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Preventing and Treating Bone Metastases in mCRPC

Colin G. Evans, PhD
Published: Saturday, Apr 30, 2016

Renal cell carcinoma Bone metastases in metastatic castration-resistant prostate cancer (mCRPC) can invade a range of sites in the skeleton where they precipitate a spectrum of pathological processes that increase morbidity, negatively affect quality of life, and decrease survival. Not surprisingly, new treatments and treatment paradigms are being developed aimed at reducing the incidence of these events.1

Bone metastases appear most commonly in the ribs, the spine (cervical, thoracic, and lumbar vertebrae, and pelvis), and have also been documented in long bones (femur).2 Metastatic growth at these sites gives rise to severe bone pain, often requiring powerful analgesia and external beam radiation treatment. Spinal cord or nerve root compression, myelosuppression, and disturbances in calcium metabolism also commonly occur.1,3,4

A recent review summarized the pathophysiology of bone pain as, “components of neuropathic, inflammatory and ischemic pain, arising from ectopic sprouting and sensitization of primary afferent sensory nerve fibers within prostate cancer-invaded bones.” It further asserted that metastases arises and is perpetuated by virtue of the cross talk between the osteoclasts and osteoblasts and other factors involved in the bone microenvironment. 5 This multifactorial pathophysiology makes it challenging to manage and an imperative to avoid.1

The management of bone pain was explored in a study that included 1305 patients with prostate cancer and bone metastases.6 Overall, 76% of the patients had been treated with bone-targeting agents for a variety of causes, including bone pain (34%), high risk of bone complications (33%), number of bone metastases (12%), locations of bone metastases (8%), and prior history of bone complications (6%). Additionally, 27% of the patients with bone metastases needed opioids for the relief of bone pain.

A recent preclinical study has highlighted an unreported mechanism that promotes the growth of bone metastases in prostate cancer.7 Using a mouse model they showed that following injection of prostate cancer cells into the intramedullary cavity of the tibia, tumor growth increased pressure within the mouse tibia. In vitro experiments subsequently revealed that pressure applied to osteocytes facilitated prostate cancer growth and invasion, and this was mediated in part by an upregulation of CLL5 and matrix metalloproteinases in osteocytes.

These findings implicate osteocytes, responding to the increased pressure generated by tumor growth, in the orchestration of the metastatic niche within the bone in patients with prostate cancer.7 This again emphasizes the clinical imperative to reduce the incidence of bone metastases in prostate cancer.

Impact of Bone Pain on Survival and Quality of Life

Several studies have assessed the impact of bone pain on survival and quality of life. A retrospective analysis examined 599 patients from three randomized controlled trials conducted from 1992 to 1998.8 Patients in this analysis had progressive CRPC adenocarcinoma of the prostate and an ECOG performance status of 0 to 2. The Brief Pain Inventory (validated scale) gauged the impact of pain on selected daily activities and quality of life (QOL).

They found a median pain interference score of 17, and a statistically significant association between pain scores and the risk of death. Comparing men with low (<17) and high (≥17) pain scores, respectively, the median survival times were 17.6 versus 10.2 months (P <.001). When comparing the same two cohorts, median times to bone progression were 6.7 months and 3.8 months, respectively (P <.001).

Men with pain scores ≥17 had a 22% greater risk of bone progression than men with pain scores <17. Median times to PSA progression followed a similar pattern, with 4.0 versus 2.9 months for scores of <17 and ≥17 respectively (P <.001).8

Additionally, a study from 2002,9 found that skeletal-related events (SREs) have clinically meaningful and significant impact on health-related QOL, with physical, emotional, and functional wellbeing all declining after pathologic fractures and radiation therapy. Significant declines in preference and utility scores were noted after fractures and radiation. Pain intensity only declined after radiation treatment, but not after other SREs.

Moreover, another study identified an association between skeletal morbidities and patient reported outcomes and survival.10,11 The trial recruited 643 patients, and they received either zoledronic acid or placebo for 15 months. Patients with no SREs at 6 months (landmark) had significantly greater survival at 360 days post landmark (49.7% vs 28.2%; P = .02).

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