The Impact of PSMA PET/CT Imaging in Prostate Cancer Radiation Treatment

Abstract

Imaging of prostate cancer is rapidly evolving with the introduction of the novel prostate-specific membrane antigen (PSMA)-targeted PET imaging tool for managing recurrent prostate cancer. One immediate impact of PSMA PET is the identification of residual or recurrent lesions that are amenable to external beam radiotherapy. Radiotherapy is used as a definitive curative treatment option for patients with localized prostate cancer alone or in combination therapy. In the setting of biochemical failure after radical prostatectomy, salvage radiation is a potential curative option, and the application of metastasis-directed radiotherapy in the setting of oligometastatic prostate cancer is currently being studied. To maximize the chances of curative therapy, the irradiated tumor volumes should completely encompass the actual extent of disease. Thus, an accurate estimation of the location and delineation of disease targets is critical for radiotherapy planning. The integration of PSMA PET imaging into the routine evaluation of prostate cancer has markedly improved sensitivity and specificity for recurrent disease, even at very low PSA values, which may enable further tailored radiation treatment plans, and help reduce the risk of radiation to adjacent normal tissues. However, while the introduction of PSMA PET will likely change behavior regarding earlier application of radiotherapy, the long-term impact of PSMA PET on patient outcomes is yet to be determined. The aim of the review is to give an overview of the use of PSMA-PET/CT imaging in the setting of radiation therapy for prostate cancer.

Introduction

Prostate cancer (PCa) is the most common cancer diagnosed in men worldwide, leading to substantial morbidity and mortality.¹ Following initial diagnosis of localized PCa, radiotherapy is one of the potentially definitive curative treatment options for either used alone or in combination with hormonal therapy. Recurrence following radiation or surgery for PCa is relatively common, occurring in up to 40% of men within 10 years, depending on the clinicopathological stage of the disease.^2,3 PCa recurrence is usually first suspected when a rise in serum prostate-specific antigen (PSA) is observed during the post-treatment monitoring. Depending on the rate of rise of PSA (doubling time), grade and stage at diagnosis and other clinical factors, many patients are immediately referred for salvage radiotherapy while others are observed with periodic CT and bone scans. However, inevitably some patients progress to metastatic disease, typically bone metastases in PCa. When only a limited number of small metastases (oligometastases) are present, metastasis-directed radiotherapy has been used in an effort to prolong metastasis-free survival and postpone palliative systemic treatments.^4,5

The ability to accurately localize sites of disease in PCa is critical for directing radiotherapy planning with potential curative intent for either the definitive or salvage settings. Considering the long-life expectancy of most men with PCa, radiation treatment-related but delayed toxicities could have an impact on patients’ quality of life later on; therefore, reliable diagnostic and prognostic imaging tools are needed.

During the past few years, radiotracers targeting the prostate-specific membrane antigen (PSMA) for positron emission tomography (PET) have been increasingly used in the setting of biochemical recurrence to detect sites of disease that would not be visible on standard-of-care imaging. These PET agents are small molecular inhibitors that bind the extracellular domain of PSMA and can be labeled with positron-emitting radioisotopes such as Gallium-68 (⁶⁸Ga) or Fluorine-18 (¹⁸F). F18-labeled PSMA-PET agents have the advantage of longer half-lives (110 vs 68 minutes), with increased positron yield, and shorter positron range compared with ⁶⁸Ga, enabling centralized radioisotope production and distribution. After the recent US Food & Drug Administration approval of ⁶⁸Ga-PSMA-11 and ¹⁸F-DCFPyL for clinical use, it is expected that their use will dramatically increase. Currently, PSMA PET/CT has emerged as the best diagnostic tool available for staging PCa patients with biochemical recurrence after definitive therapy, with improved diagnostic accuracy and good correlation with gold standard histopathology for detecting metastatic PCa at low PSA levels.

This review focuses on the influence of PSMA-PET findings in the field of radiation oncology and how to optimally adapt radiotherapy planning to PSMA-PET findings. PSMA-PET is used to decide if radiation is required and how the treatment should be planned.

