Guideline
Recommendation for bone scan
Recommendation for CT/MRI
National Comprehensive Cancer Network (NCCN) [10]
Symptomatic patients
Those with a life expectancy >5 years and …
PSA >20
T2 disease with PSA >10
T3–T4 disease
Gleason score 8–10
T3–T4
T1–T2 and nomogram-predicted probability of lymph node metastasis >10 %
European Association of Urology (EAU) [11]
Bone pain
Poorly differentiated tumors and locally advanced disease irrespective of the serum PSA level
American Urology Association (AUA) [12]
PSA >20
PSA >20
Locally advanced disease
Gleason 8–10
European Society for Medical Oncology (ESMO) [13]
T3–T4
Gleason score 8–10
PSA > 20
Intermediate risk and …
Clinical suspicion of bone metastases
Gleason 4 + 3
PSA greater than 10
Consider in high-risk patients
European Society of Urogenital Radiology (ESUR) [14]
High-risk patients
Active surveillance patients
Intermediate-risk patients to plan curative intent therapy approaches
High-risk patients
The most common diagnostic test used to screen for bone metastases in newly diagnosed prostate cancer patients is the technetium bone scan (Fig. 5.1). Numerous studies evaluating how PSA values correlate with the likelihood of detecting bone metastasis have been performed. In men with serum PSA values of at least 10 ng/dl, Tc bone scan has reportedly detected bone metastasis in between 0.6 and 45.8 % of subjects. However, in studies evaluating a cutoff of 20 ng/ml, the detection range is reported to be between 14 and 26.5 % of persons [9].
Fig. 5.1
Technetium bone scan: Numerous bone lesions throughout the axial and appendicular skeleton in a man with metastatic prostate cancer are shown. Note the heavy involvement of the spine, which is typical
In a contemporary series of over 800 newly diagnosed prostate cancer patients with Gleason 8–10 (high-risk) cancers, bone metastases were detected in 17 % of men. In men with palpable disease on digital rectal examination having lower Gleason scores , bone metastasis was discovered in 8 % of men [9].
In men with androgen-insensitive prostate care without evidence of bone metastases (i.e., those with rising PSA values despite the use of therapies designed to remove or block testosterone to castrate levels in the serum), bone metastases developed by 2 years in approximately 40 % of subjects [2, 15, 16]. In subgroup analyses of a randomized trial in patients who had androgen-insensitive prostate cancer, a baseline PSA level of >24 ng/dl or a PSA doubling time of less than 6 months was correlated with the highest risk of developing bone metastases, with a reported rate exceeding 70 % by 3 years [2, 16].
Therapy
Prevention of Bone Metastases
Role of Surgical Treatment of the Primary Cancer
Approximately 85 % of men with newly diagnosed prostate cancer have disease clinically localized to the prostate alone. The Prostate Cancer Intervention Versus Observation Trial (PIVOT) trial [17], which studied a mostly PSA-screened population randomized to radical prostatectomy or observation, reported on some nonmortality endpoints. They found an absolute risk reduction of 6 % in the prostatectomy group over the watch-and-wait group (number needed to treat of 17) to prevent bone metastasis. Notably, this change in development of bone metastases was realized almost exclusively within the first 8 years following diagnosis and treatment.
Role of Androgen Deprivation Therapy Plus or Minus Radiation Therapy
There have been three randomized trials completed comparing the efficacy of the addition or radiotherapy to androgen deprivation therapy alone in men with high-risk but clinically localized prostate cancer. All of the studies showed a significant disease-specific and overall survival benefit by the addition of radiation to the primary site [18–20]. One of the trials specifically reported on metastasis-free survival, which implies a delay in the development of bone metastases specifically. After 8 years of follow-up, 11 % of subjects on androgen deprivation alone (continuous leuprolide with flutamide) developed bone metastases, as opposed to only 3 % of those persons who had combined ADT and radiotherapy [18].
