More than 1 million individuals worldwide will be diagnosed with colorectal cancer (CRC) every year [
In metastatic CRC, surgery and/or chemotherapy are used mainly with palliative intent. However, as treatment modalities in stage IV CRC are associated with significant complications and increased costs, there is a need to identify prognostic factors which may determine treatment response and survival. It is anticipated that such an approach could refine palliative management according to the likelihood of clinical benefit [
As part of our systematic search for prognostic factors in CRC, this study expanded our previous work [
The population under study has been described thoroughly in a previous report [
Nine possible prognostic variables were selected. These included patient-related variables such as age (≤60 years or >60 years), gender, and performance status (PS) according to the Karnofsky Performance Status Scale Index. For the evaluation of continuous laboratory parameters, we used group categorisations: for haemoglobin: >13.5 g/dL, 12–13.5 g/dL, 10–12 g/dL, 8.5–10 g/dL, and <8.5 g/dL; for carcinoembryonic antigen (CEA): normal ≤5 mg/dL and elevated >5 mg/dL; for cancer antigen 19-9 (CA 19-9): normal ≤30 U/L and elevated >30 U/L; for C-reactive protein (CRP): normal <5 mg/dL, moderately elevated 5–15 mg/dL, and highly elevated >15 mg/dL; and for albumin: normal >5 gr/dL and low ≤5 gr/dL. For ploidy score (DNA index), group categorisation was also applied for analytical purposes: <2.2, 2.2–2.6, >3.6.
For DNA measurements, the Feulgen staining technique was applied as previously described [
Descriptive statistics were calculated with the measures of means, medians, and standard deviation for quantitative parameters and counts/percentages for discrete factors. Overall survival was studied with the use of Kaplan-Meier method. Survival differences between groups are studied with the use of log-rank test. A multivariate Cox-regression model was implemented to study the simultaneous effect of parameters on survival after taking into account the parallel effect of remaining factors. Best model selection was based on manual and automated forward techniques. Results of regression analyses were displayed in the form of regression estimates tables. Hazard ratios of outcomes under study were calculated for each parameter estimate as well as 95% confidence intervals. Categorical covariates were compared with a predefined reference category. All analyses were performed at a significance level of
A total of 541 patients were included in the study, with median age of 61.00 years, a mean age of 60.33 years, and standard deviation of 7.35 years. The frequencies of the clinical variables are shown in Table
Demographic, clinical, and laboratory variables in the study population (
Factor |
|
% |
---|---|---|
Gender | ||
Males | 298 | 55.1 |
Females | 243 | 44.9 |
Age | ||
≤60 years | 261 | 48.2 |
>60 years | 280 | 51.8 |
Pretreatment PS | ||
70 | 75 | 13.9 |
80 | 160 | 29.6 |
90 | 155 | 28.7 |
100 | 151 | 27.9 |
CEA | ||
≤5 mg/dL | 134 | 24.8 |
>5 mg/dL | 407 | 75.2 |
CA 19-9 | ||
≤30 | 152 | 28.1 |
>30 | 389 | 71.9 |
CRP | ||
<5 mg/dL | 405 | 74.9 |
5–15 mg/dL | 80 | 14.8 |
>15 mg/dL | 56 | 10.4 |
Anaemia | ||
Hb > 13.5 g/dL | 198 | 36.6 |
Hb 12–13.5 g/dL | 94 | 17.4 |
Hb 10–12 g/dL | 112 | 20.7 |
Hb 8.5–10 g/dL | 85 | 15.7 |
Hb < 8.5 g/dL | 52 | 9.6 |
Hypoalbuminaemia | ||
No | 440 | 81.3 |
Yes | 101 | 18.7 |
Ploidy | ||
<2.2 | 27 | 5.1 |
2.2–3.6 | 375 | 70.8 |
>3.6 | 128 | 24.2 |
PS: performance status; CA 19-9: cancer antigen 19-9; CEA: carcinoembryonic antigen; CRP: C-reactive protein; Hb: Hemoglobin.
Survival data were collected for all patients. Based on the Kaplan-Meier method, the mean survival time was recorded at 12.8 months (95% confidence interval (CI) 12.0–13.5 months), with a median survival of 9.8 months (95% CI 8.8–10.8 months) (Figure
Overall survival (
In the univariate analysis, CRP, Hb, albumin, and ploidy scores were related to survival outcome at a significance level of
Factors found to have strongest significance of a relation to survival according to the bivariate analysis were entered into the multivariate analysis model. Factors were added and excluded using the change in likelihood between models as inclusion and exclusion criteria. Forward automated procedures resulted in the final model, which is described in Table
Final Cox proportional odds regression model.
