Bladder Tumor Recurrence Research Articles

Elective management of transitional cell carcinoma of the distal ureter: can kidney‐sparing surgery be advised?

To determine the long-term oncological outcome of patients with primary transitional cell carcinoma (TCC) of the distal ureter electively treated with either kidney-sparing surgery (KSS) or radical nephroureterectomy (RNU) in a retrospective, non-randomized, single-centre study. Of 43 consecutive patients with a primary solitary distal ureter TCC, 19 had KSS, consisting of distal ureter resection with bladder cuff excision and ureter reimplantation, and 24 had RNU with bladder cuff excision. The median (range) age at surgery was 69 (31-86) years for the KSS group and 73 (59-87) years for the RNU group, patients in the latter having worse hydronephrotic kidneys. The median (range) follow-up was 58 (3-260) months. A recurrent bladder tumour was diagnosed after a median of 15 months in five of the 19 patients treated by KSS and after a median of 5.5 months in eight of the 24 treated by RNU. Five of the 19 patients treated by KSS and six of the 24 treated by RNU died from metastatic disease despite chemotherapy. Recurrence-free, cancer-specific and overall survival were comparable in the two groups. In two patients (11%) treated by KSS an ipsilateral upper urinary tract TCC recurred after 42 and 105 months, respectively. Treatment by distal ureteric resection is feasible in patients with primary TCC of the distal ureter. The long-term oncological outcome seems to be comparable with that of patients treated by RNU. Furthermore, kidney preservation is advantageous if adjuvant or salvage chemotherapy is required.

18F-FDG PET/CT Delayed Images After Diuretic for Restaging Invasive Bladder Cancer

PET with (18)F-FDG has been considered of limited value for detection of bladder cancer because of the urinary excretion of the tracer. The purpose of this study was to investigate the role of PET/CT in the detection and restaging of bladder cancer using furosemide and oral hydration to remove the excreted (18)F-FDG from the bladder. Seventeen patients with bladder cancer (11 without cystectomy, 6 with total cystectomy and urinary diversion) underwent (18)F-FDG PET/CT from head to the upper thighs 60 min after the intravenous injection of 370 MBq of (18)F-FDG. Additional pelvic images were acquired 1 h after the intravenous injection of furosemide and oral hydration. PET/CT findings were confirmed by MRI, cystoscopy, or biopsy. PET/CT was able to detect bladder lesions in 6 of 11 patients who had not undergone cystectomy. These images changed the PET/CT final reading in 7 patients: Recurrent bladder lesions were detected in 6 patients, pelvic lymph node metastases in 2 patients, and prostate metastasis in 1. This technique overcame the difficulties posed by the urinary excretion of (18)F-FDG. Hypermetabolic lesions could be easily detected by PET and precisely localized in the bladder wall, pelvic lymph nodes, or prostate by CT. Seven of 17 patients (41%) were upstaged only after delayed pelvic images. Detection of locally recurrent or residual bladder tumors can be dramatically improved using (18)F-FDG PET/CT with delayed images after a diuretic and oral hydration.

Clinically Relevant Reduction in Risk of Recurrence of Superficial Bladder Cancer Using 5-Aminolevulinic Acid-Induced Fluorescence Diagnosis: 8-Year Results of Prospective Randomized Study

Several studies have shown that 5-aminolevulinic acid (5-ALA)-induced fluorescence cystoscopy improves the detection of superficial bladder cancer. The results have suggested a reduced rate of recurrent tumors with the use of 5-ALA fluorescence before bladder tumor resection. We performed a prospective, randomized trial to investigate whether the long-term tumor recurrence and residual tumor rates can be decreased using 5-ALA fluorescence diagnosis (FD). A total of 301 patients with suspected superficial bladder carcinoma were randomized to transurethral resection (TUR) using conventional white light (WL) or FD. TUR was repeated to evaluate the residual tumor rate. In addition, patients were followed up for a median of 83 (WL) and 86 (FD) months to evaluate recurrence-free survival (RFS). Of the 301 patients, 191 were available for the efficacy analysis. The residual tumor rate was 25.2% in the WL arm versus 4.5% in the FD arm (P <0.0001). The RFS rate after 2, 4, 6, and 8 years was 73%, 64%, 54%, and 45% in the WL group and 88%, 84%, 79%, and 71% in the FD group, respectively, revealing a statistically significant difference in favor of fluorescent TUR (P = 0.0003). 5-ALA-induced FD is significantly superior statistically to conventional WL TUR with respect to the residual tumor rate and RFS. This advantage of decreased bladder tumor recurrence risk was maintained with high statistical significance for at least 8 years. The differences in RFS imply that FD offers a clinically relevant procedure to reduce the incidence of tumor recurrence.

