|Ahead of print publication
Is there a nonnegligible effect of maximum standardized uptake value in the staging and management of prostate cancer with 68Ga-prostate-specific membrane antigen positron emission tomography/computerized tomography imaging? A single-center experience
Ozgul Ekmekcioglu1, Abdullah Hizir Yavuzsan2, Pelin Arican1, Sinan Levent Kirecci2
1 Department of Nuclear Medicine, University of Health Sciences, Sisli Hamidiye Etfal Education and Research Hospital, Istanbul, Turkey
2 Department of Urology, University of Health Sciences, Sisli Hamidiye Etfal Education and Research Hospital, Istanbul, Turkey
|Date of Submission||25-Aug-2020|
|Date of Decision||26-Nov-2020|
|Date of Acceptance||29-Dec-2020|
|Date of Web Publication||30-Jul-2021|
Department of Nuclear Medicine,University of Health Sciences, Sisli Hamidiye Etfal Education and Research Hospital, Halaskargazi Cad, Etfal Sokak, Istanbul
Source of Support: None, Conflict of Interest: None
Purpose: Prostate-specific membrane antigen (PSMA) positron emission tomography/computerized tomography (PET/CT) has been shown to have significant success in detecting local and distant metastases that cannot not be detected by conventional imaging. Initial staging in intermediate- and high-risk patients with prostate cancer is important for management. In addition, PSMA uptake has been shown to have a relation with grade of disease, and thus could be considered a separate noninvasive prognostic factor. In this study, we aimed to investigate the effect of PSMA PET/CT in the staging and management of prostate cancer patients as well as the relation to maximum standardized uptake value (SUVmax).
Methods: The patients referred to our department for staging prostate cancer were evaluated retrospectively (n = 65). Patients were grouped as positive for lymph node or distant metastatic disease. Primary tumor SUVmax data were compared with the prognostic factors of the disease. In addition, decisions about treatment protocol before and after PSMA PET/CT imaging were noted.
Results: All the patients except one were accepted as positive for primary tumor. Of the patients, 46.2% were positive for lymph node and 24.6% for distant metastases. After evaluation by PSMA PET/CT, the clinical choice of treatment changed for 43.1% of our patients. Primary tumor SUVmax and tumor-to-background SUVmax ratios were found to have a significant relation with D'Amico risk classification. We found a positive correlation between SUVmax and prostate-specific antigen, Gleason scores, and age.
Conclusion: PSMA PET/CT images have a nonnegligible effect on staging, clinical decisions, and change in treatment protocol. SUVmax data have a positive correlation with risk classification and could be identified as a potential independent and non-invasive prognostic factor.
Keywords: Ga-68, maximum standardized uptake value, prostate cancer, prostate-specific membrane antigen
|How to cite this URL:|
Ekmekcioglu O, Yavuzsan AH, Arican P, Kirecci SL. Is there a nonnegligible effect of maximum standardized uptake value in the staging and management of prostate cancer with 68Ga-prostate-specific membrane antigen positron emission tomography/computerized tomography imaging? A single-center experience. J Can Res Ther [Epub ahead of print] [cited 2021 Nov 29]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=322713
| > Introduction|| |
Prostate carcinoma is the most common cancer and the second highest cause of mortality in men among noncutaneous malignancies. Clinical assessment and conventional radiology methods are still not sufficient for staging and foreseeing the clinical course due to the heterogeneity of the disease. Computerized tomography (CT), magnetic resonance imaging (MRI), and bone scan (BS) are useful for staging, but each of them has been shown to have drawbacks.,, For this reason, an assessment tool is needed to evaluate prostate carcinoma beginning from the diagnosis and continuing during management and follow-up.
Prostate-specific membrane antigen (PSMA) is a transmembrane glycoprotein that is 100–1000 times overexpressed in prostate cancer cells during tumor progression and recurrence. A study has shown that PSMA expression obtained from a histology specimen has a positive correlation with maximum standardized uptake value (SUVmax). SUVmax is an activity parameter of a specific region that is normalized to body weight and is used in positron emission tomography imaging. Gallium-68-PSMA positron emission tomography/computerized tomography (PET/CT) is used for staging and re-staging in biochemical recurrence and in detecting distant metastases., It has been shown to have a sensitivity of 67%–81% and a specificity of 71%–81% in some studies., Recently published articles have emphasized that PSMA PET/CT is a sensitive tool for primary staging.,, Furthermore, another study supported the use of PSMA PET/CT in staging prostate carcinoma, demonstrating a 28.6% change in assessing the stage of disease, which affects treatment protocol. PSMA uptake pattern has also been shown to be promising factor. A positive correlation with grade of disease and SUVmax has been shown and accordingly SUVmax has been reported a useful tool for risk assessment in Ga-68 PSMA PET/CT images. High-risk patients have been reported to have significantly higher SUVmax than low-risk patients.
