Accurate staging is the keystone of appropriate managing decisions at initial diagnosis and at recurrence of prostate cancer. Recent advances in imaging technology are driving a tectonic shift toward improvement in both these areas. Added to this is the potential of improved treatment by the linkage of tracers accurately targeting prostate cancer joined with therapeutic radioisotopes. Just as prostate cancer treatment experienced a dramatic upgrade in recent years with the introduction of Zytiga, Xtandi, Xofigo, Provenge, and Xgeva, so now clinicians and patients can expect to benefit from promising advances in imaging accuracy and “theragnostics,” the newly coined term that refers to the linkage of the targeting tracer with a radioisotope, such as Actinium 225.
This leap forward in imaging technology has already begun with the available, but difficult to access, 11C-choline and 11C-acetate total body PET/CT scans. The recently approved Axumin PET/CT (18F-FACBC) will soon make this improved staging technology available at many nuclear medicine departments across the country. The next generation of this remarkable technology will be the targeting of a surface marker on prostate cells themselves, the prostate-specific membrane antigen (PSMA).
The venerable staging tools of the past — the abdominal/pelvic CT and the Technetium bone scan, both until recently the best we’ve had to work with, are still being used because of their easy availability. However clinicians have recognized for some time that these tools are inadequate for the tasks assigned to them.
For example:
- The CT definition of an “enlarged” lymph node is one having a short axis of >8 mm.
- “A recent 68Ga-PSMA-11 PET/CT study found 49 positive lymph nodes including 38 (78%) with a diameter of <8 mm.” The mean diameter of positive nodes in the study was 5.8 mm.
- The authors concluded that the PSMA scan detected nodal recurrence in two-thirds of patients who would have been missed using conventional morphological criteria. (Giesel, Eur J Nucl Med Mol Imaging, 2015)
The Technetium scan is either overused in low-grade cancer or insufficiently sensitive in high-grade disease, as compared to the Sodium Fluoride PET/CT, which displays a significantly better sensitivity. Unfortunately, this scan is less utilized than warranted because of lack of availability and inconsistent insurance coverage.
The standard CT, being solely a morphological study (i.e. based on shape and size), fails to capture evidence of cancer in small lymph nodes or minimal bone metastases. Therefore it understages cancer. The multiparametric MRI, a remarkable functional study, is excellent in evaluating the prostate gland for the location, size, and, to some extent, the grade of cancer but, it is not a total body survey and is equally deficient as the CT in identifying malignancy in lymph nodes.
The 11C-choline, 11C-acetate, and the Axumin (based on amino acid uptake) PET/CTs are extremely informative total body scans based on the metabolic cellular uptake of basic cellular building substrates choline, acetate, and lysine Their inherent weakness, which decreases their sensitivity, is their requirement for tumors to have sufficient cellular proliferation and tumor bulk to generate a signal adequate for PET detection. The golden ring of imaging, therefore, is a tracer that targets prostate cancer cells directly, independent of growth rate and bulk. This is the goal that PSMA imaging has the potential to achieve.
So … clinicians and patients everywhere are more than ready to upgrade to the greater imaging accuracy of the 68Ga-PSMA PET/CT.
The research literature in the past several years has been bulging with articles from all over the world (with the notable exception of the USA) about this new staging technology and with studies comparing PSMA imaging with current methods. It would be challenging to summarize this. However, I am absolutely indebted to the authors of the article that I will review (with my added commentary): “Current Status of Prostate-Specific Membrane Antigen Targeting in Nuclear Medicine: Clinical Translation of Chelator Containing Prostate-Specific Membrane Antigen Ligands Into Diagnosis and Therapy for Prostate Cancer,” Seminars in NUCLEAR MEDICINE, 2016, by Kratochwil, Afshar-Oromieh, Kopka, Haberknown, and Giesel, all from Heidelberg, Germany. They are in the forefront of exciting research in this area. Their article examines the current imaging methods through the prism of the possibilities of emerging PSMA technology.
What Characteristics Makes PSMA So Ideal for Diagnosis and Therapy?
