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Revista da Associação Médica Brasileira

Print version ISSN 0104-4230On-line version ISSN 1806-9282

Rev. Assoc. Med. Bras. vol.61 no.5 São Paulo Sept./Oct. 2015

http://dx.doi.org/10.1590/1806-9282.61.05.411 

ORIGINAL ARTICLES

Adjuvant treatment delay in breast cancer patients

Atraso no tratamento adjuvante em pacientes com câncer de mama

Damila Cristina Trufelli1  * 

Leandro Luongo de Matos2 

Patricia Xavier Santi3 

Auro Del Giglio4 

1University/college education – Coordinator of the Oncology Service at the Hospital de Ensino Padre Anchieta, Santo André, SP, Brazil

1Habilitation (BR: Livre Docência) – Auxiliary Professor of Public Health (biostatistics) at Faculdade de Medicina do ABC, Santo André, SP, Brazil

3University/college education – Coordinator of the Oncology Service at Hospital Estadual Mario Covas, Santo André, SP, Brazil

4Habilitation (BR: Livre Docência) – Full Professor of Hematology and Oncology at Faculdade de Medicina do ABC, Santo André, SP, Brazil

Summary

Background:

to evaluate if time between surgery and the first adjuvant treatment (chemotherapy, radiotherapy or hormone therapy) in patients with breast cancer is a risk factor for lower overall survival (OS).

Method:

data from a five-year retrospective cohort study of all women diagnosed with invasive breast cancer at an academic oncology service were collected and analyzed.

Results:

three hundred forty-eight consecutive women were included. Time between surgery and the first adjuvant treatment was a risk factor for shorter overall survival (HR=1.3, 95CI 1.06-1.71, p=0.015), along with negative estrogen receptor, the presence of lymphovascular invasion and greater tumor size. A delay longer than 4 months between surgery and the first adjuvant treatment was also associated with shorter overall survival (cumulative survival of 80.9% for delays ≤ 4 months vs. 72.6% for delays > 4 months; p=0.041, log rank test).

Conclusion:

each month of delay between surgery and the first adjuvant treatment in women with invasive breast cancer increases the risk of death in 1.3-fold, and this effect is independent of all other well-established risk factors. Based on these results, we recommend further public strategies to decrease this interval.

Keywords: breast neoplasms; time-to-treatment; prognosis; survival; health care quality assurance

Resumo

Objetivo:

avaliar se o tempo da cirurgia até o primeiro tratamento adjuvante (quimioterapia, radioterapia ou hormonioterapia) em pacientes com câncer de mama é um fator de risco para pior sobrevivência global (SG).

Métodos:

estudo retrospectivo em que foram coletados dados dos prontuários de todas as mulheres com câncer de mama invasivo, diagnosticadas entre janeiro de 2005 e dezembro de 2010, atendidas consecutivamente em um serviço acadêmico de oncologia.

Resultados:

foram incluídas 348 mulheres, com mediana de tempo entre a cirurgia e o primeiro tratamento adjuvante de 2 meses. A sobrevivência global foi pior entre as mulheres com maior tempo entre a cirurgia e o primeiro tratamento adjuvante. Após análise multivariada, essa variável permaneceu como fator de risco independente para SG, juntamente com receptor de estrógeno negativo, presença de invasão angiolinfática e maior tamanho tumoral.

Conclusão:

o tempo entre a cirurgia e o primeiro tratamento adjuvante é um fator de risco independente para a sobrevivência global de mulheres com câncer de mama invasivo.

