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Radionuclide Therapy for Osseous Metastases in Prostate Cancer

Seminars in Nuclear Medicine, Volume 45, Issue 1, January 2015, Pages 66-80

Bone metastases are associated with increased morbidity and poor prognosis in castration-resistant prostate cancer. Since 2010, 5 systemic therapies for metastatic castration-resistant prostate cancer have been approved by the US Food and Drug Administration based on an improvement in overall survival, offering alternatives to docetaxel, a chemotherapeutic agent with modest effect and significant toxicity. These systemic treatments belong to different classes of medication such as immunotherapy, hormonal therapy, chemotherapy, and radionuclide therapy. Radium-223 dichloride (223RaCl2), approved in May 2013, is a novel α-emitting radiopharmaceutical that targets areas of increased bone turnover in bone metastases, delivering densely ionizing radiation within a short tissue range and causing more severe chromosomal damage than β-emitting radiopharmaceuticals. In this article, we review the clinical development of223RaCl2, focusing on its effects on pain relief, skeletal events, biochemical markers, overall survival, quality of life, and safety. We also outline the differences between223RaCl2and the previously developed bone-seeking β-emitters and briefly present new trials on the horizon involving223RaCl2.

Background

Prostate cancer is the most common cancer in men living in the United States, excluding in situ carcinoma, basal cell and squamous cell skin carcinomas. There are an estimated 2,617,682 men in the United States currently living with prostate cancer. It has the highest incidence rate in men with approximately 233,000 (27%) new cases projected to occur in 2014. It is the second leading cause of cancer-related deaths after bronchopulmonary cancer, with 29,480 deaths accounting for 10% of all cancer-related deaths.1 and 2The morbidity and mortality associated with prostate cancer can almost completely be attributed to the consequences of bone metastases. Bone metastases, mainly osteoblastic, occur in nearly all patients with castration-resistant prostate cancer (CRPC) during the natural course of the disease. CRPC is an advanced form of prostate cancer characterized by the progression of disease despite surgical castration or pharmaceutical androgen deprivation therapy. Compared with those with castration-sensitive disease, the prognosis of patients with CRPC is poor and survival is reduced. Patients with osseous metastases also develop bone pain and skeletal-related events (SREs) such as pathologic fracture and spinal cord compression, which may require additional surgery or radiotherapy to the bone and lead to increased analgesic consumption, decreased quality of life (QoL), and increased treatment costs.2, 3, 4, and 5

The management of painful osseous metastases requires a multidisciplinary approach. The optimal treatment should provide pain relief, decrease skeletal morbidity, and most importantly, increase survival rates. Until recently, treatment of patients with CRPC and bone metastases was aimed at controlling pain and reducing the risk of SREs using a combination of systemic and local therapies. Systemic therapies include analgesics, hormonal therapy, chemotherapy, steroids, osteoclast inhibitors such as bisphosphonates and denosumab, and radiopharmaceuticals. Local treatments involve surgery, nerve blocks, and external beam radiotherapy (EBRT). In general, nonsteroidal anti-inflammatory drugs and opioid analgesics are given following guidelines published by the World Health Organization and the National Comprehensive Cancer Network (NCCN).6 and 7EBRT is less desired when the disease is widespread, because effective radiation delivery can be limited by toxicity in normal adjacent tissues or overlapping critical organs. Alternatively, bone-seeking β-emitting radiopharmaceuticals can be used for selective irradiation of multiple metastatic sites and has clear advantages over EBRT for the treatment of multifocal metastatic bone pain. Denosumab, a human monoclonal antibody targeting the receptor activator of nuclear factor κ-B ligand, and zoledronic acid, a bisphosphonate, were shown to prevent and delay the onset of SREs, with a significantly better effect of denosumab demonstrated in a recent phase III trial. However, none of these agents have improved the QoL or overall survival (OS).8, 9, and 10

Docetaxel, a chemotherapeutic agent belonging to the taxane class of microtubule inhibitors, was the first agent to demonstrate improved OS in CRPC.11 and 12From its approval in 2004 by the US Food and Drug Administration (FDA) until 2010, docetaxel in combination with prednisone was the first-line standard of care agent for the treatment of metastatic CRPC (mCRPC). However, the magnitude of the OS benefit is modest. Docetaxel is associated with significant toxicity such as neutropenia, fatigue, nausea, diarrhea, and neuropathy. This limits its use to instances in which the clinical benefit outweighs the adverse event profile. There were also limited options for patients following docetaxel failure. Since 2010, 5 systemic therapies for mCRPC have been approved by the FDA based on an improvement in OS, offering alternatives to docetaxel. These alternatives include immunotherapy with sipuleucel-T (PROVENGE), hormonal therapy with abiraterone acetate (ZYTIGA) and enzalutamide (XTANDI), cytotoxic chemotherapy with cabazitaxel (JEVTANA), and radionuclide therapy with radium-223 dichloride (Xofigo).13, 14, 15, 16, 17, 18, and 19Because their mechanisms of action are different, it is conceivable that the antitumor activity of these agents may be additive. As trial results emerge, the treatment landscape of mCRPC is rapidly evolving, affecting the decision of administering docetaxel, the timing of docetaxel administration, and the alternative therapies after failing docetaxel. For instance, the most recent NCCN guidelines for the management of mCRPC suggested multiple therapeutic options for different clinical scenarios after being assigned a level of evidence ( Table 1 ). In these guidelines, the panel recommended223RaCl2as a first-line or second-line option for patients with symptomatic bone metastases and no known visceral disease and assigned it a category 1 based on high-level evidence (uniform NCCN consensus that intervention is appropriate).20 and 21

Table 1 223RaCl2in the Treatment Scheme of mCRPC.223RaCl2is Recommended by a Panel of Experts as a First-Line Option for Patients With Symptomatic Bone Metastases and No Known Visceral Disease, or as a Second-Line Option After Failure of Docetaxel Therapy

Clinical situation Treatment option
Chemotherapy-naïve, asymptomatic or mildly symptomatic with slow disease progression Sipuleucel, abiraterone, enzalutamide
Chemotherapy-naïve, asymptomatic with rapid disease progression Abiraterone, enzalutamide, ± docetaxel
Chemotherapy-naïve, symptomatic Docetaxel 223RaCl2
After docetaxel failure Enzalutamide, abiraterone, cabazitaxel, 223RaCl2

Adapted with permission from Kantoff and Mohler. 20

223RaCl2is a bone-seeking radiopharmaceutical that emits α particles that deposit high linear energy within a short penetration range to areas of increased bone turnover as radioactive decay occurs at or near osseous metastatic sites, selectively killing cancer cells. There are other bone-seeking radiopharmaceuticals that emit β particles rather than α particles ( Table 2 ). Rhenium-186 hydroxyethylidene diphosphonate (186Re-HEDP; approved in some European countries) as well as strontium-89 dichloride (89SrCl2) and samarium-153 ethylenediamine-tetramethylene phosphonate (153Sm-EDTMP; approved in both Europe and the United States) have been used for pain palliation secondary to osteoblastic metastases. The now abandoned phosphorus-32 (32P) sodium orthophosphate, which could be administered intravenously or orally, was the first radiopharmaceutical to be used for this purpose more than 4 decades ago. Although these agents may have an effect on OS, trials using these agents were not adequately designed to assess OS. Additional radiopharmaceuticals have been developed in the past 2 decades but remain investigational in various clinical and preclinical phases (188Re-HEDP, tin-117m diethylenetriamine pentaacetic acid [117mSn-DTPA], lutetium-177 EDTMP [177Lu-EDTMP], and lutetium-177 methylene diphosphonate [177Lu-MDP]).22, 23, 24, 25, 26, 27, 28, 29, and 30

Table 2 Physical Characteristics of Selected Radionuclides

Isotope Radiopharmaceutical Half-Life (d) Energy (MeV) (Maximum/Mean) γ Energy (keV) (%) Soft Tissue Range (mm) (Maximum/Mean) Usual Dose
32P 32P-orthophosphate 14.3 1.7/0.70 (β) 8.5/3 (β) 5-10 mCi i.v.
10-12 mCi p.o.
 
