Diagnosis and Treatment of Prostate Cancer: What

JAMES ET AL

Diagnosis and Treatment of Prostate Cancer: What Americans Can Learn From International Oncologists Nicholas James, BSc, MBBS, PhD, John Graham, MB ChB, FRCR, FRCP, Tobias Maurer, MD, Matthias Eiber, MD, and Jürgen E. Gschwend, MD OVERVIEW The three main sections in this article illustrate a number of facets of European health care. The first section looks at the influence of NICE on treatment of metastatic castration-resistant prostate cancer. The second section explores the impact of molecular imaging on diagnosis and treatment, in particular the development and clinical implementation of 68Ga PET imaging in prostate cancer. The final section of the session looks at the STAMPEDE trial and how running a trial on this scale has impacted care of prostate cancer in the United Kingdom and also at the uptake of docetaxel chemotherapy in hormone-sensitive advanced disease.

E

uropean health care systems vary enormously from country to country in terms of structure and funding models. They broadly operate, however, on the principle that the state has a duty to ensure health care is available to all members of the population. This contrasts with the situation in the United States, starkly illustrated by the recent U.S. presidential elections, with huge controversy over the Patient Protection and Affordable Care Act (also known as "Obamacare") and the idea that health care may be an individual’s rather than the state’s responsibility—an alien concept to most Europeans. This leads to the situation where U.S. citizens with adequate insurance enjoy some of the most technologically advanced health care in the world, while some of their fellow citizens struggle with huge financial burdens associated with uninsured health care costs. In contrast, implicit in social insurance or taxpayer-based systems is some form of centralized decision making. This may lead to restricted access to “cutting-edge” medicines but, at the same time, facilitates access for all affected to an accepted standard of care. Within Europe, two broad subdivisions may be identified in how health care advances are funded. With new drugs, there are two levels of decision to be made: Should a drug be approved for patients—marketing authorization—and secondly, should the public health care system fund the use of the drug? In many countries (e.g., France, Germany, Italy), no distinction is made and a marketing authorization makes the drug available via the public health care system. In a second group, notably in the United Kingdom and Scandinavia, these decisions are separated so that a marketing authorization may or may not lead to broad public access. In the United Kingdom, these decisions are made by the National Institute for Health and Care Excellence (NICE), and NICE decisions are

often then used as templates by other countries and hence are very influential. NICE attempts to judge the cost effectiveness as well as the clinical effectiveness of new agents. It is the former that drives the controversy often associated with some NICE decisions. However, the need to meet NICE cost-effectiveness requirements is undoubtedly a factor in driving down the costs of new medicines within the United Kingdom in particular, as compared with countries where marketing authorization and access are simultaneous. A further feature of the U.K. system is the state supports entry into academic trials via the National Health Service (NHS). This means the public hospital system is directly financially incentivized to support trials badged as suitable by the U.K. National Cancer Research Institute. This has led to the United Kingdom having one of the highest rates in the world of cancer trial participation. This is well illustrated by the STAMPEDE trial, which has to date recruited more than 8,000 men to a trial now encompassing 10 research arms, with two further in setup, across more than 100 hospitals. With such a broad base of participation, questions are asked and answered in a very “real-world” setting, ensuring broad applicability. It also ensures relatively easy rollout of positive results (such as the docetaxel data), as centers and clinicians are familiar with the rationale and administration of the trial therapies and have also personally invested their own time and energy into the trial data set. The three main sections in this article illustrate a number of facets of European health care. The first section looks at the influence of NICE on treatment of metastatic castrationresistant prostate cancer (mCRPC). The second section explores the impact of molecular imaging on diagnosis and treatment, in particular the development and clinical implementation

From the Institute of Cancer and Genomic Sciences, Queen Elizabeth Hospital, University of Birmingham, Edgbaston, Birmingham, United Kingdom; National Guideline Alliance, Royal College of Obstetricians and Gynaecologists, London, United Kingdom; Department of Urology, Technical University of Munich, Munich, Germany; Department of Nuclear Medicine, Technical University of Munich, Munich, Germany; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA. Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook. Corresponding author: Tobias Maurer, MD, Department of Urology, Technical University of Munich, Klinikum rechts der Isar, Ismaninger Str. 22, 81671 Munich, Germany; email: [email protected]. © 2017 American Society of Clinical Oncology

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PROSTATE CANCER: WHAT AMERICANS CAN LEARN FROM INTERNATIONAL ONCOLOGISTS

FIGURE 1. Original Trial Design

of 68Ga PET imaging in prostate cancer (PCa). The final section of the session looks at the STAMPEDE trial and how running a trial on this scale has impacted care of PCa in the United Kingdom and also at the uptake of docetaxel chemotherapy in hormone-sensitive advanced disease.

