Practice-Changing Applications of Radiology and Nuclear Medicine in Genitourinary Malignancies

Experts at Harvard Business School first coined the term disruptive innovation to describe how small, poorly resourced companies could successfully challenge larger ones.1 More than two decades later, this concept is central in medicine, where innovations in everything from proteomics and wearables to electronic health records and health economics are upending our status quo.2,41 Many of these disruptors are exciting—they aim to advance diagnostics, treatment, outcomes, and multidisciplinary patient-centered care. But they come with risks, too: Their popularity can outpace their efficacy and safety, and they can impede clinical workflows.3,4

As technology-driven specialties, radiology and nuclear medicine are often targets of disruption. In this article, I briefly discuss value-based radiology, big data, multiparametric prostate MRI, next-generation PET imaging, and targeted/radioligand therapies, all of which are transforming the role of radiology and nuclear medicine in the diagnosis, treatment, and surveillance of genitourinary malignancies. I also share tips for incorporating radiologic innovations into urology practice.

Value-based Radiology and Big Data
Value-based healthcare is a model in which hospitals and physicians are paid based on patient outcomes, not services provided.5 The goal is to make healthcare more efficient and cost-effective while improving health, quality of life, and patient satisfaction.

In the past, improved performance and change in management resulting from new imaging technologies was enough to justify reimbursement. In today’s environment of cost containment, the bar is higher; these technologies need to show a positive impact on outcomes which is challenging, especially when evaluating diagnostic tools.

In response to the changing landscape of the field, the American College of Radiology has focused efforts to provide a roadmap to value-based radiology through various tools such as clinical decision support, structured reporting, and appropriate use criteria. This Imaging 3.0 Initiative not only benefits radiology but also provides resources for our clinical colleagues regarding the additional value-added services of our specialty.6

Big data analysis and artificial intelligence have become the primary discussion topic at our national meetings. There is no question that AI and machine will revolutionize our field and provide additional tools for radiologists to improve our performance which includes accuracy and efficiency. As we embrace this shift in our field, we will become better data managers to improve diagnosis. In response to this disruptive technology, the ACR has created a Data Science InstituteTM (DSI) to guide us all on which problems in radiology need big data solutions and how best to ensure that algorithms are safe, effective, and integrable into current systems.8,7 This year, the DSI published more than 50 use cases covering relevant clinical scenarios.9 Several hundred more such cases will be freely available on the DSI website by 2020.9

For urologists, big data and artificial intelligence will enhance the services provided by your local radiology and nuclear medicine practice. As a specialty, we will not only perform and interpret exams, but we will also be able to better identify at-risk patients, determine who needs imaging, recommend the most appropriate tests, improve diagnosis, and help manage to follow up for our patients while also managing risk and costs. These tools are around the corner; and the more we understand and engage with them, the more we can use them to benefit our patients.

Prostate MRI
The characterization of local disease in prostate cancer is a crucial part of management, and multiparametric prostate MRI is becoming an important disruptor in this space. Historically, issues with cost, access, and accuracy limited the utility of mpMRI for prostate cancer surveillance.10 The best use of mpMRI remains a hot topic for debate. However, recent results from the international, randomized prospective PRECISION trial provides practice changing results that need to be discussed.11 In this study, 500 men with clinical suspicion of prostate cancer and no history of prostate biopsy underwent either standard transrectal ultrasound (TRUS)-guided biopsy with 10 or 12 core samples, or mpMRI, followed by a mpMRI-guided biopsy if mpMRI was positive.11

Clinically significant cancers, defined as biopsy cores showing disease of Gleason score 3 plus 4 (Gleason sum of 7) or greater, were identified in 38% of men who underwent mpMRI versus 26% of men who received TRUS-guided biopsy.11 Conversely, clinically insignificant cancers were identified in 9% and 22% of men, respectively. In all, 28% of men who underwent mpMRI had negative results, enabling them to forego biopsy. Consequently, the use of MRI-targeted biopsy led to fewer core biopsies and lower rates of complications of prostate biopsy, such as hematuria, pain, rectal bleeding, and erectile dysfunction.

