radium 223 dichloride: a multidisciplinary approach to metastatic castration-resistant prostate...

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10.2217/FON.14.157 © 2014 Future Medicine Ltd

Review

Radium 223 dichloride: a multidisciplinary approach to metastatic castration-resistant prostate cancer

Elisa Borsò*,1, Giuseppe Boni1, Luca Galli2, Sergio Ricci3, Azzurra Farnesi2, Sara Mazzarri1, Claudia Cianci2, Giuliano Mariani1 & Alfredo Falcone2

1Division of Nuclear Medicine, University Hospital of Pisa, Pisa, Italy 2Operative Unit of Medical Oncology 1, University Hospital of Pisa, Pisa, Italy 3Operative Unit of Medical Oncology 2, University Hospital of Pisa, Pisa, Italy

*Author for correspondence: Tel.: +39050992304; Fax: +39050993126; [email protected]

AbstrAct: The role of nuclear medicine physicians in the multidisciplinary team for the management of patients with prostate cancer has been restricted because of a lack of available tools. The only drugs approved to relieve pain related to bone metastases were β-emitting radiopharmaceuticals. These drugs did not prove to prolong survival when used as single agent and resulted associated with important adverse events. This situation has changed with the introduction of radium 223 because of evidence of improved survival in patients, the good safety profile and the opportunity to avoid clonal selection of tumor cells. Cooperation among physicians involved in cancer management will lead to improvements in the treatment of bone metastases due to prostate cancer and is thought to extend to other tumor types.

Keywords • α-emitting • β-emitting • castration-resistant prostate cancer • nuclear medicine physician • radiopharmaceuticals • radium 223 dichloride

The management of most prostate cancer cases involves committed specialists such as urologists, medical oncologists, radiotherapists, and nuclear medicine physicians. Evidence shows that in men with high-risk prostate cancer, only a patient-focused program based on a multidisciplinary approach can result in improved survival [1]. The role of nuclear medicine physicians in this multidisciplinary team so far has been restricted to providing pain relief. In castration-resistant prostate cancer (CRPC) patients with bone metastases (mCRPC), radiopharmaceuticals turned out to be useful only for noncurative purposes, exclusively aiming at improving symptomatic pain control. In addition, the available drugs have induced considerable serious adverse events, mostly hematologic, and thus have prevented subsequent therapeutic approaches [2]. Therefore, radionuclide-based therapy for symptomatic bone metastases has remained underused and limited to the late phases of the disease [3].

The lack of safe therapeutic approaches to extend survival in CRPC patients has been a challenge for nuclear medicine physicians accustomed to successfully treating other tumor types, such as thyroid tumors with radioiodine therapy, or treating hematologic malignancies with ibritumomab tiuxetan. The recent introduction of the radiopharmaceutical radium Ra 223 (Ra 223) dichloride represents a breakthrough because, for the first time, an impact of a radiopharmaceutical on survival of patients with bone metastases due to prostate cancer was demonstrated in a large Phase III trial [4]. This drug, in fact, received the category 1 recommendation as first-line and second-line option by National Comprehensive Cancer Network (NCCN) guideline similarly to chemotherapy [5], and thus the nuclear medicine physician assumed a key position in the current multidisciplinary team for the treatment of mCRPC. The team should evaluate which patients are suitable for Ra 223 dichloride without limiting access to patients in the terminal stages of the disease and should integrate the nuclear medicine physician into the team with the medical oncologist and surgeon.

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review Borsò, Boni, Galli et al.

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With future developments of Ra 223 dichloride, nuclear medicine physicians may assume an even more important role in other areas of oncology.

The aim of this paper is to look over the past and present roles of nuclear medicine physicians on the multidisciplinary team for the manage-ment of patients with mCRPC and try to identify ways in which team members might cooperate in the future.

