Page 2 - Metastatic castration-naive and castration-sensitive prostate cancer: CUA/CUOG

So et al

imaging of the chest may also be considered, as lung metas- Continuous ADT is the standard of care for metastatic
7
tases are the most common site of visceral metastases. PC, while intermittent may be considered in select patients.
Novel diagnostic imaging to stage PC, including choline- Androgen receptor signaling plays a key role in the pro-
based positron emission tomography (PET)/CT, fluciclovine gression of PC and, thus, de novo mCNPC remains highly
PET/CT, and prostate-specific membrane antigen (PSMA)- driven by testosterone. Hence, the primary step in the man-
targeted PET/CT, appear to improve the sensitivity and agement of mCNPC, which remains the backbone of treat-
specificity of conventional imaging; however, these tests ment for all men with metastatic PC until death, is ADT.
are not universally available Canada, their clinical utility ADT can be achieved by surgical castration (orchiectomy)
is not clear, and they are still considered investigational by or pharmacologically with agents that inhibit Leydig cell
Health Canada. Most importantly, all of the phase 3 trials production of testosterone (gonadotropin-releasing hor-
in mCNPC/mCSPC used conventional imaging for staging mone [GnRH] agonists or GnRH antagonists). The optimal
and risk determination, and conclusion were based on these. timing of androgen deprivation has been the subject of many
Novel imaging remains investigational. trials, with two large, recent systematic reviews suggest-
ing early treatment is associated with improved overall and
Assessment of prognosis cancer-specific survival and decreases the rate of skeletal
events compared to deferred treatment. 11,12 More impor-
Patients diagnosed with metastatic PC should be classified tantly, the early treatment of mCNPC with ADT is required
as high-volume/high-risk or low-volume/low-risk based on if other systemic treatments, such as docetaxel or androgen
conventional imaging and prostate cancer biopsy for prog- receptor-axis inhibitors, are used.
nostication (Level of evidence 2, Weak recommendation). ADT is associated with increased side effects and may
increase the risk of cardiovascular events. Intermittent andro-
Using data from two large mCNPC/mCSPC trials, gen suppression (IAS) that cycles ADT based on PSA values
SWOG8894 and GETUG15, possible prognostic features has been shown to improve quality of life; however, con-
suggestive of worse prognosis have been identified and tinuous ADT should be used in mCNPC and IAS only used
include: appendicular disease (defined as bone lesions in as an exception in select patients with close followup. 13,14
the chest, skull, and/or extremities), worse performance sta- As well, combined treatment of mCNPC with any systemic
tus, PSA >65, Gleason score ≥8, high alkaline phosphatase therapy requires continuous ADT.
(ALP), high pain intensity, anemia, and elevated lactate
4,5
dehydrogenase (LDH). Data from SWOG8894 suggests Local therapy: Treatment of the primary cancer in mCNPC
that appendicular disease is the strongest predictor prog-
nosis, whereas GETUG15 suggested, based on univariate Patients with low-volume metastatic disease burden should
analysis, that ALP is the strongest predictor of prognosis. be considered for external beam radiation to the prostate
4,5
Recent clinical trials of mCNPC/mCSPC patients have used (Level of evidence 2, Strong recommendation).
different pragmatic prognostic factors to stratify prognosis. The
CHAARTED trial classified PC based on volume of disease. Treatment of the primary PC has theoretical benefits,
“High-volume” was defined by the presence of visceral metas- including reducing local side effects that may occur due to
tases or ≥4 bone lesions with ≥1 beyond the vertebral bodies disease progression during mCRPC, as well as removing the
and pelvis, and “low-volume” was defined as all other mCNPC/ cancer that could be source of cytokines and growth factors
8
mCSPC. The LATITUDE trial classified “high-risk” patients that may induce disease progression.
based on three different criteria: visceral metastases, ≥3 bony Two recent, randomized trials assessed the impact of
metastases, or Gleason score ≥8; high-risk was defined as hav- external beam radiation therapy (EBRT) in mCNPC. The
ing two or more of these criteria, whereas low-risk was defined HORRAD trial randomized 432 men with mCNPC and PSA
9
having less than two. A comparative study of the classification >20 ng/mL to receive EBRT of the prostate with ADT or ADT
of each of these trials showed an overall discordance of 18.2% alone. The initial prescribed dose was 70 Gy in 35 fractions
between the CHAARTED and LATITUDE criterion; however, it of 2 Gy, during an overall treatment time of seven weeks.
appears that disease burden (defined radiologically or by PSA) During the study period, an optional schedule was added
and high-grade tumors portend a worse prognosis. that was considered biologically equivalent and consisted of
10
a dose schedule of 57.76 Gy in 19 fractions of 3.04 Gy three
ADT times a week for six weeks. The median PSA was 142 ng/ml
and 67% of patients had more than five bone metastases. No
ADT should be started on men newly diagnosed with meta- significant difference was found in OS (hazard ratio [HR],
static PC (Level of evidence 1, Strong recommendation). 0.90; 95% confidence interval [CI] 0.70–1.14; p=0.4), but
there was a benefit to median time to PSA progression in the

18 CUAJ • February 2020 • Volume 14, Issue 2