INVITED REVIEW
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Current concepts and trends in the treatment of bone metastases in patients with advanced prostate cancer


Department of Urology, University Hospital Tuebingen, Tuebingen 72076, Germany

Date of Submission03-May-2017
Date of Acceptance31-Oct-2017
Date of Web Publication29-Dec-2017

Correspondence Address:
Arnulf Stenzl,
Department of Urology, University Hospital Tuebingen, Tuebingen 72076, Germany

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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/aja.aja_59_17

PMID: 29286005

  Abstract 


Bone metastases have a major impact on quality of life and survival of patients with advanced prostate cancer. In the last decade, the development and approval of substances inhibiting the vicious cycle of bone metastases have enabled the reduction of complications caused by bone metastases in patients with castration-resistant prostate cancer. These drugs have raised awareness of the importance of skeletal-related events which in the meantime represent an important end point also in trials using agents not specifically designed for bone lesions. Second-generation antihormonal drugs such as enzalutamide or abiraterone have been shown to have a positive impact on the incidence of skeletal complications and therefore provide an important tool in the armamentarium used for treating bone metastases. Radiopharmaceuticals such as radium-223 dichloride ([223Ra]) have been demonstrated not only to reduce skeletal-related events and bone-related pain, but also to prolong overall survival, thereby being the first bone-targeting agent showing a survival benefit. As previous studies have not provided an obvious benefit of bone-targeted lesions in castration-sensitive disease, the use of these agents is not recommended. In oligometastatic prostate cancer, the role of local treatment of metastases using stereotactic radiation or radiosurgery is a matter of intense debates and may play an increasing role in the future.

Keywords: bone metastases; bone-targeting agents; denosumab; hormonal therapy; prostate cancer; radium-223 dichloride; zoledronic acid


Article in PDF

How to cite this URL:
Hegemann M, Maas M, Rausch S, Walz S, Bedke J, Stenzl A, Todenhöfer T. Current concepts and trends in the treatment of bone metastases in patients with advanced prostate cancer. Asian J Androl [Epub ahead of print] [cited 2018 Dec 9]. Available from: http://www.ajandrology.com/preprintarticle.asp?id=221199




  Introduction Top


Metastases and associated complications are the major cause of death for cancer patients. In prostate cancer (PCa), 90% of patients with advanced tumors develop bone metastases (BMs).[1] The reason why bones are frequently affected organs for metastases in PCa has been studied extensively. The activation of osteoclasts is crucial within the process of development of BMs.[2] Preclinical studies have shown that inhibition of osteoclasts helps to prevent bony spread of disease.[3] Seeded tumor cells produce chemokines and promote tumor cell growth. Moreover, they cause stimulation of osteoblast activity resulting in overexpression of the receptor activator of nuclear factor κB ligand (RANKL). RANKL molecules released by osteoblasts and tumor cells lead to an increased maturation and differentiation of osteoclast precursor cells. The activity of these osteoclasts promotes further release of substances which in turn promotes growth of tumor cells, resulting in a vicious cycle of tumor growth and bone destruction.[4],[5] The understanding of this pathophysiologic mechanism resulted in the approval of a new bone-targeting agent, denosumab. Denosumab is a fully humanized antibody targeting RANKL. Median time between clinical diagnosis of BMs and death is 3–5 years.[6],[7] Approximately 3% of patients have BMs at the time of initial diagnosis.[8] In 86% of PCa patients, bones are the only localization of metastatic spread.[9] Patients with a high-risk locally advanced PCa, a predominant Gleason 4 pattern, or a prostate-specific antigen (PSA) >10 ng ml−1 have a higher risk for BMs and therefore should be assessed for BMs at initial diagnosis.[10] [99mTc] (technetium-99m-methylene diphosphonate) bone scan (BS) has been the most widely used method for evaluating BMs in PCa. A PSA doubling time (PSA-DT) of <6 months or a PSA velocity >0.5 ng ml−1 per month are predictors of a positive BS.[11] Symptomatic patients should receive further diagnostic workup focused on BMs, independent of the previously mentioned risk factors. In PCa, BMs are mainly osteoblastic[12] and involve the axial skeleton, the pelvis, and the proximal femur.[13] Extra-axial extension of BMs has been described as a poor prognostic factor.[14],[15] Four or more BMs with at least one metastasis beyond the pelvis and vertebral column (also called appendicular metastases) have been defined as high-volume disease in a recent published study.[15] BMs lead to skeletal-related events (SREs). SREs are defined as pathologic fracture, spinal cord compression, radiation, or surgery to bone.[16] They are linked to pain, immobilization, hospitalisation,[17] reduced quality of life (QoL), and worse survival. Decreased survival is partially caused by the consequences of immobilization.[14] The cumulative incidence of SREs within 2 years after diagnosis of BMs is 41.9%.[18] Reducing the incidence or prolonging the time to occurrence of SREs is important for improving clinical outcomes in patients as well as reducing the financial burden of disease.[19] The term symptomatic skeletal event was introduced in order to take the clinical relevance of a skeletal-related event into account.[20],[21] Beside the structural damage in bone, BMs are often symptomatic and therefore interfere with patients' QoL. The mechanism involved in bone pain due to metastatic spread is poorly understood. One important factor is osteolysis, others include microfractures and stretching of the periosteum by tumor growth. Biochemical mechanisms of pain include the stimulation of nerve endings with mediators such as bradykinin, prostaglandin, histamine, interleukin, and tumor necrosis factor.[22] Pain is an independent prognostic factor in patients with metastatic castration-resistant prostate cancer (mCRPC).[23] Bearing this in mind, patients suffering from symptomatic BMs require optimal management to reach quick and effective symptom control. Treatment decisions must take into account if BMs are uni-, oligo-, or multilocular as well as the presence or absence of extraskeletal disease. The aim of the present review is to summarize the current clinical practice and future trends in the management of patients with BMs.


