Functional Imaging for Prostate Cancer: Therapeutic Implications

Abstract

Functional radionuclide imaging modalities, now commonly combined with anatomical imaging modalities CT or MRI (SPECT/CT, PET/CT, and PET/MRI) are promising tools for the management of prostate cancer particularly for therapeutic implications. Sensitive detection capability of prostate cancer using these imaging modalities is one issue; however, the treatment of prostate cancer using the information that can be obtained from functional radionuclide imaging techniques is another challenging area. There are not many SPECT or PET radiotracers that can cover the full spectrum of the management of prostate cancer from initial detection, to staging, prognosis predictor, and all the way to treatment response assessment. However, when used appropriately, the information from functional radionuclide imaging improves, and sometimes significantly changes, the whole course of the cancer management. The limitations of using SPECT and PET radiotracers with regards to therapeutic implications are not so much different from their limitations solely for the task of detecting prostate cancer; however, the specific imaging target and how this target is reliably imaged by SPECT and PET can potentially make significant impact in the treatment of prostate cancer. Finally, while the localized prostate cancer is considered manageable, there is still significant need for improvement in noninvasive imaging of metastatic prostate cancer, in treatment guidance, and in response assessment from functional imaging including radionuclide-based techniques. In this review article, we present the rationale of using functional radionuclide imaging and the therapeutic implications for each of radionuclide imaging agent that have been studied in human subjects.

Introduction

Prostate cancer is the most common noncutaneous malignancy among men in the United States, and rated second in mortality after lung cancer, accounting for estimated 9.3% of all cancer-related deaths of male adults (28,170 out of 301,820) in 2012.¹ This disease is age-related, therefore, as life expectancy increases, so will its incidence, creating a significant health problem.² The successful management of prostate cancer requires early detection of clinically significant disease, appropriate risk assessment, and optimum treatment.^3,4 Digital rectal examination (DRE)⁵ is considered the standard reference for detection of prostate cancer with 50% of all palpable nodules being carcinomas. Prostate cancer is currently characterized by its prostate-specific antigen (PSA) serum level, TNM stage, and Gleason score.⁶ The PSA testing is useful for screening prostate cancer, and has been a good marker for assessing response to therapy and detecting recurrent and/or metastatic disease. It is believed to have reduced the rate of death from prostate cancer, but the PSA lacks the ability to differentiate low-grade from high-grade cancers, and there remains a growing concern regarding the potential risk of overdiagnosis and, consequently, overtreatment of potentially indolent disease based on PSA levels, affecting the quality of life of patients in this group.⁴

The treatments of prostate cancer include radical prostatectomy (RP), pelvic lymph node dissection (PLND), external beam radiotherapy (EBRT), brachytherapy, cryosurgery, hyperthermia, androgen deprivation therapy (ADT), and chemotherapy. Monotherapy or combination therapy is performed based on the staging and clinical presentation of the cancer. Among the available treatment options, definitive treatments, meaning eradicating or killing the cancer tissues, include RP that often combines with PLND or extended PLND (ePLND),^7-12 EBRT that often combines with prophylactic pelvic irradiation,^13-18 and brachytherapy.^19-28 Since the definitive treatments are inevitably invasive, which could lead to unwanted, significant side effects, understanding of tumor boundaries and spread prior to the treatments has become a significant healthcare challenge. The pretherapy assessment for these definitive therapeutic approaches involves conventional noninvasive radiologic imaging such as transrectal ultrasound (TRUS), x-ray computed tomography (CT), magnetic resonance imaging (MR), and radionuclide bone scintigraphy (bone scan).²⁹ However, for these definitive treatments, identifying disease versus nondisease volumes is difficult using any of the available imaging methods.

Functional imaging proves its value in these therapeutic implications by providing information on the biologically active volume of the cancer. The currently performed functional or metabolic imaging techniques for prostate cancer evaluations are radionuclide imaging techniques such as single photon emission computed tomography (SPECT) and positron emission tomography (PET) as well as magnetic resonance imaging (MRI) techniques that provide functional and metabolic information of the cancer such as dynamic contrast-enhanced (DCE) MRI^30,31, ultrasmall superparamagnetic iron oxide (USPIO)-MRI,^32,33 proton high-resolution magic angle spinning (HR-MAS) magnetic resonance spectroscopic imaging (MRSI),^34-37 or hyperpolarized ¹³C-pyruvate metabolic MRI.^38,39 All of these functional imaging techniques have limited utilities in prostate cancer management; as no single imaging modality provides reliable methods of delineating cancerous lesions clearly from nondisease volumes, which has become a significant challenge of using noninvasive imaging results in definitive therapies of prostate cancer.

