Introduction:
With increase in breast cancer incidence, it has become the major malignancy and the most
frequent cause of cancer death in Iranian women.(1,2) The specific characteristics of breast cancer in Iran include one
decade younger patients than their western counterparts, advanced cases at presentation and increasing trend of mortality.(2-4)
The interval between diagnosis and beginning of treatment was reported variously.(5,6)
Clinicopathologic characteristics of patients at diagnostic time and treatment pathway in healthcare system of each country
are affected by the interval to treatment.(7,8)
Median time from provider referral to first definitive treatment was determined 27 days for
urgent referrals and 35 days for non–urgent in England.(5) In Canada, the overall median waiting time between the first
diagnostic procedure and surgical treatment was reported to be 34 days.(6) Two studies have reported treatment interval to range from less than two weeks in a national
early cancer detection programme, to more than one month in a population- based study on African American women.(9,10)
The association between provider delay and survival has
been paradoxical, (11) although,
there is an evidence implied that treatment delay up to two weeks after biopsy has not led to unfavorable effects on
patients' survival.(12)
One study from Great Britain showed that provider delay of longer than 90 days from family
physician referral to treatment did not influence survival. This study reported an association between shorter delays and
poorer survival resulted from more rapid treatment for advanced disease cases.(13) Another study showed that treatment delay
time longer than six weeks had an adverse impact on survival.(14)
A few studies have included patient delay in Iran, but they did not focus on provider delay.(15,16) There is no data from the estimation of treatment delay in Iranian women with breast cancer. The aim of this study was
to assess the interval between definitive diagnosis and treatment in Iranian breast cancer patients and to examine the
impact of it on patient's survival.
Methods:
In this historical cohort study, breast cancer patients who were diagnosed and treated in
both Qaem and Omid university hospitals of Mashhad were evaluated between 2003 and 2013. The follow-up protocol in every
visit included history taking, eliciting of symptoms and physical examination which were done every 3 months in the first
year, every 6 months between second and fifth year after completing treatment, and then yearly. Additionally, mammography
and gynecologic examination were recommended yearly for women. Patients with breast cancer were analyzed for the effect of
time intervals between biopsy to first treatment on survival. The interval to treatment was defined as the time between date
of pathological diagnosis, usually via open biopsy, and the date of initial therapy, either surgical or systemic.
In statistical analysis, overall survival time was calculated as the interval from the date of diagnosis to the last clinical
control or death; disease free survival time was calculated as the interval between the date of diagnosis to the metastasis
and/or recurrence or last clinical contact. Patients were excluded if exact date of biopsy and first treatment were unknown.
Clinicopathologic data including age, stage of disease, immunohistochemical status were extracted from patients' medical
records. Clinical staging of the tumor followed the TNM Classification of Malignant Tumors.(17) All patients’
survival was followed from definitive diagnosis to March 2011. Kaplan-Meier survival curves were also drawn. The log-rank
test was used to analyze the differences between groups. Multivariate analysis was undertaken using the stepwise Cox
regression model with survival from diagnosis as the outcome measure. The data were analyzed by SPSS software version 11.5
(SPSS Inc., Chicago, IL). P values < 0.05 were considered significant category. This study was approved by Ethics
Committee affiliated to the Deputy of Research, Mashhad University of medical sciences, Iran.(Ethic No: 900255).
Results:
Of the 895 medical records, data of 452 patients matched our inclusion criteria to enter the
present study. Table 1 lists the major demographic characteristics of samples.
| Table 1: Clinicopathologic characteristics of study population |
Age at presentation(y) |
N (%) |
<50 |
287 (63.5) |
>50 |
165 (36.5)
|
ER |
|
+ |
186(41.2) |
- |
158(35.0) |
Unknown |
108(23.9) |
PR |
|
+ |
177(39.2) |
- |
166(36.7) |
Unknown |
109(24.1)
|
Stage |
|
I |
37(8.1) |
II |
207 (45.8) |
III |
169 (37.4) |
IV |
16 (3.5) |
Unknown |
23(5.1) |
| |
|
Nodes involved |
|
0 |
142 (31.4) |
1-3 |
133 (29.4) |
4-9 |
90 (19.9) |
≥ 10 |
34 (7.5) |
Unknown |
53 (11.7) |
For patients treated during the study period, the median and mean of interval to treatment
were 15 and 25.98±42.31 SD days, respectively. The impact of the delay was examined upon overall and disease free survival.
The patients were divided into 2 groups based on interval to treatment: ≤15 days and >15 days. There was no association
between the interval to treatment after a diagnosis of breast cancer and overall survival (P Value= 0.676) or disease free
survival (P Value= 0.362).
Evaluation of overall and disease free survival were performed on stage of presentation for
patients in the study. Survival curves revealed worse overall survivals with higher stage at presentation (Fig. 1).
