Key words
breast carcinoma - breast malignancy - metastasis
Schlüsselwörter
Mammakarzinom - Mammamalignom - Metastasierung
Introduction
Every year, approximately 72 000 new invasive and non invasive breast carcinomas are
diagnosed in Germany. Women aged 65 to 69 are in first place, with a total of 409.6
new diagnoses per 100 000 in 2007–2008 (age-specific disease rate). The group aged
70–74 comes in second, with 333.8 new diagnoses per 100 000, closely followed by the
group of women aged 75–79 with 325.3 new diagnoses per 100 000. Women aged 80–85 had
an age-specific disease rate of 348.6/100 000, and women aged 85 and above a rate
of
361.5/100 000 per year [1]. This means that just over half
of all breast cancer patients are 65 or above and around one third are older than
70
years of age [2], [3].
The number of women aged 65 and above in Germany is expected to double in the next
20
years (NCCN) as the generation of baby boomers becomes older (in Germany, persons
born between 1955 and 1965 are defined by statisticians as part of the baby-boom
generation). This is important, because women over 70 are currently
under-represented in the adjuvant clinical trials carried out to date, meaning that
therapy decisions are often taken without being based on sufficient reliable data
[4], [5], [6], [7]. It is important to note
that certain factors may also be significant in addition to purely chronological
age. Such factors include physiological and functional reserve, co-morbidities,
cognitive function, the availability of social support and individual life
expectancy [5], [7]. For
example, 17 % of the group aged between 65 and 74 had 6 co-morbidities. For the
group of women over 75 this figure had increased to 27 %.
The preferred therapeutic management of women with breast cancer aged over 65
corresponds to the concepts formulated for younger patients and complies with the
concepts outlined in the S3 Guidelines [8] and the therapy
recommendations formulated by AGO [9]. However, as was
recently reported by Hancke et al., only some of the elderly patients in Germany
receive therapy which complies with the guidelines [10].
Another recent study by Sautter-Bihl et al. reviewed the literature on “elderly
patients and breast cancer” and came to the conclusion that “female patients with
a
life expectancy of more than 5 years and not very extensive co-morbidities should
receive adjuvant chemotherapy, trastuzumab and radiation in accordance with current
standards, while frail elderly women should receive reduced or no adjuvant standard
therapy” [11].
To investigate the current therapeutic management in Germany of women with breast
cancer over 70 years of age, a survey of the clinics of the German Breast Group
(GBG) was carried out.
Method
An online survey was done of 599 physicians registered in the database of the GBG
as
principal investigators. The physicians were contacted once by e-mail; there was no
recall system.
The main focus when the case-related 12-item questionnaire was developed was on the
clinical relevance of individual questions ([Table 1]).
The questionnaire consisted of 11 multiple-choice questions and one open-ended
question where only one answer was permitted. The questions related to the
therapeutic management selected for a patient aged between 70 and 80 with an ECOG
performance status of 1, certain stable pre-existing conditions which were managed
with medication and did not constitute a contraindication to specific cytostatic
drugs. For the purposes of the study, it was assumed that chemotherapy in different
settings (neoadjuvant, adjuvant, palliative) was indicated; the indication for
chemotherapy itself was not an issue.
Table 1 Questionnaire and characteristics of
participants.
|
Questions
|
Number
|
Percentage
|
|
Do you work in:
|
|
A tertiary care centre for oncology
|
66
|
42.0
|
|
A general hospital
|
22
|
14.0
|
|
A doctorʼs surgery
|
40
|
25.5
|
|
A university clinic
|
21
|
13.4
|
|
Unknown
|
8
|
5.1
|
|
In which capacity?
|
|
Resident physician
|
3
|
1.9
|
|
Chief physician/head of department
|
63
|
40.1
|
|
Specialist
|
26
|
16.6
|
|
Senior physician
|
52
|
33.1
|
|
Unknown
|
13
|
8.3
|
|
You have completed your medical training as, or are training
to be:
|
|
A gynaecologist
|
120
|
76.4
|
|
A medical oncologist also trained as an internist
|
24
|
15.3
|
|
Unknown
|
13
|
8.3
|
|
How many cases with breast cancer (primary diagnosis) did you
treat last year in your surgery/clinic?