89Sr 89SrCl2 50.5 1.46/0.58 (β) 0.91 (0.01) 7/2.4 (β) 4 mCi i.v.
40-60 µCi/kg i.v.
 
153Sm 153Sm-EDTMP 1.9 0.81/0.23 (β) 103 (28) 3.4/0.6 (β) 1 mCi/kg i.v.
 
186Re 186Re-HEDP 3.7 1.07/0.35 (β) 137 (9) 3.7/1.1 (β) 35 mCi i.v.
 
188Re 188Re-HEDP 0.7 2.12/0.78 (β) 155 (15) 10.4/3.1 (β) 30-118 mCi i.v.
 
223Ra 223RaCl2 11.4 5.64 (α) mean 154 (5.6) 0.05-0.08 (α) 1.35 µCi/kg i.v. × 6 every 4 wk
269 (13.6)
324 (3.9)

i.v., intravenously; p.o., orally.

In this review, the recent advances in nuclear medicine for the treatment of mCRPC are presented, focusing on the newly approved radiopharmaceutical223RaCl2by the FDA following the ALpharadin in SYMptomatic Prostate CAncer Patients (ALSYMPCA) phase III trial. 16

223RaCl2 for the Treatment of mCRPC

Physical Properties

Radium is an alkaline earth element with bone-seeking properties similar to calcium, strontium, and barium as these elements belong to the same group in the periodic table. Radium is concentrated in the bone because of inclusion in the calcium hydroxyapatite matrix, where it substitutes for calcium during new bone formation such as in and around metastatic sites. The most common and stable isotope of radium is226Ra, which can be found in nature and has a half-life of approximately 1600 years.223Ra, which can also be found in nature, is much less common and has a significantly shorter half-life of 11.4 days compared with that of226Ra. In addition,223Ra can be produced artificially from the decay of actinium-227 (half-life 21.7 years) using an actinium-227-thorium-227 (227Ac/227Th) generator system.223Ra is administered intravenously in its cationic form (223Ra2+) bound to dichloride (2Cl) forming the radiopharmaceutical223RaCl2.223Ra decays by the emission of 4 α particles and 2 β particles via daughter isotopes to stable lead-207 (207Pb) ( Fig. 1 ). Although the mean α energy released from the decay of223Ra to radon-219 (219Rn) is 5.64 MeV, the energy associated with the entire decay cascade approximates 28 MeV, 96% of which is related to α emission.223Ra and bismuth-211 (211Bi) have a characteristic γ peak at 154 keV (5.6% abundance) and 351 keV (12.8%), respectively. In addition,223Ra has a 269-keV γ photon (13.6%) that is difficult to distinguish from that of its219Rn daughter (271 keV; 9.9%). These photons can be used to determine whether daughter radionuclides redistribute in the body. However, imaging is not performed in routine clinical practice owing to the low levels of injected radioactivity resulting in a low number of events and long acquisition times. 31

gr1

Figure 1 Decay scheme of223Ra.

Differences Between α and β Particles

Alpha particles differ from β particles in energy, tissue range, linear energy transfer (LET), and number of DNA hits needed for cell killing. Alpha particles have a higher energy (5-8 MeV) and a shorter penetration range in soft tissue (50-80 μm, in the order of 2-10 cell diameters) compared with β particles, particularly in bone-seeking radionuclides (maximum of 2.1 MeV and 10.4 mm for188Re). Alpha particles also deposit a high density of ionization events along their track, 32 referred to as high LET. In contrast, low LET radiations, such as β particles, produce the same number of ionizations but sparsely along their track. Therefore, at the same dose, high LET radiations are more destructive because energy is transferred to a small region of the cell. The localized DNA damage caused by high LET radiations (ie, shattered chromosomes during mitosis and complex chromosomal rearrangements) is more difficult to repair than the diffuse DNA damage caused by the sparse ionizations of low LET radiations. 33 Thus, the cytotoxicity of α particles may be extremely effective and less dose dependent than that of β particles, and cell death may occur after a single or a few α particle emissions.34 and 35The deposition of energy over a much shorter range than β-emitters is of value in223RaCl2therapy as targeted cells might be destroyed while neighboring cells are spared, thus avoiding bone marrow toxicity.

Biodistribution

Preclinical studies in mice showed rapid blood clearance of223RaCl2after intravenous injection. Peak skeletal uptake occurred within 1 hour of injection, with no significant change in the level of uptake after 14 days, indicating excellent skeletal retention. Bone uptake was highly selective compared with soft tissue uptake. Unlike the excretion of calcium, which is renal, that of223RaCl2is mainly intestinal with less than 10% excreted renally. There is no significant redistribution of the daughter radionuclides. It has been postulated that the relatively long half-life of223Ra allows for incorporation into the bone during remodeling, contributing to better retention of daughter products which could otherwise redistribute in the body and contribute to toxicity. 31

In humans,223RaCl2is also cleared rapidly from circulating blood with 12% of the injected activity remaining in the blood at 10 minutes, 2% at 4 hours, and <1% at 24 hours. Localization to normal and diseased bone is observed within 10 minutes of injection and persistent over at least 14 days. Accumulation in skeletal lesions is similar to patterns observed in diagnostic bone scans using technetium-99m MDP (99mTc-MDP). Although old studies reported predominant excretion through the hepatobiliary or intestinal route with some renal elimination,36 and 37a recent study by Carrasquillo et al demonstrated early passage in the small bowel with subsequent fecal elimination, limited urinary excretion (~4%), and no biliary excretion. In this study, activity was observed in the small bowel within the first 10 minutes, then moved to the colon on later imaging. By 24 hours, a median of 52% of the initial activity was present in the colon ( Fig. 2 ). Therefore, the rate of elimination of223RaCl2is highly influenced by intestinal transit. Patients with slow intestinal transit could potentially receive a higher radiation dose to the bowel. By 7 days, approximately 75% of the administered dose is excreted from the body.38 and 39

gr2

Figure 2 99mTc-MDP whole-body bone scan in the left panel shows multiple metastatic disease to the bone.223RaCl2whole-body bone scan in the right panel was taken 1 day after injection. Although223RaCl2images have lower counts and are noisier than the99mTc-MDP scan, they clearly show focal accumulation in the most obvious bone metastasis, for example, left distal femur, right femur, and left proximal humerus. In addition, excretion into the ascending and transverse colon is noted. (Copyright 2013 Springer Science and Business Media. Adapted with permission from Carrasquillo et al. 38 )

