Targeted Palliative Radionuclide Therapy for Metastatic Bone Pain.

1. Introduction

Bone metastasis is a common feature of malignancies, particularly in late stages [ 1 , 2 ]. The incidence varies widely in different tumors [ 1 , 2 ]. Up to 70–80% of the cases reportedly occur in prostate, breast and lung cancers [ 3 , 4 ]. The presence of bone metastases implies poorer prognosis, shortens survival and is associated with a multitude of complications, including severe bone pain, pathological fracture, spinal cord compression, hypercalcemia, etc. [ 3 , 5 ]. Bone metastases are found using various imaging modalities, namely, plane radiography, computed tomography (CT) and magnetic resonance imaging (MRI), as well as functional examinations employing a wide range of targeted radioligands with single photon emission tomography (SPECT), positron emission tomography (PET) and hybrid SPECT/CT and PET/CT imaging [ 6 , 7 ].

One of the disabling presentations of bone metastases is refractory bone pain. The issue to enhance the quality of life of the patients in their remaining life span continues to be challenging. Bone pain is managed through multidisciplinary approaches using analgesics, bisphosphonates, chemotherapy, external beam radiotherapy (EBRT), immunotherapy, surgery, hormonal treatments and finally, bone-targeted radionuclide therapy [ 8 , 9 , 10 ].

Bone-pain palliation with easy-to-administer radionuclides offers advantages including simultaneous treatment of multiple metastatic foci, the repeatability and also the combination with other treatments [ 3 , 10 ]. In a systematic review including 57 studies, the response rate was reported 70% using β¯-emitters [ 11 ]. Not only does radionuclide targeted therapy alleviate pain, but it reduces or defers the incidence of skeletal-related events (SRE) [ 10 ]. These agents substitute calcium or bind to hydroxyapatite in bones and deliver ionizing radiation to areas with increased osteoblastic activity [ 12 , 13 ]. It is of substantial importance to deliver the utmost radiation to metastatic foci while sparing non-affected tissues. Hence, numerous radiopharmaceuticals have been investigated to achieve the optimum result. The extent of metastatic disease, renal function, bone marrow reserve, and, importantly, the availability impact the physicians’ choice of an appropriate radiopharmaceutical [ 3 ]. A slightly higher response rate has been reported in patients in whom lesions are osteoblastic [ 13 ], the skeletal involvement is limited and the performance state is higher [ 14 ].

Bone-seeking radiopharmaceuticals emitting β¯-particles have long been used for bone-pain palliation. Meanwhile, α-emitting tracers, with [ 223 Ra]radium-dichloride at the top, were also developed. Alpha-emitters provide more toxicity for tumoral cells and lesser radiation for surrounding normal tissues [ 12 ]. They dispense higher linear energy in a shorter range (<100 μm) and predominantly induce permanent DNA double-strand breaks [ 12 ]. In addition to bone-seeking agents, other targeted radiopharmaceuticals are used for systemic therapy in nuclear medicine showing therapeutic effects on bone metastases in prostate and neuroendocrine tumors [ 15 , 16 ].

In this review, we aimed to provide an overview of a number of long-established and novel bone-seeking radiopharmaceuticals used for bone-pain palliation, including [ 89 Sr]strontium-dichloride, [ 153 Sm]samarium, [ 186 Re]rhenium, [ 188 Re]rhenium, [ 177 Lu]lutetium and [ 166 Ho]holmium labeled with bone-seeking agents, as well as [ 223 Ra]radium-dichloride. Noteworthy, [ 32 P]Phosphorus-orthophosphate and [ 117m Sn]-diethylenetriamine pentaacetic acid have traditionally been used; however, their application for bone-pain palliation is currently limited and are not discussed [ 17 , 18 ]. Moreover, the effectiveness and toxicity of the radiopharmaceuticals, as well as the results of the combination therapy with other therapies are also briefly mentioned ( Table 1 ).

2. [89. Sr]Strontium-Dichloride ([ 89 Sr]SrCl)

[ 89 Sr]SrCl is used for bone-pain palliation from 1942 by Pecher [ 39 ]. Its efficacy is well-documented in the literature [ 14 , 39 ].

[ 89 Sr]strontium mimics calcium in the body and is taken up into the inorganic bone matrix [ 8 ]. Its concentration in the skeleton is a proportion of osteoblastic activity, which is 10-fold higher in metastatic foci [ 39 ]. After localization, it remains still in tumoral sites for 100 days [ 39 ]. The excretion occurs predominantly from kidneys [ 19 ], limiting its use in the setting of renal failure.

