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 |
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.