Interim and End-treatment 18F-Fluorocholine PET/CT and Bone Scan in Prostate Cancer Patients Treated with Radium 223 Dichloride

doi:10.21203/rs.3.rs-154723/v1

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Research Article

Interim and End-treatment 18F-Fluorocholine PET/CT and Bone Scan in Prostate Cancer Patients Treated with Radium 223 Dichloride

https://doi.org/10.21203/rs.3.rs-154723/v1

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published 01 Apr, 2021

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Aim

To assess the predictive and prognostic aim of interim and end-treatment ¹⁸F-fluorocholine PET/CT (FCH-PET/CT) and ^99mTc-methilen diphosphonate bone scintigraphy (BS) in patients with castration-resistant prostate cancer and bone metastases (CRPC-BM) treated with Radium 223 dichloride (²²³Ra).

Methods:

Prospective and multicentre ChoPET-Rad study including 82 patients with CRPC-BM. Baseline, after 3 (interim) and 6 doses (end-treatment) BS and FCH PET/CT were performed in patients who meet the study criteria.

Clinical variables, imaging and clinical progression were obtained and their association with progression free survival (PFS), and overall survival (OS) was studied. Agreement between BS and FCH PET/CT response was assessed using Kappa (K) analysis.

Results:

Median of PFS and OS was 3 and 16 months, respectively. Agreement between interim BS and FCH PET/CT was weak (K: 0.28; p=0.004). No agreement was observed between end-treatment diagnostic studies

Interim and end-treatment FCH PET/CT were related to PFS (p=0.011 and p<0.001, respectively). Therapeutic failure and interim BS and FCH PET/CT showed association with OS (p<0.001, p=0.037 and p=0.008, respectively).

Conclusions:

Interim and end-treatment FCH PET/CT were good predictors of biochemical progression in patients treated with ²²³Ra. Therapeutic failure and progression in interim BS or FCH PET/CT were adverse factors for OS.

Cancer Biology

Oncology

Orthopedics

F-Fluorocholine PET/CT

bone metastasis

prostate cancer

bone scintigraphy

Radium treatment

response assessment

prognosis

interim

end-treatment

progression free survival

overall survival

Radium 223 dichloride (²²³Ra) is a targeted alpha therapy introduced into clinical practice for the treatment of patients with castration resistant prostate cancer with bone metastases (CRPC-BM) [1-4].

In patients with CRPC-BM the lack of suitable biologic and imaging markers, able to guide in patient selection and response assessment, is a potential and challenging drawback for ²²³Ra as well as for other therapies. In clinical practice, monitoring of treatment with ²²³Ra is based on clinical and biochemical markers, being the role of imaging not well documented, with few works regarding to bone scintigraphy (BS) and computed tomography (CT), and only case reports for positron emission tomography/computed tomography using radiolabeled choline analogues (choline-PET/CT) [5-12]. This “evidence of absence” explains that most current guidelines [e.g. European Society of Medical Oncology, European Association of Urology and the American Urological Association] do not provide clear recommendations about diagnostic imaging assessment in clinical practice or only focused on clinical trials [3,4,13-15].

Based on the higher sensitivity and specificity of choline-PET/CT, respect to standard BS, in detecting bone metastases and the potential for diagnosing extraosseous disease in the same exploration, some advantages respect to the BS in the response assessment should be expected [16-19]. However although the Prostate Cancer Radiographic Assessments for Detection of Advanced Recurrence II (RADAR II) group and the National Comprehensive Cancer Network (NCCN) guidelines recognize the use of choline-PET/CT in patients with biochemical recurrence, no recommendations are given regarding the response assessment [20-22].

Based on: (i) the limited experience about the use of ¹⁸F-Fluorocholine (FCH) PET/CT, BS and CT in patients treated with ²²³Ra and (ii) the reduced accuracy of BS and CT in the response assessment in patients with CRPC-BM a prospective and multicentre study was designed to assess the value of FCH PET/CT and BS in the response and prognosis assessment of patients treated with ²²³Ra, aiming to validate and introduce FCH PET/CT into the diagnostic management of patients with²²³Ra indication.

The present study (FCH PET/CT in the assessment of ²²³Ra treatment response, ChoPET-Rad) was designed as a prospective, multicentre (6 hospitals) and non-randomized.

