The Role of GA⁶⁸-PSMA PET/CT in Restaging of Biochemical Recurrent Prostate Cancer After Radical Prostatectomy and/or Radiotherapy

doi:10.21203/rs.3.rs-4341791/v1

Introduction:

The aim of our study was to investigate the the diagnostic performance of PSMA PET/CT performed for restaging in subjects with biochemical recurrent prostate carcinoma after curative treatment either with radical prostatectomy (RP) or Radiation Treatment (RT).

Method

58 prostate cancer patients (Age 73 ± 8) with biochemical recurrent prostate carcinoma after curative Treatment (with RP or RT) who underwent Ga68-PSMA PET/CT between December 2015 and August 2022 were retrospectively analyzed. PSMA uptake levels were grouped as posivite or negative. Positive disease locations were classified as prostate/prostate bed, pelvic lymph node, abdominal lymph node, supradiaphragmatic lymph node, bone, visceral organ. SUVmax values were recorded for positive disease sites. According to PSMA PET/CT findings, the extent of disease was decided (pelvis limited and distant metastatic). Gleason score, ISUP grade (International Society of Urological Pathology)), PSA, PSAdt, PSAvelocity and pathological SUVmax values were recorded and compared in PET positive and negative subjects and also in RT and RP groups. Findings were correlated with histopathological results and /or radiological, clinical and laboratory findings.

Results

PSMA PET/CT was positive in 33 patients, negative in 25 patients. The sensitivity, specificity, positive predictive value and negative predictive value of PSMA PET/CT were calculated as 73.2%, 78.6%, 90.9%, 50%, respectively. Patient-based detection rate was found to be 57%. Detection rate was 24% when PSA level was < 1 ng/ml, 69% when PSA level was between 1–4 ng/ml and 81% when PSA level was above 4 ng/ml. A statistically significant correlation was found between Ga68-PSMA PET/CT positivity and age, Gleason score, ISUP grade and PSA level. PSA value was found to be significantly higher in PET-positive patients. The threshold value in the ROC analysis for PSA was calculated as 1.0050 ng/ml, and was statistically significant (p = 0.06).In the presence of bone involvement, Gleason score average and PSA were found to be higher. A statistically significant relationship was found between visceral involvement, supradiaphragmatic LN involvement and bone involvement and ISUP Grade categories. A statistically significant strong positive correlation was observed between PSA and bone SUVmax. PSA value was observed to be significantly higher in patients with distant metastases. It was noted that the PSAdt value was shorter, especially in cases with extensive metatatic disease. The uptake in local recurrence site was higher in subjects who had RT than in subcets with RP. No difference was noted for both groups in other metastatic disase sites.

Conclusion

Ga68-PSMA PET/CT has shown reliable performance in locating recurrence sites of prostate cancer. This performance is better when the PSA serum level is above 1 ng/mL. Ga68-PSMA PET/CT imaging should be considered and used as the first-line imaging modality for biochemical recurrence in prostate cancer patients who had curative treatment.

Nuclear Medicine & Medical Imaging

Ga68-PSMA PET/CT

biochemical recurrence

detection rate

restaging

radical prostatectomy (RP) or Radiation Treatment (RT)

According to World Health Organization (WHO) "GLOBOCAN 2020" data, prostate cancer is the most common cancer in men and accounts for 20% of all cancers (1).

Prostate cancer diagnostic methods are digital rectal examination (DRM), prostate specific antigen (PSA), multiparametric magnetic resonance imaging (mpMRI) and transrectal ultrasonography (TRUS)-guided biopsy, which is the gold standard method. Although it varies depending on the stage, there are many treatment options such as active surveillance, local therapies (radiotherapy[RT], brachytherapy, etc.), surgery (TUR-P, radical prostatectomy [RP]), androgen deprivation therapy and chemotherapy.

PSMA-based molecular imaging (especially Ga68-PSMA PET/CT) stands out in prostate cancer. Prostate specific membrane antigen (PSMA) is a type II transmembrane glycoprotein and its expression is increased in prostate cancer. Prostate cancer cells can be detected with high specificity with Ga68-PSMA PET/CT. Ga68-PSMA PET/CT (positron emission tomography/computed tomography) imaging is more sensitive than conventional imaging such as bone scintigraphy and CT in terms of lymph node and bone metastasis detection (2). The use of Ga68-PSMA PET/CT is becoming increasingly common in prostate cancer staging, treatment response evaluation, and biochemical recurrence.

Relapse may occur in later periods in patients who had local curative treatment. Biochemical recurrence is defined following radical prostatectomy by two consecutive rising prostate specific antigen (PSA) values >0.2 ng/mL or after primary radiation therapy by any PSA increase >2 ng/mL higher than the PSA nadir value. In these case, detecting disease localization is important as it may affect the treatment approach.

PSMA-based molecular imaging is not yet routinely recommended in the NCCN guidelines (National Comprehensive Cancer Network) (3). According to the EAU (European Association of Urology) guideline, PSMA PET is recommended in BR after radical prostatectomy and before curative salvage treatment in BR after radiotherapy (2). European Association of Medical Oncologists suggest to PSMA PET/CT medium and high risk patients due to higher sensitivity and specificity (4).