According to guidelines, 150 MBq [ 89 Sr]SrCl is administered with slow intravenous infusion [ 3 ]. The response rate has been documented to be between 60 to 95% [ 40 ]. In the latest meta-analysis, the overall response rate of 70% has been reported [ 11 ], commencing from the 4–28 days (typically in 14–28 days) of administration and lasting up to 15 months (typically 12–26 weeks) [ 9 , 20 ]. A flushing sensation may occur in case of rapid infusion [ 3 ]. The hematological toxicity is the major side-effect of [ 89 Sr]SrCl which is mild, temporary and predominantly consists of myelosuppression [ 9 , 41 ]. The nadir occurs between the 12–16 weeks [ 3 ], showing resolution in the next six weeks depending on the skeletal tumor extent and bone marrow reserve [ 20 , 41 ]. Follow-up of hematological toxicity is recommended for 12–16 weeks, for the prolonged effect on bone marrow [ 3 ].

Despite an acceptable response rate with [ 89 Sr]SrCl, a recent meta-analysis showed no significant benefit in prolonging overall survival (OS) or symptomatic SRE-free survival in metastatic castration-resistant prostate cancer (mCRPC) [ 42 ]. Besides pain reduction, significant improvement of quality of life has been reported [ 43 , 44 ]. However, the improvement in quality of life generally follows pain reduction [ 45 ].

Moreover, the combination of [ 89 Sr]SrCl with other therapies has been investigated, mainly in prostate cancer showing the overall response rate of 74% [ 11 ]. Nevertheless, the data considering the currently used agent in mCRPC patients (docetaxel) is scarce, showing improved clinical progression-free survival (PFS), but no effect on OS or SRE-free survival [ 46 ].

[ 89 Sr]SrCl and EBRT reportedly appear to perform rather similar in reducing pain and disease progression [ 47 ]. In one survey, EBRT slightly outperformed [ 89 Sr]SrCl in terms of OS [ 47 ]. In combination, however, the results are controversial. The pain relief was higher in patients receiving both [ 89 Sr]SrCl and EBRT compared to [ 89 Sr]SrCl-alone in one study [ 48 ], while there was no impact of the addition of [ 89 Sr]SrCl in another [ 49 ].

Finally, the combination therapy of [ 89 Sr]SrCl and zoledronic acid for bone metastases has shown superiority in terms of reduction of bone pain, analgesic drug use and time to decrease in pain, as well as improvement of the quality of life compared to [ 89 Sr]SrCl- or zoledronic acid-alone [ 50 ]. There has been no significant higher rate of toxicity in the combined method [ 50 ]. Moreover, using the combination therapy, pain relief has been reported in 94% of the patients, tumoricidal effect in 36%, and non-progressive disease in 86% [ 51 ]. Additionally, a significant increase in OS and time to first SRE have been noted with the combination compared to no treatment [ 52 ]. In addition, the combination of [ 89 Sr]SrCl and zoledronic acid has revealed survival benefits compared to [ 89 Sr]SrCl-alone [ 53 ].

Of note, the efficacy of [ 89 Sr]SrCl in bone-pain palliation has been compared to other radiopharmaceuticals revealing no significant difference to [ 153 Sm]samarium-ethylene diamine tetramethylene phosphonate and [ 186 Re/ 188 Re]rhenium-hydroxyethylidene diphosphonate [ 11 , 14 , 18 , 54 ]. [ 89 Sr]SrCl is still an effective method for bone-pain palliation. The combination with other treatments seem more appealing warranting further investigations to precisely evaluate the impact of these protocols.

3. [153. Sm]Samarium–Ethylene Diamine Tetramethylene Phosphonate ([ 153 Sm]Sm–EDTMP)

[ 153 Sm]Sm–EDTMP, a well-known radiopharmaceutical for bone-pain palliation, has been widely used since FDA approval in various osteoblastic metastatic lesions, especially in prostate and breast cancer [ 55 , 56 , 57 ]. It rapidly binds to hydroxyapatite crystals, leading to less than 1% availability in the blood 5 h after injection. The excretion occurs mainly through the kidneys [ 58 , 59 ].

Although the maximum tolerable dose of 111 MBq/kg of body weight has been reported in initial dosimetry studies [ 58 , 60 ], the standard dose of 37 MBq/kg is well-established [ 3 ]. In numerous affirmative studies, a response rate of 40–97% [ 22 , 23 , 61 , 62 , 63 ] with a mean of 70% [ 11 ] has been reported. In addition, a decrease in analgesic consumption and improved quality of life has been noted [ 22 , 23 , 24 ]. The pain reduction occurs as early as in the first week after injection [ 23 , 61 ], lasting for about two to three months [ 23 , 24 , 25 ].

