Drugs & Therapy Perspectives [TM]
Does Clodronate Reduce Metastases in Patients With Breast Cancer?
[Drug & Ther Perspect 15(10):1-4, 2000. © 2000 Adis International Limited]
Initial data suggests clodronate (clodronic acid) reduces the incidence of both osseous and visceral metastases in high-risk patients with breast cancer. In addition, like other bisphosphonates, clodronate significantly reduces the incidence of skeletal complications associated with breast cancer, and is an important therapeutic option in the treatment of tumour-induced hypercalcaemia.
Oral or intravenous clodronate is generally well tolerated, with few serious adverse effects reported. The most common adverse effects are mild, transient gastrointestinal disturbances.
Approximately 60 to 80% of patients with breast cancer will develop bone metastases during the course of their disease, with two-thirds of these patients experiencing severe pain. Metastatic bone disease is a frequent cause of morbidity and complications (pathological fractures, hypercalcaemia and spinal cord compression) in these patients. The median survival time of patients from first metastatic relapse to death typically ranges from 18 months to 3 years, depending on the site and extent of metastases.
Since there is a high morbidity and poor prognosis associated with metastatic disease, current treatment strategies focus on relieving symptoms, preventing complications and improving quality of life with minimal inconvenience to the patient. Palliative treatments, including antineoplastic therapy, radiation therapy or hormone therapy, form the cornerstone of treatment for painful bone lesions. However, these palliative therapies do not alleviate the substantial morbidity from progressive skeletal involvement.
Metastatic bone disease is characterised by an impaired balance between bone resorption and bone formation, with osteolytic bone destruction being a predominant feature in patients with breast cancer. Treatments that prevent and/or relieve skeletal complications should reduce much of the morbidity associated with breast cancer. The bisphosphonates have an established role in the prevention and treatment of tumour-related complications such as fractures and hypercalcaemia. These agents have a high affinity for bone and, although their exact mechanism of action is unknown, they inhibit bone resorption by directly and/or indirectly inhibiting osteoclast activity.
Reduced Skeletal Complications
Women with breast cancer commonly experience skeletal complications, whether or not there are skeletal metastases. In 2 well designed studies, oral clodronate (clodronic acid) significantly reduced the cumulative incidence of all skeletal events (including both vertebral and nonvertebral fractures, skeletal hypercalcaemia and the requirement for radiotherapy for bone pain or fracture) in high-risk patients with breast cancer (see figure 1). Compared with placebo treatment in 1 study, patients receiving clodronate 1600 mg/day had significantly fewer:
hypercalcaemic episodes (28 vs 52 per 100 patient-years)
terminal hypercalcaemic episodes (7 vs 17 per 100 patient-years)
vertebral fractures (84 vs 124 per 100 patient-years).
A Lower Incidence of Metastases
Initial data suggest that clodronate may have some beneficial effects in preventing or reducing development of skeletal metastases. In 1 study, oral clodronate treatment significantly reduced the incidence of skeletal, visceral and distant metastases at 3-year follow-up in patients with tumour cells in their bone marrow, but no skeletal metastases at baseline (see figure 2). Furthermore, Kaplan-Meier curves indicated a significantly greater probability of survival without skeletal, visceral or any metastases with clodronate treatment. In this non-blind study, 302 patients received oral clodronate 1600 mg/day or placebo for 2 years, with most patients receiving concomitant radiotherapy and/or antineoplastic therapy. There were no differences between the groups in terms of previous or concurrent therapy.
Not in All Patients?
However, the effects of clodronate on the incidence of metastases and survival rates have been inconsistent across studies. Although not significant, there was a trend to a decreased incidence of skeletal metastases in a study in 1079 nonselected patients with operable breast cancer without skeletal metastases at baseline.[6,7] Moreover, a subgroup analysis of postmenopausal women, showed that clodronate did produce a significant reduction in the percentage of these women who developed skeletal metastases (3.3 and 7.3% of clodronate and placebo recipients, respectively).[6,7] Another study found that clodronate significantly reduced the total number of metastases but not the number of patients who developed them. This double-blind study enrolled women with recurrent breast cancer and no evidence of metastases at baseline. In comparison, there was no decrease in the incidence of skeletal metastases at 5 years in nonblind study in 299 women with node-positive breast cancer. However, so far the last study has been published only as an abstract.
The evaluation of the role of clodronate in preventing metastases in women with breast cancer is made difficult by the limitations of the available data. Different groups of patients were involved in each of the 3 studies in high-risk patients,[4,5,8] and only 1 study was double-blind and placebo-controlled. Patients from the study that included only those with node-positive breast cancer were probably at higher risk of metastases than those enrolled in the Diel et al. study, where approximately equal numbers of node-positive and node-negative patients were enrolled. In addition, clear conclusions can not be drawn from studies in patients with pre-existing skeletal metastases because the studies are limited by size and short duration.
Further long-term clinical studies are required to determine whether or not clodronate can reduce the development of metastases and, if so, in which patient groups. If beneficial effects are found in certain selected patients, the practicalities and costs of appropriate screening will need to be considered. Currently, pamidronate (pamidronic acid) has been the most extensively studied bisphosphonate in clinical trials assessing skeletal complications associated with breast cancer,[1,2] although newer more potent bisphosphonates (such as ibandronate and alendronate) are being investigated.
Prescribing and Formulary Considerations
Clodronate has been launched in many countries for the treatment of tumour-induced hypercalcaemia (TIH) and in some countries (e.g France, Italy and Germany) for the treatment of cancer metastases.
Bisphosphonates are the treatment of choice for TIH, which is experienced by approximately 15% of women with metastatic breast cancer.[1,2] Intravenous clodronate, like other bisphosphonates, normalises serum calcium levels in these patients.
In TIH, the recommendations of the manufacturers are to give intravenous clodronate 300mg daily until plasma calcium normalises, usually for 2 to 5 days. Treatment duration should not exceed 10 days, although intravenous infusions may be repeated every 2 weeks if necessary. The standard recommended oral dose of clodronate is 1600 mg/day (maximum 3200 mg/day), either once daily or in 2 divided doses to reduce adverse gastrointestinal effects (if necessary). In patients with renal insufficiency (creatinine clearance 0.6 to 1.8 L/h) the dose should be reduced by half, with clodronate contraindicated in patients with a creatinine clearance <0.6 L/h. The absorption of oral clodronate is impaired by coadministration with food and calcium; thus, clodronate should be taken on an empty stomach at least 1 hour before a meal or 2 hours after and not with milk products or calcium supplements.
Prophylactic Use in Patients with Malignancies
Most clinical studies in patients with breast cancer have used clodronate 1600 mg/day, although studies conducted in patients with other malignancies (multiple myeloma and prostatic cancer) have used up to the maximum recommended dosage of 3200mg daily.  Duration of therapy varies between studies, from 3 months to the life-time of the patient. However, in clinical trials that have shown significant benefits with regard to skeletal events and metastases patients have received clodronate for 2 to 3 years.
In France, the oral dosage of clodronate for cancer osteolysis is 1600 to 3200 mg/day depending on possible hypercalcaemia.
Bulletin du Cancer, 8/01
Life Extension Foundation,2000
Eur J Cancer, 12/01
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