Does Measurement of First-Order and Heterogeneity Parameters Improve Response Assessment of Bone Metastases in Breast Cancer Compared to SUVmax in [18F]fluoride and [18F]FDG PET?

PURPOSE: To establish whether first-order statistical features from [18F]fluoride and 2-deoxy-2-[18F] fluoro-D-glucose ([18F]FDG) positron emission tomography/x-ray computed tomography (PET/CT) demonstrate incremental value in skeletal metastasis response assessment compared with maximum standardised uptake value (SUVmax). PROCEDURES: Sixteen patients starting endocrine treatment for de novo or progressive breast cancer bone metastases were prospectively recruited to undergo [18F]fluoride and [18F]FDG PET/CT scans before and 8 weeks after treatment. Percentage changes in SUV parameters, metabolic tumour volume (MTV), total lesion metabolism (TLM), standard deviation (SD), entropy, uniformity and absolute changes in kurtosis and skewness, from the same ≤ 5 index lesions, were measured. Clinical response to 24 weeks, assessed by two experienced oncologists blinded to PET/CT imaging findings, was used as a reference standard and associations were made between parameters and progression free and overall survival. RESULTS: [18F]fluoride PET/CT: In four patients (20 lesions) with progressive disease (PD), TLM and kurtosis predicted PD better than SUVmax on a patient basis (4, 4 and 3 out of 4, respectively) and TLM, entropy, uniformity and skewness on a lesion basis (18, 16, 16, 18 and 15 out of 20, respectively). Kurtosis was independently associated with PFS (p = 0.033) and OS (p = 0.008) on Kaplan-Meier analysis. [18F]FDG PET: No parameter provided incremental value over SUVmax in predicting PD or non-PD. TLM was significantly associated with OS (p = 0.041) and skewness with PFS (p = 0.005). Interlesional heterogeneity of response was seen in 11/16 and 8/16 patients on [18F]fluoride and [18F]FDG PET/CT, respectively. CONCLUSION: With [18F]fluoride PET/CT, some first-order features, including those that take into account lesion volume but also some heterogeneity parameters, provide incremental value over SUVmax in predicting clinical response and survival in breast cancer patients with bone metastases treated with endocrine therapy. With [18F]FDG PET/CT, no first-order parameters were more accurate than SUVmax although TLM and skewness were associated with OS and PFS, respectively. Intra-patient heterogeneity of response occurs commonly between metastases with both tracers and most parameters.

Is Response Assessment of Breast Cancer Bone Metastases Better with Measurement of 18F-Fluoride Metabolic Flux Than with Measurement of 18F-Fluoride PET/CT SUV?

Our purpose was to establish whether noninvasive measurement of changes in 18F-fluoride metabolic flux to bone mineral (Ki) by PET/CT can provide incremental value in response assessment of bone metastases in breast cancer compared with SUVmax and SUVmeanMethods: Twelve breast cancer patients starting endocrine treatment for de novo or progressive bone metastases were included. Static 18F-fluoride PET/CT scans were acquired 60 min after injection, before and 8 wk after commencing treatment. Venous blood samples were taken at 55 and 85 min after injection to measure plasma 18F-fluoride activity concentrations, and Ki in individual bone metastases was calculated using a previously validated method. Percentage changes in Ki, SUVmax, and SUVmean were calculated from the same index lesions (≤5 lesions) from each patient. Clinical response up to 24 wk, assessed in consensus by 2 experienced oncologists masked to PET imaging findings, was used as a reference standard. Results: Of the 4 patients with clinically progressive disease (PD), mean Ki significantly increased (>25%) in all, SUVmax in 3, and SUVmean in 2. Of the 8 non-PD patients, Ki decreased or remained stable in 7, SUVmax in 5, and SUVmean in 6. A significant mean percentage increase from baseline for Ki, compared with SUVmax and SUVmean, occurred in the 4 patients with PD (89.7% vs. 41.8% and 43.5%, respectively; P < 0.001). Conclusion: After 8 wk of endocrine treatment for bone-predominant metastatic breast cancer, Ki more reliably differentiated PD from non-PD than did SUVmax and SUVmean, probably because measurement of SUV underestimates fluoride clearance by not considering changes in input function.

Prediction of therapy response in bone-predominant metastatic breast cancer: comparison of [18F] fluorodeoxyglucose and [18F]-fluoride PET/CT with whole-body MRI with diffusion-weighted imaging.

PURPOSE: To compare [18F]-fluorodeoxyglucose (FDG) and [18F]-sodium fluoride (NaF) positron emission tomography/computed tomography (PET/CT) with whole-body magnetic resonance with diffusion-weighted imaging (WB-MRI), for endocrine therapy response prediction at 8 weeks in bone-predominant metastatic breast cancer. PATIENTS AND METHODS: Thirty-one patients scheduled for endocrine therapy had up to five bone metastases measured [FDG, NaF PET/CT: maximum standardized uptake value (SUVmax); WB-MRI: median apparent diffusion coefficient (ADCmed)] at baseline and 8 weeks. To detect the flare phenomenon, a 12-week NaF PET/CT was also performed if 8-week SUVmax increased. A 25% parameter change differentiated imaging progressive disease (PD) from non-PD and was compared to a 24-week clinical reference standard and progression-free survival (PFS). RESULTS: Twenty-two patients (median age, 58.6 years, range, 40-79 years) completing baseline and 8-week imaging were included in the final analysis. Per-patient % change in NaF SUVmax predicted 24-week clinical PD with sensitivity, specificity and accuracy of 60, 73.3, and 70%, respectively. For FDG SUVmax the results were 0, 100, and 76.2% and for ADCmed, 0, 100 and 72.2%, respectively. PFS < 24 weeks was associated with % change in SUVmax (NaF: 41.7 vs. 0.7%, p = 0.039; FDG: - 4.8 vs. - 28.6%, p = 0.005) but not ADCmed (- 0.5 vs. 10.1%, p = 0.098). Interlesional response heterogeneity occurred in all modalities and NaF flare occurred in seven patients. CONCLUSIONS: FDG PET/CT and WB-MRI best predicted clinical non-PD and both FDG and NaF PET/CT predicted PFS < 24 weeks. Lesional response heterogeneity occurs with all modalities and flare is common with NaF PET/CT.

