. Furthermore, symptomatology experience, ethnic origin, beliefs or perceptions that affect attitudes of patients represent important causal factors of PD³3. Unger-Saldaña K. Challenges to the early diagnosis and treatment of breast cancer in developing countries. World J Clin Oncol 2014; 5(3):465-477.,¹⁰10. Caplan L. Delay in Breast Cancer: Implications for stage at diagnosis and survival. Front Public Health 2014; 2:87.–¹²12. Mor V, Masterson-Alle S, Goldberg R, Guadagnoli E, Wool MS. Pre-diagnostic symptom recognition and help seeking among cancer patients J Community Health 1990; 15(4):253-266.. SD can refer to access barriers, like long distance to treating health care centers, or no availability of specialized centers and intrinsic problems of an established health care system, like disease management, problems in obtaining or scheduling diagnostic tests and communication problems between patients and physicians³3. Unger-Saldaña K. Challenges to the early diagnosis and treatment of breast cancer in developing countries. World J Clin Oncol 2014; 5(3):465-477.,¹⁰10. Caplan L. Delay in Breast Cancer: Implications for stage at diagnosis and survival. Front Public Health 2014; 2:87.,¹¹11. Martins T, Hamilton W, Ukoumunne OC. Ethnic inequalities in time to diagnosis of cancer: a systematic review. BMC Fam Pract 2013; (23):14:197.,¹³13. Schwartsmann G. Breast cancer in South America: challenges to improve early detection and medical management of a public health problem. J Clin Oncol 2001; 19(18 Supl.):118S-124S.. Furthermore, to reduce SD, health services must fit with the socio-economic and cultural or ethnic background of patients³3. Unger-Saldaña K. Challenges to the early diagnosis and treatment of breast cancer in developing countries. World J Clin Oncol 2014; 5(3):465-477.,¹¹11. Martins T, Hamilton W, Ukoumunne OC. Ethnic inequalities in time to diagnosis of cancer: a systematic review. BMC Fam Pract 2013; (23):14:197..

Despite the existence of vast literature about breast cancer care delays only few authors have compared studies conducted at different regions of the world. Review articles are mainly focused on care delays and its outcomes in developing countries³3. Unger-Saldaña K. Challenges to the early diagnosis and treatment of breast cancer in developing countries. World J Clin Oncol 2014; 5(3):465-477.,⁸8. Sharma K, Costas A, Shulman LN, Meara JG. A systematic review of barriers to breast cancer care in developing countries resulting in delayed patient presentation. J Oncol 2012; 2012:121873.. Little is known about differences of study objectives and the causal factors of PD and SD, identified by authors of distinct regions of the world. The present integrative review addressed on four main questions: 1. What are the main causal factors of PD and SD in literature? 2. What are the methods applied to analyse the contribution of causal factors on PD and SD? 3. Which types of SD are analysed in literature? 4. If care delays and their adjacent causes are different among developing and developed countries.

Method

An integrative review of care delay associated with breast cancer was conducted. The research methodology was performed according to established criteria¹⁴14. Dal Sasso Mendes K, Campos Pereira Silveira RC, Galvão CM. Revisão integrativa: Método de pesquisa para a incorporação de evidências na saúde e na enfermagem. Texto Contexto Enferm 2008; 17(4):758-764.. The operational steps were conducted as followed: Definition of exclusion and inclusion criteria and database; selection of studies; extraction of information and categorization; Analysis and interpretation of data; Interpretation of results; Synthesis and resume of results. The search was conducted in the following databases: Literatura Latino-Americana e do Caribe em Ciências da Saúde (LILACS); National Library of Medicine (MED LINE), PubMed and in the repository Scientific Electronic Library Online (SciELO).

Terms "treatment delay", "provider delay", "system delay" and "patient delay" are commonly used in public health literature, but were not identified in Medical Subject Headings (MeSH; http://www.nlm.nih.gov/mesh/MBrowser.html)of the U. S. National Library of Medicine. Terms "breast cancer" and "delayed diagnosis" were selected from MeSH. A much more common term in literature was "diagnostic delay". As shown in the results and discussion section, the term "diagnostic delay" was not very well defined. To identify a broader range of articles about any kind of care delay, the term "delayed diagnosis" was substituted by "delay". Therefore, the term "breast cancer" was used in combination with "delay" in English, Spanish ("Cáncer de mama" and "atraso") and Portuguese ("Câncer de mama" and "atraso").

The search was conducted on October 22, 2014. To establish an internal quality control, all procedure of literature selection was performed twice independently by each of the two authors. Application of search terms in MEDLINE led to the identification of 2390 articles. When filter "10 years" was applied, this number reduced to 731 articles. Additional application of filter "free full text" led to the identification of 299 articles. In the SciELO database, 18 articles were identified and in the LILACS database, no article that met criteria of both search terms in any of the three languages was identified.

Finally, 317 articles were used for further analysis. To identify articles that met selective criteria, title and abstract were analysed. The following inclusion criteria were applied: original research article or research communication, available for free and published over the last five years, in English, Spanish or Portuguese. Articles identified in more than one database, articles about breast cancer that did not deal with care delays and review articles were excluded from the study. For further method categorization, result and discussion sections were read and analysed. According to previous studies, PD was defined as a delay of medical consultation caused by the patients behaviour³3. Unger-Saldaña K. Challenges to the early diagnosis and treatment of breast cancer in developing countries. World J Clin Oncol 2014; 5(3):465-477.,¹⁰10. Caplan L. Delay in Breast Cancer: Implications for stage at diagnosis and survival. Front Public Health 2014; 2:87.. The term SD was applied in the case of any delay caused by the health care system. In the case of factors associated to PD and SD, only factors that were identified two or more times were included and factors identified only by one study were excluded. This was justified by the fact that in the case of factors like "smoking" that was identified only one time by a single study, authors did not explain any possible causal relationship with PD and/or SD.

In accordance with the International Monetary Fund (2014), the following were defined as developing economies¹⁵15. World Economic Outlook 2014 (International Monetary Found). [cited 2014 Dic 01]. Available from: http://www.imf.org/external/pubs/ft/weo/2014/02/
http://www.imf.org/external/pubs/ft/weo/... : Brazil, Cameron, Colombia, Egypt, India, Iran, Lybia, Malaysia, Nigeria, Pakistan, Poland, Thailand, Tunisia and Turkey (Table 1).

All statistical analysis was performed on Prism™ software vers.6 (GraphPad, La Jolla, California, USA). The χ^2- Test was performed to analyse categorized variables.

Results and discussion

All together 53 studies were identified that originated from 22 different countries (Table 1). Of the 53 studies, 24 were from developing and 29 from developed countries, respectively (Table 1). Single studies originated from Australia, Denmark, Estonia, China (Hong Kong), Iran, Libya, Nigeria, Pakistan, Poland, South Korea, Thailand, Turkey and Egypt (Table 1). More than one study was carried out in Brazil (N = 2), Cameroon (N = 2), Tunisia (N = 2), India (N = 2), Colombia (N = 3), United Kingdom (N = 3), Malaysia (N = 6) and the USA (N = 21). With exception of one Brazilian study written in Portuguese, a Colombian study written in Spanish and a study carried out in Tunisia written in French, all the other 50 studies were written in English (Table 1)¹⁶16. Landolsi A, Gahbiche S, Chaafii R, Chabchoub I, Ben Fatma L, Hochlef M, Gharbi O, Ahmed SB. Reasons of diagnosis delay of breast cancer in Tunisian women (160 patients in central region of Tunisia). Tunis Med 2010; 88(12):894-897.–¹⁸18. Ceballos-García GY, Giraldo-Mora CV. "Autobarreras" de las mujeres al diagnóstico y tratamiento oportuno del cáncer de mama. Aquichán 2011; 11(2):140-157..