  Imaging Top


Unfortunately, the radiologic assessment of BMs and their response to treatment is challenging. Today, it is widely accepted to use BS as the standard workup for the evaluation of BMs.[20] [99mTc] BS has shown a combined sensitivity and specificity of 79% and 82% at patient level and 59% and 75% at lesion level, respectively.[24] Within clinical trials, quantitative measure of disease burden, such as lesional number of the BS index[25] or lesion area, is also suggested.[20] A “flare phenomenon” can be seen in BS after 8–12 weeks after induction of a new and effective therapy. Within this flare period also, new bone lesions can be found resulting, for example, in a “melting” of huge bone metastasis into smaller spots, which can be mistaken as new BMs. Retrospectively, this flare is often associated with favorable response in long-term follow-up. In mCRPC, updated in 2016, the Prostate Cancer Clinical Trials Working Group (PCWG) set up special criteria for progression of BMs in clinical trials. The so-called “2 + 2” rule, initially published in 2008,[26] described two new metastatic lesions, supplemented with a confirmatory scan, as progressive disease. Scans should be performed every 8–9 weeks for the first 24 weeks, and then every 12 weeks.[20] Of note, no clear definition of response to therapy in BMs is given. Additionally, magnetic resonance imaging (MRI) should also be used in unclear BS results. Based on morphologic criteria and changes in diffusion coefficient, it is possible to distinguish benign and malignant lesions and detect early signs for response. Currently, whole-body MRI has not been widely adopted in clinical routine in terms of costs as well as patient's comfort, although it was able to show excellent results in terms of detecting BMs.[27] Positron emission tomography (PET), in combination with computed tomography (CT) or MRI, has been used increasingly in the last years. With this technique it is possible to combine biochemical with topographic information. Of note, detection rates of these imaging methods are dependent on PSA values.[28] In [68Ga]-PSMA-PET-CT, detection rates of 58% and 76% have been reported for PSA ranges of 0.2–1 and 1–2 ng ml−1, respectively. Due to its difficulties in interpretation and high costs, choline PET/CT has not made its way into clinical routine although it seems to be more sensitive in the detection of BMs than BS.[28],[29] In contrast, [68Ga]-PSMA-PET has been able to show higher negative predictive value and accuracy for the detection of locoregional recurrence and/or metastatic lesions in the first studies.[30] In comparison to [18F]-Choline-PET-CT, it can detect lesions characteristic for PCa with improved contrast, especially at low PSA levels.[31] Therefore, an increased use of this imaging modality also in patients with metastatic disease is expected.


