Imaging Response During Therapy with Radium-223 For Castration-Resistant Prostate Cancer With Bone Metastases—Analysis Of An International Multicenter Database

BACKGROUND: The imaging response to radium-223 therapy is at present poorly described. We aimed to describe the imaging response to radium-223 treatment.

METHODS: We retrospectively evaluated the computed tomography (CT) and bone scintigraphy response of metastatic castration-resistant prostate cancer (CRPC) patients treated with radium-223, in eight centers in three countries.

RESULTS: A total of 130 patients were included, the majority (n = 84, 65%) received radium-223 post docetaxel. Thirty-four of 99 patients with available data (34%) received concomitant abiraterone or enzalutamide. A total of 54% (n = 70) patients completed the planned six injections of radium-223. In patients with available data, a transient increase in bone metastases-related pain was observed in 27% (n = 33/124) and an improvement of bone metastases-related pain on treatment with radium-223 was noted in 49% of patients (n = 61/124). At 3 and 6 months of treatment with radium-223, bone imaging showed stable disease in 74% (n = 84/113) and 94% of patients (n = 93/99) with available data, respectively. An increase in the number of bone lesions was documented at 3 months compared with baseline in 26% (n = 29/113) and at 6 months compared with 3 months in 6% of patients (n = 6/99), respectively. Radiological extraskeletal disease progression occurred in 46% of patients (n = 57/124) with available CT data at 3 and/or 6 months.

CONCLUSIONS: Progression of bone metastases during radium-223 therapy is uncommon. A bone flare (pain and/or radiological) may be noted during the first 3 months, and should not be confused with progression. Imaging by CT scan should be considered after three and six doses of radium-223 to rule out extraskeletal disease progression.

INTRODUCTION
Prostate cancer is the second leading cause of cancer-related death among men in the western world1 and 90% of patients with metastatic castration-resistant prostate cancer (mCRPC) have bone metastases.2 Bone metastases are associated with skeletal-related events such as pain, fractures and spinal cord compression.3

Radium-223 is an alpha-emitting radioisotope with calcium-mimetic properties, which therefore accumulates in bone areas with an increased turnover. Radium-223 targets bone metastases, and improves overall survival in patients with bone metastases,4 but is not indicated in mCRPC patients with visceral or bulky lymph node disease. Improved overall survival was observed in the pivotal phase 3 ALSYMPCA trial.4,5 The ALSYMPCA study did not mandate baseline staging or regular monitoring of antitumor activity by imaging.4 Thus, the use of radiological examinations, and how to interpret response to therapy, in patients receiving radium-223 is at present poorly defined.6,7 Furthermore, in the ALSYMPCA trial, a ⩾ 30% decline of the tumor marker PSA was reported in only 16% of patients.4 In daily practice, management of  a  patient  receiving  radium-223  can be challenging in the absence of a PSA decline and due to uncertain imaging response data. Extraskeletal imaging may be important in patients with CRPC, since up to 50% will develop visceral metastases, that are not targeted by radium-223.8 The present study aimed to assess the radiological response in patients with mCRPC and bone metastases during radium-223 treatment. 

MATERIALS  AND METHODS
Study group

We reviewed the records of patients (unselected cohort, international multicenter database) with CRPC and bone metastases, and without visceral or bulky lymph node metastases, who were treated with radium- 223, in eight centers across three different countries: Switzerland (Kantonsspital St Gallen, Kantonsspital Chur), Denmark (Copenhagen University Hospital, Rigshospitalet) and Israel (Institutes of Oncology at Meir Medical Center, Kfar Saba; Rambam Medical Center, Haifa; Soroka Medical Center, Beer-Sheva; Rabin Medical Center, Petah Tikva; Tel Aviv Sourasky Medical Center, Tel Aviv). Patient data were retrospectively collected from electronic medical records and paper charts, including prior and ongoing therapies, baseline and ongoing clinical and biochemical variables, and imaging studies (reviewed locally by the treating physician and radiologist).

