In his comprehensive review of the current use of radiopharmaceuticals to palliate patients with osteoblastic metastases, Dr. Silberstein emphasizes the role of these agents in reducing bone pain.
Importantly, these agents tend to remain longer in bone that has been infiltrated by metastatic osteoblastic disease than in adjacent normal bone tissue. This increases the therapeutic benefit of these agents while tending to spare normal areas of bone and bone marrow from unnecessary irradiation.
Nevertheless, myelosuppression continues to be a problem, and its potential occurrence limits the use of these agents in patients with ongoing decreases in blood counts or those receiving myelosuppressive chemotherapy simultaneously. In addition, patients who receive these bone-seeking radiopharmaceuticals must be monitored at regular intervals for changes in blood counts.
Duration of Pain Relief
Although most studies found that these bone-seeking radionuclides reduce bone pain in the majority of patients with osteoblastic metastases,[2-5] the duration of this palliation varies greatly between patients and averages only about 4 to 6 months. Attempts to evaluate various doses of the different agents in an attempt to improve upon the degree and duration of pain relief have failed to clearly establish a dose-response relationship.
Moreover, the benefits of re-treatment with either the same or higher doses in patients who do not respond to initial therapy or who experience a recurrence of symptoms have not been well established. The suppression of blood counts by these agents limits the ability to re-treat these patients promptly.
Radiopharmaceuticals as Antitumor Agents
Theoretically, these bone-seeking radionuclides should be able to reduce the tumor burden via application of local radiotherapy to areas of tumor involvement. Unfortunately, there is little evidence to show that these agents actually reduce tumor burden in any significant way or improve overall survival when administered alone. Results from a single-arm trial involving prostate cancer patients treated with a combination of strontium-89 (55 mCi/kg every 3 months) and doxorubicin(Drug information on doxorubicin) were somewhat encouraging. A greater than 75% reduction in prostate-specific antigen was reported in nearly one-third of treated patients. However, the benefits of this combination compared to either agent alone can only be established with a randomized clinical trial.
Similarly, a trial involving myeloma patients treated with a combination of the bone-seeking radionuclide holmium-166 tetraazacyclododecanetetraacetic tetramethylenephosphonate and high-dose melphalan(Drug information on melphalan) (Alkeran), plus total body irradiation followed by autologous hematopoietic support, produced complete remissions in nearly half of patients with tolerable toxicity.
These encouraging results show the potential role of these bone-seeking radionuclides in the treatment of patients with osteolytic bone disease. This study has paved the way for a randomized trial evaluating this combination vs standard high-dose melphalan and total-body irradiation in patients with myeloma. Whether the bone-seeking radionuclides will also palliate bone pain in patients with osteolytic bone involvement remains to be determined.
The bisphosphonatesespecially intravenous pamidronate(Drug information on pamidronate) (Aredia)without radionuclides have demonstrated activity in palliating symptoms that result from osteolytic disease in patients with myeloma or breast cancer, and in reducing skeletal complications including pathologic fractures, spinal cord compression, surgery to bone, and radiotherapy.
Compared to the radionuclides, the ease of administration of these agents without bone marrow toxicity makes them highly attractive as antibone resorptive drugs for the treatment of cancer patients with enhanced bone loss. At this point, the ability of the bone-seeking radionuclides to reduce these skeletal complications has not been evaluated. It is important that future trials of these agents should be designed to determine their effect on these bony complications.
The potential benefits of combination therapy with bisphosphonates and radionuclides should also be studied but will require careful consideration with regard to dose and schedule. For example, it is possible that the simultaneous administration of bisphosphonates with bone-seeking radionuclides may inhibit the bone-seeking ability of the latter agents. In fact, in clinical trials involving holmium-166, patients must not have received bisphosphonates for approximately 2 months prior to administration of the radionuclide. However, the true optimal schedule of administration of these two types of agents remains unknown.
In addition, it is possible that the radionuclides may provide benefit for patients who show progressive bone involvement or who experience increasing bone pain while receiving ongoing bisphosphonate treatment. The overall chronic effect of bone-seeking radionuclides on bone strength in areas of the skeleton uninvolved with tumor also needs to be assessed. This may provide an additional rationale for chronic therapy with bisphosphonates in patients who have been treated with radionuclides.
Although studies evaluating a number of different bone-seeking radiopharmaceuticals for the treatment of patients with osteoblastic bone metastases show their ability to reduce bone pain in the majority of cases, the role of these agents as potential antitumor agents has not been thoroughly explored, particularly in combination with other chemotherapeutic agents or types of bone-seeking agents such as the bisphosphonates. Optimizing the dose and schedule of combinations of different types of agents will require well-designed clinical trials. In addition, the potential role of these bone-seeking radionuclides in patients with osteolytic disease should be explored further.