Fortunately, these advanced imaging modalities, combined with current imaging technologies, provide more direct means of being utilized in treatment planning than before because either radionuclide-based or metabolic/spectroscopic MR-based information is accompanied by structural imaging information such as CT^40-42 and conventional MRI.^35,37,43,44 The structural imaging information locates functional and metabolic signals in relation to the patient anatomy; thus help delineate or identify the volumes of biological significance for therapeutic inventions. In this report, the focus is given to radionuclide-based imaging techniques using modern SPECT/CT and PET/CT technologies, and how the functional radionuclide imaging information can be used in therapeutic interventions will be discussed in detail.

The sections that follow will describe presently studied molecular imaging radiotracers that are used in clinical prostate cancer imaging, and how the CT and MRI complement the functional information from the radionuclide imaging as mediators. The roles of functional prostate cancer imaging in guiding therapies, drug or radiation therapy response monitoring, the assessment of recurrent or residual disease after definitive treatments will be discussed.

Combined Radionuclide and Structural Imaging Modalities for Prostate Cancer Management

Examining the extent of prostate cancer spread, once PSA and DRE provides enough suspicion followed by cancer presence confirmed by TRUS-guided biopsies, noninvasive imaging, regardless of its being functional or structural, can potentially provide the information on how spread the cancer is. Although this may be true in most other cancers to some degree, noninvasive imaging has not fulfilled its promise to provide accurate information with regards to the involvement of prostate cancer (i.e., status of regional, distant, and bone metastasis). In terms of functional radionuclide imaging technologies, the advent of combined dual-modality SPECT/CT, PET/CT, and PET/MRI for clinical applications has not progressed much for the detection and diagnosis of prostate cancer. However, the structural imaging techniques from CT and MRI in the combined dual-modality scanners are still very useful if there is any complementary anatomical information that can help the therapeutic management of the prostate cancer.

SPECT/CT

SPECT/CT is currently offered as SPECT scanners combined with either low-mA CT or high-mA CT as in standalone CT scanners from major vendors.^40,45 The utility of CT in SPECT image reconstruction has been found to be significant so that SPECT images have greatly improved by having CT-based information such as attenuation map.^40,46,47 The primary difference between low-mA CT and high-mA CT is how CT is used in relation to localization of radiotracer uptake patterns from SPECT.⁴⁸ The high-mA CT offers conspicuity of anatomical references. In cancer evaluations using the radionuclide imaging techniques that do not provide clear anatomical features, high-mA CT offers more than simply providing attenuation map for SPECT reconstruction as shown in Fig. 1. For the prostate cancer, the radiation treatment or surgical guidance during PLND can benefit from the combined SPECT/CT technologies.^49,50 Although the low specificity is problematic, the common radiotracers used in gamma camera and SPECT imaging, such as ^99mTc-(hydroxyl)methylene diphosphonate (HDP or MDP), ^99mTc-labeled colloidal particles (albumin colloid or sulfur colloid), ¹¹¹In-capromab pendetide (ProstaScint), all provide useful information in guiding customized therapy planning. The details of each tracer's role, in conjunction with SPECT/CT scanners, will be provided in separate sections below.

Figure 1.

1.5 cm × 0.7 cm peripancreatic lymph node uptake of ¹¹¹In-capromab pendetide visualized by SPECT combined with 16-slice multidetector CT (Precedence, Philips Healthcare) scanner. Transverse images of SPECT alone (left); CT alone (middle); and SPECT/CT fusion (right). Arrows indicate where the ¹¹¹In-capromab pendetide uptake is in relation to its anatomical location from SPECT, CT, and SPECT/CT images. Reprinted with permission under the “Creative Commons Attribution Noncommercial License”.⁴⁸

PET/CT

PET with ¹⁸F-fluorodeoxyglucose (FDG), now more commonly as combined dual-modality PET/CT, changed the cancer management scheme significantly in recent years.^51-55 FDG has become a very important radiotracer that connects the glucose utilization and tumor growth.^56,57 In prostate cancer evaluation, its utility still is questionable as a general imaging technique for staging; however, ¹⁸F-FDG can be used for the assessment of distant metastasis.^58,59 Bone scan with PET using ¹⁸F-NaF^60-65 as an imaging tracer is increasingly used in those geographical regions where a nearby radiopharmacy can provide ¹⁸F-NaF to PET centers, as is the case for ¹⁸F-FDG. For prostate cancer in general, the increasing use of PET/CT, for which the combined CT provides powerful structural information and direct therapy planning guidance, is predictable since there are already several PET imaging radiotracers other than ¹⁸F-FDG that showed a promising clinical utility such as ¹¹C/¹⁸F-choline^66-85 (an example image is shown in Fig. 2), ¹¹C/¹⁸F-acetate,^69,75,86-98 and ¹⁸F-fluorodihydrotestosterone (FDHT).^99-101 Some of these PET radiotracers have good potential to guide treatment planning and monitor treatment response.