Treatment of Bone Metastases
Role of Bisphosphonates
There have been numerous randomized trials evaluating the efficacy of bisphosphonates versus placebo in the treatment of bone metastases for various malignancies. The majority of the studies included subjects with any histologies, most commonly those with breast prostate multiple myeloma and lung cancer [21]. There are several randomized trials that have restricted their subjects to those with prostate cancer [22–25]. The Cochrane Collaboration has performed a systematic review of these randomized trials as it pertains to pain relief. When restricting the analysis to prostate-only studies, and pain relief at 12 weeks as the endpoint, the Cochrane group reported an odds ratio of 1.81 favoring bisphosphonate treatment over control. The 95 % confidence interval ranged from 0.82 to 4.02 (Fig. 5.2). Technically, this can be interpreted as not reaching “statistical significance.” The conclusion of the reviewers as it specifically pertained to primary disease sites was that “The small numbers of studies meant conclusions could not be made regarding the relative effectiveness of bisphosphonates on patients with different primary disease sites.” Overall, however, in pooled analyses of all disease sites, the number needed to treat to achieve pain relief with bisphosphonates at 4 weeks was 11 and at 12 weeks 7 [21]. A more detailed overview of bisphosphonates in the treatment of bone metastases will be addressed elsewhere in this book.
Fig. 5.2
Meta-analysis of bisphosphonates on alleviating prostate cancer bone pain. From Wong, R. and P.J. Wiffen, Bisphosphonates for the relief of pain secondary to bone metastases. Cochrane Database Syst Rev, 2002(2): p. CD002068. Reprinted with permission from John Wiley and Sons
Role of External Beam Radiation Therapy
Randomized trials of treatment with conventional radiotherapy have shown complete pain relief rates ranging from 15 to 54 %, and partial pain relief rates ranging from 28 to 89 % for persons with bone metastases [26–38]. These trials did not restrict subjects to those with prostate cancer, although breast and prostate patients accounted for the majority of subjects. The Bone Pain Trial Working Party Group showed a median time to pain relief in all patients of approximately 1 month, and a median time to complete pain response of 3–4 months, whereas median time to first increase in pain was approximately 12 months or longer [26]. Stereotactic body radiotherapy (SBRT) is an emerging treatment modality delivering five or fewer highly conformal, high-dose radiation treatments to bone metastases. Early outcomes claim superior pain relief and control over conventionally fractionated radiations, but randomized trials are currently ongoing. A complete overview of radiotherapy as it applies to the treatment and efficacy of bone metastases is discussed in the chapter on radiotherapy elsewhere in this book.
Role of Parenteral Radionuclides
Radionuclides can be used in patients with widespread prostate cancer bone metastases where focal therapies such as surgery or radiation will not be expected to palliate the symptoms. Radionuclide therapy is generally aimed at persons with osteoblastic or mixed-type lesions, as the mechanisms of action are particularly targeted to blastic/sclerotic processes. The isotopes currently in use are strontium-89, samarium-153, and more recently radium-223. Both radium and strontium are in the same column of the periodic table of the elements as calcium, and therefore act as calcium mimetics. They emit beta-particles which exert their tumoricidal properties. As such, they intercalate into bone where calcium would otherwise be deposited and effectively act as very targeted radiotherapies. Likewise, samarium-153 is a chelated tetraphosphonian compound that selectively accumulates in places of bone transformation by binding to hydroxyapatite.
Strontium-89 and Samarium-153
Two systematic reviews evaluating the role of strontium or samarium for the palliation of painful bone metastases have been completed [39, 40]. In the most complete and contemporary review by the Cochrane Collaboration, the conclusion was that there was a “small benefit” of these isotopes in providing “complete” or “complete/partial” pain relief over 1–6 months (NNT = 5 and 4, respectively). Nevertheless, the review also reported that there was “no conclusive evidence to demonstrate that radioisotopes modify the use of analgesia with respect to placebo” (hazard ratio 1.36 favoring isotopes, 95 % CI 0.77–2.40) (Fig. 5.3). Furthermore, radioisotopes did not reduce the risk of spinal cord compression (HR = 1.10, 95 % CI 0.39–3.07) [40]. Neither strontium nor samarium treatment has been shown to impact overall survival.