Ethical Committee of the coordinator centre (University General Hospital, Ciudad Real, Spain) where all the FCH PET/CT were performed approved the study (code:C/52/2016). Informed consent was obtained from all patients.

Patients

Patients with CRPC-BM who fulfill all the inclusion criteria and none of the exclusion criteria for ²²³Ra treatment were consecutively included between January 2015 and January 2020.

The inclusion criteria for initiating ²²³Ra treatment were: (a) patients with CRPC with symptomatic bone metastases and a negative or inconclusive CT for visceral metastatic disease performed in the previous 6 weeks to request ²²³Ra treatment; (b) patients with a good bone marrow reserve that fulfills the hematologic criteria necessary to administer ²²³Ra and (c) Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 (life expectancy greater than 6 months).

The exclusion criteria were: (a) patients who denied participating in the study or (b) who not fulfill any of the inclusion criteria [23].

Patients scheduled to be treated with of ²²³Ra (55 KBq/kg, intravenously) in a 4-week cycle, for six cycles and maintained on androgen deprivation therapy.

Clinical assessment

Each patient was clinically, hematological and biochemically evaluated before each ²²³Ra administration and bimonthly or monthly, after the last ²²³Ra administration, depending on the patient clinical status and the subsequent therapeutic lines. The clinical and biochemical variables were: Gleason, prostate specific antigen (PSA), alkaline phosphatase (AP), lactate dehydrogenase (LDH), time of evolution of prostate cancer, time of evolution of bone metastases and therapeutic line that ²²³Ra represented.

LDH and AP were considered as pathological when the values were higher than 333 U/L and 147 U/L, respectively.

The percent of change in PSA of each month determination during ²²³Ra administration with respect to baseline value was calculated in order to obtain the progression free survival (PFS).

Clinical progression was assessed following the RADAR II group recommendation [22] using at least two of the following indicators: (1) convincing and consistent rise in PSA (defined as three consecutive rises, resulting in two 50% increases over the basal PSA value), (2) evidence of radiographic progression, or (3) worsening of the status performance or clinical symptoms while the patient is on therapy.

Thus at least two of three criteria (PSA progression, radiographic progression and clinical deterioration) should be fulfilled to stop ²²³Ra treatment. Finally the decision to stop treatment was addressed in multidisciplinary evaluation (oncologist and nuclear medicine physician) mostly after the third or fourth ²²³Ra treatment, based on early progression. Last follow-up was performed in June 2020.

Clinical end-points were: (a) treatment failure, defined as an incomplete ²²³Ra administration (less than 6 cycles) because of clinical progression of the disease or hematological toxicity and/or clinical impairment, (b) PFS, attending to PSA evolution, defined as three consecutive rises in PSA, resulting in two ≥50% increases over the basal PSA value and (c) overall survival (OS), defined as the elapsed time between the date of the start of ²²³Ra and the date of either death or the last follow-up.

For PSA, response was considered if a decrease in absolute PSA value of ≥30% between baseline PSA and interim (one month later the third dose) or end-treatment (one month later the sixth dose) was observed, defined as early of delayed response, respectively. Stability was considered for the rest of biochemical changes.

For AP and LDH, progression was defined as an increase of ≥25% from last available determination during treatment respect to baseline observed. Response was defined as a reduction of ≥30% from the baseline value. The rest of conditions were considered as stability.

Imaging acquisition

FCH PET/CT and BS were performed, within a time interval of 4 weeks, before the first administration (baseline), before the fourth (interim) and after the sixth (end-treatment) ²²³Ra doses.

Bone scan was acquired 3 hours after injection of 740 MBq of ^99mTc-methilen diphosphonate (MDP) in three reference centres. FCH PET/CT was performed in a unique reference hospital, 5-15min after intravenous administration of 2-4 MBq/kg, in three-dimensional acquisition mode for 3 minutes per bed position, from skull to proximal legs. Low dose CT (120 kV, 80 mA) without contrast was performed for attenuation correction and as an anatomical map. The emission data was corrected for scatter, random coincidence events, and system dead time using the provided software [23].

Imaging evaluation

Two independent observers evaluated FCH PET/CT and BS. In case of discordances, a third observed reviewed the studies to reach a consensus.