Many contributions in the form of articles, such as those carried out in Malaysia and USA could indicate a greater interest of researchers in delay issues in these countries. Alternatively, the distribution of contributions by countries may not reflect the real frequency of publications within the last five years: Contributions were not included in the present research if they were not published in open access journals or if they were published in journals that are not registered in the examined databases. Therefore, exclusion criteria could have led to a bias in the number of contributions from single countries. This is a serious limitation of the present study and results should be interpreted with care.

Methodological background of studies

The most prominent methodological approach (N = 28) to obtain data about PD and SD was interview (Table 1). Of these 28 studies, 20 were exclusively based on interviews, whereas eight studies used additionally medical records or other registered data (Table 1). Several qualitative studies (N = 7) including small sample numbers, < 20 persons applied in-depth-interview (Table 1). Furthermore, of these 28 studies, four were based on telephone interviews (Table 1)¹⁹19. Quaife SL, Forbes LJL, Ramirez AJ, Brain KE, Donnelly C, Simon AE, Wardle J. Recognition of cancer warning signs and anticipated delay in help-seeking in a population sample of adults in the UK. Br J Cancer 2014; 110(1):12-18.–²²22. Sheppard VB, Isaacs C, Luta G, Willey SC, Boisvert M, Harper FWK, Smith K, Horton S, Liu MC, Jennings Y, Hirpa F, Snead F, Mandelblatt JS. Narrowing Racial Gaps in Breast Cancer Chemotherapy Initiation: The Role of the Patient-Provider Relationship. Breast Cancer Res Treat 2013; 139(1):207-216.. Questionnaires were applied in five studies and in one case, it was combined with registered data (Table 1)²³23. Ozmen V, Boylu S, Ok E, Canturk NZ, Celik V, Kapkac M, Girgin S, Tireli M, Ihtiyar E, Demircan O, Baskan MS, Koyuncu A, Tasdelen I, Dumanli E, Ozdener F, Zaborek P. Factors affecting breast cancer treatment delay in Turkey: a study from Turkish Federation of Breast Diseases Societies. Eur J Public Health 2014; 25(1):9-14.–²⁷27. Chintamani, Tuteja A, Khandelwal R, Tandon M, Bamal R, Jain S, Narayan N, Srinivas S, Kumar Y. Patient and provider delays in breast cancer patients attending a tertiary care centre: a prospective study. J R Soc Med Sh Rep 2011; 2:76.. Of the 53 studies, 18 collected data exclusively of medical records or other source of recorded data (Table 1). Several of these authors obtained increased numbers of data from breast cancer patients, that varied from 21.818 to 147.682 by the usage of large data bases as source for sampling (Table 1)²⁸28. Yun YH, Kim YA, Min YH, Park S, Won YJ, Kim DY, Choi IJ, Kim YW, Park SJ, Kim JH, Lee DH, Yoon SJ, Jeong SY, Noh DY, Heo DS. The influence of hospital volume and surgical treatment delay on long-term survival after cancer surgery. Annals of Oncology 2012; 23(10):2731-2737.–³¹31. Partridge AH, Hughes ME, Ottesen RA, Wong YN, Edge SB, Theriault RL, Blaney DW, Niland JC, Winer EP, Weeks JC, Tamimi RM. The Effect of Age on Delay in Diagnosis and Stage of Breast Cancer. Oncologist 2012; 17(6):775-782.. One study was based on lecture of media and the other on discussed theories, concepts and models of care delay without sampling data (Table 1)³²32. Lim JNW. Empirical Comparisons of Patient Delay and Help Seeking Models for Breast Cancer: Fitness of Models for Use and Generalisation. Asian Pacific J Cancer Prev 2011; 12(6):1589-1595.,³³33. Black AR, Woods-Giscombé C. Applying the Stress and ‘Strength’ Hypothesis to Black Women's Breast Cancer Screening Delays. Stress Health2012; 28(5):389-396..

Several studies (N = 18) applied descriptive methods without any significance test (Table 1). Most studies were based on < 30 samples (N = 11) and 30 to 50 (N = 4), and only three were based on studies ≥ 100 samples (Table 1)¹⁶16. Landolsi A, Gahbiche S, Chaafii R, Chabchoub I, Ben Fatma L, Hochlef M, Gharbi O, Ahmed SB. Reasons of diagnosis delay of breast cancer in Tunisian women (160 patients in central region of Tunisia). Tunis Med 2010; 88(12):894-897.,²⁷27. Chintamani, Tuteja A, Khandelwal R, Tandon M, Bamal R, Jain S, Narayan N, Srinivas S, Kumar Y. Patient and provider delays in breast cancer patients attending a tertiary care centre: a prospective study. J R Soc Med Sh Rep 2011; 2:76.,³⁴34. Ngowa JDK, Yomi J, Kasia JM, Mawamba Y, Ekortarh AC, Vlastos G. Breast Cancer Profile in a Group of Patients Followed up at the Radiation Therapy Unit of the Yaounde General Hospital, Cameroon. Obstet Gynecol Int 2011; 2011:143506.. All in-depth-interviews belonged to this group of studies.

Other studies (N = 12) applied univariate methods, mainly using χ^2- Test or Fisher's exact test to analyse categorized variables and the t-Test to analyse continuous variables. Máslach et al.³⁵35. Maślach D, Krzyżak M, Szpak A, Owoc A, Magdalena Bielska-Lasota. Waiting time for treatment of women with breast cancer in Podlaskie Voivodeship (Poland) in view of place of residence. A population study. Anna Agric Environ Med 2013; 20(1)161-166., for example, compared time delays between patients from rural and urban regions. Crowley et al.⁵⁷57. Crowley MM, McCoy ME, Bak SM, Caron SE, Ko NY, Kachnic LA, Alvis F, Battaglia TA. Challenges in the Delivery of Quality Breast Cancer Care: Initiation of Adjuvant Hormone Therapy at an Urban Safety Net Hospital. J Oncol Pract2014; 10(2):e107-112. compared the time gap from diagnosis to start of adjuvant hormone therapy among patients of Afro-American, Hispanic and Caucasian ethnicity. In these studies, each factor potentially contributing to care delay was analysed as a univariate variable, regardless of all the other study variables. To identify independent factors and to establish a model that could explain PD or SD, most authors (N = 23) adopted multivariate regression models (Table 1). Multivariate logistic regression models were applied on dichotomized data comparing two groups: Ghazali et al.⁵¹51. Ghazali SM, Othman Z, Cheong KC, Hock LK, Rozita W, Mahiyuddin W, Kamaluddin MA, Yusoff AF, Mustafa AN. Non-Practice of Breast Self Examination and Marital Status are Associated with Delayed Presentation with Breast Cancer Asian Pacific J Cancer Prev 2013; 14(2):1141-1145. for example, determined PD as a time gap of > 3 month from symptom discovery to first medical consultation. The authors first categorized patients into two groups, those with delay > 3 month and those with no delay (≤ 3 month)⁵¹51. Ghazali SM, Othman Z, Cheong KC, Hock LK, Rozita W, Mahiyuddin W, Kamaluddin MA, Yusoff AF, Mustafa AN. Non-Practice of Breast Self Examination and Marital Status are Associated with Delayed Presentation with Breast Cancer Asian Pacific J Cancer Prev 2013; 14(2):1141-1145.. After identification of significant factors by univariate analysis (χ^2- Test), a multivariate logistic regression model was established to explain PD based on martial status (divorced or single vs. married), ethnicity (Chinese vs. Malay or Indian) and breast self examination (not performed vs. performed)⁵¹51. Ghazali SM, Othman Z, Cheong KC, Hock LK, Rozita W, Mahiyuddin W, Kamaluddin MA, Yusoff AF, Mustafa AN. Non-Practice of Breast Self Examination and Marital Status are Associated with Delayed Presentation with Breast Cancer Asian Pacific J Cancer Prev 2013; 14(2):1141-1145.. These approaches were exemplary for most studies aimed at identifying the main factors that affect PD and/or SD and multivariate regression models were standard to identify independent causal variables of PD and SD.