Radium-223 therapy
All patients had documented disease progression before the initiation of radium-223 therapy. The patients were maintained on androgen deprivation therapy. Radium-223 therapy was given intravenously every 4 weeks, at a dose of 50 kBq kg−1 for up to six cycles. Treatment was applied as per local standard guidelines. Early treatment discontinuation ( <6 cycles of radium-223) occurred in patients with disease progression, unacceptable adverse events or death. Patient follow-up generally consisted of regular assessment of pain, opiate dose, physical examinations and laboratory assessments including hematologic, alkaline phosphatase (ALP) and PSA, at every cycle, and imaging studies (Tc-99m MDP bone scintigraphy and CT) at baseline and after 3 and 6 cycles of radium-223.

Statistical analysis, descriptive definitions and treatment outcomes
Descriptive statistics were used to present baseline and on treatment clinical parameters. Continuous variables were summarized with median and range, whereas counts and percentages were used to summarize categorical variables. When needed, Fisher’s exact test was used to compare frequency and percentages. For pain evaluation, we used a simple numeric pain score (each patient was scored in the range 0–4). Pain flare during radium-223 treatment was defined as a transient increase of bone metastases-related pain, as judged by the investigators, after the first administration of radium-223 treatment. A clinical improvement during radium-223 therapy was defined as an improvement of pain with a reduction in the pain score by at least one number.

Imaging response (bone scintigraphy and/or CT scan) during radium-223 therapy was reported as per PCWG2 recommendations.9 Radiological extraskeletal progression was defined as progression in soft tissue (lymph nodes and/or visceral and/or local prostatic) or spinal cord compression. For the purpose of the present study, stable bone metastatic disease on subsequent scans, was defined as absence of at least two new lesions, or at least two new lesions that were not confirmed on follow-up imaging.

A radiological bone metastases flare during radium-223 treatment was defined as new bone lesions at the initial post-treatment assessment (after three cycles of radium-223) in an otherwise stable patient who is not progressing in an extraskeletal site (for example, soft tissue disease), and without confirmation of progression (⩽2 new lesions after six cycles) as per PCWG2.9 For the evaluation of CT scan response, the Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1 was applied.10 The response was assessed by local radiologists, nuclear medicine physicians and treating physicians.

RESULTS
Patient characteristics

Between March 2013 and August 2015, 130 patients (median age 72) with CRPC and bone metastases, were treated with radium-223. The distribution of baseline patient characteristics is shown in Table 1. The majority of patients, 84 of 130 (65%) were treated with radium-223 post docetaxel chemotherapy. Among 99 patients   with   available   data,   34%   (n = 34)   were treated concomitantly with a novel endocrine agent (enzalutamide or abiraterone). In 91% (n = 31) of these patients, the novel endocrine agent was initiated at the same time as radium-223, whereas in 9% (n = 3) it was initiated sequentially (after the initiation of radium-223 therapy), and the majority of these patients (76%, n = 26) were post docetaxel chemotherapy. A total of 105 patients (81%) were treated concomitantly with a bone-targeted agent (zoledronic acid n = 8, 6%; denosumab n = 97, 75%).



Radium-223 treatment—clinical outcomes
The median number of radium-223 doses given was 6 (range 1–6) and 70 of 130 patients (54%) completed the planned six radium-223 injections. The reasons for early radium-223 treatment discontinuation are displayed in Table 2. Among patients with bone marrow toxicity as a reason for early radium-223 treatment discontinuation (n = 14), 43% (n = 6) had prolonged pancytopenia that was assumed to be related to cancer progression in the bone marrow, while 57% (n = 8) had prolonged cytopenia assumed to be related to radium-223 therapy (leukopenia n = 2, thrombocy- topenia n = 4, leukopenia and thrombocytopenia n = 2).

A transient increase in bone metastases-related pain as judged by the investigators (pain flare) occurred in 27% (33 of 124 patients with available data). In patients with information on concomitant novel endocrine agent therapy (abiraterone or enzalutamide), a pain flare was noted in 26% (n = 9) of patients treated with a concomitant novel endocrine agent versus 40% (n = 26) of patients treated only with radium-223. In the course of treatment with radium-223, a clinical improvement of bone metastases-related pain was documented in 61 of 124 patients (49%). Among these patients, 13% (n = 8/61) had an increase of opiates dose during therapy, while 26% (n = 16) had a decrease of dose. Concurrent palliative radiation was given to 5% of these patients (n = 3). With a median follow-up time of 29 months, 48% of the patients (n = 63) died by December 2016. Median overall survival was 20 months.