Figure 2.

¹¹C-choline PET/CT showing focal (A) and multifocal (B) lesion distribution of prostate cancer within the gland (arrows). The scatter plots show the maximum standardized uptake values (SUV_max) for each scan in 36 segments within the gland, which were divided by 6 peripheral and 6 central segments, totaling 36 segments. Reprinted with permission.⁷⁸

PET/MRI

PET/MRI, an emerging field of active research investigations, is still finding its utility in clinical applications.^102-105 In potential clinical applications using PET/MRI, the importance of MRI in relation to PET may be more significant than CT to PET/CT particularly considering the MRI's excellent soft tissue contrast; thus the design of PET/MRI scanners does emphasize the performance of MRI as well as that of PET while they are put together either simultaneously or side-by-side. MR-specific techniques that have been developed for prostate cancer imaging can further benefit from PET radiopharmaceuticals that have found utilities in prostate cancer evaluation. In an ideal situation, PET/MRI could make a significant impact for prostate cancer management because the combined imaging techniques offer superior structural/functional/metabolic information in vivo than any other combinations of imaging modalities currently available in the clinical setting. However, a routine practice of using PET/MRI still needs to be defined for the prostate cancer management, which is a nontrivial question. One strong potential using PET/MRI for prostate cancer is that this combined scanner can be one-stop shopping for new drug therapy response assessment in patients, which can be applied to many cancer types. Also, when there is a strong need of performing both MR-based techniques and PET studies for patients with prostate cancer, the combined PET/MRI scanner could save some time for patients avoiding two separate visits. Most of MR techniques that are useful in prostate cancer detection and evaluation, such as DCE-MRI, USPIO-MRI, MRSI, and hyperpolarized ¹³C-pyruvate MRI, can be implemented in PET/MRI without significant compromise, while the increasingly popular efforts of PET imaging agent developments targeting specific biomarkers of prostate cancer such as prostate-specific membrane antigen (PSMA)^106-109 and prostate stem cell antigen (PSCA)¹¹⁰ will be able to strongly complement the MR-based findings as well. However, the question of using simultaneous PET/MRI will always be subject to controversies while both PET and MRI imaging information can be obtained without any compromise from separate scanners with optimized settings for each.

Therapeutic Approaches and Radionuclide Imaging for Prostate Cancer Management

In the US, National Comprehensive Cancer Network (NCCN) publishes guidelines for standardized cancer managements including prostate cancer.^111-116 The NCCN prostate cancer clinical practice guideline provides up-to-date management flow charts that contain both imaging and therapeutic approaches. The use of noninvasive imaging in the NCCN guideline is limited to the standard imaging techniques such as abdominal-pelvic CT/MRI and bone scan because, while limited for prostate cancer evaluation, these two imaging techniques are widely available. Considering that according to the NCCN guidelines in therapy planning, the imaging techniques are used for evaluating the lymphatic and bony involvement, it can be also directly implied that the imaging techniques that can provide sensitive measures of bone and lymph node involvement have great potential to be adopted in the clinical practice guidelines. It should be noted that one of the most extensively studied radionuclide imaging agents, ¹¹¹In-ProstaScint, has been removed in the most current NCCN guideline as a recommended method in the recurrent setting of the prostate cancer, indicating the frustration of not having a reliable and highly sensitive functional imaging agent.

Since the functional imaging methods are being adopted as drug therapy response monitoring for most types of cancer, nonspecific but sensitive lymph node and bone imaging methods such as ultrasmall superparamagnetic iron oxide (USPIO)-MRI and bone SPECT and PET are being considered in clinical research settings. Androgen deprivation therapy (ADT), chemotherapy (when ADT is ineffective for castration-resistant prostate cancer (CRPC)), and bisphosphonates therapy (for bone mineral density (BMD) improvement in case of bone metastasis^117-125), can potentially benefit from functional imaging-based sensitive lymph node and bone involvement assessment techniques as well.

Radionuclide Imaging Agents for Prostate Cancer

There are a number of radionuclide-based imaging agents that were developed and are under development in laboratory research settings for prostate cancer.^126-128 However, if we focus on radionuclide-based imaging agents and techniques that have been made to extensive clinical evaluations in conjunction with therapeutic implications, the list of radiotracers becomes relatively short-handed.

Bone-Seeking Agents – ^99mTc-MDP/HDP, ¹⁸F-NaF

The rationale of bone imaging for prostate cancer is that the metastasis to bones can typically change the whole course of the cancer management because of its indication of the advanced stage. Thus, the bone metastasis evaluation is important when the systemic treatment approach such as ADT and chemotherapy is considered for advanced prostate cancer patients. Bone-seeking agents using radionuclides accumulate in the lesions where increased blood flow and osteoblastic activity exist in bone. In the case of bone metastasis, this accumulation shows a typical random pattern of conspicuous osteoblastic lesions mainly along the axial and proximal appendicular skeleton. Although not specific for bone metastases of only prostate cancer, radionuclide bone scans have proven to be very useful in the assessment of bone metastases.

