Abstract
68Ga- and 18F-labeled prostate-specific membrane antigen (PSMA) molecules have created new opportunities for the unmet diagnostic needs in prostate cancer. The purpose of this article is to give an overview of studies that have examined the role of PSMA PET in treatment planning for prostate cancer patients with biochemical recurrence (BCR). Methods: Medline, Embase, Web of Science, Google Scholar, and Cochrane Central were searched for relevant articles. After excluding the articles that did not fulfill the required criteria, we included in this review 12 publications that reported the impact of PSMA PET on the treatment plan for prostate cancer patients with BCR. Results: All studies in our review emphasized the impact of PSMA PET images on therapy management in prostate cancer patients with BCR. Overall, the impact of PSMA PET/CT on therapy management varied between 30% and 76% among the 1,346 patients included in the review. Upstaging was reported in 32%–67% of the patients. Patients with low prostate-specific antigen values (<0.5 ng/mL) also demonstrated positive lesions, which could not have been detected by means of conventional imaging techniques. Important modifications to the original treatment plan included avoidance of systemic therapy (17%–40%) and PET-directed local therapy (in ≤60% of the patients). Conclusion: PSMA imaging demonstrated a high clinical impact in patients with BCR, with modifications to the original treatment plan occurring among half the patients. Detecting recurrence in BCR can prevent unnecessary toxicity and lead to individualized therapy.
Prostate cancer (PC) is the second most common malignancy in men worldwide, with an incidence of 1.1 million in 2012; it is also the fifth major cause of death in men, with an estimated cancer-related mortality rate of 6.6% (1). Although most low-risk prostate cancers remain indolent, high-risk cancers have low chances of cure and may become a menace to life. Correct diagnosis and treatment continue to pose challenges (2,3). Considering the general increase in life expectancy, treatment-related toxicities can have a strong impact on patients’ quality of life for many years. Thus, the performance status and life expectancy of each patient should be taken into consideration before a decision is made about treatment options. Therefore, reliable prognostic tools and precise diagnostic tools are needed.
Routinely applied imaging modalities are not sufficiently sensitive and specific to be able to detect minute prostate cancer lesions, with a sensitivity of only 57% for lymph node metastases of 5–6 mm (4). Multiparametric MRI might indicate false-positive results (5). However, there is growing evidence that the treatment of a limited number of small metastases (oligometastases) may increase the likelihood of metastasis-free survival and postpone palliative systemic treatments (e.g., androgen deprivation therapy [ADT]) (6–8).
In the past 3 y, prostate-specific membrane antigen (PSMA)–guided imaging and therapies have shown impressive progress and have been rapidly implemented in clinical practice. Afshar-Oromieh et al. published a large-scale study (n = 1007) on patients with recurrent prostate cancer in which 68Ga-PMSA-11 PET/CT was able to detect lesions with a 79.5% patient-based sensitivity (9).
PSMA is a type II transmembrane protein that contributes to glutamatergic neurotransmission and folate absorption. Despite the name, PSMA is expressed not only in prostate but also in salivary and lacrimal glands, kidney, nervous system, duodenum, and colon (10–13). PSMA is expressed more intensely in prostate cancer cells than in normal prostate tissues and is related to increased folate activity in cells, giving them a proliferative advantage (14,15). Therefore, PSMA has become a promising target for imaging and therapy in prostate cancer. Furthermore, the PSMA expression level in prostatectomy specimens has been shown to be an independent prognostic factor for disease outcome (16).
