Initial management and survival of patients with primary metastatic bladder cancer before the immunotherapy era: a population-based study from Norway.

Before immunotherapy became part of the management of metastatic bladder cancer (mBC), systemic anti-cancer treatment comprised primarily of platinum-based chemotherapy. The objective of this study was to describe the characteristics, the initial management, overall survival (OS) and hospitalisations of patients with mBC before 2018 when immunotherapy for mBC was introduced in Norway.  Material and methods: It is a nationwide population-based study of primary mBC patients (diagnosed 2008-16). Descriptive statistics were applied and stratified for four initial management options (≤150 days after BC diagnosis): chemotherapy, major local treatment (cystectomy/pelvic radiotherapy), multimodal treatment (chemotherapy and local) and no anti-cancer treatment beyond transurethral resection of bladder tumour (untreated). Group differences were evaluated by Chi-square and Kruskal-Wallis test; OS was estimated with Kaplan-Meier. Results: Of the 305 patients included, 76 (25%) patients had chemotherapy, 46 (15%) patients had major local treatment, 21 (7%) patients had multimodal treatment and 162 (53%) patients were untreated.  Median OS ranged from 2.3 months (untreated) to 9.8 months (chemotherapy). Patients who received treatment had a higher rate of hospitalisation, with a median stay of three to four times that of untreated patients. Conclusion: Before immunotherapy, more than 50% of patients with primary mBC did not receive any initial anti-cancer therapy and had a poor survival. Patients treated with chemotherapy had inferior median OS compared to those treated with comparable systemic strategies in contemporary trials. Our results provide a basis for future research on treatment and survival after the introduction of immunotherapy for mBC, aiming to improve the care and outcome of patients with mBC.

Downstaging and survival after Neoadjuvant chemotherapy for bladder cancer in Norway; a population-based study.

BACKGROUND: Neoadjuvant chemotherapy (NAC) before radical cystectomy is associated with pathological downstaging (DS) and improved overall survival (OS) in patients with muscle-invasive bladder cancer (MIBC). Population-based studies have not unequivocally shown improved survival. The aim of this population-based study was to evaluate the effect of NAC on DS and OS in Norwegian patients with MIBC. METHODS: Patients in the Cancer Registry of Norway undergoing radical cystectomy (2008-2015) with or without NAC diagnosed with MIBC between 2008 and 2012 were included. Follow-up data were available until 31 December 2019. Logistic regression estimated the odds of DS with NAC, and a Cox model investigated the effect of DS on OS. Cox models, a mediator analysis and an instrumental variable approach were used to investigate the effect of NAC on OS. RESULTS: A total of 575 patients were included. NAC was administered to 82 (14%) patients. Compared to cystectomy only, NAC increased the proportion (43% vs. 22%) and the odds of DS (OR 2.51, CI 1.37-4.60, p = 0.003). Independent of NAC, the proportion of pN0 was higher in patients with DS (89% vs. 60%) and DS yielded a 78% mortality risk reduction (HR 0.22, CI 0.15-0.34, p = 1.9∙10-12), compared to patients without DS. We did not find an association between NAC and OS, neither by Cox regression (HR 1.16, CI 0.80-1.68, p = 0.417) nor by an instrumental variable approach (HR = 0.56, CI = 0.07-4.57, p = 0.586). The mediation analysis (p = 0.026) confirmed an indirect effect of NAC on OS through DS. Limitations include limited information of the primary tumour, details of NAC treatment and treatment indications. CONCLUSIONS: NAC increases the probability of DS and is indirectly associated to OS. DS is related to the absence of regional lymph node metastases and is associated with an OS benefit. Improved staging and biomarkers are needed to identify patients most likely to achieve DS and to benefit from NAC.

The use of reTURB in T1 bladder cancer: a Norwegian population-based study.