Sentinel Lymph Node (SLN) Involvement Agents – ^99mTc-albumin colloid, ^99mTc-sulfur colloid

Even after definitive treatments, patients without clear evidence of metastatic disease, relapse at a very high rate.^17,129 From PLND and ePLND studies performed, the lymph node involvement of prostate cancer seems higher than typically thought.¹³⁰ As a treatment method, PLND can benefit greatly if it targets identified SLNs or lymph nodes within the lymphatic path drainage of the prostate.^130-143 As shown in the literature, the location of prostate sentinel lymph nodes and lymph node drainage varies significantly between patients.^50,144 In addition, as a prophylactic measure, pelvic lymph node irradiation for intermediate-to-high risk patients should be more reliably designed when the identification of sentinel and/or drainage lymph nodes is made before the irradiation.⁴⁹ Functional radionuclide imaging helps in this regard. For both surgeries and radiation therapy, the SLN imaging can be adopted as a routine evaluation before the treatments.

Prostate-Specific Membrane Antigen (PSMA)- Targeting Agents – ¹¹¹In-capromab pendetide (ProstaScint), ¹⁷⁷Lu-J591 (for radioimmunotherapy, but imaging can be performed), ¹²³I-MIP-1072

Prostate-specific membrane antigen (PSMA) is overexpressed in malignant prostate tissue,¹⁴⁵ and has been pursued as a preferred target for prostate cancer imaging as well as therapy as targeted radionuclide therapy. PSMA is known to be expressed in some normal cells, and when the cancer becomes metastatic to bones, the expression of PSMA is significantly diminished as undetectable PSMA levels are found in PC-3 cells that are derived from prostate cancer bone metastasis. In malignant lymph nodes, PSMA is highly expressed as in LNCaP cells, which has been confirmed by ^{in vivo} imaging experiments.^107,146 For this reason, PSMA is considered an excellent target for prostate cancer evaluation particularly of lymph node involvement, but may not be preferred as a single imaging target to cover bone metastasis of the prostate cancer. The monoclonal murine antibody, targeting the intracellular epitope of PSMA, 7E11-C5 had progressed to a clinical product for imaging when labeled with In-111 (¹¹¹In-ProstaScint). Although the promise of anti-PSMA imaging may have diminished significantly because of the low sensitivity and specificity of ¹¹¹In-ProstaScint, there has been still extensive research studies using PSMA as a target of prostate cancer imaging and therapy.

Non-prostate-specific Metabolic PET Imaging Agents – ¹⁸F-fluorodeoxyglucose (FDG), ¹¹C/¹⁸F-choline, ¹¹C/¹⁸F-acetate

PET and PET/CT imaging of ¹⁸F-fluorodeoxyglucose (FDG) to visualize the tumor glucose utilization has become the gold standard for staging most cancers. Not specifically effective in prostate cancer, FDG still finds its utility in this malignancy in terms of evaluating distant metastasis when there is a risk defined by other parameters such as PSA and Gleason score from biopsies. Metabolic PET imaging agents for the investigations of glucose, choline, and acetate metabolism have been studied in patients with prostate cancer.

Androgen Receptor and Protein Synthesis Imaging Agents – ¹⁸F-fluorodihydrotestosterone (FDHT), ¹¹C-methionine

Since androgen deprivation therapy is common to suppress growth of prostate cancer systemically, imaging androgen receptor is a natural step to follow that therapy. ¹⁸F-FDHT has been developed to follow the level of androgen receptor expression, and has been correlated with anti-androgen treatment of prostate cancer.^101,126,147

Protein synthesis and amino acid transport in tumor proliferation can be followed by radiolabeled amino acid such as ¹¹C-methionine.¹²⁶ However, the role of ¹¹C-methionine is still limited to detection of prostate cancer, and its therapeutic implications are still understudied.

Radionuclide Imaging of Prostate Cancer and Therapeutic Implications

In the following, we describe the underlying mechanism of each radionuclide imaging agent and its therapeutic implications followed by representative examples. Our manuscript is not intended to compile all available and studied radionuclide imaging agents that have shown their values in imaging prostate cancer. There are several review articles for that topic already, and this review article is focused on the radionuclide imaging of prostate cancer and their therapeutic implications.

Bone Imaging and Therapy

Bone scan, whether it is performed using SPECT (^99mTc-MDP/HDP) or PET (¹⁸F-NaF) is a standard imaging method to visualize turnover anomalies in the bone. In prostate cancer, whole-body bone scan is used as a monitor for progression of metastatic bone disease.