PSMA-PET Imaging for Planning Radiotherapy in Primary Prostate Cancer

Most patients with localized intermediate-risk or high-risk PCa are treated with either radical prostatectomy or definitive radiation therapy (ie, external beam radiation or brachytherapy) with or without additional androgen deprivation therapy^6,7 with reported similar tumor control rates and outcomes for both treatment modalities.^8–10

The effectiveness of definitive therapy usually depends on accurate disease staging, including identification of extra-prostatic extension and the presence of metastatic pelvic lymph node(s). Thus, defining the extent of disease with PSMA imaging and carefully selecting patients before radiation therapy is crucial when selecting patients with definitive curative intent. In this setting, in a recent prospective, randomized, multicenter trial (proPSMA), Hofman et al. reported improved accuracy for PSMA PET/CT imaging when compared with standard-of-care combined CT and bone scan (92% vs 65%) in men with high-risk PCa undergoing staging before curative-intent therapy (surgery or radiation),¹¹ concluding that PSMA PET/CT can be a suitable replacement for conventional imaging in the initial staging of PCa. In a large prospective, phase 2/3 multicenter trial (OSPREY), Pienta et al.¹² supported the utility of PSMA PET/CT using ¹⁸F-DCFPyL for initial staging of men with high-risk PCa for the detection of nodal or distant metastases; the median positive predictive value and negative predictive value were 86.7% (69.7%−95.3%) and 83.2% (78.2%−88.1%), respectively. Additionally, PSMA PET/CT tends to reveal disease beyond the classic pelvic lymph-node dissection or radiotherapy treatment field, a phenomenon that occurs in 16%−48% of cases,^13,14 necessitating a multi-modal and more tailored treatment plan to be proposed.

When radiation therapy is chosen as the definitive treatment, radiation oncologists make a distinction in treating tumor volumes to include the gross disease often seen on imaging, as well as volumes of disease not visible radiographically, but at high risk of harboring disease. Higher doses (radiation boosting) are prescribed within the visible gross disease, when feasible, to increase the probability of tumor control and ultimately cure, and always considering the risks of radiation to adjacent normal tissues.

Multiparametric Magnetic Resonance Imaging (mpMRI) is accepted as the technique of choice to define intraprostatic tumor targets with high sensitivity and to assist contouring for radiotherapy planning. Several studies have compared the use of mpMRI and PSMA PET imaging for targeting with highly comparable sensitivity for intraprostatic tumor delineation (Fig. 1).^15–17 Other studies also examined the role of combined PSMA PET and mpMRI information for primary PCa localization based on histology reference, reporting higher sensitivities when the two modalities were combined rather than used separately. In a large prospective multicenter clinical trial (PRIMARY) including 296 men with suspected primary PCa, improved sensitivity and higher negative predictive value was seen for the combination PSMA PET + MRI in comparison with targeted prostate biopsy.¹⁸ Considering these promising PSMA PET results in detecting intraprostatic lesions, there is growing interest in using this imaging tool for focal radiation delineation. Bettermann et al.¹⁹ prospectively reported better accuracy for PSMA PET than mpMRI for intraprostatic gross tumor volume (GTV) delineation in comparison with histopathology volumes.¹⁹ Sensitivity and specificity were 86% and 87%, for PSMA PET; 58% and 94% for mpMRI; and 91% and 84% for the combination of both techniques. Draulans et al.²⁰ reported consistent intraprostatic GTV delineation for focal boosting of primary PCa for MRI and PSMA PET using both ⁶⁸Ga-PSMA-11 and ¹⁸F-PSMA-1007. Thomas et al.²¹ proposed ⁶⁸Ga-PSMA-PET/CT for defining prostate target volumes, using PET-positive volume segmented with a 40% threshold of the maximum activity uptake; the mean dose to the tumor tissue, defined as the PSMA-positive pathological volume increased significantly without any significant increase in the mean dose to the rectum or bladder. Zamboglou et al.²² showed that GTV defined by histology corresponded better with the combined PET-mpMRI tumor volume than with tumor volumes from either PSMA PET or mpMRI alone.²² However, all of these studies consist of small cohorts usually from one institution and are characterized by heterogenous methods and often lack details regarding the determination of the PET volume. Therefore, more work needs to be done in this area before it can be concluded how best to target the GTV.

Figure 1.