PSMA is a cell surface transmembrane protein, an enzyme (glutamate carboxypeptidase II), which wags its receptor tail in its surroundings, and after being bound by incoming signaling messengers moves into the cell’s interior where the information is passed on to nearby scaffold units that govern a variety of cellular responses, i.e., cellular proliferation, migration, and invasion. This internalization, “leads to enhanced tumor uptake and retention, and it results in high-image quality for diagnostic procedures and a high local dose of therapeutic applications” (Kratochwil, ibid). PSMA is expressed on 90% of prostate cells and its expression increases in advanced stage cancers. Prostate cancer cells express PSMA 8-12 times more than non-cancerous prostate cells, and 1000 times more than other cells (i.e. in kidney, lung, liver, salivary glands and others). Of note, whereas the detection rate (sensitivity) in CRPC with the choline PET/CT declines with greater cancer aggressiveness (de-differentiation), in contrast, the expression of PSMA increases in more aggressive cancer, making it particularly useful for diagnosis and treatment of CRPC. This relatively high concentration in prostate cancer tissue, especially the feature of cellular internalization, is an advantage in reducing adverse effects on other organs when the PSMA tracer is linked with radioisotopes for treatment. As an additional bonus, PSMA is expressed on tumor neovasculature, an advantage for diagnosis and treatment.
For diagnostic imaging with PSMA a small molecule inhibitor of the PSMA enzyme is linked with the isotope 68Ga, the source of the positron sensed by the PET scanner. For treatment the PSMA tracer is linked to a therapeutic radioisotope such as the -emitter 225 Actinium.
The Seminars in NUCLEAR MEDICINE Review Article:
Kratochwil and colleagues usefully divided their review into three sections: PSMA scanning at diagnosis, at recurrence; and in the near future when the PSMA technology is developed as a “theragnostic.” I will follow their clue and add additional commentary.
- “PSMA-PET/CT for Primary Staging” (ibid)
The authors point out that there are FEW studies of PSMA PET/CT for evaluating the prostate itself. One study did compare tumor localization within the prostate gland seen on a PSMA PET/CT to that seen on a multiparametric MRI and found their accuracy similar, between 90% – 97%. Considering the wide availability of the mpMRI and the accuracy of MRI based targeted biopsies to diagnose the lesion with the highest Gleason score, the mpMRI can serve quite well in finding these lesions. The PSMA PET/CT will be less utilized in evaluating the prostate gland.
However, in the staging of higher-risk patients the PSMA PET/CT can contribute significant guidance when information about lymph node spread is required.
✭ PSMA PET/CT prior to radiation: The 68Ga-PSMA-11 PET/CT has been compared to conventional staging of the pelvis and abdomen. Two studies of 57 and 44 patients reported this comparison in men scheduled for primary radiation. In one of them “In 50.8% of the cases, therapy was changed;” and in the second the treatment plan was changed in 53.7%.
(Sterzine, Eur J Null Med Mol Imaging, 2016; Shakespeare, Radiat Oncol, 2015, respectively)
In the setting of salvage radiation after radical surgery, Heidenreich (Eur Urol 2007) reported management change in 29% based on PSMA-PET/CT findings.
✭PSMA PET/CT prior to surgery: Surgery on higher-risk patients is frequently accompanied by a limited or extended pelvic lymph node dissection. This procedure remains the gold standard for detection of positive nodes in advanced cancer. However, many studies have shown that positive lymph nodes in higher-risk patients often lie beyond the standard template of dissection. These nodes would only be detected with the fuller field imaging of the PSMA PET/CT, which has a greater application for imaging in recurrent disease.
An example: a small study was reported in the January issue of BJUI, van Leeuwen et al., of 30 patients (3 intermediate-risk and 27 high-risk) who underwent a PSMA PET/CT prior to surgery. Positive nodes were found in 37%. For the detection of positive nodes the specificity was 56%, specificity 98%, positive and negative predictive values 90% and 94%. One of 27 positive nodes was outside the ePLND template. The mean size of missed positive nodes was 2.7 mm. They concluded that the PSMA scan “had the potential to replace current imaging [i.e. CT and MRI] of LN staging of patient with PCa scheduled for RP.”
68Ga-PET/CT scans are currently available at a limited numbers of institutions. An academic consortium has been formed for joint study at Stanford, UCSF, UCLA, Iowa, Indiana, Wisconsin, Vanderbilt, MSKCC, Wash U, and more to come. Expect a barrage of reports from this research. However, it will be some time before this scan is fully vetted and available.
Even though the forthcoming FDA approved total body Axumin scan has been shown to be somewhat less accurate than the 68Ga-PET/CT, none the less it represents a significant advance over convention imaging, and as it becomes generally available it can provide improved imaging in the near future.
- “PSMA Imaging of Recurrent PC” (ibid)
Compared to the use of the PSMA scan for primary diagnosis, there has been extensive reporting, especially from European centers, of the scan’s performance at biochemical recurrence.