342: Prognostic Factors of Bladder Tumor Recurrence after Laparoscopic Radical Nephroureterectomy for Upper Urinary Transitional cell Carcinoma

342: Prognostic Factors of Bladder Tumor Recurrence after Laparoscopic Radical Nephroureterectomy for Upper Urinary Transitional cell Carcinoma

Treatment Paradigm Shift May Improve Survival of Patients With High Risk Superficial Bladder Cancer

Historically patients with recurrent T1 bladder tumors after bacillus Calmette-Guerin have been treated with bladder sparing approaches. Recently a paradigm shift has occurred since patients are increasingly offered radical cystectomy before disease progression to muscle invasion. In this study we explored the effect of this paradigm shift on progression rates and disease specific survival. The historical cohort consisted of 307 patients from 3 prospective intravesical bacillus Calmette-Guerin protocols from 1980 to 1989. An institutional review board approved review identified 589 patients treated with bacillus Calmette-Guerin in a contemporary cohort from 1992 to 2004. In the historical cohort the 85 patients with documented T1 recurrence were initially treated with repeat transurethral resection and intravesical bacillus Calmette-Guerin. Of these 85 patients 60 had progression to muscle invasive disease. At 5 years after T1 recurrence, the cumulative incidence of progression to T2 disease was 71% (95% CI 61%, 81%) and the cumulative incidence of death from disease was 48% (95% CI 39%, 60%). In the contemporary cohort 129 patients had documented T1 recurrence. In this cohort 65 of the 129 patients with recurrent T1 underwent immediate radical cystectomy. At 5 years after T1 recurrence, the cumulative incidence of progression to muscle invasive disease was 28% (95% CI 20%, 38%) and the cumulative incidence of death from disease was 31% (95% CI 22%, 42%). Preemptive radical cystectomy performed for recurrent T1 disease following intravesical bacillus Calmette-Guerin therapy may be associated with better disease specific survival.

Use of Urinary Biomarkers for Bladder Cancer Surveillance: Patient Perspectives

Interest has emerged in urinary biomarkers to replace or alternate with followup cystoscopies for routine bladder cancer surveillance. We assessed whether patients would accept a urine biomarker assay over flexible cystoscopy for monitoring bladder cancer. We enrolled 200 consecutive patients previously diagnosed with superficial bladder tumors who were undergoing outpatient flexible cystoscopy as followup. Immediately after cystoscopy each patient completed a pain intensity numerical rating and was interviewed. The standard gamble method was applied to determine the minimal accepted diagnostic accuracy at which a urine test would be favored over cystoscopy for bladder surveillance. Clinical and demographic data with potential to affect patient preferences were analyzed. Of the 200 patients 75% would accept the results of a urine test as a replacement for cystoscopy only if it was capable of detecting more than 95% of recurrent bladder tumors and an additional 21% would accept it if the urine test was at least 90% to 95% accurate. Anxiety associated with the possibility of missing cancer was the major determinant of the minimal accepted accuracy. While male gender and higher pain intensity at cystoscopy were associated with willingness to accept a small level of uncertainty on univariate and multivariate analyses, the risk of progression to muscle invasion and the convenience of followup did not appear to affect patient preferences. From the patient perspective a urinary biomarker would likely require 95% or greater diagnostic accuracy to supplant cystoscopies for routine bladder surveillance. Inadequate sensitivity may be the major impediment to general acceptance of urinary biomarkers in this setting.

Case report: differential diagnosis of isolated iliac lymphadenopathy following Bacillus Calmette-Guérin treatment for high-risk superficial bladder cancer

We report the unusual case of a patient with G3 pT1 transitional cell carcinoma (TCC) of the bladder, which was treated with repeated transurethral resection and maintenance intravesical Bacillus Calmette-Guérin (BCG) therapy. At 30 months follow-up, a symptomatic, solitary iliac lymph node mass was identified and biopsied. Histology demonstrated granulomatous tissue only, in the absence of any intravesical bladder tumour recurrence. Following 6 months of anti-tuberculous medication, the mass had progressed, and repeat biopsy revealed undifferentiated carcinoma (of a bladder primary). This is a rare case of metastatic superficial bladder cancer progression without local recurrence after BCG therapy. As such, it can be viewed as a diagnostic challenge.

