Radium 223 dichloride for prostate cancer treatment

Introduction

Prostate cancer represents the second most frequent cancer worldwide, with an incidence of 1.09 million patients in 2012.¹ Although most patients are cured by local treatment, 20%–30% will have a recurrence, especially in bone. Bone metastases often lead to pain or skeletal events (fracture, spinal cord compression) and, therefore, may decrease the patients’ quality of life. Radium-223 (²²³Ra; Xofigo^®) is an α-emitting radionuclide that, like calcium, is incorporated in the bone matrix at sites of active mineralization via osteoblasts. Therefore, it specifically targets bone metastases. In the Phase III trial ALSYMPCA, ²²³Ra showed an overall survival (OS) benefit in patients with castration-resistant prostate cancer (CRPC) and symptomatic bone metastases.² This led to its approval by the US Food and Drug Administration in 2013. This review, which is the result of a multidisciplinary collaboration by the Intergroupe Coopérateur Francophone de recherche en onco-urologie (ICFuro), discusses the place of ²²³Ra in the therapeutic landscape of prostate cancer. It will first describe the mechanism of action of this new agent against bone metastases. It will then summarize the available clinical data and the place of ²²³Ra in the current clinical practice. Finally, it will give information on the ongoing trials that assess ²²³Ra for prostate cancer management.

Treatment options for metastatic CRPC

Besides ²²³Ra, several other agents have shown efficacy in metastatic CRPC (mCRPC). Since 2004, five drugs have been approved for mCRPC treatment, leading to an improvement of progression-free survival and OS. First, docetaxel, a microtubule poison from the taxane family, was approved on the basis of a 2.5-month survival improvement (16.4 vs 18.9 months; P=0.009) compared with mitoxantrone (standard treatment).^3,4 Then, in 2010, the results of the TROPIC study in a post-docetaxel setting (OS increase of 2.4 months compared with mitoxantrone; 12.7 vs 15.1 months; P=0.0001) led to the approval of cabazitaxel, a taxane with lower affinity for drug efflux pumps compared with previous molecules of the same class.⁵ The same year, it was shown that sipuleucel-T, an autologous cellular immunotherapy, prolongs survival in chemotherapy-naive patients with asymptomatic or minimally symptomatic mCRPC compared with controls (25.8 months in the sipuleucel-T group vs 21.7 months in the placebo group).⁶ The last two drugs are “second generation” hormonal treatments that target the androgen receptor signaling pathway. The first one is abiraterone acetate (AA) that targets CYP17A1, a key enzyme involved in androgen synthesis. Its approval relied on a 4-month OS improvement in patients with bone metastatic prostate cancer after docetaxel treatment compared with placebo (15.8 months vs 11.2 months; P<0.0001) and also in chemotherapy-naive patients (34.7 vs 30.3 months; P=0.0033).^7,8 The second one is enzalutamide, an androgen receptor antagonist. When used as first-line treatment of patients with mCRPC and bone or visceral metastases, enzalutamide improved OS by 2 months compared with placebo (32.4 vs 30.2 months; P<0.001).⁹ Similar results were obtained also in a post-docetaxel setting (OS from 13.6 months to 18.4 months; P<0.001).¹⁰ However, despite the introduction of these new molecules for mCRPC clinical management, the right sequence for systemic therapies in advanced prostate cancer is not clearly defined.¹¹ Although most patients receive second-generation hormonal treatments first, emerging evidence indicates that the most critical issue for patients is to receive at least three different lines of treatment.¹²