^99mTc-phosphonate tracers such as MDP and HDP are absorbed to bone matrix where calcium phosphate exchanges with phosphonate compounds. The higher exchange or turnover rate means the higher osteoblastic activity, which presented in a specific pattern is a good indication of metastasis. ¹⁸F-NaF is also rapidly absorbed to bone matrix, and the uptake of fluoride ion of ¹⁸F-NaF shows anomalies associated with bone metabolic disorders including prostate cancer bone metastasis. Using two-dimensional anterior-posterior bone scan, SPECT, SPECT/CT, PET, or PET/CT, the bone metabolism can be tracked, and for the therapeutic implications, the radionuclide imaging of bone metabolism is an excellent resource to allow cancer progression monitoring or therapy response evaluation and monitoring.

For example, the bone scan findings were correlated as a prognostic factor of survival and a stratification tool in clinical trials of drug therapy of bone metastasis.^148,149 When outcomes and predictive factors for biochemical relapse were measured for patients without bone metastasis, the patient stratification could be made with negative radionuclide bone scan.¹⁵⁰ The lesion volume of bone involvement of prostate cancer assessed by bone scan has proven to be a strong prognostic value. In patients with primary androgen deprivation therapy (ADT), the site of bone metastasis identified by bone scan was also found to carry a good prognostic value of survival.¹⁵¹ Bone scan findings could be directly compared before and after ADT, showing the geographically inconsistent response to the therapy in bone lesions (as shown in Fig. 3), the value of noninvasive bone imaging to assess the treatment response for the metastatic prostate cancer.¹⁵²

Figure 3.

Pretherapy (left) and posttherapy (right) ^99mTc-MDP anterior-posterior bone scans showing geographic distributions of skeletal metastases. The response to the androgen deprivation therapy for the patient with metastatic prostate cancer is depicted by bone scan, and the different geographical locations of bone lesions show different responses to the therapy. Reprinted with permission under the “Creative Commons Attribution-NonCommercial-NoDerivs”.¹⁵²

The limitation of bone scan for prostate bone metastasis evaluation using any radionuclide imaging modality and agent currently available still lies within the lack of cancer-specificity of the agent. It is a major challenge to develop an imaging probe specific for metastatic prostate cancer that can reliably investigate the effect of direct cancer therapeutics targeting bone metastasis of the prostate cancer.

Sentinel Lymph Node (SLN) Imaging and Therapy

Radionuclide sentinel lymph node imaging using SPECT(/CT) or intraoperative gamma camera could make a significant contribution in both surgical and radiation interventions of prostate cancer. Both PLND and ePLND during radical prostatectomy, and pelvic irradiation during external beam radiotherapy, can target identified sentinel lymph nodes and/or lymph nodes along the prostate's lymphatic drainage more aggressively, or avoid nonsentinel nodes if the removal or irradiation of them could cause nonnegligible side effects.

The patient-specific lymphatic drainage pattern identification from the prostate gland has been possible using radionuclide-based colloidal particles. For example, Fig. 4 shows the distribution of multiple lymph nodes within the lymphatic drainage of the prostate identified by radionuclide colloidal particle imaging.¹⁵³ Earlier attempts of radionuclide imaging ^99mTc-labeled colloid (e.g., ^99mTc-antimony sulphide colloid¹⁵⁴) showed its feasibility of noninvasive imaging of SLN distribution from the prostate. Nanocolloids (colloidal particles with the size less than 100 nm) have preferential accumulation at the first landing sites, also known as sentinel lymph nodes (SLNs), through the lymphatic drainage chain as for all other colloidal particle; however because of their small sizes, the drainage from the administered site to lymph nodes is faster than larger colloids so that the imaging window is within a few hours after administration. When labeled with radionuclides such as Tc-99m and because of the size of nanocolloids, the clearance from the prostate gland and accumulation time in the lymph nodes do not require hours of wait time before imaging studies. Commercial products like ^99mTc-Nanocoll (GE Healthcare), nanocolloid of human serum albumin,^144,153,155 which is not available in the United States, and ^99mTc-sulfur nanocolloid (filtered through a 100-nm polycarbonate membrane filter) can be easily administered to the prostate gland under the guidance of TRUS.⁴⁹

Figure 4.