Baseline FCH PET/CT and BS were visually evaluated establishing the BM extension following the criteria defined in a previous publication [23].

Interim and end-treatment BS and FCH PET/CT were compared with respect to the previous one in order to establish response (baseline and interim, respectively). The appearance of at least two new areas of increased uptake, osseous on BS and osseous and/or extraosseous on FCH PET/CT or a new lesion associated to an increase of the extent of BS or FCH uptake (at least 20% in the longest direction) in another one bone was considered as progression following the criteria for response formulated by the National Prostatic Cancer Treatment Group, formerly called the National Prostatic Cancer Project (NPCP) [24].

In BS, complete response, lesion stability or partial response with a reduction by 50% in the number of increased areas of uptake were joined for statistical purposes and considered no progressive disease. In FCH PET/CT no progression was considered in cases of stability, partial response or complete response according to criteria of the European Organization for Research and Treatment of Cancer (EORTC) [25].

Statistical analysis

Statistical analysis was performed using SPSS software (v. 22). Quantitative variables were represented by mean and standard deviation and qualitative variables by frequency and percentage. Relation between qualitative variables was studied using Chi-squared Pearson test.

Cohen’s kappa coefficient was used to report the concordance regarding the response results between BS and FCH PET/CT, classifying the results as poor (<0.20), weak (0.21–0.40), moderate (0.41–0.60), good (0.61–0.80) and very good (0.81–1.00).

Kaplan-Meier survival analysis and Cox regression were considered to study the prognostic factors of the overall survival (OS) and the progression free survival (PFS).

The significance level was established at p<0.05.

²²³Ra treatment was requested in 98 patients. Evaluation of the clinical and hematological conditions dismissed 16 cases: 4 for hematological constraints, 5 attending to FCH PET/CT results consisted on metastatic disease in 3 patients (lung, liver and brain involvement, respectively) and 2 with locorregional invasiveness (seminal vesicle invasion and bladder involvement, respectively), 3 for diffuse bone marrow involvement defined by BS and/or FCH PET/CT, one for a probably second primary tumor (hypernephroma) without a definite diagnosis, 2 for clinical deterioration with ECOG >2 and one for medullar compression days previous to ²²³Ra initiation. Thus 82 patients were finally enrolled in the present study.

Sixty-one out of 82 (74.4%) patients had received docetaxel treatment before study enrollment. ²²³Ra was considered as the first or second therapeutic line in only 23 patients (28%). Tables 1 and 2 show the patient and disease characteristics.

Two thirds of patients biochemically progress during ²²³Ra treatment (54, 65.9%). 40/54 (74.1%) of these progressions were during the first three months after ²²³Ra initiation (early progression). 48 out of 82 (58.5%) patients did not complete the six administrations of ²²³Ra (therapeutic failure), 43 for clinical progression (RADAR criteria) and 5 cases for other clinical reasons (1 pulmonary thromboembolism, 2 hematological constraints and 2 clinical deterioration). On the other hand, 3 patients with clinical progression (RADAR criteria) completed the six doses of ²²³Ra treatment based on their limited therapeutic options and/or “low burden” progression on imaging, less than 5 small new lesions in non-visceral locations.

Only 13 patients experienced PSA response during ²²³Ra treatment, 9 of them early responses that kept during treatment and the rest delayed ones.

Regarding the binary response (progression vs no progression) on imaging, progression was detected more frequently on interim and end-treatment FCH PET/CT, compared to BS (tables 2 and 3). Regarding the pattern of progression on FCH PET/CT, all the cases were bone progression except in 3 cases with exclusively lymph node progression in interim and end-treatment evaluations. Visceral involvement (liver metastases on CT portion of FCH PET/CT with absent or minimal FCH uptake) was observed in 6 patients, five on interim evaluation and one on end-treatment FCH PET/CT. All the cases associated bone progression.

Agreement between interim BS and FCH PET/CT was weak (K: 0.28; p=0.004). No agreement was observed between end-treatment diagnostic studies (K: 0.13; p=0.247). The distribution of the results is showed in table 3.

Progression of AP and LDH was observed in 14/64 and 19/59 cases, respectively. Response of AP and LDH was detected in 18/64 and 9/59 cases, respectively. Stability was observed in the rest of cases, especially for LDH.

