Metastasis to bone represents an all-too-frequent complication of advanced-stage prostate cancer (PCa): 50% to 70% of these patients will ultimately develop this devastating complication. PCa preferentially metastasizes to bone, and the skeletal complications increase mortality and decrease quality of life. The clinical consequences of skeletal metastasis also include pain, skeletal-related events (SREs), and increased costs of therapy. Recent advances in our understanding of the mechanisms of metastasis and the physiologic changes that occur with it, together with the introduction of new treatments, are furthering our ability to combat this problem. In this review, we examine bone-targeted palliative agents, nontargeted systemic cytotoxic therapies, and bone-targeted agents that go beyond palliation to also potentially improve progression-free and overall survival. We specifically focus on post-treatment outcomes—including pain relief, decreased opioid use, improvement in quality of life, freedom from SREs or new bony metastases, and increases in overall survival—in men with symptomatic, metastatic PCa. Treatments discussed include varied drug classes, such as bisphosphonates and human monoclonal antibodies; beta-emitting radiopharmaceuticals; external beam radiotherapy; systemic chemotherapies; Src inhibitors; endothelin-A receptor antagonists; clusterin inhibitors; and alpha-emitting radiopharmaceuticals.
Metastasis to bone represents a frequent complication of advanced-stage prostate cancer (PCa). The exact prevalence of bony metastasis is generally unknown, but some estimate that 50% to 70% of patients with advanced-stage PCa will ultimately develop this devastating complication.[1,2] PCa preferentially metastasizes to the axial skeleton, including the vertebrae, pelvis, proximal ends of long bones, and skull. The resulting skeletal complications are widely recognized to increase mortality and decrease quality of life, since affected patients suffer loss of independence, mobility, and social functioning (Figure 1). The clinical consequences of skeletal metastasis also include pain, skeletal-related events (SREs), and increased costs of therapy. Recent advances in our understanding of the mechanisms of metastasis and of the physiologic changes that occur along with it, along with the introduction of new treatments, are improving our ability to combat this problem.
There are several important characteristics of bone that implicate it as the preferential site for metastasis of visceral cancers. In 1889, Stephen Paget first noted in his “seed and soil” hypothesis that the complementary characteristics of target organs and circulating tumor cells would determine where tumors metastasize. Bone has high blood flow to marrow, where many important growth factors and cytokines reside and are involved in the constant remodeling of bone; these factors include transforming growth factor β, endothelin-1, interleukin (IL)-1 and IL-6, prostaglandins, insulin-like growth factors, fibroblast growth factors, and platelet-derived growth factors. The final necessary step in metastasis involves tumor cell expression of adhesive molecules. The bone microenvironment milieu provides the perfect environment for tumor cell deposition and clonal expansion.
Skeletal pain from metastasis manifests as a deep nonspecific ache that worsens with movement and that can be quite severe; it progresses as metastatic disease progresses. Patients usually start on nonsteroidal anti-inflammatory drugs (NSAIDs), move to opioids, and then require more advanced, systemic palliation therapies, which will be reviewed here. Some early studies mentioned in the sections below measured the palliative effects of an intervention using pain scale questionnaires or diaries, opioid usage (either prescribed or patient-reported usage), patient-reported sleep patterns, or even doctor-reported pain scores. As the reader may realize, some of these measures are highly subjective and vary from patient to patient, making the comparison of different studies more difficult.
Unfortunately, few treatments specifically target tumor cells that reside in bone, and those that are available have drawbacks related to dose-limiting toxicities and may have only small therapeutic benefit. Further, patients who have exhausted chemotherapeutic options or who do not tolerate their side effects find themselves with a limited number of treatment options after the diagnosis of skeletal metastasis. This review will examine agents with potential activity in the palliation and treatment of skeletal metastases of PCa, and will weigh the clinical-outcomes evidence for and against their broad use (Table).