SPECT/CT example of ^99mTc-nanocolloid injected to the prostate gland, showing three sentinel lymph nodes (iliac left) identified by this imaging technique. Reprinted with permission.¹⁵³

In surgical procedures of radical prostatectomy and PLND, ^99mTc-nanocolloid images from either preoperative SPECT registered onto CT or MRI, or intraoperative gamma probe showed guiding resections of SLNs reliably.¹⁵⁶ From the data review from the surgical cases, SLN imaging techniques supported that PLND for prostate cancer should be extensive, including common iliac nodes up to the utreteric crossing.¹⁵⁵

In radiation treatment using intensity-modulated ratiotherapy (IMRT) for prostate cancer, when the individual lymphatic drainage map from radionuclide nanocolloid imaging is available, it is found to be feasible to selectively irradiate SLNs and other lymph nodes within the particular lymphatic drainage of that prostate that could be missed by CT-based planning only.^144,157 The implication of this approach is that the pelvic lymph node irradiation based on individualized lymphatic drainage of the prostate could increase the curative potential of radiotherapy in high-risk patients who have a higher probability of lymph node involvement of the cancer. In addition, the study performed in the USA using ^99mTc-sulfur nanocolloid showed a similar potential of the radionuclide SLN imaging in guiding IMRT planning and whole-pelvis radiotherapy (WPRT).¹⁵⁸ In this study, there were clear cases of substantially altered radiation fields based on the SLN imaging results.

The limitation of the radionuclide SLN imaging includes that this imaging technique is only reliably applicable for the patients who have the intact prostate that has not been treated because of the uncertainty of where the radioactive nanocolloids can be administered. Additional limitation is the lack of the long-term effect data from the altered, if any, treatment management of the prostate cancer, either surgical or radiation interventions. Hence, once the radionuclide SLN imaging is more adopted in routine clinical practice, there will be more definitive data to show the actual benefit from the therapeutic approaches based on the radionuclide SLN imaging.

Anti-PSMA Imaging and Therapy

PSMA is the most well-established imaging target of prostate cancer because of its overexpression in malignant prostate cancer.^159-162 Radionuclide imaging against PSMA using monoclonal antibody (mAb) also has been extensively performed both in clinical settings and small animal models of prostate cancer. The clinical anti-PSMA radionuclide imaging is performed using ¹¹¹In-capromab pendetide (ProstaScint), which is the only PSMA-targeting imaging agent currently approved by the US Food and Drug Administration (FDA).^163,164 The imaging information from ¹¹¹In-ProstaScint has been utilized in the therapeutic approaches of prostate cancer. However, the success of the clinical impact on the therapeutic management of the cancer is rather controversial.

Two other radionuclide imaging agents targeting PSMA have been studied in the phased clinical trials. The first is radiolabeled J591 mAb which targets the extracellular epitope of PSMA.^165-170 Unlike ¹¹¹In-ProstaScint with its antibody (7E11-C5) targeting the intracellular epitope of PSMA, ¹¹¹In-J591 has been considered a superior imaging agent for anti-PSMA imaging.¹⁶⁵ However, the current effort of using J591 mAb is toward its use in targeted radionuclide therapy (radioimmunotherapy) labeled with a therapeutic radionuclide, Lu-177 and Y-90.^170-173 By its own targeting specificity, this approach is also promising to be therapeutically effective on prostate cancer cells that express high levels of PSMA. And, the more recent effort of using J591 is to combine with a positron-emitting radionuclide, Zr-89 via a bifunctional chelate desferrioxamine B (DFO), making ⁸⁹Zr-DFO-J591 for immunoPET imaging of prostate cancer.^99,174 The second radionuclide imaging agent targeting PSMA, which has been also studied in human subjects is ¹²³I-MIP-1072,¹⁷⁵ developed by Molecular Insight Pharmaceuticals (Cambridge, MA). ¹²³I-MIP-1072 is a small molecule (535 Da), glutamate-urea heterodimer inhibiting the N-acetylated α-linked acidic dipeptidase (NAALADase) enzymatic activity of PSMA, and preferentially accumulates and internalizes in cells expressing PSMA. This imaging agent has been pursued in human subjects as a couple of Phase I clinical trials which were completed in between 2009 and 2011.

The PSMA-targeting radionuclide imaging agents, thus, have a great potential of therapy planning, particularly for the lymph node involvement of the prostate cancer or for the heterogeneity of the cancer, subject to the localized brachytherapy. For example, ¹¹¹In-ProstaScint SPECT/CT was able to make feasible dose escalation to the biological target volumes (BTVs) identified by the imaging for brachytherapy (as shown in Fig. 5).^21,176 This feasibility study was also supported by the SPECT/CT studies of ¹¹¹In-ProstaScint for the patients presented with clinically localized cancer, which found that the biochemical failure from radiotherapy was higher for the group of patients who had extra-periprostatic metastasis versus the group of patients who had confined localized cancer by the ¹¹¹In-ProstaScint SPECT/CT findings.¹⁷⁷ Although it is still controversial and not generally accepted, the prognostic value of quantitative ¹¹¹In-ProstaScint SPECT/CT imaging findings could be highly relevant and correlative with the cancer prognostic factor such as pathologic Gleason score.¹⁷⁸ The prognostic value of this imaging study will likely be strengthened when a more robust PSMA-targeting radionuclide imaging agent can be used in human subjects. Hence, imaging agents such as ⁸⁹Zr-DFO-J591, ¹²³I-MIP-1072, or any other emerging PSMA-targeting radionuclide imaging agent, have generally a great potential to help therapy guidance, while providing a prognostic value.

