– Evaluation of prostate-specific antigen (PSA) progression criteria. The figure summarises replies for Question 12. Participants were shown three different PSA biomarker scenarios for patients with bone-only disease. The percentage of participants who believed the scenario corresponded to PSA progression is shown in the pie charts. Correct response: (A) No; (B) Yes; (C) Yes.  

– Evaluation of prostate-specific antigen (PSA) progression criteria. The figure summarises replies for Question 12. Participants were shown three different PSA biomarker scenarios for patients with bone-only disease. The percentage of participants who believed the scenario corresponded to PSA progression is shown in the pie charts. Correct response: (A) No; (B) Yes; (C) Yes.  

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Background: Evaluation of responses to treatment for metastatic castration-resistant prostate cancer (mCRPC) remains challenging. Consensus criteria based on prostate-specific antigen (PSA) and clinical and radiologic biomarkers are inconsistently utilized. Circulating tumor cell (CTC) counts can inform prognosis and response, but are not routinel...

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... was a useful/very useful biomarker for monitoring response to treatment (Table 2). We asked participants to identify PSA progression in graphical examples showing consecutive PSA values to evaluate their ability to utilize PCWG2 criteria. Only 41.4% of physicians correctly recognised that at least 12 wk are required to define PSA progression ( Fig. 2A). Most physicians (84.8%) correctly identified that a 25% increase from the nadir value (confirmed by a second value at least 3 wk later) constituted progression ( Fig. 2B). Some 90.9% failed to recognise that PSA progression holds even if the confirmatory second value is lower than the first, providing both values show a 25% increase ...
Context 2
... PSA values to evaluate their ability to utilize PCWG2 criteria. Only 41.4% of physicians correctly recognised that at least 12 wk are required to define PSA progression ( Fig. 2A). Most physicians (84.8%) correctly identified that a 25% increase from the nadir value (confirmed by a second value at least 3 wk later) constituted progression ( Fig. 2B). Some 90.9% failed to recognise that PSA progression holds even if the confirmatory second value is lower than the first, providing both values show a 25% increase from the nadir (Fig. 2C). Only two physicians (2.0%) answered all three questions ...
Context 3
... physicians (84.8%) correctly identified that a 25% increase from the nadir value (confirmed by a second value at least 3 wk later) constituted progression ( Fig. 2B). Some 90.9% failed to recognise that PSA progression holds even if the confirmatory second value is lower than the first, providing both values show a 25% increase from the nadir (Fig. 2C). Only two physicians (2.0%) answered all three questions ...

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... The treatment landscape for metastatic castration-resistant prostate cancer (mCRPC) has rapidly evolved in recent years. Although several drugs have demonstrated an improvement in overall survival (OS) in this setting [1], the optimal treatment sequence has not been established. The development of early treatment response biomarkers is urgently needed to avoid unnecessary exposure to ineffective therapy with undesirable toxicities and to accelerate the process of drug development. ...
... Although the prognostic significance of PSA as an early biomarker has been consistently reported in patients treated with androgen-receptor signaling inhibitors (ARSIS) [5][6][7][8][9][10], evidence to support the PSA measure as a surrogate for OS is lacking. Due to these and other limitations, many physicians continue to rely on clinical progression to make the decision to switch therapy in these patients [1]. ...