  Systemic Treatment of BMS Top


Current therapeutics used for the treatment of BMs in PCa can be divided into bone-targeting agents and systemic therapy, showing unspecific action also being active in bone. [Table 1]summarizes bone-related end points from clinical trials using bone-targeting agents and non-bone-specific drugs in patients with advanced PCa.
Table 1: Effect of systemic treatments for advanced prostate cancer on bone-related end points

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Bisphosphonates

Zoledronic acid (ZA) has been approved in Europe in 2003 for the prevention of SREs in patients with solid tumors and BMs. As a nitrogenous bisphosphonate, it inhibits the mevalonate pathway leading to the induction of apoptosis in osteoclasts.[50] It is structurally similar to pyrophosphate and binds to hydroxyapatite crystals integrating into the bone matrix. Preclinical studies additionally suggested that ZA might also affect PCa cell adhesion and migration and promote apoptosis through the inhibition of tumor growth. In the Phase III study leading to drug approval, ZA was tested in 641 patients with BMs and CRPC. The comparator was placebo. Treatment was initially planned for 15 months with two dosages of 4 and 8 mg every 3 weeks. Due to several renal events, the 8-mg dosage was reduced to 4 mg. Saad et al.[16] were able to show that men treated with ZA had fewer SREs compared to women (38% vs 49%, P = 0.029). Also, time to occurrence of the first SRE was prolonged. Moreover, fewer pathological fractures in the ZA group were seen compared to placebo group (13.1% vs 22.1%, P = 0.015).[16] During 24 months, 122 patients completed the study treatment. The annual incidence of SREs was 0.77 for patients in the ZA group versus1.47 for patients in the placebo group (P = 0.005). Median time to the first SRE was 488 days for patients treated with ZA compared to 321 days in patients treated with placebo (P = 0.009).[51] Also, a reduction of metastases-related pain was seen. In contrast, no prolongation of progression or OS was measurable.[16] Several trials have assessed whether ZA has a positive effect in earlier stages of PCa. In a Phase III trial called the “Zometa European Study” (ZEUS), patients with localized high-risk PCa were treated with 4 mg ZA every 3 months versus placebo. Here, ZA was ineffective in the prevention of BMs.[45] The ALLIANCE trial investigated ZA versus placebo in patients with hormone-naïve metastatic PCa. Early introduction of ZA was not associated with increased time to the first SRE.[44] The STAMPEDE trial explored the treatment of hormone-naïve metastatic or locally advanced PCa in a multiple-arm design.[7] No clinically and statistically significant improvement in survival was found for adding ZA to standard of care androgen deprivation therapy (ADT). Even the time to the first SRE was not prolonged in the group additionally treated with ZA (hazard ratio [HR]: 0.89, P = 0.221). Side effects of ZA are usually Grade I–II, but also serious complications can occur in 2% of patients, including acute systemic inflammatory reaction, ocular inflammation, renal failure and nephrotic syndrome, osteonecrosis of the jaw (ONJ) as well as electrolytic imbalances, mainly hypocalcemia and hypophosphatemia.[52] Typically occurring within 48 h of infusion, fever can be seen in 21% of patients as a sign of an acute-phase reaction. This kind of adverse event is often connected with myalgia (25%) as well as pain (12%) in spines, ribs, and lower limbs, not necessarily at the side of metastases.[16] Pain is usually self-limiting or can be managed by nonsteroidal anti-inflammatory drugs. In case of renal impairment, it is important to adapt the dose of ZA to renal function to prevent renal failure.

