Role of NAC in cT0 Muscle-invasive Bladder Cancer After Maximal TURBt

Surgery Clinical Trial

Official title:

Neoadjuvant Chemotherapy Plus Cystectomy vs Cystectomy Alone for cT0 Muscle-invasive Bladder Cancer After Maximal TURBt: Multicentre Prospective Randomized Controlled Trial

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05776758
• Other study ID #: RS1779/22(2738)
• Status: Recruiting
• Phase: Phase 3
• Start date: April 2024
• Est. completion date: January 2027

Study information

• Verified date: April 2024
• Source: Regina Elena Cancer Institute
• Contact: Riccardo Mastroianni, MD
• Phone: 0652665005
• Email: riccardo.mastroianni[@]ifo.it
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This prospective randomized controlled trial (RCT) is designed to provide high level evidence describing the non-inferiority of radical cystectomy (RC) alone versus neoadjuvant chemotherapy (NAC) plus RC on survival outcomes of patients with a diagnostic transurethral resection of bladder tumor (TURBt) of non-metastatic muscle invasive bladder cancer (MIBC) (T2-T4 N0 M0) and non-radiologic or endoscopic residual tumor after a maximal TURBt (cT0). Our hypothesis is that performing NAC in the absence of residual disease, after a maximal TURBt, has no survival benefit over performing an early cystectomy. Since no downstaging could be achieved in patients with no residual tumor into the bladder, the benefits of neoadjuvant chemotherapy in this setting could be not significant and it might turn into unnecessary toxicity and a substantial delay to surgical treatment.

Description:

Radical Cystectomy (RC) is considered the reference option for treatment of urothelial muscle invasive bladder cancer (MIBC). However, RC alone has been reported 5-year survival in about 50% of patients. Therefore, to improve survival outcomes in patients with non-metastatic MIBC, cisplatin-based neoadjuvant chemotherapy (NAC) has been introduced. On the one hand, major tolerability, higher patient compliance and lower burden of micrometastatic disease are listed as potential advantages of administering NAC before planned definitive surgery. Several phase III randomized controlled trials (RCTs) reported the potential survival benefit of NAC administration.

Moreover, the updated analysis of a large phase III RCT, globally including all patients with muscle invasive bladder cancer from T2 to T4, regardless of post transurethral resection of bladder tumor (TURBt) tumor volume, with a median follow-up of 8-yrs confirmed previous results providing additional findings:

• 16% reduction in mortality risk;

• improvement in 10-yr survival from 30% to 36% with NAC;

• Benefit with regard to distant metastases;

• the addition of NAC provided no benefit for locoregional control and locoregional disease free survival (DFS).

On the other hand, the possibility to predict patients' sensitivity to chemotherapy is still limited. Therefore, the delay in performing RC and the theoretical impact of NAC on surgical morbidity are considered significant limitations to a routine administration of neoadjuvant treatments. As a result, it is growing the interest at improving selection clinical criteria to identify the ideal candidates to NAC, in order to obtain the maximal survival benefit of NAC, minimizing its possible disadvantages. Reliable predictive markers and molecular tumour profiling might guide the use of NAC in the future, but nowadays they are not currently used in clinical practice.

Despite the evidence supporting the use of NAC, its routine administration is still limited. The risk of unresponse after NAC, with the consequent delay in surgical treatment, and the possible impact on surgical morbidity after RC, are the major limitations to the wide administration of NAC. Previous evidences supported the use of NAC in patients with T2 to T4a BCa, regardless of tumor volume at the time of NAC. It is growing the interest on a tailored approach to treat genitourinary cancer, therefore it is needed much more efforts to select which patient will benefit most from NAC rather than an early RC. To answer this question, it is needed to selectively perform RCTs aiming to test specific treatments in equally specific patients. The primary objective of the trial is to demonstrate the non-inferiority of RC alone versus NAC plus RC on survival outcomes of patients with a diagnostic TURBt of non-metastatic muscle invasive bladder cancer (MIBC) (T2-T4 N0 M0) and non-radiologic or endoscopic residual tumor after a maximal TURBt (cT0). Survival benefits of cisplatin-based NAC were already described. The SWOG trial 3 reported a 33% reduction of estimated risk of death in the NAC plus cystectomy group compared to RC alone.

