|
What is the optimal local and systemic therapy
of elderly women with breast cancer?
 |
|
OVERVIEW:
As world demographics change and the population of
women over the age of 65 grows, optimal treatment of
the elderly breast cancer patient becomes an increasingly
important issue. The median age of breast cancer diagnosis
is 64; however, many key questions in the treatment
of elderly women remain. What are the age biases in
clinical decision-making, and are they valid? What is
the optimal chemotherapy regimen for elderly women in
both the adjuvant and metastatic settings? What are
the differences in surgical treatments of elderly women?
Why are fewer elderly women enrolled in clinical trials?
|
|
What adjuvant therapy would you recommend for
the following 77-year-old women with ER-positive, HER2- negative
breast cancer?
CASE 1
|
TUMOR SIZE/STATUS
|
|
ACT
|
FAC
|
AC
|
FEC
|
CMF
|
NONE/
OTHER
|
|
2.2 cm tumor
10+ nodes
|
5%
|
5%
|
10%
|
15%
|
20%
|
45%
|
|
|
TAMOXIFEN
|
ANASTROZOLE
|
LETROZOLE
|
|
50%
|
40%
|
10%
|
|
CASE 2
|
TUMOR SIZE/STATUS
|
|
|
0.8 cm tumor
neg nodes
|
|
|
TAMOXIFEN
|
ANASTROZOLE
|
LETROZOLE
|
NONE
|
|
35%
|
15%
|
10%
|
40%
|
|
|
On which dose of capecitabine do you generally start a 75-year-old
woman?
|
What first-line therapy would you recommend for
an asymptomatic 78-year-old woman with bone metastases, who received
no adjuvant therapy?
CASE 3
|
STATUS
|
|
|
PACLITAXEL
|
DOCETAXEL
|
CAPECITABINE
|
CMF
|
FAC
|
NONE
|
UNDETERMINED
|
|
15%
|
5%
|
15%
|
5%
|
5%
|
45%
|
10%
|
|
|
ER-/HER2+
|
|
|
|
|
|
|
CASE 4
|
STATUS
|
|
|
VINORELBINE
|
DOCETAXEL
|
CAPECITABINE
|
NONE/OTHER
|
|
20%
|
30%
|
15%
|
35%
|
|
|
ER-/HER2-
|
CASE 5
|
STATUS
|
|
|
|
ER+/HER2+
|
|
|
|
ANASTROZOLE
|
LETROZOLE
|
TAMOXIFEN
|
EXEMESTANE
|
|
50%
|
40%
|
5%
|
5%
|
|
|
|
|
BREAST CANCER IN THE ELDERLY: AGE BIAS IN CLINICAL
DECISION-MAKING
A lot of physicians in practice have age biases, including oncologists.
But the data demonstrate that older women in relatively good health
tolerate chemotherapy, surgery and radiation therapy as well as
their younger counterparts. There’s also good data from the
Overview, for instance, that adjuvant tamoxifen in ER-positive patients
over age 70 not only lowers the relapse rate but significantly improves
survival.
There is, unfortunately, little prospective data concerning adjuvant
chemotherapy in women over age 70. But from limited data —
including some new, unpublished findings from the Overview with
about 1,000 women over age 70 in randomized trials of chemotherapy
— older women seem to have the same proportional risk reduction
in relapse as other postmenopausal women. So, for selected patients
— for example, those with very large primary lesions or positive
nodes who are in otherwise good health — chemotherapy is worthy
of consideration, and we need to develop trials focusing on older
women. We’re slowly getting there, but I suspect in the mindset
of many medical oncologists there’s still a reluctance to be
aggressive with older women.
—Hyman Muss, MD
CLINICAL TRIALS IN ELDERLY BREAST CANCER PATIENTS
Many of our earlier clinical trials had age cutoffs — for
example at age 70. Now 70-year-old women play tennis. We did a study
in the CALGB that addressed the issue of protocol accrual in elderly
patients in which we matched older and younger women who were eligible
for a breast cancer clinical trial at the same institution, who
had the same physician. We found that women 65 and older were offered
a trial 35% of the time, but women who were less than 65 were offered
a trial 51% of the time. What was interesting was that of the patients
who were offered trial participation, about half in each group agreed.
So, if you offered an older woman a trial, she went on it with the
same frequency.
Discussions about protocol design must consider issues such as
co-morbidity and co-existing illness, which are certainly age-related.
How should that be factored in? A wonderful example of looking at
co-existing illness was the superb analysis of Mitch Gail and his
colleagues looking at the potential benefits of tamoxifen prevention
factored in with United States data concerning stroke, myocardial
infarction and endometrial cancer. This is data we really don’t
have available for adjuvant chemotherapy in older women. Perhaps
diseases that we believe shorten lives and lower quality of life
are not that bad, and women may be willing to enter adjuvant chemotherapy
trials to extend their lives, even though their general medical
health may not be that good.
