Abstract

INTRODUCTION

In 1999, the Prostate Cancer Clinical Trials Working Group 1 issued recommendations for standardizing prostate-specific antigen (PSA) outcomes in phase II castration-resistant prostate cancer (CRPC) trials.¹ In 2008, when docetaxel was the only drug proven to prolong survival in metastatic CRPC (mCRPC),^2,3 the successor group, the Prostate Cancer Clinical Trials Working Group 2 (PCWG2), outlined more extensive principles of clinical trial conduct for this disease.⁴ Incorporating the earlier recommendations on the use of PSA measurements in clinical investigations, PCWG2 applied a clinical states framework in which trial objectives, design, and outcomes were based on (1) early measures of response that represented the control, relief, or elimination of existing disease manifestations and (2) later time-to-event measures that represented the delay or prevention of manifestations that may occur as disease progressed (Appendix, online only).

The Prostate Cancer Clinical Trials Working Group 3 (PCWG3) is an international working group of clinical and translational experts in prostate cancer that convened in June 2012 and worked through February 2015 to update the recommendations of PCWG2 in light of a changing therapeutic landscape^5-11 and advances in the understanding of disease biology. The two chairs (H.I.S. and A.J.A.) developed an outline and convened eight meetings that included many of the PCWG2 investigators and 20 additional investigators. A synthesized document was developed and approved by all PCWG3 members. Key principles of trial design and conduct from PCWG3 are shown in Tables 1–5 with comparisons to the prior recommendations of PCWG2.

Table 1.

Summary of Major Changes in PCWG3 Recommendations Compared With PCWG2

Clinical states model

1. Considers mCRPC in terms of number of lines of prior therapy rather than in relation to docetaxel treatment (ie, predocetaxel, postdocetaxel; Fig 1)

2. Advocates recording the specific systemic approaches a patient has received in the order they were administered, including start and stop dates and response if available

3. Distinguishes other histologies (ie, small-cell carcinomas) from adenocarcinomas

4. Emphasizes the importance of serial biologic profiling of the disease at the start of a new therapy and time of progression

Principles of trial conduct

1. Emphasizes discovering and qualifying post-treatment outcomes that reflect patient benefit or can serve as surrogates of that benefit for use in regulatory submissions, to accelerate drug approvals

2. Highlights the distinction between the need to consistently report measures of progression in a trial v the clinical need to continue a particular therapy beyond progression as long as the patient is benefiting from the treatment (Fig 3)

Eligibility for enrollment

1. Defines eligibility criteria using clinical and biologic parameters intended to homogenize the prognosis of the patients enrolled while enriching for tumor biomarker profiles most likely to respond to a particular therapy

2. Encourages the use of testosterone assays that accurately measure levels in the 1-2 ng/dL range performed in a central laboratory

3. Assesses lymph node size on the basis of the short axis and eliminates the requirement for a lymph node to be ≥ 2 cm in size to be considered measurable

4. Encourages designing specific trials that are based on different clinical phenotypes defined by the location and distribution of radiographic metastases for which specific therapies have formal indications or exclusions

Treatment: defining dose, schedule, and pharmacodynamic markers

1. Encourages the use of pharmacodynamic outcome measures that confirm the mechanism of action and determine a dose and schedule specific to the effect of a particular agent on the malignant process

2. Places a greater focus on pharmacodynamic biomarkers that establish proof of mechanism and can also be used to determine dose and schedule on the basis of biology (and safety) rather than safety alone

3. Advises that the post-treatment biomarker measurements used to assess antitumor activity be tailored to each agent’s mechanism of action and that these measurements be performed at fixed intervals (detailed in Table 4)

Baseline disease assessments

1. Expands baseline assessments to include tumor histology; the timing, duration, and response (if available) for all prior systemic treatments; a standardized assessment of blood-based, PRO-based, and imaging-based biomarkers; and the molecular characterization of the tumor (detailed in Table 2)

2. Emphasizes molecular/biologic subtypes of CRPC in addition to the five clinical subtypes (defined by extent and location of metastases)

3. Defines the type of progression at trial entry as PSA-only progression, radiographic progression by site of disease spread, or both; for radiographic progression, records whether progression was caused by growth of existing lesions, appearance of new lesions, or both

Measuring outcomes and reporting: blood-based and molecular measures

1. When there are progressing lesions, recommends rebiopsy of the progressing metastatic site for histology and biomarker assessment

2. Suggests that PSA outcomes should be interpreted within the context of a drug’s mechanism of action, and the anticipated timing of a potential favorable/unfavorable effect on PSA should be considered

3. Includes suggestions on how to define and report outcomes related to CTC enumeration (using CellSearch platform)

Measuring outcomes and reporting: PROs

1. Recognizes the importance of the patient perspective in prostate cancer clinical trials and the need to further optimize the assessment, collection, analysis, and presentation of PRO data

2. Recommends measuring disease-related symptoms including pain intensity and interference, and physical functioning, using validated instruments

3. Recommends collecting patient-reported adverse events using the NCI’s PRO-CTCAE

Measuring outcomes and reporting: imaging and clinical measures

1. Reconsiders the mixed response designation, which may be a manifestation of disease heterogeneity

2. Advises recording whether disease progression represents growth of pre-existing lesions, development of new lesions, or both, and separately recording whether progression is occurring in a single organ or disease site v multiple sites

3. Suggests that the first post-treatment bone scan be used as the baseline scan with which all future bone scans are compared (Fig 2); also emphasizes the notion of response in bone, caused by the advent of novel bone-targeting agents

4. Advises recording the location of nodal disease (pelvic v extrapelvic) and visceral disease (lung/liver/adrenal/CNS) separately, because these sites have separate prognostic implications

5. Also advises monitoring up to five individual lesions per site of spread (eg, nodes, lung, liver as separate sites) to address disease heterogeneity

6. Proposes new criteria to define the first occurrence of metastatic disease in men with nmCRPC at enrollment

7. Highlights and defines the bone-related outcomes, SREs and SSEs, but suggests focusing on SSEs, which represent a more direct clinical benefit to patients

8. Introduces the concept of treatment beyond progression where clinical benefit by one or more disease manifestations is being observed, thus defining an objective of NLCB

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Abbreviations: CRPC, castration-resistant prostate cancer; CTC, circulating tumor cell; mCRPC, metastatic castration-resistant prostate cancer; nmCRPC, nonmetastatic castration-resistant prostate cancer; NCI, National Cancer Institute; NLCB, no longer clinically benefiting; PRO, patient-reported outcome; PRO-CTCAE, Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events; PSA, prostate-specific antigen; SRE, skeletal-related event; SSE, symptomatic skeletal event.