In univariate analysis, the effects of age, tumor stage, number of involved axillary lymph nodes, and receptor status on
overall survival and disease free survival were evaluated. Only tumor stage was significant factor for overall survival
(Table 2). Compared with the stage IV, the stage II and III were significantly associated with increased overall survival
in multivariable Cox regression analysis (Table 3).
 |
 |
Fig. 1: (a) Evaluation of overall survival for patients according to stage at presentation. |
(b) Evaluation of disease free survival for patients according to stage at presentation. |
| Table 2: Univariate analysis of risk factors for overall survival |
Variable |
HR |
95% CI |
P value |
Age |
1.46 |
0.88–2.42 |
0.142 |
Tumor stage |
1.71 |
1.12–2.62 |
0.010 |
Number of involved axillary lymph nodes |
|
|
|
<3 |
1.15 |
0.51-2.61 |
0.724 |
>3 |
0.99 |
0.35-2.80 |
0.987 |
ER/PR status |
|
|
|
ER/PR positive |
0.86 |
0.20- 3.63 |
0.848 |
ER/PR negative |
1.45 |
0.31- 6.73 |
0.632 |
| Table 3: Multivariate analysis of tumor stage for overall survival |
Variable |
HR |
95% CI |
P value |
Tumor stage |
|
|
|
Stage IV |
1 |
reference |
|
Stage I |
0.27 |
0.04-1.66 |
0.160 |
Stage II |
0.14 |
0.04- 0.49 |
0.002 |
Stage III |
0.22 |
0.08- 0.64 |
0.005 |
Discussion
The study findings indicate that median time to treatment was 15 days. This finding is
comparable with other studies. Caplan et al found this time was 10 days and old age women experienced shorter treatment
intervals.(9) In the study, more than three quarters of age composition was formed with women over 50 years whereas it was
one-third in our study. It seems that this difference is related to the characteristics of breast cancer incidence in the
lower age in Iran. Spurgeon et al reported that waiting time for urgent and non-urgent cases was 27 and 35 days, respectively.(5)
Another research found that the median time from receipt of confirmed diagnosis to treatment initiation was 0.2 months
for early stage and 0.3 months for late stage disease.(7) These findings are consistent with our result, where approximately
85% of women had advanced disease. However, in Spurgeon's study, the waiting time was considered from general practitioner
referral, not pathologic diagnosis.
In the present study, we found no statistically significant difference in survival according
to delay. On the contrary, Richards et al concluded patients with delays 12 or more weeks experienced worse 10 and 20 years
survival compared with of those with delays less than 12 weeks.(18) However, delays in the study were considered as delay in
presentation and total delay, not treatment delay. This difference may adversely influence on survival because longer duration
of symptoms is related to a more advanced stage of cancer at diagnosis.(19) Another study from the United States evaluated the
effect of treatment delay on survival in women with metastatic breast cancer. The results of the study showed that the median
treatment interval delay was 13 days and treatment waiting time over 12 weeks was related to adverse survival.(20)
One explanation for such a difference might relate to the selection of women with metastatic cancer in the research,
while in our study nearly 4% of women had a metastatic disease.
The findings of our study related to survival are consistent with the study of Eastman et al.
They concluded that interval to treatment did not impact overall survival.(21) However, authors were examined outcome of
delays in time to treatment in triple negative breast cancer. Also, results in Brazda et al's research which was calculated
survival analysis at 5 years based on the time between date of pathological diagnosis and the date of initial therapy had
similar findings with the previous study.(22)
Our results showed that shorter interval to treatment in stage II and III compared with stage
IV had better survival. The findings are comparable with a systematic review supporting the hypothesis that patients with
longer total delay in treatment had worse survival due to more advanced disease at presentation.(23) However, the association
was explored for longer total delay but our findings found the same survival effect for the most advanced stage on shorter
treatment delay.
The major limitations of our study are the retrospective nature of the data, and small
sample size from two restricted centers. Due to the retrospective nature of this study, data were obtained from reviewing the
medical records of each patient, therefore a number of factors, especially intrinsic biomarkers of tumor cells, were not
accessible. The factors may affect overall and disease free survival. Additionally, the small samples, especially in the group
experiencing waiting treatment more than 15 days, limited the statistical power and explored small impacts on survival.
Furthermore, the data gathering from two university hospitals produce some restrictions in the generalizability of the results
to national populations of women with breast cancer.
In conclusion, delay of treatment of up to two weeks has no adverse effect on survival. The lack
of association between treatment delay and survival should not be considered that long delays can be preferred. Indeed, it
seems that patients diagnosed with early stage could have a waiting time longer than two weeks. The interval can provide
an opportunity for patients to decide the most appropriate treatment according to physicians’ information, and adapt to
psychological stress of cancer diagnosis.