Reflex UroVysion Testing of Bladder Cancer Surveillance Patients With Equivocal or Negative Urine Cytology

A proportion of patients under surveillance for recurrent bladder carcinoma with no immediate evidence of bladder tumor recurrence have positive multitarget fluorescence in situ hybridization (FISH; UroVysion, Vysis, Downers Grove, IL) results. The course of these "anticipatory positive" cases and the time to bladder tumor recurrence remains unknown. We followed up 250 patients with urine cytologic results, concurrent multitarget FISH, and cystoscopic examination for recurrent urothelial carcinoma. Of 81 cases (32.4%) with FISH-positive results, tumor recurrence developed in 60 (74.0%). Of 169 (67.6%) FISH-negative cases, recurrent urothelial carcinoma developed in 22 (13.0%). Of 211 patients (84.4%) with negative cystoscopic examination results, 56 (26.5%) had positive FISH results, and in 35 (62.5%) of these patients, recurrent urothelial carcinoma developed. Approximately 27% of patients under bladder carcinoma surveillance without immediate evidence of tumor recurrence will have a positive FISH result, defining the anticipatory positive subset. In about 65% of this anticipatory positive group, recurrent bladder urothelial carcinoma developed within 29 months.

Pathologic Features of Bladder Tumors After Nephroureterectomy or Segmental Ureterectomy for Upper Urinary Tract Transitional Cell Carcinoma

To determine the pathologic features of bladder tumors after nephroureterectomy or segmental ureterectomy for upper urinary tract transitional cell carcinoma (UUT-TCC). From 1993 to 2003, 82 patients without a history of bladder cancer underwent nephroureterectomy or segmental distal ureterectomy for UUT-TCC. We reviewed the pathologic features of the subsequent bladder tumors, including stage, grade, and progression to cystectomy in these patients at a median follow-up of 44.1 months. A total of 36 (44%) of 82 patients developed bladder tumors after definitive therapy for UUT-TCC at a mean interval of 13.9 months. The mean number of bladder tumors diagnosed per patient in the follow-up interval was 2.1 (range 1 to 6), for a total of 74 bladder tumors. Of the 74 bladder tumors, 71 (96%) were superficial (Stage Ta, Tis, T1), 49 of these superficial tumors (69%) being low grade (grade 1 and 2) and 22 (31%) high grade (grade 3). Three patients had high-grade, muscle-invasive disease, and all progressed to cystectomy during follow-up. A greater than 75% concordance was found in pathologic grade between the UUT lesion and subsequent bladder tumors. The stage of the UUT malignancy, however, did not correlate with subsequent bladder tumor pathologic findings. Bladder tumors developed in 44% of patients after treatment of UUT-TCC. Of these bladder tumors, over 60% were superficial, low-grade lesions, yielding a similar pathologic distribution to that of bladder cancer de novo. The grade, but not the stage, of the UUT tumors correlated with the pathologic findings of subsequent bladder tumor recurrence. Aggressive surveillance with cystoscopy and urinary cytology after surgical management of UUT-TCC is imperative.

Intravesical instillation therapy with bacillus Calmette‐Guérin for superficial bladder cancer: Study of the mechanism of bacillus Calmette‐Guérin immunotherapy