Table 5.

Suggested Outcome Measures for Clinical Trials in Metastatic Prostate Cancer: Report by Disease Manifestation

Variable	PCWG2 (2008)	PCWG3 (2015)
Histology	Not addressed	Encourage rebiopsy of metastatic sites or local recurrence at progression to evaluate for histologic (ie, neuroendocrine/small cell) transformation; in the context of clinical trials, encourage rebiopsy for biomarker assessment
Blood-based markers
PSA	Recognize that a favorable effect on PSA may be delayed for ≥ 12 weeks, even for a cytotoxic drug	Retained
	Monitor PSA by cycle but plan to continue through early rises for a minimum of 12 weeks unless other evidence of progression	Retained
	Ignore early rises (before 12 weeks) in determining PSA response	Retained
	For control/relieve/eliminate end points:	For control/relieve/eliminate end points:
	Record the percent change from baseline (rise or fall) at 12 weeks, and separately, the maximal change (rise or fall) at any time using a waterfall plot	Retained, except with timing (8-9 or 12 weeks) depending on trial design
		Separately report the proportion of patients who have undergone radical prostatectomy and achieved a nadir less than 0.2 ng/mL v primary radiation therapy–treated patients who achieved a nadir less than 0.5 ng/mL
		Describe absolute changes in PSA over time from baseline to best response
	For delay/prevent end points (progression):	For delay/prevent end points (progression):
	After decline from baseline: record time from start of therapy to first PSA increase that is ≥ 25% and ≥ 2 ng/mL above the nadir, and which is confirmed by a second value ≥ 3 weeks later (ie, a confirmed rising trend); the requirement for an increase of 5 ng/mL was decreased to 2 ng/mL, and the requirement for a 50% increase was reduced to 25%	Retained (standards for reporting PSA progression date may not indicate a need to stop treatment)
	Recording the duration of PSA decline of little value	Retained
	No decline from baseline: PSA progression ≥ 25% increase and ≥ 2 ng/mL increase from baseline beyond 12 weeks	Relate to mechanism of drug and anticipated timing of potential favorable/unfavorable effects on PSA, if present
CTC	Not addressed	Enumerate at the start of treatment: Record as favorable (four or fewer cells per 7.5 mL of blood) or unfavorable (five or more cells per 7.5 mL)
		If unfavorable, monitor for changes after treatment
		For control/relieve/eliminate end points:
		Report as change from unfavorable (five or more cells per 7.5 mL of blood) to favorable (four or fewer cells per 7.5 mL) and separately, the percent change from baseline using a waterfall plot
		For delay/prevent end points: no validated definition exists (however, rising CTC counts are associated with a poor prognosis)
LDH, total alkaline phosphatase, bone-specific alkaline phosphatase, urine N-telopeptide, hemoglobin, NLR	Not addressed	Descriptively report changes over time, may include the proportion showing normalization of a given biomarker and/or waterfall plots of percent change from baseline in a given biomarker
		Report institutional normal ranges to determine normalization of a given biomarker
Imaging biomarkers: nodal and visceral
For control/relieve/eliminate end points
General	Record changes in nodal sites separately from visceral sites	Record changes in lymph nodes, lung, liver, adrenal, and CNS sites separately
	Use RECIST with caveats:	Record up to five lesions per site of disease
	Record changes in size using waterfall plot	Use RECIST 1.1 with caveats:
	Confirm favorable change with second scan	Record changes in size using waterfall plot
	Record complete elimination of disease at any site separately	Confirm favorable change with second scan
		Record complete elimination of disease at any site separately
Nodes	Only report changes in lymph nodes that were ≥ 2 cm in the long axis at baseline	Only report changes in lymph nodes that were ≥1.5 cm in the short axis
		Record changes in pelvic (regional) nodes v extrapelvic (distant/metastatic) nodes separately
Visceral	Use RECIST with caveats above	Use RECIST 1.1 with caveats:
		Record changes in liver, lung, adrenal, and CNS separately
		Only report changes in lesions ≥ 1.0 cm in the longest dimension
For delay/prevent end points
Nodal and visceral	Use RECIST criteria for progression, with additional requirement that progression be confirmed by a second scan ≥ 6 weeks later (the second scan is particularly important when anticipated effect on PSA is delayed, or for biologic therapies)	General:
		Record changes in nodal and visceral (lung, liver, adrenal, and CNS) disease separately
		Use RECIST 1.1 but clearly record type of progression (growth of existing lesions v development of new lesions) separately by site
		The recommendations apply to both nmCRPC and mCRPC
		Record up to five lesions per site of spread
		Report the proportion who have not progressed at fixed time points (6 or 12 months)
	Note that for some treatments, a lesion may increase in size before it decreases	Retained
Nodal	As above	Previously normal (< 1.0-cm) lymph nodes must have grown by ≥ 5 mm in the short axis from baseline or nadir and be ≥ 1.0 cm in the short axis to be considered to have progressed
		Nodes that have progressed to 1.0 to less than 1.5 cm are pathologic, subject to clinical discretion, and nonmeasurable
		For existing pathologic adenopathy (≥ 1.5 cm), progression is defined per RECIST 1.1
Imaging biomarkers: bone
Metastatic	For control/relieve/eliminate end points:	For control/relieve/eliminate end points:
	Record changes as improved or stable (no new lesions) or worse (new lesions)	Retained with addition of resolved bone lesion
	Changes in intensity of uptake alone do not constitute progression or regression	Retained
	No new lesions: continue therapy in absence of other signs of progression	Retained
	New lesions (See Progression below)	Retained
	For delay/prevent end points (progression):	For delay/prevent end points (progression):
	Progression:	Progression:
	Exclude pseudoprogression in the absence of symptoms or other signs of progression	Retained
	At least two new lesions on first post-treatment scan, with at least two additional lesions on the next scan (2+2 rule)
	If at least two additional new lesions are seen on the next (confirmatory) scan, the date of progression is the date of the first post-treatment scan, when the first two new lesions were documented	Retained
	For all scans after the first post-treatment scan, at least two new lesions	For scans after the first post-treatment scan, at least two new lesions relative to the first post-treatment scan confirmed on a subsequent scan
	Date of progression is the date of the scan that first documents the second lesion	Retained
	Changes in intensity of uptake alone do not constitute either progression or regression	Retained
		Report the proportion of patients who have not progressed at fixed time intervals (6 and 12 months)
nmCRPC	Not addressed	Nonmetastatic to metastatic progression:
		Any new unequivocal bone lesion, except if that lesion appears in the first post-treatment scan; in that case, document the event, continue treatment until 2 additional new lesions appear, and record both events
Patient-reported outcomes	Consider independently of other outcome measures	Pain palliation assessment requires a patient population with clinically meaningful pain at baseline (eg, ≥ 4 on a 10-point pain intensity scale) and response defined as a clinically meaningful score improvement at a subsequent time point (eg, a 30% relative or 2-point absolute improvement from baseline at 12 weeks, confirmed at least 2 weeks later, without an overall increase in opiate use)
	For control/relieve/eliminate end points:	For control/relieve/eliminate end points:
	Document pain and analgesia at entry with a lead-in period and measure repeatedly at 3- to 4-week intervals	Serial (eg, daily × 7 days) assessments at each time point can improve the stability of values
	Perform serial assessments of global changes in HRQoL, urinary or bowel compromise, pain management, additional anticancer therapy	Principles may be extended for any PRO for which a clinically meaningful baseline PRO score has been determined together with a responder definition that is based on a sustained clinically meaningful score improvement
	Ignore early changes (≤ 12 weeks) in pain or HRQoL in absence of compelling evidence of disease progression
	For delay/prevent end points:	For delay/prevent end points:
	Confirm response or progression of pain or HRQoL end points ≥ 3 weeks later	Patients with any level of baseline pain, including no pain, are eligible to be evaluated for prevent/delay end points; those without pain are followed for development of pain, whereas those with baseline pain are followed for progression (eg, a 2-point increase without an overall decrease in opiate use)
		Pain assessment should be administered at treatment discontinuation and once again if feasible (eg, 2 to 4 weeks later)
		Time to deterioration of physical function and/or HRQoL scores should also be included, with a priori thresholds defining clinically meaningful deterioration score changes that are based on prior published data for the selected questionnaire