HOW RANDOMIZED TRIALS OF STAMPEDE HAVE INFLUENCED TREATMENT DECISIONS IN THE UNITED KINGDOM

Background

The STAMPEDE trial was set up in 2004 and 2005 and commenced recruitment in 2005. The basic principle of the trial was to assess the addition of new treatment modalities to standard of care with the aim of improving overall survival. At the time of setup, zoledronic acid had recently been ap-

proved for mCRPC affecting bone, and docetaxel was in the final stages of phase III evaluation. Both agents seemed to be worth evaluating in the newly diagnosed, as opposed to the relapse setting. Given the large numbers of patients diagnosed with PCa, the Trial Management Group decided to seek a third agent to evaluate and eventually selected celecoxib as an agent with possible metastasis and invasion-preventing properties. The Trial Management Group also decided to look at agents both alone and in combination, giving a total of five experimental arms in original design. A second novel feature of the trial was the integration of a feasibility stage, interim efficacy stages, and a final overall survival stage to give a multiarm, multistage design. Table 1 shows the primary and secondary endpoints for the various stages. Figure 1 shows the original trial design in terms of agents being evaluated.

TABLE 1. Trial Endpoints

KEY POINTS • The PSMA represents a promising molecular target in PCa useful for PET imaging. • In patients with relapsed PCa, PSMA PET imaging improves detection of metastatic lesions even at low PSA values. • In patients with primary intermediate to high-risk PCa, PSMA PET imaging showed increased specificity and sensitivity compared with current standard imaging for detection of lymph node and bone metastases. • In combination with multiparametric MRI, PSMA PET imaging might provide additional molecular information useful for intraprostatic PCa localization. • Although current knowledge is still limited and derived mostly from retrospective series, PSMA-based imaging might enable improved patient-tailored PCa management in the future.

Comparison Stage

Primary Outcome Measure

Secondary Outcome Measures

Pilot phase

Safety*

Feasibility

Activity stages

Failure-free survival**

Overall survival Toxicity Skeletal-related events

Efficacy stage

Overall survival

Quality of life Cost effectiveness Failure-free survival** Toxicity Skeletal-related events

*Based on toxicity. **Including biochemical failure.

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JAMES ET AL

Setting Up and Running the STAMPEDE Trial

The aim of running what is effectively a suite of phase II and III trials is to reduce the bureaucracy associated with the opening and closing of multiple studies and linked inherent delays in the analysis, close down and set up when the traditional phase II and separate phase III model is used. We estimate that around 30% of phase III trials produce a positive result in the sense that the experimental arm is better than the control arm. By having multiple arms, we, simply put, had more chances to win and hence to change practice. Secondly, the fact that all patients contribute to all analyses overall means that fewer total patients are needed compared with separate phase II and III studies. In particular, separate phase III studies for each agent would each need a control arm, which is hence duplicated if multiple trials are recruiting in the same disease “space.” This again means that, overall, fewer patients are needed to answer questions about different agents compared with multiple simultaneous trials. In addition, multiple trials would be competing with each other for resources and, very importantly, for patients, leading to likely slower overall aggregate recruitment. The effects on numbers of patients and time are illustrated in Fig. 2. A second consequence of the multiarm, multistage model is that new arms can be added at a later stage, with the staged analyses for the new arm being frame shifted to the timetable for that arm. We first tested this approach in 2011 with the addition of arm G evaluating the upfront use of abiraterone. We have subsequently added three further arms: radiotherapy (RT) in M1 patients, combination abiraterone/ enzalutamide, and metformin, with two additional new arms in setup. Adding an arm is extremely efficient compared with setting up a new trial, which would compete for patients with

the original trial. All setup costs have to be reincurred for the new arm, and investigators’ time and energy are diverted. In contrast, adding an arm by protocol amendment is simple from the administration point of view in centers and avoids competition between trials for scarce resources and patients. Figure 3 shows the time to set up the original comparisons as compared with the first three arms added. The faster setup is also translated into faster recruitment, as, once open, the new arm benefits from the established ongoing recruitment for the parent trial. Figure 4 shows the recruitment to arm G (abiraterone) was originally projected to run from Q4 2011 to Q4 2014 with 1,500 patients. Due to very rapid recruitment, the target was expanded to 1,800, which was completed a year ahead of schedule in late 2013. Arms H (RT:M1) and J (abiraterone/enzalutamide) have similarly recruited well ahead of time and target again with expanded numbers to increase power and accelerate reporting. To recruit patients to a trial with oncology-based therapies such as docetaxel, we needed to change referral pathways. This required buy-in from urologists and a willingness to refer patients from urology to oncology much earlier than was previously the norm. We have involved urologists in the design, setup, and implementation of the trial, and support among urologists throughout has been huge. The U.K. system facilitates the shared financing of trials. The core resource has been funded via Cancer Research UK, with additional resources from the Medical Research Council Clinical Trials Unit. We had financial assistance from the manufacturers of the three drugs initially chosen for evaluation in terms of free or subsidized drugs and additional grant support over and above the core academic funding.