Targeted Treatments for Symptom Palliation
Bisphosphonates target the osteoclastic feedback loop that develops between a metastatic lesion and bone, thereby preventing or delaying the onset of SREs.[6,7] These drugs bind to the active site of bone resorption and turnover, enter osteoclasts, disrupt cellular signaling pathways, induce apoptosis, and prevent further resorption. The goals of bisphosphonate therapy include increasing bone mineral density (BMD), preventing new and recurrent SREs, palliating bone pain, reducing the need for other therapies, and mitigating further morbidity. The efficacy of this class of drug in attaining these clinical goals has been investigated in multiple placebo-controlled randomized trials, which have shown significant improvements in clinical outcomes with these agents.[9-11] Zoledronic acid (Zometa) is a bisphosphonate approved for the prevention of SREs in men with metastatic castration-resistant prostate cancer (CRPC). Its role was established by a study of men with metastatic CRPC by Saad et al, in which 4 mg of zoledronic acid was given every 3 weeks; the incidence of SREs was reduced from 44% in the placebo arm to 33% in the zoledronic acid arm. Follow-up phase II trials have examined other dosing regimens, such as 4 mg every 3 months—or even yearly—and have demonstrated preservation of BMD in men receiving androgen-deprivation therapy (ADT), but these studies did not specifically examine outcomes involving SREs.[13,14]
Bisphosphonates, when used for the treatment of debilitating bone pain, reduce the need for NSAIDs and opioid analgesics, which can have unintended consequences for patients with advanced cancer. Zoledronic acid is administered intravenously. Despite its systemic activity, it lacks the myelosuppressive side effects of chemotherapy or radiation, and it can be used as an adjunct to such therapies. Bisphosphonates have never been shown to prevent metastasis, but they do offer prevention of their deleterious effects and mitigation of SREs and bone pain. Some studies have demonstrated in vitro synergistic cytotoxic effects between bisphosphonates and chemotherapies, but these have never been borne out in clinical studies.[15,16]
Human monoclonal antibodies
Denosumab (Xgeva) is a fully human monoclonal antibody against receptor activator of nuclear factor-κB ligand (RANKL); it disrupts the normal homeostatic messaging that occurs between osteoblasts and osteoclasts in bone, and its administration causes a decrease in bone turnover and resorption (Figure 2). Denosumab has been well studied in several clinical areas that involve bone loss, including in postmenopausal women and in men with CRPC. It is currently FDA-approved for use in both postmenopausal women and men with advanced prostate cancer and bone metastase, to prevent bone loss and subsequent fracture.[17,18] The latter group presents a particular challenge with respect to potential loss in BMD and subsequent SREs for several reasons, including prolonged use of ADT and/or development of skeletal metastasis. Below we highlight several of the key studies of denosumab that have been published to date.
In a phase II trial of denosumab in patients with bone metastases from prostate, breast, and other cancers who were noted to have persistently elevated bone turnover markers (urinary N-telopeptide [uNTx]) while receiving intravenous (IV) bisphosphonate treatment, patients were randomly assigned to receive subcutaneous denosumab or continuation of the IV bisphosphonate. This study noted that more patients achieved normal levels of urinary bone turnover markers (about 64% vs 37%; P = .01) and that patients experienced fewer SREs (8% vs 17%; odds ratio [OR], 0.31; 95% confidence interval [CI], 0.08-1.18) with denosumab than with bisphosphonate treatment. Similar numbers of patients suffered adverse events in the two arms.
In 2009, Smith et al published the results of a phase III randomized controlled trial comparing denosumab to placebo in patients with nonmetastatic PCa who were receiving ADT. The key endpoints were percent change in BMD in the lumbar spine, total hip, and femoral neck at 24 and 36 months, and incidence of new vertebral fractures. Lumbar spine BMD increased by 5.6% in the treatment group as opposed to a BMD decrease of 1.0% in the placebo arm (P < .001). Patients who received denosumab also experienced a decreased incidence of new vertebral fractures at 36 months (1.5% vs 3.9% with placebo) (relative risk, 0.38; 95% CI, 0.19 to 0.78; P = .006). Subsequent analyses noted that patients with high baseline levels of turnover markers (serum C-telopeptide and tartrate-resistant alkaline phosphatase 5b) had the greatest increases in BMD.
Phase III studies comparing denosumab to the bisphosphonate zoledronic acid with respect to time to development of a first SRE in patients with CRPC and at least one bone metastasis were published in 2010.[22,23] Denosumab improved the median time to development of a first SRE (20.7 months vs 17.1 months for zoledronic acid, a difference of 3.6 months). Rates of osteonecrosis of the jaw were not significantly different between the two study arms, at 2.3% and 1.3%, respectively (P = .09), but hypocalcemia was observed more frequently with denosumab than with zoledronic acid (13% vs 6%). This report showed no difference in overall survival between the two groups.
Recently, results were presented regarding the ability of denosumab to prevent the development of bone metastasis. Some have hypothesized that, by limiting bone turnover and resorption, denosumab may make bone an environment that is less amenable to circulating tumor cells remaining and clonally expanding. In this report by Saad et al, denosumab increased the time to development of first bone metastasis by a median of 4.2 months compared with placebo, in a population of men deemed to be at high risk for development of metastatic disease. No difference in overall survival was noted, however.