PSMA-targeting methods were first initiated with labeling of antibodies (Supplemental Fig. 1; supplemental materials are available at http://jnm.snmjournals.org). However, the resultant drawbacks of antibodies were overcome by developing small-molecule PSMA inhibitors. A variety of PSMA-directed ligands are used for either imaging or therapy (e.g., PSMA-617, PSMA-I&T [imaging and therapy], and PSMA-11 [PSMA-HBED-CC]). PSMA-617, which can be labeled with 177Lu and 225Ac, and PSMA I&T were developed for radioligand therapy. Lately, 18F-labeled PSMA ligands (e.g., PSMA-1007 and DCFPyL) have been developed, which can also be the solution to a higher image quality (17). Furthermore, 18F-fluciclovine (Axumin; Blue Earth Diagnostics, Inc.) is another useful, promising compound that is transported by a synthetic amino acid and has been approved by the Food and Drug Administration (18).
Biochemical recurrence (BCR) in prostate cancer means that prostate-specific antigen (PSA) in serum is rising without histologic or image-guided proof. BCR is generally considered the first sign of treatment failure. In most cases, especially with low PSA levels, conventional imaging techniques are not accurate enough to determine the location of recurrence. Recent studies into identifying the location of the metastases with 68Ga-PMSA PET/CT have changed the perspective of the therapy plan and the radiotherapy region and dose, especially in oligometastatic diseases.
We reviewed the articles on 68Ga PSMA PET/CT among prostate cancer patients with BCR and the impact on modification of the treatment plan. Although several studies have recently been published on other 18F-labeled agents, this study chose to concentrate on the effect of imaging on the therapy plan, which has received great attention using 68Ga-PSMA PET. We intended to summarize the benefits and shortcomings of 68Ga-PSMA PET and understand how current knowledge on PSMA imaging can be applied to clinical practice in a sensible and practical way.
MATERIALS AND METHODS
Search Strategy
Proper key words were used in June 2018 to systematically search the scientific databases of Medline, Embase, Web of Science, Google Scholar, and Cochrane Central for studies relating to 68Ga-PSMA PET/CT imaging in prostate cancer with BCR. The search was conducted according to the search strategy and data collection guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement (19).
Data Collection and Extraction
The abstracts of 859 articles were examined by 2 observers (Supplemental Fig. 2). Articles that contained information about 68Ga-PSMA PET and data on patients with prostate cancer with BCR were included. Duplicate studies, letters to the editor, conference papers, case reports, preclinical studies, and non-English articles were excluded, as were studies on staging in PC and imaging with agents other than 68Ga-PSMA. Twelve articles matched the inclusion criteria. Differences of opinion between the reviewers were resolved through discussion.
RESULTS
Imaging protocols were specified in all 12 studies that reported 68Ga-PSMA PET findings for PC patients with BCR. Details were not given for 1 study (20); however, images of all other studies were interpreted by experienced nuclear medicine physicians and radiologists. PSMA lesions were characterized as positive if they demonstrated uptake above adjacent background and not attributable to physiologic biodistribution. Lesion locations were categorized as prostate bed, pelvic lymph nodes, extrapelvic retroperitoneal nodes, other lymph nodes, bone lesions, and viscera (21). When these studies were designed, no generally accepted guidelines were available. The studies are summarized in Supplemental Table 1.
Of the 12 articles identified, 7 were on retrospective studies and 5 were on prospective studies. Only 3 of the 5 prospective studies used questionnaires to collect data about the treatment plan before and after the results of PSMA imaging were known (22–24), with limited likelihood of bias in the results. The patients underwent initial evaluation for risk classification, TNM staging, and radiotherapy planning. Two of the 5 studies chose to follow the patients prospectively using the database (20,25). The follow-up results provided useful insights into the effect of PSMA imaging on the intended therapy plan.
In their prospective study, Habl et al. conducted imaging using either 68Ga-PSMA PET/CT (n = 71) or 68Ga-PSMA PET/MRI (n = 29) after radical prostatectomy and before radiotherapy. 68Ga PSMA PET was found to have a significant influence on TNM stage in 43% of the patients. The initial radiotherapy plan was adapted in 59% of the cases. Six patients who showed bone oligometastases and changed to M1b received stereotactic body radiotherapy (25).