As with any administered radiopharmaceutical, there is a concern about redistribution of daughter radionuclides (in undesired areas in the body), which may contribute to toxicity. In the case of223RaCl2, the α emissions following the initial decay of223Ra occur within 5 seconds. Consequently, redistribution of daughter nuclides is unlikely in this short timeframe but could theoretically occur for the final α-emitting daughter211Bi that is produced following the β decay of211Pb (half-life, 36.1 minutes). Using serial dynamic imaging and a multienergy window, Carrasquillo et al showed no redistribution of daughter radionuclides once the223Ra cleared from the blood and entered the bone and gastrointestinal tract. It is only at very early time points (<1 hour) that more activity was seen in the kidneys than expected from the parent (223Ra), possibly representing uptake of the daughters211Pb,211Bi, or both that are present at equilibrium levels in the primary injected dose. 38

Renal and hepatic impairments are not expected to affect the pharmacokinetics of223RaCl2as radium is minimally excreted in the urine, not excreted in the bile, and not metabolized. For these reasons, there is no need for dose adjustments in patients with mild hepatic or mild to moderate renal impairment. However, no recommendations have been made for patients with moderate to severe hepatic or severe renal failure (creatinine clearance <30 mL/min) owing to lack of or limited clinical data. 25

Dosimetry

Dosimetry measurements from models and patients suggest that bone, red bone marrow, and intestinal wall receive the highest radiation absorbed doses.

Using an age-dependent biokinetic model for alkaline earth elements developed by the International Commission on Radiological Protection, Lassmann et al calculated absorbed doses and dose coefficients for 25 organs or tissues, allowing comparison with other therapeutic modalities used in nuclear medicine and providing a base for further development of patient-specific dosimetry and risk estimates. The contributions of daughter nuclides, high LET radiation (α), and low LET radiation (β and γ) were taken into account. After a series of 6 treatments of 1.35-µCi/kg (50 kBq/kg)223RaCl2for a 70-kg person (total of 567 µCi), the largest absorbed α dose was to the bone endosteum (1600 rad) followed by the red bone marrow (150 rad). The dose coefficients for the bone endosteum and the red bone marrow were 1030 rad/mCi (3.8 × 10−6 Gy/Bq) and 100 rad/mCi (3.7 × 10−7 Gy/Bq), respectively, after applying a weighting factor of 5 for the quantification of deterministic effects of α radiation. 40

Clinically, the absorbed doses in major organs were calculated based on biodistribution data in 5 patients with mCRPC treated with223RaCl2using the MIRD method and OLINDA software. These were also highest in bone (4262.60 rad/mCi), followed by red marrow (513.51 rad/mCi), lower large intestine (171.88 rad/mCi), and upper large intestine (119.58 rad/mCi). 41

Clinical Development

The use of223RaCl2in a preclinical study using a nude rat skeletal metastases model showed significant antitumor effect compared with animals treated with chemotherapy (cisplatin and doxorubicin), immunotoxin, pamidronate, and131I-labeled bisphosphonates. In this study, all of the untreated control animals had to be killed because of tumor-induced paralysis 20-30 days after injection with tumor cells, whereas the rats treated with >0.27 µCi (>10 kBq) of223RaCl2had a significantly increased symptom-free survival (P< 0.05). In addition, 36% (5 of 14) of rats treated with 0.30 µCi (11 kBq) and 40% (2 of 5) of rats treated with 0.27 µCi (10 kBq) were alive beyond a 67-day follow-up period. These encouraging preclinical results led to the initiation of clinical trials in humans. 42

The clinical trials that led to the conduct of the phase III trial followed a traditional development pathway ( Table 3 ). The initial phase I clinical trial was a single-center study focusing on dose escalation and evaluation of toxicity. The following phase II and phase III clinical trials were double blind, randomized, and multicenter focusing on dose fractionation, comparison with EBRT, and best standard of care, and evaluation of dose response, biochemical response, SREs, pain relief, OS, and QoL.

Table 3 Summary of Clinical Trials Using223RaCl2

Phase Number of Patients (n) Dose Regimen Results Reference
IA 25 (15 Patients with prostate cancer and 10 with breast cancer) Single infusion of 1.24, 2.5, 4.4, 5.8, or 6.75 µCi/kg
  • No hematologic dose-limiting toxicity.
  • Reversible myelosuppression with nadirs 2-3 wk after injection.
  • Pain relief observed in >50% of patients.
  • Decline in TAP of >50% in patients with prostate cancer with elevated pretreatment values.
39
IB 6 (Patients with prostate cancer) Repeated injections of 1.35 µCi/kg given 5 times with a 3-wk interval (4 patients), or 3.38 µCi/kg given twice with a 6-wk interval (2 patients)
  • No additional toxic effects related to the repeated treatment.
  • Repeated treatment should be scheduled in a way to allow normalization of the blood count before a new injection is given.
44
I 10 (Patients with prostate cancer) Single infusion of 1.35, 2.7, or 5.4 µCi/kg
  • Early bone uptake (10 min) and small bowel excretion. Limited urinary excretion and lack of significant biliary excretion.
  • Lack of significant organ redistribution of radioactive daughters.
  • No dose-limiting toxicity.
38
Moreover, 6 patients received an additional dose of 1.35 µCi/kg
II 64 (Patients with prostate cancer) Repeated injections of 1.35 µCi/kg given 4 times with a 4-wk interval vs placebo (EBRT)
  • Significant decrease in BAP concentrations in the223Ra-treated arm vs placebo (−65.6% vs 9.3%).
  • Improved median overall survival (65.3 vs 46.4 wk) and more patients were alive at 24 mo (30% vs 13%) in the223Ra-treated arm vs placebo arm.
45 and 53
II 100 (Patients with prostate cancer) Single infusion of 0.14, 0.68, 1.35, or 2.7 µCi/kg
  • Pain response at week 8 seen in 40%, 63%, 56%, and 71% of patients in the 0.14-, 0.68-, 1.35-, or 2.7-µCi/kg groups, respectively.
  • Significant decrease in BAP concentrations in the higher dose group at 4 and 8 wk.
51
II 122 (Patients with prostate cancer) Repeated injections of 0.68, 1.35, or 2.16 µCi/kg given 3 times with a 6-wk interval Favorable dose-dependent effect on serum markers of CRPC activity (PSA, BAP, and CTX-1), skeletal-related events, and pain. 46
III 921 (Patients with prostate cancer) Repeated injections of 1.35 µCi/kg given 6 times with a 4-wk interval vs placebo
  • Improved overall survival (14.9 vs 11.3 mo; HR = 0.70; 95% CI: 0.58-0.83;P< 0.001). Improved quality of life.
  • Favorable effect on serum markers of CRPC (PSA and TAP) and symptomatic skeletal events.
  • Favorable toxicity profile.
16

CTX-1, carboxy-terminal cross-linking telopeptide of type I collagen.