In order to clarify the initial step of the mechanism by which bacillus Calmette-Guérin (BCG) exhibits antitumor activity via the immune response induced in the bladder submucosa after intravesical BCG therapy for human bladder cancer, various cytokines secreted in the urine after BCG instillation were measured. After transurethral resection of bladder cancer, a 6-week course of BCG instillation was performed. At the first and sixth weeks' dosings, spontaneously excreted urine was collected before and 4, 8, and 24 h after BCG instillation. The urinary cytokines were determined by Sandwich enzyme-linked immunosorbent assay using monoclonal antibodies against granulocyte-macrophage colony-stimulating factor (GM-CSF), tumor necrosis factor (TNF)-alpha, granulocyte colony-stimulating factor (G-CSF), interleukin (IL)-1beta, IL-8, interferon (IFN)-gamma, and IL-12. After the BCG therapy, various cytokines, such as GM-CSF, TNF-alpha, G-CSF, IL-1beta, IL-8, IFN-gamma, and IL-12 were secreted, comprising the immune response cascade. The mean urinary excretions of GM-CSF and TNF-alpha 4 h after the sixth week's instillation were significantly higher than the pre-instillation levels. There were no significant increases in the urinary IFN-gamma or IL-12 levels between 4 and 24 h after the sixth week's instillation. The TNF-alpha level 4 h after the sixth week's instillation had a strong tendency towards the absence of recurrence, with a mean follow-up of 54.1 months. The Kaplan-Meier curve showed the 2, 5, and 10-year recurrence-free survival rates were 72.4%, 65.8%, and 56.4%, respectively. We suggested that the urinary levels of TNF-alpha might be essential in antitumor activity after BCG therapy and might play an important role in the prevention of bladder tumor recurrence.

The Prognostic Significance of Elevated Serum Creatinine for the Recurrence and Progression in Superficial Bladder Tumors

Purpose: There are many prognostic indicators of bladder tumors including clinical, pathological and molecular markers based on tumor-related factors. This study was performed to evaluate the significance of an elevated level of serum creatinine for predicting progression and recurrence of superficial bladder tumors. Materials and Methods: One hundred forty-seven patients that initially presented with a superficial bladder tumor (pTa or pT1) except for a carcinoma in situ were retrospectively analyzed according to several factors such as tumor stage, grade, size, multiplicity and serum creatinine for tumor recurrence and progression after a primary transurethral resection. Results: The elevated serum creatinine group consisted of 20 patients 11 patients experienced recurrence (55.0%) and 3 patients experienced progression (15.0%). The control group consisted of 127 patients 39 patients experienced recurrence (30.7%) and 13 patients experienced progression (10.2%). The presence of an elevated level of serum creatinine and tumor multiplicity were statistically significant prognostic factors for tumor recurrence. Conclusions: These results can be helpful for predicting the prognosis of transitional cell carcinoma of the bladder and for planning therapeutic and follow-up strategies. (Korean J Urol 2007;48:927-932)

MP-15.02: Efficacy of managing small recurrent bladder tumours by diathermy using the CYF-4 Olympus flexible cystoscope in the day surgery unit

MP-15.02: Efficacy of managing small recurrent bladder tumours by diathermy using the CYF-4 Olympus flexible cystoscope in the day surgery unit

Cell-nuclear data reduction and prognostic model selection in bladder tumor recurrence

The paper aims at improving the prediction of superficial bladder recurrence. To this end, feedforward neural networks (FNNs) and a feature selection method based on unsupervised clustering, were employed. A retrospective prognostic study of 127 patients diagnosed with superficial urinary bladder cancer was performed. Images from biopsies were digitized and cell nuclei features were extracted. To design FNN classifiers, different training methods and architectures were investigated. The unsupervised k-windows (UKW) and the fuzzy c-means clustering algorithms were applied on the feature set to identify the most informative feature subsets. UKW managed to reduce the dimensionality of the feature space significantly, and yielded prediction rates 87.95% and 91.41%, for non-recurrent and recurrent cases, respectively. The prediction rates achieved with the reduced feature set were marginally lower compared to the ones attained with the complete feature set. The training algorithm that exhibited the best performance in all cases was the adaptive on-line backpropagation algorithm. FNNs can contribute to the accurate prognosis of bladder cancer recurrence. The proposed feature selection method can remove redundant information without a significant loss in predictive accuracy, and thereby render the prognostic model less complex, more robust, and hence suitable for clinical use.

