Management of Locally Advanced (Nonmetastatic) Prostate Cancer

Definitions

Currently, there is no universally agreed definition of what is known as “locally advanced” prostate cancer. In 1999, Oh and Kantoff defined locally advanced prostate cancer as a clinical diagnosis whereby the tumor has extended beyond the capsule with no evidence of nodal or distant metastatic spread. Since then there have been a number of variations in the definition for locally advanced prostate cancer by a number of different oncological and urological societies. The following listed are some of the commonly used definitions of locally advanced prostate cancer and this highlights the discrepancies:

• 1.

  NCCN guidelines: Those with clinical stage T3b to T4 (locally advanced);

• 2.

  EAU guidelines: All T3–4, Nx–N0, M0 disease;

• 3.

  AJCC guideline: Stage III disease – T3a-b, N0, M0 with any PSA and any Gleason score.

It is clear that the aggressiveness of the disease is not just based upon the clinical staging; this has been demonstrated by a number of well validated scoring or stratification systems, for example, the UCSF-CAPRA score ( Tables 51.1 and 51.2 ) and D’Amico risk stratification ( Table 51.3 ). These confirm that the Gleason grade and the PSA are also important indicators, can aid in predicting the natural history of the disease, and can be used to guide management decision-making. Therefore, these scoring systems may offer a more suitable alternative in the risk stratification of locally advanced prostate cancer.

Other than the definition variations causing confusion, the standard of clinical staging methods are also unreliable. Digital rectal examination often underestimates tumor extension, with only a positive correlation of less than 50% as demonstrated by Spigelman et al. in 1986. Using transrectal ultrasound also appears to be unreliable as it only reveals 60% of pT3 lesions as shown in the Enlund et al. study in 1990. Therefore, these diagnosing methods can wrongly stage the prostate cancer and influence treatment recommendations in a negative fashion.

MRI for Extracapsular Staging

MRI is frequently used for radiological staging of prostate cancer. Conventional anatomical MRI technique using T1 and T2 weighted sequences has a sensitivity of 13–95% and specificity of 49–97% for extracapsular extension prostate cancer, whereas, a sensitivity of 23–80% and 81–99% specificity for the seminal vesicles invasion disease. The result of MRI for staging appears to be variable within the literature. It appears to be dependent on a number of factors such as the technique used, the experience of the radiologist, the strength of the MRI magnet, use of endorectal coil, and whether the extracapsular disease is focal or extensive. The recent development of multiparametric prostatic MRI employs a combination of the T2 weighted sequence, diffusion weighted images, as well as dynamic contrast-enhanced imaging, and shows promise in improving local staging accuracy and eliminating a degree of the interobserver variability with the development of a standardized reporting system: Prostate Imaging – Reporting and Data System (PI-RADS) ( Figure 51.1 ).

MRI/CT for Nodal Staging

The conventional radiological threshold of diagnosing lymph node metastasis is using size criteria >1 cm. A meta-analysis by Hövels et al. suggested that its sensitivity is around 30%, this is because 70% of the lymph node metastasis are too small (<8 mm) to be evaluated by MRI. A more recent development is that of lymphotropic nanoparticle-enhanced MRI, which utilizes a contrast agent containing ultrasmall superparamagnetic particles of iron oxide. This is transported by macrophages into healthy lymph nodes but not within areas of malignancy, which contain few macrophages. Particularly when combined with diffusion-weighted imaging this allows differentiation of normal-sized but malignant lymph nodes with a sensitivity of at least 65–75% and specificity over 90%.

Bone Scan

Tc 99m bone scan is widely used for the assessment of bony metastatic disease. The rate of positivity depends upon multiple factors, including PSA level, clinical staging, and Gleason grades. This was well documented in a meta-analysis performed by Abuzallouf et al. in which the bone scan positive rate was 2.3%, 5.3%, 16.2%, 39.2%, and 73.4% for PSA 0–9.9, 10–19.9, 20–49.9, 50–99.9, and >100 ng/mL, respectively. It is also related to clinical staging; a number of studies suggest that the bone scan positivity rate ranges from 1.3% to 13.6% in localized disease versus 19% to 90.7% in patients with locally advanced disease. The Gleason score also influences the bone scan positivity rate; for Gleason score ≤7 the bone scan positivity rate is between 4.9% and 5.8%, whereas with Gleason score ≥8 the bone scan positivity rate is between 23.5% and 29.6%.

PET Scan

Traditionally, FDG PET scanning has not formed a component of the prostate cancer staging algorithm due to its lack of sensitivity; however, there is increasing experience in the use of non-FDG PET scanning for staging of prostate cancer. A meta-analysis by Mohsen et al. in 2013 reviewed the use of ¹¹ C-acetate PET imaging. This demonstrated a pooled sensitivity of 73% and specificity of 79% for lymph node staging and there is a suggestion by Haseebuddin et al. that ¹¹ C-acetate PET/CT may detect lymph node metastases that are not picked up by conventional staging methods. More recently, prostate-specific membrane antigen (68 Ga-PSMA) has been investigated as a ligand for PET/CT. PSMA appears to be overexpressed in prostate cancer and is also directly related to metastasis and disease progression. Therefore, this newer ligand could be a superior substrate for PET/CT scanning compared to other PET scanning techniques for prostate cancer ( Figure 51.2 ).