Ed Weber, M.D., Editor
March – April, 2015
Oligometastatic prostate cancer is a relatively new term referring to the detection of a limited number of metastatic sites developing at PSA relapse after primary treatment. The concept emerged in the mid 1990s from observations that there were some patients with just few sties of metastases with slowly progressive disease who experienced very favorable long-term outcomes with local therapy to these few sites. Observations of this sort spawned the hypothesis that there may exist an intermediate stage of cancer between primary disease and widespread metastases that could be treated successfully with limited therapy, avoiding long-term androgen suppression (Ost P,European Urology. Sept 2014).
The proper definition of this term is not rigid, but usually is restricted to 2- 3 or at most up to 5 lesions in lymph nodes — regional or more distant, or in bones.
The fulfillment of the definition requires an accurate global assessment, i.e total body imaging, in a search to identify all locations of metastases. The recent development of whole body imaging with 11C-choline and the 11C-acetate PET/CTs facilitates a better, but not perfect, documentation of the global tumor burden.
The 11C-choline PET/CT:
The currently available scans, e.g. the 11C-choline PET/CT at the Mayo Clinic, and 11C-acetate PET/CT at the Mayo Clinic, Scottsdale, Ariz, both detect the metabolic activity in cancer deposits based on the incorporation of the amino acid choline into the cell walls of proliferating tumors. Unfortunately, radioactive choline has a limited half-life of about 17 minutes and a nearby cyclotron is required.
The specificity of these scans is high. An 11C positive focus is most times cancer. But scan specificity is sub-optimal. The low sensitivity is likely related to low incorporation of choline into more slowly proliferating cancer foci. Also, successful imaging requires a sufficient volume of cancer.
Dr. Piet Ost, Ghent University, a specialist in this area (interviewed in Prostate Forum. Vol 16, Number 7), commented regarding the low specificity, “…when you see one focal positive spot, there is a very high likelihood that there is more than one positive spot in that patient — most often micrometastatic and undetectable with Choline PET-CT.” None the less, the 11C-choline PET/CT scan (arguably joined by the C11-acetate scan) is the most accurate study to date for diagnosing cancer beyond the prostate gland. (A mpMRI is the best study for detecting local recurrence within the prostate.)
Extensive research has focused on proper patient selection for these scans. The factors that need consideration are the patient’s PSA level, Gleason score, PSA density, rate of rise of the PSA, and time interval from primary therapy to PSA rise. Taken together they dictate the likelihood of a positive scan.
Regarding oligometastatic disease at PSA relapse, the goal is to find limited disease amenable to focal treatment. In this pursuit the optimal parameters are a PSA level between 1 -2 ng/ml and a PSA doubling time of more than 6 months. At PSA levels of <1.0 the detection rate is 10-20%. 11C-choline scanning in patients with higher PSA values and parameters suggestive of more aggressive disease results in detecting an increasing number of lesions, i.e in patients with a PSA doubling time <3 months, PSA density >.15 ng/cc, and high Gleason scores. Scanning men with these characteristics is more appropriate for patients initially presenting with high-risk cancer. In these instances a documentation of disease spread beyond the usual template for lymphadenectomy might indicate the need for a wider lymph node dissection, or when radiation therapy is planned, expanding the area targeted for treatment.
Outcome of Treatment of Oligometastatic Disease (“Metastasis Directed Therapy” (MDT):
The most recent and comprehensive review of this subject comes from a consortium of researchers from Belgium, Italy, France, Mayo Clinic, UCSF: “Metastasis-directed Therapy of Regional and Distant Recurrences After Curative Treatment of Prostate Cancer: Systematic Review of the Literature (Ost P,ibid). The review focused on 15 studies with 450 patients. No firm guidelines can be drawn from this retrospective review because of the different treatment regimens among the 15 studies, but it does present the best current work in this field and indicates the location of positive sites and a suggestion of outcome data.
Study summary: The 11C-choline PET/CT was used in 91% of cases; median PSA at start of MDT was 2.4 ng/mL (range 1.5 – 8.8). A short PSA doubling time was predictive of early relapse from MDT.
The location of recurrent cancer was nodal in 78% of men, osseous in 21%, and visceral in 4%. In men who initially underwent a radical prostatectomy 97% had had a pelvic lymph node dissection (PLND) in which 9 – 11 nodes were taken. In this group the 11C scan detected nodal recurrence after PLND within the pelvis in 78%, in retroperitoneal nodes in 13%, and in both areas, 65%. Salvage lymph dissection was performed in 34%. In 66% stereotactic body radiotherapy was directed to suspicious nodes, usually augmented by pelvic radiation (49%). Adjuvant androgen deprivation was used in 61% of men.
About 50% of men were progression-free at 1 – 3 years follow-up.
Patients not receiving ADT were progression-free for a median 19 months in one study and 24 months in another. Men with pelvic nodal recurrence who achieved a PSA nadir of <0.2 ng/ml after reoperation, usually accompanied by radiotherapy, remained progression-free for a mean of 4 years.
A Potentially Informative Ongoing Clinical Trial: NCT01558427:
“The potential to postpone palliative systematic treatment is being investigated in a randomized trial comparing MDT with active surveillance followed by ADT at progression.” (Ost, ibid). This study addresses the question whether metastases directed therapy in men with oligometastatic recurrence of three or fewer sites can extend the interval from MDT to starting palliative ADT. In the active surveillance cohort ADT is withheld until palliation of metastases is required. Underlying this protocol is the quest to find a regimen (i.e. MDT) that will allow postponing the initiation of ADT with its adverse side effects. This trial design will remove the ambiguity inherent in past studies resulting from uncontrolled use of ADT and prophylactic pelvic radiation therapy in MDT programs.
The study is being conducted at Ghent University, Belgium.
The Search for Treatable Oligometastatic Cancer:
Establishing a diagnosis of oligometastatic prostate cancer by detecting a minimal extent of spread that allows successful limited intervention is an illusive goal — not unattainable, but rare. Frustration in part may be the consequence of the low sensitivity of the 11C-choline PET/CT scan. Careful application of criteria to best guide patient selection for these scans is important so as to balance the expense of the study and the inconvenience of obtaining it with the potential of gaining actionable information.
Treatment targeted to minimal metastatic disease as yet must be proven in randomized trials to be superior to judicious use of androgen deprivation alone (although many studies combine the two).
The hypothesis that oligometastatic prostate cancer represents an intermediate stage of this disease in which metastases directed therapy yields a better outcome than ADT alone or combined with MDT remains a hypothesis awaiting validation.
BOTTOM LINE:
In the opinion of Dr. Ost and his collaborating authors, “MDT is a promising approach for oligometastatic PCa recurrence …but should not be considered the standard of care.”