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Abbreviations: CTC, circulating tumor cell; HRQoL, health-related quality of life; LDH, lactate dehydrogenase; mCRPC, metastatic castration-resistant prostate cancer; NLR, neutrophil/ lymphocyte ratio; nmCRPC, nonmetastatic castration-resistant prostate cancer; PCWG2, Prostate Cancer Clinical Trials Working Group 2; PCWG3, Prostate Cancer Clinical Trials Working Group 3; PRO, patient-reported outcome; PSA, prostate-specific antigen; RECIST, Response Evaluation Criteria in Solid Tumors.

CONCEPTUALIZING THE DISEASE

The decision milestones in PCWG2 were based on disease states defined by the status of the primary tumor, the presence or absence of distant disease on imaging (metastatic versus nonmetastatic), testosterone levels, and prior chemotherapy exposure.

PCWG3 presents a revised disease states model that, like its predecessor, defines trial objectives on the basis of state-specific clinical needs (Fig 1). Emphasis is placed on designing clinical trials within a biomarker context, and focusing on how biomarkers can be developed to predict outcome, guide management, and influence clinical decision making. The revised model aligns with the indications and uses of the currently approved drugs (see Appendix Table A1, online only) and provides the framework for a decision tree that closely follows contemporary clinical practice. Key new recommendations of the decision tree include (1) distinguishing adenocarcinomas from other histologies including pure small-cell carcinomas and variants with neuroendocrine differentiation; (2) replacing the pre- versus postchemotherapy distinction with a dynamic classification that considers the lines of therapy a patient has received independent of the mechanism of action, the order in which they were administered, and the sensitivity of the tumor to each; (3) designing dedicated trials for the different CRPC phenotypes defined by the pattern of spread; (4) adding recommendations for trials in the nonmetastatic CRPC (nmCRPC) state, formerly defined as the rising PSA castrate state; (5) emphasizing the importance of serial biologic profiling of the disease using minimally invasive blood-based assays of tumor material, imaging, or biopsy of a metastatic tumor site to identify and target mechanisms of primary or adaptive resistance and to better enable treatment selection to be based on disease biology; (6) including clinically relevant time-to-event end points such as symptomatic skeletal events (SSEs); and (7) with our increased recognition of disease heterogeneity and emerging resistance, focusing more on determining when a treatment should be discontinued when the patient is no longer clinically benefiting (NLCB) rather than strictly at the first evidence of progression.

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Fig 1.

Prostate cancer clinical states model, a framework for patient treatment and drug development, updated for the Prostate Cancer Clinical Trials Working Group 3. Combination therapy is considered one line of therapy. mCRPC, metastatic castration-resistant prostate cancer; nmCRPC, nonmetastatic castration-resistant prostate cancer; PSA, prostate-specific antigen.

ELIGIBILITY FOR ENROLLMENT

Eligibility criteria define the population to be considered for enrollment as one that has a high likelihood of demonstrating the hypothesized effect of a treatment. The criteria may be based on clinical features and laboratory measures that are prognostic, predictive, or important from a safety perspective.

PATIENT DEMOGRAPHICS AND PATHOLOGY

Baseline Assessment

The baseline disease assessment recommendations of PCWG2 are expanded in PCWG3 (Table 2) to include histology; prior radiation therapy; the timing and duration of, and (if available) response to all prior systemic treatment(s); a standardized assessment of blood-based biomarkers; patient-reported outcomes (PROs); imaging; profiling disease by a repeat biopsy that also determines changes in histology or through blood-based assays for molecular markers/determinants of prognosis and drug sensitivity.

Table 2.