Baseline PSA and AP showed significant association with OS. For every 100 units or 10 units that PSA or AP increases, the risk of death raises by 2% (HR=1.024; p=0.025 and HR=1.026; p<0.001, respectively).

LDH progression showed significant association with PFS in Cox-analysis (HR: 2.126; p=0.020).

Significant association of therapeutic failure with PFS and OS were found using Cox regression and Kaplan-Meier analysis. Interim and end-treatment FCH PET/CT results showed significant association with PFS whereas interim BS and FCH PET/CT results showed significant association with OS. The results are detailed on tables 4 and 5. Figure 1 shows graphically the most relevant results.

In multivariate analysis, only therapeutic failure and interim FCH PET/CT showed association with PFS (p=0.047 and p=0.078, respectively). Thus, a patient with therapeutic failure or progression in interim FCH PET/CT had 1.938 (1.008, 3.727) or 1.789 (0.938, 3.413) times more risk of PSA progression than patients without the cited conditions. On the other hand, the independent and significant variables associated with OS were therapeutic failure (p=0.034) and baseline AP (p=0.001).

Some representative cases are showed on figures 2 to 6.

Regular monitoring of bone metastases for men with CRPC, using conventional imaging (CT and/or BS), although recommended, is notoriously difficult, that explains the use of “clinical benefit”, in common daily practice, as the best evidence of response. However the combined use of clinical, biochemical and imaging assessment is of paramount importance to a correct monitoring for treatments with survival impact as ²²³Ra.

Prostatic specific antigen behavior during ²²³Ra treatment is not well known based on the limited experience. Reductions of PSA levels up to 18% have been associated to the cytotoxic effect of ²²³Ra inhibiting tumor-induced osteoblastic bone growth and suppressing bone metabolic activity [7, 26-29].

On the other hand, PSA rise during treatment with ²²³Ra has been reported and attributed to various reasons: (a) progression of metastatic soft tissue injuries no involved in the treatment, (b) bone tumor lysis, (c) bone progression, (d) non androgen dependent mechanism of action of ²²³Ra or (e) flare [30].

PSA flare is defined as a significant PSA falls after initial rise and it has been described following initiation of chemotherapy, newer hormonal therapies and even with ²²³Ra, [31]. All the previous explain the low consideration of PSA as a therapy response predictor, especially during the first 3 months of treatment initiation [21,22,32-36].

Based on the possibility of flare interference, the “restrictive” criteria for PSA progression used in the present study, practically rule out the misinterpretation of progressive disease as “flare” based on a steadily rising of PSA during ²²³Ra treatment less likely represented a flare phenomenon [37].

In cases of discordant results between PSA values and clinical evaluation during ²²³Ra treatment, is recommended the measurement of AP and LDH. AP is a marker of turnover, reflecting osteoblastic activity, not always related to tumor activity, which may explain discrepancies with related markers. On the contrary, LDH seems a more specific marker, based on its association with cellular damage and prognosis [38].

In the present work, despite the missing data, stability of AP and LDH was found in 32/64 and 31/59 cases, respectively. However LDH, contrary to AP, showed association with PFS. Thus, patients with LDH progression had a double risk to progress compared to the rest of patients (p=0.020).

Previous works and current clinical guidelines are pragmatic about needing to assess response using diagnostic imaging, explaining the poorly defined use and interpretation criteria [5,6,21,39]. However guidelines focus on imaging, as the derived from the (RADAR II) group and the European Association of Nuclear Medicine states that imaging should be used when therapeutic selection could be affected by results [ie, (1) when considering starting therapy, (2) before changing therapy to establish a new baseline, and (3) when significant deterioration of the general condition of the patient or consistent and convincing biochemical progression is identified [22,40-41].

Interim evaluation is recommended in patients with aggressive disease (high Gleason score at diagnosis or PSA doubling time <6 months before starting ²²³Ra) in order to rule out visceral metastases, using the same technique as baseline assessment. In addition, in patients presenting worsening pain after the first three cycles, increase in AP level or low PSA doubling time revealing a suspicion of progression of disease, imaging evaluation should be repeated [42].

Regarding to the election of imaging technique, radiological evaluation using CT has recently been suggested by the European Expert Consensus Panel as the ideal method for predicting response to treatment in patients with CRPC-BM, even with a proven poor sensitivity and specificity [43-44].

