Monitoring ovarian cancer patients during chemotherapy and follow-up with the serum tumor marker CA125.

Cancer antigen 125 (CA125) is frequently used in the routine monitoring of patients with epithelial ovarian cancer (EOC). The potential benefit is based on the assumption that changes in serial concentrations may provide early and reliable information on tumor growth expediting an early and potentially effective treatment. However, it has remained a challenge to interpret increments in concentrations that correlate with increasing tumor burden in the individual patient. It has been hypothesized that CA125 assessment criteria taking the random variation (analytical and biological) into account may have better accuracy and lead-time potential than criteria based only on an arbitrary percentage of increase.
 The aims of the current PhD project were to i) identify different types of assessment criteria intended to interpret CA125 increments, ii) compare their ability to signal tumor growth, and iii) estimate the time interval between marker progression and clinical progression (lead-time). 
Study 1 was a systematic review of the literature identifying 21 relevant original articles reporting on 37 different assessment criteria to interpret serial CA125 concentrations. Study 2 was a preclinical phase I trial investigating the monitoring potential of seven selected criteria in a computer-based simulation model under standardized conditions. Study 3 was a clinical phase II trial comparing the performances of the seven criteria among 189 patients with EOC stage IC-IV during first-line chemotherapy and the subsequent follow-up period.
 Study 1 reported that the median sensitivity of the investigated criteria for recurrence was 57% (range 33%-95%) during primary therapy and 85% (range 62%-93%) during follow-up. The calculated false positive (FP) and false negative (FN) rates, respectively, were in median 1% (range 0%-13%) and 44% (range 5%-67%) during primary therapy and 9% (range 0%-33%) and 15% (range 7%-38%) during follow-up. Most of the reports were heterogeneous in terms of study design and format of presentation. Study 2 reported that for increments starting from baseline concentrations ≥cut-off, the best performing criterion in terms of low number of FP signals was based on a confirmed increment ≥2.5 times the nadir concentration. For increments starting from baseline concentrations ≤cut-off, the best performing criterion, also in terms of low number of FP signals, was based on a confirmed increment from ≤cut-off to >2 times the cut-off. Accordingly, the best performing criteria in terms of low number of FP events were based on an arbitrary required percentage of change without defining the random variation. Study 3 reported that the accuracy of the seven criteria observed during first-line chemotherapy and follow-up among all histological tumor types and serous tumors only was similar with overlapping 95% confidence intervals. The sensitivities for detecting CA125 increments ranged from 30% to 55%. The FP rates ranged from 0% to 17%; however, the FN rates ranged from 45% to 70%. The median lead-times ranged from 26 days to 87 days. The performances of the CA125 assessment criteria showed low sensitivities and low ability to exclude tumor growth. The chance of developing clinical progression following CA125 progression was high (range of positive predictive value 90%-100%); however, the lead-times were short among several patients. Thus, study 3 questioned the clinical utility of CA125 monitoring. 
Overall, the PhD study showed, that the different CA125 assessment criteria basically provided similar results thus rejecting the hypothesis that criteria based on calculating the random variation would outperform criteria based on a simple percentage of change. The simulated data proved useful for a preclinical evaluation of CA125 assessment criteria. The results suggested that regardless of the approach, fine-tuning of the assessment criteria did not seem to improve the monitoring performance of CA125 probably indicating that CA125 used as a tumor marker for monitoring has inherent limitations in terms of accuracy. Supplementary markers and alternative assessment criteria are needed.