The PRECISION trial occurred at both academic and non-academic sites and included clinicians who were deemed as moderately experienced with MRI-targeted biopsy.11 In the subset of cases that underwent central radiology review, only 78% concorded with site readings. The inter-reader variability with prostate MRI remains a challenge but will continue to improve with the continual iteration of PIRADS. For the time being, I recommend finding a role for prostate MRI and MRI-guided interventions in your practice. MRI guided intervention options include MRI/ US fusion biopsies, in bore MRI guided biopsies, and cognitive registration targeted biopsy.12 In addition, I strongly recommend identifying a local radiologist who can champion prostate MRI and can work closely with the urologist through continual feedback to improve performance.

Next-Generation Imaging
Positron emission tomography-computed tomography (PET/ CT) is a valuable tool for detecting and staging prostate cancer when coupled with radiotracers that can capture physiologic processes such as tumor metabolism, hormone receptors and the presence of prostate specific membrane antigen (PSMA) or gastrin-releasing peptide.15,14,13

The use of PSMA-targeted PET/CT deserves particular attention, as it has been found superior to all other types of scans for detecting metastatic or recurrent prostate cancer in men with biochemical recurrence.18,19,17 There are various PSMA-targeted PET agents,14 none of which are yet approved by the U.S. Food and Drug Administration (FDA).

However, the results of the phase 2/3 OSPREY 2301 study are paving the way for an FDA approval.20 In OSPREY, researchers evaluated PET/CT with 18F-DCFPyL(PyLTM), a novel small PSMAtargeting molecule, for detecting tumor tissue in patients with high-risk locally advanced prostate cancer (cohort A) or distant metastases (cohort B).20

In October 2018, Progenics Pharmaceuticals reported that in cohort A, PyL-based PET/CT detected pelvic lymph node disease with a specificity of 96% to 99% and a sensitivity of only 31% to 42%.20 In cohort B, PyL detected metastatic lesions with a sensitivity of 93% to 99% and a positive predictive value of 81% to 88%. PyL-emergent adverse events were uncommon and none were serious. After discussing these data with the FDA, Progenics Pharmaceuticals is planning a phase 3 trial of PyL that will assess the positive predictive value of PyL-based PET/CT in biochemically recurrent prostate cancer.20

It is important to keep in mind that PSMA is not specific to prostate cancer. Prostate-specific membrane antigen is simply glutamate carboxypeptidase II, a transmembrane protein that is highly expressed in the neovascular endothelial cells of many types of solid tumors.22 Recently, researchers also reported that PSMA is expressed at above-background levels in neural tissue. In a PET-CT study of 417 individuals, 98.5% showed uptake by peripheral ganglia of the PSMA ligand 68Ga-HBED-CC PSMA, also known as 68Ga-PSMA-11.23 Uptake by cervical, sacral, and celiac ganglia occurred in 92%, 89%, and 46% of patients, respectively. Compared with ganglia, lymph nodes with metastases showed distinct configurations and significantly greater uptake of 68Ga-PSMA-11. Your local radiologists need to understand such findings to avoid “overcalling” PSMA PET/CT scans as metastases when they are not.

Effects on Management and Outcomes
Having established the power of next-generation imaging for the evaluation of prostate cancer, the next question is whether and how it changes management. Accordingly, the prospective, multicenter LOCATE study evaluated 18F-fluciclovine PET/CT in 213 men with suspected biochemical recurrence (median PSA, 1.00 ng/mL).16 Axumin® PET/CT identified lesions in 57% of patients, including in 30% of men whose PSA levels were between 0 and 0.5 ng/mL. These findings altered management in 59% of men, and most (78%) changes were major, such as switching from non-curative systemic therapy to salvage therapy, or from non-curative or salvage therapy to watchful waiting. Looking beyond management, we need to ask how next-generation imaging affects outcomes. We can expect a considerable amount of new data on this in the next few years, but an early signal has come from a randomized, multicenter phase II trial that linked metastasis-directed therapy guided by choline PET/ CT with a median 8-month longer androgen deprivation therapy (ADT)-free survival when compared with surveillance alone in 62 men with biochemically recurrent prostate cancer.21 Study participants had up to three extracranial metastases detected by initial choline PET/CT and serum testosterone levels above 50 ng/mL.21 They underwent choline PET/CT at baseline, with PSA follow-up every 3 months and repeat imaging in the event of PSA progression or clinical suspicion of progression. <br />PHILLIP J. KOO, MD is the Division Chief of Diagnostic Imaging at the Banner MD Anderson Cancer Center in Arizona. Prior to this, he was Chief of Nuclear Medicine and Associate Professor of Radiology at the University of Colorado School of Medicine. Dr. Koo completed his transitional internship at the University of Pennsylvania Medical Center-Presbyterian, radiology residency at Pennsylvania Hospital of the University of Pennsylvania Health System, and fellowship at the Harvard Medical School Joint Program in Nuclear Medicine. He is a diplomate of both the American Board of Radiology (ABR) and the American Board of Nuclear Medicine. Dr. Koo is an active member of multiple societies and serves on the scientific program committee for the Radiological Society of North America, nuclear radiology certifying exam committee for the ABR, and is the Chair of the Quality and Evidence Committee for the Society of Nuclear Medicine and Molecular Imaging.