FIGURE 2. Multiarm, Multistage Trials Versus Multiple Phase II and III Trials



In addition, a key feature of the U.K. NHS is that NHS hospitals receive additional funding in return for putting patients in suitably badged studies via the National Cancer Research Institute and linked National Cancer Research Network. In conclusion, the structure of clinical trial funding within the U.K. NHS greatly facilitates large-scale trials. The STAMPEDE multiarm, multistage model works well within this system, and the flexible approach to adding arms to an existing trial results in extremely rapid uptake and recruitment compared with starting multiple new trials.

Control Arm Data: Radiotherapy in Node-Positive Disease

With a trial as large as STAMPEDE recruiting in every major oncology center in the United Kingdom, data emerging from the control arm has immense value in telling us about patterns of care and the impact of different care patterns on outcomes. The best example to date is the impact of radiotherapy in locally advanced or node-positive, nonmetastatic disease. Radiotherapy was recommended but not mandatory from 2005 to 2011 when two randomized trials demonstrated the impact of radiotherapy in locally advanced disease. Within the trial, many patients up to 2011 did not receive RT for locally advanced disease due to differences in unit policies. The impact of RT in this group was to increase failure-free survival at three years from 62% to 87%, validating the SPCG71 and PR072 results in a real-world, high-risk setting. Additionally, and very importantly, we were able to look at the impact in TxN+M0 disease and saw an increase in three-year failure-free survival from 47% to 71%. There are no randomized trials in this setting; multivariate analysis suggested a hazard ratio for the improvement of 0.5 in favor of pelvic and prostate radiotherapy.3

Docetaxel Data

The first survival data from the trial were published in 20164 and showed an increase in survival from six cycles of docetaxel but no significant impact from zoledronic acid given at inception of hormone therapy.4 The docetaxel results confirmed data from the U.S. CHAARTED trial in M1 disease5 and cemented the role of upfront chemotherapy in newly diagnosed metastatic disease (Fig. 5). This was confirmed by a meta-analysis copublished with the STAMPEDE results.6 The broad base of recruitment to STAMPEDE means that these results can be seen as broadly applicable within the NHS.

Implementing STAMPEDE Trial Results

In order for results to have impact, they must be implemented in the health care system. The NHS in the United Kingdom is actually four devolved services: England, Wales, Scotland, and Northern Ireland, with around 80% of the population living in England. Within NHS England, NICE considers medical treatments and makes guidelines to NHS hospitals. This is two edged, as it can either facilitate or block implementation. After some initial delay, NHS England and NICE decided to run a rapid evidence review and issued guidance via NICE7 and commissioning guidance8 supporting the use of docetaxel in this setting. This was published January 2016, the same month as The Lancet results publication, thus ensuring broad availability from date of publication. The STAMPEDE trial illustrates a number of positive features of the “socialized” health care model: the ability to centrally support trials and the flexibility in trial legislation that has allowed the trial to evolve into a platform for serially evaluating many different interventions. Finally, the central control, although sometimes a tool for rationing,

FIGURE 3. Time to First Patient Into Trial Across STAMPEDE Centers by Trial Arm


JAMES ET AL

FIGURE 4. Recruitment in Arms Added After Trial Inception

can also be a tool for enabling the rapid implementation of clinically important results.

HAVE DECISIONS BY NICE AFFECTED OUTCOMES OF BRITISH PATIENTS WITH METASTATIC CASTRATION-RESISTANT PROSTATE CANCER?