Fig. 5.3
Beta-emitting radionuclides for bone pain meta-analysis. From Roque, I.F.M., et al., Radioisotopes for metastatic bone pain. Cochrane Database Syst Rev, 2011(7): p. Cd003347. Reprinted with permission from John Wiley and Sons
Radium-223
Recently, radium-223 has been FDA approved for the treatment of prostate cancer bone metastases in men with castration-resistant disease. Radium-223 is an alpha particle emitter, which means that it will selectively destroy cells within only a few cell diameters (less than 100 μm) of where it is intercalated into bone as a calcium mimetic. This short path of the alpha particles results in a minimization of toxic effects to the bone marrow and adjacent healthy tissues. The landmark ALSYMPCA trial (Alpharadin in Symptomatic Prostate Cancer Patients) is a phase 3, randomized, double-bind, placebo-controlled trial with mature results [41]. Unlike other parenteral radioisotopes, the use of radium-223 showed a significant overall survival benefit in men with castration resistant prostate cancer (HR = 0.7, 95 % CI 0.58–0.83; median survival 14.9 months versus 11.3 for placebo). Secondary endpoints of the study all significantly favored radium-223 including time to first symptomatic skeletal event (HR 0.66, 95 % CI 0.52–0.83—median time 15.6 months versus 9.8 months placebo); and time to increase in PSA level (HR 0.64, 95 % CI 0.54–0.77—median time 3.6 months versus 3.4 months placebo). Most notably, there were fewer adverse events in the radium-223 cohort than the placebo group. Given the overall survival benefit, decrease in SREs, and low side effect profile of radium-223, there is much excitement within the oncologic community about using this therapy in combination with other therapies such as chemotherapy, newer generation androgen deprivation therapy agents, and focal radiotherapies in men with metastatic prostate cancer.
Role of Androgen Deprivation Therapy
The 1966 Nobel Prize for Physiology or Medicine was awarded to Charles Huggins for the discovery that androgen ablation therapy causes regression of primary and metastatic prostate cancer [42]. The production of serum testosterone is primarily controlled by the hypothalamus via its production of luteinizing hormone-releasing hormone (LHRH) which acts on the anterior pituitary gland to release luteinizing hormone (LH) . Within the testicle the LH is recognized by the Leydig cells within the testes signaling the production of testosterone. This pathway accounts for about 90 % of the production of serum testosterone. The remaining 10 % is peripherally produced by adrenal steroid conversion into testosterone (Fig. 5.4). Numerous drugs have been developed that target various points along these pathways, which ultimately interfere with testosterone signaling within the cancer cell. These include LHRH agonists (leuprolide, goserelin, triptorelin), LHRH antagonists (degarelix acetate), nonsteroidal antiandrogens that bind the androgen receptor (bicalutamide, flutamide, enzalutamide), and 17 α-hydroxylase/C17,20 lyase inhibitors (abiraterone). In men with metastatic disease, initial androgen deprivation therapy results in a median progression-free survival of 12–33 months [43, 44]. However, one can use the serum PSA value after initiation of ADT to prognosticate life expectancy. The Southwest Oncology Group (SWOG) performed a randomized trial evaluating the effect of immediate and continuous androgen deprivation therapy versus intermittent androgen deprivation for men with metastatic prostate cancer. All men in this trial had 7 months of induction ADT. The median survival was 13 months for patients with a PSA of more than 4 ng/ml after induction therapy, 44 months for patients with a PSA of more than 0.2–4 ng/ml or less, and 75 months for patients with PSA of 0.2 ng/ml or less [45]. In subjects with bone pain enrolled on the trial, there was a trend towards improved overall survival for continuous androgen deprivation therapy, but overall the results of for non-inferiority of intermittent versus continuous ADT were inconclusive for the trial [46].