Strontium chloride 89 & samarium 153 ethylene diamine tetramethylene phosphonate: β-radiopharmaceuticals historically used for bone painThe official use of radiopharmaceuticals for patients with mCRPC began in 1993, following US FDA approval of Strontium 89- chloride (Sr 89) for the treatment of painful bone metastases [6]. Oncologists and nuclear medicine physicians thus began to cooperate in the use of Sr 89 and then 153Samarium-ethylene diamine tetramethyl-ene phosphonate (Sm 153 EDTMP), approved in 1997 [6]. The use of these therapies was restricted to patients with bone metastases associated with osteoblastic response detected on bone scan [6]. Sr 89 and Sm 153 EDTMP are essentially β-emitters with very different physical half-lives. Their main characteristics are summarized in Table 1: they are calcium-mimetic agents able to concentrate in bony metastatic areas through selective uptake and prolonged retention due to increased osteoblastic activity [7].

Because β-radiopharmaceuticals concen-trate in areas of high bone turnover, they can induce a sort of circumscribed radiotherapy on the surrounding tissues through ionizing radia-tion that damages DNA. One of their most attractive advantages is in multifocal disease, in which they offer greater therapeutic benefits than the standard external-beam radiation therapy, whose efficacy is limited to unifocal/uniseg-mental metastases [12]. The ionizing radiation induces a DNA single-strand break, which may affect many different cells: tumor cells, nerve terminals, osteoblasts, osteoclasts, inflammatory cells and bone marrow cells. These interactions are responsible for both the positive and nega-tive effects of this therapy. Pain relief occurs in approximately 70% of patients, generally start-ing from the second or third week after adminis-tration, with a median duration of approximately 6 months [12]. However, the energy associated with β-emitting particles is not sufficient to elicit a significant cytotoxic response by killing cancer

cells and decreasing tumor burden, although favorable biochemical response and prolonged time to appearance of new skeletal lesions have been reported [7].

The main adverse effect of β-radio-pharmaceuticals is transient myelosuppression. In particular, thrombocytopenia is common, with platelet counts at nadir generally 40–60% of baseline; however, in most patients this event leads to only grade 1 or 2 toxicity [3]. This adverse effect may keep many patients with mCRPC from accessing the treatment. Box 1 reports the absolute and relative contraindications to the use of β-radiopharmaceuticals. Significant problems with neutropenia and anemia are less common. Other uncommon adverse effects include nau-sea, loose stools, asymptomatic hematuria and heart palpitations. A flare reaction is observed in approximately 5–10% of patients, with a transient and self-limited increase of bone pain. This event is more common in patients with a significant burden of bone metastases visualized by bone scan [3].

Further complications in patients receiving β-radiopharmaceuticals relate to management. In the USA these drugs are generally admin-istered in an outpatient setting because of the lack of significant γ-emissions and subsequent need for isolation. In other countries, however, regulatory authorities may require that patients remain in the hospital for several hours (or even overnight) after administration. A summary of the procedures requested for the management of patients treated with radiopharmaceuticals at our institution is shown in Box 2.

Because of the lack of therapeutic options for patients with mCRPC until 2009, many retrospective and prospective studies were undertaken to identify whether the activity of the two available β-radiopharmaceuticals affects survival. A randomized Phase II study revealed that the use of the non-FDA-approved β-radiopharmaceutical 188Rhenium hydroxy-ethylidenediphosphonate as a single therapy increased survival [14]. A combined approach evaluating Sr 89 plus chemotherapy in patients with mCRPC enrolled in a randomized Phase II study indicated a survival superiority in the experimental arm [15]. Similarly, retrospective studies undertaken by a multidisciplinary team at our institution showed a possible synergistic effect on survival of Sm 153 EDTMP in com-bination with chemotherapy [16]. A subsequent Phase II study confirmed that the administration

10.2217/FON.14.157 Future Oncol. (Epub ahead of print)

Radium 223 dichloride: a multidisciplinary approach to metastatic castration-resistant prostate cancer review

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of docetaxel (75 mg/m2 administered intrave-nously every 21 day for at least 6 cycles) after Sm 153 EDTMP (37 MBq/kg) did not induce addi-tional toxicities and did not reduce the antitumor efficacy [17].