The association between advanced stage of breast cancer and care delays is well established in literature³3. Unger-Saldaña K. Challenges to the early diagnosis and treatment of breast cancer in developing countries. World J Clin Oncol 2014; 5(3):465-477.,¹⁰10. Caplan L. Delay in Breast Cancer: Implications for stage at diagnosis and survival. Front Public Health 2014; 2:87.. In several studies, PD was associated with or identified as a causal factor of advanced stage of breast cancer²⁶26. Fayanju OM, Jeffe DB, Elmore L, Ksiazek DN, Margenthaler JA. Patient and Process Factors Associated with Late-Stage Breast Cancer Diagnosis in Safety-Net Patients: A Pilot Prospective Study. Ann Surg Oncol 2013; 20(3):723-732.,³¹31. Partridge AH, Hughes ME, Ottesen RA, Wong YN, Edge SB, Theriault RL, Blaney DW, Niland JC, Winer EP, Weeks JC, Tamimi RM. The Effect of Age on Delay in Diagnosis and Stage of Breast Cancer. Oncologist 2012; 17(6):775-782.,⁴⁰40. Ermiah E, Abdalla F, Buhmeida A, Larbesh E, Pyrhönen S, Collan Y. Diagnosis delay in Libyan female breast cancer BMC Res Notes 2012; 21(5):452.,⁴⁹49. Piñeros M, Sánchez R, Cendales R, Perry F, Ocampo R. Patient delay among Colombian women with breast cancer. Salud Publica Mex 2009; 51(5):372-380.–⁵¹51. Ghazali SM, Othman Z, Cheong KC, Hock LK, Rozita W, Mahiyuddin W, Kamaluddin MA, Yusoff AF, Mustafa AN. Non-Practice of Breast Self Examination and Marital Status are Associated with Delayed Presentation with Breast Cancer Asian Pacific J Cancer Prev 2013; 14(2):1141-1145.,⁵³53. Norsa'adah B, Rahmah MA, Rampal KG, Knight A. Understanding Barriers to Malaysian Women with Breast Cancer Seeking Help. Asian Pac J Cancer Prev2012; 13(8):3723-3730.. In a study carried out in Tunisia, PD and also long distances to health care centres contributed to advanced stage of the disease¹⁶16. Landolsi A, Gahbiche S, Chaafii R, Chabchoub I, Ben Fatma L, Hochlef M, Gharbi O, Ahmed SB. Reasons of diagnosis delay of breast cancer in Tunisian women (160 patients in central region of Tunisia). Tunis Med 2010; 88(12):894-897.. Soares et al.⁴⁴44. Soares PBM, Quirino Filho S, Pereira de Souza W, Gonçalves RCR, Reis B. Martelli DRB, Fagundes Silveira M, Martelli Júnior H. Characteristics of women with breast cancer seen at reference services in the North of Minas Gerais. Rev Bras Epidemiol 2012; 15(3):595-604., showed that SD, caused by increased length of time between clinical suspicion and diagnostic confirmation, was associated with advanced stage of breast cancer.

Most studies have focused on breast cancer patients for sampling, but there were also some exceptions: In a study carried out in Malaysia, the authors investigated the preference of patients for western or traditional medicine and interviewed 11 breast cancer survivors⁵²52. Muhamad M, Merriam S, Suhami N. Why Breast Cancer Patients Seek Traditional Healers. Int J Breast Cancer 2012; 2012:689168.. Telephone interviews were applied to 6965 women in England, who were not breast cancer patients¹⁹19. Quaife SL, Forbes LJL, Ramirez AJ, Brain KE, Donnelly C, Simon AE, Wardle J. Recognition of cancer warning signs and anticipated delay in help-seeking in a population sample of adults in the UK. Br J Cancer 2014; 110(1):12-18.. The authors used a validated questionnaire named "Awareness and Beliefs about Cancer Measure (ABC)" to analyse causal factors of PD¹⁹19. Quaife SL, Forbes LJL, Ramirez AJ, Brain KE, Donnelly C, Simon AE, Wardle J. Recognition of cancer warning signs and anticipated delay in help-seeking in a population sample of adults in the UK. Br J Cancer 2014; 110(1):12-18.. Black and Woods-Giscombé³³33. Black AR, Woods-Giscombé C. Applying the Stress and ‘Strength’ Hypothesis to Black Women's Breast Cancer Screening Delays. Stress Health2012; 28(5):389-396., used the narratives of non-patients to apply a gender-specific, culturally responsive stress process framework to identify the reasons why Afro Americans, compared to women of other ethnic groups, have more often PD.

These publications show that sources for sampling data were heterogeneous. Exceptionally in this context was also the study by Schairer et al.⁴⁶46. Schairer C, Soliman AS, Omar S, Khaled H, Eissa S, Ayed FB, Khalafallah S, Ayoub WB, Kantor ED, Merajver S, Swain SM, Gail M, Morris Brown L. Assessment of diagnosis of inflammatory breast cancer cases at two cancer centers in Egypt and Tunisia. Cancer Med 2013; 2(2):178-184., who investigated if patients with inflammatory breast cancer, compared to those with other types of breast cancer, have a different help seeking behaviour. The authors used registered data and did not find any significant difference⁴⁶46. Schairer C, Soliman AS, Omar S, Khaled H, Eissa S, Ayed FB, Khalafallah S, Ayoub WB, Kantor ED, Merajver S, Swain SM, Gail M, Morris Brown L. Assessment of diagnosis of inflammatory breast cancer cases at two cancer centers in Egypt and Tunisia. Cancer Med 2013; 2(2):178-184..

