Section 7
Bisphosphonates in Primary
Breast Cancer
OSTEOPOROSIS
IN BREAST CANCER PATIENTS
Osteoporosis
is a long-term side effect of chemotherapy and some kinds
of hormone therapy in premenopausal patients. A bone mineral
density measurement should be done immediately after the surgery
and every two years after that. It is better to prevent osteoporosis
than to treat it, because patients who lose 10 or 20 percent
of bone mineral density do not rebuild the trabecular network
— the bone architecture. The best therapy is a bisphosphonate,
because not only is the bone mineral density increased but
there is a reduction in rate of subsequent bone metastases.
—Ingo
Diel, MD
TRIALS
OF ADJUVANT CLODRONATE
At the
moment, we have results from three randomized trials. In our
study, patients receiving clodronate had fewer subsequent
bone and non-bone metastases. The largest study was done in
Great Britain, Canada and Scandinavia. In terms of methodology,
it’s the best, because it was placebo-controlled and
double-blinded. They found a reduction in bone metastases
but no significant effect on overall survival. The third study
was done in Finland and was not placebo-controlled. In 300
node-positive patients, they observed no effect on the rate
of bone metastases and a negative effect on disease-free survival
and non-osseous metastases. No other bisphosphonate study
has reported this type of negative effect. In addition to
different methodology, the clear difference in the three studies
is the selection of patients.
When we
started our study ten years ago, we selected patients with
tumor cells in the bone marrow, because we were convinced
this was the best prognostic factor for bone metastases. Today
we know it’s a good prognostic factor for non-bone metastases,
because it reflects the early hematogenous spread of breast
cancer cells from the primary tumor. The effect we observed
on non-bone metastases could have been by chance since we
only had 300 patients, which is a small number for an adjuvant
trial. But we have a hypothesis that perhaps if you increase
the amount of bisphosphonates on the bone surface, you may
have an apoptotic effect on adjacent cells. We have evidence
that these agents have this effect on osteoclasts and also
an anti-adhesive and anti-angiogenic effect.
Clodronate
is not available in the United States, because several years
ago, the initial studies reported a number of leukemias that
were eventually demonstrated to be unrelated to clodronate.
But from that time it was not pursued as an antiosteolytic
drug in the United States. The problem with the bisphosphonates
is that the resorption rate is low, and in order to see an
effect, you need a dose that may cause side effects, particularly
on the gastrointestinal tract. I support the new NSABP clodronate
study, because it’s important to confirm our data, but
I don’t know whether it was a good decision to include
all breast cancer patients as opposed to attempting to select
those most likely to develop bone metastases.
—Ingo
Diel, MD
PHASE
III TRIALS OF CLODRONATE FOR EARLY-STAGE BREAST CANCER*
*NSABP B-34 Protocol background
|
| NSABP
B-34: Phase III Randomized Study of Adjuvant Clodronate
with or without Systemic Chemotherapy and/or Tamoxifen
in Women with Early-Stage Breast Cancer
Protocol |
|
Eligibility |
Stage
I or II breast cancer |
|
ARM 1 |
Clodronate
1600 mg qd x 3 yrs |
Patients
may receive adjuvant systemic therapy including
tamoxifen at investigator’s discretion
|
|
SELECT
PUBLICATIONS
|
Cristofanilli
M & Hortobagyi GN. Bisphosphonates in the management
of breast cancer. Cancer Control 1999;6(3):241-246.
Full-Text
Diel
IJ et al. Bisphosphonates and the prevention of
metastasis: First evidences from preclinical and clinical
studies. Cancer 2000;88:3080-8.
Abstract
Diel
IJ et al. Reduction in new metastases in breast
cancer with adjuvant clodronate treatment. N
Engl J Med 1998;339:357-63.
Abstract
Hillner
BE et al. For the American Society of Clinical Oncology
Bisphosphonates Expert Panel. American Society of Clinical
Oncology Guideline on the Role of Bisphosphonates in
Breast Cancer.
Full-Text
Perez
EA. Management of bone metastases in advanced breast
cancer. Cancer Control 1999;6(5,Suppl).
Full-Text
Powles
TJ et al. Adjuvant clodronate reduces the incidence
of bone metastases in patients with primary operable
breast cancer. Proc. ASCO 1998;
Abstract 468
Saarto
T et al. Adjuvant clodronate treatment does not
reduce the frequency of skeletal metastases in node-positive
breast cancer patients: 5-year results of a randomized
controlled trial. J Clin Oncol 2001;19:10-17.
Abstract
|
|