64-y-old male with newly diagnosed high-risk PCa, biopsy-proven Gleason 9 (4+5), and PSA of 21.26 ng/mL. ¹⁸F-DCFPyL PET/CT demonstrates an intense intra-prostatic focus at the left mid-base anterior peripheral zone, and another mild focal uptake at the right mid peripheral zone of the prostate gland, concordant with MRI findings, consistent with the primary prostate malignancy/PSMA over-expression.

While PSMA PET/CT has been shown to be superior to other staging tools in the initial staging of PCa²³; the impact of PSMA PET/CT on patient outcome is yet to be determined. Several studies suggest that PSMA-PET/CT results frequently (7%−33%) change the definitive local radiation plan, depending on the series (Table 1).^24–27 Randomized prospective trials powered for patient outcome are underway to formally address this question. Thus, Calais and collaborators²⁸ are conducting a prospective multicenter trial comparing the success rate of standard-of-care definitive radiation therapy versus PSMA PET directed definitive radiotherapy in 312 men with unfavorable indeterminate and high-risk PCa, with the intent of showing an advantage to the PET-directed therapy. Roach et al.²⁹ evaluated the frequency of treatment modification after PSMA-PET in 108 treatment-naïve intermediate and high-risk patients and found that ⁶⁸Ga-PSMA PET/CT significantly impacted radiotherapy planning for primary disease in as many as 21% of the patients. Similarly, Sterzing et al.²⁴ reported a change in TNM staging, resulting in a change in the radiated target tumor volumes or prescription dose in 13% of the cases. Calais et al.¹³ prospectively evaluated 73 patients with M0 localized PCa, and found that ⁶⁸Ga-PSMA-11 PET/CT had a major impact on intended definitive RT planning for PCa in 16.5% (12/73) of patients whose elective RT fields covered the prostate, seminal vesicles, and pelvic LNs and in 37% (25/66) of patients whose RT fields covered prostate and seminal vesicles only, but not pelvic LNs.¹³ However, the impact of such modifications on patient outcomes remains unclear.

Table 1.

Studies assessing the impact of PSMA-PET/CT on radiotherapy planning

Authors	No of patients	PSMA-PET Agent	Cohort type	Patients with PET positive (%)	Treatment/radiation planning change (%)
Dewes et al. 201625	15	68Ga-PSMA	Primary PCa	60%	33.3%
Sterzing et al. 201624	15	68Ga-PSMA	High-Risk primary PCa staging	100%	13.7%
Roach et al. 201829	108	68Ga-PSMA	Intermediate and high-risk PCa	N/A	21%
Calais et al. 201813	73	68Ga-PSMA	Intermediate and high-risk PCa	34–9.5%	7–19.5%
Hruby et al. 201850	109	68Ga-PSMA	Primary PCa, prior EBRT planning	99%	14.7%
Frenzel et al. 201851	20	68Ga-PSMA	Primary PCa, prior RT planning	N/A	15%
Calais et al. 202128	312	68Ga-PSMA	Intermediate and High-risk PCa, prior RT planning	ongoing trial	ongoing trial
Shakespeare et al. 201526	18	68Ga-PSMA	BCR PCa	N/A	46%
Van Leeuwen et al. 201652	70	68Ga-PSMA	BCR PCa	54.5%	34.5%
Sterzing et al. 201624	42	68Ga-PSMA	BCR PCa	59.5%	60.5%
Bluemel et al. 201653	45	68Ga-PSMA	BCR PCa	53.5%	42.2%
Albisinni et al. 201754	131	68Ga-PSMA	BCR PCa	75%	76%
Habl et al. 201739	100	68Ga-PSMA	BCR PCa	76%	59%
Schiller et al. 201755	31	68Ga-PSMA	BCR PCa	87.1%	58.1%
Roach et al. 201829	312	68Ga-PSMA	BCR PCa	N/A	62%
Koerber et al. 201840	71	68Ga-PSMA	BCR PCa	51%	53.5%
Frenzel et al. 201851	75	68Ga-PSMA	BCR PCa	N/A	43%
Calais et al. 201838	270	68Ga-PSMA	BCR PCa	49%	19%
Farolfi et al. 201941	119	68Ga-PSMA	BCR PCa	35%	30%
Schmidt-Hegemann et al. 201956	62	68Ga-PSMA	BCR PCa	54%	50%
Boreta et al. 201957	125	68Ga-PSMA	BCR PCa	53%	30%
Song et al. 202043	72	18F-DCFPyL	BCR PCa	85%	60%
Bottke et al. 202142	76	68Ga-PSMA	BCR PCa	54%	28%
Meijer et al. 202144	253	18F-DCFPyL	BCR PCa	66%	40%

Based on the literature and considering the widespread use of PSMA PET imaging, it is reasonable to suppose that PSMA PET may soon be a part of the routine diagnostic flowchart in many PCa patients for planning primary therapy and possibly before biopsy, even while data supporting this approach is still evolving.

