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Visceral Disease in Castration-resistant Prostate Cancer
European Urology, 2, 65, pages 270 - 273
Metastatic involvement of the viscera in men with advanced castration-resistant prostate cancer (CRPC) has been poorly characterised to date. In 359 CRPC patients treated between June 2003 and December 2011, the frequency of radiologically detected visceral metastases before death was 32%. Of the 92 patients with computed tomography performed within 3 mo of death, 49% had visceral metastases. Visceral metastases most commonly involved the liver (20%) and lung (13%). Median survival from diagnosis of visceral disease was 7.1 mo (95% confidence interval, 5.9–8.3). Survival was affected by the degree of bone involvement at detection of visceral disease, varying from 6.1 mo in men with more than six bone metastases to 18.2 mo in men with no bone metastases (p = 0.001). Heterogeneity was noted in clinical phenotypes and prostate-specific antigen trends at development of visceral metastases. Visceral metastases are now more commonly detected in men with CRPC, likely due to the introduction of novel survival-prolonging treatments.
Visceral disease was previously considered uncommon in men with castration-resistant prostate cancer (CRPC) and has been associated with neuroendocrine phenotypes and poor outcome  . In phase 3 postdocetaxel trials, 23–29% of participants had visceral metastases (VM) , , and . Autopsy studies on men who died of prostate cancer (PCa) suggested a higher prevalence of VM in up to 66% of selected cases  , but these metastases did not appear clinically relevant. Subset analyses of patients with visceral disease in the post-docetaxel abiraterone and enzalutamide phase 3 trials showed hazard ratios of 0.79 (0.60–1.05) and 0.78 (0.56–1.09), respectively, suggesting these patients may derive benefit from targeting the androgen receptor (AR)  and . However, the phase 3 clinical trial of abiraterone in men with chemotherapy-naïve CRPC specifically excluded men with visceral disease. With the introduction of several new survival-prolonging treatments  , we hypothesised that more patients will develop visceral involvement, requiring improved recognition and molecular characterisation to improve patient management.
To explore the prevalence of visceral disease in CRPC, we examined our database of clinical trial participants. This population has been described  , and all patients provided consent for data collection in institutional review board–approved protocols. Patients had regular computed tomography (CT) scans of the thorax, abdomen, and pelvis performed every 12 wk (unless otherwise specified in trial protocols) for restaging or investigation of new symptoms. Brain CT scans were performed in response to neurologic symptoms. Bone metastases were assessed using standard bone scans. These prospectively collected scans were reviewed for evidence of visceral involvement, defined as disease involving liver, lungs, adrenal glands, peritoneum or pleura, brain, and dura. Descriptive statistics, Kaplan-Meier survival analyses, and Cox regressions were performed using SPSS v.20 (IBM Corp, Armonk, NY, USA). Quantitative Venn diagrams were constructed using BioVenn  .
Patients (n = 442) were enrolled on clinical trials and expanded access programs from June 2003 to December 2011. Of the 359 patients who died, 115 (32%) had evidence of VM on the last scan before death. Therefore, we related the prevalence of VM to the timing of last CT scan ( Fig. 1 A). The prevalence of VM on CT scan at 9–12 mo, 6–9 mo, 3–6 mo, and within 3 mo prior to death was 14%, 22%, 32%, and 49%, respectively, suggesting that most patients developed VM late in the disease course. This could reflect the natural history of the disease or be a result of current treatments proving more effective in controlling non-VM. The prevalence of VM was not increased by exposure to either abiraterone or enzalutamide (32% of 198 patients who received those agents compared to 33% of 161 patients who did not).
Metastatic disease was present at prostate cancer diagnosis in 192 of 356 evaluable men (54%). The median intervals from cancer diagnosis or from CRPC development to development of visceral disease were 4.6 yr (range: 0–17.3 yr) and 1.6 yr (range: 0–7.7 yr), respectively. At detection of VM, most patients reported symptoms (Supplemental Table 1).
VM were associated with bone and nodal metastases in the majority of patients ( Fig. 1 B). The liver was the most common site of visceral involvement (71 patients), followed by lung (n = 47), peritoneum (n = 13), adrenal gland (n = 11), and brain/dura (n = 11). In most patients, only one site of visceral disease was identified. Patient outcome differed based on the degree of bone involvement at detection of visceral disease, with a median survival of 18.2 mo in men with no evident bone disease (n = 12; interquartile range [IQR]: 24.9; p = 0.001 vs more than six lesions); 8.1 mo in those with moderate bone involvement (fewer than six lesions; n = 18; IQR: 25.6; p = 0.049 vs six or more lesions) and 6.1 mo in those with more extensive bone involvement (six or more lesions; n = 84; IQR: 8.9) ( Fig. 1 C). These preliminary small-cohort data suggest that VM in the absence of extensive bone metastases may not represent a more aggressive disease phenotype. The association with worse outcome may instead relate to the increased prevalence of visceral disease as overall disease burden increases.
