Introduction: Breast cancer has remained the most commonly diagnosed disease  among women globally. Despite the advancement in biomedical sciences leading to  improve survival outcomes, some patients endure longer wait periods prior to initiation  of treatment.
Objective: To elucidate the impact of treatment delay on breast cancer patient’s  quality of life and survivorship. Second was to determine the optimal length of time  (delay) between breast cancer diagnosis and start of first treatment in order to  improve prognosis and general health and well-being of survivors.
Methods: Systematic search of the literature was conducted across five electronic  
databases: Pub Med, EMBASE, CINAHL, Scopus and Science Direct as well as the  reference list of all articles retrieved.
Results: A total of 33 articles were included in the evidence based systematic  review, which comprised of 255,366 observations. The results of the studies were  categorized under five main themes as: study characteristics, cancer staging and  classification, treatment delay time definition and interval, treatment regimen  classification and delay impact on quality of life and survival. Analyzed wait times from  diagnosis to the initiation of first therapy ranged from 7 days to a period of over 180  days. Combinations of standardized treatment including loco-regional radiotherapy,  systemic chemotherapy surgery as well as hormonal therapy were examined. Even 
though some of the studies showed mixed results, overall, findings indicated that early  detection, diagnosis and initiation of treatment within 90 days increase survival.
Conclusions: Evidence revealed that delaying the initiation of treatment for  breast cancer more than 90 days after diagnosis has a detrimental effect on disease  free and overall well-being of survivors

Breast cancer ;Treatment delay ;Treatment initiation ; Survival.

Williams F (2015) Assessment of Breast Cancer Treatment Delay Impact on Prognosis and Survival: a Look at the Evidence from Systematic Analysis of the Literature. A Pilot Study. J Cancer Biol Res 3(4): 1071.

AJCC: American Joint Committee on Cancer; NBCCEDP: National Breast and Cervical Cancer Early Detection Program; SEER: Surveillance and Epidemiology End Results; TDT: Treatment Delay Time; TNM: Tumor, Nodes and Metastases; UK: United Kingdom; USA: United States of America; WHO: World Health Organization

Breast cancer has remained the most commonly cancer diagnosed among women globally, although incidence rates in developed nations have been stable since 2003 [1-3]. While incidence rates are higher in Western countries, death rates are far much higher in developing countries such as those in SubSaharan Africa [1]. Overall, developing countries account for approximately 50% of all breast cancer incidences and more than 60% mortalities annually [1].

In spite of advances in medical technology in most developed countries leading to early diagnosis and treatment, racial and ethnic breast cancer disparities in stage at presentation and treatment outcomes continue to widen. These disparities have mainly been attributed to organizational, structural, socioeconomic and sociopolitical underlying forces of the health care system [4-7]. For instance, studies investigating the geographical differences in late stage presentation of breast cancer in the developed world have shown that women living in areas of high socioeconomic disadvantage were more likely to be diagnosed at late stage of the disease resulting in poor treatment outcomes and survival [4,5]. In developing countries, delay in diagnosis and treatment has mainly been attributed to lack of human and financial resources to ensure timely diagnosis and treatment. Other factors include: lack of knowledge on breast cancer, family history and denial or superstition of the disease, access to affordable medical care and appropriate optimal resources for effective treatment [8-13].

Even though breast cancer treatment is multifaceted, in developed countries improvement in survival for patients have been attributed to sustainable medical programs that promote screening, early diagnosis and treatment [14]. Notwithstanding the increased outcomes in survival, cancer patients sometimes experience long wait times before initiation of first treatment or therapy [14-16]. There are two major types of delay. These are patient and system or provider or doctor delay. Patient delay refers to the period from first onset of symptoms to first medical consultation. System or provider delay is defined as the period from first consultation to definite diagnosis and treatment [15,17]. Although the impact of delay in starting cancer treatment after diagnosis is poorly defined, it is well known that early diagnosis and treatment influence better prognosis and overall quality of life of patients. As a result, any of these delays, may result in adverse prognosis for women with breast cancer [15,17- 19].

According to the World Health Organization (WHO), early diagnosis of cancer greatly increases the chances for successful treatment for cancers such as breast, cervix, mouth, larynx, colon and rectum and skin [20]. Nonetheless, the optimal timing between breast cancer diagnosis and beginning of treatment are still uncertain. The purpose of this critical review was to conduct a qualitative analysis of published literature in English language on how time duration from the first presentation of breast cancer (diagnosis) to the start of first treatment affect recovery. The optimal goal was to elucidate the impact of treatment delay on breast cancer patient’s quality of life and survivorship. In addition this evidence based systematic review tries to determine the optimum length of time (delay) between breast cancer diagnosis and start of first treatment in order to improve prognosis and general health and well-being of survivors.

Search terms and databases

Systematic search was performed across the following databases. Pub Med (1951-2014), EMBASE (1966-2014), CINAHL (1982-2014), Scopus (1960-2014) and Science Direct (1997- 2014) with the following keywords: “breast cancer” OR “breast neoplasm’s” OR “breast tumor” AND “treatment delay” OR “treatment initiation” AND “survival” OR “survivors”. In addition, secondary references were retrieved within the reference lists of publications that were included for review.