Bone metastasis formation

Prostate cancer cells (PCs) have an important tropism for the bone matrix. Experimental studies in animal models showed the role of the primary tumor in preparing the bone matrix for metastasis development.^13,14 By increasing the activity of growth factors (such as vascular endothelial growth factor-A and placental growth factor), PCs activate bone marrow mesenchymal cells and progenitor endothelial cells to promote the development of a PC host structure with vascularization. Specifically, growth factors create an extracellular matrix prone to receive PCs. Then, osteoblasts, PCs, and other cells in the bone microenvironment secrete a range of additional molecules, such as growth factors (insulin-like growth factor, fibroblast growth factor, transforming growth factor-β), chemokines (CXCL-12, CCL22, and so on) and cytokines (RANKL), that can anchor PCs to the bone matrix.^15,16 Furthermore, Morris and Edwards reported the potential contribution of both white adipose tissue and bone marrow adipocytes in triggering PC migration and in supporting tumor growth and metastasis formation.¹⁷ Once installed, PCs can affect the bone homeostasis between bone matrix resorption and formation. In most cases, the nature of bone metastases in prostate cancer is osteoblastic. Indeed, histopathological analysis of PC bone metastases demonstrated the presence of a large number of osteoblasts adjacent to PCs, in contrast to normal bone or bone metastases from other cancers.¹⁸ The interaction between the bone microenvironment and PCs creates a vicious circle that favors osteoblastic bone metastases.¹⁹ Indeed, through local and systemic factors, PCs lead to the activation of osteoblast cells. In turn, osteoblasts control bone matrix resorption by activating (through the cytokine RANKL) or inhibiting (through osteoprotegerin) osteoclasts. At the beginning of bone metastasis formation, tumor-derived factors and RANKL-secreting osteoblasts can both activate osteoclasts, leading to bone resorption that subsequently creates more space for the dominant osteoblastic lesions. Thus, cytokines and growth factors released during bone resorption can foster this vicious cycle by facilitating the sustained proliferation of PCs and osteoblasts. Moreover, an increase in serum osteoprotegerin level is also observed in patients with advanced prostate cancer. These findings led Ibrahim et al to propose that osteoblasts play a predominant role in prostate cancer progression in bone through their ability to control PC and osteoclast proliferation.¹⁶

In conclusion, in prostate cancer, bone metastases result from complex interactions between PCs, bone tissue, and bone microenvironment that are regulated by many local and systemic growth factors.

²²³Ra mechanism of action

²²³Ra is a radioactive isotope that decays to stable lead (²⁰⁷Pb) after a complex disintegration path with several radioactive daughters that produce four alpha particles (Figure 1). ²²³Ra decay chain is as follows: ²²³Ra (T_1/2 =11.4 days, α) → ²¹⁹Rn (T_1/2 =3.96 seconds, α) → ²¹⁵Po (T_1/2 =1.78 milliseconds, α) → ²¹¹Pb (T_1/2 =36.1 minutes, β-) → ²¹¹Bi (T_1/2 =2.15 minutes, α) → ²⁰⁷Tl (T_1/2 =4.77 minutes, β-) → ²⁰⁷Pb (stable). ²²³Ra can be produced quite easily and in high amount from elution of an actinium-227/thorium-227 generator system (actinium-227 is produced by neutron irradiation of natural radium-226). ²²³Ra physical half-life of 11.4 days allows long-distance shipment.^20,21 The average particle energy per decay of ²²³Ra is 5.7 MeV. The combined energy for the complete decay chain of ²²³Ra including daughter radionuclides is 28.2 MeV.²² This is much higher than that of beta-emitter bone-targeting radiopharmaceuticals, such as ⁸⁹SrCl₂ and ¹⁵³Sm-EDTMP, with, respectively, 0.58 and 0.22 MeV.²³ Gamma particles are also emitted during ²²³Ra disintegration, allowing scintigraphy imaging (eg, for dosimetric studies). After intravenous injection, ²²³Ra acts as a calcium analog and about 25% is taken up by bone. It concentrates in sites of active mineralization with high osteoblastic activity (well visualized on bone scans).^{24 223}Ra is mainly excreted by the gastrointestinal tract, and <1% of the injected activity remains in the blood 24 hours after injection.²⁵ Bone endosteum is the organ with the highest dose (16 Gy) after ²²³Ra injection at therapeutic dose (six intravenous injections of 50 kBq/kg ²²³Ra chloride for a 70 kg patient), and the corresponding absorbed dose to the red bone marrow is 1.6 Gy.²⁴ No significant redistribution of ²²³Ra radioactive daughters has been observed in preclinical²² and clinical studies.²⁶

Figure 1 223Ra mechanism of action in bone metastases. Abbreviations: 233Ra, radium-223; mCRPC, metastatic castration-resistant prostate cancer.