|
|
0–30
|
1
|
0.6
|
|
30–60
|
15
|
9.6
|
|
60–100
|
21
|
13.4
|
|
100–200
|
59
|
37.6
|
|
200–300
|
30
|
19.1
|
|
300–400
|
13
|
8.3
|
|
> 500
|
9
|
5.7
|
|
How many cases of metastatic breast cancer (new patients) were
treated last year for the first time in your
surgery/clinic?
|
|
0–10
|
5
|
3.2
|
|
10–20
|
45
|
28.7
|
|
30–40
|
46
|
29.3
|
|
40–50
|
19
|
12.1
|
|
50–100
|
20
|
12.7
|
|
100–200
|
10
|
6.4
|
The time for response was set at 4 weeks; analysis was done after the data had been
anonymised. No comparison between participants and nonparticipants was done.
Descriptive analysis was done using IBM SPSS Statistics 20 [12] and Excel 2010 [13]; the results were
shown using vertical bar charts and pie charts.
Results
In all, 159 physicians (26.5 %) out of a total of 599 physicians registered as
principal investigators responded; 137 (22.9 %) answered all questions, a further
22
(3.7 %) only answered some of the questions. The characteristics of participating
physicians are given in [Table 1].
Analysis of the responses to the question of how many cases with primary breast
cancer were treated annually in the physicianʼs institution showed that most
facilities (37.6 %) treated between 100 and 200 cases of primary breast cancer every
year, 19.1 % of investigated institutions treated 200–300 cases annually, 13.4 % of
institutions treated 60–100 breast cancers per year, 8.3 % of clinics were breast
centres with between 300–400 primary cases annually, and 5.7 % of institutions
treated more than 500 primary cases over a period of 12 months. With regard to new
patients with metastatic breast cancer, one third of participating physicians
respectively reported seeing 30–40 and 10–20 patients per year (29.3 and 28.7 %,
respectively). 12.7 % of respondents diagnosed metastatic breast cancer in around
50–100 patients annually and 6.4 % of participants treated 100–200 patients with a
diagnosis of metastatic breast cancer every year ([Table
1]).
If neoadjuvant chemotherapy was indicated in a patient (this presupposed that
chemotherapy was indicated in this patient based on tumour metrics, lymph node
status, negative HR status or positive HER2/neu status), just under 40 % of all
respondents stated their preference for sequential anthracycline-/taxane-based
therapy (4 × EC followed by 12 × paclitaxel weekly) fest. To treat such cases 15 %
of physicians would prescribe a regimen of 4 × EC followed by 4 × docetaxel, and 7 %
would opt for 3 × FEC followed by 3 × docetaxel. Another 7 % of physicians would
recommend 4 × docetaxel/cyclophosphamide (DC). Around 11 % of physicians chose the
category “other” ([Fig. 1]).
Fig. 1 Question: “Which neoadjuvant regimen are you most likely to use in
this situation?” EC – epirubicin, cyclophosphamide; DC – docetaxel,
cyclophosphamide; FEC – fluorouracil, epirubicin, cyclophosphamide; TAC –
docetaxel, adriamycin, cyclophosphamide.
In the event that adjuvant chemotherapy was prescribed in the same patient, the most
commonly chosen combination (39.5 %) was 4 × EC followed by 12 × paclitaxel weekly.
Only 2.5 % of physicians opted for a regimen consisting of 4 × EC followed by 4 ×
docetaxel, while 14.6 % of physicians recommended 3 × FEC followed by 3 × docetaxel,
9.6 % would prescribe 4 × DC, and only 3.2 % of physicians opted for 4 × EC ([Fig. 2]).
Fig. 2 Question: “Imagine you are treating the same patient but this time
adjuvant chemotherapy is indicated. Which regimen would you be most likely to
prescribe in this situation?”
In the next question the clinical situation was altered such that it reflected a
situation whereby the patient presented with primary metastatic disease. Once again,
it was assumed that chemotherapy was indicated. 36.3 % of physicians recommended
primary taxane monochemotherapy and just under 30 % would recommend one of the
specified monochemotherapies in combination with bevacizumab (participants were
given a choice between the following chemotherapeutic substances: taxane,
anthracyclines, capecitabine, vinorelbine) ([Fig. 3]).