—Hyman Muss, MD
INTERGROUP TRIAL OF ADJUVANT CHEMOTHERAPY IN
OLDER WOMEN
We are currently close to launching a trial for women age 65 and
older who have either node-positive or high-risk, node-negative
breast cancer. Patients will be randomized to either capecitabine
or standard therapy with either CMF or CA. This will be an equivalence
trial to see if oral capecitabine for six courses is equivalent
to either CMF or CA.
Quality of life and the influence of co-morbidity on outcome will
also be studied, as will the functional status of the patients.
We’re very excited about this, because we believe that if capecitabine
is equivalent to more intensive regimens, it might be very attractive
for many patients as an adjuvant regimen. I believe that a lot of
physicians will be willing to put patients on this trial. The patients
are there, and I feel confident we will meet accrual.
If you look at Phase II trials in metastatic breast cancer as second-and
third-line therapies, there is now a reasonable database for capecitabine
demonstrating response rates of about 20 to 30%, which really is
comparable to taxanes, vinorelbine and other very active agents.
So, if you look at capecitabine as a single agent, it fits in. Taxanes
have been extensively compared to regimens like CAF and CMF and
have proven to be as good, if not superior, and so if you take a
Boolean approach, capecitabine should be reasonable to consider
for an equivalence trial to CA or CMF.
There is also a very small comparison of capecitabine versus CMF
in metastatic disease where the response rate was higher, although
not significantly for capecitabine. Ce rt a i n l y, it did not
look detrimental. I think that the package insert dose of 2,500
mg/m2 per day of capecitabine is too high. In our adjuvant trial,
we’re going to start at 2,000 mg, and we’re even going
to watch that very closely. I suspect that we’re not going
to lose much by lowering the dose, because lowering the dose will
still leave you with very high-quality serum levels that should
be effective.
The major toxicity we expect with capecitabine is hand-foot syndrome,
diarrhea and occasionally stomatitis, which will be monitored very
closely. I’m hoping that it won’t be that bad an experience
at all, and logistically, it should be much more user-friendly for
patients.
—Hyman Muss, MD
HORMONAL THERAPY VERSUS CHEMOTHERAPY IN THE ELDERLY
For the elderly or those who have substantial co-morbid conditions,
hormonal therapies are definitely preferred. The elderly have a
much higher probability of response to hormonal t h e rapies, but
they also t o l e rate the hormonal therapies so much better.
— Robert Carlson, MD
TREATING THE ELDERLY WITH CYTOTOXIC CHEMOTHERAPY:
FINDING A LESS TOXIC REGIMEN
The elderly is a group of patients that many physicians have been
somewhat hesitant to treat aggressively with chemotherapy, because
the benefit, although statistically significant, is small in this
patient population. Europeans have been very strong in using hormonal
therapy instead of cytotoxics in this population. We’re looking
for a more gentle but reasonably active drug combination, or, in
the case of capecitabine, a single drug.
It is interesting to look at capecitabine as an adjuvant treatment
in an elderly population, where the options currently available
are rather toxic — CMF, AC, etc.... Knowing that capecitabine
has activity at least equivalent to CMF in advanced disease, may
offer a minimally toxic regimen with benefit in a population of
patients that we all are somewhat reticent to treat.
—Daniel Budman, MD
LACK OF ELDERLY WOMEN IN CLINICAL TRIALS
Elderly women are typically not enrolled in clinical trials. In
the SWOG study of elderly women, published in the New England Journal
of Medicine in 1999, Laura Hutchins showed that although “elderly”
women comprise 49% of the breast cancer cases in the United States,
women over age 65 comprised only nine percent of the participants
in the SWOG breast cancer trials. We need to increase awareness
that women older than 65 can tolerate therapy as well as women younger
than 65, that they can derive benefit from treatment as long as
their end organ function is good, and that they should not be excluded
from the major clinical trials.
—Edith Perez, MD
BASING TREATMENT DECISIONS ON AGE ALONE
The decision for systemic therapy in older women should be based
on the biology of the disease, the patient’s performance status,
and her end organ function — not solely on her age. Seventy-five
years old does not mean that one will die the next year. Approximately
25% of 75-year-old women are expected to live another 17 years.
Even in the extreme age group of 90, life expectancy is approximately
five years. We have to think of how to manage medical problems the
best we can with the current tools and not give up on people based
simply on their age.
