ARTICLE
Auteur(s) :, Jawaid Younus, Theodore A
Vandenberg
Department of Medical Oncology, London Regional Cancer Centre,
790 Commissioners Road, East London, Ontario N6A 4L6, Canada
The relationship between estrogen and breast cancer has been
extensively investigated and hormonal manipulation against estrogen
have been used for the last several decades. Such interventions
have included tamoxifen and more recently aromatase
inhibitors/inactivators (AIs). Tamoxifen has remained a time tested
hormonal therapy for estrogen receptor (ER) or progesterone
receptor (PR) positive breast cancer. The efficacy of tamoxifen is
clearly reflected through meta-analysis by the Early Breast Cancer
Trialists’ Cooperative Group (EBCTCG). This meta-analysis showed
that adjuvant tamoxifen reduces the relative risk of breast cancer
recurrence by 47% and mortality by 26% [1]. Both pre- and
post-menopausal women, with or without the involvement of axillary
lymph nodes, benefit from the use of adjuvant tamoxifen. The
benefits are additive when tamoxifen is used after completing
adjuvant chemotherapy. At present five years of tamoxifen is
recommended as adjuvant therapy in patients with breast
cancer.Aromatase inhibitors (anastrozole and letrozole) and
inactivators (exemestane) are third generation compounds, currently
indicated for post-menopausal women with breast cancer in
metastatic and in adjuvant settings. These hormonal agents have
replaced earlier drugs like aminoglutethemide. In post-menopausal
women, estrogen is produced by peripheral conversion of androgens
mediated through the enzyme aromatase. Inhibition of this enzyme
either reversibly (anastrozole and letrozole) or irreversibly
(exemestane) leads to extremely low levels of estrogen, which in
turn is responsible for anti-tumor effects. These agents differ in
their pharmacokinetic properties and with respect to their overall
effect on various systems and tissues [2].In metastatic breast
cancer patients, aromatase inhibitors/inactivators (AIs) are
superior to tamoxifen as first or second line hormonal therapy
[3–8]. A similar effect has emerged for these agents as adjuvant
therapy for post-menopausal patients. There have been three
clinical trials completed and published after using AIs in this
setting. The uniformity of results from these trials especially
regarding the disease free survival advantage, in addition to the
better toxicity profiles makes it quite compelling to prescribe AIs
in this setting. However, several questions remain unanswered
including, which AI to use, sequentially or up front, order of
sequence, duration, optimal follow up, and side effects. At
present, these issues make decision-making challenging for
oncologists.To understand these issues further, let us review the
results of the trials, which have used AIs in adjuvant setting
(tables 1 and 2( Table 1 )( Table 2 )). All of the published trials used a
phase III, randomized, double blind, and placebo controlled
approach except the ITA study.The Arimidex and Tamoxifen Alone or
in Combination (ATAC) trial recruited 9366 women with breast cancer
and randomized them to tamoxifen, anastrozole (1 mg once daily by
mouth) or a combination of tamoxifen and anastrozole, after
completing surgery, chemo and radiation therapy [9]. The
combination arm had the same results as tamoxifen alone arm. This
interesting finding was initially seen in a nude mice model [10].
Pharmacokinetic analysis of ATAC arms showed that tamoxifen and its
metabolites levels were unaffected by Arimidex. Although Arimidex
level was 27% less in combination arm, the total oestradiol was
unchanged and therefore pharmacokinetics are unable to explain this
difference of efficacy in the two arms [11]. One possible mechanism
could be related to the significant estrogen deprivation induced by
anastrazole, which may not let any further changes take place, once
tamoxifen is bound to estrogen receptor. In this situation no
further effect will be seen beyond the expected effect of tamoxifen
[9]. The primary objectives were disease free survival (DFS) and
safety. DFS was defined as the time to earliest local recurrence,
distant metastasis, new primary breast cancer or any cause
mortality. At 47 months follow-up, more patients were recurrence
free in anastrozole arm (86.9%) compared to tamoxifen arm (84.5%),
the absolute difference of 2.4% [12]. The hazard ratio was 0.86 (CI
= 0.76-0.99, p-value: 0.03). Musculoskeletal events and fractures
were seen more frequently in anastrozole alone arm versus tamoxifen
(table 2). However, hot flashes, vaginal bleeding and discharge,
incidence of endometrial cancer, venous thromboembolic and
cerebrovascular events were significantly higher in tamoxifen arm
(p value < 0.05). This is the largest trial that compared
tamoxifen in a head to head design with anastrozole and has shown a
continued benefit over a reasonably sufficient median follow-up.