Radium-223 treatment—biochemical outcomes
Increase in PSA occurred in 80% (n = 101 of 127 patients with available data) during radium-223 treatment, whereas 20%    (n = 26) had a decline in PSA (14%, n = 18, had a PSA decline⩾ 30%; Table 2, Figures 1 and 2). Decrease of ALP ⩾ 30% during radium-223 therapy versus the baseline level occurred in 44% (n = 56 of 126 patients with available data). Among patients with baseline elevated ALP, decrease of level ⩾ 30% during radium-223 therapy was seen in 50% (n = 41/82).


Figure 1. PSA waterfall plot for PSA decline from baseline.



Figure 2. Alkaline phosphatase waterfall plot for alkaline phosphatase decline from baseline.

Radium-223 treatment—radiological outcomes
At 3 months, a stable disease was noted in 74% (n = 84 of 113 patients with bone imaging data available at baseline and at   3 months), whereas an increase in number of bone lesions was documented in 26% (n = 29). At 6 months, 94% (n = 93 of 99 patients with bone imaging data available at six months) had a stable disease, while a progression with ⩾ 2 new lesions versus the three months status was noted in 6% (n = 6; Table 2). Radiological disease progression on CT scans during radium-223 therapy was documented in 57 of 124 patients (46%) with available imaging data at baseline and at 3 months and/or at 6 months. Among these patients, the median radiological progression-free survival was 4.8 months.

Progression was documented in the following extraskeletal sites: lymph nodes (n = 27), liver (n = 19), lung (n = 10), spinal cord compression (n = 17), adrenal (n = 3), brain (n = 1) and locally (prostate) (n = 1). In 60% (n = 34/57) of patients with radiological disease progression on CT scans during radium-223 therapy, progression was seen in new areas (versus pre-treatment radiological status). Progression of multiple extraskeletal sites was noted in 14 patients. In patients with both radiological data and information on concomitant novel endocrine agent therapy (abiraterone or enzalutamide) available, progression of extraskeletal sites was noted in 32% (n = 8/25) of patients treated with concomitant novel endocrine agent therapy, versus 46% (n = 30-/65) of patients on radium-223 monotherapy (P = 0.245). Among patients with available data, progression of extraskeletal sites was noted in 37% (n = 17/46) of patients treated with radium-223 pre-docetaxel chemotherapy compared with 47% (n = 36/77) of patients who received radium-223 post docetaxel chemotherapy. Fifty percent (n = 32 of 64 with available data) of patients treated with radium-223 post a prior novel endocrine agent (abiraterone or enzalutamide), had extraskeletal radiological progression during radium-223 therapy.

DISCUSSION

Although radium-223 is the first bone-targeting agent that has shown a survival benefit in CRPC patients with bone metastases, the radiological response during radium-223 therapy is at present poorly defined.4 The present study found that in mCRPC patients treated with radium-223, development of new bone metastases, as defined by PCWG2, is uncommon (6%), while extraskeletal radiological progression (for example, soft tissue) was noted in almost half of the patients. Furthermore, similar to other therapies for metastatic prostate cancer, a flare phenomenon with increase of bone metastases-related pain, or increase in apparent number of bone metastases on imaging studies, may be noted during the first three treatment cycles, and should not be interpreted as disease progression. This information is important for counseling patients before treatment with radium-223.

Radiological extraskeletal disease progression (for example, soft tissue) was noted in 32% of patients on concomitant novel endocrine agents compared with 46% of patients on radium-223 monotherapy, and in 37% of patients treated pre-docetaxel compared with 47% of patients treated post docetaxel chemotherapy. A recent publication reported increasing frequencies of visceral metastases in CRPC patients of up to 50%, and radium-223 therapy  alone  is  unlikely  to  control  the visceral disease.8 Another publication from the global expanded access program on radium-223, with data on concomitant administration of radium-223 and abiraterone or enzalutamide, reported a longer median overall survival in patients on the combination therapy compared with radium-223 monotherapy.11