Government-funded health care systems must ensure that taxpayers’ money is being well spent. The NHS Constitution

states that “it is committed to providing the most effective, fair, and sustainable use of finite resources.”9 It is generally agreed that evidence-based medical practice improves outcomes and reduces variations in care. The Cochrane ladder of evidence (efficacy, effectiveness, and cost effectiveness) puts the assessment of cost effectiveness as the optimum goal for evidence-based practice.10 The quality-adjusted life year (QALY) is the most widely adopted method and allows cancer treatments to be compared with, for example, treatments for



FIGURE 5. Impact of Docetaxel on Overall Survival in Men With Metastatic Disease Starting Longterm Hormone Therapy for the First Time

mental illness. Inevitably, there are compromises. In the United Kingdom, NICE uses the EuroQoL EQ-5D system to measure quality-of-life benefits.11 Compared with cancer-specific measures such as the EORTC QLQC33 or FACT-P for PCa, EQ5D is less detailed, but it offers two key advantages. EQ-5D can be applied to different medical conditions, and it can be weighted to reflect the values that different societies place on health states. Estimated total costs and QALYs are collected over the modeled time horizon for each treatment. The total costs will include all costs associated with the treatment, follow-up, further treatment, and management. QALYs are calculated by multiplying the life years that patients spend in each health state by the associated quality-of-life weighting, which represents the patient’s and society’s valuation of their health state.12 Cost effectiveness is calculated by assessing the incremental change in health utility measured by QALYs. The incremental cost-effectiveness ratio (ICER) can then be calculated using the formula shown in Figure 6. NICE was set up in 1999 by Tony Blair’s Labor Government as the National Institute for Clinical Excellence to reduce

variations in availability and quality of care in the NHS in England.13 Initially, it was run as a special health authority within the NHS, but from April 2013, it has been a nondepartmental public body outside the NHS, accountable to the Department of Health, and with a broader remit for social care as well as health care. Its name was changed to the National Institute for Health and Care Excellence, but the acronym NICE was retained. NICE is an English body but provides some services for Scotland, Wales, and Northern Ireland. Its appraisal system for new drugs applies only to NHS England. Drugs approved through the Technology Appraisal (TA) system14-25 have a guaranteed funding stream for the duration of the guidance. This distinguishes TAs from all other NICE guidance (clinical guidelines, diagnostic assessments), which are advisory to the various bodies that commission health and social care. The privileged financial position of NICE TAs means that they sit separately from NICE’s clinical guidelines and are excluded from them. The two NICE guidelines on the management of PCa published in 2008 and 2014 have no guidance

FIGURE 6. Formula 1


JAMES ET AL

TABLE 2. NICE Technology Appraisals of Drugs for mCRPC Drug

Technology Appraisal

Date

Outcome

Docetaxel

14

TA101

June 2006

Approved

Cabazitaxel

TA25515

May 2012

Not recommended

Abiraterone postdocetaxel

TA259

June 2012

Approved

Enzalutamide postdocetaxel

TA31617

July 2014

Approved

Sipuleucel-T

18

TA332

January 2015

Not recommended

Radium-223

TA37619

January 2016

Approved

Enzalutamide prechemotherapy

TA377

January 2016

Approved

Abiraterone prechemotherapy

TA38721

April 2016

Approved

Cabazitaxel

TA391

May 2016

Approved

16

20

22

on the use of chemotherapy or radium-223 in mCRPC, other than the incorporated recommendations from the appraisal of docetaxel in 2005 (TA101).26 So this discussion of NICE’s decisions on treatments for mCRPC will focus on the TA process for men treated by NHS England. It will also cover treatments provided by the CDF and issues relating to NICE’s clinical guidelines on the management of PCa. NICE has appraised the following drugs for mCRPC: docetaxel, cabazitaxel, abiraterone, enzalutamide, sipuleucel-T, and radium-223. Table 2 shows the dates and outcomes of the appraisals. There are two types of appraisals for new drugs, single technology assessments (STAs)23 and multiple technology assessments.24 Most appraisals are STAs, as was the case for all the drugs for mCRPC. The advantage of an STA is that it is generally a quicker process. The manufacturer submits a case for the clinical and cost effectiveness of their product, and this is sent to an independent academic group, the evidence review group (ERG), commissioned by NICE to review the submitted evidence. Then the manufacturer and the ERG present their findings to the TA committee that makes a decision. In a multiple technology assessment, an independent group is commissioned to produce a health technology assessment of a product or multiple products with one or more indications. This assessment is presented to the TA committee along with evidence from selected stakeholders such as health care professionals, patients, and commissioners. The process is more complex than an STA and usually takes longer, but it can result in multiple recommendations on several products and their relationship to each other. In its early days, NICE was criticized for the slowness of its appraisal process, resulting in a move toward more STAs. An appraisal cannot start until a drug receives U.K. marketing authorization, but NICE works closely with the licensing authorities and tries to issue a scope for the appraisal within a few months of authorization. There are problems with the STA process: • It is restricted to a single drug for a single indication, so if several drugs are licensed for the same indication over a relatively short time, the recommendations may not reflect the way that the drugs are being used in clinical practice.