Eligibility criteria and study selection

Studies were considered eligible if they were in English language, included adult women, were peer-reviewed original research articles, included quantitative comparisons, and investigated the effect of treatment delay on recovery, recurrence and survival. Studies were removed during initial screening if they failed to meet any of these criteria. All returned citations across the searched databases were initially screened for duplicates, then for relevance by title and abstract.

Study selection

A total of 1,022 articles were retrieved from the following five databases: Pub Med, CINAHL, EMBASE, Scopus and Science Direct. Five additional articles were identified from other sources such as reference list and Google scholar search. After eliminating duplicates, 790 remained. After screening the abstracts for relevance, 557articleswere eliminated. Full text screenings of the remaining 233 articles/studies were conducted using the established inclusion criteria. A second thoroughly review of the studies further reduced the number to 105 after reading all articles. A total of 33 studies [21-53] were included in the evidence based systematic review, which included 255,366 observations (see Figure 1 for articles included based on eligibility criteria).

Figure 1 Flow Diagram of Study Eligibility Criteria for Inclusion and Exclusion

The results of the final 33 studies were categorized under these main themes: (1) study characteristics, (2) cancer staging and classification, (3) treatment delay time definition and interval, (4) treatment regimen classification and (5) delay impact on quality of life and survival.

Study characteristics

Table 1.

presents the study characteristics. Majority of the published studies were from the United States of America (USA), a total of ten [23,28,32,33,35,38,41-43,48]. There were six studies from Canada [29,37,49-52], three from Italy [22,24,26]. There were two studies from Korea [47,53], United Kingdom (UK) [39,45] and Turkey [21,44]. One study each was published from these countries; Denmark [25], Germany [27], Egypt [30], France [31], Sweden [36], Malaysia [40], Spain [34] and China [46]. Sample sizes in the studies ranged from 96 to 147,682. Patients of all ages were included in 28 of the studies [21-29,31,32,34-41,44- 47,49-53], which comprised more than two thirds of the included studies. Three studies [33,42,43] included women 65 years and over while adolescents and young adults [48] and premenopausal women [30] had one each. All the studies included in this review used existing/secondary data sources such as cancer registry and surveillance and epidemiology end results (SEER) databases.

Breast cancer staging and classification

Cancer staging is done at the time of diagnosis, in order to determine the best therapy or treatment and/or measure outcome for the patient. There were great variations in the cancer staging system used for the studies included (Table 2).

Although majority of the studies clearly stated the staging system such as the American Joint Committee on Cancer (AJCC) tumor, nodes and metastases (TNM) or clinical or pathologic, early or late, other studies did not state it. More than two-thirds (12) of the studies [25,27,30,32-35,37,39,41-43] used the number staging system (0, I, II, III etc.). Eight studies [21,22,29,31,49-52] used the AJCC TNM staging classification. Five studies [23,28,38,40, 48] simply reported using all stages. Four studies [36,44,45,53] did not mention the staging system analyzed. Another two studies (24, 47) reported using early, local and regional breast cancer treatment operable classification while the final two studies [26,46] stated using the hormone receptor status.

Treatment delay time definition and interval

Variation in definition of treatment delay or interval length was evident in the studies. A third of the studies included in this critical review 33.3% (11 out of 33) defined treatment interval as the time period from biopsy and/or diagnosis date to the start of first treatment in general or either in surgery, chemotherapy, radiation, or hormonal therapy [23,25,28,35,38,40,44,47,48,52,5 3]. Ten studies representing 30.3% of the total number of eligible articles defined it as the interval between the date of surgery and the first date of radiation [22,24,27,29,39,41,43,49-51]. Six other studies (18.2%) defined it as time between surgery and beginning of first chemotherapy treatment [21,26,30,34,37,42]. On the other hand, one study (3%) simply defined it as the interval between surgery and treatment [45] while five studies (15.2%) did not provide any definition of the interval delay used in their assessment [31-33,36,46].

Further, there was a general lack of understanding on what constitute treatment delay interval. Some studies classified the interval period in days, weeks or even months. In spite of this disagreement, more than half of the studies eighteen (55%) defined the interval period in weeks (0 week – more than 26 weeks) [24,25,27,29,32,34,35,37,39-41,43,47-52]. Additional nine (27%) studies [21-23,26,28,30,38,44,45] categorized the delay interval in days (0 day – more than 180 days), while three studies [33,42,53] classified the treatment delay interval between diagnosis and initiation of treatment in months (0 month – greater than 3 months). One (3%) study [31] defined the delay intervals in mean days. Two (6%) studies [36,46] did not provide any information on the treatment delay interval examined. However, after converting all the delay intervals to days, the length of wait period to the initiation of first treatment varies from as low as 7 days to a period of over 180 days.