The sensitivity and specificity of mpMRI in biochemical recurrence vary in the literature. After radical prostatectomy, sensitivity varies between 48-98% and specificity varies between 84-100%. After radiotherapy, 82% sensitivity and 74% specificity were reported (5). PSMA PET/CT has been shown to be more sensitive than other imaging methods, especially at <1 ng/mL PSA levels (6) (detection rates at 0–0.19 ng/ml, 0.2–0.49 ng/ml, 0.5–0.99 ng/mL levels are 33%, 45%, 59%, respectively). Disease recurrence can be detected earlier with Ga-68 PSMA PET/CT examination, and it is predicted that it can be used as an effective imaging method in disease management. Although there are reports showing that Ga68-PSMA PET/CT can cause a treatment change in more than 50% of patients with biochemical recurrence (7, 53%), there are no large studies on how much patients benefit from this situation.

In this study, we aimed to investigate the relationship between Gleason score, ISUP grade, simultaneous serum PSA values and PSMA positive lesion detectability in Ga68-PSMA PET/CT examination performed for restaging purposes in patients diagnosed with prostatic adenocarcinoma who developed biochemical recurrence. Another aim is to examine the accuracy of PSMA PET findings and treatment management decisions through patient follow-up.

2.1. Population

Ga68-PSMA PET/CT images, performed for restaging purposes at Akdeniz University Department of Nuclear Medicine between December 2015 and August 2022, were retrospectively examined for 58 patients who were histopathologically diagnosed with prostate cancer and developed biochemical recurrence during follow-up.

Clinical information of the patients, ages, histopathological features (Gleason score / ISUP Grade), previous treatments, PSA values, PSA doubling time (PSAdt, months), PSA velocity (PSAv, ng/ml/year)) values were recorded.

Inclusion criteria;

• Patients with histopathologically confirmed diagnosis of prostate adenocarcinoma

• History of curative treatment (prostatectomy, radiotherapy)

• Patients with no known history of distant metastasis

• Presence of biochemical recurrence confirmed twice by current PSA values

Exclusion criteria;

• Patients known to have distant metastases

• Patients who not have curative treatment

• Presence of persistent PSA (PSA > 0.1 ng/mL within 4-8 weeks after RP, 3)

• Presence of a second malignancy

This study was approved by Akdeniz University Faculty of Medicine Clinical Research Ethics Committee.

2.2. Ga68-PSMA PET/CT Imaging Procedure

Ga68 radionuclide was obtained by elution from the Ge68/Ga68 generator. 25 μg of PSMA-617 compound was labeled with Ga68 in the fully automatic synthesis module, and the labeling efficiency and radiochemical purity were determined using radio-high-performance liquid chromatography (radio-HPLC). The radiochemical purity of Ga68 labeled PSMA conjugates was considered ≥95%. Following the preparation and quality control of the radiopharmaceutical, an average of 3.86 ±0.77 (range 3-5) mCi Ga68-PSMA was injected intravenously into the patients. After the injection, approximately 1 liter of water with orally usable contrast material was added to it. Approximately 60 minutes after the intravenous Ga68-PSMA injection, PET/CT imaging was performed from the vertex to the mid-thigh in the supine position.

PET/CT imaging of all patients was performed with an integrated PET/CT device (Biograph 16, Siemens, Erlangen, Germany), and simultaneous PET and CT images were taken in the same session. Non-diagnostic low-dose CT (slice thickness 5 mm, 120 mAs, 130 kV) images were used for anatomical correlation and attenuation correction purposes. Following the CT images taken from the vertex to the mid-thigh, PET images were taken from the vertex to the mid-thigh in approximately 7-8 bed positions, with an emission time of 2 minutes for each bed position. Images were reconstructed on the Siemens Syngo.via PET/CT workstation and recorded in transaxial, coronal and sagittal planes.

2.3. Ga68-PSMA PET/CT Image Analysis

In visual evaluation, tracer uptakes above background activity were considered significant. PSMA positive foci were localized anatomically with nondiagnostic CT images.

Areas of increased activity uptake distinguished from the surrounding and physiological tissue in attenuation-corrected images were graded between 0 and 2 (0 = negative, 1 = low suspicious uptake from the mediastinal blood pool, 2 = high positive uptake from the mediastinal blood pool). Volumetric regions of interest (VOI) were drawn for all lesions considered positive. Care was taken to ensure that the drawn areas of interest completely covered the lesion. SUVmax (maximum standardized reception value) values of the region within the VOI were recorded.

Findings were categorized as prostate/prostate bed, pelvic lymph node, abdominal lymph node, supradiaphragmatic lymph node, bone and visceral organ involvement. In the presence of more than one lesion, the lesion with the highest SUVmax value was selected.

Based on Ga68 PSMA PET/CT results, current disease status was classified as pelvic-limited disease (local and leukoregional) and distant metastatic (extrapelvic lymph node, visceral and bone metastasis) disease.

Lecouvet et al criteria were used to distinguish oligometastatic (≤ 3 lesions) and polymetastatic (> 3 lesions) (102).

2.4. Effect of Ga68-PSMA PET/CT on Patient Management and Follow-up

After imaging, the clinical history notes of the referring department (urology, medical oncology, radiation oncology) were accessed for each patient and patient follow-up was performed. The treatment decisions they made according Ga68-PSMA PET/CT findings, current laboratory findings, and the patient's performance, were noted. A decrease of more than 50% in PSA after the treatment was considered as treatment response.