With BS, there are not specific criteria for the positive identification of benefit or response based on an apparently decrease in the number and activity of osteoblastic lesions can mean a reduction in tumor burden or be secondary to radiation effect (stunning phenomenon or cell death) [11,45]. In addition, although criteria for disease progression, as evident by the emergence of new lesions, are well established, controversy exists in explaining the increase in lesions after treatment based on it is likely that they originate from small bone metastases with minimal osteoblast activity, and therefore not sufficiently irradiated, that may increase in size, resulting in new sites on post-treatment CT or BS due to the existence of reparative changes (“flare phenomenon” also called pseudo-progression). Moreover, these defined criteria cannot be used in patients with diffuse metastatic bone disease or malignant superscan [15,46-48].

Previous works have stated the limitation of response assessment using BS and ¹⁸F-Sodium Fluoride (¹⁸NaF) PET/CT related with imaging flare phenomenon [6,49-51]. However, it seems the most probable option in case of new bone lesions at the initial post-treatment assessment (after three cycles of ²²³Ra) in an otherwise stable patient who is not progressing in an extra-skeletal site (for example, soft tissue disease), and without confirmation of progression (≥2 new lesions after six cycles) [11,22]. On the other hand, the persistence of uptake at the sites of bone metastases responding to treatment, the potential interference of biphosphonate therapy and the limited resolution of planar and SPECT techniques, as compared with PET/CT and magnetic resonance imaging (MRI) are other limitations of BS [47].

The scarcely literature has reported variable imaging features after ²²³Ra treatment. In relation to BS, paradoxical response has been documented with a decrease in osteoblastic activity in existing lesions joined to the appearance of new metastatic lesions [30,45,52]. On the other hand, Keizman et al [11], reported stable disease using BS at 3 and 6 months in 74% and 94%, respectively.

Despite the most recent evidence that support the choice of choline analogues PET/CT as the preferred Nuclear Medicine imaging modality for treatment monitoring of metastatic CRPC, rather than BS, ¹⁸NaF or ¹⁸F-fluorodeoxiglucose-(¹⁸F-FDG) PET/CT, the proper use of choline PET/CT is not yet established by guidelines [4,53,54].

In our study, imaging data from BS and FCH PET/CT before, during and after therapy were used to monitor response in patients treated with ²²³Ra. For the establishment of metabolic progressive disease using FCH PET/CT, in order to exclude the possibility of flare response, we used the same criteria that BS instead of semiquantitative EORTC criteria. We observed a weak and null agreement between interim and end-treatment BS and FCH PET/CT, respectively. Thus interim and end-treatment FCH PET/CT was superior to BS in the PFS definition, and thus more valid to monitor ²²³Ra treatment response.

Other authors described, using FCH, ¹⁸NaF or ⁶⁸Ga-prostate specific membrane antigen (⁶⁸Ga-PSMA) PET/CT, acute metabolic changes in large metastatic deposits after ²²³Ra treatment, with a dramatic drop of uptake in responders accompanied by a reduction of PSA and AP [8,9,45,55,56]. These results can be explained based on FCH and ⁶⁸Ga-PSMA represents the tumoricidal effect of ²²³Ra.

Recognizing the progression is crucial to move to other more effective therapies and to avoid toxicities. The only possible purpose of performing an imaging technique, based on its therapeutic implication, is to monitor progression. In this setting, choline-PET/CT can evaluate disease progression when discordances between biochemical, clinical and imaging response, using more recognized techniques as BS and CT, exist [9,15].

In patients treated with ²²³Ra, have been reported progression using BS in up to 28%, and soft-tissue progression with CT in 30–50% of cases, of whom 28–55% had visceral disease [5,10-12].

On the other hand, more of 2/3 of our patients underwent previous docetaxel and unless other line previous to ²²³Ra, that reflects a more biologically aggressive disease supporting the statement that the time to radiographic progression is inversely related to the number of previous therapeutic lines.

Our median PFS (3 months) was lower than the previously described using other therapies in earlier lines [57-61]. This fact might be explained, at least in part, by the cross-resistance phenomenon [62] and the close and exhaustive follow-up performed on our patients using the triple assessment (clinical, BS plus FCH PET/CT and PSA). Keizman et al [11] found similar results, with a median radiological PFS of 4.8 months, documenting extraskeletal radiological progression on CT scans in 46% with an uncommon bone progression (6%).

