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 .
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, . 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 .
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 .
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 .
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 .
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 , 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  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  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  and abiraterone .
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.