The standard of accuracy of Ga68-PSMA PET/CT findings was determined by accessing all available data such as histopathological findings, other imaging results, follow-up imaging and PSA level during the follow-up period in each patient. Histopathological findings, when available, were considered the strongest criterion. When histopathological confirmation was not available, findings were evaluated as true positive, true negative, false positive, and false negative if at least three of the following criteria were met;

• True positive; positive imaging, getting targeted treatment with imaging findings, PSA response after treatment, decrease in the number or size of lesions in follow-up imaging

• True negative; negative imaging, getting other targeted treatment and PSA response after this treatment, no change in follow-up imaging

• False positive; positive imaging, atypical localisation for prostate cancer metastasis, getting treatment for atypical findings and no PSA response, getting treatment for another target and PSA response, stable course of atypical finding in follow-up imaging

• False negative; negative imaging, local treatment and PSA response (salvage radiation therapy may be recommended according to guidelines for prostate cancer patients presenting with BR after prostatectomy and without evidence of distant metastatic disease, 6), development of abnormal findings in this area on follow-up imaging

2.5. Statistical Analysis

Statistical analysis of the data was performed with SPSS version 24. The results were evaluated at 95% confidence level. Frequencies, percentages, mean and standard deviation values were calculated within the scope of descriptive statistics. The relationships between categorical variables were analysed by "Chi-square test", while "t-test" and "Anova test" were used to compare quantitative variables in terms of groups. "Spearman correlation test" was used in correlation analyses. ROC analysis was performed to determine the cut-off values for the parameters selected in the study. Results with a p value below 0.05 were considered statistically significant.

The study included 58 patients. 42 patients (72.4%) had biochemical recurrence after RP and 16 patients (28%) had biochemical recurrence after RT. The mean age of the patients was 73,1 ± 8 years. Patient characteristics are shown in Table 1.

Table 1. Patient characteristics

			N		%		Mean (±SD)
Age							73,1 ± 8
Time since diagnosis (year)							10,2 ± 3,6
Age at diagnosis							67,7 ± 7,6
Injected activity (Mci)							3,8 ± 0,6
Group	Surgery		42		72,4
	RT		16		27,6
Previous treatments	Surgery		28		48,3
	Surgery+RT±ADT		12		20,7
	RT±ADT		18		31,0
Gleason Score							7,3 ± 1,0
ISUP Grade	1		8		18,2
	2		19		43,2
	3		4		9,1
	4		6		13,6
	5		7		15,9
ISUP Grade category	Grade 1-2		27		46,6
	Grade 3-5		17		29,3
	Unknown		14		24,1
PSA at PET (ng/ml)								7,6 ± 15,8
PSA category		<1		21		36,2
		1-4		16		27,6
		>4		21		36,2
PSAdt (month)								11,4 ± 12
PSA velocity (ng/mL/year)								6,7 ± 14,5
Time between PSA and PET (day)								18,2 ± 15,6

PSA levels were between 0.2-0.5 ng/ml in 14 patients (33.3%), between 0.5-1 ng/ml in 7 patients (16.7%), between 1-2 ng/ml in 5 patients (11.9%) and above 2 ng/ml in 16 patients (38.1%) in the BR group after RP. In the BR group after RT, it was between 2-4 ng/ml in 9 patients (56.2%) and above 4 in 7 patients (43.8%, Figure 1).

There were no statistically significant differences between the patient groups in terms of Gleason score, ISUP grade and category, PSA, PSAdt and PSAvelocity.

Table 2. Laboratory and histopathological characteristics of patient groups

														p
		BR group after RP (PSA>0,2ng/ml) (n=42)				BR group after RT (PSA>2,0 ng/ml) (n=16)				Total (n=58)
		N	%	Mean	SD	N	%	Mean	SD	N	%	Mean	SD
Gleason Score				7,2	1,0			7,40	1,3			7,3	1,0	0,648
ISUP Grade	1	5	14,7			3	30,0			8	18,2			0,360
	2	17	50,0			2	20,0			19	43,2
	3	3	8,8			1	10,0			4	9,1
	4	5	14,7			1	10,0			6	13,6
	5	4	11,8			3	30,0			7	15,9
ISUP Grade category	Grade 1-2	22				5				27				0,250
	Grade 3-5	12				5				17
	Unknown	8				6				14
PSA at PET (ng/ml)				4,7	8,5			15,2	25,8			7,6	15,8	0,131
PSAdt (month)				7,9	6,2			20,1	17,8			11,4	12,0	0,060
PSA velocity (ng/mL/year)				8,0	16,9			3,6	4,8			6,7	14,5	0,241

3 patients had suspicious uptake (pelvic and abdominal lymph node, bone). PSMA PET/CT detection rate was 57% (n=33) in all patients when suspicious uptake was evaluated together with positive uptake. The detection rate in the BR patient group after RT was 75% (n=12), which was higher than the BR patient group after RP (50%, n=21), but this difference was not statistically significant (p=0.086). 67% (n=20) of the patients had pelvis limited disease and 33% (n=10) had distant metastasis. Statistically more positive uptake was observed in the prostate lobe in the BR patient group after RT (p=0.01). No significant statistical difference was found in other anatomical regions and their SUVmax values, disease extent (Table 3).