The bone marrow toxicity is mild in most the patients [ 61 , 64 ]. The lowest platelet and white blood cell (WBC) counts have been observed in 3–5 weeks, recovering in 6–8 weeks after therapy [ 23 , 24 , 62 , 64 ]. Patients with severe grades of myelotoxicity had predisposing underlying conditions including recent chemotherapy, EBRT or malignant bone marrow involvement [ 65 ]. Similarly, mainly minimal and transient bone marrow toxicity has been observed after administering repeated doses of [ 153 Sm]Sm–EDTMP [ 66 , 67 ]. Other complications are rare with [ 153 Sm]Sm–EDTMP compared to systemic therapies like chemotherapy [ 55 ].

Moreover, the impact of combining [ 153 Sm]Sm–EDTMP with other therapies has been evaluated in a few studies. Adding [ 153 Sm]Sm–EDTMP to docetaxel for mCRPC patients has revealed favorable results regarding pain control, safety and a decrease in PSA level [ 68 , 69 , 70 ]. The PFS has been reported 5.2 to 7 months [ 68 , 69 , 70 ].

In addition, combined therapy with local EBRT has resulted in higher analgesic effect than monotherapy with [ 153 Sm]Sm–EDTMP, showing no significant difference in bone marrow toxicity in mCRPC [ 71 ]. Similar outcomes were reported for combination therapy with bisphosphonates such as zoledronic acid, leading to significantly better pain control [ 72 , 73 ], higher quality of life [ 73 ] and shorter time to analgesia [ 72 ].

Overall, [ 153 Sm]Sm–EDTMP has been successfully used for pain control in more than three decades. It seems the combination with other therapies results in a better outcome. However, the studies are not sufficient to suggest a definite conclusion. Also, earlier initiation of [ 153 Sm]Sm–EDTMP may be more effective [ 74 ]. Hence, the optimal timing of administration of [ 153 Sm]Sm–EDTMP requires further assessment.

4. [186. Re]Rhenium-Hydroxyethylidene Diphosphonate ([ 186 Re]Re–HEDP)

[ 186 Re]rhenium is a combined β¯/γ-emitter isotope labelled with a phosphonate complex (HEDP), localized in bones attaching hydroxyapatite crystals [ 17 ]. The shorter physical half-life of 3.8 days may produce a faster onset of pain relief in comparison to the radiopharmaceuticals with longer half-lives [ 75 ]. The usual recommended dose of [ 186 Re]Re–HEDP for bone-pain palliation therapy is 1295 MBq (35 mCi) [ 26 ]. Approximately 70% of the administrated activity is excreted in the urine within the first 24 h after injection [ 17 ].

The successful pain reduction has been noted in different studies using [ 186 Re]Re–HEDP [ 76 , 77 , 78 ]. However, the large cohorts addressing [ 186 Re]Re–HEDP is lacking. The overall response rate has been reported to be between 38% and 82% using doses of 1295 MBq to 1406 MBq [ 17 ]. While it has been mainly used for breast and prostate cancers, limited studies in other malignancies, such as lung cancer, have revealed similar performance [ 78 , 79 , 80 ]. Additionally, improved quality of life and reduction of analgesic medication has been reported [ 79 , 81 ]. Usually, the response occurs in 1–3 weeks after injection [ 76 , 82 ] and lasts for 3 weeks to 12–15 months [ 76 , 81 , 82 , 83 ]. After therapy, a temporary decrease in platelets and WBC counts frequently occurs [ 76 , 78 , 83 ], reaches the nadir after 1–5 weeks [ 26 , 83 ] and recovers in the following 2–4 weeks [ 83 , 84 ].

Although survival benefits have not been proved for β¯-emitters, a study on 57 mCRPC patients, high-dose treatment (>3500 MBq) has shown an increase in OS, in the univariate analysis. However, in the multivariate analysis, only the lower disease burden was associated with increased OS [ 85 ]. There is literally little studies evaluating the combination with other therapies. However, the safety in co-administration with docetaxel and zoledronic acid has been documented [ 86 , 87 ].

No significant difference in rates of pain palliation, therapeutic efficacy or the possibility of toxicity has been reported for [ 186 Re]Re–HEDP compare to other β¯-emitters, including [ 188 Re]Re–HEDP, [ 153 Sm]Sm-EDTMP and [ 89 Sr]SrCl [ 54 , 88 ]. Hence, [ 186 Re]Re–HEDP can be considered as a reasonable choice for bone-pain palliation therapy regarding logistic feasibility. Further studies are required to establish its role in combination with other treatments.