Dose Escalation and Maximum Tolerated Dose

The 2 phase I trials that were performed did not reach a maximum tolerated dose owing to the absence of hematologic dose-limiting toxicity 39 and the favorable biologic effect of the lower repeated activities. 38 The first study by Nilsson et al enrolled 25 patients (15 patients with prostate cancer and 10 with breast cancer) who received a single infusion of223RaCl2ranging in activity from 1.24-6.75 μCi/kg (46-250 kBq/kg). Reversible myelosuppression, mainly neutropenia and leukopenia, occurred with nadirs 2-4 weeks after injection. For platelets, only grade 1 toxicity was observed even at the highest dosage levels. 39 The second study enrolled 10 patients and evaluated activities ranging from 1.35-5.4 μCi/kg (50-200 kBq/kg) in single infusion and optional repeated infusion.223RaCl2was also well tolerated without dose-limiting toxicity. Hematologic toxicity, mostly grades 1 and 2, was observed. 38

Dose Fractionation

Repeated treatment with223RaCl2should be scheduled in a way to allow normalization of the blood count before a new injection is given. A small phase Ib study on 6 patients with prostate cancer evaluated the safety profile of repeated injections at 2 dosage levels: 1.35 μCi/kg (50 kBq/kg) given 5 times at 3-week intervals (4 patients) or 2 injections of 3.38 μCi/kg (125 kBq/kg) with a 6-week interval (2 patients). The 4 patients in the 1.35-μCi/kg × 5 dose group did not experience additional toxic effects related to the repeated treatment regimen compared with those in the single-injection phase Ia study by Nilsson et al. 39 The hematologic profiles were smoothed out because of the fractionation schedule compared with a single dosage totaling the same as the 5 fractions combined.43 and 44Subsequent phase II and III trials used 4 injections 45 or 6 injections 16 at 4-week intervals or 3 injections at 6-week intervals. 46

Biochemical Changes and Dose Response

The ground of biochemical markers used as a surrogate to predict clinical benefit and OS in CRPC is constantly shifting with the advent of novel therapeutic agents. These markers, which reflect bone metabolism and tumor metabolism, are variably affected after therapy with223RaCl2and may have different prognostic values.

Bone-specific alkaline phosphatase (BAP) is a bone-formation marker reflecting osteoblastic activity. Elevated serum levels of BAP have been shown to correlate with the extent of osseous metastatic disease, adverse skeletal outcomes, and poor survival in CRPC.47, 48, and 49Total alkaline phosphatase (TAP) levels have also been shown to predict OS independent of prostate-specific antigen (PSA) levels. 50 Although the utility of BAP vs TAP is unclear,223RaCl2has consistently demonstrated a significant decrease of BAP in all the phase I and phase II trials38, 39, 45, 46, and 51and TAP in the phase III ALSYMPCA trial and 1 phase II trial.16 and 45

Interestingly, in the phase I dose-escalation study that included 15 patients with prostate cancer and 10 with breast cancer who received single infusion of223RaCl2ranging from 1.24-6.75 μCi/kg (46-250 kBq/kg), the reduction in BAP from baseline was stronger in the prostate cancer group compared with the breast cancer group (52.1% vs 29.5%,P= 0.0028). The reduction was also more significant in patients with elevated baseline levels (50.1% vs 30.6,P= 0.0042). 39

In a phase II study including 100 patients with prostate cancer who were randomized to receive different doses of a single injection of223RaCl2(0.14, 0.68, 1.35, or 2.7 µCi/kg or 5, 25, 50, or 100 kBq/kg) and then assessed at 2, 4, 8, 12, and 16 weeks after injection, the median relative changes in BAP from baseline were statistically significant only in the 2.7-µCi/kg dose group at weeks 4 and 8 (P< 0.0001 andP= 0.0067). However, the single injection achieved pain relief at all dose levels, emphasizing the fact of distinguishing the pain-relieving effect of223RaCl2from its antitumor effect. 51

The reduction of BAP following repeated injections of223RaCl2was assessed in a randomized study (n= 64) where 33 patients received 4 injections of 1.35 µCi/kg every 4 weeks and 31 patients received a placebo. The median relative change in the BAP level from baseline to 4 weeks after the last injection was −65.6% and 9.3% in the223RaCl2and placebo groups, respectively (P< 0.0001). In addition, the median change in TAP was −46.2% in the radium group vs 30.7% in the placebo group (P< 0.0001). 45

Parker et al finally demonstrated a dose-response relationship in another phase II study randomizing 122 patients to receive 3 injections of223RaCl2at 6-week intervals, at doses of 0.68 µCi/kg (n= 41), 1.35 µCi/kg (n= 39) or 2.16 µCi/kg (n= 42) (25, 50, or 80 kBq/kg). A ≥50% decrease in BAP levels was identified in 6 patients (16%), 24 patients (67%), and 25 patients (66%) in the 0.68-, 1.35-, and 2.16-µCi/kg dose groups, respectively (P< 0.0001). 46

The ALSYMPCA trial (n= 921) that led to the FDA approval of223RaCl2employed 6 injections of 1.35 µCi/kg every 4 weeks rather than 4 injections and assessed the serum levels of TAP rather than BAP. This phase III, randomized, double-blind, multinational study compared the efficacy and safety of223RaCl2plus best standard of care (n= 614) vs placebo plus best standard of care (n= 307) in patients with CRPC and bone metastases. The primary end point was OS. The secondary efficacy end points were the time to increase in the TAP level, a TAP response, and normalization of the TAP level ( Table 4 ). The primary and other secondary end points (time to first symptomatic skeletal event [SSE] and time to increase in PSA level) are discussed elsewhere in this article.223Ra, as compared with placebo, significantly prolonged the time to increase in the TAP level (7.4 vs 3.4 months,P< 0.001). In addition, a significantly higher proportion of patients in the223Ra group than in the placebo group had a response according to the TAP level (≥30% reduction, 233 of 497 patients vs 7 of 211 patients,P< 0.001) and normalization of this level (109 of 321 patients vs 2 of 140 patients,P< 0.001). 16

Table 4 Definition of Selected Secondary End Points From the ALSYMPCA Trial

  • 1) Time to increase in TAP level: Increase of ≥25% from baseline at ≥12 wk or increase of ≥25% above the nadir confirmed ≥3 wk later in patients with an initial decrease from baseline
  • 2) TAP response: Reduction of ≥30% from the baseline value confirmed ≥4 wk later
  • 3) Normalization of TAP level: Return to a value within the normal range at 12 wk, confirmed by 2 consecutive measurements ≥2 wk apart, in patients with baseline TAP values above the upper limit of the normal range
  • 4) Time to increase in PSA level: Relative increase of ≥25% from baselineandabsolute increase of ≥2 ng/mL at ≥12 wk, in patients with no initial decrease in PSA level from baseline or relative increase of ≥25%andan absolute increase of ≥2 ng/mL above the nadir, confirmed ≥3 wk later, in patients with an initial decrease in PSA level from baseline

