Predicting Response to Neoadjuvant Chemotherapy in Muscle-invasive Bladder Cancer
NCT ID: NCT06325423
Last Updated: 2024-03-26
Study Results
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Basic Information
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NOT_YET_RECRUITING
50 participants
OBSERVATIONAL
2024-04-30
2027-06-30
Brief Summary
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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.
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Detailed Description
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* 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.
Conditions
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Study Design
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COHORT
OTHER
Study Groups
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MIBC patients who received NAC
Patients with muscle-invasive bladder cancer who received neoadjuvant chemotherapy before radical cystectomy or bladder preservation
neoadjuvant chemotherapy
platinum-based chemotherapy before radical cystectomy or bladder preservation
Interventions
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neoadjuvant chemotherapy
platinum-based chemotherapy before radical cystectomy or bladder preservation
Eligibility Criteria
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Inclusion Criteria
* 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
* Not muscle invasive \< T2.
* Metastatic bladder cancer.
* No available paraffin-embedded TUR specimens for IHC.
19 Years
ALL
No
Sponsors
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Assiut University
OTHER
Responsible Party
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Gehad Ahmed Abd El-Razik
Assistant Lecturer
Principal Investigators
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Amal R Ibrahim, Ass.Prof
Role: STUDY_DIRECTOR
Assiut University
Hanan G Mostafa, Professor
Role: STUDY_DIRECTOR
Assiut University
Central Contacts
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References
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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/caac.21660. Epub 2021 Feb 4.
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.
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 for muscle-invasive urothelial bladder cancer. Eur Urol. 2012 Jun;61(6):1229-38. doi: 10.1016/j.eururo.2011.12.010. Epub 2011 Dec 13.
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 Genitourin Cancer. 2019 Feb;17(1):38-45. doi: 10.1016/j.clgc.2018.09.021. Epub 2018 Oct 4.
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;65(4):778-92. doi: 10.1016/j.eururo.2013.11.046. Epub 2013 Dec 12.
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 muscle-invasive bladder cancer in the neoadjuvant chemotherapy setting. Br J Cancer. 2022 Mar;126(4):606-614. doi: 10.1038/s41416-021-01628-y. Epub 2021 Nov 15.
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.
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.
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.
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.
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.
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 platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2017 Mar;18(3):312-322. doi: 10.1016/S1470-2045(17)30065-7. Epub 2017 Jan 26.
Other Identifiers
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response to NAC in MIBC
Identifier Type: -
Identifier Source: org_study_id
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