Different types of SD and the terminology of diagnosis delay

The different types of SD were analysed by the authors and summarized in Chart 1. In the case of 11 studies, a specific time gap of SD has not been defined (Chart 1). With the exception of one study²⁰20. Thind A, Hoq L, Diamant A and Maly RC. Satisfaction with Care among Low-Income Women with Breast Cancer. J Womens Health (Larchmt) 2010; 19(1):77-86., in 10 of these 11 studies focused on PD and SD, underlying causal factors were generally attributed either to PD or SD. A time gap of SD was defined in 16 studies carried out in developed countries and six studies carried out in developing countries (Chart 1). In contrast, four studies of developed and seven of developing countries, have not defined a time gap of SD (Chart 1; p = 0.0439). This indicates that studies carried out in developing countries had a more generalized approach to SD compared to studies carried out in developed countries, which more often defined a specific time gap of SD.

The most common form of SD analysed was the time gap between first medical consultation and start of any type of therapy (Chart 1)¹⁷17. Barros FA, Uemura G, Soares de Macedo JL. Tempo para acesso ao tratamento do câncer de mama no Distrito Federal, Brasil Central. Rev Bras Ginecol Obstet 2 013; 35(10):458-463.,²³23. Ozmen V, Boylu S, Ok E, Canturk NZ, Celik V, Kapkac M, Girgin S, Tireli M, Ihtiyar E, Demircan O, Baskan MS, Koyuncu A, Tasdelen I, Dumanli E, Ozdener F, Zaborek P. Factors affecting breast cancer treatment delay in Turkey: a study from Turkish Federation of Breast Diseases Societies. Eur J Public Health 2014; 25(1):9-14.,²⁴24. Yau TK, Choi CW, Ng E, Yeung R, Soong IS, Lee AWM. Delayed presentation of symptomatic breast cancers in Hong Kong: experience in a public cancer center. Hong Kong Med J 2010; 16(5):373-377.,⁴⁸48. Piñeros M, Sánchez RM, Perry F, García OA, Ocampo R, Cendales R. Demoras en el diagnóstico y tratamiento de mujeres con cáncer de mama en Bogotá, Colombia. Salud Publica Mex 2011; 53(6):478-485.. Other studies focused on more specific SD attributed it to different phases of breast cancer treatment, for example between diagnosis and chemotherapy, hormone therapy or surgical treatment (Chart 1)²⁸28. Yun YH, Kim YA, Min YH, Park S, Won YJ, Kim DY, Choi IJ, Kim YW, Park SJ, Kim JH, Lee DH, Yoon SJ, Jeong SY, Noh DY, Heo DS. The influence of hospital volume and surgical treatment delay on long-term survival after cancer surgery. Annals of Oncology 2012; 23(10):2731-2737.,⁵⁷57. Crowley MM, McCoy ME, Bak SM, Caron SE, Ko NY, Kachnic LA, Alvis F, Battaglia TA. Challenges in the Delivery of Quality Breast Cancer Care: Initiation of Adjuvant Hormone Therapy at an Urban Safety Net Hospital. J Oncol Pract2014; 10(2):e107-112.,⁵⁸58. Bustami RT, Shulkin DB, Nancy O’Donnell N, Whitman ED. Variations in time to receiving first surgical treatment for breast cancer as a function of racial/ethnic background: a cohort study. JRSM Open 2014; 5(7):2042533313515863.,⁶³63. Vandergrift JL, Niland JC, Theriault RL, Edge SB, Wong YN, Loftus LS, Breslin TM, Hudis CA, Javid SH, Rugo HS, SilverSM, Lepisto EM, Weeks JC. Time to Adjuvant Chemotherapy for Breast Cancer in National Comprehensive Cancer Network Institutions. J Natl Cancer Inst. 2013; 105(24):1912.. Yun et al.²⁸28. Yun YH, Kim YA, Min YH, Park S, Won YJ, Kim DY, Choi IJ, Kim YW, Park SJ, Kim JH, Lee DH, Yoon SJ, Jeong SY, Noh DY, Heo DS. The influence of hospital volume and surgical treatment delay on long-term survival after cancer surgery. Annals of Oncology 2012; 23(10):2731-2737.defined in their study "surgical treatment delay" as the time gap between diagnosis and first surgical treatment.

Different definitions were applied for the term "diagnostic delay": Several authors defined diagnostic delay as the time gap from recognition of first symptoms to histological diagnosis²¹21. Maly RC, Leak B, Mojica CM, Liu Y, Diamant AL, Thind A. What Influences Diagnostic Delay in Low-Income Women with Breast Cancer J Womens Health (Larchmt) 2011; 20(7):1017-1023.,⁴⁰40. Ermiah E, Abdalla F, Buhmeida A, Larbesh E, Pyrhönen S, Collan Y. Diagnosis delay in Libyan female breast cancer BMC Res Notes 2012; 21(5):452.,⁵⁴54. Norsa'adah B, Rampal KG, Rahmah MA, Nyi N, Naing NN, Biswal BM. Diagnosis delay of breast cancer and its associated factors in Malaysian women. BMC Cancer 2011; 11:141.. In this case, there was no clear distinction between PD and SD by the time gap analysed, but underlying causal factors such as access barriers or patient attitudes have been attributed either to PD or SD. Other studies have defined diagnostic delay as the time gap between first presentation and final diagnosis³⁶36. Beattie A. Detecting breast cancer in a general practice - Like finding needles in a haystack? Aust Fam Physician 2009; 38(12):1003-1006.,⁶⁶66. Simmons PS, Jayasinghe YL, Wold LE, Melton LJ. Breast Carcinoma in Young Women. Obstet Gynecol 2011; 118(3):529-536., or suspected breast cancer and confirmed diagnosis⁴⁴44. Soares PBM, Quirino Filho S, Pereira de Souza W, Gonçalves RCR, Reis B. Martelli DRB, Fagundes Silveira M, Martelli Júnior H. Characteristics of women with breast cancer seen at reference services in the North of Minas Gerais. Rev Bras Epidemiol 2012; 15(3):595-604.. Finally, "diagnostic delay" was also defined as the time gap from abnormal mammogram to diagnostic resolution⁶⁷67. Wujcik D, Shyr Y, Li M, Clayton MF, Ellington L, Menon U, Mooney K. Delay in Diagnostic Testing After Abnormal Mammography in Low-Income Women. Oncol Nurs Forum 2009; 36(6):709-715.,⁶⁸68. Lobb R, Allen JD, Emmons KM, Ayanian JZ. Timely Care After an Abnormal Mammogram Among Low-Income Women in a Public Breast Cancer Screening Program. Arch Intern Med 2010; 170(6):521-528.. Other terms also applied were "provider delay"⁴¹41. Ukwenya AY, Yusufu LMD, Nmadu PT, Garbaa ES, Ahmed A. Delayed treatment of symptomatic breast cancer: The experience from Kaduna, Nigeria. S Afr Surg 2008; 46(4):106-110.,⁴⁸48. Piñeros M, Sánchez RM, Perry F, García OA, Ocampo R, Cendales R. Demoras en el diagnóstico y tratamiento de mujeres con cáncer de mama en Bogotá, Colombia. Salud Publica Mex 2011; 53(6):478-485., "doctor delay"⁵³53. Norsa'adah B, Rahmah MA, Rampal KG, Knight A. Understanding Barriers to Malaysian Women with Breast Cancer Seeking Help. Asian Pac J Cancer Prev2012; 13(8):3723-3730.,⁵⁶56. Yusoff N, Taib NAM, Ahmad A. The Health Seeking Trajectories of Malaysian Women and their Husbands in Delay Cases of Breast Cancer: A Qualitative Study Asian Pac J Cancer Prev 2011; 12(10):2563-2570. and "treatment delay"²⁸28. Yun YH, Kim YA, Min YH, Park S, Won YJ, Kim DY, Choi IJ, Kim YW, Park SJ, Kim JH, Lee DH, Yoon SJ, Jeong SY, Noh DY, Heo DS. The influence of hospital volume and surgical treatment delay on long-term survival after cancer surgery. Annals of Oncology 2012; 23(10):2731-2737.. In general, there is no standardized nomenclature, as identical terms have distinct meanings and may refer to different time gaps.

