Current status of theranostics in prostate cancer

Abstract

The aim of this review is to report on the current status of prostate-specific membrane antigen (PSMA)-directed theranostics in prostate cancer (PC) patients. The value of ⁶⁸Ga-PSMA-directed PET imaging as a diagnostic procedure for primary and recurrent PC as well as the role of evolving PSMA radioligand therapy (PRLT) in castration-resistant (CR)PC is assessed. The most eminent data from mostly retrospective studies currently available on theranostics of prostate cancer are discussed. The current knowledge on ⁶⁸Ga-PSMA PET/CT implicates that primary staging with PET/CT is meaningful in patients with high-risk PC and that the combination with pelvic multi parametric (mp)MR (or PET/mpMR) reaches the highest impact on patient management. There may be a place for ⁶⁸Ga-PSMA PET/CT in intermediate-risk PC patients as well, however, only a few data are available at the moment. In secondary staging for local recurrence, ⁶⁸Ga-PSMA PET/mpMR is superior to PET/CT, whereas for distant recurrence, PET/CT has equivalent results and is faster and cheaper compared to PET/mpMR. ⁶⁸Ga-PSMA PET/CT is superior to ¹⁸F / ¹¹Choline PET/CT in primary staging as well as in secondary staging. In patients with biochemical relapse, PET/CT positivity is directly associated with prostate-specific antigen (PSA) increase and amounts to roughly 50% when PSA is raised to ≤0.5 ng/ml and to ≥90% above 1 ng/ml. Significant clinical results have so far been achieved with the subsequent use of radiolabeled PSMA ligands in the treatment of CRPC. Accumulated activities of 30 to 50 GBq of ¹⁷⁷Lu-PSMA ligands seem to be clinically safe with biochemical response and PERCIST/RECIST response in around 75% of patients along with xerostomia in 5-10% of patients as the only notable side effect. On the basis of the current literature, we conclude that PSMA-directed theranostics do have a major clinical impact in diagnosis and therapy of PC patients. We recommend that ⁶⁸Ga-PSMA PET/CT should be performed in primary staging together with pelvic mpMR in high-risk patients and in all patients for secondary staging, and that PSMA-directed therapy is a potent strategy in CRPC patients when other treatment options have failed. The combination of PSMA-directed therapy with existing therapy modalities (such as ²²³Ra-chloride or androgen deprivation therapy) has to be explored, and prospective clinical multicenter trials with theranostics are warranted.

Keywords: 68Ga-PSMA; PET-guided personalized therapy; PET/CT; PET/MR; Prostanostics; Prostate cancer; Theranostics.

Fig. 1

PET/MRI demonstrating the primary PC (PSA 16 ng/ml, GS 3 + 4) in the right prostate lobe (red arrow) invading the seminal glands with markedly increased ⁶⁸Ga-PSMA uptake. The tumor presents with restricted diffusion on apparent diffusion coefficient (ADC) mapping and is hypointense on T2-weighted MRI

Fig. 2

Detection rate in PC patients with low biochemical relapse of PSA < 1.0 ng/ml scanned either by ¹⁸F/¹¹C–choline (orange bars) or ⁶⁸Ga-PSMA-ligand (green bars)

Fig. 3

⁶⁸Ga-PSMA-11 PET/CT images of a 72-year-old PC-patient with BR after RP (PSA 4.26 ng/ml). Early dynamic imaging of the pelvis over the first 8 min p.i. and a whole-body scan at 60-min p.i. were performed. At 60-min p.i., a clear distinction between urinary activity within the neck of the urinary bladder and local recurrence is not possible as presented on axial (1a) and sagittal (1b) fused PET/CT images (red arrow). In contrast, on the axial and sagittal fused PET/CT-images (2a, 2b) at 4 min p.i. of the early dynamic PET-acquisition a focal tracer accumulation with a SUV_max value of 4.45 adjacent to the urinary bladder is visible (red arrow) with no tracer uptake in the urinary bladder present (green arrow) consistent with local recurrence

Fig. 4

Potential effect of bicalutamide on ⁶⁸Ga-PSMA-11 PET-uptake. On initial PET/CT (a, red arrow) moderately increased tracer accumulation with a SUV_max of 4.47 in a LN (5.7 mm in diameter) was found in the region of the left internal iliac vessels as shown on axial fused PET/CT-images. On follow-up PET/CT performed 7 days after initiation of bicalutamide (160 mg/day; 1 week), no pathologic tracer accumulation was found in the left iliac LN, which morphologically remained unchanged (b; yellow arrow). PSA decreased from 0.94 to 0.18 ng/ml under treatment with bicalutamide

Fig. 5

Follow-up ⁶⁸Ga-PSMA-11 PET/CT (low-dose CT) of an 80-year-old CRPC-patient who had received treatment with ¹⁷⁷Lu-PSMA-617. On the PET scan prior to therapy, local tumor in the prostate bed (red arrow), multiple abdominopelvic and one cervical LN metastases (green arrows) were clearly visible on maximum intensity projection (MIP) (1a) and on fused axial PET/CT-images (1b, 1c). Restaging PET/CT performed 8 weeks after administration of four cycles of ¹⁷⁷Lu-PSMA-617 with a total accumulated activity of 24.9 GBq showed a significant reduction of the primary tumor (red arrow) and an impressive partial response of LN metastases with only small metastases left in the right iliac region (green arrows), as displayed on MIP (2a) and fused axial PET/CT-images (2b, 2c)

Fig. 6

Current status of theranostics in prostate cancer ("Prostanostics"). The current status of PSMA-directed theranostics in PC patients is based on retrospective studies. ⁶⁸Ga-PSMA PET/CT in primary staging is meaningful in patients with high-risk PC for local tumor assessment. The combination with pelvic multi parametric (mp)MR (or PET/mpMR) reaches the highest impact on patient management. In secondary staging for local recurrence, ⁶⁸Ga-PSMA PET/mpMR is superior to PET/CT, whereas for distant recurrence, PET/CT has equivalent results and is faster and cheaper compared to PET/mpMR. ⁶⁸Ga-PSMA PET/CT is superior to ¹⁸F / ¹¹choline PET/CT in primary staging as well as in secondary staging. Significant clinical results have so far been achieved with the subsequent use of radiolabeled PSMA ligands in the treatment of CRPC, especially with ¹⁷⁷Lu-PSMA ligands. Potential results have been demonstrated for α-emitting ligands and the combination treatment of β- and α-emitters is discussed