Evaluation of Bone Metastases by 18F-Choline PET/CT in a Patient with Castration-Resistant Prostate Cancer Treated with Radium-223

Introduction

Bone is the most frequent site of metastatic disease in patients with prostate cancer (PCa). Nearly 90% of men with metastatic castration-resistant PCa (mCRPC) display radiological evidence of bone metastases, which cause significant morbidities, including pain, pathologic fractures, spinal cord compression, and orthopedic surgery, referred to as symptomatic skeletal events (SSEs) (1). In turn, SSEs are associated with poor survival, worse quality of life (QoL), and increased costs (1). Therefore, the sensitive, specific, and accurate detection of bone metastases is of the utmost importance to tailor treatment, monitor disease response, and adjust therapy during the course of mCRPC. In this regard, the use of 18F-choline positron emission tomography (PET)/computed tomography (CT) is emerging as a feasible option for the early detection of bone lesions. PET/CT has been shown to impact on patient management and, compared with conventional bone scans, provide more specific data on the metabolic activity of the disease rather than only on bone remodeling (2–3–4). However, although commonly employed in daily practice, its use has not been tested in clinical trials designed ad hoc, and available data are limited.

Until 2004, prior to approval of docetaxel, the goal of mCRPC treatment was pain relief. Thereafter, the introduction of new agents has yielded a clinical benefit to patients in terms of SSE improvement and survival prolongation. In particular, the pivotal phase III ALSYMPCA trial demonstrated a survival advantage in mCRPC patients with bone metastases randomized to receive radium-223 dichloride, compared with placebo, regardless of previous therapy (5). Also, administration of this radiopharmaceutical was associated with a significantly lower risk of SSE and was able to delay the time to first SSE (6) and improve QoL in a significantly higher percentage of patients, and at a significantly higher extent, than placebo (5, 7). This is a first-in-class α-emitter approved by the Food and Drug Administration (FDA) for the treatment of mCRPC men with symptomatic bone metastases and no known visceral metastases. It is a calcium-mimetic, bone-seeking drug that selectively targets areas of high bone turnover, such as those of bone metastases. The highly energetic radiation kills adjacent tumor cells by inducing DNA double-strand breaks, with a limited damage to the surrounding normal tissues, including bone marrow, because of the very short range (100 μm) of α-particles.

We took advantage of 18F-choline PET/CT to evaluate bone metastases in a man with mCRPC before and after treatment with radium-223.

Case Description

In July 2015, a 74-year-old man was referred to our Nuclear Medicine Unit (Aosta Hospital, Aosta, Italy) with symptomatic bone mCRPC, prostate-specific antigen (PSA) equal to 37 ng/ml, alkaline phosphatase (ALP) of 173 U/l, and plasma testosterone <50 ng/ml.

His clinical history began in 2003 with radical prostatectomy, the histological report confirming the diagnosis of PCa with a Gleason Score of 4 + 3. Six years later, in 2009, the patient experienced disease recurrence with increased PSA levels, a left iliac lymph node metastasis (<3 cm in size), multiple bone metastatic lesions, and no visceral lesions. Up to 2012, he underwent hormonal therapy along with zolendronic acid and radiotherapy on lesions of dorso-lumbar spine D12-L2. In 2013, when the disease became refractory to hormonal treatment, the patient started chemotherapy with docetaxel (60 mg/m²) and prednisone (10 mg/day) for 8 cycles. However, after an initial PSA reduction, bone pain progressed. From October 2013 to June 2015, he received abiraterone (1000 mg/day), but both symptomatic and biochemical progression occurred. Therefore, from July to December 2015, he was switched to radium-223 (50 KBq/kg), which was given for six cycles in association with luteinizing hormone-releasing hormone (LHRH) analogues, every 4 weeks. Currently, the patient is on follow-up, free of progression.