PSMA-PET Imaging in Salvage Radiotherapy Planning

After definitive primary PCa therapy, the PSA values should be less than 0.2 mg/L after surgical treatment.³⁰ A measurable rising PSA level ≥0.2 ng/mL after prostatectomy or a PSA level greater than 2.0 ng/mL above nadir after radiotherapy is considered biochemical recurrence (BCR) PCa. For patients experiencing BCR in the absence of distant metastasis, salvage radiation with or without androgen deprivation therapy can be offered as a potential curative treatment option. Salvage radiation after radical prostatectomy offers long-term biochemical control in approximately 50%−60% of the patients achieving undetectable PSA values.³¹ After 5 years, 80% of these men are progression free.³² Several studies have shown that the level of PSA before sRT is a predictive factor for progression, with most effective results at PSA levels of 0.5 ng/ml or less.^30,33 However, traditional conventional imaging will not be able to locate recurrence at this PSA range; thus, target tumor(s) volume delineations for salvage radiotherapy are often drawn in the absence of visible recurrence and are often directed at the region with the highest chance of recurrence (ie, prostatic fossa). Fortunately, the implementation of PSMA PET imaging has substantially improved the diagnostic accuracy for detecting PCa recurrence with superior sensitivity compared to conventional standard-of-care imaging, at PSA levels low enough that may affect target delineations for routine salvage radiation. In a systematic review and meta-analysis including 4790 patients, Perera et al. reported detection rates of 33% for PSA<0.2 and 45% at PSA 0.2–0.5 ng/ml for ⁶⁸Ga-PSMA.³⁴ Similarly, in a large retrospective study with 2,533 BCR PCa patients after radical prostatectomy, Afshar-Oromieh et al.³⁵ reported detection rates of 43% for PSA levels ≤0.2 ng/ml, 58% for PSA >0.2 to ≤0.5 and 72% for PSA>0.5 to ≤1.0 using ⁶⁸Ga-PSMA PET/CT imaging. Similar detection rates of 50% for PSA< 0.5 have been shown for ¹⁸F-DCFPyL in a prospective trial with 90 BCR PCa patients with negative conventional imaging.³⁶ In the CONDOR trial which included 208 patients with BCR who underwent ¹⁸F-DCFPyL, Morris et al.³⁷ demonstrated disease detection rate of 73.3% at low PSA (<0.5) when conventional imaging was negative.