Specifically, Authors reported that survival benefit of NAC appeared to be strongly related to downstaging of the tumor to pT0: 38% and 15% in NAC plus RC and RC alone cohorts, respectively (p<0.001). At 5yr, 85% of the patients with a pT0 surgical specimen were alive. Analysis of survival according to treatment group (NAC plus cystectomy vs cystectomy alone) and pathologically free of cancer (pT0) or residual disease at the time of cystectomy evidenced comparable outcomes between groups in pT0 patients (2yr OS: 90% vs 94% in NAC plus RC and RC alone cohorts, respectively) while a slight difference occurred in patients with residual disease at the time of cystectomy (2yr OS: 66% vs 52% in NAC plus RC and RC alone cohorts, respectively). As a result, the impact of NAC seems to play a negligible role in pT0 patients, while major benefits were observed in presence of residual disease. However, all the available RCTs did not discuss the endoscopically feasibility to achieve a cT0 stage, after a maximal TURBt, prior to RC. Moreover, systematic therapies are not devoid of limitations and they need to be carefully administered, in order to reduce toxicity, to minimize the risk of cystectomy delay in patients not sensitive to chemotherapy and to reduce the impact of NAC on surgical and health related quality of life (HRQoL) outcomes. Therefore, it is necessary to improve the selection criteria of patients' candidates for NAC plus cystectomy.

The hypothesis of investigators is that performing NAC in the absence of residual disease, after a maximal TURBt, has no survival benefit over performing an early cystectomy. Whenever endoscopically feasible, the complete resection of MIBC during TURB, particularly for T2 bladder cancer, will define a condition of cT0 stage, where probably no benefits would be observed in terms of downstaging for patients receiving NAC plus RC than those undergoing an early RC alone.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 236
• Est. completion date: January 2027
• Est. primary completion date: January 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• diagnostic TURBt with cT2-4, cN0, cM0;

• non-radiologic or endoscopic residual tumor after a maximal TURBt (cT0);

• patients eligible to curative intent, candidate to surgical treatment and/or NAC (all patients must meet all the criteria required to be able to undergo RC and/or NAC);

• = 18 yrs old;

• compliants patients able to follow the study protocol and fill in EORTC quality of life questionnaires;

• patients able to provide a written informed consent for the trial

Exclusion criteria:

• anaesthesiologic contraindications to surgery;

• palliative intent;

• patients ineligible for cisplatin-combination chemotherapy

Related Conditions & MeSH terms

• Chemotherapy Effect
• Muscle-Invasive Bladder Carcinoma
• Surgery
• Urinary Bladder Neoplasms

Intervention

Drug:
• cisplatin based neoadjuvant chemotherapy
cisplatin based neoadjuvant chemotherapy

Procedure:
• Radical cystectomy alone
RC alone

Locations

Country	Name	City	State
Italy	Riccardo Mastroianni	Rome

Sponsors (1)

Lead Sponsor	Collaborator
Regina Elena Cancer Institute

Country where clinical trial is conducted

Italy, 

References & Publications (11)

Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg. 2004 Aug;240(2):205-13. doi: 10.1097/01.sla.0000133083.54934.ae. — View Citation

Driscoll JJ, Rixe O. Overall survival: still the gold standard: why overall survival remains the definitive end point in cancer clinical trials. Cancer J. 2009 Sep-Oct;15(5):401-5. doi: 10.1097/PPO.0b013e3181bdc2e0. — View Citation

Grossman HB, Natale RB, Tangen CM, Speights VO, Vogelzang NJ, Trump DL, deVere White RW, Sarosdy MF, Wood DP Jr, Raghavan D, Crawford ED. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J — View Citation

International Collaboration of Trialists; Medical Research Council Advanced Bladder Cancer Working Party (now the National Cancer Research Institute Bladder Cancer Clinical Studies Group); European Organisation for Research and Treatment of Cancer Genito- — View Citation