Fig. 3 Question: “Imagine you are treating the same patient except that
evidence is found at staging of visceral metastases (e.g. liver metastasis;
primary metastatic situation). Which regimen would you propose as your
first-line option?”
In the event that metastasis was first found in the same patient after a disease-free
interval of 2.5 years and chemotherapy was considered necessary, 42.7 % of
respondents opted for a taxane-based monotherapy if the patient had previously been
treated with anthracyclines in a neoadjuvant/adjuvant setting ([Fig. 4]). In contrast, 2.5 % of physicians preferred a taxane-based
approach if an anthracycline and taxane-based therapy had been previously
administered in a non-metastatic situation; capecitabine and vinorelbine therapy
were the substances of choice used for first-line therapy (29.3 and 19.1 %,
respectively). In both groups the percentage of respondents opting for a combination
with bevacizumab was 30.6 and 25.5 %, respectively ([Fig. 5]).
Fig. 4 Question: “Let us assume that liver metastasis has been found in
the same patient after a 2.5 year disease-free interval and previous
(neo)adjuvant anthracycline-based therapy. Which regimen would you use as your
first-line option?”
Fig. 5 Question: “Let us assume the same patient had previously been
treated with anthracycline and taxane in a (neo)adjuvant setting. Which regimen
would you use as your first-line option?”
Finally, all participants were asked whether they would be interested in
participating in clinical studies of elderly patients. 54.1, 81.5 and 58.6 % of
physicians, respectively, would be interested in participating in a neoadjuvant,
adjuvant or palliative study ([Table 2]). 31 colleagues
also proposed various study designs: 30 % proposed a mono-regimen with
nab-paclitaxel, liposomal doxorubicin, eribulin, capecitabine or vinorelbine in
every setting; a chemotherapy-free concept with trastuzumab and endocrine therapy
was preferred for HER2/neu-positive patients. The second most commonly proposed
variant was doublet therapy with 4–6 × docetaxel/cyclophosphamide vs. 4 × EC
followed by 12 × paclitaxel. The idea of comparing monochemotherapy with
polychemotherapy in a (neo)adjuvant setting was discussed by around 25 %; 10 % also
mentioned a combination with the angiogenesis inhibitor bevacizumab. Overall, the
proposed study designs were tailored with a view to encouraging compliance and took
account of co-morbidities and quality of life.
Table 2 Open questions about trials portfolio.
|
|
Number
|
Percentage
|
|
Would you be interested in participating in a study on
chemotherapy for elderly female patients in a neoadjuvant
setting?
|
|
Not ticked
|
72
|
45.9
|
|
Yes, I would be interested
|
85
|
54.1
|
|
Would you be interested in participating in a study on
chemotherapy for elderly female patients in an adjuvant
setting?
|
|
Not ticked
|
29
|
18.5
|
|
Yes, I would be interested
|
128
|
81.5
|
|
Would you be interested in participating in a study on
chemotherapy for elderly female patients in a metastatic
setting?
|
|
Not ticked
|
65
|
41.4
|
|
Yes, I would be interested
|
92
|
58.6
|
Discussion
The aim of this study was to obtain a representative overview of chemotherapy
management concepts in Germany in 2012 for female patients aged 70–80 with an ECOG
1
performance status. Participants in the survey consisted of physicians registered
as
principal investigators of studies by the GBG; thus it can be assumed that this
amounts to a pre-selection of participants as these physicians would have a greater
clinical and scientific interest in management strategies for these elderly
patients. The rate of return was satisfactory, with around 25 % of physicians
responding; however the return rate was lower than in other countries [14], [15]. More than 40 % of
respondents worked at tertiary care centres for oncology and 13 % at university
clinics. Surprisingly, fully one quarter of respondents were not hospital-based but
had their own practice, making them the second largest group of respondents. The
largest group (40 %) consisted of chief physicians and heads of departments; this
demonstrates that the heads of departments are usually responsible for monitoring
and managing studies and trials, and underscores their importance in this context.
Whether the distribution of medical specialties – two thirds of the physicians in
this study were gynaecologists and 15 % were medical oncologists who had also
trained as internists – corresponds to the reality outside the confines of the GBG
is doubtful.