To the best of our knowledge, only a Phase III studies evaluated the efficacy and safety of β-radiopharmaceuticals plus chemotherapy in patients with histologically documented CRPC and bone metastases. SAMDOCET was a randomized and multicentric study of Sm 153 EDTMP and docetaxel compared with docetaxel alone in taxane-naive patients with mCRPC [18]. The study evaluated the time to progression and overall survival of the combination of docetaxel (75 mg/m2 for 9 cycles) and Sm 153 EDTMP (37 MBq/kg at cycles 1, 5, and 9) compared with the control arm of docetaxel alone, and the pre-liminary results reported a trend in survival for the combination arm.

Even though these results seem to justify further investigation of the possible synergis-tic effects of chemotherapy in combination with β-radiopharmaceuticals, no sound data concerning the effectiveness on survival of β-radiopharmaceuticals as single agents are avail-able, and no Phase III studies have been planned to settle this issue.

A progressive decrease in the use of β-radiopharmaceuticals thus occurred, minimiz-ing the role of nuclear medicine physicians on the multidisciplinary team for the management of mCRPC [3,12–13]. This underuse may be chiefly related to the exclusive palliative role of the radi-opharmaceuticals, which may have caused the prostate unit to lose confidence in these agents. Additional problems could have limited the use of β-radiopharmaceuticals in clinical practice. The first problem might be fear of treatment-related toxicities, chiefly bone marrow toxicity, which prevented medical oncologists from con-sidering the palliative activity of radionuclide therapies on the bone pain of patients already being treated with chemotherapy [3,12]. In addi-tion, access to β-radiopharmaceuticals was dif-ficult for small hospitals lacking nuclear medi-cine facilities, and adequate information was lacking [3,12]. Another problem is the absence of predictive markers to identify patients who will fully respond to β-radiopharmaceuticals [3,12]. Finally, support for national and multi-institu-tional cooperative clinical trials on the use of β-radiopharmaceuticals in men with different stages of prostate cancer has been scant [3,12]. Ta

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10.2217/FON.14.157



First α-emitting radiopharmaceutical for CRPCRadiopharmaceuticals have been able to play a role in addition to palliation only since the 2013 approval of the new α-emitter Ra 223 dichlo-ride, which showed a survival benefit in CRPC patients with bony metastases regardless of prior treatment with docetaxel. The pivotal Phase III comparative study (ALSYMPCA), carried out on 921 symptomatic CRPC patients with two or more bone metastases, showed that Ra 223 dichloride induces a statistically significant survival improvement compared with placebo (median: 14.9 vs 11.3 months; hazard ratio [HR]: 0.70; 95% CI: 0.58–0.83; p < 0.001) [4]. The trial involved patients without visceral metastases who had received, were not eligible for or had refused docetaxel. In addition, the study demonstrated that Ra 223 dichloride delays the time to the onset of the first symp-tomatic skeletal-related event (median: 15.6 vs 9.8 months; HR: 0.66; 95% CI: 0.52–0.83; p < 0.001) and reduces bony metastases pain [4].

A prespecified subgroup analysis showed that the drug was able to reduce symptomatic skeletal events and improve survival independently of previous docetaxel therapy at study entry [19]. Authors reported that treatment with Ra 223 dichloride could be a reasonable alternative to treatment with docetaxel, because this agent has much less toxicity [20].

With regards to a possible concomitant ther-apy with bisphosphonate, the result of a second preplanned subgroup analysis reported that patients received benefit regardless the adminis-tration of bisphosphonate, consequently Ra 223

and bisphosphonates appear independent in their actions of reducing symptomatic skeletal events [19].

As far as toxicity is concerned, the incidence of myelosuppression related to Ra223 resulted 3% or less, without any report of acute mye-loid leukemia, myelodysplastic syndromes or primary bone cancer. Presently, the long-term follow-up study for ALSYMPCA is ongoing and the safety data refer to a median of 1.5 years of follow-up. These data report no additional safety concerns [21].