After a median follow-up of 3 years, median ADT-free survival was 21 months with metastasis-directed therapy (stereotactic radiotherapy or surgery) versus 13 months with surveillance (hazard ratio, 0.60; 80% confidence interval [CI], 0.40 to 0.90; P = .11). Although the effect of PET/CT-guided therapy did not reach statistical significance, these findings nonetheless suggest that PET/CT might lead to better outcomes for patients with advanced prostate cancer.

Stage Migration and the Will Rogers Effect
“When the Okies left Oklahoma and moved to California, they raised the average intelligence level in both states.” This quote by Will Rogers reflects a statistical paradox—in some cases, moving the elements of one set to another increases the mean value of both.24, 25 The Will Rogers effect is of central importance in diagnostic radiology. In oncology, a prime example is stage migration, in which the advent of more sensitive diagnostics leads to the detection of previously undetectable metastases and causes patients to be reclassified as higher-risk. For example, patients who would have been classified as M0 based on conventional imaging might now be classified as having low-volume metastatic (M1) disease. Diluting an M1 cohort with these patients will improve key outcomes in the group, including survival. Removing these patients from the M0 group will have the same effect.26 Consequently, researchers might conclude that therapy has improved outcomes when patients actually are faring no better than before.24, 25 The shift towards outcomes-based healthcare makes it more vital than ever to avoid the Will Rogers effect in clinical trials. Fortunately, we are seeing changes in study design that should help. For example, researchers are exploring how to define “high risk” to reflect a truly lethal disease and how to analyze risk as a continuous variable (0% to 100%) rather than a binary one (low versus high-risk).26

Current and Future Challenges 
Next-generation imaging of prostate cancer involves several challenges now and in the near future. First, in the face of (currently) sparse outcomes data, clinicians must decide when to use next-generation imaging, which agents to use, and when and how to use the results to change management. To address these questions, we recently convened the Prostate Cancer Radiographic Assessments for the Detection of Advanced Recurrence (RADAR) III group to review and discuss current data and our clinical experiences with next-generation imaging.27 Based on these discussions, we unanimously agreed that detecting progression to metastatic disease is a seminal event in prostate cancer management, that next-generation imaging can

reveal previously undetectable metastases, and that these findings can facilitate earlier treatment.27 When deciding whether to order next-generation imaging, we recommend considering symptoms, biomarker values, and comorbidities.27 Based on the available data, we recommend 18F-fluciclovine as the exam of choice in the United States based on performance and availability. That being said, the future FDA approval of PSMA targeted agents will surely change this discussion in the near future. Looking forward, we will be faced with the challenge of having to choose among several approved next-generation imaging agents. Access and cost will affect this decision, but hopefully, so will robust outcomes data. For now, I suggest reviewing the RADAR III recommendations to start incorporating next-generation imaging into your prostate cancer clinics. I also recommend determining which next-generation imaging tools you have available and which radiologists you can consult and exchange feedback with, which is vital for learning and improvement. It’s also crucial to think ahead—before ordering next-generation imaging, know how the results will affect management.