Imaging αvß3 integrin expression in skeletal metastases with 99mTc-maraciclatide single-photon emission computed tomography: detection and therapy response assessment.

PURPOSE: Osteoclast activity is an important factor in the pathogenesis of skeletal metastases and is a potential therapeutic target. This study aimed to determine if selective uptake of 99mTc-maraciclatide, a radiopharmaceutical targeting αvß3 integrin, occurs in prostate cancer (PCa) bone metastases and to observe the changes following systemic therapy. METHODS: The study group comprised 17 men with bone-predominant metastatic PCa who underwent whole-body planar and single-photon emission computed tomography/computed tomography (SPECT/CT) imaging with 99mTc-maraciclatide before (n = 17) and 12 weeks after (n = 11) starting treatment with abiraterone. Tumour to normal bone (T:N) ratios, tumour to muscle (T:M) ratios and CT Hounsfield units (HU) were measured in up to five target metastases in each subject. An oncologist blinded to study scans assessed clinical responses up to 24 weeks using conventional criteria. RESULTS: Before treatment, metastases showed specific 99mTc-maraciclatide accumulation (mean planar T:N and T:M ratios 1.43 and 3.06; SPECT T:N and T:M ratios 3.1 and 5.19, respectively). Baseline sclerotic lesions (389-740 HU) showed lower T:M ratios (4.22 vs. 7.04, p = 0.02) than less sclerotic/lytic lesions (46-381 HU). Patients with progressive disease (PD; n = 5) showed increased planar T:N and T:M ratios (0.29 and 12.1%, respectively) and SPECT T:N and T:M ratios (11.9 and 20.2%, respectively). Patients without progression showed decreased planar T:N and T:M ratios (0.27 and -8.0%, p = 1.0 and 0.044, respectively) and SPECT T:N and T:M ratios (-21.9, and -27.2%, p = 0.3 and 0.036, respectively). The percentage change in CT HU was inversely correlated with the percentage change in SPECT T:M ratios (r = -0.59, p = 0.006). CONCLUSIONS: 99mTc-maraciclatide accumulates in PCa bone metastases in keeping with increased αvß3 integrin expression. Greater activity in metastases with lower CT density suggests that uptake is related to osteoclast activity. Changes in planar and SPECT T:M ratios after 12 weeks of treatment differed between patients with and without PD and 99mTc-maraciclatide imaging may be a potential method for assessing early response.

Multi-technique imaging of bone metastases: spotlight on PET-CT.

There is growing evidence that molecular imaging of bone metastases with positron-emission tomography (PET) can improve diagnosis and treatment response assessment over current conventional standard imaging methods, although cost-effectiveness has not been assessed. In most cancer types, 2-[(18)F]-fluoro-2-deoxy-d-glucose ((18)F-FDG)-PET is an accurate method for detecting bone metastases. For example, in breast cancer, combined (18)F-FDG-PET and computed tomography (CT) is more sensitive at detecting bone metastases than (99m)technetium (Tc)-labelled diphosphonate planar bone scintigraphy (BS) and there is increasing evidence to support the use of serial (18)F-FDG-PET for the assessment of osseous response to treatment. Preliminary data suggest improved diagnostic accuracy of (18)F-FDG-PET-CT in a number of other malignancies including lung, thyroid, head and neck, gastro-oesophageal cancers, and osteosarcoma. As a bone-specific tracer, there is accumulating evidence to support the use of sodium (18)F-fluoride ((18)F-NaF) PET-CT in the diagnosis of skeletal metastases in breast and prostate cancer, although relatively little data are available to support its use for assessment of treatment response. In prostate cancer, (11)C-choline and (18)F-choline PET-CT have better specificities than (18)F-NaF-PET-CT, but equivalent sensitivities in the detection of bone metastases. We review the current literature for staging and response assessment of bone metastases in different cancers.

Imaging Bone Metastases in Breast Cancer: Staging and Response Assessment.

Bone metastases are common in patients with advanced breast cancer. Given the significant associated morbidity, the introduction of new, effective systemic therapies, and the improvement in survival time, early detection and response assessment of skeletal metastases have become even more important. Although planar bone scanning has recognized limitations, in particular, poor specificity in staging and response assessment, it continues to be the main method in current clinical practice for staging of the skeleton in patients at risk of bone metastases. However, the accuracy of bone scanning can be improved with the addition of SPECT/CT. There have been reported improvements in sensitivity and specificity for staging of the skeleton with either bone-specific PET/CT tracers, such as (18)F-NaF, or tumor-specific tracers, such as (18)F-FDG, although these methods are less widely available and more costly. There is a paucity of data on the use of (18)F-NaF PET/CT for response assessment in breast cancer, but there is increasing evidence that (18)F-FDG PET/CT may improve on current methods in this regard. At the same time, interest and experience in using whole-body morphologic MRI augmented with diffusion-weighted imaging for both staging and response assessment in the skeleton have been increasing. However, data on comparisons of these methods with PET methods to determine the best technique for current clinical practice or for clinical trials are insufficient. There are early data supporting the use (18)F-FDG PET/MRI to assess malignant disease in the skeleton, with the possibility of taking advantage of the synergies offered by combining morphologic, physiologic, and metabolic imaging.