²²³Ra radiobiological effects are mainly based on the direct damage of tumor cell DNA (nonreparable DNA double-strand breaks, leading to tumor cell death)²⁷ by alpha particles. Thanks to their high linear energy transfer (LET) (80 keV/μm) and a very short range (<100 micrometers), alpha particles produce a dense ionization around the disintegration site.²³ The high LET leads to cytotoxic effects that are independent of the oxygen concentration; this is particularly interesting in bone (and bone metastases) because it is a quite hypoxic organ.

Clinical results

Different from cytotoxic chemotherapy, ²²³Ra dose is not determined based on the patient’s body surface area but on his weight, as reported by a Phase II, randomized, double-blind study that compared three ²²³Ra doses (25, 50, and 80 kBq/kg) administered every 6 weeks for a total of six injections at most.²⁸ Of note, because of its mechanism of action, ²²³Ra biological response is better evaluated by assessing the decrease of alkaline phosphatase (ALP) than prostate-specific antigen (PSA) level. Although the study observed a dose–response relationship, the biological benefit on ALP was not significantly different in the 50 and 80 kBq/kg dose groups. Therefore, the regimen chosen for the Phase III trial was 50 kBq/kg every 6 weeks.

The ALSYMPCA randomized Phase III trial compared ²²³Ra efficacy versus placebo in 921 patients with CRPC and symptomatic bone metastases.²⁹ This study included only patients with disease progression after or during docetaxel treatment (the only available agent at the time of the trial that showed some OS benefit in mCRPC), or unfit to receive chemotherapy (43% of the enrolled men). Conversely, it excluded patients with visceral metastases. Analysis of the results showed an OS benefit (primary endpoint of the study) in patients treated with ²²³Ra compared with patients who received placebo (14.9 months vs 11.3 months, HR =0.7 [95% CI 0.58–0.83]; P<0.001). Patients treated with ²²³Ra also had a longer time to symptomatic skeletal events (15.6 months vs 9.8 months, HR =0.66 [95% CI 0.52–0.83]; P=0.00037) and a better biological response (Table 1). The treatment was well tolerated. The rate of grade 3/4 adverse events was not statistically different between groups. More than half of the patients (58%) received the six planned injections. ²²³Ra main toxicities were anemia and thrombocytopenia and diarrhea (Table 2). The predictive factors associated with G2/4 hematological toxicities were the number of bone metastases (6–20 vs <6, odds ratio [OR] =2.76; P=0.022) and PSA concentration (OR =1.65; P=0.006) for anemia; preuse or not of docetaxel (OR =2.16; P=0.035) and baseline hemoglobin and platelet decrease (OR =1.35; P=0.008 and OR =1.44; P=0.030, respectively)³⁰ for thrombocytopenia. The number of ²²³Ra injections was not associated with higher risk of adverse events. The quality of life during treatment was evaluated with two self-report questionnaires (EuroQol-5D and FACT-P v4) and was better in patients treated with ²²³Ra than in controls.³¹

Table 1 223Ra efficacy in metastatic castration-resistant prostate cancer Abbreviations: AA, abiraterone acetate; ALP, alkaline phosphatase; Enza, enzalutamide; mCRPC, metastatic castration-resistant prostate cancer; mo, months; NR, not reported; 233Ra, radium-223; OS, overall survival; PSA, prostate-specific antigen; w, weeks.

Table 2 223Ra toxicity in patients with metastatic castration-resistant prostate cancer Abbreviations: 233Ra, radium-223; NR, not reported.