Our study has limitations. First, this is a multicenter retrospective study, which may be associated with various biases. Second, because of missing patient data (for example, biochemical and radiological), at present our conclusions remain descriptive. Another limitation is the absence of standardized guidelines for performing bone scintigraphy and CT scan and lack of subsequent central radiological review. Third, assessment of bone pain was not done in a standardized way. Nonetheless, the present study reflects a typical population of advanced CRPC patients. The baseline patient and the treatment characteristics of the present study are similar to previous data, for example, the pivotal ALSYMPCA trial4 and the international and United States early access trial.11,12 The radiological response reported in the present study is similar to that previously reported in a smaller retro- spective study where 34% of patients had extraskeletal radi- ological progression.6 Fourth, radiological bone flare as defined in the present study may reflect slow disease progression, and thus further follow-up is needed. Fifth, some of the patients with a clinical improvement during radium-223 therapy, had an increase of the opiate dose or palliative radiation during therapy, which can mask pain, and limit the benefit evaluation of radium-223 therapy.

Moreover, among the patients that were treated concomitantly with a novel endocrine agent, this was initiated in the majority at the same time as radium-223, while in some it was initiated sequentially (after the initiation of radium-223 therapy). This heterogeneity may have an impact on interpretation of results. Furthermore, the number of patients with extraskeletal disease progression is relatively small, and thus the results must be interpreted with caution. Also, owing to lack of radiological data in some patients, the low incidence (6%) of radiological bone flare described in the present study must be interpreted with caution. Finally, per the PCWG2 imaging criteria, there are no criteria for response of bone metastases, but only criteria for disease progression, as evident by the emergence of new lesions. Also, these criteria cannot be used in patients with diffuse metastatic bone disease or malignant superscan. Furthermore, the diagnostic accuracy of bone scan may be low (62–80%) compared with other imaging methods,12,13 and patients may progress without new lesions visible on a bone scan.14 Thus, while the present study found that in mCRPC patients treated with radium-223, progression of bone metastases is uncommon, and while data suggests that radiological progression-free survival may be associated with overall survival,15 the imaging assessment of bone metastases based on PCWG criteria is hindered by the reduced sensitivity of bone scan in diagnosing disease progression in the absence of new lesions, and by the lack of criteria for stable disease or response to therapy in bone metastases, especially in patients with bone metastases-only disease.

Despite the limitations, our clinical observation that a significant number of patients may have extraskeletal (for example, soft tissue) disease progression on radium-223, should prompt clinicians to consider radiologic evaluation of patients with a CT scan during (for example, at 3 months) and after (at 6 months) radium-223 therapy.

Spinal cord compression was reported in the ALSYMPCA trial in 4% and in our series in 14% of patients, reflecting the advanced state of disease where patients received radium-223. In patients with extensive bone metastases of the spine, a magnetic resonance imaging (MRI) of the entire spine may be considered and in case of detection of significant epidural soft tissue disease prophylactic radiation therapy may be applied before or while patients undergo treatment with radium-223. If no MRI is readily available, the recently published CT-based radiological signs that precede spinal cord compression can be analyzed and if positive, MRI evaluation should be performed.16 The practical implications of bone scintigraphy during radium-223 therapy is unclear, as new lesions at 3 months may represent bone flare, and in the present study only 6% of patients had additional new bone lesions at 6 months. However, by repeating a bone scintigraphy during radium-223 therapy, one might consider flare versus progression and the associated implications for the next line of therapy. If at least two additional lesions were found after three cycles of radium-223 therapy, and these were stable after six cycles, it would be considered as stable disease, for which a patient may not require immediate additional therapy.