Palavras-chave: neoplasias da mama; tempo para o tratamento; prognóstico; sobrevivência; garantia da qualidade dos cuidados de saúde

Introduction

Breast cancer is the most prevalent neoplasm in women in Brazil and around the world.1In less-developed countries, breast cancer is frequently diagnosed in advanced stages, which leads to a decrease in overall survival rates.2There are other variables that also influence the prognosis of these patients, including age, lymph node status, hormone receptor status, histologic grade and tumor size.3-5In addition to these variables, some studies have shown that delays in the initiation of breast cancer treatment can also lead to a worse prognosis.2,6

However, this remains a controversial issue in the literature; while some studies define that a three-month or longer delay between diagnosis and treatment can decrease survival in up to 12%,7-9others argue that time until treatment does not influence the survival rates of women with breast cancer.10,11This conflict cannot be easily resolved, because a prospective study to evaluate this variable and its possible confounding factors would be unethical.12

Therefore, we conducted a retrospective cohort study to determine if an increased delay between surgery and the first adjuvant treatment is a risk factor for lower overall survival among women with invasive breast cancer.

Methods

This was a retrospective cohort review. After ethics committee approval, we obtained from the digital program used to attend patients in the ambulatories a list with all cases registered in medical records coded as C50, according to the "International Code of Diseases". These women presented consecutively at the Oncology Service of a public academic hospital (Hospital Estadual Mário Covas – Santo André – Brazil) between January 2005 and December 2010. Data were, then, extracted from the medical records of all female patients with epithelial line invasive breast cancer already submitted to curative surgery. Since the authors were granted a waiver of consent by the ethics committee, these women were not contacted at all.

Women with metastatic breast cancer at diagnosis, those who received neoadjuvant treatment, and those who did not undergo curative surgery or adjuvant treatment for any reason were excluded from the analysis. Patients who were missing any important medical record data (regarding their surgery or first adjuvant treatment) were also excluded.

For each case, the time between the date of definitive surgery and the date of the first adjuvant treatment was calculated. A cutoff for delay until treatment of 4 months or 120 days was established according to the guideline proposed by the American Society of Clinical Oncology (ASCO).13The overall survival was calculated as the time from diagnosis until death. Cases with follow-up loss were censored on the last date of contact.

Clinical and pathological data were also collected from original medical records, including age at diagnosis, histologic type (ductal vs. non-ductal), pathological stage according to the American Joint Committee on Cancer14(I / II vs. III), number of positive axillary lymph nodes, tumor size, angiolymphatic invasion, perineural invasion, histologic grade (I / II vs. III), estrogen receptor status, HER2 status and type of adjuvant treatment (chemotherapy vs. radiotherapy vs. hormone therapy).

For statistical analysis, the categorical data were expressed as absolute numbers and relative rates, and the continuous data were expressed as the means and standard deviation (SD) or median and range. A Cox regression model was used for the univariate and multivariate analyses (backward likelihood ratio method) to calculate the hazard ratio (HR) with a 95% confidence interval (95CI). For the multivariate analysis, only the variables with p<0.20 on univariate analysis were included. The Kaplan-Meier method was used to estimate the overall survival, and the log rank test was used to compare the survival curves. All analyses were performed using SPSS® 17.0 (SPSS® Inc.; Illinois, USA). A p-value of less than 5% was considered significant.

Results

We included 348 consecutive women, with a median age of 57 years and a median time between surgery and first adjuvant treatment of 2 months (range: 0-11 months). The majority had invasive ductal carcinoma (75%) and was classified as having early stage breast cancer (77%). The mean tumor size was 2.6 cm, and the mean number of positive axillary lymph nodes was 2.6. Estrogen receptor was positive in 78% of the patients, and only 10% of the patients were Her2-positive. The first adjuvant treatment was chemotherapy in 59%, radiotherapy in 28% and hormone therapy in 13% of the women. Nearly 10% of the women experienced delay in treatment longer than 4 months. A total of 23 deaths (6.6%) occurred, including 18 out of 312 patients (5.8%) in the group with delay between surgery and the first adjuvant treatment shorter than or equal to 4 months, and 5 out of 36 patients (13.9%) in the group with delay longer than 4 months. Other relevant characteristics and the corresponding percentages of cases are listed inTable 1.