• It relies on evidence provided principally by the manufacturer (albeit with an independent review). • Early assessment of cost effectiveness can be difficult due to a lack of evidence, particularly of downstream consequences. • It has become less transparent as more confidential drug discounts, called patient access schemes, are being negotiated. • It relies on the cooperation of the manufacturer. Although an STA is an accelerated approval process, it is not exactly quick, as the timeline for the approval of enzalutamide prechemotherapy, TA377, shows (Table 3). The entire process from scoping to publication of the final decision took 2 years and 3 months. However, NICE did start the TA a year before marketing authorization for the change in license for this indication. A detailed look at this TA highlights some of the complexities in approving new drugs. A draft scope for TA377 was developed in October 2013 by NICE. This was exactly one year ahead of the decision of the European Medicines Agency on Oct. 23, 2014, that approved a variation to the EU marketing authorization for enzalutamide for “the treatment of adult men with meta-

TABLE 3. Timeline for the Appraisal of Enzalutamide Prechemotherapy Step

Date

Draft scope for the appraisal

October 2013

European Medicines Agency approval for EU marketing authorization

October 2014

Final scope for the appraisal

November 2014

U.K. marketing authorization

November 2014

First TA committee meeting

May 2015

Appraisal consultation document

June 2015

Second TA committee meeting

July 2015

ERG critique of Astellas’ revised patient access scheme submission

November 2015

Final appraisal determination

December 2015

TA377 published

January 2016

Abbreviations: TA, technology appraisal; ERG, evidence review group.



static castration-resistant PCa who are asymptomatic or mildly symptomatic after failure of androgen deprivation therapy in whom chemotherapy is not yet clinically indicated.” The draft scope used a PICO format (P: Patient, Population, Problem; I: Intervention, prognostic factor, or exposure; C: Comparison or intervention; O: Outcome) to outline the population, comparators, and outcomes. It also posed several questions to stakeholders who were invited to comment, as were a number of invited topic experts. The final scope was published in November 2014, and an ERG at the University of Aberdeen was commissioned by NICE to appraise the manufacturers’ submission. NICE’s TA Committee B met in public in May 2015 to discuss the evidence with the manufacturer, the ERG, and invited experts, including patient representatives. The committee then moved to a closed session to agree on the appraisal consultation document (ACD), which was published in June 2015. The initial recommendation was not to recommend the drug as not cost effective. There is a very detailed summary of the committee discussions in the ACD relating to the interpretation of the data from the PREVAIL trial,27 the appropriate comparator, and other issues affecting the health economic calculations. After public consultation on the ACD and a resubmission of evidence by the manufacturer Astellas, which included a revised patient access scheme (discounted price), the ERG produced a critique in November 2015. This resulted in a final appraisal determination that reversed the previous decision and, in January 2016, recommended approval of enzalutamide. What changed between the ACD and final appraisal determination? A decision was made to use only the comparator of enzalutamide versus best supportive care, changes were made to the downstream modeling to reflect the type of treatments NHS patients would receive after progression on enzalutamide, and Astellas offered a discount on the list price of enzalutamide. Due to the confidential nature of the patient access schemes, NICE does not publish detailed cost calculations. However, we know from the ACD25 that the incremental cost-effectiveness ratio for enzalutamide compared with best supportive care was between £40,000 and £50,000 in the ERG’s base case. In the final appraisal determination, this had fallen to below £30,000, and enzalutamide was considered a cost-effective treatment.

Cancer Drug Fund

From October 2010, patients in England have had access via the Cancer Drug Fund (CDF) to many drugs not approved by NICE. The fund was set up by the coalition government (Conservative and Liberal Democratic coalition in power from May 2010 to May 2015) “to enable patients to access the cancer drugs their doctors think will help them.”28 Initial implementation was variable because the fund was managed separately by 10 regions in NHS England, each of whom had different drugs available. From April 2013, the fund has been centrally administered with a single list for all of England. The annual budget of £200 million was ex-