Denosumab

Denosumab is a fully humanized antibody targeting the RANKL and has been approved in Europe for the prevention of SREs in patients with solid tumors and BMs, including PCa. Denosumab inhibits binding of RANKL to RANK on the surface of osteoclasts, preventing their differentiation and function and leading to the inhibition of bone loss. In a Phase III trial with mCRPC patients, patients were randomized to receive either denosumab subcutaneously 120 mg or ZA intravenously every 4 weeks.[46] The study included 1904 CRPC patients with at least one bone metastasis and no prior bone-targeting therapy. Twenty-four percent of patients already had a SRE at screening. Regular intake of calcium and Vitamin D was strongly recommended. Median time to the first SRE was 20.7 months in patients treated with denosumab and 17.1 months in patients treated with ZA. Post hoc analysis showed a number needed to treat five patients for the prevention of the first or subsequent SRE[53] and risk reduction of 18% for achieving the first SRE in favor of denosumab treatment. Denosumab was also able to prolong time to concomitant SRE, a secondary end point of the trial.[46] In an additional subgroup analysis, symptomatic skeletal events (SSEs) were assessed: denosumab also reduced the risk of developing first and subsequent SSE compared to ZA.[54] Of note, no difference in OS was reported.[46] Patients with no or mild pain at baseline receiving denosumab showed a lower frequency and delay of pain deterioration compared to patients treated with ZA and reported better QoL scores.[47],[48] Denosumab was shown to suppress bone resorption independently of prior bisphosphonate treatment, even in patients who did not exhibit normalization of bone resorption markers under prior bone-targeting treatment.[55] Denosumab has been additionally assessed for its effectiveness for the prevention of BMs in a Phase III trial in CRPC patients without BMs and high-risk features for developing these.[49] In a Phase III trial, the antibody showed a significant benefit in increase of BMs-free survival of 4.2 months (29.5 vs 25.2 months, HR: 0.85). Denosumab therapy delayed the median time to first BM (3.7 months) and showed a risk reduction in the development of symptomatic BMs of 33%. Progression-free survival (PFS) and overall survival (OS) did not differ between the two investigational arms. Thirteen percent of patients receiving denosumab showed some degree of hypocalcemia (5% Grade 3 or higher).[46] Hypocalcemia most commonly occurs within the first 6 months of treatment. Therefore, it is of great importance to inform patients about the need of regular intake of calcium and Vitamin D as well as routine laboratory work to check calcium levels.[56] Patients receiving denosumab can also develop ONJ.[57] Several risk factors have been identified, but the exact mechanism of ONJ has not been fully elucidated. One risk factor is concomitant chemotherapy,[46] others are poor dental hygiene or dental extractions.[58] In the pivotal study of denosumab in mCRPC, 2.3% developed ONJ (vs 1.3% in patients receiving ZA, P = 0.09).[49] Currently, no recommendations for treating patients with osteoprotective agents in a metastases-free as well as in a hormone-sensitive setting can be given because conclusive data is missing. In contrast, in patients with CRPC, current guidelines recommend treatment with osteoprotective agents in combination with calcium and Vitamin D in allpatients with BMs.[59],[60]