The unexpected success of this radionuclide could be explained by analyzing its biophysi-cal characteristics: like β-radiopharmaceuticals, Ra 223 dichloride is a calcium-mimetic agent targeting hydroxyapatite crystals in the high-turnover bony areas [2]. In contrast to previous agents, however, Ra 223 is an α-emitting radio-nuclide delivering higher energy with a shorter run; this results in higher potential lethality for cancer cells and less toxicity for normal tissue outside the tumor microenvironment [2]. In other words, Ra 223 can hit fewer cells with higher energy compared with the β-particles, inducing DNA double-strand breaks sufficiently severe to make them nearly irreversible [22] and thus affecting survival (Table 1). Because the cell damage is largely beyond repair, α-emitting radiation can sterilize the contiguous cells [22] so that this agent does not seem to induce tumor resistance. In addition, the low serum half-life and the lower invasiveness compared with β-emitters limit damage to the surrounding tis-sues, especially the bone marrow hematopoietic tissue [2].

Box 1. Absolute and relative contraindications to the use of β-radiopharmaceuticals.

Relative contraindications ● Uncontrolled extraskeletal disease burden ● Asymptomatic skeletal metastases ● Skeletal lesions limited to fewer than three sites ● Poor bone marrow reserve: hemoglobin 90–100 g l-1; total white cell count 2.4–3.0 × 109l-1; platelet count 60–100 × 109l-1

Absolute contraindications ● Presence of epidural spinal cord compression ● Life expectancy less than 3 months ● Pending or active pathological fracture of weight-bearing bone ● Purely osteolytic lesions (no uptake on bone scan) ● Poor bone marrow reserve: hemoglobin <90 g l-1; total white cell count <2.4 × 109l-1; platelet count <60 × 109l-1

● Renal failure (creatinine >180 lM; glomerular filtration rate <30 ml/min)Data taken from Paes et al. [13], Rubini et al. [6].




Patient selectionThus began a new phase of cooperation between oncologists and nuclear medicine physicians. Our institution began active involvement of nuclear medicine physicians in the prostate unit during the selection of patients suitable for Ra 223 treatment, as well as in screening patients suitable for the currently available clinical pro-tocols for use of the α-emitting drug in different oncologic diseases.

Patient selection may be the key to the efficacy of the drug. Even though Ra 223 may be consid-ered a new standard of care for men with CRPC bony metastases, the drug should not represent the only solution for all patients with CRPC with bony metastases.

Box 3 reports the main points in categoriz-ing patients suitable for Ra 223 on the basis of our experience. Men identified as candidates for Ra 223 therapy should have at least two bone metastases due to prostate cancer identified by 99m Technetium-labeled phosphonates (Tc 99m) bone scan, the standard technique worldwide.

Alternative diagnostic methods, such as radio-logical imaging and carbon 11-choline PET/CT, are associated with greater diagnostic accuracy and can overcome the problem related to low specificity of bone scintigraphy. However, the Tc 99m bone scan is the only technique that can identify the areas of highest bone turnover, the sites of Ra 223 accumulation after admin-istration. Noteworthy is that skeletal PET with 18F-fluoride represents a technique similar to Tc 99m bone scan, but, to the best of our knowl-edge, this methodology has not yet been widely used to detect patients suitable to Ra 223 so far.

We also treat patients with very early symp-toms. In fact, in line with the consensus of the Prostate Cancer Working Group 2 [23], the very early presence of bone metastasis symptoms should be taken into consideration to avoid fur-ther pain increase. According to the authors, this approach could also limit the biologic activity of the earlier oligometastatic bone lesions that could be responsible for the development of late-occurring visceral metastases [3]. In agreement

Box 2. Main indications for the management of patients treated with radiopharmaceuticals at our institution.

