We are beginning to recognize that prostate cancer is a much more subversive adversary that we have conventionally thought. This awareness is largely coming from information from studies with the total body PSMA PET/CT. The (68)Ga-PET/CT is rapidly becoming the gold standard for prostate cancer imaging. There is ample support in the literature to establish that the PSMA PET/CT outperforms in accuracy the (11)C-choline, (11)C-acetate, the Axumin, and (18)F-FDG PDT/CT scans. Importantly, the PSMA PET/CT performs well at low PSA values, i.e. < 1 ng/mL, where the awareness of early disease spread allows appropriate management decisions.
A quote of Fabio Almeida, MD, the Medical Director of the Phoenix Molecular Imaging and Southwest PET/CT Institute and a guru in the field especially as regards the (11)C-acetate PET/CT, offered an assessment of the future of the PSMA PET/CT: “Despite some limitations, PSMA-targeted imaging appears to provide high sensitivity and specificity, and is likely to become part of the routine evaluation and management of men with prostate cancer in the near future,” December, 2016, in the Prostate Cancer Research Institute document “Overview of Positron Emission Tomography (PET) Scans.”
A very large number of reports have been published, especially in the European literature, regarding the results of the (68)Ga-PSMA PET/CT at various stages in the progression of the prostate cancer. This Commentary, however, will focus on the PSMA scan findings at points of high clinical relevance: 1) biochemical recurrence at a PSA of >0.2 ng/mL, the threshold for “biochemical failure” following surgery; 2) PSA values of <0.5 ng/mL, the point below which salvage radiotherapy is recommending following biochemical recurrences after surgery (RP); and 3), PSA values above the “Phoenix” criteria for biochemical failure, i.e. a PSA of 2 ng/mL above the nadir PSA after radiation therapy (RT).
For those readers who need to cut to the chase, the 32 studies reviewed for this Commentary uniformly make two important points:
1) the (68)Ga-PSMA scan provides information about the location and extent of prostate cancer at clinically significant low PSA values of <1 ng/mL , information not available with other scans based on cancer morphology or metabolism, and
2) this information can substantially change management decisions compared to pre-PSMA treatment plans.
What does the PSMA PET/CT reveal following surgery at PSA values above 0.2 ng/mL, the consensus threshold for biochemical failure?
- A major study addressing this point came from Ali-Afshar et al. University of Heidelberg: “The diagnostic value of PET/CT imaging with the (68)Ga-labelled PSMA ligand HBED-CC in the diagnosis of recurrent prostate cancer,” Eur j Nuc Med Mol Imaging, 2015. A total of 319 patients were scanned after surgery (226) or radiation (89), 27 prior to salvage RT, and 38 prior to radioisotope therapy with 177-Lutetium radiolabeled PSMA. Of interest, the rate of positive scans in men being evaluated for suspected recurrence who had Gleason scores of 7, 8, and 9 were 80%, 79%, and 92.5%, respectively. In this group 82.8% (264/319) showed at least 1 lesion.
The probability of a positive scan in relation to the PSA at the time of the scan was:
50% (5/10) at PSA 0.21 – 0.5 ng/mL
58.3% (14/24) at PSA 0.51 – 1.0 ng/mL
71.8% (11/39) at PSA 1.1 – 2.0 ng/mL
85.9% (9/73) at PSA 2.1 – 5.0 ng/mL
Of the total of 910 individual lesions detected, 13 were local following RP, 328 were lymph node metastases, and 129 soft tissue metastases. Following radiation, lesions within the prostate gland were noted in 72 men either at recurrence post RT or as part of the initial work-up to exclude metastases.
Management decisions were guided by the PSMA scan findings: Of 116 patients where follow-up information was available 50 received local treatment (27 – focal radiation to PSMA positive sites, 19 – operated, 4 – HIFU); 34 were treated with 177-Lutetium-labelled PSMA; and 36 received ADT and/or chemotherapy.
- Another major article was focused on: “Evaluation of Hybrid (68)Ga-PSMA Ligand PET/CT in 248 Patients with Biochemical Recurrence After Radical Prostatectomy,” Eiber et al. J Nuc Med, May 2015. Detection was greater in patients with Gleason score 7 or less vs 8 or more. The median PSA of the group was 1.99 ng/mL and 89.5% had suspicious lesions detected on the PSMA scan. The detection rate at PSA levels was: 0.2 – <0.5 ng/mL – 57.9%; 0.5 – <1.0, 72.7%; 1 – <2 ng/mL – 93.0%; and at PSA values > 2, 96.8%. These results are “substantially higher than those reported for choline-based tracers …”
The study observed that the PSMA PET/CT scan exclusively provided relevant diagnostic information” in 32.7% of patients and in 24.6% of patients “was able to identify additional involved regions compared to 6.9 % where the CT showed additional positive regions. At PSA > 2 ng/mL the detection rate in the Eiber study was 96.8%. This is toward to lower range for the Phoenix threshold of recurrence after radiation therapy.
