The discovery of metastatic spread to the skeleton is a management changing diagnosis. The search for this adverse development can now be accomplished with newer tools significantly more accurate than the venerable technetium bone scan — the standard workhorse for this task for several decades.

Up to 90% of men who are not cured of prostate cancer by primary intervention will exhibit skeletal metastases at some time in the course of their disease — and many men unknowingly harbor micrometastatic spread at a very early stage. The explanation of this preferential spread of prostate cancer to bones is not known. There is emerging science that tiny mobile encapsulated vesicles termed exosomes emerge from the primary tumor, sequester in the bony matrix, prepare a metastatic niche and beckon prostate cells to follow. (This is well established in regard to lung cancer spread.) Another possible explanation may be anatomical. The venous plexsus (Batson’s veins) flowing upwards from the pelvis along the spine may give the vertebra first pass opportunity to receive circulating tumor cells.

The technetium bone scan (99mTc-methylene diphosphate [Tc 99m MDP]) has had long-term service. Its accuracy (a derived term combining sensitivity and specificity) is limited. It is a 2-dimenstional study recording osteoblastic repair of the cancer damaged bony matrix.

Simply stated, the currently available total body 18F-Sodium Fluoride PET/CT (18F-NaF PET/CT) is significantly more accurate than the technetium scan.

The uptake of 18F Na in bone, like the Tc 99m MDP, is determined by the relationship between osteoblastic and osteolytic activity, but the 18F NaF is a more highly avid bone-seeking tracer. The 11C-Choline PET/CT and 11C-Acetate PET/CT are also clear advances over the technetium scan and also have the advantage of detection both bone and soft tissue metastases. However, neither is readily available.

Magnetic resonance imaging offers comparable accuracy to the PET/CT in bone studies and may be employed in various types of MRI scanning, i.e. whole body (wbMRI); axial, i.e. spine and pelvis only; or targeted (focal) studies. One sequence, Diffusion Weighted Imaging (DWI) is particularly useful in tumor detection. DWI measures the rate at which water molecules diffuse through tissue and can detect differences in density between cancer and normal tissue at both the primary site and metastases.

MR often serves as the reference comparator for studies assessing the diagnostic efficacy of various scans.
BONE SCANNING continued:

COMPARISON of the Tc99m MDP planer bone scan with studies employing the 18F-NaF PET/CT and MRI:

The first prospective evaluation of diagnostic accuracy of the technetium bone scan (BS), the 18F-NaF PET/CT, and whole body 1.5T MRI scans was reported by Jambor et. al. Acta Oncologica. 2015. The study was small, e.g. 27 men with high-risk prostate cancer, but was carefully conducted, reviewed by 5 experienced radiologists, with clinical and imaging follow-up at 6 – 32 months (NCT01339780).
High-risk PC was defined as > T3a and/or Gleason score 4+3; alkaline phosphatase >105 units, localized pain, or a rapid PSA doubling time after prostatectomy. All patients underwent all scans.

Findings: Among the five interpreters there were differences in opinion in some cases. However, the diagnostic accuracy of the BS ranged from 86 – 90; for the 18F-NaF PET/CT, 97 – 98; and for wbMRI, 96 – 97.

A significant drawback for the BS was the 39% of equivocal lesions. A significant issue for wbMRI is the 50-60 minutes of table time required for imaging and the general unavailability of this extensive study.

In the evaluation of a patient for skeletal metastases is it sufficient to image only the
axial spine?

The pathologic anatomy guiding the spread of malignant cells upward from the gland via the spinal veins allows an affirmative answer to that question.

This issue was directly addressed by Lecouvet and Timbal et al. in “Magnetic Resonance Imaging of the Axial Skeleton for Detecting Bone Metastases in Patients with High-Risk Prostate Cancer: Diagnostic and Cost-Effectiveness and Comparison with Current Detection Strategies,” JCO. 2007.

The study compared the imaging results of 66 men using four modalities: (1) Tc 99m MDP (BS);
(2) BS completed with targeted X-rays (TXR); and (3) MRI obtained on request (MRIor). (4) An axial MRI (MRIas) was done in all patients. The study included 26 newly diagnosed patients with biopsy Gleason score >8 and PSA level > 20 ng/mL, 12 patients with PSA recurrence within 3 years of surgery, and 28 who had recurrence on ADT. The men with recurrence each had a PSA doubling time of 20; T2 and PSA >10; Gleason score >8; stage T3 or T4; or in men who are symptomatic.

Considering its greater accuracy, have the guidelines changed for scanning at initial diagnosis with the 18-F NaF PET/CT?

Guidance in this emerging issue has been provided by Drs. David Crawford and Philip Koo in “18F-NaF PET/CT and 11C-Choline PET/CT for the Initial Detection of Metastatic Disease in Prostate Cancer …” in which they “provide potential utilization strategies based on available data” (ONCOLOGY. Dec 2014). They summarize information to support the superiority of the 18F-NaF PET/CT compared to the bone scanning with Tc 99m MDP. Based on data from Tateishi (Ann Nuc Med. 2010) they cite, “The pooled sensitivity and specificity for 18F-NaF PET and 18F-NaF PET/CT on a patient basis were 96.2% and 98.5%, respectively.”

The resolution of the NaF (and the 11C-Choline PET/CT) is 3 – 5 mm.

Crawford provides the recommendations from the Prostate Cancer Radiographic Assessments for Detection of Advanced Recurrence (RADAR) Working Group for performing the NaF scan in three scenarios (pointing out that the guidelines should not be regarded as limiting):

1) At Initial diagnosis: At least 2 of the following 3 — PSA >10 ng/mL; Gleason score > 7; palpable disease (> stageT2b).

2) At Biochemical-recurrence:

a) If PSA is >2 ng/mL or PSA doubling time < 6 mo or PSA velocity >1 ng/mL/year “Consider 11C-choline PET/CT for the detection of soft-tissue and osseous metastases”.

b) If PSA >5 ng/mL or a doubling of the PSA after a previous scan, “Consider 18F-NaF PET/CT for the detection of osseous metastases.

3) In non-metastatic castration-resistant patients: PSA > 2 ng/mL or a doubling of the PSA after a previous scan.

Bone Scanning continued:

In an interview regarding the RADAR recommendations, Dr. Crawford refers to the data from Yu et al., J Urol. 2012 Jul, that “approximately 33% of men with MO [i.e. non-metastatic] CRPC actually have metastatic disease.” He reiterated that the “Sodium Fluoride (NaF) is more sensitive and has been shown to detect micrometastases up to 12 months sooner than standard bone scans.” This earlier diagnosis of metastases would legitimize using vaccine therapy, e.g. Provenge (now approved only for metastatic disease) and soon, PROSTVAC, earlier in the course of the disease where it has been shown to be more effective.

BOTTOM LINE: The traditional role of Tc 99m MDP bone scintigraphy is being challenged by the greater accuracy of both the 18F-NaF PET/CT and axial MRI in diagnosing skeletal metastases, allowing clinicians to make stage-appropriate management decisions.

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