There is no overall survival benefit yet seen.The National Cancer
Institute of Canada – Clinical Trials Group jointly with North
American Intergroup and the Breast International Group conducted
the MA-17 trial with over five thousand postmenopausal women [13].
These patients received adjuvant tamoxifen for four to six and a
half years. Within three months of discontinuing tamoxifen, they
were randomized to receive letrozole 2.5mg orally once daily or
placebo. The primary objective was disease-free survival defined in
this trial as loco-regional or metastatic disease or new primary
breast cancer in the contra-lateral breast. Secondary cancer, death
without a recurrence or a diagnosis of contralateral breast cancer
was not considered in the analysis of the results. The data and
safety monitoring committee at a median follow-up of 2.4 years
unblinded the two arms at 207 events when the pre-defined
O’Brien-Fleming boundary reached the value of 0.0008. The estimated
four year DFS was 93% in the letrozole group versus 87% in the
placebo, an absolute benefit of 6%. The hazard ratio was 0.57 (95%
CI = 0.43 to 0.75; p value = 0.00008). The over all survival (OS)
was same in both arms. An update in 2004 revealed the improvement
in the OS and DFS to be more prominent in node positive women [14].
The letrozole arm had more patients with hot flashes, arthralgia
and myalgia. The difference in clinical fracture rates and
osteoporosis (self-reported) was not statistically significant.
Based on this trial, letrozole may provide extended adjuvant
benefits to postmenopausal women after five years of tamoxifen
therapy. Interestingly, two thirds of women from placebo group,
after unblinding, elected to go on letrozole therapy. With this
cross over, any meaningful evaluation of the DFS, OS or side
effects will not be further possible. However, this cross over also
shows the preference of these patients to continue with the
apparent benefits of letrozole, despite the short follow up and
lack of information regarding the long-term side effects.The
Intergroup Exemestane Study (IES) recruited 4742 patients [15].
These patients had received two to three years of adjuvant
tamoxifen. They were then randomized to either continue on
tamoxifen or to switch to exemestane (25 mg once daily) to complete
five years of therapy. The primary objective was DFS defined as
local or metastatic disease, contralateral breast cancer or death.
After 30.6 months of follow-up, the hazard ratio in the exemestane
arm compared with tamoxifen was 0.68 (95% CI = 0.56 to 0.82 and
p-value < 0.001). The absolute benefit was 4.7%. Over all
survival was not significantly different in the two arms. Survival
free of distant disease was better in exemestane treated patients
with hazard ratio 0.66 (95% confidence interval: 0.52 to 0.83; p
value = 0.0004). A higher incidence of arthralgia and diarrhea was
seen in exemestane group but gynecologic symptoms, vaginal
bleeding, muscular cramps and thromboembolic events were more
common in tamoxifen group. Fractures were reported more frequently
in exemestane group (3.1% versus 2.3%) but without reaching
statistical significance. This study has shown the advantage of
utilizing AIs (exemestane) after tamoxifen in a sequential manner.
In addition to improved DFS, more importantly distant disease free
survival was significantly better in patients treated with
exemestane.The last study was presented at San Antonio Breast
meeting in 2003 and published in the abstract form. The Italian
Tamoxifen Arimidex trial (ITA) used anastrozole after two to three
years of initial tamoxifen to complete a total of five years of
therapy [16]. The competitor arm had women treated with tamoxifen
for five years. A total of 426 women, all axillary lymph node
positive, were randomized on this trial. Initial results after a
median follow-up of two years showed a significant benefit in
anastrozole group with hazard ratio of 0.36 for risk of relapse
(95% confidence interval = 0.17 to 0.75; p value = 0.006). The
hazard ratio of death was 0.18 (CI = 0.02-1.57; p value = 0.07).
