PSMA theranostics in prostate cancer

This thesis focusses on the current role and future implementation of the theranostic PSMA in prostate cancer imaging and therapy.
Part I:Prostate cancer imaging
The field of non-invasive prostate cancer staging is rapidly evolving and prostate-specific membrane antigen positron emission tomography (PSMA PET) has shown promising results for the detection of locoregional lymph node, and distant metastases. However, its role in local tumor staging (i.e. extraprostatic extension (EPE) and seminal vesicle invasion (SVI)) is less clear. Chapter 2 evaluate diagnostic accuracy of PSMA PET imaging in primary clinical TNM staging.
Previous studies (SALT-, PEPPER-, MINT- trials) have shown similar diagnostic accuracy (sensitivity and specificity) of the different PSMA tracers for the detection of lymph node metastases, compared with histopathology, in primary staging of prostate cancer patients. Chapter 3 compares three different types of PSMA tracers, [68Ga]Ga-PSMA-11, [18F]DCFPyL, and [18F]PSMA-1007 by evaluating the difference in semi-quantitative measurements of three prospective intermediate- to high-risk prostate cancer patient cohorts with histopathologic confirmation.
Despite its high specificity, PSMA PET/CT has a moderate to low sensitivity of 40–50% for pelvic lymph node detection, implicating that a negative PSMA PET/CT cannot rule out lymph node metastases and that for adequate prostate cancer staging an extended pelvic lymph node dissection (ePLND) is still needed in selected patients. In chapter 4, a strategy of implementing PSMA PET/CT for initial prostate cancer staging and treatment planning instead of conventional diagnostic work-up (i.e. standard ePLND) will be evaluated. In the investigated PSMA PET/CT strategy, ePLND is only performed in case of a negative PSMA PET/CT (due to the low sensitivity); in case of a positive scan treatment planning is solely based on PSMA PET/CT results.
The current EANM/SNMMI guideline recommends a 60-minute time interval (also known as uptake time) between [68Ga]Ga-PSMA administration and scan acquisition. This recommendation is based on one study evaluating the biodistribution of [68Ga]Ga-PSMA-11 after 60 and 180 minutes. Other time intervals were not investigated in this study. A shorter time interval between [68Ga]Ga-PSMA administration and scan acquisition may offer benefits. This will be evaluated in chapter 5.
Part II:Prostate cancer therapy
In chapter 6, a brief overview of the literature will be given about Lutetium-177-PSMA therapy for prostate cancer patients.
Some have suggested that competition between the uptake of the radiopharmaceutical [177Lu]Lu-PSMA in prostate tumour tissue and healthy tissue may influence the biodistribution by inducing a ‘steal’ phenomenon, resulting in diminished uptake in healthy tissue. In chapter 7, this thesis clarifies whether a ‘steal’ phenomenon exists by investigating if PSMA uptake in tumour tissue correlates with the uptake in healthy tissue. If a ‘steal’ phenomenon indeed exists, PSMA-targeted radioligand therapy may be individualized based on the total tumour load and potentially reduce/avoid unwanted side effects.
Earlier studies have mostly identified pre-therapeutic clinical and laboratory parameters for the prediction of treatment response to [177Lu]Lu-PSMA-617 in metastatic castration resistant prostate cancer patients (mCRPC). Chapter 8 evaluates whether imaging-derived factors on baseline [68Ga]Ga-PSMA-11 PET/CT can potentially predict the response after two cycles of [177Lu]Lu-PSMA-617 treatment, in a lesion- and patient-based analysis in men with mCRPC.
[177Lu]Lu-PSMA-617 has shown impressive clinical and biochemical responses with low toxicity in salvage settings in metastatic castration-resistant prostate cancer. In chapter 9 a protocol is described to prospectively evaluate the use of [177Lu]Lu-PSMA-617 in curative intent treatment. Patients with locoregional lymph node disease at diagnosis (N1M0), standard of care treatment (external beam radiation therapy (EBRT) and androgen deprivation therapy (ADT)) will be treated with a single administration of [177Lu]Lu-PSMA-617. Hypothetically, this combined approach will enhance EBRT to better control macroscopic tumour localizations, and treat undetected microscopic disease locations inside and outside EBRT fields.