In summary, denosumab is a fully human monoclonal antibody against RANKL; it inhibits osteoclast activity, limiting bone turnover and resorption. It is approved for the prevention of SREs in high-risk postmenopausal women and men with advanced prostate cancer and bone metastasis. Denosumab does not have any direct antitumor activity, and while there is some recent evidence that denosumab prevents development of bone metastasis, it has not yet been approved for this use. Studies published to date have demonstrated its ability to help prevent and reduce SREs in men with and without bone metastasis, compared with bisphosphonates and placebo, to increase BMD over placebo, and to improve the time to development of a first SRE compared with zoledronic acid. Clinicians will ultimately have to grapple with cost-benefit issues, since denosumab is more expensive than zoledronic acid. Clinicians will also have to weigh the convenience of a subcutaneous injection of denosumab against the intravenous administration of zoledronic acid and fewer cases of renal toxicity with denosumab. As mentioned, in a head-to-head study, denosumab delayed SREs by 3.6 months compared with zoledronic acid.
Patients with multifocal metastases from visceral cancers, primarily breast and prostate, have long had their symptoms palliated with radiopharmaceuticals. These patients typically suffer marked decreases in quality of life as a result of pain, which has been described as "deep nonspecific ache rising in intensity as the disease progresses, incident pain on movement (allodynia), which renders patients virtually immobile, and spontaneous pain that can be severe." Patients generally progress from NSAIDs to opioids, and then to more advanced, systemic palliation therapies.
Mechanism of action, side effects, range, and safety considerations. While discrete sites of metastasis can be amenable to external beam radiotherapy for the palliation of pain, diffuse bony metastatic disease requires agents that preferably localize to bone, have limited toxicity but long enough half-lives to kill tumor cells, have favorable pharmacokinetic properties, and are safe to handle. To date, phosphorus-32, strontium-89 (Metastron), samarium-153 (Quadramet), rhenium-186, and rhenium-188 have all been used in this setting. 32P was noted early on to cause marked bone marrow suppression and thus is not used or approved for clinical use. The beta particles (which consist of electrons) emitted by these radioisotopes cause the destruction of malignant cells through DNA damage and the induction of apoptosis. They have a relatively low, linear energy transfer (LET) radiation that tracks 2.5 to 11 mm. The limited range of these particles minimizes danger to healthcare personnel, but the deceleration of beta particles as they pass through shielding (eg, lead) can result in the formation of more dangerous, high-energy x-rays. In addition to emitting beta particles, 153Sm, 186Re, and 188Re also decay to gamma photons, allowing for external monitoring of radionuclide biodistribution after administration. Bone marrow suppression, primarily in the form of thrombocytopenia and leukopenia, is the most common side effect seen with clinical use. 89Sr and 153Sm are FDA-approved for the palliation of bone pain associated with metastasis, while 186Re and 188Re are still considered experimental.
Strontium-89. The therapeutic benefit of 89Sr was first established in 1942 by Pecher, who administered 3 doses over 5 months to a patient with advanced prostate cancer metastasized to bone. The patient was noted to have an excellent clinical and radiographic response. Since that time, many observational and randomized controlled trials examining the use of 89Sr have been published. Strontium sits below calcium in the periodic table, and it thus follows the path of calcium in the human body and localizes to areas of bone where calcium turnover is the greatest. In general, although subjective pain scales and definitions of responders differ between many of these studies, published reports have largely demonstrated that the palliative effect of 89Sr is substantial (absolute risk reduction for achieving pain relief, 0.321; 95% CI, −0.035 to 0.678) and not secondary to a placebo effect. Comparison of 89Sr and local external beam radiation showed similar response rates but no difference in overall survival.
Samarium-153. 153Sm was approved by the FDA in 1997 for palliation of pain from cancer metastasized to bone. The radioactive element is chelated to ethylenediaminetetramethylene phosphonic acid to form 153Sm-EDTMP. This compound is cleared renally within 6 hours of intravenous administration. The element itself has a half-life of 1.9 days, but it is cleared from the blood with a t1/2 of 5.5 minutes. Although its mechanisms of targeting bone are not completely understood, 153Sm preferentially accumulates and associates with hydroxyapatite crystals in areas of high bone turnover. Examinations of metastatic lesions have noted concentrations of 153Sm that are five times those seen in normal tissue, thus exposing these tumors to greater amounts of radiation and protecting healthy tissues. The range of emitted beta particles from 153Sm is only 0.5 to 3 mm, shorter than that for beta particles from 89Sr.