Most breast centres in this survey treated between 100 and 200 cases with primary
cancer very year. Around 14 % of institutions treated between 300 and 500 cases with
breast cancer over a period of 12 months. 60 % of physicians treated between 10 and
40 new patients with metastatic breast cancer per year. Around 6 % of respondents
reported that they treated between 100–200 new patients with metastasis over a 12
month period. It would be possible to use this information in the context of the
existing discussion on poor recruitment into palliative studies and select the most
suitable study centres accordingly.
As regards the choice of chemotherapies for women without metastasis the results were
as follows: anthracycline/taxane-based therapy was found to play a central role in
the therapy of women aged 70–80 years, both in a neoadjuvant and an adjuvant
setting, despite the fact that the current guidelines are based on data obtained
from female patients under 65.
The choice of therapies in a palliative setting was a clear indication of the
participating physiciansʼ preferences: taxane-based monotherapy was the therapy of
choice, both for patients with primary metastatic breast cancer and for women with
secondary metastatic carcinoma. The combination of chemotherapy plus bevacizumab
reported in one third of the responses shows that this substance has also found a
place in the management of elderly patients. If the patient had had previous
treatment with anthracyclines and taxanes, a majority of physicians recommended a
monotherapy with capecitabine or vinorelbine. It was clear that a combination
therapy played no role as first-line option for the management of women with
metastatic breast cancer aged 70 or above.
When asked about possible study designs, most physicians reported that they would
recommend monotherapy with its reduced side-effects in a (neo)adjuvant setting, even
though the current standard consists of a sequential regimen of three
substances.
The issue of the “undertreatment” of elderly patients was and is controversial. In
2013, Malik et al. published a study in the USA in which they found no difference
in
5-year (local and distant) disease-free survival between “undertreated” patients and
patients treated according to conventional criteria [16].
Despite all the limitations of this study (it was a retrospective, single-centre
analysis; the data acquisition period was 1978–2012) the authors questioned the role
of therapy carried out in accordance with conventional guidelines in this cohort of
patients.
A number of prospective randomised studies were able to show that older patients also
benefited from anthracycline or taxane-based chemotherapy with regard to survival
[17], [18], [19]. However, the inclusion criteria in these studies were
“unfavourable tumour biology” and “hormone receptor negativity” or “positive lymph
node status”. Loibl et al. carried out a pooled analysis of 4 (neo)adjuvant studies
and showed for this cohort that age can have an impact on the feasibility of therapy
and on side-effects [20]. Further important information
obtained in this study was that toxicity was less pronounced with sequential
regimens compared to a combined regimen.
The recommendations for the therapeutic management of elderly patients made by the
International Society of Geriatric Oncology (SIOG) and the European Society of
Breast Cancer Specialists (EUSOMA) emphasise that the decision as to whether
chemotherapy is indicated should not be based on age alone; it was recommended that
patient examination must also include a standardised geriatric assessment [21]. The review article by Sautter-Bihl et al. cited above
stated that, outside of the guidelines, due to the limited data on the toxicity of
adjuvant regimens in elderly patients, management could consist of an anthracycline
monotherapy or alternately 4 cycles respectively of docetaxel/doxorubicin or
doxorubicin/cyclophosphamide [11]; however, this regimen
was not recommended in our current GBG survey. Nevertheless it is indisputable that
therapeutic management of this group of patients must be flexible in view of the
co-morbidities generally present in this cohort and indications for therapy must
therefore be assessed very carefully. The limited data on toxicity and
chemotherapeutic management for this group of patients can only remedied by
designing and carrying out further clinical studies; the ICE-II study of the GBG
could serve as a good example in this context [22]. The
current therapeutic recommendations of the AGO Breast Committee suggest that such
patients should preferably receive chemotherapy as part of a study (LOE: 2a/c, AGO
recommendation +) [9].
In summary it can be stated that the chemotherapeutic management in Germany of female
patients with breast cancer aged 70 and above appears to be relatively standardised
and complies with the recommendations of the S3 Guidelines [23] and made by the AGO Breast Committee [9] as
well as those of SIOG and EUSOMA [21].