Whether early radium-223 treatment before docetaxel chemotherapy, and concurrent therapy with a novel endocrine agent (abiraterone or enzalutamide) are associated with a decrease in the risk of radiological extraskeletal disease progression will be tested and confirmed in ongoing large randomized phase III trials, namely ERA-223 (NCT02043678, abiraterone plus/minus radium-223) or PEACE III (NCT02194842, enzalutamide plus/minus radium- 223). Both these trials test radium-223 in the early CRPC setting where bone metastases are the predominant site of disease and both trials do not include a radium-223 monotherapy arm. Our data add evidence to the data suggesting that radium-223 can be safely combined with abiraterone or enzalutamide, and that this combination may positively impact outcome compared with treatment with radium-223 monotherapy. However, the prospective phase III clinical data have to be awaited.11

In conclusion, in this retrospective analysis evaluating imaging data of CRPC patients treated with radium-223, absence of progression in the bone was noted in a high percentage of patients. However, imaging with a CT scan at baseline and after three and six applications of radium-223 should be considered to rule out extraskeletal disease progression. Patients should be advised about possibility of a bone metastases-related pain and radiologic flare during the first radium-223 doses.

CONFLICT OF INTEREST

DK is a member of the advisory boards and speaker for Astellas, Bayer, BMS, Janssen, MSD, Novartis, Pfizer, Sanofi, Teva. AO is a member of the advisory boards (compensated, institutional) for Bayer, Astellas, Janssen, Sanofi, Pfizer. Travel support was provided by Bayer, Astellas, Janssen, Sanofi. Research support was provided by Janssen, Teva. J Mortensen is a member of the advisory board (without honorarium) in Bayer. SG is an advisor for Active Biotech, Astellas, Bayer, Bristol-Myers Squibb, Curevac, Dendreon, Ferring, Janssen Cilag, Janssen Diagnostics MaxiVAX, Millennium, Novartis, Orion Pharma, Pfizer, Sanofi Aventis, ProteoMediX, ESSA Pharmaceuticals Corp, Nectar. Speakers Bureau comprises Amgen, Astellas, Bayer, Janssen Cilag, Novartis, Sanofi Aventis. Patent application for a method for biomarker WO 2009138392 A1 is pending. RC is a member of the advisory board for Astellas, Bayer, Janssen, Sanofi. GD has an advisory board role in Bayer, Janssen Cilag, Pfizer, Sanofi Aventis. PMP has an advisory board role in Bayer. The remaining authors declare no conflict of interest.


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Prostate Cancer and Prostatic Diseases (2017) 00, 1– 5

© 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved 1365-7852/17

Written By:
D Keizman 1,11, MO Fosboel 2,11, H Reichegger 3,4, A Peer 5, E Rosenbaum 6, M-C Desax 3,4, V Neiman 6, PM Petersen 7, J Mueller 3,4, R Cathomas 8, M Gottfried 1, H Dresler 1, D Sarid 9, W Mermershtain 10, K Rouvinov 10, J Mortensen 2, S Gillessen 3,4, G Daugaard 7,12 and A Omlin 3,4,12

1 Genitourinary Oncology Service, Institute of Oncology, Meir Medical Center, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel; 2 Department of Clinical Physiology, Nuclear Medicine and PET, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark;
3 Department of Oncology and Haematology, Kantonsspital St Gallen, St Gallen, Switzerland;
4 Department of Radiology and Nuclear Medicine, Kantonsspital St Gallen, St Gallen, Switzerland;
5 Department of Oncology, Rambam Medical Center, Haifa, Israel;
6 Department of Oncology, Rabin Medical Center, Petah Tikva, Israel;
7 Department of Oncology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark;
8 Department of Oncology, Kantonsspital Chur, Chur, Switzerland;
9 Department of Oncology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel and
10 Department of Oncology, Soroka Medical Center, Beer-Sheva, Israel. Correspondence: Dr D Kejzman, Genitourinary Oncology Service, Institute of Oncology, Meir Medical Center, Sackler School of Medicine, Tel Aviv University, Tshernichovsky 59, Kfar Saba 44281, Israel.
11 These two authors contributed equally to this work.
12 These two authors contributed equally to this work.

Read More: A Commentary from the Associate Editor of PCAN

Part of the data was presented (poster) at the annual meeting of the American Society of Clinical Oncology (ASCO), Chicago, June 2016, and published in abstract form (J Clin Oncol 34, 2016, suppl; abstr 5057).

Received 21 September 2016; revised 12 December 2016; accepted 20 December 2016

Prostate Cancer and Prostatic Diseases advance online publication, 28 February 2017; doi:10.1038/pcan.2017.6

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