Roach et al. asked the referring clinicians to record the therapy plan by completing a questionnaire before and after PSMA imaging. The results of 62% of the cases demonstrated a change in the treatment schedule. Even 67% of the patients with low PSA levels (<0.2 ng/mL) exhibited management changes, but quite unexpectedly, no significant difference was found between the PSA cohorts of the BCR patients. The PSMA images revealed either oligometastatic or polymetastatic disease in 76% of the patients, which resulted in a strong increase in systemic therapies, including ADT (22).
The survey conducted by Calais et al. documented a 53% rate of change in treatment. Specifically, there was a significant relationship between either N1 or N1M1 status in PSMA findings and management changes (23). In the study of Frenzel et al., when 68Ga PSMA PET/CT images were retrospectively compared with CT alone, a change rate of 43% was observed. One specific patient was identified with a very low PSA level (0.02 ng/mL) and microscopic residual disease. In this instance, a decision was made not to prescribe radiotherapy, mainly because of the negative findings on PSMA images (26).
Considering the cardiovascular disadvantages and impact on the quality of life, 77% of a subgroup of patients with a preimaging decision to give ADT were withdrawn from ADT after 68Ga-PSMA imaging (27). More than half the patients (i.e., 14/22) who were planned to receive ADT before PSMA imaging received locoregional treatment instead, and 1 patient did not even receive any treatment at all (28). The decision to start with ADT was also reconsidered quite frequently (64%) in the study of Albisinni et al. Furthermore, other modifications included changes in the treatment plan concerning clinical surveillance (22%), stereotactic radiotherapy (12%), and salvage radiotherapy (11%) (29).
The impact of 68Ga-PSMA imaging on the treatment plan has been emphasized in the prospective study by Shakespeare. The overall revision of treatment plan was 53.7%, and radical radiotherapy appeared less promising after PSMA imaging. Moreover, instead of radical radiotherapy, palliative radiotherapy of oligometastatic disease was implemented. Additionally, the number of patients (50%) without any treatment decision significantly diminished (18.5%) after PSMA imaging (20).
Sterzing et al. observed a 50.8% change in radiotherapeutic management after PSMA imaging. The treatment plan was changed to an additional integrated lymph node boost, enlarged lymphatic field irradiation, and systemic therapy arising from a change from N0 to N1 in 62.1%, M0 to M1a in 27.5%, and M0 to M1b in 13.8% among 29 (50.8%) patients (30). Bluemel et al. and Farolfi et al. have also recommended a change in treatment rates based on the findings of 68Ga PSMA PET/CT scans (i.e., 42.2% and 30.2%, respectively) (31,32).
In the study by Hope et al., a 53% therapeutic change was highlighted after 68Ga PSMA scanning. This study emphasized that 31.7% of the patients received focal targeted therapy instead of systemic therapy, and the intended treatments were affected by 59.6% overall (of which 53.2% were major changes) (24). Grubmüller et al. reported a detection rate of 85.5% of PSMA-positive lesions in a patient group with BCR. The therapeutic strategy was changed among 74.6% (50/67) of the patients. Furthermore, 60% of the patients received PET-guided radiotherapy (33).
Here, all available data on PSMA imaging in patients with BCR are summarized, although not all studies in our review reported the modification rates identically. Overall, the impact of 68Ga PSMA PET/CT on therapy management varied between 30.2% and 76% among the patients with BCR. Furthermore, the number of upstaged patients was in the range of 32%–67%, which was also remarkable.
Among 60% of the patients, the main modifications consisted of avoidance of systemic therapy (17%–40%) and PET-directed local therapy, which includes radiotherapy to the prostatic or pelvic bed (7.5%–48.7%) or treatment of oligometastatic disease (10%–28%). The results from PSMA-enhanced adaptations of the radiotherapy field were as follows: stereotactic body radiotherapy, 10%–50%; simultaneous integrated boost to lymph nodes, 15%–62.1%; and salvage radiotherapy, 11%–24.4%. The avoidance in ADT treatment was emphasized in 33.3%–64% of the studies that specified these data separately. Changing the treatment plan in active surveillance was mentioned in 2.5%–22% of cases, and lymphadenectomy after PSMA rates were reported as not negligible (1%–13%).