Standard Baseline Disease Assessments Recommended by PCWG3 in Comparison With PCWG2 Recommendations

Assessment	PCWG2 (2008)	PCWG3 (2015)
Histology	Not addressed	Adenocarcinoma
		Adenocarcinoma with small-cell or neuroendocrine features
		Small-cell carcinoma
		Report Gleason sum for primary
		Consider rebiopsy of metastatic disease
Clinical	History and physical examination	Age, pain, analgesic consumption, performance status, comorbidity assessment, history, and physical examination; prior local therapy; TNM stage at diagnosis; and PSA
Prior systemic treatment	Pre- and postchemotherapy	Record each line of systemic therapy (single agent or combination) in order of administration, including start and stop dates, dose(s), and schedule(s), the disease state in which it was administered, and response (resistant v sensitive) on the basis of PSA if appropriate
		Record type of progression on prior therapy (PSA, radiographic [bone, nodal, visceral], clinical [eg, pain escalation])
Prior radiation therapy	Not addressed	Site, administered dose per fraction and treatment duration
Blood-based biomarkers	PSA Testosterone	Host: CBC with differential, ALK, kidney/liver function, albumin, LDH, testosterone*
		Tumor: PSA and cPSA kinetics
		Optional: CEA, chromogranin A, neuron-specific enolase, CTC enumeration
Imaging
Prostate/ prostate bed	Endorectal MRI	Retained, cross-sectional imaging of prostate region if applicable
Nodal	CT: Only nodes ≥ 2 cm were assessed for change in size	CT or MRI:
		Nodes ≥ 1.5 cm in the short axis are considered measurable; nodes ≥ 1.0 and less than 1.5 cm in the short axis are considered pathologic according to clinical discretion, and nontarget; nodes less than 1.0 cm in the short axis are nonpathologic
		Record pelvic and extrapelvic (retroperitoneal, mediastinal, thoracic, other) nodal disease separately; up to five nodes in total
		Record new lesions v growth of pre-existing lesions, and sites of new lesions
Visceral	CT: reported as visceral per RECIST	CT or MRI:
		Record individual sites of spread (lung, liver, adrenal, CNS) separately; up to five lesions per site
		Lesions ≥ 1.0 cm in the longest dimension are considered measurable
		Record new lesions v growth of pre-existing lesions, and sites of new lesions
Bone	99mTc MDP	Record new lesions and sites of new lesions
Tumor profiling for determinants of prognostic, predictive, and resistance biomarkers	Not addressed	Consider rebiopsy of metastatic or locally recurrent lesion(s) for biologic characterization
Patient-reported outcomes	None	Pain assessment, opiate analgesia consumption, physical functioning (functional status), health-related quality of life; consider fatigue and PRO-CTCAE. Validated PRO instruments strongly recommended

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Abbreviations: ALK, alkaline phosphatase; CBC, complete blood count; CEA, carcinoembryonic antigen; CT, computed tomography; CTCs, circulating tumor cells; CTCAE, Common Terminology Criteria for Adverse Events; LDH, lactate dehydrogenase; MRI, magnetic resonance imaging; PCWG2, Prostate Cancer Clinical Trials Working Group 2; PCWG3, Prostate Cancer Clinical Trials Working Group 3; PRO, patient-reported outcome; PRO-CTCAE, Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events; PSA, prostate-specific antigen; RECIST, Response Evaluation Criteria in Solid Tumors; ^99mTc MDP, ^99mTc methylene diphosphonate.

^*Ultrasensitive testosterone measures may be indicated where appropriate on the basis of drug under study and context.

Prior Systemic Treatment

To better define and characterize a patient’s disease at the time of trial enrollment and to explore potential favorable or unfavorable interactions among therapies, PCWG3 recommends recording all lines of therapy (represented as a single agent or combination) in the order they were administered. Ideally, reporting should include the start and stop dates, or at least the duration, for each prior line of therapy; the dose and schedule of the agent(s); the disease state in which it was administered; and the type of progression (biochemical [ie, a rising PSA], radiographic, and/or symptomatic). Response (resistant versus sensitive) should be categorized on the basis of the post-therapy PSA or radiographic change pattern for agents that reduce tumor burden. For example, Appendix Fig A1 (online only) shows that post-therapy PSA change patterns with agents that effect cell kill allow one to categorize response as resistant versus sensitive. Similar response patterns to prior therapy that were based on other clinical biomarkers such as imaging or pain may be considered and reported, recognizing the challenges in obtaining such historical data.

The definition of a prior hormonal intervention is changed to include only the addition of a hormonal therapy that had the intent of treating the cancer. Assessing for a withdrawal response to an antiandrogen is no longer considered an intervention and is not required, but should be considered for 4 to 6 weeks for patients who have been on long-term antiandrogen therapy with apparent benefit. A response, if it was observed on discontinuation, should be recorded.

Prior Radiation Treatment

Details of the dates, portals, number of fractions, dose per fraction, and total administered dose by portal should be recorded for all courses of radiation therapy, including those directed at the primary and metastatic site(s). Details of prior radioisotope therapy should also be recorded.

Histology and Pathologic Subtype

To better inform future decision making, PCWG3 encourages the direct biologic characterization of the tumor at the time a new treatment is being considered by performing a biopsy of a metastatic site or with blood-based diagnostics such as circulating tumor cells (CTCs), circulating nucleic acids, or host factors (eg, markers of bone turnover or immune function).

Although a number of prostate cancer histologic subtypes have been described, only the pure small-cell phenotype is a distinct entity that is diagnosed consistently.^12,13 It represents less than 1% of newly diagnosed prostate cancers but leads directly to treatment with cytotoxic regimens similar to those used to treat small-cell lung carcinomas of the lung and should thus be noted specifically. Treatment-emergent histologic variants that contain nonadenocarcinomatous elements are still being defined but are anticipated to differ from the de novo small-cell phenotype.¹³

IMAGING

Imaging provides critical information on disease distribution, prognosis, extent, biology, and host reaction to the tumor.

Baseline by Site of Disease

PCWG3 retains the PCWG2 recommendations with modifications that include developing, recording, and validating measures of disease burden. Imaging of the chest, abdomen, and pelvis using a contrast-enhanced computed tomography (CT) scan with ≤ 5-mm axial slices is advised for all patients. For those intolerant of contrast, a cross-sectional magnetic resonance imaging (MRI) scan of the abdomen and pelvis, with a noncontrast CT scan of the chest, may be considered. In phase I and II trials, recognizing that individual lesions may be biologically distinct, PCWG3 recommends reporting whether progression on entry was in the growth of pre-existing lesions, the development of new lesions, or both. PCWG3 advises following Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 for extraskeletal disease but recommends that up to five lesions per site of metastatic spread (eg, lung, liver, lymph nodes as separate sites) be recorded to address disease heterogeneity and to track patterns of metastatic progression. Bone lesions should be recorded separately (see Bone section on this page).