Radiopharmaceuticals

Radium-223 dichloride ([223Ra]; Xofigo®, Bayer, Leverkusen, Germany) has been approved for the treatment of patients with BMs in mCRPC since 2013.[21] As an alpha-emitting compound, the agent produces a high-energy output over a short range (<0.1 mm or 2–10 tumor cell diameters), facilitating selective destruction of tissue within the bone in the region of osteoblastic lesions while sparing the surrounding normal tissue. The alpha emitter induces mainly double-strand DNA breaks that result in a potent and highly localized cytotoxic effect. [223Ra] shows calcium mimetic properties and therefore accumulates in bone areas with an increased turnover. Similar to previously used radiopharmaceuticals, [223Ra] can reduce pain in a palliative setting in patients with M1b CRPC but without visceral disease. The ALSYMPCA trial compared six injections of [223Ra] (at a dose of 50 kBq per kg body weight intravenously) to placebo in patients being previously treated or unfit for taxane-based chemotherapy. [223Ra] improved OS (14 vs 11.2 months, HR: 0.70) with a 30% reduction of the risk of death for treatment with [223Ra], irrespective of pretreatment with taxane-based chemotherapy.[21] Time to the first SRE was also statistically significant prolonged in favor of [223Ra] with a median of 15.6 and 9.8 months (P < 0.001) for the first and concomitant SRE, respectively. Also, time to SSE could be improved. Symptomatic pathological fracture occurred in 6% patients, spinal cord compression in 5%, and tumor-related orthopedic surgical intervention in 2%, but 32% patients needed radiation to bone. Mainly reported side effects were of gastrointestinal due to the intestinal route of excretion. Nausea was present in 36% patients, diarrhea in 25% as well as fatigue in 26%, loss of weight in 12%, and peripheral edema in 13%. Also, a flare phenomenon has been described in 50% of patients, presenting as pain and/or changes in BSs within the first 3 months under treatment. Bone marrow suppression leads to anemia, which could be observed in up to 31% as well as thrombocytopenia (12%) and neutropenia (5%). The mode of action suggests that combination of treatment regimens including [223Ra] can improve therapeutic effects. Former combinations with radiopharmaceuticals have shown clinical advantages, especially in terms of pain response.[61] Studies are currently investigating the combination of [223Ra] and hormonal therapy (NCT02194842, NCT02225704) as well as reduced docetaxel regimen in addition to [223Ra] (NCT01106352). The effect of vitamin D and calcium supplementation and denosumab on the activity of [223Ra] has been discussed critically, as [223R]a as a calcium analogon is dependant on bone turnover. Concerns that denosumab or ZA may decrease the effectiveness of [223Ra] were counteracted by a subgroup analysis of the ALSYMPCA results, showing that the time to symptomatic SREs was longer in patients receiving bone-targeting agents as well as [223Ra] compared to patients without antiresorptive drugs.[62] Other radiopharmaceuticals such as [153Sm] and [89Sr] are mainly beta-emitters, while [153Sm] also emits a small proportion of gamma radiation. These agents have a relatively far-reaching tissue penetration (0.6–3.1 mm) and low linear energy transfer, which results in a more pronounced bone marrow toxicity. After intravenous injection, the uptake in metastases is 5–10 times higher compared to healthy bone. Leukocyte and platelet nadirs generally occur between weeks 3–6, in more than 50% of patients, with slow recovery after 8–12 weeks. Repetitive re-treatments as well as therapy pauses can be necessary due to upcoming adverse events, which should be taken into account even for subsequent therapies. [153Sm] and [89Sr] can reduce pain within 1–4 weeks and up to 18 months. No Phase III data exist if these beta emitters can have a positive influence on SREs.[61] Their use in routine practice is therefore limited and, in terms of [89Sr], it is widely regarded as being obsolete. Nevertheless, [89Sr] and [153Sm] are approved in the USA and Europe for palliative indications.[63]

Systemic drugs with nonbone-specific effects

Abiraterone acetate is a selective inhibitor of androgen biosynthesis that potently and irreversibly blocks CYP17 (also called steroid 17α-monooxygenase, 17α-hydroxylase, 17,20-lyase, or 17,20 desmolase), a crucial enzyme in testosterone and estrogen synthesis, resulting in virtually undetectable serum and intratumoral androgens and antitumor activity in patients with mCRPC. Abiraterone was initially approved in the postdocetaxel setting, demonstrating benefit in OS compared to placebo in the COU-AA-301 trial.[37] Ninety percent of patients in this trial had BMs. As an exploratory end point, time to the first skeletal event (9.9 vs 4.9 months, P = 0.0001) was improved in the abiraterone group. Patients treated with abiraterone had also reduced pain levels in comparison to baseline.[38],[39] More recently, a second Phase III study (COU-AA-302)[40] has led to a further approval in the treatment of chemotherapy-naïve patients. Abiraterone showed superiority over prednisone alone with respect to time to opiate use for cancer-related pain and longer time to decline in performance status. The median time to increase in pain was 26.7 months among patients receiving abiraterone and 18.4 months undergoing treatment with prednisone alone (HR: 0.82; 95% confidence interval [CI]: 0.67–1.00; P = 0.049). A post hoc analysis from COU-AA-302 demonstrated that, in patients with BMs at baseline, treatment with bone-targeting agents in combination with abiraterone was associated with improved outcome, including OS (HR: 0.754, P = 0.012; risk reduction: 25%), time to opiate use (HR: 0.801, P = 0.036; risk reduction: 20%), and time to ECOG deterioration (HR: 0.750, P < 0.001; risk reduction: 25%) compared to no use of bone-targeting agents.[41] In contrast, the use of bone-targeting agents was not associated with significantly longer time to induction of chemotherapy or to PSA progression. Besides these results, abiraterone has been approved and recommended for asymptomatic-to-mild symptomatic patients.