Study objectives differ quantitatively and qualitatively between developing and developed countries

Of the 53 studies, 19 and 15 focused exclusively on PD or SD, respectively, whereas other 19 studies analysed both PD and SD (Table 1). All together, studies exclusively focused on SD were more frequently carried out in developed countries (N = 12) compared to developing countries (N = 3), whereas in the case of studies more focused on PD or both, PD and SD, the difference between developed (N = 17) and developing countries (N = 21) was smaller (p = 0.0313). Five out of six studies, that attributed poor knowledge or no information about breast cancer to affected women, were from developing countries³⁴34. Ngowa JDK, Yomi J, Kasia JM, Mawamba Y, Ekortarh AC, Vlastos G. Breast Cancer Profile in a Group of Patients Followed up at the Radiation Therapy Unit of the Yaounde General Hospital, Cameroon. Obstet Gynecol Int 2011; 2011:143506.,⁴²42. Memon ZA, Shaikh AN, Rizwan S, Sardar MB. Reasons for Patient's Delay in Diagnosis of Breast Carcinoma in Pakistan. Asian Pac J Cancer Prev 2013; 14(12):7409-7414.,⁴⁷47. Bodapati SL, Babu GR. Oncologist Perspectives on Breast Cancer Screening in India - Results from a Qualitative Study in Andhra Pradesh. Asian Pac J Cancer Prev 2013; 14(10):5817-5823.,⁵⁵55. Taib NA, Yip CH, Low WY. Recognizing Symptoms of Breast Cancer as a Reason for Delayed Presentation in Asian Women - The Psycho-sociocultural Model for Breast Symptom Appraisal: Opportunities for Intervention. Asian Pacific J Cancer Prev 2011; 12(6):1601-1608.,⁵⁶56. Yusoff N, Taib NAM, Ahmad A. The Health Seeking Trajectories of Malaysian Women and their Husbands in Delay Cases of Breast Cancer: A Qualitative Study Asian Pac J Cancer Prev 2011; 12(10):2563-2570. (Chart 2). The basic assumption that women are not well informed about breast cancer may lead authors from these countries to develop a stronger focus on PD or PD and SD compared to authors from developed countries.

Identified causal factors of PD and SD were summarized in Table 3 and Table 4, respectively. Overall, in 53 studies, 208 factors were identified two or more times (Chart 2 and Chart 3). Of these 208 identified causal factors, 124 contributed to PD and 84 to SD (Chart 2 and Chart 3). The number of identified factors that contributed to PD was higher for studies carried out in developing countries (N = 74) compared to developed countries (N = 50) and in the case of SD, the opposite was observed: More factors were identified in studies carried out in developed countries (N = 57), compared to developing countries (N = 27; p = 0.0001). This underlines the strong interest of authors from developing countries to better understand the reasons of PD.

Causal factors and PD terminology

Non-attribution of symptoms to cancer (N = 14), fear of disease, treatment adverse effects, examination and chemotherapy (N = 10), low educational level and literacy level (N = 10), and old or young age (N = 9) were the four most often identified causal factors of PD (Chart 2). The following factors were exclusively identified by studies carried out in developing countries: Reliance on traditional healers or preference for alternative treatment (N = 7), no breast self examination (N = 4), poor knowledge of the disease and its outcomes (N = 3), fear of social isolation (N = 2) and painless breast lump vs. other symptoms (N = 2; Chart 2). Comorbid condition (N = 3) was the only factor identified exclusively in studies carried out in developed countries (Chart 2)²⁹29. Fedewa SA, Ward EM, Stewart AK, Edge SB. Delays in Adjuvant Chemotherapy Treatment Among Patients With Breast Cancer Are More Likely in African American and Hispanic Populations: A National Cohort Study 2004-2006. J Clin Oncol2010; 28(27):4135-4141.,⁵⁷57. Crowley MM, McCoy ME, Bak SM, Caron SE, Ko NY, Kachnic LA, Alvis F, Battaglia TA. Challenges in the Delivery of Quality Breast Cancer Care: Initiation of Adjuvant Hormone Therapy at an Urban Safety Net Hospital. J Oncol Pract2014; 10(2):e107-112.,⁶⁵65. Heisey R, Clemons M, Granek L, Fergus K, Hum S, B. McCready DR, Fitzgerald B. Health care strategies to promote earlier presentation of symptomatic breast cancer: perspectives of women and family physicians Curr Oncol 2011; 18(5):227-237..