Prostate or prostate bed.

Specific imaging of the prostate or prostate bed is not required for every patient. If there is a question of locally persistent or recurrent disease, a directed MRI of the prostate or prostate bed and/or biopsy of the site is recommended.

Nodes or viscera.

PCWG3 advises that nodal disease be measured in the short axis and recorded by location: pelvic disease should be classified as locoregional, and extrapelvic disease (retroperitoneal, mediastinal, thoracic, or other) as metastatic. Nodes ≥ 1.5 cm in the short axis are considered pathologic and measurable. As per RECIST 1.1, lymph nodes that are ≥ 1.0 cm but less than 1.5 cm in the short axis may be pathologic and can be considered nonmeasurable/nontarget lesions.³⁷ Visceral disease in metastatic patients should be designated separately as lung, liver, adrenal, or CNS and is considered measurable if an individual lesion is ≥ 1 cm in its longest dimension. Given that lung metastases are relatively frequent in mCRPC trials (7% prevalence), chest CT imaging is recommended.³⁸

PCWG2 did not formally address trials in the nmCRPC population, where the aim is to delay/prevent the development of radiographically evident metastatic disease and death. To establish nonmetastatic status, note that nodes less than 1.0 cm in the short axis are nonpathologic; nodes 1.0 to less than 1.5 cm may be considered pathologic, but with clinical discretion; and nodes ≥ 1.5 cm are both pathologic and measurable. PCWG3 advises that trial entry be based on PSADT, and that the same standard imaging modalities (eg, bone scan, CT, and/or MRI) used to determine eligibility be used for monitoring the patient receiving treatment.

Bone.

The use of ^99mTc-methylene diphosphonate radionuclide bone scintigraphy as the standard for bone imaging is retained in PCWG3, with the presence or absence of metastasis recorded first. A quantitative measure of disease burden, such as lesional number,³⁹ the bone scan index,^40,41 or lesion area,⁴² is also suggested, recognizing that these measures require further analytical and prospective clinical validation. Changes in lesions considered metastatic on bone scintigraphy should be followed and assessed serially using a bone scan assessment form (Appendix Fig A3, online only). Areas/lesions on bone scintigraphy that are suggestive can be assessed further with CT or MRI and followed separately, but such supplemental imaging should not be used to establish indicator lesions for the purposes of a trial.

Different modalities for imaging bone metastases can provide different information for the same patient (Appendix Fig A2). However, because of the lack of standards for reporting disease presence or changes after treatment, positron emission tomography imaging with sodium fluoride, fluorodeoxyglucose, choline, or prostate-specific membrane antigen, bone marrow MRI (body MRI), and other modalities that are in use to image bone, should be approached as new biomarkers subject to independent validation.

Neurologic.

PCWG3 upholds the PCWG2 recommendation to perform an MRI or CT of the brain for patients with small-cell/neuroendocrine tumors and to maintain a low threshold for performing an MRI of the base of the skull or spine to diagnose and/or detect impending neurologic compromise. Routine imaging of the brain for adenocarcinoma is not recommended.

Type of progression at entry into a trial.

PCWG3 advises recording whether progression was manifested by PSA alone, bone ± nodes by location, nodes by location only, or viscera (± other sites), and the proportion of patients who progress in each of these categories, because this is prognostic.^5,6,10,11 PCWG3 also advises reporting whether progression by imaging at study entry involved the growth or enlargement of pre-existing lesions, the development of new lesions, or both. The criteria for progression can be found in Table 3.

Table 3.

Criteria for Progression at Trial Entry by Disease Manifestation

Variable	PCWG2 (2008)	PCWG3 (2015)
Blood-based
PSA	Obtain sequence of rising values at a minimum of 1-week intervals	Retained
	2.0 ng/mL minimal starting value	1.0 ng/mL is the minimal starting value if confirmed rise is only indication of progression unless pure small-cell carcinoma
	Estimate pretherapy PSADT if at least three values available ≥ 4 weeks apart	Retained
Imaging
Nodes	Nodal progression sufficient for trial entry independent of PSA	Retained
	Measurable lesions not required for entry	Retained
	Use RECIST to record nodal lesions as target or nontarget	Modified RECIST 1.1 criteria, separate pelvic and extrapelvic disease, up to five nodal lesions total recorded
	Only lymph nodes ≥ 2 cm in diameter (long axis) were actionable as progressive disease	Previously normal (< 1.0-cm) lymph nodes must have grown by ≥ 5 mm in the short axis from baseline or nadir and be ≥ 1.0 cm in the short axis to be considered to have progressed
		If the node progresses to ≥ 1.5 cm in the short axis, it is measurable; nodes that have progressed to 1.0 to less than 1.5 cm are pathologic, subject to clinical discretion, and nonmeasurable
		For existing pathologic adenopathy, progression is defined per RECIST 1.1
	Record presence of nodal and/or visceral disease separately	Retained with modification
		Nodal sites:
		Locoregional: pelvic only
		Extrapelvic: retroperitoneal, mediastinal, thoracic, or other
Viscera	Visceral progression sufficient for trial entry independent of PSA	Retained but recorded separately by site of spread (lung, liver, adrenal, CNS); up to five lesions per site of spread
	Measurable lesions not required for entry	Retained
	Use RECIST to record visceral lesions as target or nontarget	Retained
	Record presence of nodal and/or visceral disease separately	Retained with modification
		Visceral sites: lung, liver, adrenal, CNS
Prostate/prostate bed (primary site)	Record prior treatment of primary tumor	Retained
	Perform directed pelvic imaging (CT, MRI, PET/CT, endorectal MRI, transrectal ultrasound) to document presence or absence of disease	Retained
Bone	Two new lesions	Retained
	Confirm ambiguous results by other imaging modalities (eg, CT or MRI)	Retained, but only positivity on the bone scan defines metastatic disease to bone
Other sites of disease	Patients with treated epidural lesions and no other epidural progression are eligible	Retained
Type of progression at trial entry	Not addressed	Report separately:
		PSA only
		Bone only ± nodal disease
		Nodal disease only (no bone disease present)
		Visceral (lung, liver, adrenal, CNS) disease (± other sites)
		Record new lesions and site of new lesions v growth of pre-existing lesions, or both
Other markers
Patient-reported outcomes	Not addressed	For pain palliation analyses, presence of clinically meaningful pain at baseline (eg, ≥ 4 on a 10-point pain intensity scale) is a prerequisite; for pain progression analyses, patients may have any level of pain at baseline, including no pain

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Abbreviations: CT, computed tomography; MRI, magnetic resonance imaging; PCWG2, Prostate Cancer Clinical Trials Working Group 2; PCWG3, Prostate Cancer Clinical Trials Working Group 3; PET, positron emission tomography; PSA, prostate-specific antigen; PSADT, PSA doubling time; RECIST, Response Evaluation Criteria in Solid Tumors.

