Predicting Response to Neoadjuvant Chemotherapy in Muscle-invasive Bladder Cancer

Muscle-Invasive Bladder Carcinoma Clinical Trial

Official title:

The Impact of Tumor Microenvironment and Clinicopathological Features in Predicting Response to Neoadjuvant Chemotherapy in Muscle Invasive Bladder Cancer

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06325423
• Other study ID #: response to NAC in MIBC
• Status: Not yet recruiting
• Start date: April 2024
• Est. completion date: June 2027

Study information

• Verified date: March 2024
• Source: Assiut University
• Contact: Gehad A Abdelrazik, ass.lecturer
• Phone: 01097381211
• Email: dr.gehadahmed95[@]gmail.com
• Is FDA regulated: No
• Study type: Observational [Patient Registry]

Clinical Trial Summary

Bladder cancer (BC) is the 10th most commonly diagnosed cancer worldwide and the second most common cancer among Egyptian males.

The mainstay of treatment of muscle-invasive BC( MIBC) is neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC) or bladder preservation(BP) using maximal transurethral resection of the bladder tumor followed by chemoradiation. The rationale to use NAC before RC or BP is to eradicate micro-metastasis and to downstage the primary tumor.

The 5-year cancer-specific survival for responders to NAC is 90%, in contrast to 30-40% for those not obtaining an objective response. Drawbacks of NAC are disappointing delay of surgery in non-responders and the potential toxicity. So, predictors of response to NAC are necessary to identify patients who may achieve pathologic complete response and will benefit from BP, and the others who may not respond to NAC and spare them NAC toxicity and RC delay.

Tumor microenvironment (TME), including neutrophil extracellular traps (NETs), and CD8+ T lymphocytes is a promising predictor of response to NAC in MIBC.

NETs are reticulated DNA structures decorated with various protein substances (e.g., histones, myeloperoxidase, neutrophil elastase).NETs are involved in tumor growth, metastasis, and treatment resistance. Moreover, NETs can inhibit T cell responses, thereby promoting tumor growth.

On the other hand, immune cells that are present in the TME play a major role in slowing down tumor progression. CD8+T lymphocytes play a central role in immune-mediated control of cancer . Also, they have been found to be a prognostic tool for advanced BC.

Description:

Formalin fixed paraffin embedded tissue specimen of the baseline TUR of MIBC will be obtained from pathology laboratory, Pathology Department, Assiut University.

• Histological diagnosis of H&E stained sections will be confirmed.

• Immunohistochemical staining for Citrullinated histone H3 (H3Cit) antibody as a hallmark of NETs, and CD8 antibody to quantity density of NETs and CD8 expression, then calculate NETs/CD8 ratio.

• Baseline clinicopathological features of MIBC patients who received neoadjuvant chemotherapy will be collected from patients' records.

• Correlation between NETs expression, CD8 expression, NETs/CD8 ratio, and the baseline clinicopathological features with the response to neoadjuvant chemotherapy.

• develop a risk score based on the significant predictors of response to identify patients who may achieve pathologic complete response and will benefit from BP, and the others who may not respond to NAC and spare them NAC toxicity and RC delay.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 50
• Est. completion date: June 2027
• Est. primary completion date: June 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 19 Years and older

Eligibility

Inclusion Criteria:

• Pathologically proven pure urothelial carcinoma, or morphologic variant of urothelial carcinoma.

• Patients with =T2, N0-1, M0, according to American Joint Committee on Cancer (AJCC) TNM Staging System for Bladder Cancer 8th ed., 2017.

• Patients who received platinum-based neoadjuvant chemotherapy before RC or BP.

• Available paraffin-embedded TUR specimens for Immunohistochemistry (IHC).

Exclusion Criteria:

• Non urothelial carcinoma.

• Not muscle invasive < T2.

• Metastatic bladder cancer.

• No available paraffin-embedded TUR specimens for IHC.

