Bone is the most frequent and important site of metastatic cancer and is responsible for an enormous clinical burden and demand on health-care resources. Blum and colleagues comprehensively review the management of bone metastases, argue for a more integrated care pathway, and underscore the importance of bone-specific treatments in reducing skeletal complications to maintain quality of life and physical functioning.
Traditionally, cancer care has concentrated more on the underlying tumor and somewhat ignored the target organ for metastasis. Skeletal health in malignancy deserves a higher profile, especially now that welltolerated, specific, and convenient bisphosphonate treatment can prevent treatment-induced bone loss and reduce skeletal morbidity. We now appreciate that the interaction between cancer and bone is largely mediated by osteoclasts, irrespective of the underlying tumor type.
Accelerated bone resorption is thus at least as important in prostate cancer as it is in breast cancer and multiple myeloma. As a result, bisphosphonate treatment-most convincingly demonstrated by the recent trials of zoledronic acid (Zometa)-is a rational and effective treatment for all solid tumors affecting bone. The recent trials reviewed by Blum show about a 30% to 40% reduction in the risk of a skeletal complication across a broad range of solid tumors.
Timing and Cost Issues
Questions persist as to the timing and duration of treatment, and whether patients in greatest need of treatment can be identified to improve the cost-effectiveness of bisphosphonate therapy. Health economic analyses have shown that bisphosphonates are a relatively expensive intervention, especially in the United States, where the drug and administration costs of bisphosphonates are highest.
The use of specific bone resorption markers, such as type I collagen crosslinks, may enable better selection of patients and allow clinicians to tailor therapy to maintain a normal rate of bone resorption. This is an intense area of current investigation, as it is perhaps both unrealistic and unaffordable to administer long-term bisphosphonate treatment to every cancer patient with bone metastases. Evidence is accruing that, as in benign bone diseases, the aim of bisphosphonate treatment in metastatic bone disease should be to normalize bone resorption. Bone resorption levels correlate with both subjective improvement and the incidence of skeletal-related events (SREs). Patients with accelerated bone resorption are at higher risk for SREs, and thus, most likely to benefit from the use of a bisphosphonate.
Directions in Bisphosphonate Therapy
The optimum choice of bisphosphonates is confounded by varied and somewhat naive assessments of clinical benefit, although zoledronic acid seems to be the best agent currently available. SREs are important end points but are of varying importance; the clinical relevance of an asymptomatic vertebral fracture is completely different from that of spinal cord compression causing paraplegia. Multiple- event analyses, such as the Andersen-Gill model, that evaluate both the number and time between individual events are most informative. Robust economic modeling based on multiple-event analyses, and ideally incorporating clinical weighting of SREs, would help define the value of bisphosphonate administration more precisely.
How can we improve on the current situation? It is unlikely that other bisphosphonates in development are going to be more effective than the currently available agents like zoledronic acid. Investigators need to turn their attention to agents that target other aspects of the interaction between cancer and bone. Numerous promising compounds are in development, including endothelin-1 antagonists, antibodies to parathyroid hormone-related protein (PTHrP), and agents that interact with the RANK/RANK ligand/ osteoprotegerin cell-signaling system between osteoclasts and osteoblasts, which may prove to be useful additions to bisphosphonate treatment.
Guidelines for Optimal Care
As Blum and coauthors point out, proactive orthopedic surgery is an important component of care. In many centers, orthopedic surgeons are not a recognized part of the oncology team, and a lack of well-defined referral pathways limits timely surgical intervention to prevent long-bone fractures and treat spinal instability or reversible spinal cord compression.
Old habits die hard, and, in particular, fractionated radiotherapy for bone pain remains widely practiced despite level 1 evidence showing that single radiation doses are as effective as more protracted schedules. For the relief of pain, especially in patients with widespread disease, there is no clinical reason for fractionated treatment. The expenditure on unnecessarily protracted radiotherapy treatments would go a long way toward funding wider use of bonespecific treatments and orthopedic intervention.
In the United Kingdom, we have made progress in ensuring a more comprehensive and integrated management of bone metastases with the publication of treatment guidelines. Although these guidelines focus on breast cancer, many of the issues are applicable to other tumor types affecting bone, and the guidance has helped inform health-care providers and purchasers alike on improvements in care for this major area of clinical need.
The American Society of Clinical Oncology has also produced guidelines on the use of bisphosphonates in both breast cancer and multiple myeloma. It is important that comprehensive practice guidelines that stress the importance of skeletal health in cancer patients and define high-quality care for metastatic bone disease are produced. The review by Blum et al provides a useful overview of the subject upon which such guidance could be constructed.
Financial Disclosure: The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
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