12 February 2008
Improvements in breast cancer survival over
time, related to adjuvant treatment and node
status.
AK Imkampe*a, T Bates
Breast Unit, William Harvey Hospital, Ashford, Kent TN24 0LZ, UK
*Corresponding author. Breast Unit, William Harvey Hospital, Ashford, Kent TN24
0LZ, UK.
Tel: 0044-1233-633331 Fax: 0044-1233-616019
e-mail address: a.imkampe@gmx.de
a
present address: 89 Hunter Road, Ashford, Kent, TN24 0RT, UK
Summary
Background:
There has been an increase in the use and effectiveness of adjuvant treatment for
operable breast cancer and the aim of this study was to examine whether this has
resulted in improved survival for all prognostic groups.
Methods:
A retrospective study of 1517 patients with invasive breast cancer treated between
1980 and 2002 was carried out. The use of adjuvant treatment was compared between
two time periods in patients divided by nodal status and survival was calculated by
Kaplan-Meier Life Table Analysis. Independent predictors for Recurrence Free
Survival (RFS) were determined by Cox regression analysis.
Results:
The use of adjuvant therapy increased for all prognostic groups. On multivariate
analysis the use of radiotherapy and endocrine therapy was positively associated with
RFS which was significant in the second time period. Outcome in node positive
patients improved: Five-year RFS from 59% to 76%, p < 0.01 and Breast Cancer
Specific Survival (BCSS) from 70% to 83%, p < 0.01.
However, there was no
survival improvement in the larger group of node negative patients; BCSS 93% versus
95%, p = 0.99. Within the node negative group, patients with tumours ≥ 2cm had an
improved RFS from 80% to 88%, p < 0.02.
Conclusion:
The increased use of adjuvant therapy was associated with an improved outcome in
node positive patients. For node negative patients with good prognostic features the
evidence of benefit was marginal.
Keywords: Breast cancer survival, lymph node status, adjuvant treatment
2
Introduction
Breast cancer survival is improving [1] and studies have shown that use of adjuvant
treatment is one of the main reasons. Chemotherapeutic drugs have become
increasingly effective over the past decades and have produced a significant reduction
in breast cancer mortality rates [2, 3]. This, in turn, has led to a general rise in the use
of systemic adjuvant therapies [4]. But, depending on stage of the disease and tumour
characteristics, there has been debate about the indications for and absolute benefit
from adjuvant treatment in different prognostic groups.
The present study examined two groups of patients, those who were node negative
and those who were node positive at the time of diagnosis. The aim was to compare
the use of adjuvant therapy between two time periods and to relate changes to
differences in breast cancer recurrence and survival.
3
Methods
Patient selection
The study was a review of breast cancer patients diagnosed between 1980 and 2002.
Patient details were collected prospectively on an actively managed database and the
follow-up is near-complete. Only patients with operable breast cancer were included
in the study and those who had no node status recorded, solely in situ carcinoma or
bilateral disease were excluded.
Tumour characteristics and adjuvant treatment
The remaining 1517 patients were divided into two groups according to the nodal
status at the time of diagnosis. The following data were compared for those with
positive or negative nodes, between two time periods (1980 – 1995 and 1996 – 2002):
median age, tumour type, tumour size, tumour grade, type of operation and the use of
adjuvant chemotherapy, endocrine therapy and radiotherapy.
The adjuvant chemotherapy regime in patients diagnosed during the first time period
consisted of combination therapy with cyclophosphamide, methotrexate and 5fluorouracil (CMF). During the year of 1996 this was switched to the routine use of
doxorubicin and cyclophosphamide (AC) when studies had confirmed the superiority
of anthracycline combinations.
Statistical analysis
The results were analysed using the chi-square and Mann-Whitney U test.
Time to first recurrence and length of survival were determined from the date of
diagnosis until the date of recurrence or death or the last clinic date if no event had
occurred. Data were included until July 2007. Median follow up time was 140 months
4
for patients diagnosed between 1980 and 1995 and 71 months for patients diagnosed
between 1996 and 2002. The Kaplan-Meier method was used to calculate Recurrence
Free Survival (RFS), Breast Cancer Specific Survival (BCSS) and Overall Survival
(OS) and survival curves were compared using the log-rank test. Independent
predictors for RFS were determined with Cox regression analysis. Differences were
considered to be statistically significant at p < 0.05.
5
Results
Overall survival improvement
There was a significant improvement in RFS and BCSS when comparing the two time
periods 1980 – 1995 and 1996 – 2002. RFS increased from 76% to 85% (HR 1.63,
95% CI 1.32 – 2.01, p < 0.01), and BCSS from 84% to 90% (HR 1.4, 95% CI 1.1 –
1.82, p < 0.01). Use of adjuvant therapy was significantly increased during the latter
period, in both node positive and node negative patients including prognostic
subgroups (Table 1). In Cox regression analysis the use of adjuvant radiotherapy and
endocrine therapy were independent predictors for RFS irrespective of time period. In
separate analyses use of radio- and endocrine treatment were significant in the second
but not in the earlier time period (Table 2).
Survival in node positive disease
There was a higher proportion of infiltrating ductal carcinomas diagnosed during the
earlier time period (88% versus 78%, p < 0.01, Table 3) but in general tumour
characteristics for node positive patients were comparable between the two groups.
Five-year RFS improved form 59% in the first to 76% in the second period (HR 1.92,
95% CI 1.46 – 2.53, p < 0.01), Figure 1. Local RFS alone increased from 84% to 95%
(HR 2.97, 95% CI 1.74 – 5.25, p < 0.01). BCSS improved from 70% to 83% (HR
1.67, 95% CI 1.23 – 2.28, p < 0.01) and OS from 68% to 79% (HR 1.39, 95% CI 1.06
– 1.83, p = 0.02).