5. [188. Re]Rhenium-Hydroxyethylidene Diphosphonate ([ 188 Re]Re-HEDP)

[ 188 Re]Re–HEDP is a bone-seeking therapeutic radiopharmaceutical with favorable characteristics for application in bone-pain palliation therapy [ 89 ]. In clinical studies with [ 188 Re]Re–HEDP, various dosage have been used, mainly between 1300–4400 MBq [ 27 , 28 , 90 ]. The maximum tolerated dose of 3300 MBq has been proposed in one study [ 29 ]. Approximately 40% of the administered activity is cleared within 8 h after injection, via the urinary system, resulting in a low radiation-dose to the whole-body [ 30 ]. Approximately 40% is localized in the skeleton at 24 h [ 90 ]. The localization in the bone metastases, however, is rather prolonged (half-life of 269 ± 166 h in bone metastases versus short whole-body biologic half-life of 51 ± 43 h) [ 30 ].

The response rate of 70–80% has been reported in painful bone metastases in various malignancies [ 90 , 91 , 92 , 93 , 94 ]. In addition, an increase in Karnofsky performance score and improved quality of life have been noticed after treatment with [ 188 Re]Re–HEDP [ 28 , 93 , 94 , 95 ]. Generally, serious hematological side-effects are not expected [ 92 , 95 , 96 ]. The nadir for platelet and WBC counts occurs in 2–5 weeks and resolves in 8–12 weeks after therapy [ 28 , 54 , 94 ].

Although β¯-emitters are so-called “palliative”, repeated doses of [ 188 Re]Re–HEDP, compared to a single administration, have shown improvement in PFS and OS [ 97 ], as well as a reduction in prostate-specific antigen (PSA) levels in approximately half of the patients [ 97 , 98 ]. Another retrospective study on sixty mCRPC patients has revealed that repeated treatment with [ 188 Re]Re–HEDP can improve OS up to 15.6 months [ 99 ]. The apparent antitumoral effect may be explained by higher β¯-energy and tissue penetration, as well as a higher dose rate of [ 188 Re]Re–HEDP.

Moreover, the efficacy of combination therapy has been investigated. Repeated doses of [ 186 Re]Re–HEDP combined with docetaxel and prednisone versus docetaxel and prednisone alone have shown no significant improvement in PFS nor pain scores in 88 mCRPC patients [ 100 ]. In contrast, the combination with pamidronate in 48 breast cancer patients has revealed a better therapeutic effect, compared to either [ 188 Re]Re–HEDP or pamidronate alone [ 101 ]. Furthermore, zoledronic acid has been labeled with [ 188 Re]Re and has demonstrated promising results requiring confirmation in larger studies [ 102 ].

In conclusion, [ 188 Re]Re–HEDP has not been approved in many countries for clinical use, and the number of prospective trials with large populations is limited. However, respecting physical characteristics, favorable pain control, the potential impact on OS, availability (on-site generator) and cost-effectiveness, it seems a proper radiopharmaceutical for bone-pain palliation and deserves further investigations.

6. [177. Lu]Lutetium-Ethylene Diamine Tetramethylene Phosphonate ([ 177 Lu]Lu-EDTMP)

[ 177 Lu]Lutetium labelled with somatostatin analogs and prostate-specific membrane antigen (PSMA) are generally used for the treatment of soft-tissue and bone metastases of neuroendocrine tumors and prostate cancer, respectively, revealing acceptable response rates [ 15 , 16 ]. Beside to this common application, [ 177 Lu]Lu–EDTMP has been studied as a safe and effective potential palliative therapy in painful bone metastases, regarding binding to hydroxyapatite crystals, rapid skeletal accumulation and minimal uptake in other organs [ 103 ]. [ 177 Lu]Lu–DOTMP (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetramethylene phosphonate) has also been investigated revealing rather similar characteristics to [ 177 Lu]Lu–EDTMP. Yet, the latter exhibits slightly higher skeletal uptake as well as retention in the liver and kidneys [ 33 ].

The combined complete and partial response rate of 77–100% has been documented in different studies using [ 177 Lu]Lu–EDTMP for pain palliation of bone metastases [ 21 , 31 , 34 ]. The decrease in pain has been reported as early as 8–14 days after therapy lasting up to 12 weeks [ 31 , 34 ]. In addition, significant improvement in the quality of life has been noted in patients received [ 177 Lu]Lu–EDTMP [ 21 , 31 ]. Comparing low- and high-dose therapy (1295 vs. 2590 MBq) in two studies, higher response rates have been reported in the high-dose group, although not statistically significant [ 21 , 31 ]. The hematological toxicity is the major complication which ends up with a decrease in peripheral blood cell count with a nadir in 4–8 weeks and gradual recovery in 12 weeks [ 21 ]. This side-effect is commonly insignificant [ 21 , 34 ]; However, transient grade III/IV hematotoxicity has been reported in 23% of patients [ 31 ].