Although serious adverse events were reported more frequently in
patients on Tamoxifen arm, the detailed results from this study are
awaited.How can we apply these results to our adjuvant therapy
decision-making in postmenopausal women with breast cancer? The
pertinent issues are now discussed under the following
sub-headings:The first question is which AI to use and in which
situation. The following two approaches are considered and
discussed as below.
Timeline approach
These trials have used three landmarks on the treatment timeline
for breast cancer patients (( figure 1 )). Considering
the evidence based medicine approach, each trial has proved the
superiority of a particular AI at one particular time point in the
adjuvant phase of treatment. Thus logically, an individual patient
would be best treated with a particular AI proven efficacious at
that treatment time. Taking this approach, anastrozole appears best
for patients starting the adjuvant hormonal therapy. Patients who
have completed five years of adjuvant tamoxifen will be best suited
to start Letrozole and the patients who have been on tamoxifen for
two or three years will benefit from switching over to
exemestane.
Table 1 Summary of adjuvant AI trials
|
Trial
|
ATAC
|
MA-17
|
IES
|
ITA
|
|
Plan of treatment
|
Anastrozole alone, tamoxifen alone, anastrozole + tamoxifen for
5 yrs
|
Tamoxifen for 5 yrs then letrozole or placebo for
5 yrs
|
Tamoxifen for 5 yrs vs. tamoxifen for 2-3 yrs then exemestane for
2-3 yrs
|
Tamoxifen for 5 yrs vs. tamoxifen for 2-3 yrs then anastrozole for
2-3 yrs
|
|
No. of patients
|
9,366
|
5,157
|
4,742
|
426
|
|
Median follow-up (at the time of analysis)
|
47 months (6% patients completed randomized treatment; 47% patients
completed at least 4 yrs)
|
30 months (< 1% patients completed randomized treatment)
|
30.6 months (> 90% patients completed randomized treatment)
|
36 months (all patients completed randomized treatment)
|
|
ER-positive (%)
|
84% (8% unknown)
|
98% (2% unknown)
|
81% (17% unknown)
|
86% (tamoxifen, 14% unknown) vs 91% (anastrozole, 8% unknown)
|
|
Tumor size < 2 cm
|
63.9%
|
57%
|
Unknown
|
44-49%
|
|
Node-positive (%)
|
35% (5% unknown)
|
46% (4% unknown)
|
44% (4% unknown)
|
100%
|
|
Chemotherapy
|
22%
|
46%
|
32%
|
67%
|
|
Improvement in absolute risk of recurrence
|
2.4% for anastrozole
|
Estimated at 4 yr: 6%
|
4.7% for exemestane
|
10% for anastrozole
|
|
Overall survival reported to date
|
No difference
|
No difference
|
No difference
|
No difference
|
|
Treatment withdrawals
|
More with tamoxifen
|
Equal in both arms
|
More with exemestane
|
Equal in both arms
|
|
Comments
|
DFS benefit consistent and increasing with time
|
Unblinding and cross-over may not reveal safety, optimal duration
and efficacy etc.
|
Fractures and osteoporosis found more in Exemestane arm as were
treatment withdrawals
|
Relatively Small number of patients. All were node-positive
therefore earlier and prominent difference
|
Table 2 Adverse events in AIs adjuvant therapy trials
|
Toxicity (%)
|
ATAC (A vs T)
|
MA-17 (L vs P)
|
IES (E vs T)
|
ITA (A vs T)
|
|
Endometrial cancer
|
0.1 vs 0.7 a
|
NA
|
NA
|
NA
|
|
Vaginal bleeding
|
4.8 vs 8.7 a
|
4.3 vs 6 a
|
4 vs 5.5 a
|
NA
|
|
Cerebrovascular events
|
1.1 vs 2.3 a
|
4.1 vs 3.6
|
NA
|
NA
|
|
Thromboembolism
|
2.2 vs 3.8 a
|
NA
|
1.3 vs 2.4 a
|
1.8 vs 1.3
|
|
Hot flashes
|
35 vs 40 a
|
47.2 vs 40.5 a
|
42 vs 39.6
|
|
|
Musculoskeletal disorders
|
30.3 vs 23.7 a
|
NA
|
NA
|
7.2 vs 5.8
|
|
Fractures
|
7.1 vs 4.4 a
|
3.6 vs 2.9
|
NA
|
0.9 vs 0.9
|
|
Arthralgia
|
NA
|
21.3 vs 16.3 a
|
5.4 vs 3.6 a
|
NA
|
|
Myalgia
|
NA
|
11.8 vs 9.5 a
|
|
NA
|
|
Diarrhea
|
NA
|
NA
|
4.3 vs 2.3 a
|
NA
|
|
Gynecologic symptoms
|
NA
|
NA
|
5.8 vs 9 a
|
6.3 vs 4
|
|
Osteoporosis
|
NA
|
5.8 vs 4.5 (self reported)
|
7.4 vs 5.7 a
|
NA
|
|
Gastrointestinal symptoms
|
NA
|
NA
|
NA
|
6.3 vs 1.3 a
|
aStatistically significant.