Table 3. Ga-68 PSMA PET/CT results

														p
		BR group after RP (PSA>0,2ng/ml) (n=42)				BR group after RT (PSA>2,0 ng/ml) (n=16)				Total (n=58)
		N	%	Mean	SD	N	%	Mean	SD	N	%	Mean	SD
PSMA PET status	Negative	21	50,0			4	25,0			25	43,1			0,086
PSMA PET status	Positive	21	50,0			12	75,0			33	56,9			0,086
Disease status	Pelvis limited	13	72,2			7	58,3			20	66,7			0,429
Disease status	Distant metastatic	5	27,8			5	41,7			10	33,3			0,429
Prostate/prostatic lodge	Negative	35	83,3			8	50,0			43	74,1			0,010
Prostate/prostatic lodge	Positive	7	16,7			8	50,0			15	25,9			0,010
Prostate lesion SUVmax				20,9	9,1			14,8	11,7			17,7	10,7	0,286
Pelvic lymph node	Negative	33	78,6			13	81,3			46	79,3			0,822
Pelvic lymph node	Positive	9	21,4			3	18,8			12	20,7			0,822
Pelvic lymph nodes SUVmax				16,0	16,0			16,6	12,1			16,1	14,6	0,954
Abdominal lymph node	Negative	40	95,2			13	81,3			53	91,4			0,090
Abdominal lymph node	Positive	2	4,8			3	18,8			5	8,6			0,090
Abdominal lymph node SUVmax				17,4	16,8			12,7	7,1			14,6	10,1	0,678
Viscera	Negative	40	95,2			15	93,8			55	94,8			0,819
Viscera	Positive	2	4,8			1	6,3			3	5,2			0,819
Viscera SUVmax				19,8	8,1			16,5				18,7	6,1
Supradiaphragmatic lymph node	Negative	41	97,6			13	81,3			54	93,1			0,105
Supradiaphragmatic lymph node	Positive	1	2,4			3	18,8			4	6,9			0,105
Supradiaphragmatic lymph nodes SUVmax				6,00				36,6				29,0
Bone	Negative	36	85,7			12	75,0			48	82,8			0,334
Bone	Positive	6	14,3			4	25,0			10	17,2			0,334
Bone SUVmax				13,2	13,0			28,4	18,2			19,3	16,3	0,159

PSA level was significantly higher in PSMA PET positive patients (11.8 vs. 2.1 p=0.010, Table 4). PSMA PET was positive in 23.8%, 68.8% and 81% of patients with PSA levels <1 ng/ml, between 1-4 ng/ml and >4 ng/ml, respectively (p=0.000). The mean Gleason score of PET positive patients was higher than negative patients (7.5 vs. 6.9 p=0.046). While 63% of patients with low ISUP grade were PET negative and 37% were PET positive, 23.5% of patients with high ISUP grade were PET negative and 76.5% were PET positive. This distribution was statistically significant (p=0.017).

Table 4. Comparison of clinical, histopathological and laboratory findings with PSMA PET/CT

		PET status							p
		Negative				Positive
		Mean		SD		Mean		SD
Age		70,3		7,3		75,3		7,9	0,018
Age at diagnosis		66,2		6,2		68,9		8,3	0,183
Time since diagnosis (BR time, year)		9,1		4,2		11,0		2,9	0,047
Gleason score		6,9		0,4		7,5		1,3	0,046
PSA at PET		2,1		3,5		11,8		19,9	0,010
PSAdt (month)		11,7		12,3		11,2		12,0	0,898
PSA velocity (ng/mL/year)		2,3		3,8		9,7		18,1	0,083
			N		%	N	%
Patient group After RP After RT			21 4		50,0 25,0	21 12	50,0 75,0		0,155
Previous treatments	Surgery		18		64,3	10	35,7		0,007
	Surgery + RT ± ADT		3		25,0	9	75,0
	RT ± ADT		4		22,2	14	77,8
ISUP Grade category	Grade 1-2		17		63,0	10	37,0		0,017
	Grade 3-5		4		23,5	13	76,5
	Unknown		4		28,6	10	71,4
PSA	<1 ng/ml		16		76,2	5	23,8		0,000
	1-4 ng/ml		5		31,3	11	68,8
	>4 ng/ml		4		19,0	17	81,0

PSA value was found to be significantly higher in PET positive patients; however, faster PSAdt and PSA velocity values were not observed in PET positive patients. PSA, PSAdt and PSAvelocity values and their diagnostic values calculated by ROC analysis are given in Table 4.6. The threshold value for PSA was calculated as 1.0050 ng/ml, 3.8 months for PSAdt and 1.25 mg/ml/year for PSAvel.

Table 5. PSA, PSAdt and PSAvel ROC analysis results

Variables	Area	sh	p-value	95% confidence interval for mean (CI)		Cut-off value	Sensitivity	Specificity
Variables	Area	sh	p-value	Lower bound	Upper bound	Cut-off value	Sensitivity	Specificity
PSA at PSMA PET (ng/ml)	0,779	0,084	0,006	0,614	0,943	1,0050	0,857	0,643
PSAdt (month)	0,509	0,105	0,933	0,302	0,715	3,800	0,857	0,357
PSA velosite (ng/mL/yıl)	0,723	0,090	0,027	0,547	0,899	1,250	0,714	0,786

PSA with the highest AUC value has a better diagnostic value than the other two variables, while PSAdt has the lowest diagnostic value.

When PSMA uptake localisations were examined according to Gleason score and PSA, Gleason score and PSA were higher in the presence of bone involvement (p=0.008 and p=0.049, Table 6).