ceeded in 2013 and, by 2014/2015, was overspent by 48%. A National Audit Office report in 2015 noted that it was “difficult to evaluate in a meaningful way the £733 million spent through the Cancer Drugs Fund since October 2010.”29 The fund was substantially restructured in July 2016. It is now managed by NICE, whose TA committees can recommend adding a drug to the CDF list if there is insufficient evidence to either approve or reject the treatment. Drugs will be provided via the CDF for up to two years, and NICE will reassess the drug based on data collected centrally by the systemic anticancer therapy (SACT) database (www.chemodataset. nhs.uk). The SACT data set is a mandatory collection of chemotherapy data from cancer centers in England who upload the information monthly.30 Have the decisions by NICE affected outcomes for men with metastatic PCa? There is no doubt that approval by NICE following market authorization takes many months, sometimes several years. However, the introduction of the CDF has significantly reduced the period between market authorization and the drug becoming available to patients in NHS England. In fact, enzalutamide prechemotherapy, the subject of the TA discussed previously, was available via the CDF before it received market authorization. Figure 7 shows the timelines of the treatments that have received marketing authorization for mCRPC since 2005: when they were licensed, when they were assessed by NICE, and when they were made available via the CDF. The only treatment not available in the United Kingdom was sipuleucel-T, which received marketing authorization in September 2013 but had it withdrawn in May 2015. Latest cancer statistics show the mortality from PCa in England falling between 2005 and 2014, the last year for which figures are available. In 2005, the age-standardized mortality rate per 100,000 men in England was 53.92, and in 2014, it was 48.15.31 A similar fall in PCa mortality has been seen in many developed countries over this period. To date, in the United Kingdom, we have not had enough information to determine whether treatment availability has affected outcomes. The restructuring of the CDF and the collection of chemotherapy prescribing information via SACT, which has only been available for a few years, should allow us to establish the efficacy and cost effectiveness of new anticancer treatments when used in routine clinical practice. Approvals of treatments for men in England with mCRPC have not substantially delayed availability and are unlikely to have substantially affected outcomes. All treatments that have been licensed for mCRPC since 2005 (bar sipuleucel-T) are currently available in NHS England, most at a substantial discount to the list price.

HOW ADVANCES IN MOLECULAR IMAGING HAVE CHANGED OUR UNDERSTANDING OF STATE AND STAGE OF THE DISEASE

Currently, CT, MRI, and bone scintigraphy represent standard imaging procedures in PCa. Over the last two decades, PET evolved as novel imaging technology for detection or staging in PCa patients. For PET imaging, several tracers asco.org/edbook | 2017 ASCO EDUCATIONAL BOOK 351

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JAMES ET AL

FIGURE 7. Dates of Marketing Authorization, Cancer Drug Fund Approval, and NICE Technology Assessment

have been used in the past, but recently with the introduction of small molecular tracers targeting the prostate-specific membrane antigen (PSMA), PET imaging has gained increasing interest. PSMA is a transmembrane protein that shows overexpression on most PCa cells and thus represents an ideal molecular target. In biochemical recurrent PCa, PET imaging using 68Ga-labeled PSMA inhibitors has been shown to increase detection of metastatic sites even at low PSA (prostate-specific antigen) values in comparison with conventional imaging or PET studies with different tracers. In primary intermediate to high-risk PCa, PSMA-based PET imaging has been reported to improve detection of metastatic disease as compared with CT or MRI, possibly rendering additional cross-sectional imaging or bone scintigraphy unnecessary. Furthermore, 68Ga-PSMA PET imaging in combination with multiparametric MRI might provide additional molecular information useful for intraprostatic PCa localization. Thus, although current knowledge is still limited and derived mostly from retrospective series, PSMA-based PET imaging holds great promise to substantially influence PCa management in the future. Until recently, imaging procedures for detection or staging of PCa depend mainly on morphology or bone metabolism and cannot always meet the diagnostic needs for clinical decision making. Consequently, imaging specialists have tried to identify specific molecular targets on PCa cells that can be used for molecular-based PET imaging.32 Several radiotracers have been proposed, including choline, as a marker of membrane cell proliferation. For recurrent PCa, choline-based (i.e., 18F-choline or 11C-choline) PET/CT is currently widely used in clinical routine in Europe and is beginning to be adopted in the United States. Numerous studies reported an increased sensitivity and specificity compared with standard cross-sectional imaging; however, the diagnostic potential especially in early biochemical recurrence is still

limited.33,34 Other radiotracers evaluated for PET imaging of PCa include 11C-acetate, bombesin analogs, and 18F-FACBC (18F-fluciclovine, a radiolabeled leucine analog).32,35-38

PSMA as Molecular Target in PCa

In recent years, the PSMA, a transmembrane protein that shows overexpression on most PCa cells, has gained increasing interest as a molecular target for PCa PET imaging.39 Instead of targeting metabolism, PSMA tracers directly target PCa cells based on PSMA expression, independently of their metabolic state. So far, several small compounds directed against PSMA (also known as PSMA ligands) have been developed and are currently being investigated. The majority of data available report experience using the 68Ga-labeled PSMA inhibitor Glu-NH-CO-NH-Lys(Ahx)-HBED-CC (also termed: 68Ga-PSMA, 68Ga-PSMA HBED-CC, 68Ga-PSMA-11).40-44 Compared with previously used PSMA antibodies for imaging, PSMA ligands seem to provide superior contrast images due to extracellular binding followed by internalization into PCa cells and fast blood clearance reducing background activity.45-47

