How to determine disease progression in a patient with metastatic prostate cancer?

Determining Disease Progression in Metastatic Prostate Cancer

Disease progression in metastatic prostate cancer should be determined using a multimodal approach that integrates PSA kinetics, radiographic imaging (bone scan and CT for conventional assessment, or PSMA PET for next-generation imaging), and clinical symptoms, with specific criteria varying by disease manifestation (bone, nodal, or visceral). 1

PSA-Based Progression Assessment

PSA progression alone is insufficient to define disease progression in metastatic prostate cancer and must be confirmed with radiographic or clinical evidence. 1

• PSA doubling time (PSADT) <6 months strongly suggests metastatic progression rather than local recurrence 1
• PSA velocity (change in PSA over time) provides additional prognostic information, with rapid rises indicating more aggressive disease 1
• Critical caveat: PSA may not reliably reflect disease status in patients on androgen deprivation therapy, making imaging essential for accurate progression assessment 2

Radiographic Progression Criteria by Disease Site

Bone Metastases (Most Common Site - 84% of Cases)

The "2+2 rule" is the standard for defining bone progression: at least two new bone lesions on the first post-treatment scan, confirmed by at least two additional new lesions on the next scan 1

• The date of progression is the date of the first post-treatment scan when the initial two new lesions were documented, not the confirmatory scan 1
• Changes in intensity of uptake alone do not constitute progression or regression 1
• Important pitfall: Bone metastases may paradoxically appear worse on imaging despite effective treatment (flare phenomenon), which is why confirmation is required 3, 2
• For patients with non-metastatic CRPC transitioning to metastatic disease, any new unequivocal bone lesion constitutes progression, except if it appears on the first post-treatment scan—in that case, continue treatment until 2 additional new lesions appear 1

Nodal Disease

Lymph node progression requires growth of ≥5 mm in the short axis from baseline or nadir AND the node must be ≥1.0 cm in the short axis. 1

• Nodes that progress to ≥1.5 cm in short axis are pathologic and measurable 1, 3
• Nodes between 1.0-1.5 cm are pathologic but non-measurable, subject to clinical discretion 1, 3
• Pelvic nodal disease is locoregional, while extrapelvic nodes (retroperitoneal, mediastinal, thoracic) are classified as distant metastases (M1a disease) 3

Visceral Metastases

Use RECIST 1.1 criteria for visceral progression, but only report changes in lesions ≥1.0 cm in the longest dimension. 1

• Record changes in liver, lung, adrenal, and CNS separately 1
• Visceral metastases indicate more aggressive disease and poorer prognosis than bone-only disease 3, 2
• Common sites: liver (10.2%), lung (9.1%), adrenal glands 3, 2
• For delay/prevent endpoints: Progression must be confirmed by a second scan ≥6 weeks later, particularly important when anticipated PSA effect is delayed or for biologic therapies 1

Imaging Modalities for Progression Assessment

Conventional Imaging

Bone scintigraphy remains the standard for detecting skeletal metastases, while contrast-enhanced CT of chest/abdomen/pelvis (≤5 mm axial slices) assesses nodal and visceral disease. 1, 3

• Bone scans are rarely positive without symptoms or relatively high PSA levels (typically PSA >5 ng/mL with PSADT <10 months) 1
• CT and MRI have limited accuracy for nodal staging due to dependence on size criteria 1

Next-Generation Imaging (NGI)

PSMA PET/CT is now the preferred imaging modality when available, offering superior accuracy for detecting progression compared to conventional imaging. 1, 3

• FDA-approved PET agents for prostate cancer recurrence: 18F-fluciclovine and 11C-choline 1
• PSMA PET progression criteria: (1) appearance of 2 or more new PSMA-positive distant lesions, OR (2) 1 new PSMA-positive lesion plus consistent clinical/laboratory data with confirmation by biopsy or correlative imaging within 3 months, OR (3) increase in size or PSMA uptake of existing lesions by ≥30% plus consistent clinical/laboratory data or confirmation within 3 months 4
• PSMA PET can detect disease at much lower PSA levels (<1 ng/mL for local recurrence) compared to conventional imaging 1

When to use NGI: 1

• When conventional imaging is negative in patients with high risk of metastatic disease
• When conventional imaging is suspicious or equivocal
• When disease progression is suspected based on laboratory values, comorbidities, and symptoms 1

Clinical Progression Indicators

Clinical symptoms and laboratory parameters must be integrated with imaging findings to define true progression. 1

• Pain progression requires clinically meaningful pain at baseline (≥4 on 10-point scale) and response defined as 30% relative or 2-point absolute improvement from baseline at 12 weeks, confirmed at least 2 weeks later without increased opiate use 1
• Serial assessments of health-related quality of life, urinary/bowel compromise, and need for additional anticancer therapy should be documented 1
• Testosterone levels must be confirmed at castrate levels (<50 ng/dL) at time of progression to establish castration-resistant disease 5

Monitoring Schedule and Confirmation Requirements

Imaging intervals should be 8 weeks for metastatic CRPC trials, but 16 weeks for non-metastatic CRPC trials to better distinguish true progression from flare. 1

• Report the proportion of patients who have not progressed at fixed time intervals (6 and 12 months) 1
• For patients developing equivocal bone lesions, avoid using supplemental scanning modalities (MRI, PET) that were not used to determine study eligibility, as this introduces bias 1

Common Pitfalls to Avoid

• Do not define progression based on PSA rise alone without radiographic or clinical confirmation 1
• Do not interpret early post-treatment bone scan changes as progression without confirmation (flare phenomenon) 3, 2
• Do not use different imaging modalities for follow-up than were used at baseline 1
• Do not assume a single negative imaging study rules out metastatic disease when clinical suspicion is high 3
• Do not discontinue androgen deprivation therapy based solely on progression—castrate testosterone levels must be maintained even when disease progresses to CRPC 6