In our opinion, a significant deterioration of the general condition of the patient as main criteria to perform imaging and check biomarkers, as current guidelines recommend [32,39,40], is a restrictive criteria that limits the early detection of progression.

Guidelines and consensus state that treatments with a proven survival benefit should not be stopped for PSA progression alone (in the absence of radiographic or clinical progression) and although symptomatic or radiographic progression is a more reliable trigger for either therapeutic layering or change, the use of at least two of three criteria (PSA progression, radiographic progression and clinical deterioration) should be fulfilled to stop treatment [15,21,22]. In our work, clinical and/or radiological progression was required, in association with PSA progression, to stop ²²³Ra treatment, although all the cases were discussed on multidisciplinary team. In fact, the strong association of therapeutic failure with PFS was due to the direct dependence between these two variables, explained by progression determined stopping ²²³Ra treatment.

Previous experiences, mainly focused on baseline information derived from PET/CT, addressing the importance in prognosis of skeletal tumor burden [23,63]. A more extensive bone disease or initial PSA levels >10 ng/mL, before the initiation of treatments with a proven survival benefit, have been associated to a higher risk of progression [64,65].

Connections between radiological responses, using other PET/CT radiotracer with, PFS and OS have been previously reported, although the experience is limited [11,66]. The utility of FCH PET/CT for early prediction of outcome and monitoring response to therapy has been reported in patients treated with enzalutamide [67] and abiraterone [68].

In the present work, interim and end-treatment FCH PET/CT was associated to PFS. Neither interim nor end-treatment BS was associated to PFS although interim BS and FCH PET/CT showed association with OS. On the other hand, the independent predictors of PFS and OS in multivariate analysis, apart from therapeutic failure, were interim FCH PET/CT and baseline AP.

The present study has some drawbacks. The relatively small population in end-treatment evaluation by imaging, based on the high rate of progressive disease that promoted stopping ²²³Ra treatment, probably limited the statistical capability of our results. In addition the multicentre nature limited the obtaining of some biochemical parameters as AP and LDH.

Regarding the strengths, this is the first documented evidence of ²²³Ra response and prognostic assessment using FCH PET/CT and BS in a prospective and parallel evaluation.

In patients treated with ²²³Ra, interim and end-treatment FCH PET/CT were good predictors of biochemical and clinical progression. Moreover interim FCH PET/CT and BS, joined to therapeutic failure, offered prognostic information.

The obtained results define the potential value of FCH PET/CT, with respect to BS, to monitor ²²³Ra response and guide treatment discontinuation in a safe and effective way.

No disclaimer.

All the authors have participated in the writing and revision of this article and take public responsibility for its content.

The present publication is approved by all authors and by the responsible authorities where the work was carried out.

All the authors confirm the fact that the article is not under consideration for publication elsewhere.

Author’s contribution:

A. Garcia-Vicente: designed and directed the study, obtained the figures and wrote the main manuscript; M. Amo-Salas: performed the statistical analysis and wrote the results; R. Gomez-Diaz and J. Cassinello-Espinosa collected and processed data; Ángel Soriano-Castrejón proposed the hypothesis and designed research. All the authors read and reviewed the manuscript.

Compliance with Ethical Standards:

No funding.

Authors declare that have not conflict of interest.

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent was obtained from all individual participants included in the study.

QUESTION:

Is the ¹⁸F-Fluorocholine PET/CT superior to bone scan (BS) in response evaluation and prognosis of patients with castration-resistant prostate cancer and bone metastases (CRPC-BM) treated with Radium 223 dichloride?

PERTINENT FINDINGS:

In a prospective and multicentre study including 82 patients, interim and end-treatment ¹⁸F-Fluorocholine PET/CT were related to progression free survival. Interim BS and FCH PET/CT showed association with overall survival.

IMPLICATIONS FOR PATIENT CARE:

¹⁸F-Fluorocholine PET/CT results complement biochemical and clinical evaluation of response, guiding the non-effective treatment discontinuation.

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Interim and End-treatment 18F-Fluorocholine PET/CT and Bone Scan in Prostate Cancer Patients Treated with Radium 223 Dichloride

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