Targeted Radiopharmaceuticals and Radioligand Therapies
Targeted radiopharmaceuticals and radioligand therapies are poised to become extraordinary disruptors in oncology, nuclear medicine, and radiology. First, let’s consider radium (Ra)-223 dichloride (Xofigo®), an alpha-particle therapy that was FDA approved in 2013 for the treatment of castration-resistant prostate cancer in patients with symptomatic bone metastases and no known visceral metastatic disease.28 In the associated randomized, double-blind, phase III ALSYMPCA trial, up to six cycles of Ra-223 were well tolerated and significantly improved overall survival over placebo when added to best standard of care (respective medians, 14.9 vs. 11.3 months; P&lt;.001).29 Radium-223 also significantly prolonged median time to first symptomatic skeletal events (SSEs) (15.6 vs. 9.8 months; P&lt;.001). This was the first indication that nuclear medicine could significantly improve prostate cancer survival. The next question was whether adding a novel androgen-directed therapy to Ra-223 could further improve outcomes. In the phase 3, double-blind ERA 223 trial, 806 men with asymptomatic or mildly symptomatic chemotherapy-naïve bone-metastatic disease were randomly assigned to receive Ra-223 or placebo plus abiraterone acetate and prednisone/prednisolone.30 All patients received protocol-specified treatment, but the trial subsequently was unblinded because of concerns about increased fractures and mortality with Ra-223-abiraterone-prednisone.30 As a result, the FDA added a warning to the Xofigo label.28 At the 2018 meeting of the European Society for Medical Oncology, ERA 223 investigators confirmed that adding Ra-223 to abiraterone-prednisone led to an increased fracture rate in this patient population (29% vs. 11% for placebo-abiraterone-prednisone).30 However, Ra-223 did not alter SSE-free survival (medians, 22.3 vs. 26.0 months for placebo-abiraterone-prednisone; HR, 1.12; 95% CI, 0.92 to 1.37; P=.26) or any secondary endpoint, including overall survival (respective medians, 30.7 vs. 33.3 months; HR, 1.20; 95% CI, 0.95 to 1.51). This was a failed trial—the value of Ra-22329 as monotherapy did not translate to an added benefit when it was combined with a second-generation anti-androgen therapy. However, this was a “successful failure;” the link between Ra-223 and fractures was a new and important finding. Post-hoc analyses showed that the use of bone health agents significantly attenuated the risk of fracture in both trial arms.30 This underscores the need to preserve bone health when treating prostate cancer. Bone health agents are generally well tolerated, but hypocalcemia can occur at treatment initiation, zoledronic acid requires renal dose adjustments, and bone health agents can cause osteonecrosis of the jaw in approximately 1% to 2% of patients during the first year of treatment, with a rise in risk thereafter.31 Thus, these agents should be considered in combination with lifestyle changes such as diet and exercise.

diet and exercise. In summary, there remains a significant role for Ra-223 in our advanced prostate cancer clinics, but not in combination with abiraterone-prednisone. More importantly, we all need to raise do our part to focus on bone health especially since our advanced prostate cancer patients are living longer. Researchers are studying whether other Ra-223 combinations can improve prostate cancer survival without increasing fracture risk. We await the results of such studies as the phase III, placebo-controlled PEACE III trial of Ra-223 plus enzalutamide. In theranostics, radioligand therapy is used alongside next-generation diagnostics to personalize treatment. In prostate cancer, for example, PSMA-targeted PET/CT is being used to identify PSMA-expressing tumor tissue, after which patients receive a PSMA-binding antibody or small molecule that is conjugated to a cytotoxic radioisotope.34,35 This allows us to confirm and quantify the presence of a target before initiating therapy. A recent study in Germany illustrates the innovative, disruptive role of theranostics in prostate cancer. Among 30 men with metastatic castration-resistant disease that had progressed despite standard treatments such as chemotherapy, abiraterone, and enzalutamide, clinicians used 68Ga-PSMA-11 PET/CT to confirm the presence of PSMA-expressing tumor and then administered up to three cycles of the 177Lu-PSMA-617 radioligand therapy.32 Two-thirds of patients showed a PSA response within 8 weeks after their first treatment. Furthermore, among 11 patients who received three treatment cycles, eight had at least a 50% decrease in PSA level that persisted through 24 weeks. 177Lu-PSMA-617 may soon be approved in the United States for the treatment of metastatic castration-resistant prostate cancer based on the results of the ongoing randomized phase III VISION trial.36 While its primary endpoint is overall survival, the FDA has accepted radiographic progression-free survival (rPFS) as an<br /> <br />