TABLE 1 Distribution of included patients according to the studied characteristics 

Characteristic Cases
n %
Age* 57 years (27-92)
Time from surgery until 1st 2 months (0-11)
adjuvant treatment*
Delay to treatment
≤ 4 months 312 89.6%
> 4 months 36 10.4%
Adjuvant treatment (1 st )
Chemotherapy 205 58.9%
Radiotherapy 98 28.2%
Hormone therapy 45 12.9%
Histologic type
Ductal carcinoma 262 75.3%
Non-ductal carcinoma 86 27.7%
Pathological stage
I / II 268 77.0%
III 80 23.0%
Tumor size** 2.6 cm±1.7
Positive lymph nodes** 2.6±4.2
Angiolymphatic invasion
No 168 70.0%
Yes 72 30.0%
Perineural invasion
No 181 75.4%
Yes 59 24.6%
Histologic grade
Grade I/II 258 74.1%
Grade III 90 25.9%
Estrogen receptor
Positive 269 78.2%
Negative 75 21.8%
HER2 status
Negative 290 89.5%
Positive 34 10.5%

N = number of patients;

*Median (range);

**Mean ± standard deviation.

The characteristics associated with worse overall survival in the univariate analysis were younger age, pathological stage, tumor size, number of positive axillary lymph nodes, angiolymphatic invasion, perineural invasion, histologic grade, estrogen receptor status, type of adjuvant treatment and time between surgery and the first adjuvant treatment (Table 2).

TABLE 2 Univariate and multivariate analysis with delay as a continuous variable 

Characteristic Univariate analysis Multivariate analysis
HR 95CI p* HR 95CI p*
Time from surgery until first adjuvant treatment 1.13 0.96 – 1.33 0.146 1.35 1.06 – 1.71 0.015
1 st adjuvant treatment
Chemotherapy 1.00 1.00
Radiotherapy 0.35 0.12 – 1.04 0.059 0.39 0.04 – 4.10 0.369
Hormone therapy 0.19 0.03 – 1.44 0.108 1.43 0.13 – 15.6 0.927
Age 0.96 0.93 – 0.99 0.039 1.01 0.96 – 1.06 0.637
Histologic type
Ductal carcinoma 1.00 N/A
Non-ductal carcinoma 1.22 0.50 – 3.00 0.669
Pathological stage
I/II 1.00 1.00
III 5.69 1.83 – 17.7 0.030 1.76 0.27 – 11.3 0.552
Tumor size 1.34 1.13 – 1.59 0.001 1.36 1.06 – 1.75 0.016
Positive lymph nodes 1.09 1.01 – 1.18 0.022 0.91 0.78 – 1.05 0.208
Angiovascular invasion
No 1.00 1.00
Yes 5.37 1.96 – 14.7 0.001 4.85 1.21 – 19.4 0.025
Perineural invasion
No 1.00 1.00
Yes 1.96 0.74 – 5.17 0.172 0.83 1.17 – 4.13 0.818
Histologic grade
Grade I/II 1.00 1.00
Grade III 5.27 0.67 – 41.3 0.114 0.71 0.17 – 2.94 0.635
Estrogen receptor
Positive 1.00 1.00
Negative 3.20 1.38 – 7.40 0.007 3.58 1.01 – 12.7 0.049
HER2 status
Negative 1.00 N/A
Positive 1.53 0.45 – 5.18 0.493

HR = hazard ratio; 95CI = 95% confidence interval;

*= Cox regression; N/A: not applied.

The multivariate analysis then indicated that time between surgery and the first adjuvant treatment (continuous variable) is an independent risk factor (HR=1.35, 95CI 1.06 – 1.71, p=0.015, Cox regression) for worse overall survival, along with negative estrogen receptor, the presence of angiolymphatic invasion and larger tumor size (Table 2). When the delay to adjuvant treatment was categorized using the 4-month cutoff and multivariate analysis was once again performed, the results were similar (HR=5.34, 95CI 1.22 – 23.26, p=0.026, Cox regression).

The overall survival curves using ASCO's suggested cutoff also demonstrated that women with a delay between surgery and the first adjuvant treatment longer than 4 months had worse overall survival (72.6 vs. 80.9%; p=0.041, log rank test,Figure 1).