The term PD was generally used for care delays that were dependent on patient behaviour. The authors who categorized data from patients defined PD as the time gap > 3 month from recognition of first symptoms to first medical visit⁴²42. Memon ZA, Shaikh AN, Rizwan S, Sardar MB. Reasons for Patient's Delay in Diagnosis of Breast Carcinoma in Pakistan. Asian Pac J Cancer Prev 2013; 14(12):7409-7414.,⁴³43. Poum A, Promthet S, Duffy SW, Maxwell Parkin D. Factors Associated With Delayed Diagnosis of Breast Cancer in Northeast Thailand. J Epidemiol2014; 24(2):102-108.,⁴⁸48. Piñeros M, Sánchez RM, Perry F, García OA, Ocampo R, Cendales R. Demoras en el diagnóstico y tratamiento de mujeres con cáncer de mama en Bogotá, Colombia. Salud Publica Mex 2011; 53(6):478-485.,⁴⁹49. Piñeros M, Sánchez R, Cendales R, Perry F, Ocampo R. Patient delay among Colombian women with breast cancer. Salud Publica Mex 2009; 51(5):372-380.,⁵¹51. Ghazali SM, Othman Z, Cheong KC, Hock LK, Rozita W, Mahiyuddin W, Kamaluddin MA, Yusoff AF, Mustafa AN. Non-Practice of Breast Self Examination and Marital Status are Associated with Delayed Presentation with Breast Cancer Asian Pacific J Cancer Prev 2013; 14(2):1141-1145.,⁶²62. Sharma K, Costas A, Damuse R, Hamiltong-Pierre J, Pyda J, Ong CT, Shulman LN and Meara JG. The Haiti Breast Cancer Initiative: Initial Findings and Analysis of Barriers-to-Care Delaying Patient Presentation. J Oncol 2013; 2013:206367.. Alternatively, no time gap was identified and patients were not categorized. In this case, PD was determined as a continuous variable or described by more detailed in-depth-interviews based on patients’ perspective²³23. Ozmen V, Boylu S, Ok E, Canturk NZ, Celik V, Kapkac M, Girgin S, Tireli M, Ihtiyar E, Demircan O, Baskan MS, Koyuncu A, Tasdelen I, Dumanli E, Ozdener F, Zaborek P. Factors affecting breast cancer treatment delay in Turkey: a study from Turkish Federation of Breast Diseases Societies. Eur J Public Health 2014; 25(1):9-14.,²⁴24. Yau TK, Choi CW, Ng E, Yeung R, Soong IS, Lee AWM. Delayed presentation of symptomatic breast cancers in Hong Kong: experience in a public cancer center. Hong Kong Med J 2010; 16(5):373-377.,²⁶26. Fayanju OM, Jeffe DB, Elmore L, Ksiazek DN, Margenthaler JA. Patient and Process Factors Associated with Late-Stage Breast Cancer Diagnosis in Safety-Net Patients: A Pilot Prospective Study. Ann Surg Oncol 2013; 20(3):723-732.,²⁷27. Chintamani, Tuteja A, Khandelwal R, Tandon M, Bamal R, Jain S, Narayan N, Srinivas S, Kumar Y. Patient and provider delays in breast cancer patients attending a tertiary care centre: a prospective study. J R Soc Med Sh Rep 2011; 2:76.,³⁴34. Ngowa JDK, Yomi J, Kasia JM, Mawamba Y, Ekortarh AC, Vlastos G. Breast Cancer Profile in a Group of Patients Followed up at the Radiation Therapy Unit of the Yaounde General Hospital, Cameroon. Obstet Gynecol Int 2011; 2011:143506.,³⁹39. Rastad H, Khanjani N, Khandani BK. Causes of Delay in Seeking Treatment in Patients with Breast Cancer in Iran: a Qualitative Content Analysis Study. Asian Pac J Cancer Prev 2012; 13(9):4511-4515.,⁴⁶46. Schairer C, Soliman AS, Omar S, Khaled H, Eissa S, Ayed FB, Khalafallah S, Ayoub WB, Kantor ED, Merajver S, Swain SM, Gail M, Morris Brown L. Assessment of diagnosis of inflammatory breast cancer cases at two cancer centers in Egypt and Tunisia. Cancer Med 2013; 2(2):178-184.,⁵²52. Muhamad M, Merriam S, Suhami N. Why Breast Cancer Patients Seek Traditional Healers. Int J Breast Cancer 2012; 2012:689168.,⁵³53. Norsa'adah B, Rahmah MA, Rampal KG, Knight A. Understanding Barriers to Malaysian Women with Breast Cancer Seeking Help. Asian Pac J Cancer Prev2012; 13(8):3723-3730.,⁵⁵55. Taib NA, Yip CH, Low WY. Recognizing Symptoms of Breast Cancer as a Reason for Delayed Presentation in Asian Women - The Psycho-sociocultural Model for Breast Symptom Appraisal: Opportunities for Intervention. Asian Pacific J Cancer Prev 2011; 12(6):1601-1608.,⁵⁹59. Bourdeanu L, Luu T, Baker N, Swain-Cabriales S, Chung CT, Mortimer J, Hurria A, Helton S, Smith D, Ferrell B, Juarez G, Somlo G. Barriers to Treatment in Patients With Locally Advanced Breast Cancer. J Natl Compr Canc Netw2013; 11(10):1193-1198.,⁶⁵65. Heisey R, Clemons M, Granek L, Fergus K, Hum S, B. McCready DR, Fitzgerald B. Health care strategies to promote earlier presentation of symptomatic breast cancer: perspectives of women and family physicians Curr Oncol 2011; 18(5):227-237.. Attitudes can also cause PD during the process of breast cancer treatment²²22. Sheppard VB, Isaacs C, Luta G, Willey SC, Boisvert M, Harper FWK, Smith K, Horton S, Liu MC, Jennings Y, Hirpa F, Snead F, Mandelblatt JS. Narrowing Racial Gaps in Breast Cancer Chemotherapy Initiation: The Role of the Patient-Provider Relationship. Breast Cancer Res Treat 2013; 139(1):207-216.,⁴⁶46. Schairer C, Soliman AS, Omar S, Khaled H, Eissa S, Ayed FB, Khalafallah S, Ayoub WB, Kantor ED, Merajver S, Swain SM, Gail M, Morris Brown L. Assessment of diagnosis of inflammatory breast cancer cases at two cancer centers in Egypt and Tunisia. Cancer Med 2013; 2(2):178-184.: Sheppard et al.²²22. Sheppard VB, Isaacs C, Luta G, Willey SC, Boisvert M, Harper FWK, Smith K, Horton S, Liu MC, Jennings Y, Hirpa F, Snead F, Mandelblatt JS. Narrowing Racial Gaps in Breast Cancer Chemotherapy Initiation: The Role of the Patient-Provider Relationship. Breast Cancer Res Treat 2013; 139(1):207-216. identified high religiosity and negative attitudes toward chemotherapy as independent causal factors of PD, between surgery and chemotherapeutic treatment (Chart 2).

Causal factors of SD

Poor insurance status and insurance authorization delays (N = 7), older or younger age (N = 7), false negative diagnostic tests (N = 6) and longer distance to health care centre (N = 6) were the four most common identified causal factors of SD (Chart 3). In the case of older patients increased time gap between diagnosis and adjuvant chemotherapeutic treatment was explained by postoperative complications and diagnostic or therapeutic interventions²⁹29. Fedewa SA, Ward EM, Stewart AK, Edge SB. Delays in Adjuvant Chemotherapy Treatment Among Patients With Breast Cancer Are More Likely in African American and Hispanic Populations: A National Cohort Study 2004-2006. J Clin Oncol2010; 28(27):4135-4141.,⁶³63. Vandergrift JL, Niland JC, Theriault RL, Edge SB, Wong YN, Loftus LS, Breslin TM, Hudis CA, Javid SH, Rugo HS, SilverSM, Lepisto EM, Weeks JC. Time to Adjuvant Chemotherapy for Breast Cancer in National Comprehensive Cancer Network Institutions. J Natl Cancer Inst. 2013; 105(24):1912.. Vandergrift et al. additionally showed that missing supplemental insurance of Afro-American women also increased this time gap⁶³63. Vandergrift JL, Niland JC, Theriault RL, Edge SB, Wong YN, Loftus LS, Breslin TM, Hudis CA, Javid SH, Rugo HS, SilverSM, Lepisto EM, Weeks JC. Time to Adjuvant Chemotherapy for Breast Cancer in National Comprehensive Cancer Network Institutions. J Natl Cancer Inst. 2013; 105(24):1912.. Authors of studies carried out in Colombia and Thailand argued that poor insurance status was associated with delayed diagnosis and referral for specialist treatment⁴³43. Poum A, Promthet S, Duffy SW, Maxwell Parkin D. Factors Associated With Delayed Diagnosis of Breast Cancer in Northeast Thailand. J Epidemiol2014; 24(2):102-108.,⁴⁸48. Piñeros M, Sánchez RM, Perry F, García OA, Ocampo R, Cendales R. Demoras en el diagnóstico y tratamiento de mujeres con cáncer de mama en Bogotá, Colombia. Salud Publica Mex 2011; 53(6):478-485..

The factors comorbidity, communication, hospital volume, preoperative components, comparison of disease management program, several histopathological characteristics and ethnicity were exclusively identified to cause SD by authors of developed countries (Chart 3). Studies of developed countries had generally a stronger focus on the performance of the health care system and patient navigation during the treatment process.