The ALSYMPCA study main limitation was the absence of patients previously or concomitantly treated with new hormonal therapies (NHT), such as abiraterone or enzalutamide, that are now widely used for mCRPC management. A subsequent single-arm Phase III-b trial, conducted to enable early access to ²²³Ra before regulatory approval, included patients concomitantly treated with NHT.³² Moreover, 60% of patients had previously received docetaxel, 40% AA, and 8% enzalutamide. Patients (n=696) received one ²²³Ra dose (50 or 55 kBq/kg) every 4 weeks (one to six injections in total). During the trial, ²²³Ra was associated with NHT in 27% of patients (AA in 20%, enzalutamide in 5%, and both in 2%). Results are quite similar to those of the ALSYMPCA trial, with an OS of 16 months. The OS was longer in patients concomitantly treated with NHT compared with those without NHT and in docetaxel-naive patients who received also NHT compared with those pretreated with docetaxel. The biological response (PSA and ALP levels) at week 12 was consistent with the ALSYMPCA results. Specifically, PSA and ALP decreased by >30% in 14% and 47% of patients, respectively (Table 1). Toxicities were less frequent than in the ALSYMPCA study, but this could be explained by the shorter follow-up. Nevertheless, 75% of patients experienced at least one treatment-related adverse event. The most frequent G3/4 toxicities were anemia (12%), thrombocytopenia (3%), back/bone pain (3%/4%), and spinal cord compression (3%). The median number of ²²³Ra injections was six and only 21% of patients discontinued the ²²³Ra treatment because of adverse events. Since ²²³Ra approval, several retrospective studies have reported the comparable efficacy and safety of this treatment in the clinic.^33,34 The results of the published clinical trials on ²²³Ra are summarized in Table 1 (²²³Ra efficacy) and Table 2 (²²³Ra toxicity profile).

Unfortunately, ²²³Ra treatment for mCRPC is not reimbursed in all European countries, although its OS benefit has been demonstrated by the ALSYMPCA trial and robust data about ²²³Ra efficacy and safety in combination with NHT have been reported. However, studies with high level of evidence on the optimal sequence of administration of all these treatments are lacking.

Clinical management

The decision to administer ²²³Ra should be taken by a multidisciplinary committee that includes at least one oncologist and one nuclear medicine physician. As previously stated, this treatment may be proposed to patients with mCRPC and symptomatic bone metastases but no evidence of visceral metastases. Patients should have a medical consultation with the nuclear medicine physician before starting this treatment in order to check the indication and contraindications based on the clinical, biological, and bone scan data. Moreover, the physician should clearly explain to the patient the expected ²²³Ra benefits (mainly on survival and pain relief) and potential side effects. The most relevant side effects reported in studies were related to quality of life (eg, ²²³Ra vs placebo: deterioration of Utility score: 36.0% vs 54.0%; P<0.001; OR =0.48; 95% CI 0.34–0.67 or deterioration of FACT-P: 44.3% vs 51.6%; P=0.095; OR =0.75: 95% CI 0.53–1.05)³¹ or to medullar compression (HR =0.52; 95% CI 0.29–0.93; P=0.03).³⁶ Some contraindications may be specifically investigated: jaw osteonecrosis, spinal cord compression, recent fractures, and inflammatory bowel disease (such as Crohn’s disease and ulcerative colitis). Data about pain should be collected: pain localization and score (based on a visual analog pain scale), number and type of antalgic treatment. The bone metastasis osteoblastic activity must be confirmed by functional bone imaging (bone scan or sodium fluoride positron emission tomography/computed tomography). Before starting the ²²³Ra treatment, patients need to have platelet count ≥100*10⁹/L, hemoglobin level ≥10 g/dL, and absolute neutrophil count ≥1.5*10⁹/L. Patients can undergo ²²³Ra treatment and follow-up as outpatients because the estimated radiation dose to caregivers and household members is very low: <2 μSv h⁻¹ MBq⁻¹ on contact and 0.02 μSv h⁻¹ MBq⁻¹ at 1 m immediately after administration.³⁷ Nuclear medicine services dispensing ²²³Ra treatments must comply with the national regulations on radioactive materials. This is the first alpha emitter approved for routine clinical treatment, and health professionals working in nuclear medicine departments (nuclear medicine physicians, physicists, radiopharmacists, and technologists) must be specifically trained. Activity meters must be calibrated with a standard source before treatment initiation. Staff exposure is low, but ²²³Ra has to be manipulated carefully with gloves and masks. The main potential issue is internal exposure (ie, accidental ²²³Ra intake by ingestion and/or inhalation). There is no specific procedure for patients’ care, except to wear gloves if in contact with fluids/feces (²²³Ra is mainly excreted with the feces). ²²³Ra injected activity (usually below 8 MBq) is very low compared with standard nuclear medicine diagnostic procedures (500–1,000 MBq of technetium-99 m for a bone scan, for example). At the end of the administration, surface contamination should also be checked.