Two weeks before and one month after the treatment with radium-223, bone metastases were visually evaluated through imaging with 18F-choline PET/CT and PSA (37 ng/ml) and ALP (173 U/L) levels were measured. 18F-choline PET/CT imaging before treatment (Figs. 1A, 2A) revealed the presence of multiple bone metastases with a very high tracer uptake; PET/CT imaging repeated 4 weeks after the end of treatment (Figs. 1B, 2B) showed almost absent or only faint tracer uptake, definable as “near complete” metabolic bone lesion response. Moreover, images revealed no pathologic modifications of lymph nodes. Notably, results from the PET/CT imaging post-treatment were accompanied by a 54% reduction of serum PSA levels (17 ng/ml) and a 74% decrease of ALP levels (45 U/l).

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Fig. 1

18F-choline CT (left panel)/PET (right panel) imaging before treatment with radium-223 (A) and after 4-week treatment-off period (B).

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Fig. 2

Maximum intensity projection image before treatment with radium-223 (A) and after 4-week treatment-off period (B).

Discussion

Over the past decade, the development and introduction of several new drugs and treatment strategies into clinical practice has revolutionized oncological therapies. Evidence shows that in men with high-risk PCa, only a patient-tailored program based on a multidisciplinary approach can improve survival (8). To date, the role of the nuclear medicine physician as part of a multidisciplinary team has been restricted to pain relief and, consequently, radionuclide-based therapy for symptomatic bone metastases has been confined and limited to the late phases of the disease (9). After the implementation of radium-223 among the therapeutic options for mCRPC men with bone metastatic disease, nuclear medicine has assumed a key role in the multidisciplinary team for the treatment of these patients. However, the choice of therapy is strictly dependent on the stage of the disease. Bone scan is still considered the standard method of choice and continues to be used in clinical practice, as it has advantages in terms of cost, availability, and execution, even if it has a low diagnostic specificity. In this context, PET/CT has emerged as a useful method in staging of bone metastases in PCa men. In the absence of data from clinical trials, information on the use of PET/CT derived from case reports and case series remain an important alternative. Here, we report the case of a mCRPC male patient with bone metastases who, following radium-223, displayed an improvement of metastatic disease by visual assessment on 18F-choline PET/CT, which was accompanied by a 54% reduction in PSA levels and a 74% reduction in ALP levels, that fell within the normal range. Worth noting, the patient is currently free of progression. These findings are in line with results from the ALSYMPCA trial (5), in which, after 12 weeks of treatment, a significantly higher percentage of patients in the radium-223 arm had a reduction of ≥30% of PSA and ALP levels, and even normalization of the latter. A previous report described the acute changes in skeletal tumor activity by 18F-choline PET/CT 2 days before treatment and at week 13, after the third administration in two patients with mCRPC undergoing radium-223 treatment (10). The first patient, a 63-year-old male diagnosed with Gleason 7 prostate adenocarcinoma, had been heavily pretreated before starting radium-223. At that time, he was receiving morphine to control bone pain. PSA was 2524 ng/ml and ALP 328 U/l. 18F-choline PET/CT showed a heterogeneous tumor response, which was accompanied by an 8% reduction of PSA (2313 ng/ml) and a 43% decrease of ALP (187 U/l). The second patient was a 76-year-old male with Gleason 9 prostate adenocarcinoma. Before therapy with radium-223, he had received different agents. PSA was 25 ng/ml and ALP 160 U/l. When the tumor burden was compared before and after radium-223 by 18F-choline PET/CT, a near-complete disappearance of abnormal skeletal activity was observed, with 88.8% reduction of PSA (down to 2.8 ng/ml) and 69% of ALP (down to 50 U/l, within normal range). However, further studies are needed to address this topic.

Conclusions

This case report shows that, in clinical practice, treatment of mCRPC patients with radium-223 can yield an excellent metabolic response and 18F-choline PET/CT is an alternative novel approach of metabolic evaluation of treatment response, which seems more effective than simple morphological (e.g., RECIST criteria) or biochemical data. These results warrant further investigations in larger patient series.