Extrapolated approach
Is it reasonable to consider that the AIs exert their effect as a
class of drugs? Based on this assumption, could we replace
tamoxifen or anastrozole with letrozole or exemestane and use them
at time points different than how they were used in their
respective trials? Following the evidence from the published
trials, this does not appear to be an acceptable approach. The
results from different adjuvant hormonal therapy trials using
exemestane and letrozole are awaited and will provide the answer to
this question. It certainly seems possible that AIs with their
demonstrated superiority in metastatic setting will continue to
enjoy similar importance in adjuvant stage of treatment.
Is sequential therapy better?
Sequential therapy will utilize the maximum therapeutic benefit of
tamoxifen and then a continued (and perhaps a better) coverage by
an AI. There is certainly a hint from both ITA (anastrozole) and
IES (exemestane) study that AIs after an initial use of tamoxifen
provide additional benefit of disease free survival compared to
tamoxifen alone. In addition, distant disease free survival seen in
IES trial is an important finding and perhaps a better marker for
overall efficacy [17]. It is possible that the results of adjuvant
trials with letrozole and or exemestane may provide even superior
results compared to sequential therapy (IES/ITA trials) and may
become the standard therapy. At present, it certainly seems better
to switch patients who have completed two to three years of
tamoxifen to exemestane (based on IES trial results). The result
from Big Femta trial specifically (comparing letrozole with
tamoxifen both in a head to head and in a cross over design) may
shed more light on this issue and possibly in a more conclusive
manner.
Selection of patients
The American Society of Clinical Oncology (ASCO) technology
assessment report recommended AIs to reduce the risk of recurrence
for postmenopausal women with hormone receptor positive breast
cancer [18]. This report has noted that the only subgroup to
achieve a survival advantage comprised of lymph node positive
patients in MA-17 study. Many postmenopausal breast cancer patients
will have a relatively small risk of recurrence to begin with and
with adjuvant treatment this risk may significantly decrease.
Therefore it may appear attractive to just treat patients with AIs
only if they have a high-risk disease. However, the trials using
AIs did not include only high-risk patients. In fact, majority of
participating patients were lymph node negative or with tumors less
than or equal to 2 cms (table 1). Therefore we recommend discussing
risks and benefits of the treatment with AIs with all women
considered eligible for ATAC, EIS and MA.17 trials, or who are
considered eligible for adjuvant tamoxifen therapy.
Any role of tamoxifen?
Is there now a role for adjuvant tamoxifen? The efficacy and side
effects of tamoxifen are extremely well known and discussing the
use of tamoxifen with the patients in an adjuvant setting is quite
easy.
Although the results of adjuvant trials with AIs are showing
improved DFS but there has been no survival advantage evident. In
addition, due to a lack of long term follow up or cross over of
treatments, the toxicities related to AIs are not well defined.
Therefore, it is difficult to discuss the exact risk-benefit ratio
and have a balanced picture for the patients to decide about using
AIs and not to use tamoxifen.
From a global angle however, it appears that AIs are at least as
effective as tamoxifen (considering the overall survival) or better
(considering DFS). These agents lack the more serious side effects
of tamoxifen and have an overall better toxicity profile. Certainly
more time is needed to draw absolute conclusions but at present AIs
appear a better choice in adjuvant therapy plans for postmenopausal
women with breast cancer.