Enzalutamide is a compound targeting the androgen receptor (AR), competitively binding to the ligand-binding domain of the AR and inhibiting AR translocation to the cell nucleus. Enzalutamide has been initially approved in the postchemotherapy setting based on the results of the AFFIRM trial.[42] The PREVAIL study[43] demonstrated that the agent can prolong OS in the predocetaxel setting. In both trials, a delay in the time to first SRE (P < 0.001) could be shown (AFFIRM: time to the first SRE 16.7 vs 13.3 months; PREVAIL: time to first SRE 31.1 vs 31.3). In the PREVAIL dataset, 32% of patients undergoing enzalutamide treatment experienced a SRE (37% in the placebo group; HR: 0.72; P < 0.001).

Docetaxelhas been approved for the treatment of mCRPC showing OS advantage compared to mitoxantrone and estramustine phosphate.[32],[33] No significant differences in pain relief were found in pivotal SWOG 99-16. Grade 3 pain was more frequently reported in the docetaxel group (34 vs 18).[32] In TAX 327, secondary end points were predefined reductions in pain and an improvement in the quality of life. Forty-five percent of patients throughout the trial presented with pain at baseline. Improvement of pain was seen in 35% (P = 0.01) of patients treated with docetaxel every 3 weeks and 31% (P = 0.08) in the weekly regimen. Twenty-two percent (P = 0.009) of patients reported better QoL within the application every 3 weeks and 23% (P = 0.005) in the weekly regimen. In the ASCENT study, docetaxel in combination with high-dose Vitamin D was used in mCRPC patients and showed a trend toward increased SRE-free survival (planned secondary end point).[34] Time to SRE and SSE was not assessed as an exploratory end point in the most recent studies of docetaxel. Early introduction of docetaxel in patients with hormone-naïve, high-volume disease in combination with ADT was shown to be beneficial in the CHAARTED trial,[15] showing a 17-month OS benefit when adding six cycles of docetaxel to ADT (HR: 0.62; P = 0.0012). Criteria for high-volume disease included the presence of more than four BMs, including one appendicular metastasis, underlining the importance of wide bony spread as a poor prognostic factor. Also, the STAMPEDE trial[7] showed significant improvement in OS with the addition of docetaxel to hormonal therapy in men with CRPC, irrespective of any risk groups. Therefore, chemohormonal therapy or docetaxel “upfront” should be considered as a new standard for men presenting with metastases at the first diagnosis.[60]

Cabazitaxel, a taxane structurally similar to docetaxel, was tested versus mitoxantrone in patients with relapse after docetaxel. The TROPIC study[35] demonstrated OS benefit in favor of cabazitaxel, with a median of 15.1 versus 12.7 months and a 30% relative risk reduction of death (HR: 0.70; 95% CI: 0.59–0.83; P < 0.0001). Pain response rates were similar in both groups. Also, no significant difference in time to pain progression was reported. Similar proportions of patients in each group had either reduction or increase in pain.[35] In the updated TROPIC data, average daily pain performance index was lower for cabazitaxel versus mitoxantrone (all cycles; P = 0.035), and analgesic scores were similar.[36] The TROPIC study did not include SREs as a relevant end point.