There is still no consensus on the optimal initial treatment for low- and intermediate-grade prostate cancer. In the Prostate Testing for Cancer and Treatment (ProtecT) study, a 10-year follow-up showed no statistically significant difference for the cancer-specific survival rate (99.8%) and all-cause mortality between active surveillance, radical prostatectomy, and conformal radiation therapy in randomized groups of local prostate cancer patients. Four hundred and ninety-two advanced and high-risk prostate cancer patients with a median of 7.4 years of follow-up who were not included in the ProtecT study were shown to have a 10% cancer-specific mortality rate. This study shows the importance of an early and correct diagnosis in prostate cancer patients.
Classification of risk is important in making decisions about treatment. The D'Amico classification, which estimates the risk of recurrence within five years, is still the most popular method, even though other methods have been identified. This assessment is based on three clinical factors: prostate-specific antigen (PSA), Gleason score, and T stage of the disease. Gleason score is a pathological grading system that defines the aggressiveness of the tumor, which is determined by differentiating the grade of the cancer cells (a score of ≤6 = well differentiated, a score of 7 = moderately differentiated, and a score of 8–10 = poorly differentiated). In addition, prognostic factors are defined for aggressiveness and the possibility of early recurrence, which leads the clinician to a treatment decision. More than one-third of patients show upgrade and upstage of the disease even with the recent methods that identify the risk scales.
The aim of this study is to investigate the impact of Ga-68 PSMA PET/CT imaging on patients with recently diagnosed prostate cancer, including effects on staging and treatment approach and on the correlation of SUVmax values with other prognostic factors.
| > Methods|| |
Patient selection and image analysis
We retrospectively evaluated prostate cancer patients who were referred to our department between January 2017 and December 2019 for staging with Ga-68 PSMA PET/CT. The patients had been previously diagnosed with prostate cancer using a transrectal ultrasound-guided 12-core trucut biopsy. Patients were divided into groups according to their Gleason score, PSA levels, and D'Amico risk classification. Furthermore, patients' clinical TNM stages were noted before the Ga-68 PSMA PET/CT scan. Two nuclear medicine physicians (OE and PA) evaluated the Ga-68 PSMA PET/CT images separately, and where their opinions differed, they reached a consensus. Higher than background activity in the prostate gland and in other tissues were considered positive for tumoral uptake. Region of interest was drawn from the prostate gland to measure SUVmax. In addition, to decrease the effect of unnoticed activity uptake, region of interest was also drawn from the gluteal muscles to measure background SUVmax. Furthermore, two urologists (AY and SK) evaluated the patients separately to make treatment decisions both before and after they received the PSMA PET/CT reports. Not all of the patients were referred from our hospital; however, all the patients had received a pelvic MRI. The patients who were scheduled to have a radical prostatectomy received a CT scan of the abdominal region. All the patients were provided with detailed information and gave their informed consent.
After on-site synthesis of Ga-68 from the germanium generator and labeling with peptide (PSMA-11, 30 µg), a quality control with high-performance liquid chromatography technique was performed before injecting the radiopharmaceutical. The patients received approximately 111–370 Mbq (3–10 mci) of Ga-68 PSMA. After 45–60 min with an empty bladder, a whole-body CT scan (from head to midthigh) was performed (130 kV, 50–80 mAs, slice thickness of 3 mm), and then a PET scan was performed (GE Healthcare, Wisconsin, USA). Oral contrast was used in all patients.
