Discussion
cancer, tumor, tumors, MY-RADS
BONE DISEASE, DISEASE PROGRESSION, TUMOR, PROSTATE CANCER, CANCER, DISEASE, METASTASES, MYELOMA, TUMORS, METASTATIC CASTRATION-RESISTANT PROSTATE CANCER, BONE METASTASES, DISEASE, DISEASE PROGRESSION
This study provides evidence that DWI is a useful method for assessment of disease response in bone metastases. It also gives new insights into the mechanism of action of radium-223 in men with metastatic castration-resistant prostate cancer, particularly regarding heterogeneity of response, dose response, and patterns of disease progression.Baseline whole-body DWI is prognostic of outcomes in a range of cancer types. The apparent diffusion coefficient is thought to provide a measure of tissue cellularity, and it is plausible that more cellular tumors should have worse outcomes. An increase in the apparent diffusion coefficient of bone and soft tissue lesions has been associated with reduction in tumor cellularity following successful therapy. Increasingly, serial whole-body DWI is being used to assess disease response, particularly in relation to bone metastases (eg, MET-RADS-P for prostate cancer, MY-RADS for myeloma) because it is not possible to image response in bone using conventional imaging with computed tomography or Tc99m phosphonate bone scans. Although it is often assumed that changes on whole-body DWI reflect tumor response, there has been a lack of compelling evidence linking imaging changes over time to other measures of disease response and clinical outcomes. In this study, we have shown that whole-body DWI response is associated with PSA response and overall survival. This finding strengthens the rationale for using whole-body DWI to assess response in bone metastases. Whole-body DWI is set to be a valuable tool in the clinic, particularly in patients with bone-only metastases, to document early response, early progression, and heterogenous response without the need for a confirmatory scan, thus enabling a more accurate tailoring of treatment, such as early stopping of ineffective treatment or potentially combinations of systemic therapy with targeted radiation therapy. It will also be useful in clinical research for providing an early outcome measure without the need for long-term follow-up for more established clinical outcomes.This study is the first to observe the pattern of whole-body DWI response to radium-223 in men with metastatic castration-resistant prostate cancer. We found marked interpatient and intrapatient heterogeneity of response. The ALSYMPCA trial found an overall survival benefit for radium-223, with a median improvement of 4 months, in a relatively unselected population of patients with bony metastatic castration-resistant prostate cancer. It was not clear, however, whether the survival benefit was similar in all patients or whether some patients benefitted much more than others. The current study provides clear evidence that response to treatment with radium-223 varies markedly between patients. Whole-body DWI may therefore be useful in monitoring response during treatment with radium-223 and facilitate early stopping for lack of response. In addition, it will now be possible to test potential prognostic markers with respect to disease response on whole-body DWI. A small study suggested that the level of uptake on baseline fluoride-PET may predict radium-223 response (Disease response to radium-223 varies markedly not just between patients but also between different metastases within the same patient. The reasons for this heterogeneity of response are unclear but will be important to understand to inform patient selection for treatment. It has been suggested in a mouse model of bone metastases that radium-223 is more effective against micrometastases and less effective against larger metastases (We observed an association between the administered activity of radium-223 and disease response on whole-body DWI. Higher administered activity was associated with a greater reduction in apparent diffusion coefficient in bone metastases present on baseline imaging. When using global median apparent diffusion coefficient, however, this association was no longer statistically significant. This apparent discrepancy may be explained, at least in part, by the appearance of new bone metastases during treatment. Thus, although there is a dose response for baseline lesions, patients are less likely to benefit from radium-223 dose escalation because of disease progression at other sites. This finding may explain the lack of benefit seen for radium dose escalation in a large, randomized phase 2 trial (This study has some limitations. The sample size was chosen to analyze disease response on whole-body DWI, and the study was not powered to analyze overall survival in relation to radium-223 dose. New imaging modalities—notably, prostate-specific membrane antigen–PET—have become more widely used since the study was designed. The utility of prostate-specific membrane antigen–PET to assess response to radium-223 is not known. We acknowledge that whole-body DWI use is limited because of lack of MRI availability and radiologist expertise, but the increasing evidence for its multiple benefits, especially in patients with dominant bone disease, coupled with ongoing efforts toward technique standardization (both in acquisition and reporting) and software development for automatic reading are likely to accelerate its development.In summary, whole-body DWI can be used to assess disease response in bone metastases. MRI response to treatment with radium-223 is heterogeneous, both between patients and between different metastases in the same patient. There is evidence for a dose-response relationship for radium-223. Disease progression can occur during treatment, with the development of new bone metastases. Therefore, an unmet need to identify pretreatment predictive markers of response to radium-223 remains.