Table 6. Association of PSMA uptake with Gleason score and PSA

		Gleason score		p	PSA		p
		Mean	SD	p	Mean	SD	p
Prostate/prostatic lodge	Negative	7,2	0,8	0,454	5,2	10,1	0,186
Prostate/prostatic lodge	Positive	7,5	1,5	0,454	14,5	25,4	0,186
Pelvic lymph node	Negative	7,2	1,0	0,284	7,0	16,5	0,551
Pelvic lymph node	Positive	7,6	1,3	0,284	10,1	13,1	0,551
Abdominal lymph node	Negative	7,3	1,0	0,287	5,2	9,5	0,193
Abdominal lymph node	Positive	6,5	0,7	0,287	32,7	39,3	0,193
Viscera	Negative	7,2	1,0	0,493	7,9	16,2	0,493
Viscera	Positive	7,7	0,6	0,493	1,4	1,2	0,493
Supradiaphragmatic lymph node	Negative	7,3	1,0	0,713	5,7	9,7	0,315
Supradiaphragmatic lymph node	Positive	7,0	0,0	0,713	33,5	46,2	0,315
Bone	Negative	7,1	0,9	0,008	3,7	5,4	0,049
Bone	Positive	8,4	1,1	0,008	26,2	31,2	0,049

When PSMA involvement localisations were examined according to ISUP Grade category (Table 7), a statistically significant relationship was found between visceral involvement (p=0.022), supradiaphragmatic LN involvement (p=0.036) and bone involvement (p=0.026).

Table 7. Association of PSMA uptake with ISUP grade ilişkisi

		ISUP Grade Category						p
		Grade 1-2		Grade 3-5		Unknown
		N	%	N	%	N	%
Prostate/prostatic lodge	Negative	21	77,8	12	70,6	10	71,4	0,839
Prostate/prostatic lodge	Positive	6	22,2	5	29,4	4	28,6	0,839
Pelvic lymph node	Negative	24	88,9	12	70,6	10	71,4	0,243
Pelvic lymph node	Positive	3	11,1	5	29,4	4	28,6	0,243
Abdominal lymph node	Negative	25	92,6	17	100,0	11	78,6	0,102
Abdominal lymph node	Positive	2	7,4	0	0,0	3	21,4	0,102
Viscera	Negative	27	100,0	14	82,4	14	100,0	0,022
Viscera	Positive	0	0,0	3	17,6	0	0,0	0,022
Supradiaphragmatic lymph node	Negative	27	100,0	16	94,1	11	78,6	0,036
Supradiaphragmatic lymph node	Positive	0	0,0	1	5,9	3	21,4	0,036
Bone	Negative	26	96,3	13	76,5	9	64,3	0,026
Bone	Positive	1	3,7	4	23,5	5	35,7	0,026

The correlation of SUVmax values in different regions with Gleason score and PSA is shown in Table 8. There was a moderate positive correlation between Gleason score and prostate lesion SUVmax (r=0.533) and a weak positive correlation between Gleason score and visceral SUVmax (r=0.315), which were not statistically significant (p >0.05). There was a very weak positive correlation between PSA value and pelvic LN SUVmax (r = 0.102, p = 0.753) which was not statistically significant. A statistically significant strong positive correlation was observed between PSA and bone SUVmax (r = 0.748, p = 0.013).

Table 8. Correlation of SUVmax values with Gleason score and PSA

		Gleason score	PSA
Prostate lesion SUVmax	r	0,533	-0,318
Prostate lesion SUVmax	p	0,091	0,249
Pelvic lymph node SUVmax	r	-0,293	0,102
Pelvic lymph node SUVmax	p	0,482	0,753
Viscera SUVmax	r	0,315	-0,544
Viscera SUVmax	p	0,796	0,634
Bone SUVmax	r	-0,491	0,748
Bone SUVmax	p	0,401	0,013

The comparison of disease extensity with clinical, pathological and laboratory values is given in Table 9. A statistically significant difference was found between disease extent and mean PSA values (p=0.034). The mean PSA was 24.9 ng/ml in distant metastatic patients and 6.9 ng/ml in pelvis limited patients. PSA value was significantly higher in distant metastatic patients. Although no significant differences were found in terms of PSAdt, it was noteworthy that the PSAdt value was shorter especially in cases of increased involvement (metastatic status, positive involvement). No statistically significant correlation was observed between the number of metastatic foci and age, BR time, Gleason score, PSA, PSAdt and PSAvelocity (p>0.05).

Table 9. Comparison of disease extensity and number of metastatic foci with clinical, pathological and laboratory values

	Disease extensity							Metastatic foci
	Pelvis limited		Distant metastatic		False posivite		p	Oligometastasis		Polymetastasis		p
	Mean	SD	Mean	SD	Mean	SD	p	Mean	SD	Mean	SD	p
Age	75,8	6,5	73,5	1,0	77,7	10,7	0,061	74,7	9,3	74,4	4,8	0,949
BR time (year)	10,9	2,8	10,6	3,4	12,7	2,1	0,568	10,7	3,4	10,6	2,7	0,936
Gleason score	7,4	1,4	8,2	1,2	6,5	0,7	0,270	7,8	1,6	7,8	0,8	0,977
PSA	6,9	9,9	24,9	30,3	0,7	0,5	0,034	9,6	14,2	24,5	31,8	0,162
PSAdt (month)	12,8	13,8	7,5	9,3	14,4	10,6	0,623	9,7	8,3	7,2	7,7	0,589
PSAvelocity (year)	9,7	22,1	12,3	12,4	0,5	0,5	0,740	6,9	9,9	10,7	11,7	0,543

Visceral (liver) involvement observed in 2 patients in the operated group was considered as false positive involvement. In one of them malignancy was excluded because the biopsy result was reactive hepatitis and chronic cholestasis. In the other patient, metastasis excluded in order to PSA level decreased in a short time and disappeared on follow-up imaging.