Finally, other markers of bone metabolism were studied in the phase I and II trials and were shown to be significantly decreased in patients treated with223RaCl2. These included serum N-telopeptide, procollagen-I N-propeptide, C-terminal cross-linking telopeptide of type I collagen, and type I collagen cross-linked C-telopeptide.38, 45, and 46

Serum PSA is the principal biomarker in prostate cancer. Although several prostate cancer-associated antigens have been identified, PSA is the most commonly used. A ≥30% decrease of PSA from baseline has been shown to correlate more closely with survival than the initial ≥50% guideline. 47 Although PSA levels are not affected after single injections of223RaCl2at doses <2.7 µCi/kg,38 and 51repeated injections have demonstrated a significant decrease. In the randomized phase II trial that compared 33 patients after receiving 4 injections of 1.35 µCi/kg223RaCl2every 4 weeks with 31 patients after receiving a placebo, the median relative change in PSA from baseline to 4 weeks after the last study injection was −23.8% in the radium group vs 44.9% in the placebo group (P= 0.003). The median time to PSA progression was 26 weeks in the radium group vs 8 weeks in the placebo group (P= 0.048). 45 In another trial where 122 patients were randomized to receive 3 injections of223RaCl2at 6-week intervals at a dose of either 0.68, 1.35, or 2.16 µCi/kg, the median relative PSA changes from baseline were −14.3%, −39.6%, and −25.3%, respectively (P= 0.28). A statistically significant dose-response relationship (≥30% PSA decrease) was also noted after a post hoc analysis in 2 patients (5%), 6 patients (17%), and 10 patients (26%) receiving 0.68-, 1.35-, and 2.16-µCi/kg223RaCl2, respectively (P= 0.0179). 46

Although both PSA and BAP levels are commonly used as early markers of efficacy in CRPC and bone metastases, PSA may not be the best predictor of response. 47 Up to 20% of men experience an initial increase the first 12 weeks (PSA flare) before a subsequent decline in patients responding to chemotherapy (docetaxel and mitoxantrone). 52 Patients treated with sipuleucel-T, a type of therapeutic cancer vaccine consisting of autologous peripheral blood mononuclear cells that have been activated ex vivo with a recombinant prostate antigen protein, showed prolonged OS but minimal PSA response. 15 In addition, PSA decline may be a better surrogate for hormonal therapy than for cytotoxic therapy. Recent studies with chemotherapeutic agents have shown better accuracy of BAP as a predictor for survival compared with PSA levels, although this has not yet been observed in223RaCl2. 50

SRE vs SSE

Although the initial trials included asymptomatic fractures—detected by routine radiographs or bone scans—in the definition of SREs, only symptomatic pathologic fractures were considered in the phase III ALSYMPCA trial. This more symptom-driven method for detection of pathologic fractures led the FDA review team to term the end point as “symptomatic skeletal event (SSE)” rather than “skeletal-related event (SRE)” to differentiate from the prior results ( Table 5 ). Regardless of the definition,223RaCl2demonstrated a prolonged effect in both situations. In the phase II trial that compared 33 patients who received 4 injections of 1.35 µCi/kg223RaCl2every 4 weeks, with 31 patients who received a placebo, the median time to first SRE was 14 weeks in the radium group and 11 weeks in the placebo group. 45 In the phase III ALSYMPCA trial that compared 614 patients who received 6 injections of 1.35 µCi/kg every 4 weeks, with 307 patients who received a placebo, the median time to first SSE was 15.6 months in the radium groups and 9.8 months in the placebo group (hazard ratio [HR] = 0.66; 95%, confidence interval [CI]: 0.52-0.83;P< 0.001) ( Fig. 3 A). 16

Table 5 Definition of Skeletal-Related Events (SRE) and Symptomatic Skeletal Events (SSE)16 and 45

Skeletal-related events
 25% increase in pain severity index compared with baseline after day 15
 Increased analgesic consumption
 Neurologic symptoms secondary to skeletal manifestations of prostate cancer
 New pathological bone fracture
 Tumor-related orthopedic surgical intervention
 Use of external beam radiation therapy to relieve skeletal pain
 Use of radioisotopes to relieve new skeletal symptoms
 Use of corticosteroids for skeletal pain palliation
 Use of chemotherapy, bisphosphonates, or hormones to treat progression of skeletal disease
 
Symptomatic skeletal events
 Use of external beam radiation therapy to relieve skeletal symptoms
 New symptomatic pathologic bone fracture
 Spinal cord compression
 Tumor-related orthopedic surgical intervention
gr3

Figure 3 Kaplan-Meier plots of time to first symptomatic skeletal event (A) and overall survival (B) in patients treated with223RaCl2. (Copyright 2013 Massachusetts Medical Society. Adapted with permission from Parker et al. 16 )

Pain Relief

Multiple studies showed effective pain relief in patients treated with223RaCl2whether the patient received a single injection or repeated injections. However, no definite dose-response relationship was demonstrated.

The initial phase I trial (n= 25) using single-infusion activities ranging from 1.24-6.75 µCi/kg (46-250 kBq/kg) demonstrated pain relief at all dose levels. This occurred in 52%, 60%, and 56% of patients at 1, 4, and 8 weeks after injection, respectively. A transient increase in bone pain (flare response) was reported in 9 patients of 25 (36%), 7 of which during the first week after treatment. 39

In a phase II study (n= 100) using single injections of 0.14, 0.68, 1.35, and 2.7 µCi/kg (5, 25, 50, and 100 kBq/kg) of223RaCl2, there was statistically significant pain reduction with increasing activities at 2 weeks after therapy (P> 0.035) but not at 4, 8, 12, and 16 weeks. For example, there were 40%, 63%, 56%, and 71% of pain responders at week 8 in the respective 0.14-, 0.68-, 1.35-, and 2.7-µCi/kg dose groups, but thePvalue was 0.04. The authors explained these results by the fact that more patients in the higher dose groups dropped out of the study (11 patients) compared with patients in the lower dose groups (6 patients), introducing a possible bias in favor of the lower dose groups. As it is probable that the dropouts were patients who had more pain, the mean pain was consequently reduced. On a different note, there was no statistical difference in the mean pain relief duration in the 1.35- and 2.7-µCi/kg dose groups (44 days) vs the 0.68-µCi/kg (35 days) and 0.14-µCi/kg (28 days) dose groups (P> 0.05). 51

Another phase II study randomized 122 patients to receive 3 injections of223RaCl2at 6-week intervals, at a dose of either 0.68, 1.35, or 2.16 µCi/kg. Pain response occurred in 29%-75% of patients with a trend toward greater response in the 1.35-µCi/kg dose group than in the other 2 groups across all time points. This trend was not sufficient to reach statistical significance. 46

Overall Survival

223RaCl2improves OS, unlike the previously approved β-emitting radiopharmaceuticals.

