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