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Simple Summary The prognostic role of CTC enumeration in mCRPC patients has been established in several studies, demonstrating a higher prognostic performance than post-treatment changes in PSA levels in patients treated with AR signaling inhibitors, but not taxanes. We carried out a pooled analysis of two prospective studies in mCRPC patients treated with docetaxel. The results of this study showed a greater ability of early changes in circulating tumor cells (CTCs) compared to PSA response endpoints to predict overall survival in metastatic castration-resistant prostate cancer (mCRPC) patients treated with docetaxel. These results encourage the clinical usefulness of CTC enumeration to determine the outcome of mCRPC patients. Abstract Circulating tumor cell (CTC) enumeration and changes following treatment have been demonstrated to be superior to PSA response in determining mCRPC outcome in patients receiving AR signaling inhibitors but not taxanes. We carried out a pooled analysis of two prospective studies in mCRPC patients treated with docetaxel. CTCs were measured at baseline and 3–6 weeks post treatment initiation. Cox regression models were constructed to compare 6-month radiographical progression-free survival (rPFS), CTCs and PSA changes predicting outcome. Among the subjects, 80 and 52 patients had evaluable baseline and post-treatment CTC counts, respectively. A significant association of higher baseline CTC count with worse overall survival (OS), PFS and time to PSA progression (TTPP) was observed. While CTC response at 3–6 weeks (CTC conversion (from ≥5 to <5 CTCs), CTC30 (≥30% decline in CTC) or CTC0 (decline to 0 CTC)) and 6-month rPFS were significantly associated with OS (all p < 0.005), the association was not significant for PSA30 or PSA50 response. CTC and PSA response were discordant in over 50% of cases, with outcome driven by CTC response in these patients. The c-index values for OS were superior for early CTC changes compared to PSA response endpoints, and similar to 6-month rPFS. Early CTC declines were good predictors of improved outcomes in mCRPC patients treated with docetaxel in this small study, offering a superior and/or earlier estimation of docetaxel benefit in comparison to PSA or rPFS that merits further confirmation in larger studies.
... Given the number of new agents approved by the FDA in mCRPC setting, identification of early or primary resistance to the treatment is of great value on clinical practice, allowing us to consider an early switch to the next agent and preventing unnecessary treatment that does not benefit for the patient outcome, as well as treatment-related toxicities. However, a recent report that inquired decision-making of clinical management for physicians treating mCRPC had revealed that, despite being considered an important bio-marker, 41.4% of the interviewed physicians disregard PSA changes before 12 weeks of the treatment, whereas the majority of physicians (90.5%) switched treatment based only on clinical progression [33]. This implies that the appropriate timing of next-line treatment is still controversial for mCRPC patients. ...
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Simple Summary Serum prostate-specific antigen (PSA) level is the most valuable biomarker in prostate cancer. This study investigates the predictive value of achieving >30% PSA decline at four weeks of first-line androgen signaling inhibitors (ASIs) using a multi-institutional cohort dataset of 254 mCRPC patients. The achievement of >30% PSA decline at four weeks is an independent predictor for overall survival (OS). Interestingly, in patients who did not achieve >30% PSA decline at four weeks—an achievement of the >30% PSA decline at 12 weeks is eventually observed in 30.9% of those patients. To identify the variables that discriminate the patient survival in 97 patients without achieving >30% PSA decline at four weeks of the first-line treatment, a multivariate analysis is conducted. The duration of androgen deprivation therapy before CRPC < 12 months and Eastern Cooperative Oncology Group Performance Status ≥ 1 are identified as independent predictors for shorter OS for those patients. Abstract The identification of early or primary resistance to androgen signaling inhibitors (ASIs) is of great value for the treatment of metastatic castration-resistant prostate cancer (mCRPC). This study evaluates the predictive value of prostate-specific antigen (PSA) response at dour weeks of first-line ASIs treatment for mCRPC patients. A total of 254 patients treated with ASIs (abiraterone acetate: AA and enzalutamide: Enz) at the first-line treatment are retrospectively analyzed. Patients are stratified according to the achievement of >30% PSA decline at 4 and 12 weeks from the treatment initiation. At four weeks of the treatment, 157 patients (61.8%) achieved >30% PSA decline from the baseline. Thereafter, 177 patients (69.7%) achieved >30% PSA decline at 12 weeks of the treatment. A multivariate analysis exhibits >30% PSA decline at four weeks as an independent predictor for overall survival (OS). We note that 30 of 97 (30.9%) patients who did not achieve >30% PSA decline at four weeks consequently achieved >30% PSA decline at 12 weeks, and had a comparable favorable three years OS rate as the 147 patients achieving >30% PSA decline at both 4 and 12 weeks. To identify the variables that discriminate the patient survival in 97 patients without achieving >30% PSA decline at four weeks, a multivariate analysis is performed. The duration of androgen deprivation therapy before CRPC ≤ 12 months and Eastern Cooperative Oncology Group Performance Status ≥ 1 are identified as independent predictors for shorter OS for those patients. These data offer a concept of early treatment switch after four weeks of first-line ASIs when not observing >30% PSA decline at four weeks—particularly in patients with a modest effect of ADT and poor performance status.