In the randomized phase II trial that compared 33 patients after receiving 4 injections of 1.35 µCi/kg of223RaCl2plus EBRT with 31 patients who received a placebo plus EBRT (initially published in the Lancet Oncology 45 ), 10 patients (30%) were alive at 24 months in the radium group compared with 4 patients (13%) in the placebo group. The most frequently reported cause of death was progression of metastatic disease. The median OS was higher in the radium group (65.3 vs 46.4 weeks, HR = 0.476), although interpretation was cautious owing to the small sample size. Further analysis of OS based on the extent of disease (defined by the number of osseous lesions at baseline on scintigraphy) showed the largest absolute difference in patients with less than 6 metastases: 107 vs 68 weeks in the223Ra and placebo groups, respectively (log-rankP= 0.263). OS increased with the number of injections. 53

In another study where 122 patients received 3 injections of either 0.68 (n= 41), 1.35 (n= 39), or 2.16 µCi/kg/kg (n= 42) of223RaCl2at 6-week intervals, 70 deaths were recorded at 24 months after the first injection. There was no significant difference among dose groups with respect to the proportion of patients who died or in the median time to death. 46

The most conclusive results that led to the FDA approval of223RaCl2came from the ALSYMPCA trial that was a well-powered prospective randomized double-blind international phase III study. The study enrolled 921 patients with progressive symptomatic CRPC, at least 2 bone metastases and no visceral disease, and compared the efficacy of223RaCl2plus best standard of care (n= 614) with placebo plus best standard of care (n= 307). The patients were randomly assigned in a 2:1 ratio to receive 6 intravenous injections of223RaCl2(at a dose of 1.35 µCi/kg of body weight) or matching placebo. A single injection was administered every 4 weeks. OS in the radium group at 36 months was 14.9 months vs 11.3 months in the placebo group (HR = 0.70; 95% CI: 0.58-0.83;P< 0.001) ( Fig. 3 B). Improvement in survival was also consistent across all subgroups regardless of prior docetaxel treatment, current bisphosphonate use, extent of disease, TAP level, opioid use, and Eastern Cooperative Oncology Group performance status score at baseline. 16 An additional FDA analysis by weight quartiles suggested that higher total body weight—resulting in higher administered total dose—was associated with improved OS. 25

Quality of Life

The effect of223RaCl2on QoL was assessed as a secondary end point in the ALSYMPCA trial using the Functional Assessment of Cancer Therapy—Prostate (FACT-P) questionnaire. 54 The FACT-P score is composed of 22 general questions about physical, social, emotional, and functional well-being and a 17-item questionnaire about prostate-related concerns. It is available in multiple languages. A maximum score of 156 points indicates the highest level of QoL. QoL response was defined in the protocol by a ≥10-point increase in the FACT-P score. In the trial, a significantly higher percentage of patients who received223RaCl2had a meaningful improvement in the QoL as compared with the placebo group according to the FACT-P total score during the period of study-drug administration (25% vs 16%,P= 0.02). The mean change in the FACT-P total score from baseline to week 16 also favored the223RaCl2group compared with the placebo group (−2.7 vs −6.8,P= 0.006). 16

Toxicity

223RaCl2is well tolerated and has a better safety profile than β emitters, with minimal myelotoxicity and mild-to-moderate nonhematologic toxicity. In fact, during the phase I dose-escalation trials, a maximum tolerated dose was not reached owing to the absence of hematologic dose-limiting toxicity 39 and the favorable biologic effect of the lower repeated activities. 38 Reversible myelosuppression infrequently occurs, with nadirs 2-4 weeks after injection and complete recovery during the follow-up period. In a group of 33 patients who received 4 total injections of 1.35-µCi/kg223RaCl2at 4-week intervals, 3 patients reported either grade 3 neutropenia, leukopenia, or anemia. This was reversible and seen during the first 4 weeks of treatment, with no evidence of cumulative myelotoxicity. 45

Nonhematologic toxicities are more common, transient, and manageable. These consist of diarrhea, fatigue, nausea, and vomiting. In the dose-escalation study performed by Carrasquillo et al, 38 diarrhea was reported in 6 of 10 patients, with median time to onset of 8 days, lasting for approximately 13 days. Fatigue and nausea had a slower onset ranging from 22-25 days. Treatment is symptomatic.

In the ALSYMPCA trial, the number of patients who had adverse events was 558 of 600 patients (93%) in the223RaCl2group and 290 of 301 patients (96%) in the placebo group. The most commonly reported adverse reactions (≥10%) in the223RaCl2group were nausea, diarrhea, vomiting, and peripheral edema. There was no significant difference in the grades 3 and 4 adverse events reported in the223RaCl2and placebo groups (57% and 63% of patients, respectively). Laboratory measurements were obtained monthly but not at the time of expected nadir (2-3 weeks after injection) as observed in the previous phase I study by Nilsson et al. 39 The most common hematologic toxicities (≥10%) in the223RaCl2group were anemia, lymphocytopenia, leukopenia, thrombocytopenia, and neutropenia. Grades 3 and 4 thrombocytopenia was reported in 6% of patients on the223RaCl2arm and in 2% of patients receiving placebo. Only 1 grade 5 adverse event was observed in the223RaCl2group: a patient with thrombocytopenia who died of pneumonia and hypoxemia without evidence of hemorrhage. One patient in each study group (<1%) reported grade 3 febrile neutropenia. 16

No late toxicity has been reported so far, in particular myelodysplastic syndrome, leukemia, aplastic anemia, or primary bone cancer.46, 51, and 53

Handling of 223RaCl2, Delivery, and Radiation Protection

223Ra can be produced efficiently in large amounts and is simple to use. Its long physical half-life (11.4 days) provides sufficient time for preparation, distribution, and administration. As previously mentioned,223Ra emits α particles, which have very little penetrating power. These particles can be stopped by a sheet of paper, skin, or a few inches of air. The dead outer layer of the skin absorbs all the α particles from external radioactive sources. As a result, they do not pose an external radiation hazard. In addition, the low level of γ emission in the decay cascade of223Ra is favorable from the point of view of handling, radiation protection, and treatment on an outpatient basis.

223RaCl2injection (Xofigo) is an injectable sterile solution that is supplied in single-dose vials. The currently approved dose regimen is 1.35 µCi (50 kBq) per kg of body weight given every 4 weeks for 6 times. Safety and efficacy beyond 6 injections have not been studied at the time of this writing, but clinical trials are underway. The injection volume for the weight-adjusted dose used to be determined based on the vendor-supplied activity concentration in a solution at the reference date, then corrected for physical decay using factors provided with every injection in a table. To minimize the probability of a misadministration, a radioassay system such as a dose calibrator is now favored as with any radiopharmaceutical. However, this would require calibration of the radioassay system using, for example, a National Institute of Standards and Technology traceable223Ra standard. The dose is administered by a board-certified nuclear medicine physician listed on the Nuclear Regulatory Commission or Agreement State license or specifically designated under a broad license. Excellent patency of the intravenous access should be confirmed and documented. The radiopharmaceutical is then infused slowly over 1 minute. After the infusion is complete, flushing of the syringe and intravenous line with normal saline decreases residual activity and helps to deliver the entire desired dosage to the patient. Drug handling follows the normal procedures for handling of radiopharmaceuticals, including use of universal precautions for administration. No additional specialized equipment for detection, monitoring, or shielding is required. Radioactive waste should be stored for approximately 4 months (10 half-lives), then discarded as normal clinical waste. 41

223RaCl2 in Combination Therapy—Ongoing Trials

With the confirmed clinical benefit of223RaCl2in prolonging OS and delaying SSEs in patients with CRPC, osseous metastases, and no visceral disease, FDA approval was granted in May 2013. The low toxicity profile of223RaCl2makes it an attractive agent for use in combination with other therapies. Although no data are available at this time, clinical trials are in progress ( Table 6 ) evaluating223RaCl2in conjunction with docetaxel (NCT01106352), abiraterone acetate (NCT02043678), and enzalutamide (NCT02034552). Treatment with higher dosing regimen and extended dosing regimen as well as repeated treatment using the standard dosing regimen is also being evaluated in CRPC (NCT02023697 and NCT01934790).

