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BISPHOSPHONATES IN PALLIATIVE CARE
The clinical consequences of bone involvement by cancer can be severe, including pain, fractures, immobility, neurologic compromise and hypercalcemia. While effective analgesics, systemic cancer treatment and local radiation remain the pillars of therapy, the last few years have seen significant advances in the use of bisphosphonates to improve the quality of life of affected patients and reduce their pain and risk of skeletal complications. More potent second generation agents have entered widespread use and there are now convincing studies supporting them, particularly for multiple myeloma and breast cancer.
Mechanism: In myeloma and metastatic carcinoma, lytic lesions are usually seen and destruction is mediated by "osteoclast activating factors", liberated by immune effector cells and monocytes. Bisphosphonates inhibit osteoclasts, possibly by altering bone structure/binding sites and affecting lysosomal function (the primary mechanism is not known).
Drugs: Etidronate (Didronel") has not been effective in these settings. The two bisphosphonates now in common usage include the first generation clodronate (Bonefos", Ostac", abbrev. CLOD) and the second generation drug pamidronate (Aredia", also known as APD, abbrev PAM). While both have poor oral bioavailability, CLOD can be given orally (800 mg po bid, bioavailability 1-2%), although sometimes causes GI adverse effects. It is not available in the USA and key studies supporting it used older statistical methodologies that are now known to be deficient9. PAM is more potent and is given usually at a dose of 90 mg iv q 4 wks (in about 500 mL N/S over 2-4 h). Lower doses may be used to treat mild hypercalcemia and q 3 wkly dosing may be more effective in the treatment of bone pain. Both agents are well tolerated iv with side effects being quite rare, including brief fever, flu-like symptoms, cramps, GI complaints, dizziness, rash/itching and eye irritation. In our practice, these are very rare and often occur only with the first dose. Alendronate (Fosamax") has not been studied in malignancy. A newer drug, zoledronate (Zometa"), is more potent and results of randomized trials comparing it to PAM should be available in the next few years. It may be administered more rapidly.
Many end points have been studied in bisphosphonate trials, including radiographic changes. However, the most meaningful results relate to clinically important parameters such as pathologic fractures, cord compression, the need for surgery or radiation (skeletal related events, SRE); hypercalcemia; and pain control, quality of life (QOL).
CLOD has been shown to decrease the radiographic progression of lytic lesions in myeloma but not to affect the more important end points mentioned above1. In breast cancer, several smaller studies show CLOD can reduce the incidence of hypercalcemia and vertebral fracture4 but the statistical methods used in the key studies have been refuted. PAM has more supportive data of high quality behind it. In myeloma, in a randomized study of 377 evaluable pts, fewer pts on PAM had SREs at 9 mos compared with placebo (41 vs 24%) with fewer events per year and the time to first SRE was delayed. In metastatic breast cancer, PAM has been shown to decrease the incidence of SREs significantly5. Over 24 months, fractures were decreased by 27% (relative reduction) and all SREs were reduced (51% compared with 64% on placebo). A more recent multicentre study6 of 372 pts confirms a decreased skeletal morbidity rate even up to 24 cycles of therapy with a decreased SRE rate (56% vs 67% with placebo) and delay until first SRE. When used for pain control, clinically significant improvements in pain scores , QOL indices , and analgesic requirements are seen, often after the first 2 doses. Overall survival has not been improved, however, in bisphosphonate trials (except perhaps with PAM in high risk myeloma pts).
Costs: These are all costly agents. The parenteral agents are covered by the homecare program (without restriction) and many of our patients are treated at home. The costs of PAM are reimbursed to approved cancer clinics by Cancer Care Ontario (through a special program for novel or expensive cancer therapies) for most myeloma pts and metastatic breast cancer pts who cannot tolerate oral CLOD. The data supporting iv CLOD currently is not strong enough to support its routine use for these indications9. Oral CLOD is covered by the ODB as a limited use drug (for hypercalcemia, code #280; for myeloma or bone mets, code #281). Despite the drug costs, they are cost effective for the system as a whole since the costs of treating skeletal complications is so high. In metastatic breast cancer, over 60% of inpatient care costs relate to the treatment of SREs and bone pain.
Summary: In our experience, we have observed a clear improvement in the overall QOL of our patients since the widespread use of PAM began a few years ago. In patients with metastatic diseases with a very short survival prognosis (< 3 mos) or with other visceral metastases, bisphosphonates are not likely to be of much benefit. However, if cost were not an issue, most other patients with lytic bone lesions would be reasonable candidates. Currently, bisphosphonates should be discussed with all patients with myeloma or breast cancer with lytic metastases (in whom it can double the time until 1st SRE) and considered in any cancer patient with painful bone mets as an adjunct to other analgesia and cancer treatment. We find PAM effective for pain control in other cancers with bone metastases and anecdotally we find it to be superior to CLOD (even effective in CLOD "failures"). PAM is also effective in Pagets disease of bone. The future may also find such agents useful in the prevention of metastases in high risk breast cancer patients. While bisphoshonates by no means replace effective palliative radiation or analgesia, they clearly are an exciting addition to our armamentarium!
S.R. Sehdev, MD, FRCPC, B.C. (ABIM),
William Osler Health Centre, Brampton Memorial Hospital Campus
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