Short-Schedule Intravesical Gemcitabine with Ablative Intent in Recurrent Ta–T1, G1–G2, Low- or Intermediate-Risk, Transitional Cell Carcinoma of the Bladder

ObjectivesPrimary objective: to assess ablative efficacy and tolerability of short-schedule intravesical gemcitabine for intact, low- and intermediate-risk, recurrent superficial bladder tumours. Secondary objective: to assess effect on prophylaxis. MethodsPatients with a diagnosis of recurrence and a history of previous superficial, low- or intermediate-risk bladder tumours were selected for the study. They received 2000mg gemcitabine in 50ml, that is 40mg/ml, intravesically, weekly for 4 wk, followed by resection of any residual lesions. Complete responses consisted of absence of any macroscopic, histologically confirmed, residual lesion, and no response in the presence of residual lesions. The effect on prophylaxis was measured in months as disease-free interval to first recurrence, and as percentage of patients recurring within the first 12 mo. Toxicity was assessed as local and systemic. ResultsOf 34 recruited patients, 28 consecutive patients were evaluable, with complete responses observed in 13 of 28 (46.4%) and no response in 15 (53.6%). Median time to first recurrence was 9.1 mo (range: 2.9–26.5) for 19 of 28 (67.8%) patients experiencing recurrence during the first year. Local or systemic toxicity was observed in 9 of 34 (26.4%) patients, resulting in protocol interruption in 6 patients. ConclusionsIntravesical gemcitabine alone showed ablative efficacy in nearly one half of the patients under study. Drug tolerability was good, both locally and systemically.

The Outcome of Patients on Dialysis With Upper Urinary Tract Transitional Cell Carcinoma

Transitional cell carcinoma is the most common upper urinary tract cancer in Taiwanese patients on dialysis. It is a unique finding compared with Western countries. Unfortunately, the long-term outcomes of patients with upper urinary tract transitional cell carcinoma on dialysis are largely unknown. This study presents clinical outcome of patients on dialysis with upper urinary tract transitional cell carcinoma. We retrospectively reviewed the medical records of all patients with upper urinary tract transitional cell carcinoma who had end stage renal disease and underwent dialysis. Traditional prognostic factors including age, sex, tumor grade, stage and tumor location were analyzed with respect to disease recurrence and survival. A total of 73 patients were included in this study. The major complaints were painless gross hematuria and urethral bloody discharge. Disease relapsed in 40 (54.8%) patients at average time of 15 months (2 to 92). Univariate analysis failed to identify significant prognostic factors for recurrence. The average duration between primary and contralateral metachronous upper urinary tract transitional cell carcinoma recurrence was 36 months (range 5 to 96). Patients on dialysis with upper urinary tract transitional cell carcinoma who had previous or concurrent bladder tumor, or who had a history of recurrent bladder tumor, had high contralateral upper urinary tract transitional cell carcinoma recurrence. (p = 0.038) The statistically significant prognostic factor for disease-free survival was pT stage (p = 0.041). Patients on dialysis with painless gross hematuria or bloody urethral discharge must undergo detail urinary system evaluation. Since patients with upper urinary tract transitional cell carcinoma on dialysis have a high recurrence rate and metachronous or even multiple, early synchronous tumor characteristics that may be missed by imaging, total urinary tract exenteration is a recommended therapeutic option.

Superficial transitional cell carcinoma of the ureteral orifice: Higher risk of developing subsequent upper urinary tract tumors

Reports specifically addressing transitional cell carcinoma (TCC) of the ureteral orifice are scarce. This paper presents our experiences of such tumors, including the characteristics of the disease and the incidence of subsequent upper urinary tract recurrence. This study included 572 new cases of TCC of the urinary bladder diagnosed in our institute during a period of 5 years. Thirty-one (5.4%) patients had superficial tumors involving ureteral orifices. All 31 patients underwent transurethral resection of the bladder tumors, including the involved ureteral orifices. After the surgery, patients received regular follow up with cystourethroscopy, urine cytology and periodic intravenous pyelography (IVP). Ureterorenoscopy was performed in cases of suspicious IVP or urine cytology findings. Thirty-one patients with superficial tumors involving the ureteral orifice were followed up for 5-8 years or until death. The pathological stage was Ta in 16 cases and T1 in 15 cases. Bladder tumor recurrence was noted in three (18.8%) of the pTa patients and in seven (46.7%) of the pT1 patients. Subsequent upper urinary tract tumors developed in four (12.9%) patients between 33 and 67 months (mean: 33.5) after the first transurethral resection. All four cases of upper tract recurrence had pT1 primary bladder tumor, which recurred for 1-3 times (mean 1.8) before upper tract recurrence. None of these patients had ureteral stenting after bladder tumor resection. Three of four patients with upper tract recurrence had single lower ureteral tumor, while the remaining one patient had multiple tumors. Patients with subsequent upper urinary tract tumors underwent nephroureterectomy and bladder cuff excision. One died of the disease; the other three cases were free of the disease after the therapy. Patients with primary superficial bladder transitional cell carcinoma involving the ureteral orifice have a higher risk of developing subsequent upper urinary tract tumors, particularly for pT1 primary bladder tumors. Frequent and close follow up is recommended.