Multiple observational studies have reported improvements in pain scores for patients with bony metastases from CRPC. Phase II randomized controlled trials have demonstrated that higher doses of 153Sm-EDTMP (37 megabecquerel/kg) were more effective than lower doses (18.5 megabecquerel/kg) or placebo at lowering pain scores and reducing analgesic use.[30,31] A phase III randomized controlled trial randomly assigned patients to receive either radioactive 153Sm-EDTMP or nonradioactive 152
Sm-EDTMP. The investigators noted significant reductions in analgesic use in the active treatment group at 4 weeks, 9% of complete responders had a greater than 50% reduction in serum prostate-specific antigen (PSA), and myelosuppression accounted for the majority of side effects. Sartor et al also demonstrated that 153Sm-EDTMP can be safely redosed in patients after loss of analgesic effect.
Comparisons of various beta emitters. Multiple studies have performed head-to-head comparisons of different beta particle–emitting radionuclides reviewed here. No clinically significant differences in pain, analgesic usage, or performance status have been noted. Recommendations to date have maintained that clinician or patient preference, ease and safety of handling, pharmacokinetics, and cost remain the primary determinants of which therapy should be used. There have been shortages in supplies of radionuclides in recent years, and this may pose some limitations on the choice of radiopharmaceutical.
Beta emitters in combination with chemotherapy and bisphosphonates. Although beta particle–emitting compounds have shown mixed data with regard to PSA response rates after therapy, researchers have investigated combinations of these radioactive, bone-targeted therapies with chemotherapeutic drugs and/or bisphosphonates to determine whether any synergistic effects might be seen. Several have hypothesized that the radiation might sensitize tumor cells to further damage by chemotherapeutic agents. A phase II trial randomly assigned patients to chemotherapy either with or without 89Sr. Overall survival improved considerably in the combination arm compared with chemotherapy alone (28 vs 17 months). Another phase II trial examined the combination of docetaxel and 153Sm-EDTMP in men with bone metastases from CRPC: PSA response was seen in 77%, pain response was seen in 69%, and the combination was well tolerated. The primary endpoint was PSA progression–free survival, which was 6.4 months, with all patients ultimately relapsing. Median survival was 29 months.
In summary, these agents offer palliation of pain and can reduce opioid use. While the radiation produced by these compounds is cytotoxic, PSA response is not the primary indicator of effect, and no study has shown these compounds by themselves to affect overall survival. They are relatively well tolerated, with the most common side effect being myelosuppression that is reversible. These drugs may be re-dosed for continued effect, and combinations with other accepted treatments for metastatic CRPC may provide synergistic effects. Given the concerns regarding radiation safety of clinical personnel and patients, they should always be administered in special facilities by qualified personnel.
External beam radiation therapy
Bony metastasis of primary cancers results in considerable morbidity for patients, primarily causing pain, neurologic and functional sequalae, and hypercalcemia. External beam radiotherapy has been a mainstay of palliation and treatment for these lesions, but the exact mechanism of action is not well defined. The doses required to provide pain relief are far less than those required to destroy tumorous lesions, implying effects on bone homeostasis and alteration of signaling pathways involved in bone turnover. Palliative goals of external beam radiotherapy include improvement in quality of life through pain reduction, prevention of further bone destruction, maintenance of the functional capacity of the patient, and prevention of neurologic sequalae, particularly in metastases to the spinal column.
Most studies report complete or partial pain relief in 70%, with 40% to 60% of those reporting partial relief. Onset of relief is variable, ranging from as soon as 48 hours after therapy to 4 weeks. Focal therapy can treat single lesions confirmed by imaging and correlated with patient symptoms. Considerations of site, surrounding tissues, margin, performance status, and current hematologic parameters should be taken into account when making decisions regarding treatment volume and dosing. Hemibody radiation should be considered in patients with multiple metastases. One trial compared local radiation to local radiation plus hemibody radiation. Development of new, symptomatic lesions was similar between the two groups, but time to progression was significantly longer in the combination group (12.6 vs 6.3 months).
The optimum dose and timing of delivery has been a hotly contested issue, but a meta-analysis showed no significant differences between the different schedules. A review of 12 randomized trials on the duration of pain relief and median overall survival by Ratanatharathorn et al largely concluded that no patients had durable responses that lasted the remainder of the life of the patient and that higher doses trended to the greatest pain relief. With respect to the cost-benefit ratio of a single-fraction dose (4 to 8 Gy) vs multifraction higher doses of radiotherapy (30 to 45 Gy total), this meta-analysis concluded that while the former does provide some relief in a large percentage of patients, the higher-dose fractionated regimens were much better. In the United States, a survey of radiation oncologists showed that most employ 30 Gy in 10 fractions.
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