Abstract. Combined trimodality therapy, including transurethral resection and platinum-based chemoradiotherapy, has shown promising results for muscle-invasive bladder cancer. However, this type of treatment may decrease survival as a result of delayed cystectomy in patients with non-responding tumors. DNA repair proteins may affect survival of bladder cancer patients receiving combined trimodality therapy, by affecting the perioperative nature of the tumor cells or by repairing DNA damaged by platinum agents and radiation. We investigated the associations of excision repair cross-complementing group 1 (ERCC1), X-ray repair cross-complementing group 1 (XRCC1) and apurinic/apyrimidinic endonuclease 1 (APE1) expression with response and survival in 157 locally advanced bladder cancer patients receiving combined trimodality therapy, in order to determine the predictive value of the expression of these proteins in patient selection for therapy. We examined ERCC1, XRCC1 and APE1 expression in tumor specimens using immunohistochemistry. Patients positive for ERCC1, positive for XRCC1 and positive for either ERCC1 or XRCC1, exhibited significantly improved disease-specific survival rates (P=0.023, 0.025 and 0.0091, respectively). In multivariate analysis, combined ERCC1 and XRCC1 expression was independently associated with disease-specific mortality [risk ratio (RR): 0.64; 95% confidence interval (CI), 0.43-0.94 and P=0.024]. Thus, combined ERCC1 and XRCC1 expression may serve as an independent prognostic marker for survival in bladder cancer patients receiving combined trimodality therapy. Prospective studies with a larger sample size are required to confirm these results.

Platinum-based chemoradiotherapy (CRT) as bladder conservation therapy has shown promising results for muscle-invasive bladder cancer. However, CRT might diminish survival as a result of the delay in cystectomy for some patients with non-responding bladder tumors. Because the p53 tumor suppression pathway, including its MDM2 counterpart, is important in chemotherapy-and radiotherapy-associated effects, functional polymorphisms in the TP53 and MDM2 genes could influence the response to treatment and the prognosis following CRT. We investigated associations between two such polymorphisms, and p53 overexpression, and response or survival in bladder cancer patients treated with CRT. The study group comprised 96 patients who underwent CRT for transitional cell carcinoma of the bladder. Single nucleotide polymorphisms (SNPs) in TP53 (codon 72, arginine > proline) and MDM2 (SNP309, T > G) were genotyped using PCR-RFLP, and nuclear expression levels of p53 were examined using immunohistochemistry. None of the genotypes or p53 overexpression was significantly associated with response to CRT. However, patients with MDM2 T / G + G / G genotypes had improved cancer-specific survival rates after CRT (P = 0.009). In multivariate analysis, the MDM2 T / G + G / G genotypes, and more than two of total variant alleles in TP53 and MDM2, were independently associated with improved cancer-specific survival (P = 0.031 and P = 0.015, respectively). In addition, MDM2 genotypes were significantly associated with cystectomy-free survival (P = 0.030). These results suggest that the TP53 and MDM2 genotypes might be useful prognostic factors following CRT in bladder cancer, helping patient selection for bladder conservation therapy. (Cancer Sci 2009; 100: 2376-2382 T he standard treatment for muscle-invasive urinary-bladder cancer is radical cystectomy followed by urinary diversion. However, this procedure is likely to impair the quality of life of the patient.(1) In many areas of cancer treatment, the trend in the 1990s was aimed at organ conservation using combined chemotherapy and radiation with or without conservative local surgery.(2) In invasive bladder cancer, several groups have reported the value of combined-modality therapy, including transurethral resection (TUR), radiation therapy, and platinum-based systemic chemotherapy.(1-3) With these programs, cystectomy is reserved for patients with an incomplete response or local relapse after combined-modality treatment. Five-year survival rates in the range of 50-65% have been published in these series, and approximately three-quarters of the surviving patients maintained their own bladders.(4-6) However, combined-modality therapy is not only potentially toxic but might also diminish survival as a result of the delay in cystectomy for some patients with non-responding bladder tumors.(7) It would therefore be useful to have predictors for response to the therapy and prognosis, to assist with choosing appropriate patients for bladder preservation. TP53 is a tumor suppressor gene that play...

Introduction: Open radical cystectomy (ORC) is currently the standard treatment for muscle-invasive bladder cancer (MIBC) without metastasis, while many patients with MIBC are not always appropriate candidates due to multiple comorbidities. To evaluate the bladder-preservation strategy, we compared the results with those obtained by ORC. Patients and Methods: We retrospectively analyzed the data of 50 patients with MIBC treated by trimodal chemoradiotherapy with cisplatin (CDDP-radiation [CDDP-R]). Transurethral resection of the bladder tumor (TURBT) was performed before treatment to confirm pathological stage ≥T2. Extensive TURBT was performed after chemoradiotherapy to evaluate the pathological response to treatment. We compared the survival outcomes of our CDDP-R with those of ORC (retrospective cohort, n = 205) by propensity score matching analysis. Results: The 2- and 5-year progression-free survival, bladder-intact survival, cancer-specific survival, and overall survival (OS) rates after treatment were 70.8 and 63.9%, 64.0 and 49.8%, 86.7 and 71.8%, and 84.3 and 64.8%, respectively. The 2- and 5-year OS rates after CDDP-R were 90.5 and 74.3%, respectively, and those after ORC were 71.8 and 59.9%, respectively, indicating a significant survival advantage conferred by CDDP-R over ORC (p < 0.05, HR 0.45, 95% CI 0.21-0.94). Conclusions: In selected patients, CDDP-R for MIBC may provide comparative oncological outcomes as ORC.

ERG, p53, prostate cancer, TMPRSS2-ERG fusion.

Cases with a primary cT2 tumor could be good candidates for BPT with radiation combined with cisplatin.