PSMA PET was negative in 25 patients and positive in 30 patients included in the study. In 3 patients, PSMA PET findings were suspicious. One of these was celiac ganglion, one was nonspecific bone involvement (PSA level became negative without treatment) and one was true positive pelvic lymph node.

Based on the clinical/laboratory and histopathological data of the patients, 51.7% (n=30) of the findings were evaluated as true positive, 19% (n=11) as true negative, 5.2% (n=3) as false positive and 19% (n=11) as false negative. Follow-up data of 3 patients were not available. When the data of these 3 patients were excluded, the calculated sensitivity, specificity, positive predictive and negative predictive values of PSMA PET/CT were 73.2%, 78.6%, 90.9% and 50%, respectively.

Follow-up was decided for 12 patients, RT ± ADT for 7 patients, RT ± ADT for 4 patients (unknown in 2 patients) in whom with negative PSMA PET. PET uptake was suspicious in the other 2 patients in whom follow-up was decided (ganglion and nonspecific bone uptake). PSA decreased in 10 of 14 patients in whom follow-up groupe, while PSA increased in 2 patients. Salvage RT± ADT was performed in patients with increased PSA and PSA response was observed. PSA level was stable in one patient and the other was unknown.

Of the 20 patients with pelvis limited disease, salvage RT ± ADT was decided for 7, ADT for 10, and CT (docetaxel) for one (2 patients unknown). Of the 10 patients with distant metastatic disease, 3 patients were given CT± ADT, 5 patients were given ADT, one patient was given palliative thoracic RT+ ADT and one patient was unknown.

Ga68-PSMA PET/CT is an increasingly frequently used imaging modality in prostate cancer staging, treatment response evaluation and restaging.

PSA recurrence is commonly seen after radical prostatectomy and radiotherapy. Biochemical recurrence is defined as a serum PSA value above 0.2 ng/ml after RP and an increase of more than 2 ng/ml from the lowest value after RT. The main aim in these patients is to differentiate between local and systemic disease, as this may affect the treatment approach (8). Ga68-PSMA PET/CT can visualise recurrence areas that other conventional imaging techniques cannot find even at low PSA levels.

Published data suggest that there are a large number of BR patients with favourable prognostic features (ISUP ≤ 2, pT2 stage, negative surgical margins, PSAdt > 12 months; BR interval > 18 months) who may not experience a clinically significant recurrence (9). One of the unmet clinical needs is to identify the group of BR patients who may benefit from salvage radiation therapy and a surveillance-based approach.

In this study, we evaluated the efficacy of Ga68-PSMA PET/CT in the localisation and detection of recurrent disease in patients with biochemical recurrent prostate cancer. Our study group consisted of 42 post-RP and 16 post-RT patients with biochemical recurrence.

According to the results of biochemical recurrence patients evaluated in the study group (mean PSA 7.6 ng/ml, range 0.24-100 ng/ml), Ga68-PSMA PET/CT patient-based detection rate was found to be 57%. These results are similar to most publications in the literature (9-12); however, there are also publications in the literature with higher (7, 13-15) and lower detection rates (16).

In a meta-analysis including 3693 patients and 24 studies (primary and recurrent disease), it was concluded that PSA was a predictor of a positive PSMA PET scan, and increased pre-PET PSA levels were associated with Ga68-PSMA PET positivity (17). According to this meta-analysis, PSMA PET/CT positivity rates were 45%, 59%, 75% and 95% when PSA levels were 0.2-0.49 ng/ml, 0.5-0.99 ng/ml, 1.00-1.99 ng/ml and >2.00 ng/ml, respectively. When the post-RP studies were evaluated separately, a non-statistically significant higher positivity rate was observed at 1-1.99 ng/ml PSA level (82% vs. 64%). In another study, PSMA PET/CT detection rates at PSA values of 0-0.19 ng/ml, 0.20-0.99 ng/ml, 1.00-1.99 ng/ml and ≥2 ng/ml were 21%, 41%, 91% and 92%, respectively (18). Statistically significant correlation between PSMA PET/CT positivity and PSA level has been reported in other studies in the literature (11, 12, 14, 18). In our study, PSA level was found to be significantly higher in PSMA PET positive patients. However, as the PSA level increased, PSMA PET/CT detection rate increased (23.8%, 68.8%, 81% for PSA levels <1 ng/ml, 1-4 ng/ml and >4 ng/ml, respectively). In this respect, the study results are compatible with the literature. Due to the heterogeneous distribution of the patient population in the study, PSA levels could not be categorised as 0.2-0.5 ng/ml, 0.5-1 ng/ml, 1-2 ng/ml and >2 ng/ml as in most publications in the literature and PSMA PET/CT detection at very low PSA values could not be investigated.

In the study, the site of recurrence could be demonstrated at low PSA values (<1 ng/ml) with a rate of 23.8%. This rate is lower than the rate of 44% obtained by Ceci et al (332 patients, 10) and Verburg et al (155 patients,19). The reason for this may be difference number of patients. Pelvic recurrence site was detected in 3 of 11 low PSA patients and pelvic radiotherapy was applied to 8 patients including these patients. There were no distant metastatic patients in low PSA patients in the study group. However, it should be kept in mind that these patients may have distant metastasis and pelvic salvage radiotherapy may not be an appropriate treatment option.