Scan performance in two large studies of men with biochemical recurrence showed a sensitivity of 88.1% and 89.5%. In one, detection did not correlate to PSA doubling time. In a second, “Among the patients with PSA <2 ng/mL, the detection rate was 85% if the PSAdt was <6.5 months, but only 19% if the PSAdt was >6.5 months. Three studies reported positive scans in “patients with PSA values between 0.2 and 0.5ng/mL. The detection rates were in good accordance: 57.9%, 50%, and 50%.”
Eiber et al., Journal of Nuclear Medicine 2015 reported on 393 patients with biochemical recurrence following surgery. “The detection rates were 96.8%, 93.0%, 72.1%, and 57.9% for PSA levels of >2, 1 to <2, 0.5 to <1, and 0.2 to <0.5 ng/mL.” Their conclusion: Hybrid 68 GA-PSMA ligand PET/CT shows substantially higher detection rates than reported for other imaging modalities. Most importantly, it reveals a higher number of positive findings in the clinically important range of low PSA values (<0.5 ng.mL), which in many cases can substantially influence the further clinical management.” Detection at this low PSA value is especially informative since it is now conventional to offer salvage radiation to men with PSA recurrence following surgery before the PSA rises to >0.5 ng/mL.
A recent study in BJUI, January 2017, Albisinni et al., reported PSMA scan findings in 131 men with persistent PSA elevations after surgery, or at biochemical recurrence after surgery, radiotherapy or both. At least one lesion suspicious for prostates cancer was identified in 75% of patients and the pre-scan management plan was changed in 76%. “The main modifications included continuing surveillance (withholding hormone therapy), hormone manipulation, stereotactic radiotherapy, salvage radiotherapy, salvage node dissection or salvage local treatment (prostatectomy, high-intensity focussed ultrasound).”
The essential point arising from all these studies is that the PSMA scan performs well at low PSA values and the results often change the pre-scan management plans. Kratochwil cites three studies in which the PSMA outperformed choline PET/CTs in this setting of biochemical recurrence.
- “PSMA-Targeted Radionucleotide Therapy of CRPC” (ibid) A View Towards A Promising Future, which is already in progress in some research centers.
“Theragnostics,” the linkage of PSMA targeting tracers and a therapeutic radioisotope has the potential of being a powerful and cancer-specific therapy. Examples of the effectiveness of this modality are encouraging, particularly as reported from the University of Heidelberg, Germany, the research site for the authors of this article.
Regarding their work, Kratochwil comments, “… it seemed more promising that PSMA ligands that target tumor cells directly and which are internalized into the cell will be effective in delivering high doses of systemic PSMA-Radiolabeled Therapy.” A short range -emitter, 225 Actinium (Ac), seemed appropriate because of its lesser toxicity to the bone marrow, (as opposed to the -emitter 177 Lutetium).
Since the cancers of 10% of men with CRPC do not express PSMA, it is mandatory that a PSMA scan be positive before treatment.
An article by Kratochwil and colleagues from Heidelberg examples the promising research in theragnostics: “225Ac-PSMA-617 for PSMA-Targeted -Radiation Therapy of Metastatic Castration-Resistant Prostate Cancer, J Nucl Med 2016. Although their case series is still ongoing, they thought it important to “report in advance about two patients in highly challenging clinical situations who showed a complete response to 225Ac-PSMA-617 therapy.”
– In both the post treatment scans showed dramatic responses. In patient #1 after four bi-monthly cycles, the pretreatment PSA of 2923 fell to <0.1 ng/mL and the restaging scan was clear. Patient #2 had progressed after therapy with 177Lu-PSMA-617. After three cycles of 225Ac-PSMA-617 the PSA fell from 419 to 0.1ng/mL and his scan showed a complete response. “No relevant hematologic toxicity was observed.” The full reporting of this series and their longer-term follow-up will be very interesting.
Of real practical importance, as noted in Seminar article, “the first 68Ga/68Ga generator system was approved by the European Medicines Agency and a single-vial kit solution for radiolabling 68Ga-PSMA-11 at room temperature has been developed.” This should allow the PSMA scan (not the theragnostic combination) to be available in nuclear medicine departments similar to the availability of the Technetium bone scan tracer.
BOTTOM LINE: With the introduction of the 68Ga PET/CT a new era in prostate cancer imaging and therapy is underway with promising possibilities.