... The type of disease progression-serologic alone, radiographic or clinical-has been shown to impact the choice of subsequent therapy in clinical practice. 5 The clinicopathological factors associated with such clinical progression and the relationship between the occurrence of clinical progression and overall survival has not been well studied. COU-AA-302 was a phase 3, randomised, double-blind, multinational registration clinical trial in which asymptomatic or mildly symptomatic patients with progressive chemotherapy-naïve mCRPC were randomised to receive abiraterone acetate 1000 mg daily plus prednisone 5 mg two times per day (AAP group) or placebo plus prednisone 5 mg two times per day (prednisone group). ...
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Objectives Unequivocal clinical progression (UCP)—a worsening of clinical status with or without radiographic progression (RAD)—represents a distinct mode of disease progression in metastatic prostate cancer. We evaluated the prevalence, risk factors and the impact of UCP on survival outcomes. Methods A post-hoc analysis of the COU-AA-302, a randomised phase 3 study of abiraterone plus prednisone (AAP) versus prednisone was performed. Baseline characteristics were summarised. Cox proportional-hazards model and Kaplan-Meier method were used for survival and time to event analyses, respectively. Iterative multiple imputation method was used for correlation between clinicoradiographic progression-free survival (crPFS) and overall survival (OS). Results Of 736 patients with disease progression, 280 (38%) had UCP-only and 124 (17%) had UCP plus RAD. Prognostic index model high-risk group was associated with increased likelihood of UCP (p<0.0001). Median OS was 25.7 months in UCP-only and 33.0 months for RAD-only (HR 1.39; 95% CI 1.16 to 1.66; p=0.0003). UCP adversely impacted OS in both treatment groups. Lowest OS was seen in patients with prostate specific antigen (PSA)-non-response plus UCP-only progression (median OS 22.6 months (95% CI 20.7 to 24.4)). Including UCP events lowered estimates of treatment benefit—median crPFS was 13.3 months (95% CI 11.1 to 13.8) versus median rPFS of 16.5 months (95% CI 13.8 to 16.8) in AAP group. Finally, crPFS showed high correlation with OS (r=0.67; 95% CI 0.63 to 0.71). Conclusions UCP is a common and clinically relevant phenomenon in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with AAP or prednisone. UCP is prognostic and associated with inferior OS and post-progression survival. A combination of PSA-non-response and UCP identifies patients with poorest survival. When included in PFS analysis, UCP diminishes estimates of treatment benefit. Continued study of UCP in mCRPC is warranted.
... 6,34 The ability to predict the efficacy of AA at an early time point can be crucial in patient management, since this allows a prompt change in treatment strategy, preventing clinical deterioration which can hinder the administration of subsequent therapies. At present, the majority of physicians switch therapy based on clinical progression, 35 and while the absence of early PSA response may not in itself be a sufficient rationale for changing therapy, it will help identify those patients who require closer monitoring. ...
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Background Abiraterone acetate (AA) is widely used in the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC). However, a significant percentage of patients will still progress, highlighting the need to identify patients more likely to benefit from AA. Parameters linked to prostate-specific antigen (PSA) kinetics are promising prognostic markers. We have examined clinical and PSA-related factors potentially associated with overall survival (OS) in patients treated with AA. Methods Between 2011 and 2014, 104 patients with mCRPC treated with AA after progression to docetaxel at centers of the Catalan Institute of Oncology were included in this retrospective study. Patients were assessed monthly. Baseline characteristics and variables related to PSA kinetics were included in univariate and multivariate analyses of OS. Results Median OS was 16.4 months (range 12.4–20.6) for all patients. The univariate analysis identified the following baseline characteristics as significantly associated with OS: ECOG PS, location of metastases, time between starting androgen deprivation therapy and starting AA, time between stopping docetaxel treatment and starting AA, neutrophil-lymphocyte ratio (NLR), alkaline phosphatase levels, and PSA levels. Factors related to PSA kinetics associated with longer OS were PSA response >50%, early PSA response (>30% decline at four weeks), PSA decline >50% at week 12, PSA nadir <2.4ng/mL, time to PSA nadir >140 days, the combination of PSA nadir and time to PSA nadir, and low end-of-treatment PSA levels. The multivariate analysis identified ECOG PS (HR 37.46; p<0.001), NLR (HR 3.7; p<0.001), early PSA response (HR 1.22; p=0.002), and time to PSA nadir (HR 0.39; p=0.002) as independent prognostic markers. Conclusion Our results indicate an association between PSA kinetics, especially early PSA response, and outcome to AA after progression to docetaxel. Taken together with other factors, lack of an early PSA response could identify patients who are unlikely to benefit from AA and who could be closely monitored with a view to offering alternative therapies.