PSMA PET for Staging of Recurrent PCa

A major challenge for imaging is localization of PCa lesions in patients with biochemical relapse. The differentiation between localized disease and metastatic spread is of great importance, especially at low PSA values, as it might influence further disease management (targeted radiotherapy, salvage surgery vs. systemic treatment). As mentioned above, choline-based PET examinations improve staging and show enhanced detection rates in recurrent PCa compared with conventional cross-sectional imaging.36 However, they still lack the ability to identify smaller or less metabolic lesions, especially at low PSA velocity or PSA values below 2 ng/mL.33,48



FIGURE 8. Patient With PCa Relapse (PSA of 1.26 ng/mL) and Histologically Proven Lymph Node Metastasis Corresponding to 68Ga-PSMA PET Imaging A

B

(A) CT. (B) Fused 68Ga-PSMA PET/CT.

In 2015, two large patient cohorts on 68Ga-PSMA PET have been published evaluating the staging of recurrent PCa.49,50 In the study by Afshar-Oromieh et al, 319 patients with recurrent PCa (226 after radical prostatectomy; median PSA value, 4.6 ng/mL) were examined.49 The authors reported detection rates of 50% and 58% for PSA values below 0.5 ng/ mL and between 0.5 and 1 ng/mL, respectively. In a subset of 42 patients, histologic confirmation of suspicious lesions could be obtained. In these patients, all 68Ga-PSMA PET– positive lesions could also be histologically confirmed to contain metastatic PCa. In this study, Gleason scores as well as antiandrogen deprivation therapy did not significantly influence detection rates. Our group confirmed those results in a homogeneous consecutive cohort of 248 patients with biochemical recurrence after radical prostatectomy (mean PSA value, 1.99 ng/mL).50 Here, 68Ga-PSMA PET revealed suspicious lesions in 89.5% of the patients. Similarly, detection rates increased from 57.9%, 72.7%, 93.0%, to 96.8% for PSA values of 0.2 to less than 0.5, 0.5 to less than 1, 1 to less than 2, and above 2 ng/mL, respectively. Compared with contrast-enhanced CT, 68Ga-PSMA-11 PET exclusively showed suspicious findings in 32.7% of patients and provided information about additional involved anatomic regions in 24.6%. Compared with absolute PSA value, the effects of PSA velocity and PSA doubling time were less pronounced, although they also influenced detection rates. Most recently, Perera et al summarized data from literature for 68Ga-PSMA, including 16 studies with over 1,300 patients. The predicted positivity rates in a meta-regression analysis were 58%, 76%, and 95% for PSA values of 0.2 to 1.0, 1.0 to 2.0, and over 2.0 ng/mL, respectively.51 These values are considerably higher than reported for choline-based PET tracers.33,48,52-54 Furthermore, two studies comparing 18 F-choline and 68Ga-PSMA in a head-to-head analysis both show higher detection rates for PSMA-based PET imaging.45,46 A major limitation of all the above-mentioned PET studies in patients with recurrent PCa is the lack of systematic histologic confirmation. Thus, in general, results of those imaging studies still have to be considered with caution.

However, due to their high sensitivity and specificity, PSMA ligands have also been successfully applied in intraoperative tracking of metastatic PCa lesions during radioguided surgical procedures.55,56 With the technology of PSMA-radioguided surgery, even small metastatic soft-tissue PCa deposits could be localized and successfully removed during salvage surgery procedures (Fig. 8).

PSMA PET for Primary Staging

For primary staging of PCa, evidence for 68Ga-PSMA PET is still limited. The goal of primary staging is to detect metastatic spread to lymph nodes, bone, or other visceral organs. In low-risk PCa, metastatic spread is very unlikely and consequently current guidelines suggest staging examinations only for intermediate to high-risk PCa. In these patients, exact staging can have great impact on further treatment (e.g., radical prostatectomy vs. radiation therapy vs. palliative systemic treatment; extent of lymph node dissection during surgery, planning of radiation field; multimodal therapy concepts). Conventional cross-sectional imaging almost exclusively depends on morphologic information, and metastatic lymph nodes are mainly detected by size. However, almost 80% of metastatic lymph nodes in PCa are smaller than the threshold size of 8 mm and therefore cannot be detected by anatomic imaging.57,58 In the currently largest series of 130 patients with intermediate to high-risk PCa undergoing radical prostatectomy and template lymph node dissection, 68 Ga-PSMA PET imaging significantly improved lymph node metastases prediction compared with standard imaging.59 On a patient-based analysis, the sensitivity, specificity, and accuracy of 68Ga-PSMA PET were 65.9%, 98.9%, and 88.5%, respectively, compared with anatomic standard imaging with 43.9%, 85.4%, and 72.3%, respectively (p = .002). However, data from this study and others also showed that lymph node metastases smaller than 3 to 4 mm are also regularly missed by 68Ga-PSMA.59-61 Thus, especially in patients with high-risk disease, a negative 68Ga-PSMA PET examination should not preclude a proper treatment of local lymph node drainage fields. asco.org/edbook | 2017 ASCO EDUCATIONAL BOOK 353

