Managing Bone Metastases Through a Multidisciplinary Approach
Bone metastases are exceedingly common among patients with cancer and can significantly affect quality of life. Approximately 65% to 75% of patients with advanced breast or prostate cancer have bone metastases, which can lead to devastating complications, according to Winston Tan, MD, FACP, Chair, Associated Professor of Medicine, Mayo Clinic, Jacksonville, FL.
“Very often we talk about bone loss, but we should be talking about the patient,” said Dr Tan. “Is the patient debilitated, having difficulty walking, or unable to walk? We need to understand what’s happening to them, because these complications lead to debilitation.”
At the 2018 Multinational Association of Supportive Care in Cancer meeting, Dr Tan discussed the challenges of and current strategies for dealing with bone health maintenance in patients with advanced cancer.
Bone metastases are most prevalent in patients with advanced breast (70%-80%), prostate (70%-80%), thyroid (60%), lung (10%-50%), and renal (30%) cancers. Patients can be asymptomatic or could have bone pain, a bone fracture, or manifestations of hypercalcemia when they present with metastases, which underlines the importance of careful patient evaluation.
The consequences of having bone metastases include reduced survival, morbidity, and pain, as well as skeletal-related events.
Among patients with bone metastases, skeletal-related events are extremely common and may include bone fractures, spinal cord compression, bone pain, and hypercalcemia. Delaying skeletal-related events and simultaneously delivering appropriate treatment can be another major hurdle in caring for these patients, said Dr Tan.
Radiation is a vital treatment approach in preventing skeletal-related events. According to the 2017 ASTRO clinical practice guidelines, external beam radiotherapy continues to be the mainstay treatment for bone metastases–related pain and morbidity.1
Dr Tan noted that smaller doses of radiation can be just as effective as fractionated doses for controlling pain. Multiple prospective randomized clinical trials have demonstrated similar rates of pain relief from single-dose or fractionated radiation treatment courses for patients with painful, previously unirradiated bone metastases.
Although a patient will have an increased risk for disease recurrence after receiving a single 8-Gy fraction of radiation, it can be a preferable treatment approach if a patient lives in a rural area with little access to radiation treatments, and can optimize patient and caregiver convenience, Dr Tan pointed out.
Bisphosphonate and Denosumab Treatments
Bisphosphonates and denosumab (Xgeva) are also vital parts of the armamentarium in the treatment of multiple bone complications in various cancers.
The American Society of Clinical Oncology/Cancer Care Ontario joint clinical practice guideline on the use of adjuvant bisphosphonates and other bone-modifying agents in breast cancer recommends the use of the bisphosphonates zoledronic acid (Zometa) or clodronate (Bonefos).2 These agents should “be considered as adjuvant therapy for postmenopausal patients with breast cancer who are deemed candidates for adjuvant systemic therapy.”2
Two to 5 years of therapy with adjuvant bisphosphonate therapy have been shown to reduce the risk for breast cancer mortality by 18%, Dr Tan reported.
One Cochrane Review of randomized controlled trials in breast cancer showed that bisphosphonates decreased the risk for skeletal-related events across all of the studies.3
In a 2010 study, denosumab was compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer. “The primary end point was time to first on-study” skeletal-related event, and “improved efficacy with denosumab was observed as early as 6 months.”4 According to Dr Tan, although the results in this particular study did not translate to improved survival outcomes, it still has significant implications for patients’ quality of life.
“A skeletal-related event, such as a fracture in a patient with cancer, can lead to significant morbidity and complications in the short term, sometimes in less than a year,” Dr Tan said.
The use of bisphosphonates and denosumab, however, does not replace the need for external beam radiotherapy in appropriate patients.
Promising Research on the Horizon
Early clinical studies of cabozantinib (Cabometyx) in patients with metastatic prostate cancer demonstrated significant and rapid effects on bone scan lesions, as well as on markers of bone formation and resorption, bone pain, and narcotic use. In addition, a significant improvement in progression-free survival was seen with cabozantinib compared with placebo, although no improvement was found in overall survival, Dr Tan reported.
Of a subset analysis of 108 patients with renal-cell cancer and bone metastases in a 2018 study of cabozantinib, 21 patients had complete resolution of their bone lesions, and 61 patients had partial lesion shrinkage.5
Other encouraging research has shown that among patients with prostate cancer, apalutamide (Erleada) and enzalutamide (Xtandi) can prevent bone metastases altogether. Studies of radium-223 (Xofigo) and pembrolizumab (Keytruda) are ongoing, and focus on changing the microenvironment so that immunotherapy will be more effective.
In the treatment of bone metastases in patients with cancer, there are still many questions without answers. Dr Tan suggests that future research topics should include (1) determining whether osteoclasts are the only stromal cell type that should be targeted therapeutically, or if there are new cancer or bone stromal targets that should be developed; (2) furthering our understanding of the biologic mechanisms of pain associated with bone metastasis; and (3) learning why bisphosphonates and denosumab do not prolong overall survival in patients with metastatic bone cancer.
- Lutz S, Balboni T, Jones J, et al. Palliative radiation therapy for bone metastases: update of an ASTRO evidence-based guideline. Pract Radiat Oncol. 2017;7:4-12.
- Dhesy-Thind S, Fletcher GG, Blanchette PS, et al. Use of adjuvant bisphosphonates and other bone-modifying agents in breast cancer: a Cancer Care Ontario and American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2017;35:2062-2081.
- Pavlakis N, Schmidt RL, Stockler MR. Bisphosphonates for breast cancer. Cochrane Database Syst Rev. July 2005:CD003474.
- Stopeck AT, Lipton A, Body JJ, et al. Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study. J Clin Oncol. 2010;28:5132-5139.
- Escudier B, Powels T, Motzer RJ, et al. Cabozantinib, a new standard of care for patients with advanced renal cell carcinoma and bone metastases? Subgroup analysis of the METEOR trial. J Clin Oncol. 2018;35:765-772.
Mechanism of Pathway: Considerations of Cytogenetic and Molecular Mutation Status for Patients with Acute Myeloid Leukemia: A Deeper Look at the Role of Diagnostic and Ongoing Testing Across the Care Continuum
Acute myeloid leukemia (AML) is a heterogeneous disease that is characterized by uncontrolled proliferation of undifferentiated myeloid progenitors. While these leukemic blasts accumulate in the bone marrow and peripheral blood, impairment of normal hematopoiesis may lead to a reduction in the number of differentiated myeloid cells (granulocytes, neutrophils, monocytes, erythrocytes, megakaryocytes). Associated symptoms and consequences include anemia, bleeding, and an increased risk for infection.
According to data from a preliminary phase 1b clinical trial, a novel approach using the investigational toll-like receptor 9 (TLR-9) agonist CMP-001 in combination with pembrolizumab may have the potential to reverse resistance to anti–PD-1 therapy.