The earlier detection of recurrence with PSMA PET/CT imaging will likely prompt clinicians to consider treatment (Fig. 2). PSMA PET/CT findings can guide clinical decisions, choice of therapy and alter decisions regarding the use of aggressive loco-regional sRT or systemic palliative therapy. Changes in management based on imaging are common and generally result in escalation of the radiation treatment, with either radiation volume, radiation dose (with possibly inclusion of a boost dose) or intensification of concurrent androgen deprivation therapy or even de-escalation treatment may occur. The potential impact of PSMA PET/CT on salvage radiotherapy planning has been assessed in several studies (Table 1). A prospective multicenter study of 420 patients (312 of them with BCR PCa) reported that ⁶⁸Ga-PSMA PET/CT findings influenced management decisions in 62% of the patients with BCR; specially in men planned for sRT, positive ⁶⁸Ga-PSMA PET/CT scans resulted in larger treatment zones (12% of patients), or resulted in a radiation boost (15% of patients), or lower doses/volumes in 4% of patients as determined by ⁶⁸Ga-PSMA PET/CT findings.²⁹ In a prospective study, Calais et al.³⁸ evaluated the success rate of sRT in a cohort of 270 patients with BCR after prostatectomy but before sRT, who underwent PSMA PET/CT at PSA less than 1 ng/mL; PSMA PET was positive in 49% of patients with disease localized in the bones or in perirectal lymph nodes, which led to a major change in management in 19% of the patients. The most common change from the original plan based on PET-positive disease was extending the planning target volumes and expanding the target volumes to cover both the prostate bed and pelvic lymph nodes.³⁸ Bluemel et al. evaluated 45 patients with BCR after prostatectomy who underwent ⁶⁸Ga-PSMA PET/CT; the scan was positive in 53.3% of patients, resulting in a change in sRT plan in42.2% of patients. These changes included expansion of the target volumes, dose escalations, or cancelation of the sRT in 47%, 32%, and 10% of patients, respectively. Habl et al. assessed 100 patients with BCR PCa (median PSA of 1.0 ng/mL) before sRT, reporting ⁶⁸Ga-PSMA PET/CT positivity in 76% of patients, affecting the sRT plan in 59% of cases.³⁹ Koerber et al. found a change of radiotherapy management in 53.5% of patients,⁴⁰ whereas Sterzing et al. observed a radiation treatment change in 60.5% of patients with BCR after radical prostatectomy, with a high median PSA value at the time of the scan (2.8 ng/mL).²⁴ Farolfi et al. (41) showed that in men with BCR PCa with low PSA values <0.5 ng/ml, ⁶⁸Ga-PSMA PET-CT caused a change in treatment in 30% of the cases. In another recent study, Bottke et al.⁴² found that ⁶⁸Ga-PSMA PET/CT led to changes of the RT target volume in 28% of patients with PSA ≤0.5 ng/ml after radical prostatectomy. Less data on ¹⁸F-DCFPyL is available; however, a prospective trial by Song et al.⁴³ evaluated the performance of ¹⁸F-DCFPyL in 72 patients with BCR after definitive prostatectomy (median PSA of 3.0 ng/mL) and reported a high overall tumor detection rate of 85%, with changes in management occurring in 60% of the patients.⁴³ In another study with lower median PSA of 0.8 ng/mL, Meijer and collaborators assessed the impact of ¹⁸F-DCFPyL in 253 BCR PCa patients after definitive therapy with either prostatectomy or external beam radiation, resulting in change of the treatment plan in 40% of the cases.⁴⁴ Overall management impact has been reported in 51%−76% of BCR patients and specific changes in radiation therapy have occurred in 19%−60%. The main limitations of these reports are the inhomogeneity of the patients with wide range of PSA values at the time of imaging and lack of details on the anatomic patterns of relapse.

Figure 2.

72-y-old male with history of PCa, Gleason 3 + 3 = 6, who opted for brachytherapy as initial therapy. He presents with biochemical recurrence 8 years after initial therapy, with pre-scan PSA of 6.3 ng/mL. ¹⁸F-DCFPyL PET/CT demonstrates foci of intense DCFPyL uptake at the left mid-base anterior transition zone of the prostate bed, consistent with disease recurrence. Patient received SBRT at this location. Post-treatment ¹⁸F-DCFPyL PET/CT (with PSA of 0.2 ng/mL) at 6 mo post-SBRT shows resolution of the abnormal DCFPyL avid foci.

Although PSMA PET/CT agents alter patients’ clinical management, their impact on the overall survival of PCa patients is yet to be determined. Few retrospective studies have addressed the patients’ outcome with even short-term follow-up after PSMA PET/CT-based sRT. The mean response rate from these studies is 74% (range 60%−83%) after a mean follow-up time of 19 months (range 10.5–29 months). Recently in a prospective study, Emmett et al.⁴⁵ reported 3-year freedom from progression in 64.5% (120/186) of men who underwent ⁶⁸Ga-PSMA-11 PET/CT imaging prior to sRT planning, with a median follow-up of 38 months. Freedom from progression dropped to 45% in those who had disease outside of the prostate bed identified on PSMA and rose to 81% in patients who had fossa-confined disease or no disease. This translated to a hazard ratio for progression of 2.73 in men with extra-prostatic disease compared to men with either fossa-confined disease or no disease on PSMA.⁴⁵ Prospective trials evaluating long-term patient outcome are clearly needed. This is especially important in patients at the very early stages of biochemical recurrence, who would ordinarily be missed by conventional imaging.