Some patients may still opt for tamoxifen, especially who have a
relatively low risk of recurrence and/or less likelihood of
developing serious side effects (for example a patient with
hysterectomy). Patients with severe osteoporosis or arthritis,
especially with a low risk of recurrence, may be better off with
tamoxifen. In addition, personal preference and cost may be other
factors in choosing tamoxifen. The field of adjuvant hormonal
therapy is in rapid flux and therefore it may seem reasonable in a
few cases to just start with tamoxifen and reconsider the options
when further trial results are available.
Follow up of patients on AIs
A decision to use an AI should only be made after a full discussion
of the benefits and risks of treatment and an appropriate plan of
follow up. We usually recommend that all women starting adjuvant
AIs should have a baseline bone density test with follow up testing
every one or two years. Patients with no prior history of
osteopenia or fragility fracture should be started on calcium 1500
mg and vitamin D 800U daily. Furthermore at least 30 minutes of
physical activity three times a week is recommended. Those with
documented osteopenia or osteoprosis or with prior fragility
fracture should be started on an oral bisphosphonate.
Is economy a possible problem?
AIs are more expensive than tamoxifen. On the other hand, several
papers have described AIs as cost-effective compared to other
medical interventions. Therefore the cost consideration should not
pose any significant problem in using Ais [19,20].
Quality of life
The results of two different trials show that the quality of life
appears unaffected with the use of AI compared to tamoxifen or
placebo, in the women who participated in the adjuvant AI trials
[12,21]. The relatively low toxicity profile of AIs observed in
these trials is apparently not significant in magnitude compared to
placebo or tamoxifen, to affect the quality of life. However, the
quality of life can be dependent on several related and unrelated
factors to the therapy used and therefore may not reflect the sole
impact from AIs. As an example, women treated with anastrazole in
ATAC trial significantly less often felt hot flashes and vaginal
discharge. But these women experienced vaginal dryness, dysparuenia
and loss of interest in sex more frequently [22].
Postmenopausal status
AIs are only indicated for postmenopausal women. The use of AIs in
premenopausal women may induce an initial drop in estrogen levels
followed by a feed back increased secretion of gonadotropic
hormones and eventually raise the total estrogen levels. The IES
trial used stringent criteria to ascertain postmenopausal status
(age > 55 years with amenorrhea > 2 years or amenorrhea >
1 year at the time of diagnosis). The ATAC and MA-17 trials
included women who were initially premenopausal but became
amenorrhic after chemotherapy, for more than one year or had
postmenopausal range follicle stimulating hormone (FSH) with less
than one year of amenorrhea. Such women were small in number in
both these trials and a generalized approach to routinely treat
such women with uncertain menopausal status with AIs is clinically
concerning.
HER-2/Neu and AIs
In the ATAC trial a subgroup analysis for patients with ER+ but PR-
tumors found that these patients had a significantly prolonged time
to recurrence when treated with tamoxifen [23]. The hazard ratio
for ER+/PR- was 0.43 with anastrozole compared to 0.84 if the
tumors were ER+/PR+. This is a retrospective analysis but with a
large number of patients. It remains as an interesting point to be
considered for patients chosen to be treated with an initial AI.
Several studies have pointed out lower response of hormonal
therapy, particularly tamoxifen, in breast cancer patients in whom
HER-2/neu is over-expressed [24,25]. Although this effect was not
seen in other studies [26,27], AIs tend to be favored by the
oncologists in such patients. At present, with all the published
studies, a decision to use specific hormonal therapy based on the
HER-2/neu status is not justified [28].
Conclusion
It is an exciting time period for oncology to see the rapidly
changing face of the adjuvant therapy for breast cancer patients.
Although tamoxifen remains as a standard therapy, the results from
AI trials provide compelling evidence that AIs have emerged as
superior hormonal agents and offer significant advantage over
tamoxifen. It is expected that with the support of completed AIs
trial data, these agents will be used more frequently in the
adjuvant setting. As patients are now better educated through media
and the Internet, the demand for the AIs has significantly
increased. We have certainly seen this to be the case at our cancer
centre. The long term follow up of completed trials and the results
from the ongoing AI trials are eagerly awaited and will help
present a better risk-benefit picture to our breast cancer
patients.
Acknowledgements
We appreciate the secretarial skills of Ms. Mahnoor Jawaid in
preparation of this manuscript.
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