Related Conditions & MeSH terms

• Muscle-Invasive Bladder Carcinoma
• Urinary Bladder Neoplasms

Intervention

Combination Product:
• neoadjuvant chemotherapy
platinum-based chemotherapy before radical cystectomy or bladder preservation

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Assiut University

References & Publications (12)

Durgeau A, Virk Y, Corgnac S, Mami-Chouaib F. Recent Advances in Targeting CD8 T-Cell Immunity for More Effective Cancer Immunotherapy. Front Immunol. 2018 Jan 22;9:14. doi: 10.3389/fimmu.2018.00014. eCollection 2018. — View Citation

Hadrup S, Donia M, Thor Straten P. Effector CD4 and CD8 T cells and their role in the tumor microenvironment. Cancer Microenviron. 2013 Aug;6(2):123-33. doi: 10.1007/s12307-012-0127-6. Epub 2012 Dec 16. — View Citation

Ikarashi D, Kitano S, Tsuyukubo T, Takenouchi K, Nakayama T, Onagi H, Sakaguchi A, Yamashita M, Mizugaki H, Maekawa S, Kato R, Kato Y, Sugai T, Nakatsura T, Obara W. Pretreatment tumour immune microenvironment predicts clinical response and prognosis of m — View Citation

Jiang DM, Jiang H, Chung PWM, Zlotta AR, Fleshner NE, Bristow RG, Berlin A, Kulkarni GS, Alimohamed NS, Lo G, Sridhar SS. Neoadjuvant Chemotherapy Before Bladder-Sparing Chemoradiotherapy in Patients With Nonmetastatic Muscle-Invasive Bladder Cancer. Clin — View Citation

Kaltenmeier C, Yazdani HO, Morder K, Geller DA, Simmons RL, Tohme S. Neutrophil Extracellular Traps Promote T Cell Exhaustion in the Tumor Microenvironment. Front Immunol. 2021 Nov 24;12:785222. doi: 10.3389/fimmu.2021.785222. eCollection 2021. — View Citation

Koebel CM, Vermi W, Swann JB, Zerafa N, Rodig SJ, Old LJ, Smyth MJ, Schreiber RD. Adaptive immunity maintains occult cancer in an equilibrium state. Nature. 2007 Dec 6;450(7171):903-7. doi: 10.1038/nature06309. Epub 2007 Nov 18. — View Citation

Rosenblatt R, Sherif A, Rintala E, Wahlqvist R, Ullen A, Nilsson S, Malmstrom PU; Nordic Urothelial Cancer Group. Pathologic downstaging is a surrogate marker for efficacy and increased survival following neoadjuvant chemotherapy and radical cystectomy fo — View Citation

Sharma P, Retz M, Siefker-Radtke A, Baron A, Necchi A, Bedke J, Plimack ER, Vaena D, Grimm MO, Bracarda S, Arranz JA, Pal S, Ohyama C, Saci A, Qu X, Lambert A, Krishnan S, Azrilevich A, Galsky MD. Nivolumab in metastatic urothelial carcinoma after platinu — View Citation

Skinner DG, Lieskovsky G. Contemporary cystectomy with pelvic node dissection compared to preoperative radiation therapy plus cystectomy in management of invasive bladder cancer. J Urol. 1984 Jun;131(6):1069-72. doi: 10.1016/s0022-5347(17)50809-5. — View Citation

Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021 May;71(3):209-249. doi: 10.3322/caa — View Citation

Witjes JA, Comperat E, Cowan NC, De Santis M, Gakis G, Lebret T, Ribal MJ, Van der Heijden AG, Sherif A; European Association of Urology. EAU guidelines on muscle-invasive and metastatic bladder cancer: summary of the 2013 guidelines. Eur Urol. 2014 Apr;6 — View Citation

Zhao J, Jin J. Neutrophil extracellular traps: New players in cancer research. Front Immunol. 2022 Aug 19;13:937565. doi: 10.3389/fimmu.2022.937565. eCollection 2022. — View Citation

* Note: There are 12 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Evaluation of the expression of NETs and CD8 in paraffin-embedded TUR biopsies	evaluation of the density of Citrullinated Histone H3 as a hallmark of NETs and the density of CD8 in the baseline FFPE TUR specimens	6 months
Primary	- Response to platinum-based chemotherapy in localized MIBC in relation to: NETs expression, CD8 expression, NET/CD8 ratio and baseline clinicopathological features	Correlation between NETs expression, CD8 expression, NETs/CD8 ratio and the baseline clinicopathological features of MIBC and the response to neoadjuvant chemotherapy	6 months
Secondary	Local recurrence-free survival (RFS)	the length of time from radical cystectomy/ bladder preservation to local recurrence.	2 years