Elsevier

The Lancet Oncology

Volume 10, Issue 3, March 2009, Pages 233-239
The Lancet Oncology

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Circulating tumour cells as prognostic markers in progressive, castration-resistant prostate cancer: a reanalysis of IMMC38 trial data

https://doi.org/10.1016/S1470-2045(08)70340-1Get rights and content

Summary

Background

Intermediate or surrogate endpoints for survival can shorten time lines for drug approval. We aimed to assess circulating tumour cell (CTC) count as a prognostic factor for survival in patients with progressive, metastatic, castration-resistant prostate cancer receiving first-line chemotherapy.

Methods

We identified patients with progressive metastatic castration-resistant prostate cancer starting first-line chemotherapy in the IMMC38 trial. CTCs were isolated by immunomagnetic capture from blood samples at baseline and after treatment. Baseline variables, including CTC count, titre of prostate-specific antigen (PSA), and concentration of lactate dehydrogenase (LDH), and post-treatment variables (change in CTCs and PSA) were tested for association with survival with Cox proportional hazards models. Concordance probability estimates were used to gauge discriminatory strength of the informative factors in identifying patients at low-risk and high-risk of survival.

Findings

Variables associated with high risk of death were high LDH concentration (hazard ratio 6·44, 95% CI 4·24–9·79), high CTC count (1·58, 1·41–1·77), and high PSA titre (1·26, 1·10–1·45), low albumin (0·10, 0·03–0·39), and low haemoglobin (0·72, 0·64–0·81) at baseline. At 4 weeks, 8 weeks, and 12 weeks after treatment, changes in CTC number were strongly associated with risk, whereas changes in PSA titre were weakly or not associated (p>0·04). The most predictive factors for survival were LDH concentration and CTC counts (concordance probability estimate 0·72–0·75).

Interpretation

CTC number, analysed as a continuous variable, can be used to monitor disease status and might be useful as an intermediate endpoint of survival in clinical trials. Prospective recording of CTC number as an intermediate endpoint of survival in randomised clinical trials is warranted.

Funding

The Prostate Cancer Foundation, Immunicon Corporation, Memorial Sloan-Kettering Cancer Center.

Introduction

In clinical trials and practice, outcome measures are designed to assess disease activity so that the effects of an intervention can be assessed accurately. In the monitoring of patients with metastatic, castration-resistant prostate cancer, bone scans are insensitive to changes in disease status;1 and, although change in titre of prostate-specific antigen (PSA) is used to guide treatment decisions, it cannot be used as a surrogate for clinical benefit.2 Trials in metastatic breast, colorectal, and prostate cancer showed that patients about to start new lines of chemotherapy could be divided into groups with favourable and unfavourable prognosis on the basis of the number of circulating tumour cells (CTCs) measured with the analytically valid CellSearch system (Veridex, Raritan, NJ, USA).3, 4, 5 The US Food and Drug Administration (FDA) cleared the CTC counts to be used in conjunction with other clinical methods as an aid in the monitoring of patients with these diseases.6

In the IMMC38 trial, the groups were defined in the protocol as four CTCs or fewer per 7·5 mL blood for the favourable group and five cells or more per 7·5 mL blood for the unfavourable group. This trial enrolled patients with castration-resistant prostate cancer who were about to begin a new first-line, second-line, or third-line chemotherapy regimen.5 In a separate group of patients with the same disease treated at Memorial Sloan-Kettering Cancer Center, we also showed an association between baseline CTC number and survival, but the association did not have a threshold effect;7 a third study suggested that a 30% decline in CTC number was most predictive of longer survival.8 In all three series, the discriminatory power for risk was increased by accounting for known pretreatment prognostic factors.2, 7, 8, 9, 10, 11, 12, 13

Use of discrete cutoff values in clinical practice suggests that a patient with a 90% decline in CTC number from 100 to ten cells is worse off than a patient with a 33% decline from six to four, and that therapy should be discontinued in the patient with a post-treatment value that remains in the unfavourable range, independent of whether or not the value has declined from the pretreatment baseline. We reanalysed the IMMC38 data, taking into account baseline and post-treatment CTC number as a continuous variable. The analysis assessed the contribution of other pretreatment prognostic factors and outcome and addressed the inherent survival difference between patients receiving first-line, second-line, and third-line chemotherapy14 by only including patients about to receive first-line therapy. Median follow-up was 6 months longer than that in the original report.5 We investigated the association of different CTC and PSA progression definitions and survival on the basis of either one or two rising values to further assess its use in both clinical practice and as a potential intermediate endpoint for clinical trials.

Section snippets

Patients and procedures

Patients in IMMC38 who had histologically confirmed progressive metastatic prostate cancer (as defined in the PSA Working Group criteria)15 and concentrations of testosterone after medical or surgical castration of less than 1·7 nmol/L (50 ng/dL) and who were starting first-line chemotherapy were screened.5 Eligibility requirements included an Eastern Cooperative Oncology Group performance status of 0, 1, or 2, a pretreatment PSA titre of 5 ng/mL or more, progression after a trial of

Results

276 patients were enrolled in IMMC38, of whom 164 were about to begin first-line chemotherapy. Of these 164 patients, eight did not have evaluable baseline blood draws. Table 1 shows the baseline characteristics of this first-line chemotherapy group. For 147 patients (90%), the ECOG performance status was 0 or 1. The first-line chemotherapy was docetaxel or a docetaxel-containing regimen (consistent with the established standard of care). At the time of analysis 103 (61%) of the 164 patients

Discussion

CTC count as a continuous variable is prognostic for survival of patients with castration-resistant prostate cancer who are starting first-line chemotherapy. As univariate measures, both indicators of disease burden (high LDH concentration, CTC count, and PSA titre) and the constitutional status (low albumin and haemoglobin concentrations) were predictive of short survival. The models that best predicted survival were those incorporating only baseline LDH concentrations and CTC counts and

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