Radiopharmaceutical administration ● The patient presents fasting before administration ● The radiopharmaceutical is administered as a single intravenous solution ● Intravenous access is obtained and flushed prior to the procedure ● Often patients are hydrated prior to the injection, either orally or with up to 500 ml of normal saline, to allow for efficient elimination of the radionuclide not incorporated into bone

● The radionuclide is administered through the intravenous injection over approximately 1 min ● The line is flushed with 20–30 ml of normal saline, and access is removed by the nurse using appropriate procedures ● Because radiopharmaceuticals are eliminated mainly with feces and urines, the patient should stay in the nuclear medicine unit for 4 h subsequent to administration to appropriately collect radioactive dejections

● Especially after β-radiopharmaceutical administration, weekly blood counts should be performed for up to 8 weeks to monitor the predictable transient decline and recovery of platelet and leukocyte counts

Rules of conduct after administration ● Use a normal toilet, if available, instead of a urinal ● Flush the toilet twice after using to prevent contamination of the environment ● Wipe any spilled urine with a tissue and flush it away ● Wash hands after using or cleaning the toilet ● Wash clothes and bed linens immediately if they become soiled with urine or blood, and wash them separately from other clothes ● In case of being cut, wash away any spilled blood ● With abnormally low white blood cell counts (frequently reported after β-radiopharmaceutical administration) ● Avoid people with infections. Check with the doctor immediately in case of getting an infection a fever or chills, cough or hoarseness, lower back or side pain, or painful or difficult urination

● Be careful with the use of a regular toothbrush, dental floss or toothpick. Check with the medical doctor before having any dental work done

● Do not touch the eyes or the inside of the nose ● With abnormally low platelet blood counts (frequently reported after β-radiopharmaceutical administration) ● Be careful not to be cut during the use of sharp objects such as a safety razor or fingernail or toenail clippers ● Avoid contact sports or other situations where bruising or injury could occur

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with the Phase III study, even having more than 20 bone metastases is not considered a criterion for exclusion. However, when bone scan evidence correlates with very advanced disease and low life expectancy, we believe that supportive analgesic treatment should be proposed.

In accordance with the EMA label, we excluded from access to Ra 223 patients with vis-ceral metastases, who usually represent 23–29% of advanced patients who progressed from doc-etaxel treatment [24]; the only exception was men showing single-nodal disease no greater than 3 cm. Another exclusion was related to life expec-tancy and stage of disease: in terminal stages of disease (life expectancy less than 3 months) we prefer to propose treatment with symptomatic drugs such as opioids and analgesics.

ConclusionAfter years of stagnation because β-radio-pharmaceuticals as single agents have only a pal-liative role, the introduction of the α-emitting radiopharmaceutical Ra 223 now can renew and reinforce cooperation between oncologists and nuclear medicine physicians. The favorable efficacy and safety profile of this new agent, as well as its lack of induction of tumor resistance, may allow it to leap the barriers that have lim-ited the use of previous radiopharmaceuticals. It seems reasonable to assume that the initial cross- disciplinary cooperation between physi-cians, which so far has been established only in mCRPC, will become a cornerstone of future cancer therapy.

Future perspectiveThe availability of a new radiopharmaceutical agent for prostate cancer that is able to extend survival and offer a very favorable safety profile [25] encourages cooperation between oncologists

and nuclear medicine physicians. Indeed, nuclear medicine physicians will feel challenged by the opportunity to utilize the first radiopharmaceu-tical that is really effective for mCRPC, and oncologists will welcome the chance to broaden the therapeutic approach to mCRPC patients. We strongly believe, in fact, that Ra 223 may represent for oncologists a sort of magic bul-let that, at least theoretically, should be able to bypass cancer cell resistance by way of α-particle emission that limits the development of resistant clone selection in tumor tissue [22].

A renewed interest in radiopharmaceuti-cals could overcome the obstacles that led to the underuse of β-radiopharmaceuticals. The absence of markers able to predict the clinical efficacy of the drug could be overcome by careful patient selection and by development of quantita-tive bone scan assessment techniques and dosi-metric evaluations (Box 3).

The well-known limitations related to the dif-ficulty of access to the drug at peripheral cent-ers without a nuclear medicine unit suitable to handle radiopharmaceuticals could be overcome through a training action performed by the main centers. In fact, as mentioned, the limitations to the radiometabolic therapy in centers of nuclear medicine located in peripheral hospitals are gen-erally identified with the severe measures of radi-oprotection and to the fear of toxicities associated with radiopharmaceutical therapies.