The studies in our review had a wide range of PSA values—from 0.01 to 653.2 ng/mL. Despite the low PSA values, Habl et al. found that nearly 50% of the patients with a PSA level of less than 0.5 ng/mL had a modified therapy plan after PSMA imaging (25). Additionally, Roach et al. mentioned no significant relationship between therapy management and PSA values (26). Moreover, Sterzing et al. documented 16 PSMA-negative patients in the 0.5–21.7 ng/mL PSA range (30). On the other hand, positive rates between 21% and 65% were reported for patients with a PSA level of less than 0.5 ng/mL in 5 of 12 studies in our review. Finally, it should be noted that low PSA values with a low risk of systemic disease have a positive effect on therapy management, and vice versa.
DISCUSSION
This review aimed to summarize 12 studies on the effect of PSMA PET/CT on treatment perspective and outcome among BCR patients. Of the 12 studies, only 5 were prospective. Other important drawbacks included the small size of the study groups and lack of long-term outcomes and validation of histology. Only 2 of the studies have evaluated a group of patients by using PET/MRI (25,33).
PSA should be less than 0.1 μg/L after surgical treatment and radiotherapy (34). A measurable and rising PSA level after prostatectomy or a PSA level greater than 2.0 μg/L above nadir is referred to as a biochemical prostate cancer recurrence (BCR). In BCR, salvage treatments can be offered. Moreover, several studies have shown that salvage radiotherapy is most effective at PSA levels of less than 0.5 μg/L (34,35). But at this PSA range, traditional imaging will not be able to locate recurrence; therefore, salvage treatments were directed at the region with the highest chance of recurrence (i.e., prostatic fossa).
Knowing that locoregional salvage therapies are most effective at PSA levels of less than 0.5 μg/L, it became evident that more sensitive imaging is essential to avoid the unnecessary toxicity of treatments. A recent metaanalysis with 1,052 patients showed an overall positive 68Ga-PSMA PET/CT detection rate of 76% among the PC patients with BCR (36). In another study, the efficacy of the 68Ga PSMA PET/CT detection rate was 58% among patients with a PSA level of less than 0.5 ng/mL; it was also deemed important as it is the upper limit for salvage radiation therapy, as determined by the European Association of Urology guidelines (37). Furthermore, a greater detection efficacy of 81.8% was found among another group of BCR patients with PSA values between 2 and >5 ng/mL (38). To date, PSMA-based imaging has proven to be the most promising detection technique at low PSA levels (30,32).
In patients with tumor recurrence outside the prostate bed, the possibility of an efficient salvage therapy depends on the number and localization of lesions (39). In cases with numerous or diffuse lesions, it is mainly antihormonal treatment or other systemic therapies that can be administered. ADT has even been proven to improve survival rates, decrease the quality of life arising from sexual dysfunction, and lead to cardiovascular disease and metabolic complications with negative effects on bone density and cognitive function (27,40,41). However, growing evidence has recently shown that low-volume metastatic disease can effectively be treated by local therapies (e.g., individualized selective pelvic irradiation). Because it has been shown that prostate cancer with initial low numbers of metastases is more likely to show local progression when treated with ADT, local metastasis-directed therapy can be considered a viable option (42,43).
Preventing unnecessary radiotherapy or postponing palliative ADT can have a major effect on patients’ quality of life. Such a goal can be achieved by PSMA imaging, which enables assessing the extent of disease and localizing oligometastatic disease or local recurrence in the prostate bed. There is also evidence of benefits arising from locoregional treatment of the oligometastatic prostate cancer (44,45).