FIGURE 1 Kaplan-Meier curves showing that women with delay between surgery and the first adjuvant treatment longer than 4 months had a worse overall survival than those with this interval shorter than or equal to 4 months (72.6 vs. 80.9%; p=0.041, log rank test). 

Discussion

In the present study, delay longer than 4 months between surgery and the first adjuvant treatment was found to be related to worse overall survival in patients with invasive breast cancer. Moreover, when considering time interval as a continuous variable, the risk of death was increased 1.3-fold for each month of delay, independently of other well-established factors.

Since 2006, our group has been studying treatment delays in patients with breast cancer. In our first report, we analyzed the intervals between the first symptom and medical evaluation, biopsy and treatment, and found that the largest delay was that from the first abnormality noted by the patient and scheduling of the first medical appointment.15Then, we conducted another study to identify potential delays in the management of patients with breast cancer, including medical suspicion, diagnosis and treatment. In this report, we found that the longest delay occurred between mammographic suspicion and biopsy, and that such delay was significantly longer in patients with advanced-stage breast cancer. We also found that the median time between surgery and the first adjuvant treatment was 1 month (varying between 0.5 to nearly 21 months).2In this paper, our aim was to evaluate the delay between surgery and the first adjuvant treatment, based on a larger and more homogeneous group of consecutive patients with non-metastatic invasive breast cancer attended within a six-year period in a public hospital, and also to account for possible confounding factors.

The present study was conducted in a public hospital in a developing country where delays may be very long; we found a median interval of 2 months, a maximum delay of 11 months, and a rate of nearly 17% of patients who experienced an interval longer than 120 days (4 months). In an American study analyzing patients from the NCCN (National Comprehensive Cancer Network) database, Vandergrift et al.16determined a median interval of approximately 6 weeks (1.5 months) between surgery and first adjuvant treatment; they also reported that 13% of the patients had a delay of more than 120 days.

The ideal interval between surgery and first adjuvant treatment is not yet well established in the literature. Richards et al.17reported that delays longer than 12 weeks to first adjuvant treatment negatively affect survival of breast cancer patients. Lohrisch et al.18also found lower overall survival in patients with intervals longer than 90 days. In contrast, there are several studies that indicate otherwise, i.e., that delays in adjuvant treatment do not influence survival.9,12,19,20This controversy can be due to confounding factors, such as different patients selected and different cutoffs to establish an interval as a delay. In a recent report, Gagliato et al.21showed that overall survival was influenced by adjuvant treatment delays longer than 60 days only in patients with known factors for worse prognosis, such as triple negative breast cancer or trastuzumab-treated Her2-positive breast cancer. A guideline from ASCO suggests that the duration between diagnosis and treatment should not exceed 120 days; they consider this a "reasonable estimate of the time need to deliver the preceding components of therapy that would not jeopardize outcome".13Because this reasonable time estimate was given by a panel of specialists and was based on the current literature, this was the cutoff established to categorize the delay of treatment in the present study.

The limitations of this study were inherent to a retrospective design: missing data, loss of follow-up, different adjuvant treatments over time, as well as different treating physicians. Also, demographic data were lacking in medical records which can somehow bias our results, although this was a very homogeneous cohort once all patients were from underprivileged areas, with no medical insurance. Regarding its strengths, the most important aspect of this study was its use of delay as a continuous variable (it was the first study to do this, to our knowledge), which was adjusted for possible confounding factors; this method produced a more precise and clinically relevant result, i.e., that each month of delay progressively worsens overall survival.

Conclusion

This study showed that greater time intervals between surgery and the first adjuvant treatment lead to a worse prognosis among women with invasive breast cancer. These findings cannot be confirmed in a prospective trial, and observational studies are the most powerful evidence. Based on these results, we recommend further strategies to decrease the interval between surgery and the first adjuvant treatment.

Study conducted at Oncology Department, Faculdade de Medicina do ABC, Santo André, SP, Brazil

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Received: December 03, 2014; Accepted: May 05, 2015

*Correspondence: Address: Av. Principe de Gales, 821 Santo André, SP – Brazil Postal code: 09060-650damilatrufelli@yahoo.com.br

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