Figure 5.

Transverse view (left) of ¹¹¹In-capromab pendetide SPECT fused with CT from a patient undergoing ultrasound-guided brachytherapy using Pd-103 seeds. Additional seeds were used during implantation for the regions identified by ¹¹¹In-capromab pendetide SPECT/CT, showing the feasibility of dose escalation based on the imaging data. The dose distribution map (right) of the brachytherapy shows the isodose map at 9mm superior to the midplane of the seed-implanted volume. Reprinted with permission.¹⁷⁶

Non-prostate-specific Metabolic PET Imaging and Therapy

The use of FDG-PET/CT in the cancer management has greatly impacted on the patient welfare for many cancer types. Although its utility in prostate cancer detection is relatively low, FDG-PET/CT provides still very relevant information to stage the prostate cancer when the distant lymph node involvement is suspected. FDG PET/CT has shown that disseminated and aggressive lymph node metastasis of the prostate cancer can be visualized.^71,179 In terms of therapeutic interventions, the finding of disseminated lymph node metastasis can be significant, and response to either ADT or chemotherapy can be monitored when there are lesions identified by this imaging modality. Other cancer nonspecific, but still metabolically cancer-avid radionuclide imaging agents have been used in PET imaging of prostate cancer. For this reason, the metabolic activity of prostate cancer can be used in relation to the treatment management. The metabolism of prostate cancer that can be assessed by PET includes glucose (¹⁸F-FDG), acetate (¹¹C-acetate and ¹⁸F-fluoroacetate), and choline (¹¹C-choline, ¹⁸F-fluorocholine, and ¹⁸F-fluoroethylcholine). Although these metabolic PET imaging agents except ¹⁸F-FDG are not generally available, the synthesis of these radiotracers are well published, and the availability depends on the dedicated onsite or regional radiopharmacy facilities for PET imaging centers.

It has been understood that primary prostate cancer cells display limited expression of GLUT-1 transporters, resulting in low accumulation of ¹⁸F-FDG in tumor sites.¹⁸⁰ The tumor generally is characterized by increased choline metabolism in the cell to meet increased phosphatidylcholine synthesis, an important element of cell membrane phospholipids.⁸⁵¹¹C-choline PET for imaging recurrent prostate cancer and its metastases has been used for this reason.⁹¹ Prostate epithelial cells undergo a metabolic transition from citrate-producing normal cells to citrate-oxidizing malignant cells.¹⁸¹ This alteration in citrate metabolism in prostate epithelial cells also leads to an increased turnover of acetate. This prostate-specific citrate metabolism may contribute to high radiopharmaceutical uptake of ¹¹C-acetate, and several studies have shown that ¹¹C-acetate has marked uptake in prostate cancer and its metastasis.^93,94,96,97 In comparison to ¹⁸F-FDG, ¹¹C-acetate PET studies showed higher accuracies for pelvic lymph node metastases.^87,93

At a clinical practice where a PET/CT scanner exists without an onsite cyclotron, ¹⁸F-labeled versions of choline or acetate (¹⁸F-fluoroacetate,^182,18318F-fluorocholine,^141,184-190 and ¹⁸F-fluoroethylcholine^191-195) is presumably an alternative;¹⁸² however the clinical use of ¹⁸F-labeled choline or acetate is somewhat inconsistent with the results from the studies using ¹¹C-labeled choline or acetate because of the difference in pharmacokinetics.

Although FDG is not routinely used for prostate cancer evaluation, when there is uptake identified in patients with prostate cancer by FDG, the lesion and FDG uptake can be followed for the treatment. For example, the relationship between the effect of androgen ablation and the glucose utilization (by FDG uptake measures) has been studied.¹⁹⁶ In this study, there was some indication of FDG uptake affected by the treatment decrease in the lesion identified before and after androgen ablation. Brachytherapy or any focal therapy such as hyperthermia¹⁹⁷ does not benefit greatly from FDG because of the usual high uptake of FDG found in bladder obscuring the visualization and quantification of FDG uptake in the nearby organs including the prostate.