Considering the benefits of cyclotron production and longer half-life, 18F is a feasible PET agent. 18F-PSMA PET imaging in prostate cancer has recently been introduced. In 2 separate studies (n = 25 and n = 14), more lesions were detected on 18F-PSMA PET images than on 68Ga-PSMA PET/CT images (46,47). In their recently published study on the detection efficacy of 18F-PSMA-1007 imaging in patient groups with BCR, Giesel et al. found that the detection rate was 61.5% among patients with PSA levels of 0.2 to less than 0.5 ng/mL; they also reported that less excretion to the urinary tract was a clear advantage (48). Another study on 18F-fluciclovine has reported a 59% rate of change in the therapy management plan for patients with BCR. However, because the patients’ outcomes were not available for this study, further prospective trials are required (49). In addition, when 18F-PSMA (DCFPyL) images were compared with 18F-fluciclovine for the same patient, it was possible to detect metastatic lesions in both studies. PSMA images demonstrated higher lesion uptake with lower background activity; however, low urinary excretion of 18F-fluciclovine could give better results in demonstrating pelvic lesions (50).
A few studies have already shown the high impact and good response of PSMA-based therapy on outcome (51–53). However, limitations such as small samples of patients, exclusion of those with metastatic disease, and short-term follow-up might account for nonidentical categories of data. A prospective multicenter study demonstrated the clinical performance and patient-outcome results for 18F-fluoromethylcholine, multiparametric MRI, and 68Ga-PSMA PET/CT in BCR after 3 y of follow-up. The study reported high detection rates of disease, especially in extrapelvic fossae. Moreover, the impact on the therapy management plan and on treatment response to salvage radiotherapy was greater among the patient group with negative imaging results (54). Another recently published retrospective biinstitutional study, by Schmidt-Hegemann et al., has provided valuable insights about PET-based salvage radiotherapy in 90 patients with BCR after 23 mo of follow-up. The data emphasized a protracted treatment response as well as a low toxicity profile and a 78% BCR-free survival rate after 68Ga-PSMA imaging. The limitation of this retrospective analysis includes treatment and a nonidentical follow-up, which requires more prospective studies with larger cohorts (55).
The limitations of this review originate mainly in a lack of grouping of the results because of the availability of a variety of management plans in each study, which either were different or lacked sufficient detail. The results of the studies demonstrate that early and accurate detection of BCR or ruling out oligometastases will influence decisions concerning curative therapy and eventually change the outcome of the disease and the quality of life. More longitudinal studies are required to examine the outcome of the PSMA PET/CT imaging–guided therapy plan and modification.
CONCLUSION
68Ga-PSMA PET/CT scan has a 52.8% positive impact on therapy management in patients with BCR. Our achievements today in PSMA molecules are beyond what we could have imagined a decade ago; however, more prospective randomized trials are required to understand the impact on disease-free survival rates and treatment outcome. In addition to improving progression-free survival rates, we also need to avoid and postpone treatment toxicity.
DISCLOSURE
No potential conflict of interest relevant to this article was reported.
KEY POINTS
QUESTION: What is the impact on treatment planning of the 68Ga-/18F-PSMA scan in prostate cancer patients with PSA recurrence after primary treatment?
PERTINENT FINDINGS: In 12 studies, including 1,346 patients, PSMA PET/CT scans resulted in modification of the originally planned treatment schedule in 30%–76% of the patients. Important modifications included avoidance of systemic therapy and PET-directed local therapy.
IMPLICATIONS FOR PATIENT CARE: In almost every patient with PSA recurrence after radical prostatectomy or radiation treatment, a PSMA PET/CT scan is strongly recommended to determine the next treatment phase.
Footnotes
Published online Mar. 8, 2019.
- © 2019 by the Society of Nuclear Medicine and Molecular Imaging.
REFERENCES
- Received for publication November 3, 2018.
- Accepted for publication March 4, 2019.