Table 6 Ongoing Clinical Trials

Trial Number Official Title Dose Regimen
NCT01106352 A phase I-IIa study of safety and efficacy of Alpharadin with docetaxel in patients with bone metastasis from castration-resistant prostate cancer (CRPC)
  • 223RaCl2: 1.35 µCi/kg i.v. every 6 wk × 5 in combination with the approved step-down dose of docetaxel (60 mg/m2i.v.) every 3 wk with 5-mg prednisone twice a day continuously and premedication with dexamethasone
  • Docetaxel: 75 mg/m2i.v. every 3 wk and 5-mg prednisone twice a day continuously and premedication with dexamethasone
  • Step-down to 60 mg/m2is allowed as per the approved label
NCT02043678 A phase III randomized, double-blind, placebo-controlled trial of radium-223 dichloride in combination with abiraterone acetate and prednisone or prednisolone in the treatment of asymptomatic or mildly symptomatic chemotherapy-naïve subjects with bone-predominant metastatic CRPC
  • 223RaCl2: 1.35 µCi/kg i.v. every 4 wk × 6
  • Abiraterone: 1000 mg p.o. once daily
  • Prednisone or Prednisolone: 5 mg p.o. twice daily
NCT02034552 A randomized open-label phase IIa study evaluating the efficacy and safety of radium-223 dichloride in combination with abiraterone acetate or enzalutamide in subjects with CRPC who have bone metastases
  • 223RaCl2: 1.35 µCi/kg i.v. every 4 wk × 6
  • Abiraterone: 1000 mg p.o. once daily
  • Prednisone: 5 mg p.o. twice daily
  • Enzalutamide: 160 mg p.o. once daily
NCT02023697 A 3-arm randomized open-label phase II study of radium-223 dichloride 1.35 µCi/kg vs 2.16 µCi/kg, and vs 1.35 µCi/kg in an extended dosing schedule in subjects with CRPC metastatic to the bone
  • 223RaCl2(standard dose): 1.35 µCi/kg i.v. every 4 wk × 6
  • 223RaCl2(high dose): 2.16 µCi/kg i.v. every 4 wk × 6
  • 223RaCl2(extended standard dose): 1.35 µCi/kg i.v. every 4 wk × 12
NCT01934790 A retreatment safety study of radium-223 dichloride in subjects with CRPC with bone metastases who received an initial course of 6 doses of radium-223 dichloride 1.35 µCi/kg every 4 wk
  • 223RaCl2: 1.35 µCi/kg i.v. every 4 wk × 6
NCT01070485 An open-label phase IIa, nonrandomized, study of Alpharadin in patients with breast cancer with bone-dominant disease no longer considered suitable for endocrine therapy
  • 223RaCl2: 1.35 µCi/kg i.v. every 4 wk × 4
NCT01833520 Phase I dose escalation of monthly intravenous Ra-223 dichloride in osteosarcoma
  • Phase I Starting Dose of223RaCl2: 1.35 µCi/kg i.v. every 4 wk
  • Phase II Starting Dose of223RaCl2: MTD from Phase I

i.v., intravenously; MTD, maximum tolerated dose; p.o., orally.

Furthermore, the bone-seeking properties of223RaCl2make it an attractive agent to test in other bone-spreading and bone-forming tumors. A preclinical study in a mouse model of breast cancer bone metastases demonstrated increased survival when223RaCl2was used alone or in combination with doxorubicin or zoledronic acid. 55 A phase IIa trial is planned in patients with breast cancer and bone-dominant metastases no longer considered suitable for hormonal therapy (NCT01070485). Additional application of223RaCl2is under investigation in patients with progressive, recurrent, or metastatic osteosarcoma (NCT01833520).

Research is also being performed in the field of tumor response assessment after223RaCl2therapy using imaging. A pilot study published in 2011 evaluated treatment response of bone metastases from CRPC using18F-sodium fluoride PET (18F-NaF PET) in 5 patients. The study found an increased diagnostic accuracy of the semiquantitative18F-NaF PET compared with the qualitative99mTc-MDP. There was also a correlation with the PSA response and alkaline phosphatase activity, making18F-NaF PET a potential imaging biomarker for monitoring treatment response of bone metastases following223RaCl2therapy. 56

Is There Still a Role for the β Emitters With the Advent of 223RaCl2?

Unlike the bone-seeking β-emitters, radium׳s claim to fame has been its ability to improve OS, therefore elevating radiopharmaceuticals from the realm of pain palliation to the realm of treatment, and placing them on par with other drugs that showed an effect on OS such as chemotherapy and immunotherapy. However, is there still hope for the β emitters to demonstrate a similar effect after championing the advantages of α particles? Until now, β-emitting radiopharmaceuticals have not convincingly demonstrated antitumor effects. Physical properties, trial design flaws, patient selection, and toxicity profile have all been identified as possible explanations.

The physical properties of bone-seeking β emitters are similar to radium in selectively delivering ionizing radiation to areas of increased osteoblastic activity, targeting several osseous metastases at the same time, whether symptomatic or asymptomatic. Although89Sr has a natural affinity for reactive bone,153Sm,186Re, and188Re form stable complexes with bone-seeking cations, such as phosphate and diphosphonate. The half-life, energy, nature of emission, and range of penetration in tissue all play a role in delineating the efficacy and toxicity profile of the radiopharmaceutical. For example, shorter half-lives could facilitate more rapid bone marrow recovery, allowing for safe repeated administration.89Sr is a pure β emitter and has a long physical half-life (50 days), in contrast to153Sm,186Re, and188Re, which have much shorter physical half-lives (<4 days) and emit γ rays in addition to β particles. Gamma emitters permit dosimetric measurements and posttreatment scintigraphic imaging but pose more of a radiation safety concern to the public. In contrast to α particles which have a short range of penetration in tissue (<100 µm), β particles have a longer range (up to a few millimeters) and a potential to irradiate surrounding normal tissues. Finally, β emitters deposit a relatively lower amount of energy along the track length (low LET) compared with α emitters, which are more densely ionizing and more likely to induce nonrepairable DNA damage.32 and 33