Clinical subtypes of CRPC that are based on pattern of spread.

The five clinical subtypes defined in PCWG2 on the basis of the pattern of spread in individual patients are retained with modifications: (1) locally recurrent CRPC after radical prostatectomy or persistent disease in the prostate or prostate bed after radiation therapy on ADT, with no evidence of metastases on imaging; (2) nonmetastatic (nmCRPC): a rising PSA with no detectable disease in the primary site, in lymph nodes beyond the true pelvis by CT/MRI (lymph nodes ≤ 1.5 cm in the short axis in the pelvis are eligible), in bone by radionuclide bone scan or CT, or in visceral organs; (3) nodal spread within the pelvis (lymph nodes > 1.0 cm) and/or beyond the pelvis (specify) and no evidence of bone or visceral disease⁴³; (4) bone disease with or without nodal disease and no evidence of visceral spread; (5) visceral disease with or without spread to other sites; includes spread to lung, liver, or adrenal and CNS sites, each reported separately. It is recommended that research studies report the proportion of patients in each subtype. Stratification by pattern of metastatic spread is also encouraged.

INTERVENTION

In PCWG3, the term intervention includes both the therapy itself and the post-treatment assessments to determine dose, schedule, and antitumor effects. PCWG3 emphasizes the importance of developing trials that provide the following information tailored to the mechanism and postulated therapeutic target(s) of the agent: population-specific pharmacokinetics in the castrate state, the use of pharmacodynamic measures specific to the postulated effect of a particular agent on the malignant process to confirm or refute the hypothesized mechanism of action, and the optimal timing to assess the pharmacodynamic measures and to inform the determination of the optimal dose and schedule to study in future trials. The optimal time to assess for antitumor effects, which can be delayed for many types of treatment including those that affect immune function, should also be determined by assessing disease status at fixed intervals.

MEASURING OUTCOMES AND REPORTING

PCWG3 reaffirms the recommendation to use control/relieve/eliminate end points to assess antitumor effects of therapies that are anticipated to kill tumor cells, particularly in early clinical development. For therapies not expected to kill tumor cells, delay/prevent end points should be used. PCWG3 discriminates between activity-estimating end points in early-phase trials (such as declines in PSA, changes in CTCs, and time to progression) where the objective is to demonstrate sufficient antitumor activity to justify further study, versus registration trials for regulatory approval where clinical benefit is the objective. For instance, in early-phase trials, time to progression, which censors deaths, may be used, whereas in registration trials, progression-free survival, which includes deaths as events, is preferred. The suitability of efficacy end points to demonstrate clinical benefit is context dependent, and consultation with regulatory authorities is strongly recommended when selecting and defining end points for a trial intended to support drug approval.⁵³ Although demonstrating overall survival may be challenging as a primary end point, it is assumed that all trials will continue to follow patients for survival and analyze and report survival results, particularly in randomized clinical trials. PCWG3 also recommends that all therapies administered subsequent to the intervention, including start and stop dates when available, be recorded, until death. This is essential because the availability and use of life-prolonging treatments post protocol may reduce the ability to demonstrate the survival benefit of an effective treatment.

On-treatment evaluations should include physical examinations, symptom assessments, and laboratory studies to assess safety, with appropriate attribution to the disease or therapy. Imaging should include cross-sectional imaging of the chest, abdomen, and pelvis, as well as bone scintigraphy, regardless of whether patients have involvement of those sites at baseline. Imaging strategies restricted to known sites of disease risk missing disease progression at new sites.

PCWG3 advises that disease assessments be performed at fixed intervals to better understand when antitumor effects occur (Table 4). To minimize patient exposure to ineffective treatment, and to better assess the timing of the antitumor effects of an agent for which the optimal timing is not known, an 8- to 9-week assessment interval for the first 6 months and every 12 weeks thereafter is advised. This recommendation is based on the findings of several trials.^5,10,54 The shorter interval also helps clarify bone scan flare (the development of new lesions on a first follow-up scan that may actually represent a favorable response to treatment). Using the shorter interval will also inform the optimal assessment interval in subsequent trials, particularly important for biologic therapies whose antitumor effects may be delayed. Notable is that the applicability of the immune-modified RECIST criteria to prostate cancer has not been established, in particular, whether an early increase in the size of a nodal or visceral lesion represents the recruitment of immune effector cells or tumor growth.⁵⁵ It is also noteworthy that neither the RECIST criteria nor the immune-modified RECIST criteria address changes in osseous disease.

Table 4.

Suggested Frequency of Assessment for Commonly Used Measures in Metastatic Prostate Cancer Clinical Trials

Measure*	PCWG2 Frequency (2008)	PCWG3 Frequency (2015)†
Clinical
Symptoms/ performance status	Every cycle	Retained
Blood-based markers
PSA	By cycle (every 3 or 4 weeks)	Retained
ALK, LDH	By cycle (every 3 or 4 weeks)	Retained
Serum chemistry, CBC	Not addressed	By cycle (every 3 to 4 weeks)
Circulating tumor cells	Not addressed	By cycle (every 3 to 4 weeks) if available
Imaging
Bone scans	Every 12 weeks	Every 8 to 9 weeks for first 24 weeks, then every 12 weeks†
CT/MRI	Every 12 weeks	Every 8 to 9 weeks for first 24 weeks, then every 12 weeks†
Patient-reported outcomes	Not addressed	By cycle (every 3 to 4 weeks)
Analgesic consumption (opioids/no opioids)	Not addressed	By cycle (every 3 to 4 weeks)

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Abbreviations: ALK, alkaline phosphatase; CT, computed tomography; LDH, lactate dehydrogenase; MRI, magnetic resonance imaging; PCWG2, Prostate Cancer Clinical Trials Working Group 2; PCWG3, Prostate Cancer Clinical Trials Working Group 3; PSA, prostate-specific antigen.