We observed heterogeneity in the clinical and biochemical behaviors at diagnosis of new visceral disease. Of the 91 patients with three prostate-specific antigen (PSA) values within the 2 mo prior to detection of visceral disease, 37 (41%) had confirmed PSA progression by Prostate Cancer Clinical Trials Working Group criteria, 53 patients had PSA stability, and one had a >50% decline in PSA level. This dissociation between PSA and radiologic progression may reflect previous analyses that failed to prove PSA as a survival surrogate  . Figure 2 shows two examples of discordant PSA kinetics at development of AR-negative VM. Studies have suggested an increasing prevalence of AR-negative disease in advanced PCa  . Such disease may be unlikely to respond to further AR-targeting therapies.
Our data suggest that metastatic PCa involves the viscera commonly, particularly in the advanced stages of disease. We show for the first time the detection of visceral disease in 49% of patients with a CT scan performed within 3 mo of death. VM in the presence of bone metastases were associated with poor survival but do not predict poor response to treatment. We believe that the presence of VM should not automatically exclude patients from trial participation. In 59% of evaluable patients, VM emerged in the absence of PSA progression. Timely identification of visceral disease provides opportunities to obtain fresh biopsy material for histologic and molecular examination. As shown by the two examples ( Fig. 2 A and 2B), biopsies at development of visceral disease, especially without PSA progression, may provide information of clinical relevance. Biopsies can be obtained safely, with low patient morbidity. The optimal choice of therapy could be informed by biopsy, although the heterogeneity within tumours, across metastases, and over time is likely to add further complexity to these analyses. If the differences in clinical characteristics are due to differences in biology, these will best be dissected by further molecular analyses and could lead to subgroup-directed treatment choices.
Author contributions: Johann S. de Bono had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Pezaro, Omlin, Mukherji, de Bono, Attard.
Acquisition of data: Pezaro, Omlin, Lorente, Nava Rodrigues, Ferraldeschi, Bianchini, Mukherji, Altavilla.
Analysis and interpretation of data: Pezaro, Omlin, Lorente, Attard.
Drafting of the manuscript: Pezaro, Omlin.
Critical revision of the manuscript for important intellectual content: Pezaro, Omlin, Lorente, Nava Rodrigues, Ferraldeschi, Bianchini, Mukherji, Riisnaes, Altavilla, Crespo, Tunariu, de Bono, Attard.
Statistical analysis: Pezaro, Omlin, Lorente.
Obtaining funding: None.
Administrative, technical, or material support: Riisnaes, Crespo, Tunariu.
Supervision: de Bono, Attard.
Other (specify): None.
Financial disclosures: Johann S. de Bono certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/ affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: The authors are employees of the Section of Medicine of the Royal Marsden National Health Service (NHS) Foundation Trust that is supported by a Cancer Research UK program grant and an Experimental Cancer Medical Centre (ECMC) grant from Cancer Research UK and the Department of Health (Ref: C51/A7401). A. Omlin is a recipient of a 2-yr bursary from the Swiss Cancer League (No. BIL KLS-02592-02-2010). R. Ferraldeschi is funded by the Wellcome Trust (Ref: 094413/Z/10/Z). G. Attard is supported by a Cancer Research UK clinician scientist fellowship. The authors acknowledge NHS funding of the Royal Marsden NIHR Biomedical Research Centre.
Funding/Support and role of the sponsor: None.
The authors thank Ulrike Naumann in the Cancer Biomarkers Group, Institute of Cancer Research, for statistical support.
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Prostate Cancer Targeted Therapy Group and Drug Development Unit, The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, Sutton, Surrey, UK
Corresponding author. Prostate Cancer Targeted Therapy Group, Royal Marsden NHS Foundation Trust, Section of Medicine, The Institute of Cancer Research, Downs Road, Sutton, Surrey SM2 5PT, UK. Tel. +44 2087224029.
† These authors contributed equally as first authors.
‡ Cosenior authors.
© 2013 European Association of Urology, Published by Elsevier B.V.