ADT

ADT is the backbone in the treatment of advanced PCa. ADT has significant side effects (e.g., cardiovascular disease and diabetes). It is undoubted that long-term ADT also mediates bone loss. These changes in bone structure have an important impact, because osteoporosis can lead to factures, pain, and reduction in QoL. ADT has been shown to prolong time to symptomatic disease and progression-free survival.[64] Therefore, ADT is recommended in the metastatic setting as first-line treatment - independent of localization of metastases.[60] Contemporary data of patients (a subset of the STAMPEDE trial, the control group) undergoing standard of care ADT refresh the knowledge in outcome of patients with BMs undergoing only ADT. Presence of BMs was associated with lower 2-year OS compared to men with soft-tissue metastases, from 85% to 60% (HR: 3.42), and the presence of BMs (regardless of visceral spread) was shown to be associated with worse failure-free survival (FFS) and OS in multivariate analysis.[65] Wong et al.[66] also studied the impact of SRE on survival in patients with metastatic PCa undergoing ADT. In this retrospective cohort, 43.7% patients developed SRE. Median OS as well as cancer-specific survival (CSS) in patients with SREs was shorter compared to patients without SREs (23 vs 48 months, P = 0.003, and 26 vs 97 months, P < 0.001). Multivariate analysis showed that a SRE had significant influence on both OS and CSS with HRs of 2.73 (P = 0.002) and 3.92 (P < 0.001), respectively. The authors concluded that the presence of SRE is an independent poor prognostic factor for patients undergoing ADT.[66]

Radiation and surgery

External beam radiotherapy (EBRT) is effective for palliation of BMs. A variety of doses and fractionation schedules were described, but of note that rates of response, pathological fracture, and spinal cord compression are similar, relatively independent of the regimen.[67] Besides pain, the risk for pathological fracture and neurological complications such as spinal cord compression, nerve root pain, or cranial involvement are indications for radiation. Fifty percent to 80% of patients experience improvement in pain and 20%–50% of the treated patients have complete pain relief. Onset of effect occurs generally very rapidly showing benefit within 1–2 weeks.[59] Pain reduction lasts in at least 50% of patients for more than 6 months.[68] Current evidence indicates that single-fraction radiotherapy (with at least 6 Gy) is the treatment of choice for quick pain relief.[69] However, fractionated radiation leads to more effective remineralization of bone. Re-irradiation of painful BMs is also possible with similar effectiveness, whether initial treatment has been single or in multiple fractions. A newer indication for radiation is the so-called metastasis-directed therapy (MDT). This term describes an early palliative approach in oligometastatic cases, including radiation attempting to decrease local complications and delay time to systemic treatment.[70] First studies were able to show that modern radiation can achieve this goal.[71] Moreover, it is still important to offer palliative surgery, which can be effective for managing osteoblastic metastases.[72] Cementation can be a good treatment for painful spinal fracture, improving pain and QoL.[73] In cases of spinal cord compression, immediate surgery (as decompression) is needed. Postoperative radiation can increase the success of surgery in terms of needed re-operations. Postoperative radiotherapy is associated with a higher probability of normal extremity use compared with surgery alone.[67] Recently, image-guided single-fraction robotic stereotactic radiosurgery (CyberKnife®) and stereotactic body radiotherapy have been discussed as potential options in patients with oligometastatic disease and BMs. To date, few series including a limited number of patients indicate promising local control rates.[74] A study including 51 patients treated either by CyberKnife® or stereotactic ablative radiation therapy showed 2-year local control rates of 70%. Moreover, a positive effect on pain control was observed. In a multi-institutional analysis including 119 patients treated by stereotactic body radiotherapy, the median distant PFS was 21 months.[75] A study from Munich including 54 patients with 64 BMs treated with CyberKnife® showed local control rate of 95.5%.[76] Although these data are promising, clinical factors determining the optimal patient for this therapeutic approach remain to be defined before implementing this method in routine clinical practice.


  Conclusions and Future Directions Top


BMs require particular attention in the management of patients with advanced PCa. Fortunately, both bone-targeted agents and second-generation antihormonal drugs are able to positively affect the incidence of skeletal complications in mCRPC. The role of bone-targeted agents in metastatic castration-sensitive PCa is still discussed controversially and no clear benefit has been shown so far. Future studies will have to assess whether local treatment of BMs in patients with oligometastatic disease by stereotactic radiation or radiosurgery improves oncologic outcome of these patients.


  Author Contributions Top


MH, MM, SR, JB, SW, AS, and TT contributed to data acquisition. MH, AS, and TT were responsible for the draft of the manuscript. MM, SR, SW, and JB contributed to review of the manuscript. All authors read and approved the final manuscript.


  Competing Interests Top


Arnulf Stenzl and Tilman Todenhöfer have served as consultants for Amgen and Astellas. Tilman Todenhöfer has received research funds from Astellas.



 
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