In a study by Ceci et al. with 70 patients, significant differences were found between 68Ga-PSMA PET/CT positive and negative patients in terms of PSA level (higher in positive patients) and PSAdt (faster kinetics in positive patients). In addition, PSAdt was shown to be a significant predictor of positive PSMA PET scan and detection of distant lesions. In ROC analysis, threshold values of 6.5 months for PSAdt (AUC: 0.868, 95% Confidence Interval: 0.767 - 0.969) and 0.83 ng/mL for PSA (AUC: 0.764, 95% Confidence Interval: 0.647 - 0.882) were found (13). In our study, a correlation was observed between PSA and PSMA PET/CT positivity, but no statistically significant difference was observed between PSAdt and PSA velocity. In addition, the PSA threshold value was found to be 1.005 with 86% sensitivity and 64% specificity (AUC: 0.779, 95% Confidence Interval: 0.614 - 0.943). PSAdt and PSAvel could be statistically analysed in only 35 patients. Threshold values were found to be 3.8 months with 86% sensitivity and 36% specificity for PSAdt (AUC: 0.509, 95% Confidence Interval: 0.302 - 0.715) and 1.25 ng/ml/year with 71% sensitivity and 79% specificity for PSA velocity (AUC: 0.723, 95% Confidence Interval: 0.547 - 0.899), but not statistically significant.

In a study by Verburg et al. local prostate tumour, extrapelvic lymph node and bone metastasis rates were higher in patients with higher PSA levels. Shorter PSAdt was associated with pelvic and extrapelvic lymph node, bone metastasis, visceral metastasis; higher Gleason score was associated with pelvic lymph node metastasis. Both PSA and PSAdt were found to be the only independent markers of scan positivity and extrapelvic lymph node metastasis, and PSAdt was found to be the only independent marker of bone metastases (19). In our study, PSA and Gleason score mean were found to be higher in the presence of bone involvement. In addition, PSA value was significantly higher in distant metastatic patients (mean 24.86 vs. 6.9). Although there was no difference in terms of PSAdt, it was observed to be shorter in distant metastatic patients and in positive uptake.

In the meta-analysis performed by Perera et al. in 2020, the overall positivity rates were 28% in the prostate bed, 38% in pelvic lymph nodes, 13% in extrapelvic lymph nodes, 22% in bone and 5% in visceral organs (17). In our study, the most common sites of involvement were the prostate gland (n=15, 26%), pelvic lymph nodes (n=12, 21%) and bone (n=10, 18%) in parallel with this meta-analysis. In the same meta-analysis, statistically more positivity was found in the prostate bed in the post-radiotherapy group (52% vs. 22%). In this study, statistically more uptake was observed in patients with BR in the prostate lodge after RT, which is consistent with the literature. This may be due to the lack of surgical removal of the minimal residual source However, there was no significant difference between PSMA PET/CT positivity and Gleason score according to the publications including staging and restaging in the same meta-analysis, positivity was 72% in patients with Gleason score 7 and 80% in patients with Gleason score 8. In our study, the mean Gleason score was higher in PET positive patients. In the same time, more positivity was found in patients with high ISUP grade. Similarly, in the study published by Celli et al. in 2021, ISUP categories were defined as the only significant risk factor for clinical recurrence. More clinical relapses have been reported in ISUP grade 4-5 compared to grades 1-2 and 3 (9) and recurrence-free survival is longer in patients with lower ISUP grades (20.5 months in grade 1-2; 12.6 in grade 3 and 12.1 in grade 4-5). In our study, supradiaphragmatic lymph node and bone involvement leading to distant metastatic staging were more common in patients with high ISUP grade.

In the study by Ertürk et al. evaluating the relationship between PSMA PET/CT findings and ALP, LDH and PSA in 61 unoperated prostate cancer patients, no significant correlation was found between prostate SUVmax and PSA. Significant correlation was observed between high ALP levels and serum PSA and extensive bone metastasis (20). Another study reported a correlation between prostate SUVmax and ISUP grade (21). In our study, no significant correlation was found between prostate SUVmax and PSA and Gleson score. In the correlation analysis, only a positive correlation was observed between PSA and bone SUVmax.

The overall sensitivity and specificity of PSMA PET/CT were calculated as 75% and 99% on a lesion basis and 77% and 97% on a patient basis, respectively (17). The sensitivity value calculated in our study was 73%, which is at a similar level, but the specificity value was lower (78.6%). Other diagnostic performance parameters calculated in the study were positive predictive value (90.9%) and negative predictive value (50%). The reason for the low specificity and negative predictive value compared to the literature may be that the correlation is mostly made with clinical follow-up based on PSA and other imaging methods, not histopathological confirmation. However, due to its high sensitivity and positive predictive value, we can say that PSMA PET/CT provides a high probability of disease localisation in biochemical recurrence. In this study, 9 of the 11 patients who were evaluated as false negative had negative PSA after RT and/or ADT, and the other 2 patients had a decrease in PSA after salvage RT after PSA increase became apparent in the follow-up.

PSA value was below 1 ng/ml in 9 of 11 patients who were evaluated as false negative in the study. In 6 of them, the PSA value was between 0.2-0.5 ng/ml. In one patient (postoperative 5th month), the follow-up PSA value was 33.9 ng/ml, and since the control PSA value decreased to 16 ng/ml at the time of PSMA PET without treatment, it was thought that this may be secondary to laboratory error or postoperative fluctuation. The PSA value of the last remaining patient was 4.77 ng/ml.