Acknowledgments:
We are grateful to the physicians and staffs of the Qaem and Omid Hospitals of Mashhad
University of Medical Sciences for their assistance with researchers in data gathering. Additionally, we thank Mr Mehrab
Sayadi for data analysis and interpretation.
Conflict of interest:
All authors reported no conflict of interest.
References:
- GLOBOCAN: Estimated Cancer Incidence, Mortality and Prevalence Worldwide in 2015. Available at:
http://globocan.iarc.fr/Pages/burden_sel.aspx
- Mousavi SM, Montazeri A, Mohagheghi MA, et al. Breast Cancer in Iran: An Epidemiological Review.
Breast J. 2007;13(4):383-91.
- Harirchi I, Karbakhsh M, Kashefi A, et al. Breast cancer in Iran: results of a multi-center study.
Asian Pacific J Cancer Prev. 2004;5(1):24-7.
- Taghavi A, Fazeli Z, Vahedi M, et al. Increased trend of breast cancer mortality in Iran.
Asian Pacific J Cancer Prev. 2012;13:367-70.
- Spurgeon P, Barwell F, Kerr D. Waiting times for cancer patients in England after general practitioners' referrals: retrospective national survey.
BMJ. 2000;320:839-9.
- Mayo NE, Scott SC, Shen N, et al. Waiting time for breast cancer surgery in Quebec.
Can Med Assoc J. 2001;164(8):1133-38.
- Bright K, Barghash M, Donach M, et al. The role of health system factors in delaying final diagnosis and treatment of breast cancer in Mexico City, Mexico.
The Breast. 2011;20:S54eS9.
- Williams DL, Tortu S, Thomson J. Factors associated with delays to diagnosis and treatment of breast cancer in women in a Louisiana urban safety net hospital.
Women Health. 2010;50(8):705-18.
- Caplan LS, May DS, Richardson LC. Time to diagnosis and treatment of breast cancer: results from the National Breast and Cervical Cancer Early Detection Program, 1991-1995.
Am J Public Health. 2000 Jan;90(1):130-4.
- Gorin SS, Heck JE, Cheng B, et al. Delays in breast cancer diagnosis and treatment by racial/ethnic group.
Arch Intern Med. 2006 Nov 13;166(20):2244-52.
- Unger-Saldana K, Infante-Castaneda C. Delay of medical care for symptomatic breast cancer: a literature review.
Salud Publica Mex. 2009;51 Suppl 2:s270-85.
- DeVita VT, Lawrence TS, Rosenberg SA. Cancer: Principles and Practice of Oncology 8th ed. Philadelphia: Lippincott Williams and Wilkins; 2008.
- Sainsbury JR, Johnston C, Haward B. Effect on survival of delays in referral of patients with breast-cancer symptoms: a retrospective analysis.
The Lancet. 1999;353(9159):1132-5.
- Smith Ec ZAA-CH. Delay in surgical treatment and survival after breast cancer diagnosis in young women by race/ethnicity.
JAMA Surg. [doi: 10.1001/jamasurg.2013.1680]. 2013:1-8.
- Harirchi I, Ghaemmaghami F, Karbakhsh M, et al. Patient delay in women presenting with advanced breast cancer: an Iranian study.
Public Health. 2005 Oct;119(10):885-91.
- Montazeri A, Ebrahimi M, Mehrdad N, et al. Delayed presentation in breast cancer: a study in Iranian women.
BMC Womens Health. 2003 Jul 7;3(1):4.
- Greene FL PD, Fleming ID, et al (Eds). AJCC (American Joint Committee on Cancer). Cancer Staging Manual. 6 ed. New York Springer-Verlag; 2002.
- Richards MA, Smith P, Ramirez AJ, et al. The influence on survival of delay in the presentation and treatment of symptomatic breast cancer.
Br J Cancer. 1999 Feb;79(5-6):858-64.
- Hiranyatheb P, Kongdan Y, Lertsithichai P. Effects of waiting time and biopsy methods on invasive breast cancer survival.
The Thai journal of Surgery. 2009;30: 58-65.
- Jung SY, Sereika SM, Linkov F, et al. The effect of delays in treatment for breast cancer metastasis on survival.
Breast Cancer Res. Treat. 2011;130(3):953-64.
- Eastman A, Tammaro Y, Moldrem A, et al. Outcomes of delays in time to treatment in triple negative breast cancer.
Ann Surg Oncol. 2013;20(6): 1880-85.
- Brazda A, Estroff J, Euhus D, et al. Delays in time to treatment and survival impact in breast cancer.
Ann Surg Oncol. 2010;17(3):291-6.
- Richards MA, Westcombe AM, Love SB, et al. Influence of delay on survival in patients with breast cancer: a systematic review.
Lancet. 1999 Apr 3;353(9159):1119-26.
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