Kim HS, Jeong CW, Kwak C, Kim HH, Ku JH. Disease-Free Survival at 2 and 3 Years is a Significant Early Surrogate Marker Predicting the 5-Year Overall Survival in Patients Treated with Radical Cystectomy for Urothelial Carcinoma of the Bladder: External Ev — View Citation

Neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: a randomised controlled trial. International collaboration of trialists. Lancet. 1999 Aug 14;354(9178):533-40. Erratum In: Lancet 1999 Nov 6;354(9190):16 — View Citation

Stein JP, Lieskovsky G, Cote R, Groshen S, Feng AC, Boyd S, Skinner E, Bochner B, Thangathurai D, Mikhail M, Raghavan D, Skinner DG. Radical cystectomy in the treatment of invasive bladder cancer: long-term results in 1,054 patients. J Clin Oncol. 2001 Fe — View Citation

Stein JP, Skinner DG. Radical cystectomy for invasive bladder cancer: long-term results of a standard procedure. World J Urol. 2006 Aug;24(3):296-304. doi: 10.1007/s00345-006-0061-7. Epub 2006 Mar 4. — View Citation

Takata R, Katagiri T, Kanehira M, Shuin T, Miki T, Namiki M, Kohri K, Tsunoda T, Fujioka T, Nakamura Y. Validation study of the prediction system for clinical response of M-VAC neoadjuvant chemotherapy. Cancer Sci. 2007 Jan;98(1):113-7. doi: 10.1111/j.134 — View Citation

Takata R, Katagiri T, Kanehira M, Tsunoda T, Shuin T, Miki T, Namiki M, Kohri K, Matsushita Y, Fujioka T, Nakamura Y. Predicting response to methotrexate, vinblastine, doxorubicin, and cisplatin neoadjuvant chemotherapy for bladder cancers through genome- — View Citation

Witjes JA, Bruins HM, Cathomas R, Comperat EM, Cowan NC, Gakis G, Hernandez V, Linares Espinos E, Lorch A, Neuzillet Y, Rouanne M, Thalmann GN, Veskimae E, Ribal MJ, van der Heijden AG. European Association of Urology Guidelines on Muscle-invasive and Met — View Citation

* Note: There are 11 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	To demonstrate the non-inferiority of radical cystectomy (RC) alone versus neoadjuvant chemotherapy plus RC on 2 years Overall Survival (OS) rates, defined as the length of time from surgery until death from any cause.	Overall Survival rates	2 years
Secondary	To compare disease free survival (DFS) rates, defined as the length of time from surgery to local disease recurrence	To evaluate early (6 months), mid-term (1 year) and long-term (2 years) DFS rates	6 months, 1 year, 2 years
Secondary	To evaluate metastasis free survival (MFS) rates, defined as the length of time from surgery to metastasis recurrence.	To evaluate early (6 months), mid-term (1 year) and long-term (2 years) MFS rates	6 months, 1 year, 2 years
Secondary	To evaluate recurrence free survival (RFS), rates defined as the length of time from surgery to disease recurrence.	To evaluate early (6 months), mid-term (1 year) and long-term (2 years) RFS rates	6 months, 1 year, 2 years
Secondary	To evaluate impact of NAC on perioperative complications rate (described accordingly to Clavien Dindo classification into minor o major complications)	To evaluate impact of NAC on perioperative complications rate within hospital stay	Within hospital stay
Secondary	To evaluate impact of NAC on postoperative complications rate described accordingly to Clavien Dindo classification into minor o major complications)	To evaluate impact of NAC on postoperative complications rate at 30 days, 90 days and 180 days	30 days, 90 days and 180 days
Secondary	To evaluate impact of NAC on readmission rates (defined as postoperative rehospitalization)	To evaluate impact of NAC on readmission rates at 30 days, 90 days and 180 days	30 days, 90 days and 180 days
Secondary	To compare health-related quality of life (HRQoL) outcomes, using EORTC self-assessed questionnaires	To compare health-related quality of life (HRQoL) outcomes at 3 months, 6 months, 1 year and 2 years	3 months, 6 months, 1 year and 2 years