Moreover, the effect of [ 177 Lu]Lu–EDTMP has been compared to [ 153 Sm]Sm–EDTMP. Reportedly, they both have subjected bone metastases to similar radiation doses [ 104 ]. Likewise, the response rate of approximately 75–80% has been noted for both radiopharmaceuticals [ 104 , 105 , 106 ]. In addition, the cocktail therapy of [ 177 Lu]Lu-/[ 153 Sm]Sm–EDTMP has shown safety in administration and pain relief/reduction in 24/25 patients [ 107 ].

[ 177 Lu]Lu labeled with zoledronic acid ([ 177 Lu]Lu-DOTA ZOL ) is another investigational radiopharmaceutical with promising preliminary biodistribution and post-therapy dosimetry results. It also possess a potential theragnostic application (labeled with [ 68 Ga]gallium–DOTA ZOL ) for treatment of bone metastases [ 108 ].

To recapitulate, [ 177 Lu]lutetium may be more available considering the established use in radionuclide therapy for neuroendocrine tumors and prostate cancers. Also, the features of relatively inexpensive [ 177 Lu]lutetium, such as favorable half-life, production in high-specific activity, efficient therapeutic β¯-particles, longer effect with a single administration, lower radiation of bone marrow and sufficient γ-photons for imaging make it an interesting radioisotope in bone-pain palliation therapy [ 32 , 33 , 34 , 109 , 110 ]. The impact of [ 177 Lu]Lu-phosphonate complexes in increasing survival indices is not addressed, fairly. More studies are required to investigate the clinical value of these radiopharmaceuticals, especially in combination with other therapies.

7. [166. Ho]holmium-Ethylene Diamine Tetramethylene Phosphonate ([ 166 Ho]Ho-EDTMP)

Different phosphonate complexes have been labelled with [ 166 Ho]holmium targeting bone and bone marrow lesions [ 111 , 112 , 113 , 114 ]. [ 166 Ho]holmium is an inexpensive β¯-emitter, majorly used in the treatment of multiple myeloma [ 112 , 115 ].

[ 166 Ho]Ho-phosphonates are taken up rapidly by bone and show [ 112 , 114 , 116 ] significant in-vitro stability after 72 h [ 112 ]. The free cation and the complex are excreted via kidneys [ 112 ]. One of the advantages of [ 166 Ho]Ho-phosphonates is the negligible accumulation in extra-skeletal organs [ 112 ]. A dose of 1110 MBq has been used for therapy [ 114 ]. Also, administered activity less than 55,500 MBq estimated to be safe for kidneys to be used for bone marrow ablation in multiple myeloma patients [ 114 ]. Its potential efficacy in bone-pain palliation of multiple myeloma and bone metastases is being contemplated [ 112 , 116 , 117 ]. In a pilot study, [ 166 Ho]Ho–DOTMP was used for the treatment of bone metastases in breast cancer patients showing median time to progression of 10.4 months [ 118 ]. In addition, owing to the remarkably higher radiation dose to the bone marrow, combination of [ 166 Dy]dysprosium/[ 166 Ho]Ho-EDTMP is proposed as an agent for bone marrow ablation [ 113 ].

Finally, the successful experience with radioisotopes labeled with phosphonate in addition to physical characteristics of [ 166 Ho]Ho maybe encouraging to perform further studies investigating the efficacy of [ 166 Ho]Ho-phosphonates in bone-pain palliation/treatment of multiple metastases or multiple myeloma. In addition, its potential in bone marrow ablation is intriguing. However, far more studies are needed before these investigational radiopharmaceuticals become a part of the clinical practice.

8. [223. Ra]radium-Dichloride ([ 223 Ra]RaCl)

Similar to [ 89 Sr]strontium, [ 223 Ra]radium is a calcium mimetic isotope and deposits on hydroxyapatite [ 12 ]. [ 223 Ra]Ra with a half-life of 11.4 days decays via a cascade of α, β¯ and γ emissions [ 12 ]. Ninety-four percent of the total decay energy is released from α-particles [ 12 ].

The approved injection dose is 55 KBq/kg body weight every month for a total of 6 cycles [ 119 ]. The excretion is mainly through gastrointestinal system, raising concern in the co-existence of constipation and inflammation in bowels [ 35 ].

Given the substantially shorter range of [ 223 Ra]Ra in tissues, hematological toxicity is expected to be less in comparison with β¯-emitters [ 36 ]. Mild and reversible myelosuppression occurs with a nadir in 2–4 weeks after intravenous injection resolving in 6 weeks after administration [ 10 , 20 ]. In addition, diarrhea, nausea and vomiting occur in ≥ 10% of cases [ 35 ].