All data were analyzed with SPSS (Statistical Package for the Social Sciences) software for Windows (v21.0; IBM, Armonk, NY, USA). Individual and aggregate data were summarized using descriptive statistics including mean, standard deviation, median (min–max), frequency distribution, and percentage. The normality of all data distribution was verified by the Kolmogorov–Smirnov test. For the variables that were not normally distributed, the Mann–Whitney U and Kruskal–Wallis tests were conducted to compare groups. The presence of correlation was analyzed with Spearman's rho tests. P < 0.05 was considered statistically significant.
| > Results|| |
Our study group comprised 65 patients with a mean age of 65.69 ± 9.67 (age range: 36–86) years [Table 1]. The mean value of PSA values was 129.90 ± 346.53 µg/L (3.9-1957). Initial clinical TNM staging was performed with a pelvic MRI. A BS was done when suspected metastases (n = 31; 47.7%). Only six patients' staging was performed with CT scan. If there was no suspicion of metastases, CT was not performed for the patients scanned with MRI for staging. CT evaluation was performed in four patients because of contraindications for MRI scan (pacemaker and metallic instrumentation) and in two patients due to suspicion of pulmonary metastasis.
The mean and median values of SUVmax (2.01–38.9) in primary tumors were 10.07 ± 7.14 and 7.59, respectively [Figure 1]. All the patients (n = 64) except one showed significant uptake in the primary tumor lesion side in the prostate gland. The one patient with normal PSMA uptake in the prostate gland was a low-risk patient with a 9.2 µg/ml PSA level and a Gleason score of 3 + 3. In addition, 46.2% of patients (n = 30) had positive findings for lymph node metastases, and 24.6% of patients (n = 16) had positive findings for distant metastases. The mean PSA values for the patients with positive findings for lymph node and distant metastases were 47.5 and 424.7 µg/ml, respectively [Figure 2].
|Figure 1: A 73-year-old patient with a prostate-specific antigen level of 61.31 μg/L and Gleason score 4 + 3 has the highest prostate maximum standardized uptake value of 38, 9|
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|Figure 2: A high-risk 72-year-old patient with positive findings for lymph node metastases prostate-specific antigen level of 117 μg/L, Gleason score of 4 + 5 and maximum standardized uptake value of prostate gland was 21, 2|
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The patients were grouped according to their Gleason score and D'Amico risk classification. With regard to their Gleason scores, 9 patients had a score of G3 + 3, 14 patients had a score of G3 + 4, 9 patients had a score of G4 + 4, 16 patients had a score of G4 + 3, 15 patients had a score of G4 + 5, and 2 patients had a score of G5 + 4. In addition, 5 (7.7%) patients were low risk, 16 (24.6%) were intermediate risk, and 44 (67.7%) were high risk [Table 1].
The correlation of PSMA uptake with the absence or presence of metastatic findings was evaluated with the Mann–Whitney U-test [Table 2]. There was no significant correlation with either lymph node metastasis (46.2%) or distant metastasis (24.6%) findings with mean primary tumor SUVmax values [P = 0.107 and 0.599; [Figure 3].
|Figure 3: The youngest patient in our study group with an age of 36 years demonstrated multiple bone metastases and prostate-specific antigen level of 284 μg/L; Gleason score was 4 + 5; primary tumor|
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Patient age had no effect on PSMA uptake patterns in either patients <60 years (23.1%; n = 15) or patients >60 years (76.9%; n = 50) (Mann–Whitney U-test, P = 0.127). However, Spearman's rho test revealed a significant positive correlation between primary tumor SUVmax values and the age of patients (r = 0.299, P = 0.016). In addition, the D'Amico classification revealed an increasing PSMA uptake pattern from low-risk (3.38 ± 1.34) to intermediate-risk (5.67 ± 3.27) to high-risk (12.43 ± 7.34) patients using the Kruskal–Wallis test [P < 0.001; [Figure 4]]. Similarly, primary tumor SUVmax showed a positive correlation with patients' PSA levels and Gleason scores (r = 0.493, P = 0.000 and r = 0.365, P = 0.003, respectively) [Table 3] and [Figure 5], [Figure 6].
|Figure 4: The relation of maximum standardized uptake value values with D'Amico risk classification|
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|Figure 5: Correlation between prostate-specific antigen levels and maximum standardized uptake value|
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|Figure 6: Correlation between Gleason scores and maximum standardized uptake value|
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The correlation of primary tumor SUVmax with the grouped data did not change when the background activity was also calculated. There was no difference between the results of the correlation either with primary tumor SUVmax or with primary tumor to background SUVmax (tm/bg SUVmax) ratios [Table 4].
