This article was co-written by David Djang, MD, specialist in Nuclear Medicine, Swedish Medical Center, Seattle, WA
The spread of cancer from the prostate into the lymph node system has been regarded as an orderly and sequential involvement of the “regional” pelvic nodes near the prostate gland spreading further peripherally as the nodal burden increases. Based on nomograms indicating the likelihood of spread to lymph nodes, surgeons perform a pelvic lymph node dissection (PLND) and follow a standard template for nodal excision. In an extended PLND the external iliac, obdurator, hypogastric, and common iliac nodes are removed. In some cases nodes from the pre-sacral region are included. Surgical outcome studies have shown that when only one or a few nodes near the prostate are involved and excised, the outcome can be very satisfactory. Correspondingly, when radiation is employed, it also focuses on this conventional pattern and treats the same areas. The downside of adhering to these set patterns is that, even at diagnosis, as the burden of nodal disease increases, as it often does in aggressive high-risk cancer, nodal metastases have already spread to areas beyond the convention treatment targets. Depending on the cancer’s aggressiveness, spread beyond the usual treatment pattern may occur in as many as 40% of instances based on studies with the (11)C-choline or (11)C-acetate total-body scans. These more widespread nodal metastases remain untreated and can serve as the source of PSA relapse.
Unfortunately, useful as the choline and acetate scans are, these scans have limited practical availability because of requiring a nearby cyclotron. This limitation results from the short half-life of these tracers which limits their transit, i.e. 20 minutes for radioactive choline.
An Unmet Need:
There is clearly a pressing need for an available and accurate total body scan. As only one example, Garcia et al., Quarterly Journal of Nuclear Medicine and Molecular Imaging, 2015 Sept, using (11)C-choline PET/CT in the study of 61 patients with medium-to-high-risk prostate cancer found nodal involvement beyond the usual template in 21.3%. This information is essential for appropriate radiation therapy treatment planning and surgical management. Studies have found that when this information about the unexpected extent becomes known, radiation and surgical management changes. At PSA recurrence this wider nodal spread is often not imaged by the usual CTs and bone scans. “Impact of (18)F-choline PET/CT in Decision-Making Strategy …[for] Radiation Therapy,” Clinical Nuclear Medicine, 2015 Nov, “ reported that in 57 men with low-, intermediate-, and high-risk prostate cancer the Choline PET/CT shifted treatment indication in 13 cases (21%).”
The Current Status is About to Change:
A new radiotracer for total body scanning, trade named (18)F-fluciclovine (also referred to as (18)F-FACBC, and trade named Axumin) was approved by the FDA in May 2016 for the diagnosis of suspected prostate cancer recurrence after primary therapy. It will likely have widespread availability in many nuclear medicine departments across the nation and already is available in 11 pilot locations.
18F-fluciclovine is a synthetic amino acid analog taken up and concentrated by prostate cancer cells through an amino acid transporter. The 18F-fluciclovine PET/CT scan can help identify a recurrence of prostate cancer at an early stage.
The half-life of 18F-fluciclovine is 110 minutes, which allows it to be produced and then distributed. This longer half-life allows the tracer to be produced at a centralized location, so that imaging centers would not need to have cyclotrons on site, a significant logistical advantage over the 11C tracers. From the patient’s perspective, the scan itself can be completed in less than one hour.
18F-fluciclovine was developed at Emory University, commercialized by Blue Earth Diagnostics, and is being distributed by PETNET. 18F-fluciclovine is only minimally excreted by the kidneys, which allows for accurate imaging of the prostate bed. The 18F-fluciclovine PET/CT scan can detect prostate recurrence in both bones and soft tissue, which has been routinely assessed by a combination of CT and bone scans.
Comparison of F-fluciclovine PET/CT with (11)C-choline PET/CT for recurrence:
This comparison was reported by Nanni et al., European Journal of Nuclear Medicine and Molecular Imaging, Mar 2016, based on 86 men with CRPC and a rising PSA after prostatectomy. The men were off androgen suppression and the comparison between the two scans was made within 1 week. The scans were compared on a per-person and per-lesion basis yielding an accuracy of 38% for the FACBC and 32% for the choline study. The positive predictive value was 97% and 90%, respectively.
In an earlier article based on the same cohort of men (Nanni et al., Clin Nucl Med 2015 Aug) the authors expressed their findings more forcefully: “On a patient-based analysis, (18)F-fluciclovine detection turned out to be significantly superior to (11)C-choline ( P<0.00001)” in men with low, intermediate, and high PSA levels. Their conclusion: “The 18F-FACBC can be considered an alternative tracer superior to 11C-choline in the setting of patients with biochemical relapse after prostatectomy.”
A study of 115 patients at Emory University found a whole-body positivity rate of 39.0% (7/18) at PSA 0 – 1; 76.9% (10/13) at PSA 1.1 – 2; and 90% (27/30) at PSA 2 – 3.5 ng/mL.
One review article (von Eyben, Ann Nucl Med. July 2016) found the two scans to be equivalent in the detection of metastatic sites when scanning at a median PSA of 3.6+/- 2.7 ng/ml ( range 0.5-10.7).
However, the thrust of this article is not to detail a comparison of the fluciclovine and choline scans but rather to indicate the importance of having the forthcoming availability of the the Axumin scan in an accessible facility. Up to now, evaluation of recurrent prostate cancer has been made using ultrasound, CT of abdomen/pelvis, and bone scanning.
In 2016 the guidelines by the European Association of Urology and the National Comprehensive Cancer Network (NCCN Version 3.2016) changed their recommended studies for selected patients with recurrent disease from those studies to the (11)C-choline PET/CT. When the Axumin scan enters the clinical scene, their recommendation is likely to extend to this scan.
What management decisions might follow from early and accurate information as to the location of recurrence diagnosed on an Axumin scan in men with prostate cancer?
- Awareness of the location of persistent disease at the time of PSA recurrence, if exclusively found within or in the region of the prostate, could provide the indication for further local therapy. Disease found beyond the primary treatment target could strengthen the case for the earlier application of androgen deprivation, chemotherapy, or immunotherapy, a promising emerging modality under current study. Repeat scans could augment the PSA test in monitoring the effectiveness of early therapy.
- In carefully selected cases of PSA recurrence with minimal sites of metastases (“oligometaststic,” i.e optimally 3 but <5 sites, ) and low and slowly rising PSA values, targeted CyberKnife treatment to the affected sites could be offered — a treatment whose effectiveness is under active study.
A recent check of ClincialTrials.gov found nine clinical trials addressing the treatment of oligometastatic prostate cancer in Phase II one-arm studies, some with accompanying ADT, and one with immune therapy (prembrolizumab). They are mostly single institution trials, but promise useful information.
- If the scan were employed at the time of initial diagnosis, the information could result in choosing a wider field of nodal resection or a selectively widening of coverage by radiotherapy, as is already being done in Europe.
The local availability and accuracy of the Auxmin scan will very likely have significant influence on management decisions in the treatment of recurrent prostate cancer, the indication for which it is approved. In the future after further study, it may well become approved in the US for use at the time of initial diagnosis for high-risk aggressive prostate cancer.
[The PCa Commentary will notify its readers of the availability of the Axumin scan and how to order the study.]