... Circulating tumor cells (CTCs) and large (> 1 μm) tumor-derived extracellular vesicles (tdEVs) measured with the CellSearch are both associated with poor survival of metastatic castration-resistant prostate cancer (mCRPC) patients [1][2][3][4]. Furthermore, changes in concentrations of CTCs and tdEVs after initiation of therapy can be used to monitor treatment response. ...
Article
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Large (> 1 μm) tumor-derived extracellular vesicles (tdEVs) enriched from the cell fraction of centrifuged whole blood are prognostic in metastatic castration-resistant prostate cancer (mCRPC) patients. However, the highest concentration of tdEVs is expected in the cell-free plasma fraction. In this pilot study, we determine whether mCRPC patients can be discriminated from healthy controls based on detection of tdEVs (< 1μm, EpCAM⁺) and/or other EVs, in cell-free plasma and/or urine. The presence of marker+ EVs in plasma and urine samples from mCRPC patients (n = 5) and healthy controls (n = 5) was determined by flow cytometry (FCM) and surface plasmon resonance imaging (SPRi) using an antibody panel and lactadherin. For FCM, the concentrations of marker positive (⁺) particles and EVs (refractive index <1.42) were determined. Only the lactadherin⁺ particle and EV concentration in plasma measured by FCM differed significantly between patients and controls (p = 0.017). All other markers did not result in signals exceeding the background on both FCM and SPRi, or did not differ significantly between patients and controls. In conclusion, no difference was found between patients and controls based on the detection of tdEVs. For FCM, the measured sample volumes are too small to detect tdEVs. For SPRi, the concentration of tdEVs is probably too low to be detected. Thus, to detect tdEVs in cell-free plasma and/or urine, EV enrichment and/or concentration is required. Furthermore, we recommend testing other markers and/or a combination of markers to discriminate mCRPC patients from healthy controls.
... Rapid treatment discontinuation in patients showing inherent resistance to a drug may have decisive implications for the clinical outcome to the following treatments (19). In a recent study inquiring about specialists9 experience in treating mCRPC outside clinical trials, it was reported that 41.4% of the interviewed physicians disregarded changes in PSA before 12 wk of treatment, making decisions about treatment discontinuation based only on clinical progression (20). Traditionally, an evaluation of PSA changes earlier than 12 wk of treatment has been discouraged (12), since flare reactions have been described in greater than or equal to 20% of patients treated with taxanes (13,21). ...
