Microscopic Prostate Cancer Recurrence: Needle in a Haystack?

Recurrent prostate cancer after treatment

Treating prostate cancer (PCa) is better than ever. There are safe and effective treatments for the whole gland, half of the gland containing the disease, or focusing just on the tumor plus a margin of safety. If this is true, how is it that PCa can recur (come back) after treatment?

Here are two main reasons:

  1. Undetectable cancer had already left the gland at the time of treatment.
  2. Based on favorable clinical factors, the patient had a subtotal gland treatment, but was later found to have been understaged (extent of cancer) or undergraded (aggression of cancer), and it is now growing in the untreated area of the prostate.

Since no treatment has a 100% guarantee of cure, post-treatment patients must be monitored at prescribed intervals. A rising PSA after surgery, radiation, or ablation is a possible sign that PCa is back, either local (in the prostate bed or treated gland), regional (pelvic lymph nodes) or metastatic (other organs or bone). This is called biochemical recurrence. The problem is, how to find it as early as possible; MRI or CT scans can’t pick it up if it’s still too small to register. It’s like looking for a needle in a haystack.

Fortunately, there are new PET scan imaging agents that utilize a cell surface protein called Prostate Specific Membrane Antigen (PSMA, not to be confused with PSA).

PSMA-detecting agents for use with PET scans

PSMA is expressed by all types of prostate cells, including PCa. In fact, it apparently plays a role in enabling the cancer to obtain and use the fuel it needs, since PSMA is expressed 10-80 times more in PCa. Therefore, it has become a prime target for PET detection of very early recurrence. The cancer cells are “hungry” for a type of fuel called glutamine that PSMA helps bind with the cell. The basic imaging principle to detect these “needles in the haystack” is to “feed” the cells a short-lived radioactive substance (radiotracer) taken up by PSMA that will show up on PET (positron emission tomography) scans. PET registers the radioactivity before it dies away, so the spot of cancer is highlighted on the scan.

How do you feed the radiotracer to the cell? Man-made forms of glutamine are taken up by cancer cells using the same PSMA processes they would use for natural glutamine. The synthetic forms are molecules that are “tagged” with a radiotracer. The greedy cancer cells take up the tagged molecules, and the radiotracers light up on a PET scan. Thus, even small amounts of recurrent PCa in the prostate bed, lymph nodes, bone or elsewhere that are undetectable by MRI or CT will be picked up by PET.

Two PSMA detecting agents

The use of radiotracers for detecting recurrent PCa is not new. However, earlier forms for PCa imaging (e.g. 11C-Acetate, F18-Choline, and C11- Choline) did not produce consistently reliable results until a patient’s PSA reached a high level, implying greater difficulty in treating and controlling the disease. However, specifically targeting PSMA requires tagging one of these isotopes onto a molecule sure to be taken up by PSMA and therefore attaching to each PCa cell.

More recently, two types of PSMA-detecting agents are demonstrating high levels of performance when PSA levels are still low. They are still in clinical testing, but identifying recurrence before treatment influences the treatment choice.

  1. Fluciclovine is a synthetic amino acid that can be tagged with F18-Choline (called 18-F fluciclovine). The “amino acid transporters” involved in PSMA recognize fluciclovine as a glutamine, and deliver it into the cell to metabolize (use as fuel). However, since 18-F fluciclovine is not a true glutamine, it doesn’t “undergo additional metabolism in the cell, which lends to its intracellular accumulation particularly in prostate cancer cells…”[i] In other words, since the cell doesn’t digest it fully, it accumulates and can be detected by PET. Fluciclovine is known by the trade name Axumin and it detects recurrent PCa in the prostate, prostate bed, lymph nodes and bone. CLINICAL RESULTS: In one study of 42 post-prostatectomy patients with detectable PSA levels, 81% (34 patients) had positive imaging findings. It was recommended that radiation therapy be offered to these patients. Overall, 40.5% of the patients had their radiation strategy changed due to the location of their recurrence as identified by PSMA-detecting 18-F fluciclovine.[ii]
  2. 68-Gallium is a radiotracer that can be formulated to tag various synthetic glutamide molecules for uptake by the transporter processes of PSMA. Thus, PET scans for PCa using this radiotracer are called 68-Ga PSMA PET scans. The imaging principle is the same. When compared with conventional F-18 Choline PET scans, the detection rate of PCa recurrence was significantly higher for 68-Ga PSMA PET. According to one paper, it has “…revolutionized prostate cancer imaging. Outperforming standard imaging, it allows complete staging of the local tumor and possible lymph nodes, visceral or bone metastases with high accuracy in only one examination.”[iii] CLINICAL RESULTS: In a study of 101 patients with biochemical recurrence whose treatment plans were documented before and after imaging results, 76 had positive imaging findings. Of these, 53% ultimately went through a different treatment than originally recommended, based on 68-Ga PSMA results.[iv]

[i] Evans JD, Jethwa KR, Ost P, Williams S et al. Prostate cancer-specific PET radiotracers: A review on the clinical utility in recurrent disease. Pract Radiat Oncol. 2018 Jan – Feb;8(1):28-39.

[ii].Akin-Akintayo OO, Jani AB, Odewole O, Tade FI et al. Change in Salvage Radiotherapy Management Based on Guidance With FACBC (Fluciclovine) PET/CT in Postprostatectomy Recurrent Prostate Cancer. Clin Nucl Med. 2017 Jan;42(1):e22-e28

[iii] Kesch C, Kratochwil C, Mier W, Klaus K, Giesel F. Gallium-68 or Fluorine-18 for prostate cancer imaging? J Nucl Med. 2017 Apr 13. doi:10.2967/jnumed.117.190157

[iv] Calais J, Fendler WP, Eiber M, Gartmann J et al. Actual impact of 68Ga-PSMA-11 PET/CT on the management of prostate cancer patients with biochemical recurrence. J Nucl Med. 2017 Dec 14. pii: jnumed.117.202945. doi: 10.2967/jnumed.117.202945. [Epub ahead of print]