Validation of the prognostic relevance of plasma C-reactive protein levels in soft-tissue sarcoma patients

Abstract

Background: The concept of the involvement of systemic inflammation in cancer progression and metastases has gained attraction within the past decade. C-reactive protein (CRP), a non-specific blood-based marker of the systemic inflammatory response, has been associated with decreased survival in several cancer types. The aim of the present study was to validate the prognostic value of pre-operative plasma CRP levels on clinical outcome in a large cohort of soft-tissue sarcoma (STS) patients.

Methods: Three hundred and four STS patients, operated between 1998 and 2010, were retrospectively evaluated. CRP levels and the impact on cancer-specific survival (CSS), disease-free survival (DFS) and overall survival (OS) were assessed using Kaplan-Meier curves and univariate as well as multivariate Cox proportional models. Additionally, we developed a nomogram by supplementing the plasma CRP level to the well-established Kattan nomogram and evaluated the improvement of predictive accuracy of this novel nomogram by applying calibration and Harrell's concordance index (c-index).

Results: An elevated plasma CRP level was significantly associated with established prognostic factors, including age, tumour grade, size and depth (P<0.05). In multivariate analysis, increased CRP levels were significantly associated with a poor outcome for CSS (HR=2.05; 95% CI=1.13-3.74; P=0.019) and DFS (HR=1.88; 95% CI=1.07-3.34; P=0.029). The estimated c-index was 0.74 using the original Kattan nomogram and 0.77 when the plasma CRP level was added.

Conclusion: An elevated pre-operative CRP level represents an independent prognostic factor that predicts poor prognosis and improves the predictive ability of the Kattan nomogram in STS patients. Our data suggest to further prospectively validate its potential utility for individual risk stratification and clinical management of STS patients.

Figure 1

Kaplan–Meier curve for cancer-specific survival regarding low vs C-reactive protein levels (P<0.001).        .

Figure 2

Kaplan–Meier curve for disease-free survival regarding low vs high C-reactive protein levels (P<0.001).        .

Figure 3

Kaplan–Meier curve for overall survival regarding low vs high C-reactive protein levels (P<0.001).        .

Figure 4

Original published Kattan nomogram for predicting 12-year sarcoma-specific survival. Size: 0<5 cm, 1 5–10 cm, 2>10 cm; Depth: 1=superficial, 2=deep; Site: 1=upper extremities, 2=lower extremities, 3=visceral, 4=thoracic, 5=retro/intraabdominal, 6=head/neck; histology: 1=fibrosarcoma, 2=liposarcoma, 3=leiomyosarcoma, 4=malignant fibrous histiocytoma, 5=malignant peripheral nerve tumour; Grade: 1=low grade, 2=high grade (Kattan et al, 2002).

Figure 5

Calibration of the Kattan nomogram supplemented by C-reactive protein. Horizontal axis is one minus the nomogram's predicted probability of 12 years sarcoma-specific death. Vertical axis is the actual sarcoma-specific survival estimated at 12 years using the Kaplan–Meier method. Diagonal line indicates the reference line on which an ideal nomogram would lie. Solid black line indicates performance of the present nomogram. •, subcohorts of database; × , bootstrap-corrected estimate of nomogram's performance with 200 resamples. Error bars indicate 95% confidence interval.