Effects of several factors depend on the context, but are not decisive themselves and some factors can cause PD and SD

Long distances to health care centres and rural vs. urban areas were identified in several studies to cause SD as they are relevant access barriers (Chart 3)¹⁶16. Landolsi A, Gahbiche S, Chaafii R, Chabchoub I, Ben Fatma L, Hochlef M, Gharbi O, Ahmed SB. Reasons of diagnosis delay of breast cancer in Tunisian women (160 patients in central region of Tunisia). Tunis Med 2010; 88(12):894-897.,²³23. Ozmen V, Boylu S, Ok E, Canturk NZ, Celik V, Kapkac M, Girgin S, Tireli M, Ihtiyar E, Demircan O, Baskan MS, Koyuncu A, Tasdelen I, Dumanli E, Ozdener F, Zaborek P. Factors affecting breast cancer treatment delay in Turkey: a study from Turkish Federation of Breast Diseases Societies. Eur J Public Health 2014; 25(1):9-14.,²⁷27. Chintamani, Tuteja A, Khandelwal R, Tandon M, Bamal R, Jain S, Narayan N, Srinivas S, Kumar Y. Patient and provider delays in breast cancer patients attending a tertiary care centre: a prospective study. J R Soc Med Sh Rep 2011; 2:76.,⁴¹41. Ukwenya AY, Yusufu LMD, Nmadu PT, Garbaa ES, Ahmed A. Delayed treatment of symptomatic breast cancer: The experience from Kaduna, Nigeria. S Afr Surg 2008; 46(4):106-110.,⁴⁵45. Price AJ, Ndom P, Atenguena E, Nouemssi JPM, Ryder RW. Cancer Care Challenges in Developing Countries. Cancer 2012; 118(14):3627-3635.,⁶³63. Vandergrift JL, Niland JC, Theriault RL, Edge SB, Wong YN, Loftus LS, Breslin TM, Hudis CA, Javid SH, Rugo HS, SilverSM, Lepisto EM, Weeks JC. Time to Adjuvant Chemotherapy for Breast Cancer in National Comprehensive Cancer Network Institutions. J Natl Cancer Inst. 2013; 105(24):1912.. In a study carried out in Poland, the opposite was observed, as women living in urban areas suffered from SD³⁵35. Maślach D, Krzyżak M, Szpak A, Owoc A, Magdalena Bielska-Lasota. Waiting time for treatment of women with breast cancer in Podlaskie Voivodeship (Poland) in view of place of residence. A population study. Anna Agric Environ Med 2013; 20(1)161-166.. In this case, the authors argued that physicians concentrate treatment procedures for patients from rural regions to reduce the number of visits. Similarly, comorbidities or clinical-histopathological characteristics like tumour stage and hormone receptor status influenced decisions of physicians in different context-dependent ways (Chart 2).

Lobb et al.⁶⁸68. Lobb R, Allen JD, Emmons KM, Ayanian JZ. Timely Care After an Abnormal Mammogram Among Low-Income Women in a Public Breast Cancer Screening Program. Arch Intern Med 2010; 170(6):521-528., pointed out that improved communication between patient and physician can reduce health system barriers. Sheppard et al.²²22. Sheppard VB, Isaacs C, Luta G, Willey SC, Boisvert M, Harper FWK, Smith K, Horton S, Liu MC, Jennings Y, Hirpa F, Snead F, Mandelblatt JS. Narrowing Racial Gaps in Breast Cancer Chemotherapy Initiation: The Role of the Patient-Provider Relationship. Breast Cancer Res Treat 2013; 139(1):207-216. identified in their study an ambivalent nature of better communication that was dependent on the ethnic origin of patients (Chart 3): Better communication between patients and physicians led to decreased SD among Afro-American patients and to increased SD among patients of Caucasian origin²²22. Sheppard VB, Isaacs C, Luta G, Willey SC, Boisvert M, Harper FWK, Smith K, Horton S, Liu MC, Jennings Y, Hirpa F, Snead F, Mandelblatt JS. Narrowing Racial Gaps in Breast Cancer Chemotherapy Initiation: The Role of the Patient-Provider Relationship. Breast Cancer Res Treat 2013; 139(1):207-216.. According to their interpretation, Afro-American women may have relied on provider suggestion, whereas women of Caucasian origin with higher income and education rather seek information outside the patient-provider relationship to make their decisions²²22. Sheppard VB, Isaacs C, Luta G, Willey SC, Boisvert M, Harper FWK, Smith K, Horton S, Liu MC, Jennings Y, Hirpa F, Snead F, Mandelblatt JS. Narrowing Racial Gaps in Breast Cancer Chemotherapy Initiation: The Role of the Patient-Provider Relationship. Breast Cancer Res Treat 2013; 139(1):207-216..