It is wishful that as soon as the main reference centers expand their knowledge on the use of Ra 223, validating the manageability and the lim-ited needs of radiation protection measures, such experience could be delivered to the peripheral centers, enabling the widespread dissemination of the therapy. A global plan of studies has been scheduled to expand the effectiveness and knowl-edge of Ra 223. The first study will explore the

Box 3. indications for patient selection for the use of Ra 223 based on experience at our institution.

Suitable for Ra 223 ● Disease with at least two bone metastases induced by castration-resistant prostate cancer ● Presence of more than two lesions not suitable for radiotherapy intervention ● Bone metastases detectable with 99mTc-phosphonate bone scan or 18F-NaF PET/CT scan ● Adenopathy with 3 cm as diameter maximum

Unsuitable for Ra 223 ● Presence of visceral metastases (lung, liver, brain, diffuse nodal disease) ● Presence of chronic and/or active intestinal disease (e.g., Crohn’s disease, ulcerative colitis) ● Presence of micrometastases of bone detectable only with 11C-choline PET/CT scan ● Life expectancy <3 months




feasibility of different doses, alternative schedules and long-term treatments [26]. A second program will evaluate the possibility of combining Ra 223 with treatments already used for mCRPC, thus reinforcing once more the cooperation between oncologists and nuclear medicine physicians. Based on theoretical assumptions, a ration-ale exists for such an approach because of the

different mechanisms of action of the different agents. This approach, which is excluded from the present label indication, could extend the use of Ra 223 to patients with both bone and visceral metastases. Although these combined treatments, especially with chemotherapy, are not at present indicated outside clinical trials, in some areas of the USA the combination of

executive summAryBackground

● The treatment of men with advanced prostate cancer in a multidisciplinary team prostate unit can affect survival.

● In such a prostate unit, the role of nuclear medicine physicians has been historically disregarded because of the lack of tools with an impact on survival.

Strontium chloride 89 & samarium 153 eDTMP: β-radiopharmaceuticals historically used for bone pain

● β-emitting radiopharmaceuticals represented the first weapon for nuclear medicine physicians in the management of castration-resistant prostate cancer (CRPC).

● These drugs turned out to be effective for relief of bone pain in men with bony metastases due to CRPC, but no Phase III studies demonstrated an impact of the drugs on survival without association with chemotherapy.

● Hematologic toxicities limited the use of radiopharmaceuticals. Thus, the use of radiopharmaceuticals has generally applied only to patients with very advanced disease.

The first α-emitting radiopharmaceutical for CRPC

● The favorable biophysical properties of α-emitting radiopharmaceuticals indicate that these drugs are more suitable for the therapy of CRPC than the previous ones.

● Ra 223 dichloride is the first radiopharmaceutical able to affect survival in men with CRPC and bone metastases.

● The drug was able to reduce symptomatic skeletal events and survival independently of previous docetaxel therapy at study entry.

● Clinical studies reported a toxicity profile associated with α-emitting radiopharmaceuticals different from and more favorable than that of β-emitting radiopharmaceuticals.

● Safety data referred to a median of 1.5 years of follow-up do not report additional safety concerns.

Patient selection

● Patient selection for α-emitting radiopharmaceuticals is a key issue and differs from selection for β-emitting radiopharmaceuticals.

● The use of Ra 223 dichloride should not be limited to patients with very advanced disease.

Conclusion

● The α-emitting radiopharmaceutical Ra 223 dichloride represents a new opportunity for active cooperation between nuclear medicine physicians and the other specialists in the prostate unit.

● Because the use of Ra 223 dichloride may be extended to other tumors or combined with other agents, this initial collaboration represents an important step in oncology.

Future perspective

● Despite their disadvantageous safety profile, combination strategies using β-emitting radiopharmaceuticals and chemotherapy appear feasible.

● Higher safety and clinical benefit can be achieved with the combination of α-emitting drugs and chemotherapy or hormonal agents already approved for CRPC.

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Ra 223 with abiraterone or enzalutamide is already being prescribed [20].

