Aromatase inhibitors in advanced breast cancer
- Systematic review
- Results
- Comment
Bandolier
is dimly aware of the difficulties of evaluating cancer treatments. New
treatments are usually evaluated against best current treatment, a moving
target that can make trials difficult, let alone trying to get a coherent
picture from overviews. Cancer treatments differ from early after diagnosis to
when the disease is more advanced. Then there is the difficult issue of
outcomes, with survival as the hardest, though not necessarily always the most
important; getting good survival data means long trials, and results are
neither quick nor easily come by.
Looking
at cancer, then, is a bit of a minefield. But when a new meta-analysis of
aromatase inhibitors in breast cancer swims into our ken [1], it deserves that
at least we stir the neurone to try and understand what it says.
Systematic
review
Randomised
trials were eligible if they compared an aromatase inhibitor or inactivator
with tamoxifen or progestagens (like medroxyprogesterone acetate) in patients
with advanced breast cancer, defined as metastatic and inoperable locally
advanced or recurrent breast adenocarcinoma. Any line of treatment was
considered, whether first line or second or subsequent line in patients who had
received such therapy in the past. Excluded were trials in earlier stages or
with other histological types of cancer.
Data
were analysed according to the generation of the agent: first
(aminoglutethimide), second (formestate, fadrazole), and third (anastrazole,
examestane, letrazole, vorozole) versus standard hormonal treatment. Also
analysed were third generations versus tamoxifen as first line and progestogens
as second or subsequent lines of treatment.
Results
Twenty-three
trials with survival data with 8,500 women were eligible for the
meta-analysis, published between 1982 and 2004; 11 were double blind, and nine
investigated treatment as first line therapy. Trial size varied between 40 and
about 800 patients. The typical median age of women in the trials was about 65
years.
Only
third generation aromatase inhibitors and inactivators demonstrated any
significant survival benefit compared with standard hormonal treatment (Table
1).
Table 1: Comparisons of different generations and line of use of aromatase inhibitors, and the relative hazard for mortality in breast cancer trials
| Comparison |
Number of comparisons
|
Relative hazard
(95%CI)
|
| Generation (vs standard hormone
treatment) |
| First |
6
|
0.96 (0.84 to 1.09)
|
| Second |
7
|
1.00 (0.89 to 1.13)
|
| Third |
12
|
0.87 (0.82 to 0.93)
|
| Comparator |
| First line vs tamoxifen |
4
|
0.89 (0.80 to 0.99)
|
| Second line vs progestagens |
8
|
0.86 (0.79 to 0.84)
|
In
cumulative meta-analysis, statistical significance only occurred in 2000, and
remained subsequently, with the addition of the third generation aromatase
inhibitors. Only four individual trials showed statistical significance on
their own, and three of these were third generation aromatase inhibitors.
The
survival benefit for third generation agents was similar in both first line
treatment compared with tamoxifen and second or subsequent line versus
progestogens (Table 1).
Comment
This
meta-analysis shows a small but significant benefit of third generation
aromatase inhibitors (anastrazole, examestane, letrazole, vorozole) over
standard hormonal treatment in advanced breast cancer. It also shows them to
have a benefit over tamoxifen and progestogens, and it is of sufficient
importance to be considered when making decisions about care pathways in breast
cancer. It might well change some of them.
It
exemplifies the need for meta-analysis when trials are relatively small
(average size of 360 patients in these trials), when the outcome of the trial
is survival, when there are relatively few deaths because of relatively short
duration of trials (median survival was typically two years or more), and when
differences between groups was relatively small (10-15% reduction with third
generation aromatase inhibitors).
For
a theoretical median survival of 20 months with standard treatment with
standard hormone therapy, change to or addition of third generation aromatase
inhibitor would confer an additional four months or so of life. By such small
steps are improvements in cancer treatment achieved.
Reference:
- D Mauri et al. Survival with aromatase inhibitors and inactivators versus standard hormonal therapy in advanced breast cancer: meta-analysis. Journal of the National Cancer Institute 2006 98:1285-1291.