Variable |
|
SE | Wald |
|
Hazard ratio | 95.0% CI for Exp( |
|
---|---|---|---|---|---|---|---|
Lower | Upper | ||||||
CRP 5–15 mg/dL versus <5 mg/dL | 0.552 | 0.131 | 17.652 | 0.000 | 1.737 | 1.343 | 2.248 |
CRP > 15 mg/dLversus <5 mg/dL | 0.924 | 0.153 | 36.303 | 0.000 | 2.520 | 1.866 | 3.404 |
| |||||||
Hb 12–13.5 g/dL versus >13.5 g/dL | 0.259 | 0.133 | 3.780 | 0.052 | 1.295 | 0.998 | 1.681 |
Hb 10–12 g/dL versus >13.5 g/dL | 0.471 | 0.128 | 13.543 | 0.000 | 1.602 | 1.246 | 2.059 |
Hb 8.5–10 g/dL versus >13.5 g/dL | 0.407 | 0.137 | 8.843 | 0.003 | 1.503 | 1.149 | 1.965 |
Hb < 8.5 g/dL versus >13.5 g/dL | 0.636 | 0.168 | 14.406 | 0.000 | 1.889 | 1.360 | 2.622 |
| |||||||
Hypoalbuminaemia (Yes versus No) | 0.347 | 0.116 | 8.994 | 0.003 | 1.415 | 1.128 | 1.776 |
| |||||||
Ploidy score 2.2–3.6 versus <2.2 | 1.081 | 0.209 | 26.740 | 0.000 | 2.947 | 1.957 | 4.439 |
| |||||||
Ploidy score >3.6 versus <2.2 | 1.606 | 0.225 | 50.780 | 0.000 | 4.982 | 3.203 | 7.748 |
SE: standard error, CI: confidence interval; CRP: C-reactive protein; Hb: hemoglobin.
Probability of death increased with increased CRP at presentation; patients with CRP > 15 mg/dL had 2.52 higher risk of death and patients with CRP 5–15 mg/dL had 1.72 times higher risk of death than patients with CRP < 5 mg/dL (Figure
Survival data according to CRP (a), anaemia (b), hypoalbuminaemia (c), and DNA ploidy (d).
This pooled analysis based on the individual data of 541 stage IV colorectal cancer patients treated with palliative chemotherapy confirms the prognostic value of previously identified factors such as CRP, Hb, and albumin and strengthens the existing data from other studies supporting the prognostic significance of DNA ploidy in stage IV colorectal cancer.
CRP is synthesized by the liver and is a nonspecific but sensitive marker of inflammation. Its production is induced by proinflammatory cytokines such as Interleukin-6 (IL-6), IL-8, and tumour necrosis factor alpha (TNF-
The association between anaemia and inferior survival capability has been widely validated in previous studies including a multivariate analysis of 3.825 patients with stage IV CRC treated with palliative 5FU-based chemotherapy in the setting of 22 multinational trials by Köhne et al. [
The prognostic significance of DNA content (DNA ploidy or index) in CRC has been extensively investigated in the past with controversial results. The majority of the reported studies have employed flow cytometric derived DNA ploidy, and the American Society of Clinical Oncology Tumour Markers Expert Panel has reviewed fifteen articles (encompassing 14 independent series) evaluating the prognostic role of flow cytometric derived ploidy in CRC to support its recommendation regarding the unsuitability of this marker as a prognostic determinant due to largely controversial results [
The limitations of our study centre mainly on the retrospective nature of the analysis and the objectivity of the methodology applied to assess DNA ploidy. Despite these limitations, the study has clinical significance as it validates the usefulness of a number of factors to assess the likelihood of clinical benefit of palliative chemotherapy in stage IV CRC. Clearly, however, these results need to be evaluated in a prospective manner.
The present study represents a comprehensive analysis of the prognostic significance of a number of factors in a large cohort of stage IV unoperable colorectal cancer patients receiving palliative chemotherapy. Our analysis demonstrated that DNA ploidy, along with simple haematological and biochemical parameters such as Hb, CRP, and albumin, carries the most significant independent effect on the outcome of stage IV CRC.
All authors declare no conflict of interests.
The authors thank Mrs. Madalena Zlovotska for data collection and Mr. Dimitrios Boulamatsis for performing the statistical tests.