The Eiber conclusion: “PSA relapse after RP is a common clinical scenario. In this context, biochemical failure defined by a confirmed PSA values of >0.2 ng/mL after RP occurs long before recurrent disease can be localized clinically or by imaging.”
What does the PSMA PET/CT reveal following radiotherapy with curative intent?
- A study by Meredith et al., BJU Int, 2016, addresses this issue: “The use of (68)Ga-PSMA PET/CT in men with biochemical recurrence after definitive treatment of acinar [i.e., the common type] prostate cancer.” The detection rate in relation to the PSA values was reported in 107 men treated with either external beam radiotherapy or brachytherapy:
At PSA levels: 0.01 – <0.2 the detection rate was 33.3% (1/3);
At PSA between 0.2 – <0.5, 71.4% (5/7);
For PSA between 1 – <2, 93.3% (14/15); and
At PSA >2 ng/mL, 100% (82/82) had a positive scan.
At PSA values above 2 ng/mL 45% had suspected lymph nodes, of which 45% were outside the pelvis. These are small numbers, but the message is that well before the Phoenix criteria is met there is substantial spread, as was also indicated in the Ali-Afshar study.
- Einspieler et al. (J. Nuc. Med., 2017) reported on the detection rate of (68)Ga-PSMA in 118 patients with biochemical failure after primary radiation defined by the Phoenix criteria. In the PSA range post treatment of 2 to <5 ng/mL 81.8% showed pathologic findings on scan. In their full study range of 2 to <10 ng/mL: 63.5% recurrences were local, 59.8% were only distant, and 23.4% were both local and distant.
To provide some perspective on the relatively poor effectiveness of the Phoenix criteria for detecting spread early there is a study from the Mayo Clinic (Klein, Tendular et al., Int J Rad Oncl, Biol, Phys, Jul 2016). They reported that 0.1 ng/mL was the median nadir at 6 months after highdose radiation therapy for men with intermediate- and high-risk cancer. At 6-months 58.3% had a PSA of < 0.1 ng/mL. A recent German Study of men treated with stereotactic radiation found the “median nadir for all patients was 0.3 ng/mL for all patients, and 0.6 ng/mL for patients without hormone therapy (Stralhlentherpaie und Onkologie, July 2016). These low median PSA nadir suggests that by employing the Phoenix criteria, the PSA is allowed to rise, with its consequent spread, in the majority of cases from PSA levels such as 0.1 ng/mL to slightly greater than 2 before “biochemical failure” is declared. The PSMA scans clearly show a greater extent of spread at or above the Phoenix definition of biochemical failure as compared to the surgical threshold of 0.2 ng/mL or less. Perhaps awareness of this difference led Merrick, Wallner et al. (Int. J. Rad. Oncol. Biol. Phys., 2007) in their study of brachytherapy therapy to set the criteria for biochemical failure following radiation at > 0.40 ng/mL after nadir and not at the Phoenix level.
(68)Ga-PSMA-11 PET/CT findings influence and change pre-scan management decisions.
Because of the current imaging inadequacy of the conventional CT and bone scans to detect early recurrences following primary surgery or radiation, clinicians have been deprived of the necessary information to make evidence based decisions. Multiple studies have shown that information exclusively available based on PSMA PET/CTs have changed clinical management in greater than 50%, or in one study in 76% of cases, from the treatment planned before the PSMA scan findings were known.
A variety of treatment options were offered in the Ali-Afshar study based on the finding of early spread. Among 116 patients with follow-up, “… 40% could be treated locally with resulting delayed systemic therapy.” Fifty patients received local treatment: 27 received focal radiation to PSMA positive sites, 19 were operated, 4 were treated with HIFU; and 34 underwent therapy with 177Lutetium-labelled PSMA; and 36 received ADT and/or chemotherapy. “We believe that such patients who can delay systemic therapy have a greater potential for improved quality of life.”
It is likely that the (68)Ga-PSMA PET/CT will become the gold standard for early detection of lowvolume prostate cancer Emerging Technology Advances Staging Accuracy PCa Commentary Feb 2017 [control+click to follow] but, if detecting prostate cancer much earlier than is currently possible only leads to the earlier application of androgen suppression, not a great deal will have been accomplished, considering that ADT runs its course over middle range of 2 – 4 years before inviting castration resistance. Our efforts now should be directed toward treatments that can be effective at low tumor burdens, such as immunotherapy, alone or in combination, i.e., the clinical trial NCT02463799 combining Provenge with Xofigo; or targeted radiotherapy with stereotactic body radiation, or radioisotope therapy targeting the PSMA molecule, such a 177-Lu PCa Commentary March 2017 Lutetium-177 a promising radioisotope [control+click to follow] as offered on protocol at Cornell Medical College by Dr. Tagawa. The stem and progenitor cells should be next in line in the crosshairs.