PSMA-PET Imaging for Targeting (Oligo-)Metastases in Prostate Cancer

PSMA PET/CT scans have highlighted the occurrence of oligometastatic disease, particularly in the bones. In the past, oligometastatic disease could occasionally be detected on conventional bone scans but it was often assumed these lesions were simply the “tip of the iceberg”. Now with a more sensitive tumor detection method, patients with oligometastatic disease are being considered for high dose lesion-directed radiotherapy. This is an area of significant interest for radiation oncologists as PSMA PET appears to have the potential to identify early oligometastatic disease (Fig. 3) and can also help direct radiotherapy, although whether this improves patients’ progression free survival and overall survival is not yet known.

Figure 3.

57-y-old male, status post radical prostatectomy for PCa, Gleason 4 + 5 = 9. pT3bN0, who received sRT, with PSA nadir0.2 ng/mL. Patient developed metastatic nodal disease 2 y later (PSA = 3.3 ng/mL) receiving stereotactic ablative radiation in a right iliac lymphadenopathy. PSA continued to rise (8.75 ng/mL) and patient underwent ¹⁸F-DCFPyL PET/CT that demonstrated DCFPyL avid foci in the left humeral head, anterior left 6th rib and in an enlarged right iliac node. Patient was scheduled to received metastatic-directed radiotherapy.

For many clinicians, it seems reasonable to individualize treatment in patients with oligometastatic disease and treat them differently from patients with diffuse metastatic disease (the definition of oligometastatic disease is inconsistent and varies from as few lesions as one up to between three and five distant metastases). The role of metastasis-directed radiotherapy (MDT), via stereotactic body radiation therapy (SBRT), with or without systemic therapy in patients with oligometastatic disease is an strategy under evaluation in several ongoing and planned prospective clinical trials.

Given its increased sensitivity for early metastases, PSMA PET imaging has been incorporated into trials of MDT in PCa. A recent publication by Henkenberens et al.⁴⁶ presented the efficacy of PSMA-PET-guided MDT in a homogeneous cohort of 42 patients with early oligometastatic castrate-resistant PCa (defined as ≤5 visceral or bone metastases) staged with ⁶⁸Ga-PSMA PET/CT, who received radiation to all metastases to delay the initiation of systemic therapy. PSMA PET-guided MDT represented a viable treatment to delay further systemic therapies, with a median biochemical progression-free survival of 12 months after PSMA PET-based MDT and a median second-line systemic treatment free survival of 15 months.⁴⁶ In a prospective single center study of 57 patients with oligometastatic PCa on PSMA PET imaging, Kneebone and colleague⁴⁷ achieved a median biochemical disease-free survival of 11 months after treating visible lesions with stereotactic body radiotherapy and no systemic therapy. In the ORIOLE phase 2, randomized clinical trial, Phillips et al. showed that among men with oligometastatic PCa (1–3 metastases), those treated with stereotactic ablative radiotherapy were significantly less likely to have disease progression than those undergoing observation alone (6-month progression rate of 19% versus 61%).⁴⁸ A prospective multicenter randomized phase 2 trial (STORM)⁴⁹ is underway comparing the survival benefit of combining whole pelvic radiation therapy and MDT versus MDT alone in patients with pelvic nodal oligorecurrence (≤5 nodes).

Even though systemic therapy with androgen deprivation therapy remains the standard of care for patients with metastatic castrate sensitive PCa, regardless of the number of lesions. There are promising clinical results supporting the use of PSMA PET in conjunction with MDT in patients with oligometastatic PCa. Nonetheless, it is obvious that further research is required to determine whether earlier detection and tailored radiation treatment translates into better survival and quality of life benefits.

Conclusion

As PSMA PET imaging tools become more routinely incorporated into the clinical practice, it is expected that the use of this imaging modality would upstage a substantial proportion of patients with PCa, whose disease is underestimated with standard conventional imaging. This may have implications for the current treatment paradigms, enabling further individualized treatment plans and possibly changing management of patients with PCa. Further, PSMA PET/CT imaging may help reduce the risk of radiation to adjacent normal tissues. Despite the demonstrated impact of PSMA PET on the patient’s selection for radiation planning at initial staging, for salvage radiation in the setting of PCa recurrence and for metastatic-directed radiotherapy in early oligometastatic PCa, it remains to be determined whether these new treatment plans may result in improved overall survival. Future ongoing prospective studies will begin to clarify the effect of PSMA imaging on patient long-term outcomes.