The therapeutic procedure consists in the slow intravenous injection of 55 kBq/kg ²²³Ra (about 1 minute), in the department of nuclear medicine, under medical supervision (one injection every 4 weeks for a total of six injections). To avoid the risk of extravasation, the intravenous peripheral blood catheter should be inserted in a large vein by experienced personnel. The ALSYMPCA study did not report any specific reaction at the injection site; however, in the case of ²²³Ra extravasation a specific procedure³⁸ and dermatological follow-up should be proposed. Recently, a possible case of cutaneous cancer was observed after ²²³Ra extravasation.³⁹ After the injection, the patient is monitored for a short time and then he can go home. He needs to follow good hygiene practices for at least 1 week after the injection, including flushing the toilet several times after use, but specific radiation safety precautions are usually not required (like sleeping arrangements or limited time contact with children). The decision to administer the next cycle is based on clinical and biological parameters (platelet count ≥50*10⁹/L, absolute neutrophil count ≥1*10⁹/L).

²²³Ra place in therapy

Two studies reported a benefit of ²²³Ra on both OS and quality of life in chemotherapy-naive patients with mCRPC and symptomatic bone metastases.^2,31 Currently, there is no indication for ²²³Ra in patients with visceral metastases. Similar results (improved OS, time to biological progression, time to bone progression, pain, and quality of life) were reported in patients with bone metastases and no known visceral metastasis who received docetaxel prior to ²²³Ra administration.³² No published data are available on ²²³Ra efficacy in consolidation settings following docetaxel treatment. In conclusion, ²²³Ra is recommended only in the absence of visceral metastases.

Several ongoing trials (summarized in Table 3 and full list available at ClinicalTrials.gov) are validating ²²³Ra efficacy in patients with CRPC with bone metastases, alone or in combination with NHT, chemotherapy, or radiation therapy.

Table 3 Ongoing clinical trials

Use in different countries

Since its clinical approval in 2013, >27,000 patients have received Xofigo^® worldwide, among whom 12,000 were in Europe. It is currently prescribed and reimbursed in 23 European countries. More than 3,600 patients have been treated with Xofigo in Germany since 2013. If we only consider the prescriptions for 2016, 4,500 patients received Xofigo in the USA, 988 patients in England, 500 patients in Canada, 456 patients in Italy, 356 patients in the Netherlands, and 327 patients in Spain.

Conclusion

²²³Ra has an original activity, and is the first drug in its class to have demonstrated a significant impact on OS in patients with mCRPC. Therefore, it has enriched the panel of therapeutic options for this disease, together with new-generation hormonal treatments and chemotherapy. Thanks to its relatively good toxicity profile, it could become the best option for a minority of patients with only bone metastases and who are unfit for docetaxel. Unfortunately, this drug is not reimbursed in all western countries. More clinical-economic analyses are needed to confirm the positioning of this novel drug in mCRPC therapeutic armamentarium.

Acknowledgments

This work has been facilitated by the Intergroupe Coopérateur Francophone de Recherche en Onco-urologie (ICFuro). This consortium brings together cooperating groups, scientific associations, and researchers working on clinical, basic, and translational research in urologic oncology in France and French-speaking countries. ICFuro objective is to promote all aspects of urologic oncology research and to allow the emergence of interdisciplinary, large-scale research programs.

The authors would like to thank ICFuro and specifically the “radium 223 – CPRC” French working group experts for bibliography reviewing and clinical data appraisal: oncologists (P Beuzeboc, Paris – N Houédé, Nîmes – I Krakowski, Bordeaux – C Thibault, Paris); urologists (JL Descotes, Grenoble – X Rebillard, Montpellier, M Roumiguie, Toulouse, F Rozet, Paris); nuclear physicians (F Cachin, Clermont-Ferrand – F Courbon, Toulouse – E Deshayes, Montpellier – D Huglo, Lille – JP Vuillez, Grenoble); radiotherapist (C Hennequin, Paris); geriatrician (V Fossey-Diaz, Paris); pharmacist (F Corréard, Marseille); and ICFuro methodologist (D Kassab-Chahmi, Paris).

Disclosure

The authors report no conflicts of interest in this work.

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