A total of 276 patients were enrolled on IMMC38, of whom 164 were about to begin first-line chemotherapy. Of these 164 patients, 8 did not have evaluable baseline blood draws. The baseline characteristics of this first-line chemotherapy group are presented in . 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 had died, with a median survival of 19 months (95% confidence interval [CI] 14 to 23 months). The median follow-up for the 51 patients still alive was 22 months (range, 0.03 to 33 months). The Kaplan-Meier estimate of survival is provided in .
Characteristics of the 164 patients receiving first-line chemotherapy
Overall survival of 1st line patients
The distribution of CTC counts at baseline is detailed . The median and interquartile range of CTC number based on pattern of spread are shown in . The median CTC number was higher for patients with bone disease than for patients with visceral spread, although this difference did not reach statistical significance (p=0.06).
Circulating tumor cell numbers at baseline and after initiation of first-line chemotherapy
Baseline CTC number by metastatic site
also shows the distribution of CTC counts at 4, 8, and 12 weeks posttherapy. The number of patients assessed at these time points was similar. At baseline, the proportion of patients with CTC counts in the range of 0 to 4 was 46%, (71/156) which increased to 63% (100/158), 69% (107/156), and 69% (107/154) at 4, 8, and 12 weeks respectively. Overall, the proportion of patients with CTC counts of 4 or less at baseline, 4, and 8 weeks showed no further change at 12 weeks.
shows the association between each biomarker and survival. At baseline, high LDH, CTC number, and PSA were associated with increased risk of death. Low albumin and low hemoglobin were also associated with death, while the Gleason score at diagnosis was not. Relative to baseline, the fold change after treatment in CTC number remained a strong indicator for the risk of death, whereas the association between the fold change in PSA and survival was attenuated.
Association of individual biomarkers with the risk of death.
shows the estimated median survival time based on CTC number, PSA, and LDH before the start of therapy. Estimated median survival monotonically decreased with increasing baseline CTC number, although patients with low baseline CTC number had a range of survival times. The pattern for PSA was similar although the relationship was not as strong, while the pattern for LDH showed a sharper decline in median survival for LDH values above the normal range. The larger hazard ratio for LDH is indicative of this sharp decline.
Estimated median survival time based on CTC number, PSA, and LDH
Landmark analyses were performed for the postbaseline models (). At each time point, only CTCs and the baseline LDH value were jointly informative for survival; after accounting for CTCs at the specific time point and LDH at baseline, PSA either at baseline or after treatment, baseline albumin, and baseline hemoglobin did not provide additional information on risk of death. Individually, the baseline values of CTC and LDH were superior in identifying patient risk (CPE=0.69) in comparison to the baseline PSA value (CPE=0.59) (). The combination of baseline CTC, baseline LDH, and CTC fold change at each follow-up interval (CPE=0.74, 0.75) produced the strongest discriminatory power. A CPE equal to 0.75 indicates that for a pair of patients, the odds that the patient with a lower risk of death as indicated by CTC and LDH will live longer, is three to one. The posttreatment CTC models also produced a CPE approximately equal to 0.75.
Cox models for prognostic factors associated with survival time.
Concordance Probability Estimates (CPE) to assess the strength of prognostic factors to discriminate patient risk.
In addition to assessing the prognostic value of the biomarkers, we also examined their utility as intermediate endpoints for a clinical trial. To this end, we measured the association between the time to biomarker progression, defined as either a single rise or two increases in the biomarker over time. Because we had longitudinal data on only the CTCs and PSA, these were the markers analyzed. The association between biomarker progression and survival, both time-to-event variables, was measured by Kendall’s tau and adjusted for possible censoring in both variables. This measure of association varies between −1 and 1, with 1 representing perfect concordance between the two endpoints and −1 representing perfect discordance between them; a measure of zero represents no relationship between the two variables. The results showed a lack of association between the time to a single rise in PSA and survival (τ =0.07; 95% CI −0.04, 0.19) and a modest association between the time to a second PSA increase and survival time (τ =0.21; 95% CI 0.07, 0.33). In contrast, a single rise in CTCs was moderately associated with survival time (τ =0.30; 95% CI 0.18, 0.42), and waiting for the second increase in CTCs gave little benefit (τ =0.33; 95% CI 0.19, 0.46). Thus, from these data, CTCs are a more robust measure of progression than PSA.