Bony metastases are the leading cause of morbidity and mortality from PCa. A continuing challenge for the clinical management of this disease is the lack of imaging tools that can assess response in bone accurately [39
]. This has negatively impacted drug development in this disease [40
]. Although imaging modalities such as BS, CT, and MRI play important diagnostic and staging roles, the complex nature of osseous lesions limit the utility of these imaging technologies for accurately measuring response [41
]. Part of the difficulty in using conventional anatomic imaging (CT and MRI) for assessing tumor volumetric changes as is typically accomplished in nonskeletal tumor sites for treatment response assessment is the fact that the bone undergoes constant remodeling with a strict coordination in the dynamic interaction between osteoclasts and osteoblasts to maintain proper homeostasis. Lesions residing in the bone deregulate this dynamic process and thus can present as osteolytic lesions, osteoblastic lesions, or mixed lesions when visualized by imaging, complicating interpretation and potentially confounding assessment of treatment-specific effects. Thus, current recommendations on the use of these imaging techniques for monitoring treatment response widely differ depending on recommendations established from various studies, hence no consensus has been established for the validity of using BS, CT, or MRI for assessing treatment response in bone cancer patients.
Although the data presented here are limited to one patient with multifocal disease, the results presented clearly establish the feasibility of acquiring and processing fDM data for metastatic bone lesions. The results confirm previous findings, which have reported that bone scintigraphy following treatment can yield false-positive images termed the flare phenomenon
where an apparent increase in radiotracer uptake after treatment occurs [42,43
]. The increased uptake can occur with increased sclerosis of the abnormality; however, whether the increased sclerosis is due to bone healing of a lytic tumor or a potentially blastic component of a tumor cannot be differentiated, thus making its use in early treatment response assessment problematic. In fact, data presented in show that at 8 weeks following treatment, an increased uptake of the radiotracer probe (Tc-99m MDP) was observed. Similar lack of treatment response information was also encountered in the anatomic CT () and MR () scans, where increased density from CT and increased low signal on MRI could represent a positive response to therapy from necrosis and healing. However, a blastic component of a negative response could not be clearly ruled out, thereby resulting in false-positive assessments. Furthermore, radiologic response of tumors outside of the skeletal system is currently quantified in terms of the magnitude of reduction in tumor volume after a specific time interval following conclusion of treatment. As shown in , tumor volumes for each of the lesions evaluated in this patient were not significantly reduced at 2 or 8 weeks post-treatment initiation revealing the lack of prognostic information obtained from this imaging metric. In most solid tumors, volume is proportional to the radiographic observed lesion size. However, this fact is not necessarily the case for bone metastasis following cytotoxic treatment as most radiologists rely on the extent of bone destruction, which is at best an indirect assessment of tumor extent [9
]. The killing of tumor cells located in bony tumors may not result in a detectable loss of tumor size as the lesion volume can be contained within a bone structural deficit and, because bone regrowth does not take place, a decrease in the size of the radiographic lesion does not occur. In fact, this is consistent with the findings in the patient's images shown in and , which do not reveal a reduction in tumor volume over time.
Quantification of the Brownian motion of water molecules within the tumor tissue can be accomplished using MRI by using an image acquisition sequence which makes the MR signal intensity dependent on water mobility [44
]. Clinical translation of diffusion MRI for cancer treatment assessment was initially accomplished in brain tumor patients [13
] with other tumor sites reported in subsequent additional studies [45,46
]. However, the analysis of diffusion data in clinical cancer trials has been hampered by the tremendous heterogeneity of pretreatment diffusion values and therapeutic-induced changes over time. Whereas analysis of mean ADC has proved useful for syngeneic and human xenograft tumor models, the sensitivity of this approach for the detection of treatment-induced changes in tumor diffusion values has been more limited in human trials due to the underlying histologic heterogeneity commonly exhibited in human cancers.