[ 223 Ra]RaCl has been primarily evaluated for pain palliation of bone metastases, which has demonstrated a reduction of bone pain in 40–71% of patients in one study and 29–75% in another, showing a trend of higher response rates with the currently approved dose [ 37 , 38 ]. Also, significantly improved quality of life and higher pain relief, as well as longer time to first symptomatic SRE, need for EBRT and initial opioid use have been demonstrated [ 120 , 121 ] [ 35 , 121 , 122 ]. The typical time to decrease in pain intensity and duration of pain palliation is 1–8 and 6 weeks, respectively [ 20 ]. [ 223 Ra]RaCl results in pain relief only in a portion of patients; however, the completion of all 6 courses of the therapy is indicated for achieving OS benefit in most cases [ 123 ]. Discontinuation of [ 223 Ra]RaCl therapy should be considered in cases of significant hematologic derangements as well as evidence of rapid disease progression and visceral metastases [ 124 ].

Recently, the probability of benefits of [ 223 Ra]RaCl administration in earlier stages of bone metastases in mCRPC has been proposed showing that patients with lower numbers of bone metastases have better outcome [ 125 ]. Metastases to the axial skeleton and the value of alkaline phosphatase were reported as significant predictors of the survival [ 125 ]. In addition, in a study, asymptomatic patients with two or more skeletal lesions have revealed more favorable results, demonstrating lower adverse events [ 126 ]. These findings may provoke further studies using [ 223 Ra]RaCl at initial diagnosis of bone metastases.

Evaluation of response to therapy for bone metastases is challenging. This is not readily possible with CT or bone scintigraphy. Although PET/CT imaging using bone-seeking and tumor-specific tracers are not yet approved for this indication, the published studies, as well as our clinical experience revealed promising role of PET/CT in the assessment of treatment response ( Figure 1 and Figure 2 ) [ 7 , 127 ]. Also, recent studies have shown that diffusion-weighted MRI may be of value in this setting [ 128 ]. Other traditional measures, like a decline in PSA level, are not reliable means to assess response following therapy with [ 223 Ra]RaCl [ 127 ].

Although it is well-known that visceral metastases preclude patients from participation in [ 223 Ra]RaCl therapy, an investigator has a contradictory view and propose that although survival benefit may be lower in these group of patients, it does not necessarily translate to poor response to therapy [ 129 ].

Therapy of mCRPC includes different strategies involving androgen receptor inhibitors, EBRT, chemotherapy (docetaxel) and immunotherapy [ 130 ]. Androgen receptor inhibitors are the main modality of treatment in mCRPC patients. However, patients can become resistant to both enzalutamide and abiraterone [ 127 , 131 ]. Considering the different mechanism of action, [ 223 Ra]RaCl can become a qualified alternative to the common practice, switching to another androgen receptor inhibitor in cases of drug resistance [ 13 ].

The combination of hormonal therapy and [ 223 Ra]RaCl is the subject of ongoing clinical studies [ 130 ]. [ 223 Ra]RaCl has been used in combination with either abiraterone or enzalutamide; however, its impact on OS is still under investigation [ 132 , 133 ]. Preliminary data have demonstrated increase in survival with combination therapy. These studies are still ongoing to establish the impact on survival. Noteworthy, an improvement in event-free survival in mCRPC patients treated with abiraterone, corticosteroids and [ 223 Ra]RaCl has not been achieved [ 134 ]. Interestingly, in the combination group, an increased risk of fracture has been reported, compared to the placebo arm [ 134 ].

Moreover, EBRT has been used safely along with [ 223 Ra]RaCl [ 127 ]. EBRT prior to [ 223 Ra]RaCl administration has not shown an association with compromised hematologic reserve [ 135 ]. The different mechanism of action of these two modalities advocates more studies on the combination therapy to evaluate the impact on the outcome.

Additionally, bone-pain palliation with denosumab or bisphosphonate in combination with [ 223 Ra]RaCl has been investigated. Increase in OS has been observed only with denosumab [ 132 ]. In addition, the treatment with [ 223 Ra]RaCl plus bisphosphonates has prolonged time to symptomatic SRE [ 136 ].

The safety of docetaxel administration prior to [ 223 Ra]RaCl therapy has previously been studied [ 137 ]. Although this sequence of therapy seems to be well-tolerated, there has been an increased incidence of grade III/IV thrombocytopenia as well as a risk of decreased time to SRE, in the [ 223 Ra]RaCl group [ 137 ]. However, [ 223 Ra]RaCl has increased survival, regardless of previous docetaxel treatment [ 137 ]. In addition, the concomitant treatment with docetaxel and [ 223 Ra]RaCl, compared to docetaxel, has demonstrated a favorable antitumor activity has prolonged biochemical suppression [ 138 ] and time to progression [ 139 ].