In case of ¹¹C- or ¹⁸F-labeled choline, because of its wider availability or interest than other ¹¹C- or ¹⁸F-labeled nonFDG PET radiotracers for prostate cancer, it has been considered to use the lesions identified by choline-PET in radiation treatment planning¹⁹⁸ or surgical interventions such as RP and PLND. Although it is still hard to recommend as a routine clinical practice, some very promising results were reported recently about using ¹¹C-choline PET/CT to guide lymph node dissections while radical prostatectomy was performed in patients.¹⁹⁹ In this study, 3 out of 6 patients with single lymph node metastasis identified by ¹¹C-choline showed a complete permanent PSA remission without adjuvant therapy for approximately 2 years of follow-up. A further study from the same authors, using both ¹¹C-choline and ¹⁸F-fluoroethylcholine, showed a similar result that reported 4 out of 9 patients with single lymph node metastasis had a complete permanent PSA remission for approximately 2.5 years of follow-up.²⁰⁰ In these investigations, one example PET/CT image showing a single lymph node metastasis identified by ¹¹C-choline is illustrated in Fig. 6.

Figure 6.

Transverse view of 11C-choline PET/CT showing a single lymph node metastasis of prostate cancer in the right iliac region. The metastatic cancer was confirmed by histopathology after resection. Reprinted with permission under the “Created Commons Attribution License”.²⁰⁰

In case of ¹¹C- or ¹⁸F-labeled acetate, the same principle of its choline counterparts can be applied in terms of its therapeutic implications. PET imaging using radiolabeled choline, acetate, and FDG all detect lymph nodes and even bone metastasis when its corresponding metabolism is avid in these lesions. A dual-isotope study using ¹¹C-acetate and ¹⁸F-FDG showed that the detected bone lesions by both imaging agents were affected by androgen deprivation therapy.²⁰¹ It is not surprising to find out this result because the tumors that depend on glucose utilization or acetate metabolism should be affected by the systemic ADT. In radiation treatment planning, it is natural to believe that the information from ¹¹C/¹⁸F-acetate PET can be included for possible boost of radiation to the biological target volume (BTV). A theoretical study has shown that it is indeed feasible²⁰², but the validation study of using ¹¹C-acetate (or even ¹⁸F-acetate or ¹¹C/¹⁸F-choline compounds) still needs to be performed to be widely accepted.

A significant limitation of using metabolic PET imaging agents for therapy planning or therapy response assessment is that none of these imaging agents is cancer specific. Because of this reason, both choline and acetate-based PET imaging agents also showed a high rate of false-negative findings.^203,204 In addition, since there are also too many trials and errors to find this general tumor imaging agent in case that FDG fails to reliably deliver a good diagnosis, there is no focused effort of pursuing a limited set of imaging agents and careful investigations are hard to achieve.

Androgen Receptor Imaging and Therapy

Another ¹⁸F-labeled PET imaging agent, ¹⁸F-fluorodihydrotestosterone (FDHT) targets androgen receptors, and has been evaluated for imaging prostate cancer. Dihydrotestosterone (DHT) is directly correlated with the expression of androgen receptor^100,205 that has a major role in tumor growth even in castration-resistant prostate cancer (CRPC). As an imaging agent, ¹⁸F-FDHT may not be superior to other metabolic PET imaging agents mentioned earlier; however, since ¹⁸F-FDHT is correlated with the androgen reception expression, it is a promising imaging agent to show the effect of anti-androgen therapy of prostate cancer as shown in Fig. 7. However, only limited studies have been performed to correlate ADT and ¹⁸F-FDHT uptake changes in advanced prostate tumors.^100,147

Figure 7.

Maximum-pixel-intensity reprojection images of ¹⁸F-FDHT before and after flutamide (androgen receptor antagonist) treatment. Images show anterior (left) and posterior (right) views, and pretherapy (upper row) and posttherapy (lower row) views. Arrows indicate the lymph nodes that had strong ¹⁸F-FDHT uptake before flutamide therapy. After the therapy, the ¹⁸F-FDHT uptake disappeared in these lymph nodes. Reprinted with permission.¹⁴⁷

Imaging Agents Under Development and Therapeutic Implications

There are a number of radionuclide-based imaging agents that were developed and are under development in research settings for prostate cancer. It should be again clearly noted that his paper is not intended to compile the list of imaging agents that still need extensive research before clinical translation. For that topic, there are some recent excellent review articles published.^{99,126,127,206}

The management of clinical localized prostate cancer has improved significantly in recent years with the survival rates being very high, much of the attention is paid to identifying and systemically treating disseminated disease. For example, the imaging target such as PSMA is actively pursued also for therapeutic target of radioimmunotherapy.^146,171,172 In addition, there is much interest in using anti-PSMA antibodies or small molecules as a vehicle for the drug payload. For the PSMA-targeted systemic therapy, the role of radionuclide imaging using the same vehicle could be significant as a tool for patient stratification. The same principle of imaging and therapy can be applied to any other antibodies^110,207 or small molecules^106,107,109 that target PSMA or other antigens specific to prostate cancer.