BCa is an aggressive disease and is associated with high morbidity and mortality rates if not treated optimally(11). Even though BCa is common, it is often mismanaged. Despite RC with extended lymph node dissection, there is a high risk of tumor progression(12−14). Approximately 50% of the patients with a T stage higher than T2 and/or LVI develop metastases within 5 years(12) and up to 15% present with local recurrent disease(15). It is assumed that these patients already bear lymphogenous and haematogenous micro-metastases at time of surgery(16). Several meta-analyses of adjuvant treatment trials have shown a 22 to 25% reduction in the risk of death with cisplatin-based adjuvant treatment(17, 18), however, they might have been underpowered to draw final conclusions. The selection of patients with a higher risk of disease progression after RC and a valuable tool to predict the outcome for OS and CSS in patients after RC and to identify those patients who will benefit from early adjuvant treatment are therefore needed.
The aim of this study was to evaluate CRP as a prognostic parameter in patients with BCa undergoing RC, to validate the TNR-C score, and based on the findings, to develop a new score to measure OS in patients with BCa after RC. In univariate analysis, the OS was significantly associated with T-stage (pT2 vs pT3 or higher, p = 0.001), R-status (p≤0.001), and LVI (p = 0.011). All of these pathologic parameters have been identified as being of prognostic importance in MIBC(12) and were therefore used for the multivariate analysis and score development. Furthermore, preoperative CRP levels showed a significant association (p = 0.002) with the later T stage (pT2 vs. pT3–4) in MIBC after RC, lymph node infiltration (lymph node positive vs negative; p = 0.006), and a lower OS (86.2 months vs. 61.7 months, p = 0.02). In the recent past, our own and several other groups identified CRP as a prognostic predictor in cancer patients(5, 6, 19−21). High CRP levels yielded a worse survival in renal cell carcinoma, prostate cancer, BCa, and upper tract urothelial carcinoma (UTUC). The main advantages of CRP as a serum biomarker are its widespread availability due to its routine use as an inflammation marker and its inexpensive assessment. The main disadvantage is the possibility of false negative results due to true infectious inflammation(5).
In multivariate analysis, R-status, LVI, and the preoperative CRP level were independent prognostic markers for OS. The final model consisting of these three parameters, the RLC score, yielded a high predictive accuracy of 0.752. Our model used OS as an endpoint instead of CSS, in contrast to other score systems such as the TNR-C score of Gakis et al.(4) or the TNM-C score of Iimura et al.(9), since in the authors opinion, CSS is a difficult parameter to assess. Despite our intense analysis of multiple sources, such as the central German cancer registry, the given clinical chart data, and data from the patients’ general practitioners, no certain CSS was evaluable. Nevertheless, there was a correlation of OS with stratification of TNR-C risk groups (Fig. 1). The survival curves showed a significantly lower OS for TNR-C high risk group members than low and intermediate risk group members. Whereas Gakis et al. included LN positive patients, our RLC-score excluded this group. This limits the direct comparison of results but might be an advantage of the RLC score since we assessed a patient group not highly suspected to develop a metastatic disease.
In the low risk group of our RLC score, more than a fifth (22.4%) showed tumour progression. In comparison to the aforementioned scores, the survival rates showed a significantly lower OS for RLC high risk group members compared to the other groups. The R-status represented the most important independent prognostic factor. It is noteworthy that CRP is, per se, a marker for inflammation processes and occurs ubiquitously in the human body. However, it has clinical relevance because it is a standard parameter of the preoperative evaluation of patients with BCa in most urologic clinics. Overall, the RLC score can identify patients with a higher risk of progression who would benefit from a close follow-up or early adjuvant chemotherapy. The RLC score itself now needs an external validation.
Due to the retrospective nature with a small cohort, this study bears limitations. Despite of primary LN invasion absence, many patients died after a couple of months from disease progression or developed metastases. In the RLC intermediate risk group, 75% of the patients showed metachronous metastases, whereas in the high risk group, only one patient was diagnosed with metastases. This can be explained by the short OS (median 6.5 months) of the high risk group.
It is important to mention that the mean age in the RLC high risk group exceeded the other two groups by around five years (73.5 years vs 67.5 and 68.9 years). A correlation of age at the time of RC and OS has be shown(23−25), although comorbidities were found to be more important. In our study, comorbidities were not registered and therefore could not be analysed.