Fluorescence diagnosis of bladder cancer

Standard management of newly presenting superficial bladder tumours is to remove the tumour endoscopically and to administer a single dose of a chemotherapeutic agent into the bladder postoperatively. However, between 20-40% of patients will develop a tumour in the bladder again within 12 months (Herr, 1997). There is controversy about whether these tumours are genuine recurrences or previously undetected tumours. Photodynamic diagnosis is currently the subject of clinical trials for detection and surveillance of bladder cancer. A solution is administered into the bladder preoperatively which is absorbed by the cancer cells. These areas within the bladder then fluoresce under blue light, aiding the surgeon to detect tumours that may not have been visible to the naked eye. The authors present a review of this developing technique and their early experiences of photodynamic diagnosis in clinical trials which appear to be clinically relevant in decreasing recurrent bladder tumours.

Dynamic Analysis of Recurrent Event Data Using the Additive Hazard Model

We propose a method for analysis of recurrent event data using information on previous occurrences of the event as a time-dependent covariate. The focus is on understanding how to analyze the effect of such a dynamic covariate while at the same time ensuring that the effects of treatment and other fixed covariates are unbiasedly estimated. By applying an additive regression model for the intensity of the recurrent events, concepts like direct, indirect and total effects of the fixed covariates may be defined in an analogous way as for traditional path analysis. Theoretical considerations as well as simulations are presented, and a data set on recurrent bladder tumors is used to illustrate the methodology.

Watchful Waiting Policy in Recurrent Ta G1 Bladder Tumors

ObjectiveTo determine the outcome of a watchful waiting policy in patients suffering from small, recurrent, papillary bladder tumors. MethodsWatchful waiting has been considered an option when a small (<10mm) papillary, asymptomatic tumor with negative urinary cytology was found on follow-up cystoscopy in patients who had previous resection(s) of superficial, low-grade (Ta) bladder tumor(s). The watchful waiting protocol included cystoscopy and urinary cytology every 3 months for 2 years (and then every 6 months). Surveillance was stopped if the patient had developed either symptoms related to the tumor or positive cytology, or if there had been a significant alteration in tumor morphology or size. ResultsThirty-eight watchful waiting periods were documented in 28 patients (mean age 67.7 years). Mean period length was 13.5 months (SD 14.4 months; range 3–60 months). Thirty periods were terminated with tumor resection. The main reasons for termination of surveillance were the appearance of additional tumors (19 patients) and excessive tumor growth (9 patients). Hematuria indicated tumor removal in only one patient. All resected tumors were stage Ta (23 were grade 1, and 7, grade 2). The rate of tumor growth during the watchful waiting period depended highly on the tumor’s largest diameter at the beginning of surveillance. If the initial tumor diameter was smaller than 5mm (32 cases), the tumor growth rate was 4±5.1mm3/mo (mean±SD); if the initial tumor diameter was ≥5mm (6 cases), the tumor growth rate was 870±1116mm3/mo (p<0.05). ConclusionsSmall, recurrent papillary bladder tumors after resection of low-grade Ta tumor(s) pose minimal risk for the patient. A watchful waiting policy— without resection of the tumor—may be considered in these patients.

Persistence, Recurrence, and Progression Rates of Superficial Bladder Tumours after Resection Using the Differentiated Technique

Objective: To investigate whether the differentiated resection technique for excising superficial bladder cancer leads to higher recurrence and progression rates as compared with regular resection. Subjects and Methods: We evaluated 163 patients, 66 undergoing a differentiated and 97 a regular resection. All patients underwent a routine second resection within 6–10 weeks. Recurrence and progression rates as well as tumour persistence on second resection were analyzed. Results: Patients with differentiated resections of bladder tumours did not have higher tumour recurrence and progression rates. Also, these patients had a significantly higher percentage of tumour-free second resections (p = 0.03). Conclusion: The differentiated resection technique for excising superficial bladder cancer has no negative influence on recurrence and progression rates, but it leads to a reduced tumour persistence.