Survival in node negative disease
Node negative patients diagnosed during the second time period had on average
smaller sized tumours (Table 3). BCSS and OS were similar in both time periods,
6
BCSS 93% versus 95% (HR 1.0, 95% CI 0.65 – 1.53, p = 0.99) and OS 89% in both
time periods (HR 0.85, 95% CI 0.64 – 1.15, p = 0.3).
Subgroup analysis of node negative patients by tumour size showed a significant
difference in RFS for patients with tumours ≥ 2cm. Five-year RFS was 80% for
patients diagnosed during the first compared to 88% for patients diagnosed during the
second time period (HR 1.72, 95% CI 1.11 – 2.7, p = 0.02), Figure 2. There was no
difference in RFS for patients with tumours < 2cm in size (93% versus 91%, HR 0.82,
95% CI 0.47 – 1.41, p = 0.46), Figure 3, and no difference in local RFS for this group
(97% in both time periods, HR 1.07, 95% CI 0.44 – 2.63, p = 0.88). Subgroup
analysis by tumour grade did not show any statistical difference in RFS for patients
with Grade I tumours (95% in both periods, HR 1.29, 95% CI 0.58 – 2.98, p = 0.53)
Grade II tumours (86% versus 91%, HR 1.23, 95% CI 0.73 – 2.07, p = 0.44) or Grade
III tumours (82% versus 87%, HR 1.29, 95% CI 0.88 – 1.91, p = 0.19).
7
Discussion
Adjuvant treatment and survival in node positive patients
The present study shows that breast cancer recurrence rates and survival have
significantly improved over time, correlating with a general increase in the use of
adjuvant treatment in all prognostic groups and a switch from CMF to AC
chemotherapy regimens. The importance of the increasing use of adjuvant
radiotherapy and endocrine therapy on RFS in the second time period was confirmed
in a multivariate analysis. The increased use of adjuvant chemotherapy did not show a
significant improvement in outcome although there was a switch from CMF to
anthracycline based therapy in 1966. This may explained by the limited number of
patients in the present study but there may also have been unknown confounding
factors not adjusted for in the Cox analysis. Hormone receptor status for example was
not routinely determined during the first time period.
The assessment of oestrogen-receptor (ER) status during the second time period
would have enabled more targeted treatment with hormone medication thus
explaining the survival advantage for patients diagnosed during this period.
Subgroup analysis showed that survival advantages were maximal for node positive
breast cancer patients and the beneficial effect of adjuvant treatment on this patient
group has been reported in many studies [5-8].
Controversy in node negative patients
However, the majority of patients who are diagnosed with breast cancer are node
negative (62%) and these patients generally have a good prognosis. Within the node
negative group there were more patients with small sized invasive cancers in the
8
second time period and this may be a reflection of the increasing number of patients
diagnosed in screening programmes.
There has been controversy about the appropriateness of adjuvant therapy in node
negative patients and a number of studies have looked at the effectiveness of adjuvant
radio-, chemo- or hormonal therapy in patients with good prognostic features. Some
authors suggest that there may be subgroups of patients for whom adjuvant treatment
is of no additional benefit [9-11] but Fisher et al [12] looked at survival in node
negative patients with small tumours of 1cm or less and found that hormonal therapy
and chemotherapy significantly improved RFS and BCSS in ER positive patients. A
later report from the same study group showed that the addition of adjuvant
chemotherapy to tamoxifen in ER positive patients significantly benefited pre- and
postmenopausal node negative breast cancer patients, although the response to
additional chemotherapy decreased in older women [13]. In the present study
documentation of ER status in the earlier time period was insufficient for analysis but
it is unlikely that the overall levels and distribution of hormone receptors was
substantially different in the two periods.
The EBCTC group [2] confirmed in a meta-analysis that endocrine treatment
improves survival in ER positive disease and that chemotherapy is effective in all
patients regardless of their nodal status or ER status and substantially reduces breast
cancer mortality at 15 years. Radiotherapy has similarly been shown to reduce local
recurrences in both node positive and node negative patients and to potentially
produce improved overall survival at 15 years [3]. In the present study patients who
had radiotherapy or a mastectomy had an improved (?local) RFS, as expected (Table
2).
9
Adjuvant treatment and survival in node negative patients by subgroups
The length of follow up is known to be important in breast cancer and in patients
with good prognostic features recurrences may occur many years after the initial
diagnosis [14, 15]. Although studies have shown improved outcome for node negative
patients in relation to adjuvant treatment, the absolute benefits are small and improved
recurrence rates may only become apparent after 10 or more.
The results of the current study correlate with these reports in the literature and there
was no significant difference in survival of node negative patients between the two
time periods after a median follow up of over 6 years in spite of the increased use of
adjuvant treatment.
Subgroup analysis by tumour size showed that RFS had improved partially in patients
with large tumours at diagnosis but not in patients with small sized tumours of less
than 2cm. There was a possible trend towards improved prognosis in patients with
higher grade tumours but this did not reach statistical significance.
In patients with good prognostic features (Grade I, ≤ 1cm), who have disease free
survival rates reported between 88 - 95% after 9 - 10 years without systemic adjuvant
treatment [16-18], the decision for appropriate adjuvant management may be
challenging and the potential side effects have to be weighed against the expected
benefit in the individual patient.
Conclusion:
Adjuvant treatment is effective in reducing recurrence and mortality in node positive
breast cancer patients and in node negative patients with larger tumours. The outcome
in node negative patients with low grade and small sized tumours is very good and it
is difficult to improve on an already good prognosis in this patient group.
10
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