To better illustrate this point in this study, we also compared the mean ADC approach to evaluate the sensitivity of this method for the detection of treatment response in osseous lesions from serial diffusion ADC maps. The fDM approach has been proposed as a means to standardize the analysis of clinical diffusion data that relies on a voxel by voxel comparison of diffusion changes over time. This is accomplished by acquiring a pretreatment ADC map of the tumor and digitally registering the same tumor acquired at an additional time point post-treatment initiation. The fDM analysis provides an opportunity to quantify spatiotemporal alterations in tumor diffusion values in an individual tumor in terms of total change in diffusion values as a function of percent of total tumor volume [16,35–37
]. The feasibility of applying the fDM imaging biomarker to assess treatment response in multifocal metastatic PCa to the bone in the clinical setting was evaluated in this study. MRI data from three lesions arising from the femoral head, sacral, and ilium were analyzed at 2 and 8 weeks post-treatment initiation to evaluate for changes in tumor fDM values. fDM analysis of each of the three lesions revealed that as early as 2 weeks, significant increases in diffusion values were found for each tumor site. The fDM analysis revealed a very interesting finding that an average 24.0% (range 21.1% to 26.4%) of the total analyzed tumor volume had a significant increase in ADC at as early as the 2-week measurement (). At 8 weeks following treatment initiation, fDM analysis of the femoral head, sacral, and ilium lesions revealed an average of 37.5% (range 29% to 47.1%) of the total tumor volume was found to exhibit increased diffusion values over pretreatment baseline measurements. Although PSA levels are not definitive measures of patient outcome, PSA measurements from this patient revealed a decline of 88% and 97% at weeks 2 and 8, respectively. This is a consistent but not definitive proof of an overall positive response [10
]. Although the data presented herein are from only a single patient, the results obtained raise very interesting opportunities for future studies. For example, it is interesting to note that in a patient with multifocal metastatic disease, each of the tumors evaluated was significantly impacted by the treatment as detected by the fDM biomarker readout. This is consistent with current clinical data, which have shown that hormone naive patients have a high (85%) response rate [47
The preliminary data presented in also reveal that the fDM analysis of bone tumors was significantly different from mean ADC analysis (P
= .004 and P
= .006 at 2 and 8 weeks, respectively) and provided for amuchmore sensitive and robust detection of treatment-induced diffusion changes versus
the conventional mean ADC approach. In fact, the lack of significant change in tumor diffusion based on mean ADC values obtained from data at 2 and 8 weeks (P
= .116) would suggest that androgen deprivation therapy had little effect on the femoral head, sacral, and ilium lesions potentially leading to the conclusion that the treatment was ineffective. In stark contrast, the fDM analysis of the same lesions revealed that large changes in tumor diffusion values had in fact occurred and significantly increased over time (P
= .034). Although further clinical data need to be acquired to verify this fact, it appears that fDM measurements from this patient with PCa and with evidence of bone metastases are consistently more sensitive to treatment response than the traditional mean ADC values, as has been reported in the mouse PCa study [16
] and clinical brain tumor studies [35,37
]. Overall, these data show the feasibility of pursuing the use and validation of fDM for assessment of metastatic PCa treatment monitoring as it provides a potential, standardized approach for the analysis of diffusion clinical tumor response data.
Optimally, routine implementation of an imaging biomarker for treatment assessment should not be overly time consuming, cost-prohibitive, or difficult to access or implement in the myriad of clinical settings worldwide. In these regards, acquisition of diffusion MRI data in the clinical setting requires only a few additional minutes of scan time which can be accomplished without the need for contrast. Calculation of diffusion ADC maps is available on commercial scanners and fDM analysis will soon be accomplished using commercially available software (I-Response, Cedara Software, Mississauga, ON, Canada). Moreover, as diffusion MRI measurements are a biophysical measurement of water mobility, diffusion values are considered to be independent of magnet field strength and scanner type. Therefore, implementation of this technology within a multicenter trial would be relatively straightforward, allowing for validation of this approach in a large-scale clinical trial. Finally, the ability to conduct whole-body diffusion MRI interrogation of disseminated skeletal disease will offer a unique opportunity to assess overall tumor response [48–50
]. As shown in this present study, three lesions were followed using fDM over time, thus revealing the overall feasibility of using this imaging biomarker for whole-body response assessment.
Validation of fDM in further studies as a quantitative and early imaging biomarker for assessment of treatment response in patients with metastatic PCa would be a major leap forward for designing clinical trials and for overall patient management. Ultimately, acceptance of the fDM biomarker would require multicenter trials and a consensus to revise the International Union Against Cancer, World Health Organization, and RECIST response criteria to incorporate this imaging biomarker. The successful validation and inclusion of fDM into clinical response criteria could provide for an integrated consensus regarding how to evaluate most accurately the treatment response of osseous lesions.