^*All measures should be assessed at baseline to determine changes over time.

^†There may be exceptions to these suggestions: in nonmetastatic castration-resistant prostate cancer trials, for example, imaging assessment intervals of 16 weeks are advised. Likewise, in long-term responders (> 2 to 3 years of clinical benefit and no signs of clinical or biomarker progression), reduced frequency of imaging is reasonable, such as every 16 to 24 weeks (4 to 6 months).

APPLYING THE CONTROL/RELIEVE/ELIMINATE VERSUS DELAY/PREVENT FRAMEWORK

PCWG3 retains the recommendation to report outcomes by manifestation (eg, host or tumor biomarkers, symptoms, site of spread) and not to report grouped categorizations of response such as complete response, partial response, or progression on the basis of multiple manifestations. In patients who show evidence of benefit, PCWG3 advises continuing therapy in the case of an isolated PSA rise after an initial decline until radiographic or clinical progression is manifest. Table 5 describes the updated PCWG3 recommendations for reporting outcomes by disease manifestation. Of particular note is the use of the 2+2 rule to distinguish flare from true progression in patients with osseous disease at baseline (Fig 2).^4,6 Also recommended are reporting the proportion of patients who have not progressed at fixed time intervals (eg, 6 or 12 months) and reporting separately the time receiving treatment.

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Fig 2.

Controlling for flare by applying the 2+2 rule using the first post-treatment scan as baseline.

NLCB: PROGRESSION VERSUS THE DECISION TO DISCONTINUE THERAPY

PCWG2 encouraged the continuation of treatment if a rising PSA or worsening of an isolated disease site that was not clinically significant was the sole indicator of disease progression and the patient was otherwise tolerating therapy. Now, recognizing the biologic heterogeneity of individual metastatic lesions, PCWG3 draws the distinction between documenting progression for consistency of reporting (eg, recording the date of documented progression in a site of disease such as a lymph node that is unlikely to adversely affect prognosis) versus the decision to stop therapy.

To address this, PCWG3 introduces the no longer clinically benefiting (NLCB) reporting metric defined as the date and the specific reason(s) a therapy was ultimately discontinued. This end point permits individualized provider-patient decisions to continue or discontinue a treatment based on the primary therapeutic objective for which it is being administered and assessed, be it quality of life, PROs, or survival. As an example, in cases in which multiple sites of disease continue to respond but one to two sites grow, focal therapy such as radiation or surgery could be administered to the resistant site(s) and systemic therapy continued. Similarly, therapy may be continued if progression by PSA or imaging is slow and the disease-related symptoms that were present at baseline remain controlled. Important here is to record in detail the specific reasons why a therapy was ultimately discontinued, which may include clinical deterioration (clarifying whether it is disease or therapy related) or need for a change in systemic therapy. PCWG3 cannot define the risks/benefits at the individual level for continuation of therapy beyond progression, but sets the goal of prospectively defining the circumstances in which scenarios are identified where continuing a therapy is justified. Clinical trials evaluating whether therapy A should be stopped and a new one started, continued alone, or continued with a new one added, are ongoing.

To illustrate the concept of NLCB, we recommend use of a swimmers plot (Fig 3), in which each lane documents the individual patient experience on a trial over time. This plot includes significant adverse events encountered, treatment discontinuations, and the points at which the criteria for progression by a specific disease manifestation were met while treatment was continued up through the time treatment was ultimately discontinued. The information in each swim lane can also be used to record the dates a focal therapy (eg, external beam radiation) was used to treat nonresponding sites in cases in which multiple other sites of disease are still responding. In both cases, the patient may still be benefiting overall from a treatment, justifying its continuation. These plots are suggested for phase I and II studies and may be particularly useful in trials designed to assess the patient experience across treatment groups.

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Fig 3.

Swim lanes illustrating the patient experience on a trial. For early-phase trials, the swimmers plot is used to track individual patients on a trial, including time on and off therapy, adverse events, progression events, and the point at and the reason for which therapy is stopped. Progression in individual disease manifestations and other significant events are recorded, including those that did not lead to trial discontinuation and those that did. Pragmatically, each line shows the duration on therapy. Note that this particular example depicts a trial in progress. NLCB, no longer clinically benefiting; PSA, prostate-specific antigen; rPFS, radiographic progression-free survival; SAE, serious adverse event.

SUMMARY

PCWG3 seeks to move the drug development process closer to common clinical scenarios encountered in routine practice. It also aims to allow a more complete characterization of the host and his disease, not only at the start of therapy, but also over time as it evolves under treatment, which may help establish the value and the benefit of continuing a therapy when there are signs that the disease is beginning to progress.

PCWG3 emphasizes the distinction between adenocarcinomas and other histologies, moves away from the pre- and post-taxane categorization, and recommends eligibility on the basis of prior therapies received. This should result in a greater focus on developing specific protocols for the distinct clinical phenotypes. An important addition to PCWG3 is the recommendation to describe the percentage of patients with a specific disease pattern; in some cases, stratification for a specific pattern of disease may be indicated. Focusing PROs on core concepts of disease-related symptoms, physical functioning, and adverse events of therapy is advised, with the goal of improving the standardization of PRO in prostate cancer clinical trials.

Serial biologic profiling of the disease before treatment, while receiving treatment, and at progression is also advised. To establish clinical significance, PCWG3 advises evaluating the strength of the association between early changes in individual outcome measures, be they clinical, biochemical, PROs, imaging, CTCs, or other molecular determinants, and later events such as rPFS or clinical progression-free survival and/or overall survival. Standards for the interpretation of outcomes for therapies that affect the immune system are also needed. Although improvements in symptoms and/or functional status can be clinical benefits in their own right, determining the clinical significance of a statistically significant change in a PRO measure is another area of focus. Finally, PCWG3 underscores the distinction between the need to consistently report progression by individual disease manifestation in the order in which they occur (be it PSA, imaging, or other surrogate) from the need to terminate a treatment because the patient is NLCB from the therapy he is currently receiving.