alternative primary endpoint. Hence, an interim analysis of rPFS will occur in late 2019 and if it is positive, will serve as the basis of a new drug application (NDA).36 There will also be a need for alternative therapies to manage patients who did not respond or were not candidates for 177Lu-PSMA-617. In a patient who showed PET/CT and PSA progression after two cycles of 177Lu-PSMA-617, three cycles of alpha-particle radioligand therapy with 225Ac-PSMA-617 produced a complete PET/CT response and an undetectable PSA.33 A similarly dramatic response to 225Ac-PSMA-617 occurred in a patient who was not a candidate for 177Lu-PSMA-617. It also is noteworthy that the only treatment-emergent side effect of 225Ac-PSMA-617 therapy was xerostomia, while 177Lu-PSMA-617 was associated with myelosuppression, especially among patients with bone marrow metastases.32, 33 177Lu-PSMA is a beta-particle therapy. Alpha-particle therapies are highly cytotoxic but are active over a much shorter distance. Attaching them to a PSMA ligand creates a highly targeted treatment that might be more tolerable than a beta-particle emitter. Billion-dollar investments underline the extent to which radioligand therapies may soon disrupt cancer care. Novartis recently announced that it will spend $2.1 billion to acquire Endocyte Pharmaceuticals, the maker of 177Lu-PSMA-617.37 This is in addition to the $3.9 billion spent last year to acquire Advanced Accelerator Applications, a French nuclear medicine company that has developed a radioligand therapy for patients with metastatic GI neuroendocrine tumors.38 As radiopharmaceuticals diffuse into clinical practice, we will need well-designed studies of how best to choose and layer these novel therapies. Fortunately, there are studies in progress including a phase II trial (NCT03392428) in Australia which compares 177Lu-PSMA vs cabazitaxel in patients with progressive, metastatic, castration-resistant prostate cancer who have previously received docetaxel and whose disease shows high levels of PSMA expression based on 68Ga-PSMA PET/CT. In Canada, Dr. Fred Saad of the University of Montreal also is opening a trial that will compare 177Lu-PSMA with docetaxel.

In preparation for these new class of therapeutic options, I would recommend incorporating radium 223 into your practice as the only FDA approved therapeutic radiopharmaceutical with an overall survival benefit. This will require practices to identify your authorized user, who is the physician who possesses the expertise and also meets licensing and regulatory requirements to treat patients with these unsealed sources of radiation. This will help create the foundation on which a practice will be prepared to offer additional novel radioligand therapies when available.

Bladder
We shift our discussion to briefly discuss bladder cancer. So far, diagnostic radiopharmaceuticals are not showing the same potential in bladder cancer compared to prostate cancer. When my colleagues and I performed a meta-analysis of 10 studies of C-11 choline and C-11 acetate PET/CT for lymph node staging in bladder cancer, the pooled sensitivity was 66% (95% CI, 54% to 75%) and the pooled specificity was 89% (95% CI, 76% to 95%).39 A more exciting frontier will likely focus on multiparametric MRI which has the potential to reveal bladder tissue planes similar to its use in rectal malignancies.40A global group of experts has recently developed the Vesical Imaging and Reporting (VI-RADS) System to standardize imaging protocols and reporting criteria for bladder mpMRI. This is the first step toward higher quality bladder imaging. Amidst all of the excitement of advances in diagnostic and therapeutic radiopharmaceuticals, we must remain steadfastly focused on pursuing data-driven answers with regards to how best to treat our patients with genitourinary malignancies. This is a challenging but not insurmountable task. Working across specialties and disciplines, I have no doubt we will be able to harness these disruptive technologies in order to improve cancer care and eventually end cancer.

Written by: Phillip J. Koo, MD is the Division Chief of Diagnostic Imaging at the Banner MD Anderson Cancer Center in Arizona. Prior to this, he was Chief of Nuclear Medicine and Associate Professor of Radiology at the University of Colorado School of Medicine. Dr. Koo completed his transitional internship at the University of Pennsylvania Medical Center-Presbyterian, radiology residency at Pennsylvania Hospital of the University of Pennsylvania Health System, and fellowship at the Harvard Medical School Joint Program in Nuclear Medicine. He is a diplomate of both the American Board of Radiology (ABR) and the American Board of Nuclear Medicine. Dr. Koo is an active member of multiple societies and serves on the scientific program committee for the Radiological Society of North America, nuclear radiology certifying exam committee for the ABR, and is the Chair of the Quality and Evidence Committee for the Society of Nuclear Medicine and Molecular Imaging

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