Trial design flaws and selection bias: The recent publication of the ALSYMPCA trial 16 has sparked comments criticizing223RaCl2as the only radiopharmaceutical to show a survival advantage and claiming a similar benefit with patients who are repeatedly treated with188Re-HEDP. These were met by replies emphasizing small sample sizes, the retrospective and non–placebo-controlled nature of the studies in question, and the fact that OS was not the primary end point.22, 57, and 58The studies using186Re-HEDP, in particular the PLACORHEN phase III trial, focused mainly on pain relief and did not find an effect on survival between the placebo and treated groups. 59

The89SrCl2data are also not convincing with respect to OS modification. The Trans-Canada study, despite being a double-blind multicenter placebo-controlled prospective trial, failed to demonstrate a positive effect of89SrCl2on survival. The study included 126 patients with bones metastases from CRPC, all pretreated with local field radiotherapy, then randomized to receive a single injection of 10.8-mCi (400 MBq)89SrCl2or placebo. This study showed a delay in the development of new pain at preexisting clinically silent sites of disease 27 but was later contradicted by a Norwegian study in 2003, 60 probably owing to the fact that higher activity was used in a subset of patients in the Trans-Canada study (10.8 mCi) compared with the licensed 4-mCi (148 MBq) activity used in the Norwegian study. Another prospective randomized controlled trial evaluating89SrCl2with low-dose carboplatin in patients with CRPC was small (70 patients) and did not show increased OS. 61 The first study to report a possible improvement in OS with89SrCl2was a randomized phase II trial that evaluated 103 patients with mCRPC after induction chemotherapy (ketoconazole and doxorubicin alternating with estramustine and vinblastine). Those who were clinically stable or responders after induction chemotherapy (72 patients) were randomized to receive doxorubicin alone or in combination with89SrCl2every week for 6 weeks at a dose of 55 µCi/kg of body weight per injection. The median survival for all 103 patients was 17.5 months. OS for the 36 patients who received89SrCl2and doxorubicin was 27.7 months compared with 16.8 months for the 36 patients who received doxorubicin alone (P= 0.0014). However, these results were affected by a selection bias. The patients randomized to receive consolidation therapy were judged by the treating physician to be threatened by osseous progression and to be clinically responsive to induction chemotherapy. 62 A recent study used PSA and total analgesic consumption as criteria for evaluation of cancer control in 31 patients with prostate cancer with osseous metastases treated with89SrCl2. The study showed increased survival in PSA and pain responder groups, compared with nonresponder groups. However, the study was retrospective, non–placebo controlled, nonrandomized, and assessed a small population (31 patients). 63 Finally, a prospective randomized phase III study by the European Organization for Research and Treatment of Cancer showed disappointing results on OS for89SrCl2when compared with palliative local field radiation therapy. In this study, which included 203 patients with mCRPC, the OS in the radiotherapy group was longer than in the89SrCl2group (11 vs 7.2 months,P= 0.0457). 64

Lastly, there has been no evidence for improved OS using153Sm-EDTMP as a single agent. However, a few studies reported a possible effect on survival when used sequentially 65 or in combination with docetaxel, 66 estramustine, and mitoxantrone plus prednisone, 67 indicating a possible synergistic effect owing to chemosensitization or radiosensitization or both. These studies were either retrospective or prospective phase II, with a small sample size.

Regardless of trial design, the question of whether rhenium, strontium, or samarium has a survival advantage is intricate without putting in perspective their toxicity profile compared with that of radium.

As mentioned earlier in this article,223RaCl2has minimal reversible myelotoxicity and common mild-to-moderate nonhematologic toxicity that is transient and manageable consisting of mainly diarrhea, nausea, vomiting, and fatigue. In contrast, myelosuppression is common with β-emitting radiopharmaceuticals with complete or partial recovery over the next 3 months. Furthermore, gastrointestinal side effects are virtually unknown, even with strontium, which is also a calcium analogue similar to radium. Beta emitters often cause thrombocytopenia and less commonly neutropenia, likely secondary to the long range of the β particles (a few millimeters) that reach the marrow from their emission site in the cortical bone. This has been a limiting factor for repeated administration of β-emitting radiopharmaceuticals, but also subsequent chemotherapy. Although Sartor et al demonstrated that repeat administration of153Sm-EDTMP may be feasible, platelet and white blood cell counts dropped progressively with each treatment and did not return to baseline. Nadirs were approximately half of baseline at approximately 4 weeks after injection with recovery by week 8 in 90% of patients. 68 Toxicity associated with89SrCl2has a relatively more delayed onset and is longer in duration compared with samarium. Some authors reported leukocyte and platelet nadirs 4-6 weeks after treatment, others between 12 and 16 weeks. Recovery is also slower with89SrCl2, usually over the next 6 weeks after the nadir. Therefore, periodic blood count monitoring may be useful up to 6 weeks after treatment, then as needed until there is evidence of blood count recovery.8, 26, 69, 70, and 71223Ra emits α particles, which have a much shorter range of penetration in tissue (<100 µm) resulting in minimal infrequent myelotoxicity. Nadirs usually occur 2-4 weeks after injection with complete recovery during the follow-up period. This allows for safe repeated injections every 4 weeks, in congruence with the current FDA-approved dosing regimen. Extended regimens for a year are therefore under investigation to evaluate for better efficacy (NCT02023697). It is noted that no significant difference in grades 3 and 4 myelotoxicities was observed between the treated group and placebo group in the ALSYMPCA trial. Only 1 patient with thrombocytopenia in the223RaCl2group died of pneumonia and hypoxemia without evidence of bleeding. 16

Few indications remain for β emitters. Patients with CRPC and bone pain who are not eligible to receive223RaCl2owing the presence of visceral metastases may still benefit from β emitters for pain relief. Beta emitters remain also indicated for bone pain palliation in patients with osteoblastic metastases from primaries other than prostate.

Conclusion

In conclusion, the radiopharmaceuticals have finally joined the armamentarium available against mCRPC owing to the disease modifying effects of223RaCl2. Although223RaCl2may not be sufficient as a single agent for the treatment of mCRPC, its use with other therapeutic agents could potentially be additive owing to its favorable safety profile. Trials exploring combination therapy with223RaCl2as well as optimization of the current dosing regimen and evaluation of its role in other osteotropic malignancies are already underway. The future role of β-emitting radiopharmaceuticals remains uncertain. Ethical issues may preclude direct comparative studies with223RaCl2. Lastly, owing to its incorporation into the treatment scheme of prostate cancer,223RaCl2will foster relationships between clinicians and nuclear medicine physicians, bringing new hopes in the treatment of mCRPC and adding another level of collaboration between medical and surgical disciplines for better patient care.

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Footnotes

lowast Department of Radiology, Upstate Medical University, State University of New York, Syracuse, NY

Division of Nuclear Medicine, Department of Radiology, Upstate Medical University, State University of New York, Syracuse, NY

Division of Nuclear Medicine, Department of Imaging, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA

lowast Address reprint requests to Alain S. Abi-Ghanem, MD, Department of Radiology, Upstate Medical University, State University of New York, 750 E Adams St, Room 3428, Syracuse, NY 13210.


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