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JAMES ET AL

FIGURE 9. Patient With PCa With Metastatic Bone Lesions A

C

B

D

Although bone lesions were hardly detectable on initial CT (A), fused 68Ga-PSMA PET/CT (B) showed lesions already highly suggestive for bone metastases. Follow-up imaging clearly revealed bone metastases on CT (C) and fused 68Ga-PSMA PET/CT (D).

Furthermore, bony and visceral lesions of PCa that might not be detectable by standard imaging can be visualized by 68 Ga-PSMA PET (Fig. 9). However, data are even more limited. In a comparative study of 126 PCa patients, 68Ga-PSMA PET significantly outperformed planar bone scintigraphy for the detection of affected bone regions as well as determination of overall bone involvement.62 Especially for identification of small metastatic bone lesions, 68Ga-PSMA PET performed superior.

accurate (area under the curve: 0.83 vs. 0.73; p = .003). It could be observed that PSMA-based PET provided a high uptake ratio between malignant versus nonmalignant tissue. However, although simultaneous 68Ga-PSMA PET/MRI might improve the diagnostic accuracy for PCa localization and thus might be useful for example biopsy targeting or boost irradiation, availability of this technology as well as cost-efficiency issues might preclude 68Ga-PSMA PET/MRI from widespread use (Fig. 10).

PSMA PET for Local Detection

Limitations of PSMA-Based PET Imaging of PCa

In recent years, multiparametric MRI evolved as imaging of choice for local detection of PCa as well as evaluation of capsule penetration or seminal vesicle involvement.63,64 The introduction of whole-body hybrid PET/MRI scanners with simultaneous acquisition and anatomic coregistration of PET imaging and multiparametric MRI opened the window to combine these functional MRI-derived sequences with molecular information from PET.65,66 Although the spatial resolution of PET imaging is clearly inferior to MRI, 68 Ga-PSMA PET could still be of value to localized PCa by adding molecular information from PET. In a recent retrospective study on 53 patients who underwent radical prostatectomy after imaging, 68Ga-PSMA PET/MRI improved the diagnostic accuracy for PCa localization both compared with multiparametric MRI as well as PET imaging alone.67 On a sextant-based analysis, simultaneous 68Ga-PSMA PET/MRI statistically outperformed multiparametric MRI (area under the curve: 0.88 vs. 0.73; p < .001) and sole 68 Ga-PSMA PET (area under the curve: 0.88 vs. 0.83; p = .002) for localization of PCa. Furthermore, compared with multiparametric MRI, 68Ga-PSMA PET imaging was more

Although PSMA-based PET imaging might be on its way to revolutionize PCa imaging, several limitations have to be addressed. It has to be noted that not all PCa exhibits a significant PSMA overexpression. Up to 10% of primary PCa can be negative on PSMA PET.59,67 Thus, not only the local tumor, but also metastases might not be detectable. In addition, a variety of reports describe positive PSMA PET in several benign and malignant conditions.47 Thus, accurate analysis of PSMA PET studies by experienced imaging specialists is mandatory.

CONCLUSION

Imaging with 68Ga-PSMA PET has already achieved high potential to influence PCa management.46 In biochemical recurrent PCa, 68Ga-PSMA PET imaging has been shown to increase detection of metastatic sites even at low PSA values in comparison with conventional imaging or PET examination with different tracers. Furthermore, especially in high-risk PCa patients, 68Ga-PSMA PET could enable a complete and more accurate staging of local tumors, lymph node involvement, and bone and organ metastases within



FIGURE 10. 65-Year-Old Patient With Histologic Proven Intraprostatic PCa Within the Right Basal Peripheral Zone A

B

C

D

T2 sequence of multiparametric MRI (A) shows a hypointense area in the right prostate base with corresponding diffusion restriction (B). 68Ga-PSMA PET (C) and fused 68Ga-PSMA PET/MRI (D) reveal an area with increased tracer accumulation. Gleason score, 3 + 4; PSA, 10.3 ng/mL.

a single examination, thus outperforming current standard imaging. Thus, although current knowledge is still limited

and derived mostly from retrospective series, PSMA-based imaging holds great promise to advance PCa management.

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