Several studies have identified older age as an causal factor of PD (Chart 2)¹⁹19. Quaife SL, Forbes LJL, Ramirez AJ, Brain KE, Donnelly C, Simon AE, Wardle J. Recognition of cancer warning signs and anticipated delay in help-seeking in a population sample of adults in the UK. Br J Cancer 2014; 110(1):12-18.,²⁷27. Chintamani, Tuteja A, Khandelwal R, Tandon M, Bamal R, Jain S, Narayan N, Srinivas S, Kumar Y. Patient and provider delays in breast cancer patients attending a tertiary care centre: a prospective study. J R Soc Med Sh Rep 2011; 2:76.,³⁸38. Innos K, Padrik P, Valvere V, Eelma E, Kütner R, Lehtsaar J, Tekkel M. Identifying women at risk for delayed presentation of breast cancer: a cross-sectional study in Estonia. BMC Public Health 2013; 13:947.,⁴⁰40. Ermiah E, Abdalla F, Buhmeida A, Larbesh E, Pyrhönen S, Collan Y. Diagnosis delay in Libyan female breast cancer BMC Res Notes 2012; 21(5):452.,⁴⁹49. Piñeros M, Sánchez R, Cendales R, Perry F, Ocampo R. Patient delay among Colombian women with breast cancer. Salud Publica Mex 2009; 51(5):372-380.,⁶²62. Sharma K, Costas A, Damuse R, Hamiltong-Pierre J, Pyda J, Ong CT, Shulman LN and Meara JG. The Haiti Breast Cancer Initiative: Initial Findings and Analysis of Barriers-to-Care Delaying Patient Presentation. J Oncol 2013; 2013:206367.. In their study, Inos et al.³⁸38. Innos K, Padrik P, Valvere V, Eelma E, Kütner R, Lehtsaar J, Tekkel M. Identifying women at risk for delayed presentation of breast cancer: a cross-sectional study in Estonia. BMC Public Health 2013; 13:947., pointed out that older women tend to underestimate the risk of breast cancer as breast cancer screening programs are mainly addressed to women aged 50-62 years. This is in agreement with findings of Brazilian studies that revealed decreased numbers of elderly women participating in mammography screening programs⁶⁹69. Dias dos Santos G, Sato Chubaci RY. O conhecimento sobre o câncer de mama e a mamografia das mulheres idosas frequentadoras de centros de convivência em São Paulo (SP, Brasil). Cien Saude Colet 2011; 16(5):2533-2540.,⁷⁰70. Xavier Gouveia de Oliveira E, Sobrino Pinheiro R, Praates Melo EC, Sá Carvalho M. Condicionantes socioeconômicos e geográficos do acesso à mamografia no Brasil, 2003-2008. Cien Saude Colet 2011; 16(9):3649-3664.. Similarly, in a study carried out in Lybia, PD was attributed to older aged women with poor knowledge about breast cancer⁴⁰40. Ermiah E, Abdalla F, Buhmeida A, Larbesh E, Pyrhönen S, Collan Y. Diagnosis delay in Libyan female breast cancer BMC Res Notes 2012; 21(5):452.. In contrast, a study carried out in Turkey, the authors showed that young women aged 30-39 years more often ignored breast cancer symptoms compared with older patients²³23. Ozmen V, Boylu S, Ok E, Canturk NZ, Celik V, Kapkac M, Girgin S, Tireli M, Ihtiyar E, Demircan O, Baskan MS, Koyuncu A, Tasdelen I, Dumanli E, Ozdener F, Zaborek P. Factors affecting breast cancer treatment delay in Turkey: a study from Turkish Federation of Breast Diseases Societies. Eur J Public Health 2014; 25(1):9-14.. Ozmen et al.²³23. Ozmen V, Boylu S, Ok E, Canturk NZ, Celik V, Kapkac M, Girgin S, Tireli M, Ihtiyar E, Demircan O, Baskan MS, Koyuncu A, Tasdelen I, Dumanli E, Ozdener F, Zaborek P. Factors affecting breast cancer treatment delay in Turkey: a study from Turkish Federation of Breast Diseases Societies. Eur J Public Health 2014; 25(1):9-14., also identified in their study decreased SD among patients aged > 60 years. Their interpretation was that older patients are prioritized by physicians and receive a faster diagnostic process. Similarly, Bleicher et al.³⁰30. Bleicher RJ, Ruth K, Sigurdson ER, Ross E, Wong YN, Patel SA, Boraas M, Topham NS, Egleston BL. Preoperative Delays in the US Medicare Population With Breast Cancer. J Clin Oncol 2012; 30(36):4485-4492., identified increased preoperative delay in patients aged 65-79 years compared to patients > 80 years. Interestingly, authors of a study based on 21,818 breast cancer cases, argued that symptomatic presentation of disease was more common in younger women³¹31. Partridge AH, Hughes ME, Ottesen RA, Wong YN, Edge SB, Theriault RL, Blaney DW, Niland JC, Winer EP, Weeks JC, Tamimi RM. The Effect of Age on Delay in Diagnosis and Stage of Breast Cancer. Oncologist 2012; 17(6):775-782.. In this case young age ≤ 40 years, was a significant variable of PD in univariate analysis, but did not represent an independent variable of the final regression model.

In several cases, the authors did not explain why a determined factor had a unexpected effect: While in two studies, low family income was associated with PD, in a study carried out in Thailand, the opposite was verified and authors did not represent a causal argument of their result (Chart 2)²⁴24. Yau TK, Choi CW, Ng E, Yeung R, Soong IS, Lee AWM. Delayed presentation of symptomatic breast cancers in Hong Kong: experience in a public cancer center. Hong Kong Med J 2010; 16(5):373-377.,⁴³43. Poum A, Promthet S, Duffy SW, Maxwell Parkin D. Factors Associated With Delayed Diagnosis of Breast Cancer in Northeast Thailand. J Epidemiol2014; 24(2):102-108.,⁴⁹49. Piñeros M, Sánchez R, Cendales R, Perry F, Ocampo R. Patient delay among Colombian women with breast cancer. Salud Publica Mex 2009; 51(5):372-380..

As shown above in the case of age, some factors caused PD and SD. Lower educational level and lower family income were also associated with PD and SD (Chart 2 and 3). Lower educational level and literacy status were the most often cited factor to cause PD (Chart 2). A Colombian study revealed that SD was not only associated with poor health insurance status, but also with low family income and educational level⁴⁸48. Piñeros M, Sánchez RM, Perry F, García OA, Ocampo R, Cendales R. Demoras en el diagnóstico y tratamiento de mujeres con cáncer de mama en Bogotá, Colombia. Salud Publica Mex 2011; 53(6):478-485.. Fedewa et al.²⁹29. Fedewa SA, Ward EM, Stewart AK, Edge SB. Delays in Adjuvant Chemotherapy Treatment Among Patients With Breast Cancer Are More Likely in African American and Hispanic Populations: A National Cohort Study 2004-2006. J Clin Oncol2010; 28(27):4135-4141., used a large database to compare the time gap between surgical resection of the primary tumour and initiation of chemotherapy among patients from different regions of the USA. Their study revealed that SD > 90 days was not only more prominent among Afro-Americans, compared to patients of Caucasian origin, but that proportionally more often patients from regions with low education levels, measured by the frequency of school diploma, also suffered from SD²⁹29. Fedewa SA, Ward EM, Stewart AK, Edge SB. Delays in Adjuvant Chemotherapy Treatment Among Patients With Breast Cancer Are More Likely in African American and Hispanic Populations: A National Cohort Study 2004-2006. J Clin Oncol2010; 28(27):4135-4141.. The authors reported that lower socio-economic and educational status can also difficult navigation through the health care system⁶⁶66. Simmons PS, Jayasinghe YL, Wold LE, Melton LJ. Breast Carcinoma in Young Women. Obstet Gynecol 2011; 118(3):529-536.,⁶⁸68. Lobb R, Allen JD, Emmons KM, Ayanian JZ. Timely Care After an Abnormal Mammogram Among Low-Income Women in a Public Breast Cancer Screening Program. Arch Intern Med 2010; 170(6):521-528..

These studies showed that several factors are not decisive, but depend on patient's social and cultural environment and on differences among health care systems and their personal decisions. Furthermore, several socio-economic factors have an influence on both PD and SD.

Final considerations

Studies carried out in developing countries more often focus on the general aspects of SD. In contrast, studies carried out in developed countries analysed more often a determined time gap of treatment. In general, authors from developing countries are more interested in PD or PD and SD combinations, and identified also more causal factors of PD compared to studies carried out in developed countries. In contrast, studies carried out in developed countries more often focus on specific aspects of SD. The stronger focus on PD in the case of studies carried out in developing countries is probably influenced by the author's assumption that patients in their country are not well informed about breast cancer. However, this does not necessarily mean that women from developed countries are really well informed. One should always keep in mind that questions of studies and their objectives are not only influenced by the social and cultural reality of researchers, but that there also can exist underlying "fashions of research" that differ timely and locally among countries.

The present review study showed that methodological approaches of studies were highly different. Interviews of few persons contrasted with the analysis of large databases, and while some studies were purely descriptive, others applied multivariate regression models to identify a reduced number of independent variables. Neither methodological approaches nor nomenclature about PD and SD are standardized.

Socio-economic factors, symptomatology experience and attitudes of patients contributed to PD. Socioeconomic and ethnic differences affected both PD and SD. Additionally, diagnostic factors, factors that affect decisions of physicians, access barriers, communication between patient and physician, disease management and histopathological characteristics of disease also affected SD. Some of these factors were not decisive, but mainly dependent on the social and cultural context.

References

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