—Edith Perez, MD
|
| CALGB 49907: A RANDOMIZED TRIAL OF ADJUVANT
CHEMOTHERAPY WITH STANDARD REGIMENS, CYCLOPHOSPHAMIDE,
METHOTREXATE AND FLUOROCURACIL “CMF” OR DOXORUBICIN
AND CYCLOPHOSPHAMIDE “AC,” VERSUS CAPECITABINE
IN WOMEN 65 YEARS AND OLDER WITH EARLY STAGE BREAST CANCER OPEN PROTOCOL |
|
|
|
| |
| Tamoxifen given after completion of chemotherapy
for all ER+ or PR+ patients |
|
|
STUDY CONTACT:
Richard L Schilsky, Chair, Ph: 773-834-3914
Cancer and Leukemia Group B
|
| |
|
| CNR-9502, EU-95020: PHASE III RANDOMIZED
TRIAL OF QUADRANTECTOMY WITH VS WITHOUT AXILLARY LYMPH
NODE DISSECTION IN WOMEN OVER 65 YEARS OLD WITH STAGE
I BREAST CANCER OPEN
PROTOCOL |
|
|
|
| |
| Patients in both arms receive oral tamoxifen
for 5 years |
|
|
STUDY CONTACT:
Gabrielle Martelli, Ph: 39-2-2390-324
Instituto Nazionale per lo Studio e la Cura dei Tumori
|
| |
|
| CLINICAL TRIAL PARTICIPATION BY ELDERLY
BREAST CANCER PATIENTS |
|
|
|
Older
|
Younger
|
P
|
|
Mean age
|
76.5
|
50.4
|
|
|
Offered protocol
|
35%
|
51%
|
0.06
|
|
Consented when offered
|
50%
|
56%
|
0.67
|
|
| |
| Kemeny M et al. Barriers to participation of older women
with breast cancer in clinical trials. Proc ASCO 2000; Abstract
2371. |
|
| |
|
| PROPORTIONAL RISK REDUCTIONS WITH TAMOXIFEN
AND POLYCHEMOTHERAPY IN WOMEN AGES 70 OR GREATER |
|
|
Treatment
|
Recurrence
as 1st Event
|
Mortality
(Death from any cause)
|
|
|
Events/
Pts Treatment
|
Events/
Pts Control
|
Reduction
in recurrence rates
|
Deaths/Pts
Treatment
|
Deaths/Pts
Control
|
Reduction
in death rates
|
| Tamoxifen~1yr |
200/442
|
231/420
|
22% SD 9
|
330/442
|
339/420
|
8% SD 8
|
| Tamoxifen~2yrs |
189/726
|
275/750
|
42% SD 8
|
273/726
|
353/750
|
36% SD 7
|
| Tamoxifen~5yrs |
48/186
|
87/204
|
54% SD 13
|
85/186
|
113/204
|
34% SD 13
|
Polychemo-
Therapy |
104/307
|
100/302
|
-
|
103/307
|
120/302
|
-
|
|
| |
|
Early Breast Cancer Trialists’ Collaborative Group.
Tamoxifen for early breast
cancer: An overview of the randomised trials. Lancet 1998;
351(9114):1451-67. Abstract
Early Breast Cancer Trialists’ Collaborative Group.
Polychemotherapy for early
breast cancer: An overview of the radomised trials. Lancet
1998;352(9132):930-42. Abstract
|
|
| |
|
| MULTICENTER PHASE II TRIAL OF WEEKLY PACLITAXEL
FOR METASTATIC BREAST CANCER BASED ON AGE No Link Protocol |
|
|
|
|
Overall Results:
* Mean dose = 77 mg/ m2/week in women < 65
* Mean dose = 76 mg/ m2/week in women > 65
* Well tolerated in both age groups
* Similar small incidence of major toxicities in both age
groups
* Equal efficacy in both age groups
Conclusion: Age alone should not be used
as a reason to
exclude weekly paclitaxel 80 mg/m2 as a reasonable treatment
for patients with metastatic breast cancer
|
| Adapted from a presentation by Edith Perez, MD at the Chemotherapy
Foundation meeting 10/23/01 |
|
| |
|
| IBCSG-10-93: PHASE III RANDOMIZED STUDY
OF SURGERY WITH OR WITHOUT AXILLARY NODE CLEARANCE FOLLOWED
BY ADJUVANT TAMOXIFEN IN ELDERLY WOMEN WITH BREAST CANCER
OPEN
PROTOCOL |
|
|
|
Patients in both arms receive oral tamoxifen for 5 years
|
| |
|
|
STUDY CONTACT:
Diana Crivellari, Chair Ph: 39-434-659206
International Breast Cancer Study Group
|
| |
View References
Back | Top of Page
|
|