Unspecific bone involvement and celiac ganglion involvement were present in 2 of the 3 patients with suspicious uptake. In a multicentre retrospective cohort analysis of 298 patients in which biochemical recurrence was investigated in 2022 (53 patients eligible for final diagnostic analysis, 81 positive bone lesions), Ga68-PSMA PET results were evaluated (22). Accordingly, most bone involvement was due to benign lesions. Bone involvement was observed in 32.9% of patients and metastasis rate was 34.6% (28/81 lesions). Initial Gleason score ≥ 8, age at recurrence ≤ 71 years and SUVmax > 6.21 were found to be independent predictors of prostate cancer metastasis. In a recent retrospective analysis of 348 patients, unspecific bone involvement was observed in 51.4% and the most common localisation was the costa and pelvis (23). In another study with F18-PSMA and Ga68-PSMA (24), similar metastasis detection rates were found with both radiopharmaceuticals (n=72 vs 64). Unspecific bone uptake was more common with F18-PSMA PET/CT than with Ga68-PSMA PET/CT (34.2% vs. 16.7%). There was no significant difference between PSA groups (<1, 1-5, >5 ng/ml) in the detection of metastasis and unspecific bone involvement. It has been emphasised that focal bone involvement in biochemical recurrent patients with PSA ≤ 5 ng/ml and SUV > 4 is likely to be false positive. In our study, unspecific bone involvement was found in the left femoral neck and SUVmax was 2.9 (PSA: 0.45).

Sympathetic ganglia are among the tissues where Ga68-PSMA expression is increased and is one of the potential causes of false positives that may lead to direct treatment regimen change. In histological studies, glutamate carboxypeptidase II was found to be highly expressed in non-myelinated schwann cells in the ganglia of the sympathetic nervous system. This explains the increased Ga68-PSMA-ligand uptake in sympathetic ganglia. Sympathetic ganglia are located along the vertebral column and can be easily confused with lymph node metastases located near the cervical, celiac or sacral ganglia. In the study by Rischpler et al. (25), Ga68-PSMA uptake was highest in the celiac ganglion (SUVmax: 2.9 ± 0.8) and SUVmax values in the cervical and sacral ganglia were 2.4 ± 0.6 and 1.7 ± 0.5, respectively. In addition, PSMA expression was significantly higher in lymph node metastases (cervical SUVmax: 18.0 ± 16.2, celiac 13.5 ± 12.3, ;sacral SUVmax: 13.4 ± 11.6). In addition, ganglia were predominantly band or teardrop shaped and rarely nodular in shape resembling lymph node metastasis. Therefore, PSMA ligand uptake and lesion configuration should be carefully examined in the differentiation of lymph node metastases and sympathetic ganglia. In our study, one patient (PSA: 0.46 ng/ml, Gleason score: 3+3) had a fusiform nodular lesion in the upper abdomen showing low level PSMA receptor activity. When it was re-evaluated due to the absence of morphological change in the follow-up, it was found to be celiac ganglion and SUVmax value was higher compared to the literature (SUVmax:5,6).

Increased PSMA expression due to neovascularisation in hepatocellular carcinoma has been reported in the literature (26). However, reports of increased PSMA uptake due to hepatitis are rare. In a case report published by Adediran et al. increased uptake on Ga68-PSMA PET/CT due to radiation hepatitis in the liver dome after radiotherapy in a patient diagnosed with invasive lobular carcinoma of the right breast (27). In our study, one patient with false positive liver uptake had histopathological confirmed cholestatic hepatitis.

The study has some limitations. One of these is that the study was retrospective. In addition, histopathological correlation of most of the positive uptake could not be performed and correlation was made with clinical follow-up/laboratory/other radiological methods. In addition, some patients were followed up in an external centre and referred to our centre only for imaging. Therefore, detailed clinical, laboratory and pathological data of each patient could not be obtained. Another limitation is that the total number of patients included in the study was small and therefore the number of patients in some subgroups was insufficient in statistical analysis. Because of these limitations, the promising performance and efficacy of Ga-68 PSMA PET/CT on disease management in prostate cancer restaging should be confirmed in a larger prospective study.

The detection rate of Ga68-PSMA PET/CT in biochemical recurrent prostate cancer was 57% and showed reliable performance. This diagnostic performance is better when the PSA serum level is above 1 ng/mL. Pelvic recurrence was demonstrated in more than half of the patients (67%). In these patients, PSMA PET/CT may also affect radiotherapy planning as it better shows lymph nodes that may be missed by conventional imaging methods.

Ga68-PSMA PET/CT findings were found to be correlated with PSA, Gleason score and ISUP grade. Especially in the presence of bone involvement, Gleason score and PSA were higher; a strong positive correlation was found between bone SUVmax and PSA. Although not statistically significant, shorter PSAdt was observed with extensive disease.

False positives and negatives should be kept in mind in reporting. It should be remembered that celiac ganglion, unspecific bone involvement and active hepatitis may cause false positivity. Correlation with clinical/laboratory and other radiological imaging and biopsy should be recommended if necessary.

Ga68-PSMA PET/CT imaging should be considered and used as the first-line imaging method for biochemical recurrence in curatively treated prostate cancer patients. Early detection of recurrence may offer more targeted treatment options. PSMA-labelled radionuclide therapies may be considered in patients who do not respond to conventional treatment.

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The authors declare no competing interests.

The Role of GA⁶⁸-PSMA PET/CT in Restaging of Biochemical Recurrent Prostate Cancer After Radical Prostatectomy and/or Radiotherapy

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