The choice between the sequence of [ 223 Ra]RaCl and docetaxel therapy is mainly based on the involved organs. The absence of visceral involvement favors the use of [ 223 Ra]RaCl as the primary agent [ 13 ]. Further larger studies on the risks and benefits of concurrent administration of chemotherapy and [ 223 Ra]RaCl are required. The same is true for co-administration of β¯-emitting bone-targeted therapies and [ 223 Ra]RaCl, as their safety profile needs further investigation [ 127 ].

Other newer agents such as programmed cell death (PD-1) inhibitors have also been approved for types of mCRPC that are microsatellite instability (MSI)-high and DNA mismatch repair-deficient [ 130 ]. The combination of these agents (atezolizumab) with [ 223 Ra]RaCl in mCRPC with bone metastases is currently under investigation [ 130 ]. Other newer agents include DNA damage response inhibitors, such as Olaparib, that has revealed a favorable response rate in mCRPC patients, in a phase II trial. Ongoing trials are also investigating the effect of these newer agents in association with [ 223 Ra]RaCl [ 130 ].

Not surprisingly, [ 223 Ra]RaCl is the subject of ongoing trials in other bone dominant metastatic cancers such as breast [ 140 , 141 ] and lung cancers [ 142 ]. In a phase II trial, [ 223 Ra]RaCl has been administered with different hormonal therapy agents [ 141 ]. The primary end-point was disease control at 9 months, achieved in 49% of patients [ 141 ]. In addition, the study evaluating the efficacy of combined therapy of [ 223 Ra]RaCl in association with hormonal therapy and a chemotherapy drug (capecitabine) is still in progress [ 140 ].

Ultimately, the studies are in progress, evaluating the further benefits of [ 223 Ra]RaCl. [ 223 Ra]RaCl seems a promising therapeutic agent beside its palliative effects, used alone or in combination with other treatments or palliative agents in mCRPC patients and it may find its way in other bone dominant metastatic malignancies.

9. Discussion

Bone metastases develop in approximately 30% of cancer patients and occur in up to 60–90% in late phases [ 26 ]. Therapeutic approaches have been extensively investigated to reach for an optimum method. Since the first introduction of radionuclide therapy in bone-pain palliation in the 1940 s, numerable radioisotopes and pharmaceuticals have been exploited to target the bone lesions and alleviate the pain. Each demonstrates particular characteristics, benefits and drawbacks ( Figure 3 ). However, the choice extremely rests on the logistic feasibility of the tracer and then on the patient’s status (renal function, bone marrow reserve), cancer extent (extraskeletal lesions, the bulk of the tumor) and physical properties of radioisotopes ( Figure 4 ).

No significant superiority in pain reduction has been documented using different β¯-emitters [ 18 ]. The α-emitter, [ 223 Ra]RaCl, also shows a response rate of 50–60% [ 146 ], not beyond the reported range for β¯-emitters. However, the effects on extending survival parameters make [ 223 Ra]RaCl a more appealing agent to be employed.

Noteworthy, patients must comply with requirements for radionuclide treatment, that is, to have osteoblastic activity in symptomatic bone metastases, sufficient renal function, bone marrow reserve and life expectancy [ 147 ]. In addition, presence of spinal cord compression, high risk of fracture in weight-bearing bones, pregnancy and breastfeeding are contraindication for radionuclide therapy [ 3 , 147 ].

9.1. Concomitant Extraskeletal Involvement

When the disease is not confined to the skeleton, other than exclusively bone-seeking agents are mandatory to target all tumoral lesions. Disease-specific radiopharmaceuticals (including [ 177 Lu]Lu–PSMA in prostate cancer, [ 177 Lu]Lu/[ 90 Y]Y-conjugated peptides in neuroendocrine tumors, [ 131 I]Iodine in differentiated thyroid cancer, [ 131 I]I-MIBG in pheochromocytomas/paragangliomas, etc.) provide simultaneous radiation to the skeletal and visceral lesions. In addition, bone-seeking agents may be administered when the disease-specific radiopharmaceuticals fail to reduce pain, considerably. This hypothetical application needs trials to depict safety and efficacy.

9.2. Life Expectancy

Patients with very short life expectancy may not be optimal candidates for bone-pain palliation with radiopharmaceuticals since the response to therapy commonly commences with a delay of 1–4 weeks with reports of exacerbation of pain (flare-response) in a few first days [ 3 ]. If patients with shorter predicted life expectancy are to receive this therapy, radioisotopes with shorter half-lives would be better options, such as [ 188 Re]rhenium and [ 153 Sm]samarium, as well as [ 186 Re]rhenium and maybe [ 166 Ho]holmium. In contrast, in case of predicted long life expectancy, other than [ 223 Ra]radium and [ 89 Sr]strontium revealing longer palliation effects may be proper options. In addition, repeated doses of other radiopharmaceuticals or combination with other therapies may be reasonable.