|Table 4: Comparison of mean tumor/background maximum standardized uptake value values in clinical features of the patients|
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Treatment protocol decisions before and after evaluation of PSMA PET/CT images were observed; the treatment protocol was changed for 43.1% (n = 28) of the patients after evaluation of the patients' PSMA PET/CT scans [Table 5]. The PET/CT scan changed the stage in 35% of the patients in the group. Radical prostatectomy was the most chosen treatment protocol (33.8%; n = 22) before evaluation of the PSMA images. Similarly, radical prostatectomy was the most chosen treatment protocol (35.4%; n = 23) even after evaluation of the PSMA PET/CT images. Hormone therapy with chemotherapy was chosen for 29.2% (n = 19) and 27.7% (n = 18) of the patients before and after evaluation of the PSMA PET/CT images, respectively.
|Table 5: Treatment protocols and change rates in management before and after prostate-specific membrane antigen positron emission tomography/computerized tomography|
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| > Discussion|| |
Absolute staging in prostate cancer is one of the most important factors in determining the treatment method. The European Association of Urology (EAU) recommends that patients be evaluated with at least one abdominopelvic image (CT or MRI) as well as bone scintigraphy for staging and metastasis screening in intermediate-to-high-risk patients. In our study, 92% of our patients were intermediate- or high-risk patients; abdominopelvic imaging was performed with conventional MRI or CT in all patients before PSMA, and BS was performed in almost half of our patients. However, the diagnostic success of these conventional imaging methods is limited.,, Hence, non-invasive prognostic tools are needed to choose an effective treatment and to understand the disease behavior, especially for patients who are not eligible for invasive procedures. PSMA PET/CT scans often result in a change in staging and treatment protocols for prostate cancer patients. SUVmax also provides valuable data to understand the prognosis in some type of cancers.,
Gleason score is recognized as one of the most significant progression-associated indicators. A significant relation has already been found between SUVmax and PSA levels; however, no relation has been noted between Gleason score and PSMA PET/CT imaging., A recent article emphasized the positive correlation between SUVmax and PSA levels in staging patients. Furthermore, El Hajj et al. and Demirci et al. showed a significant correlation between Gleason score and SUVmax., Similarly, in our study, SUVmax data showed a positive correlation with PSA levels and Gleason scores from the prostate gland biopsy before PSMA PET/CT scan.
To our knowledge, there is no data related to the correlation between age and SUVmax, which significantly increased in our patients with age. Older age is a prognostic indicator for recurrence. Herold et al. found in their study group that patients older than 65 years had significantly more distant metastases after 5 years than younger men. We found a positive correlation between primary tumor SUVmax and age in our patient group.
In a meta-analysis of 15 studies investigating the effect of PSMA PET/CT on treatment decisions, a change in the treatment decision was reported in 29%–77% of cases after secondary staging with PSMA PET/CT. In addition, it has been shown that the only statistically significant factor affecting the heterogeneity of meta-analysis is PET positivity, and that every 1% increase in PET positivity results in a 0.55% increase in the rate of treatment change. Another study demonstrated that a treatment change followed scanning with PSMA PET/CT for staging in 27% of 115 patients. In our study, the 43.1% rate of change in our choice of treatment after secondary staging with PSMA PET/CT contributes to the literature and shows that conventional staging can be inadequate in primary staging.
Our patients were scanned either with MRI or CT before the PET/CT for staging, and almost half of the patients had bone scintigraphy. These imaging techniques were not grouped due to the heterogeneity of our patients. Our patients showed similar results as those of Roach et al., of whose 108 patients, 16% were upstaged, and 21% had a change in treatment protocol. A large study of 1,253 patients indicated a 12.1% detection rate of metastatic disease in staging with PSMA PET/CT. We believe our higher metastasis detection rate is a result of our smaller patient group.
Our study has some limitations. First of all, it is a retrospective study, and we had only the prostate gland biopsy results for correlation. We were not able to confirm the metastases with biopsy results since not all the patients were operated on or treated in our hospital. Therefore, positive lesions in PSMA PET/CT were identified by the criteria of uptake and clinical diagnosis. We are planning to follow-up with all of the patients over the long term as part of another study.
| > Conclusion|| |
The present retrospective study demonstrated that PSMA PET/CT is highly effective for initial staging in newly diagnosed prostate cancer patients. Furthermore, the change rate in treatment protocols in our study shows the importance of PSMA PET/CT to clinical management. In addition, primary tumor SUVmax is a nonnegligible, noninvasive tool for understanding the behavior of the disease.
Informed consent was taken.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patients have given their consent for their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]