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Background: Prostate-specific antigen (PSA) is widely used to monitor treatment response in patients with metastatic castration-resistant prostate cancer (mCRPC). However, PSA measurements are considered only after 12 wk of treatment. We aimed to evaluate the prognostic value of early PSA changes following 177Lu-labelled prostate specific membrane antigen (LuPSMA) radionuclide treatment in mCRPC patients. Methods: Men who were treated under a compassionate access program with LuPSMA at our institution and had available PSA values at baseline, at 6 wk after treatment initiation were included in this retrospective analysis. Patients were assigned to three groups based on PSA changes: 1) response: ≥30% decline, 2) progression: ≥25% increase and 3) stable: <30% decline and <25% increase. The co-primary endpoints were overall survival and imaging-based progression-free survival. The secondary end points were PSA changes at 12 wk and PSA flare-up. Results: We identified 124 eligible patients with PSA values at 6 wk. A ≥30% decline in PSA at 6 wk was associated with longer overall survival (median 16.7 mo; 95%CI 14.4-19.0) compared with patients with stable PSA (median: 11.8 mo; 95%CI 8.6-15.1; P = 0.007) and progression (median: 6.5 mo; 95%CI 5.2-7.8; p<0.001). Patients with ≥30% decline in PSA at 6 wk also had a reduced risk of imaging-based progression compared with patients with stable PSA (HR: 0.60; 95%CI 0.38-0.94; P = 0.02), while patients with PSA progression had a higher risk of imaging-based progression compared with those showing stable PSA (HR: 3.18; 95%CI 1.95-5.21; p<0.001). The percentage changes of PSA at 6 wk and 12 wk were highly associated (r=0.90; p<0.001). 29 of 31 (94%) patients who experienced early PSA progression at 6 wk achieved biochemical progression at 12 wk. Overall, only 1 of 36 (3%) patients with PSA progression at 6 wk achieved any PSA decline at 12 wk (1% of the entire cohort). Limitations of the study included its retrospective nature and the single center experience. Conclusion: PSA changes at 6 wk after LuPSMA initiation are an early indicator of long-term clinical outcome. Patients progressing by PSA after 6 wk of treatment could benefit from a very early treatment switch decision. PSA flare-up during LuPSMA treatment is very uncommon. Prospective studies are now warranted to validate our findings and potentially inform clinicians earlier on the effectiveness of LuPSMA.
... The results at 12wk time point were similar, with a !30% PSA decline associated with longer OS (median: 22 mo; 95% CI: 19-24; HR: 0.71, 95% CI: 0.50-1.02, p < 0.001) compared with patients with no change (median: 16 mo; 95% CI: [12][13][14][15][16][17][18] and progression (median: 11 mo; 95% CI: 8-13; Fig. 2). When abiraterone and enzalutamide groups were considered separately, there was no evidence that the association between OS and PSA falls differed by first-line treatment. ...
... On the contrary, in the metastatic setting, consensus criteria based on PSA and radiologic biomarkers are inconsistently utilised. A recent study inquiring into clinical management decisions of physicians in mCRPC has shown that despite being considered an important biomarker, 41.4% of the interviewed population disregarded changes in PSA before 12 wk of treatment had elapsed, while the majority of physicians (90.5%) switched treatment based only on clinical progression [15]. A PSA decline by !30% after 12 wk of treatment start has been associated with OS in mCRPC [4][5][6]; more recently, PSA ...
Article
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Background: Declines in prostate-specific antigen (PSA) levels at 12wk are used to evaluate treatment response in metastatic castration-resistant prostate cancer (mCRPC). PSA fall by ≥30% at 4wk (PSA4w30) has been reported to be associated with better outcome in a single-centre cohort study. Objective: To evaluate clinical relevance of early PSA decline in mCRPC patients treated with next-generation hormonal treatments (NGHTs) such as abiraterone and enzalutamide. Design, setting, and participants: This was a retrospective multicentre analysis. Eligible patients received NGHT for mCRPC between 6 January 2006 and 31 December 2017 in 13 cancer centres worldwide, and had PSA levels assessed at baseline and at 4 and/or 12wk after treatment. PSA response was defined as a ≥30% decline (progression as a ≥25% increase) from baseline. Outcome measurements and statistical analysis: Association with overall survival (OS) was analysed using landmark multivariable Cox regression adjusting for previous chemotherapy, including cancer centre as a shared frailty term. Results and limitations: We identified 1358 mCRPC patients treated with first-line NGHT (1133 had PSA available at 4wk, and 948 at both 4 and 12wk). Overall, 583 (52%) had a PSA4w30; it was associated with longer OS (median: 23; 95% confidence interval [CI]: 21-25) compared with no change (median: 17; 95% CI: 15-18) and progression (median: 13; 95% CI: 10-15). A PSA12w30 was associated with lower mortality (median OS 22 vs 14; hazard ratio=0.57; 95% CI=0.48-0.67; p<0.001). PSA4w30 strongly correlated with PSA12w30 (ρ=0.91; 95% CI=0.90-0.92; p<0.001). In total, 432/494 (87%) with a PSA4w30 achieved a PSA12w30. Overall, 11/152 (7%) patients progressing at 4wk had a PSA12w30 (1% of the overall population). Conclusions: PSA changes in the first 4wk of NGHT therapies are strongly associated with clinical outcome from mCRPC and can help guide early treatment switch decisions. Patient summary: Prostate-specific antigen changes at 4wk after abiraterone/enzalutamide treatment are important to determine patients' outcome and should be taken into consideration in clinical practice.