9.3. Bone Marrow Status

Bone marrow reserve can generally be the dose-limiting factor. Before administration of bone-seeking agents, hematological indices typically should meet the values of hemoglobin ≥90 g/L, WBC ≥3 × 10 9 /L and platelet ≥100 × 10 9 /L in most of the cases [ 3 ]. These indices are as follows for [ 223 Ra]RaCl: hemoglobin ≥10 g/L, absolute neutrophil count ≥1.5 × 10 9 /L and platelet ≥100 × 10 9 /L [ 35 ]. In patients with compromised bone marrow reserve, radiopharmaceuticals with less hematological toxicities or shorter particle range are favored, including [ 153 Sm]samarium and [ 177 Lu]lutetium, as well as [ 223 Ra]radium.

9.4. Renal Function

The clearance of radiopharmaceuticals excreted via kidneys is prolonged in renal insufficiency, increasing the whole-body dose and myelosuppressive side effect [ 3 ]. Hence, in case of mild to moderate decreased renal function, [ 223 Ra]radium (with negligible renal excretion) and β¯-emitters with a shorter half-life and with reduced doses ([ 153 Sm]samarium, [ 186 Re]rhenium and maybe [ 177 Lu]lutetium, [ 188 Re]rhenium or [ 166 Ho]holmium) are favored.

9.5. Tumor Size

The size of the tumoral lesions can also play a role in opting the proper radiopharmaceutical. The energy of the emitted β¯-particle is proportional to the range of penetration in the tissue. Hence, radiopharmaceuticals with higher β¯-particle energy, such as [ 188 Re]rhenium and [ 166 Ho]holmium can be more effective in larger lesions than small ones. As a rule of thumb, [ 177 Lu]lutetium and [ 153 Sm]samarium can be used in small-sized lesions. Moreover, α-particles deliver substantially high energy in a short distance and can be employed in small-sized metastases, as well.

Historically, regarding the merely palliative effects of traditional β¯-emitters, radiopharmaceuticals become a part of patient treatment when physicians are at the end of their rope and the life expectancy is poor. However, this approach may change in the guidelines, in the future, regarding: first, β¯-emitters are more effective when they are used in early stages and limited skeletal involvement and when the patient’s performance state is higher [ 74 , 85 ]; second, the combination therapy is being more evaluated and demonstrate promising results. Other than chemo- or radiotherapy, combination with bisphosphonates or denosumab, a RANK ligand inhibitor, are barley investigated; third, it is well-known that α-emitters are more toxic for tumoral cells and show significant survival benefits.

Future directions are concisely mentioned for each radiopharmaceutical in the pertinent section. On the whole, further studies evaluating the role of radiopharmaceuticals in the earlier course of the disease and the combination with other therapies may clarify the role of nuclear medicine in the palliation or treatment of bone metastases.

10. Conclusions

In summary, the management of painful bone metastases is still a challenging issue. Bone-pain palliation with β¯-emitting isotopes is being conducted for decades, revealing acceptable results. Several radiopharmaceuticals have been and still are being investigated to find an optimum agent. Based on the current data, each therapeutic radioligand has its own advantages and limitations without any substantial superiority over others. The impact of radionuclide therapy on overall and disease-free survival as well as SRE has been shown in the published studies. However, further investigations with larger patient populations are needed to confirm their prognostic roles. Nevertheless, t he introduction of [ 223 Ra]radium with its advantageous impact on survival cast a shadow over other radiopharmaceuticals; however, unfortunately, the expensive [ 223 Ra]radium is not globally available. Combination treatments using bone-seeking radiopharmaceuticals with other therapies have demonstrated safety and favorable results in some studies. Hence, further investigations are mandatory to establish the role of bone-seeking and tumor-targeted radionuclide therapy, optimal timing and combined protocols, in the palliation or treatment of bone metastases.

Acknowledgments

We wish to express our deep appreciation and gratitude to Werner Langsteger, Department of Nuclear Medicine and Endocrinology, PET-CT Center LINZ, St. Vincent’s Hospital, Linz, AUSTRIA, for providing sequential PET/CT images of the patients, as well as Elham Mirzaian, Department of Pathology, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran, for providing the histopathology image that greatly improved the manuscript.

Author Contributions

Conceptualization: M.B.; Data and Writing: R.M.-F., F.M., B.S., G.D. and B.A. original draft preparation: R.M.-F.; review & editing, M.B., R.M.-F., F.H., G.S.-Z. and A.M.; visualization: R.M.-F.; supervision, Mohsen Beheshti. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Conflicts of Interest

The authors declare no conflicts of interest.

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