Treatment regimenclassification

Of the total 33 articles included in the review, ten (30.3%) reported on standard radiation treatment option for breast cancer patients [22,29,33,36,39,41,43,49-51] and nine (27.3%) studies focused on combinations of standardized treatment like surgery, radiation, chemotherapy and hormonal types [21,24,27,35,38,40,44,48,53]. Eight (24.2%) reported on the impact of delaying chemotherapy treatment on survival [25,26,30,32,34,37,42,45] whereas three (9.1%) described the effect of survival in terms of delay of undergoing breast conserving surgery, partial or modified radical mastectomy [28,47,52]. Brazda et al [23] did not provide information of the type of treatment regimen while Gouy et al [31] and Shi et al [46] reported on any kind of adjuvant treatment and hormonal therapy.

Treatment delay impact on quality of life and survival

Although not all studies included in the review mentioned either the cancer stage at diagnosis, defined treatment delay, treatment regiment, or associated treatment delay interval examined, all indicated the impact of breast cancer treatment delay on the patient’s quality of life and survival. Of the nine studies that measured the delay interval in days, three noted that delaying the onset of treatment significantly affect overall survival [21,30,38]. The treatment delay wait period analyzed ranged between 21 and 84 days. Six studies reported no statistically difference [22,23,26,28,44,45]. However, three studies that measured the delay in months (0 > 3 months) all started that initiating treatment more than one month after breast cancer diagnosis is significantly associated with poor quality of life and survival [33,42,53]. Results of the eighteen studies that assessed interval delays in weeks (0 - >= 26 weeks) also varies significantly. Whereas ten studies [24,25,27,29,32,34,40,41,49,51] noted no substantial difference between early initiation of treatment and late initiation on recovery, recurrence and survival, seven [35,37,39,43,48, 50,52] reported statistical difference. One study  [47] stated no clear pattern of increased risk was observed in those who initiated early and late treatment.

According to the National Breast and Cervical Cancer Early Detection Program (NBCCEDP) benchmark, there should be no more than 60 days between identification of an abnormal or suspicious mammogram screening test and diagnosis, and no more than 60 days between diagnosis and initiation of treatment [54]. Early initiation of treatment are highly encouraged because treatment delays of more than 90 days may result in poorer treatment out comes and overall survival for the patients [33,37,38,42,55-57]. After converting all treatment delay time intervals to days, 13 studies [21,30,33,35,37- 39,42,43,48,50,52,53] collaborated previous findings that delay in the initiation of first treatment significantly impact increased risk of overall quality of life and breast cancer related deaths in patients. In spite of the NBCCEDP recommendation and previous studies [55-58] indicating poorer survival among women receiving treatment more than 90 days after diagnosis, majority of the studies included in this review suggested no statistical difference in patients who initiated treatment early compared to those who waited long in terms of general quality of life, recurrence and or survival. In all a total of 17 studies [22- 29,31,32,34,40,41,44,45,49,51] reported this conclusion. The statistically non-significant delay time intervals reported for these studies ranged from as low as 21 days to over 180 days.

However, a critical examination of all17 study results taking into account the NBCCEDP benchmark for treatment delay revealed discrepancies in the results of these studies (17). For instance, ten [26,28,29,31,32,34,40,41,44,45] (59%) out of the 17 studies which concluded there was no statistically significant difference in recurrence of cancer and disease free survival quality of life between those who initiated early treatment and delayed it, compared delay intervals that were not long enough. These studies examined delay intervals (7 days verses90 day wait period) which were actually within the NBCCEDP recommended benchmark. Only seven [22-25,27,49,51] (41%) of the 17 studies investigated treatment delay that was outside the NBCCEDP standard treatment delay guideline (7 day verses over 175 day period). Taking this evidence into account, overall, this review suggests that early initiation of breast cancer treatment is associated with higher quality of life and general survival. In all twenty-three [21,26,28-35,37-45,48,50,52,53] (77%) out of 30 studies which clearly mentioned the treatment delay interval investigated supported this conclusion.

There are a number of limitations that are associated with this evidence based systematic review. First the search strategy was limited to English language publications and thus, some studies may have been overlooked which were indexed in other languages or which appeared in electronic databases that were not retrieved. As all the included studies were observational, it is possible that there is a risk of selection or self-report bias. The possibility of publication bias needs to be considered because studies which have null results tend not to be published.

The aim of this study was to examine the impact of treatment delay on breast cancer survivorship, as well as to determine appropriate length of time (delay) between breast cancer diagnosis and start of first treatment in order to improve general quality of life for survivors. Overall, this systematic review of the literature suggests that delaying the initiation of treatment or therapy for breast cancer more than 90 days after diagnosis has a detrimental effect on disease free and overall well-being of survivors. Although some studies reported that delaying initiation of treatment does not impact survival, a critical analysis of those studies revealed that the length of delay interval analyzed, fell within the benchmark of NBCCEDP standard. Subsequently, considering the evidence, it is clear that to enhance quality of life for breast cancer patients, it is important not to wait more than 90 days after diagnosis to begin treatment.

Dr. Williams was supported by the National Cancer Institute at NIH U54 CA155496.

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