AUTHOR CONTRIBUTIONS

Conception and design: Howard I. Scher, Michael J. Morris, Walter M. Stadler, Celestia Higano, Ethan Basch, Karim Fizazi, Emmanuel S. Antonarakis, Tomasz M. Beer, Michael A. Carducci, Kim N. Chi, Paul G. Corn, Johann S. de Bono, Robert Dreicer, Daniel J. George, Elisabeth I. Heath, Maha Hussain, Wm. Kevin Kelly, Glenn Liu, Christopher Logothetis, David Nanus, Mark N. Stein, Charles J. Ryan, Oliver Sartor, Eric J. Small, Matthew Raymond Smith, Cora N. Sternberg, Mary-Ellen Taplin, George Wilding, Peter S. Nelson, Lawrence H. Schwartz, Susan Halabi, Philip W. Kantoff, Andrew J. Armstrong

Provision of study materials or patients: Howard I. Scher, Michael J. Morris

Collection and assembly of data: Howard I. Scher, Michael J. Morris, Celestia Higano, Tomasz M. Beer, Lawrence H. Schwartz, Susan Halabi, Andrew J. Armstrong

Data analysis and interpretation: Howard I. Scher, Michael J. Morris, Walter M. Stadler, Ethan Basch, Emmanuel S. Antonarakis, Tomasz M. Beer, Michael A. Carducci, Robert Dreicer, Daniel J. George, Maha Hussain, Dana E. Rathkopf, Susan F. Slovin, Charles J. Ryan, Oliver Sartor, George Wilding, Lawrence H. Schwartz, Susan Halabi, Andrew J. Armstrong

Manuscript writing: All authors

Final approval of manuscript: All authors

Supplementary Material

Acknowledgment

Appendix

The Dual-Objective Framework for Therapeutic Objectives

The Prostate Cancer Clinical Trials Working Group 3 (PCWG3) retains the dual-objective structure described by the Prostate Cancer Clinical Trials Working Group 2 (PCWG2), categorizing therapeutic objectives as control/relieve/eliminate versus delay/prevent. Delay/prevent objectives include manifestations that are clinically significant trial end points in their own right, such as symptomatic skeletal events or prolonged survival. This model aligns with the indications and uses of the currently approved drugs (see Appendix Table A1). Notable is that pain is the only control/relieve/eliminate end point for which therapies are approved or indicated.

The Biomarker Context of PCWG3

Drug development programs are designed to demonstrate clinical benefit with acceptable safety in well-controlled studies.⁶³ Optimally, the clinical benefit should fulfill an unmet need. PCWG3 considers all aspects of the clinical trial process within a biomarker context, from discovery or definition, to analytical assay validation, to clinical validation.^64,65 The biomarker may be a clinical measure (eg, functional status), patient-reported outcome, tumor or host biochemical measure, imaging parameter, or molecular determinant. PCWG3 encourages defining and evaluating biomarkers for specific contexts of use during the early phases of drug development to enable validation in later-phase trials. The demonstration of a biomarker’s clinical usefulness (which shows that the risk/benefit outcome for the patient is improved when the biomarker test result is used in making the therapeutic decision) is also emphasized.⁶⁶

Calculating Prostate-Specific Antigen Doubling Time

Prostate-specific antigen (PSA) doubling time should be calculated using a linear regression model of the normal logarithm of PSA and time.⁶⁷ The calculation should be based on (1) at least three consecutive PSA values with each value ≥ 0.2 ng/dL, (2) inclusion of the most recent PSA values during androgen deprivation therapy, and (3) interval between first and last PSA values of ≥ 8 weeks but ≤ 12 months.^20,21,67

Table A1.

Indications and Regulatory Labels for the Currently Approved Drugs for CRPC, Aligned With the PCWG3 Manifestation-Specific Outcome Framework

Early manifestations (response): control, relieve, or eliminate

Approved to control pain or indicated for patients with symptoms

Mitoxantrone plus prednisone for the treatment of patients with pain related to advanced hormone-refractory prostate cancer

89Sr for the relief of bone pain in patients with painful skeletal metastases

153Sm for relief of pain in patients with osteoblastic metastatic bone lesions that enhance on radionuclide bone scan

Radium-223* (symptoms from bone metastases with no involvement of other organs)

No FDA drug approvals on the basis of:

PSA declines

Tumor shrinkage

Bone scan improvement

Changes in circulating tumor cell number

Later manifestations (progression): delay or prevent

Approved or shown to delay SREs or SSEs

Zoledronic acid (SRE)

Denosumab (SRE)

Abiraterone acetate (SRE)*,†

Enzalutamide (SRE)*,†

Radium-223 (SSE)*,‡

Approved for delay of death (survival)

Docetaxel

Sipuleucel-T

Cabazitaxel

Abiraterone acetate plus prednisone

Enzalutamide

Radium-223

Delay of radiographic progression using PCWG2-based criteria, coprimary with survival

Abiraterone acetate plus prednisone

Enzalutamide

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Abbreviations: CRPC, castration-resistant prostate cancer; FDA, United States Food & Drug Administration; PCWG2, Prostate Cancer Clinical Trials Working Group 2; PCWG3, Prostate Cancer Clinical Trials Working Group 3; PSA, prostate-specific antigen; SREs, skeletal-related events; SSEs, symptomatic skeletal events.

^*Indicated for patients with symptoms.

^†Shown to delay SREs.

^‡Shown to delay SSEs.

Fig A1.

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Three patterns of biomarker (eg, PSA) response to agents that effect cell kill. Shown are a substantial and durable decline consistent with marked sensitivity (gray line); a decline followed by a slow rise, indicative of partial sensitivity followed by acquired resistance (gold line); and a transient drop (or none at all) followed by an immediate rise, consistent with either de novo or intrinsic resistance (blue line). PSA, prostate-specific antigen.

Fig A2.

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Radionuclide bone scan, sodium fluoride PET scan, and FDG PET scan of the same patient. Only FDG PET is tumor directed; Tc-99 MDP and NaF PET are bone directed. Note that neither the target of the tracer nor the clarity of the image necessarily implies a superior biomarker, and each modality must be validated analytically and clinically. ^99mTc MDP, ^99mTc methylene diphosphonate; NaF, sodium fluoride; FDG, fluorodeoxyglucose; PET, positron emission tomography.

Fig A3.

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Bone scan assessment form.

Footnotes

REFERENCES