Our experience with docetaxel in combina-tion with agents that are notoriously more myelo-toxic than Ra 223 suggests that this combined approach is feasible [17]. As proof, the first data from a Phase I study showed that the combina-tion of Ra 223 (fivefold dose of 50 kBq/kg every 6 weeks) with docetaxel (60 g/m2 every 3 weeks) appeared to be very well tolerated [25], and the next step in evaluating the efficacy is ongoing [27]. Similarly, combination studies with abirater-one [28,29] and enzalutamide [30] are in progress. The success of these studies could offer new and important therapeutic strategies for patients with visceral and encephalic metastases, who represent an increasing population [24]. These new combi-nation approaches with a double mechanism of action (hormonal and radiologic) could represent a step beyond today’s standard chemotherapy regimens. Worth mentioning is that the authors proposed also to evaluate an earlier use of Ra

223 in patients with castration-sensitive disease to estimate a possible benefit in terms of survival and skeletal symptomatic event prevention, but this approach has not yet been confirmed in clin-ical studies [31]. A third phase of the studies will concern the use of Ra 223 in patients with bone metastases induced by different tumors, such as breast cancer [32], non-small-cell lung cancer, thyroid cancer and multiple myeloma, as well as in primary tumors such as osteosarcomas [33,34].

Financial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a finan-cial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Writing assistance was utilized in the production of this manuscript. Editorial support was provided by Dragonfly Editorial and funded by Bayer SpA.

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•• ImportantpaperthatmakesthepointofstudydesignandmainendpointsthatshouldbeselectedforstudiesinCRPC.

24 Pezaro CJ, Omlin A, Lorente D et al. Visceral disease in castration-resistant prostate cancer. Eur. Urol. 65(2), 270–273 (2014).

• DescribestheimpactofnewdrugsonpatientswithCRPCandvisceralmetastases.

25 Michael J, Morris HJH, Sweeney C et al. Safety of radium-223 dichloride (Ra-223) with docetaxel (D) in patients with bone metastases from castration-resistant prostate cancer (CRPC): a Phase I Prostate Cancer Clinical Trials Consortium study. J. Clin. Oncol. 31(Suppl.), Abstract 5021 (2013).

26 NCT01934790: Re-treatment safety of radium-223 dichloride in castration-resistant prostate cancer with bone metastases. www.clinicaltrial.gov/ct2/show/NCT01934790

27 NCT01106352: A study of Alpharadin® with docetaxel in patients with bone metastasis from castration-resistant prostate cancer (CRPC). http://clinicaltrials.gov/ct2/show/NCT01106352

28 NCT02097303: Open label Phase two trial of radium Ra 223 dichloride with concurrent administration of abiraterone acetate plus prednisone in symptomatic castration-resistant (hormone-refractory) prostate cancer subjects with bone metastasis (eRADicAte). www.clinicaltrial.gov/ct2/show/NCT02097303

29 NCT02043678: Radium-223 dichloride and abiraterone acetate compared with placebo and abiraterone acetate for men with cancer of the prostate when medical or surgical

castration does not work and when the cancer has spread to the bone, has not been treated with chemotherapy and is causing no or only mild symptoms. www.clinicaltrial.gov/ct2/show/NCT02043678

30 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. www.clinicaltrial.gov/ct2/show/NCT02034552

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32 NCT01070485: A study of Alpharadin® in breast cancer patients with bone dominant disease no longer considered suitable for hormone therapy. www.clinicaltrial.gov/ct2/show/NCT0107048520

33 NCT01833520: Phase I dose escalation of monthly intravenous Ra-223 dichloride in osteosarcoma. www.clinicaltrial.gov/ct2/show/NCT01833520

34 Anderson PM, Subbiah V, Rohren E. Bone-seeking radiopharmaceuticals as targeted agents of osteosarcoma: samarium-153-EDTMP and Radium-223. Adv. Exp. Med. Biol. 804, 291–304 (2014).

10.2217/FON.14.157

radium 223 dichloride: a multidisciplinary approach to metastatic castration-resistant prostate...

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