AIM: To evaluate the use of repeat transurethral resection of the bladder (reTURB) in stage T1 bladder cancer and its impact on treatment and survival in a Norwegian population-based cohort. MATERIAL AND METHODS: 1130 patients registered at the Cancer Registry of Norway between 2008 and 2012 with primary urothelial T1 cancer were included. Information on surgical and medical procedures was provided by the Norwegian Patient Registry. Descriptive statistics were used to evaluate characteristics of patients receiving reTURB or not within 12 weeks from primary TURB (primTURB). Survival models identified risk factors and estimated cause-specific survival rates (CSS) adjusted for sex, age, WHO grade, concomitant cis and detrusor muscle at primTURB and treatment. RESULTS: The 648 (57%) T1 patients with reTURB were significantly younger and had more WHO high grade tumors compared to those without reTURB. Of 275 patients without detrusor muscle at primTURB 114 (41%) had no reTURB. Of reTURB patients, 45 (7%) had muscle invasive tumor, 110 (17%) T1 and 378 (58%) Ta, cis or T0. Two-thirds of 81 patients receiving early cystectomy after reTURB had T1 or muscle invasive bladder cancer at reTURB. ReTURB did not impact adjusted CSS, but patients with T1 at reTURB had significantly lower CSS than those with < T1 conditions. CONCLUSIONS: Almost half of the T1 patients did not undergo reTURB as recommended in guidelines. We show that reTURB makes the histology result more reliable with impact on both treatment and survival. Our results support the use of reTURB as recommended by EAU guidelines.

T1 bladder cancer in Norway: treatment and survival.

AIM: Evaluation of treatment and survival of pT1 stage (T1) bladder cancer (BC) patients diagnosed with transitional cell carcinoma of the urinary bladder in Norway. MATERIAL AND METHODS: According to the Cancer Registry of Norway, 1,108 patients were diagnosed with T1 BC between 2008-2012. Information on surgical and medical procedures was provided by the Norwegian Patients Registry. Regression and survival models were applied to characterize patients receiving bacillus Calmette-Guerin (BCG) and radical cystectomy (RC) as early and delayed treatment and to estimate overall and cause specific survival rates (OS; CSS). Adjustments for sex, age, WHO grade and concomitant cis were made. RESULTS: In total, 449 (41%) patients received BCG treatment, 162 (15%) as early treatment. RC represented the early treatment in 96 (9%) patients and the delayed treatment in 84 (8%). Overall, 850 (77%) patients received neither BCG nor RC as early treatment, of whom 287 (26%) were treated with BCG and 66 (6%) with RC during follow-up. Patients <75 years and patients with high grade tumors or concomitant cis were more likely to receive BCG and RC as early treatment. 5-year survival rates for all T1 BC patients were 84% (CSS) and 65% (OS). Delayed RC was associated with the lowest 5-year CSS (70%). After adjustment, gender did not impact treatment choice and CSS. CONCLUSIONS: The use of BCG as early treatment indicates low adherence to existing guidelines. Delayed RC was associated with low survival rates. An increased focus on the management of T1 patients is needed in Norway.

"Two hits - one stone"; increased efficacy of cisplatin-based therapies by targeting PCNA's role in both DNA repair and cellular signaling.

Low response rate and rapid development of resistance against commonly used chemotherapeutic regimes demand new multi-targeting anti-cancer strategies. In this study, we target the stress-related roles of the scaffold protein PCNA with a cell-penetrating peptide containing the PCNA-interacting motif APIM. The APIM-peptide increased the efficacy of cisplatin-based therapies in a muscle-invasive bladder cancer (MIBC) solid tumor model in rat and in bladder cancer (BC) cell lines. By combining multiple omics-levels, from gene expression to proteome/kinome and metabolome, we revealed a unique downregulation of the EGFR/ERBB2 and PI3K/Akt/mTOR pathways in the APIM-peptide-cisplatin combination treated cells. Additionally, the combination treatment reduced the expression of anti-apoptotic proteins and proteins involved in development of resistance to cisplatin. Concurrently, we observed increased levels of DNA breaks in combination treated cells, suggesting that the APIM-peptide impaired PCNA - DNA repair protein interactions and reduced the efficacy of repair. This was also seen in cisplatin-resistant cells, which notably was re-sensitized to cisplatin by the APIM-peptide. Our data indicate that the increased efficacy of cisplatin treatment is mediated both via downregulation of known oncogenic signaling pathways and inhibition of DNA repair/translesion synthesis (TLS), thus the APIM-peptide hits both nuclear and cytosolic functions of PCNA. The novel multi-targeting strategy of the APIM-peptide could potentially improve the efficacy of chemotherapeutic regiments for treatment of MIBC, and likely other solid tumors.