... However, despite increasing evidence that CTCs could be used to monitor disease progression in mCRPC [18], CTC use is still limited to clinical trials in academic centers. Clinical utility of CTCs, reflecting the ability of this test to favorably change outcomes, is still an unmet clinical need in prostate cancer [74]. The first interventional clinical trial in prostate cancer that will show the clinical utility of CTCs should start in 2019 (TACTIK project-NCT03101046). ...
... It is common practice to change mCRPC treatment if there are signs of progressive disease and in EXTREQOL 54% of patients had switched to next line therapies. According to a recent survey of 118 prostate cancer specialists, most clinicians favour clinical progression over prostate-specific antigen or imaging to drive treatment switch decisions [28]. Another recent survey of 109 specialists showed that treatment decisions are also influenced by whether patients live alone [16]. ...
Article
Aims: Delaying progression, ameliorating symptoms and maintaining quality of life (QoL) are primary aims of treatment for metastatic castrate-resistant prostate cancer (mCRPC). Real-world rather than clinical trial data about symptoms and side-effects are sparse. In EXTREQOL, patients' QoL, pain and information needs were recorded during treatment. Material and methods: Men with mCRPC from 20 UK cancer centres starting various systemic mCRPC treatments completed QoL, pain and information needs questionnaires at baseline, 3 and 6 months. Results: In total, 132 patients were recruited. Overall QoL declined significantly by 6 months (Functional Assessment of Cancer Therapy-Prostate [FACT-P] mean = -3.89, 95% confidence interval -6.7 to -1.05, P = 0.007; Trial Outcome Index [TOI] analysis mean = -3.10, 95% confidence interval -5.34 to -0.83, P = 0.007). Those who came off novel therapy and remained on luteinising hormone-releasing hormone agonist therapy alone had worse scores than patients receiving concomitant chemotherapy (Prostate Concerns Subscale mean difference = -4.45, 95% confidence interval -7.06 to -1.83, P = 0.001; TOI mean difference = -5.62, 95% confidence interval -10.97 to -0.26, P = 0.040). At 3 and 6 months, men who reported pain at baseline improved (43%, 40%), but for others pain levels remained the same (45%, 42%) or worsened (13%, 18%). Information regarding supportive care was lacking throughout the period of time on the study. Conclusion: Most mCRPC treated patients experience reduced QoL and inadequate pain control. More help with pain management and better information provision regarding supportive care is warranted.
... The following list presents all peer-review published papers under the CTC-Trap project, which contains reviews about CTC, the CellSearch or DLA 1-6 , experimental papers describing isolation of CTC, CTC in a clinical context or CTC in mouse models [7][8][9][10][11][12][13][14][15][16][17][18] and methodology papers presenting the value of CTC in health economics or personalized medicine [19][20][21][22] . ...
Chapter
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My dissertation “Circulating Tumor Cells and Beyond” (doi: 10.3990/1.9789036545662) was written during the project Circulating Tumor Cells TheRapeutic APheresis: a novel biotechnology enabling personalized therapy for all cancer patients, or CTC-Trap in short. In this chapter, I describe the objectives and results after the finalization of this European project, funded by the FP7-HEALTH-2012-INNOVATION (grant #305341). This project of collaboration between 11 universities, research institutions and small & medium-sized enterprises. This consortium shared the common effort to use the therapeutic apheresis to collect circulating tumor cells from peripheral blood in cancer patients.