Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Clinical Trial
. 2023 Sep;84(3):341-347.
doi: 10.1016/j.eururo.2023.06.014. Epub 2023 Jul 4.

Long-term Outcomes from a Phase 2 Study of Neoadjuvant Chemotherapy for Muscle-invasive Bladder Cancer (SWOG S1314; NCT02177695)

Thomas W Flaig  1 , Catherine M Tangen  2 , Siamak Daneshmand  3 , Ajjai Shivaram Alva  4 , M Scott Lucia  5 , David James McConkey  6 , Dan Theodorescu  7 , Amir Goldkorn  8 , Matthew I Milowsky  9 , Rick Bangs  10 , Gary R MacVicar  11 , Bruno R Bastos  12 , Jared S Fowles  13 , Daniel L Gustafson  13 , Melissa Plets  2 , Ian M Thompson Jr  14 , Seth P Lerner  15
Affiliations
Clinical Trial

Long-term Outcomes from a Phase 2 Study of Neoadjuvant Chemotherapy for Muscle-invasive Bladder Cancer (SWOG S1314; NCT02177695)

Thomas W Flaig et al. Eur Urol. 2023 Sep.

Abstract

Background: The COXEN gene expression model was evaluated for prediction of response to neoadjuvant chemotherapy for muscle-invasive bladder cancer (MIBC).

Objective: To conduct a secondary analysis of the association of each COXEN score with event-free survival (EFS) and overall survival (OS) and by treatment arm.

Design, setting, and participants: This was a randomized phase 2 trial of neoadjuvant gemcitabine-cisplatin (GC) or dose-dense methotrexate-vinblastine-adriamycin-cisplatin (ddMVAC) in MIBC.

Intervention: Patients were randomized to ddMVAC (every 14 d) or GC (every 21 d), both for four cycles.

Outcome measurements and statistical analysis: EFS events were defined as progression or death before scheduled surgery, a decision to not undergo surgery, recurrence, or death due to any cause after surgery. Cox regression was used to evaluate the COXEN score or treatment arm association with EFS and OS.

Results and limitations: A total of 167 evaluable patients were included in the COXEN analysis. The COXEN scores were not significantly prognostic for OS or EFS in the respective arms, but the GC COXEN score had a hazard ratio (HR) of 0.45 (95% confidence interval [CI] 0.20-0.99; p = 0.047) when the arms were pooled. In the intent-to-treat analysis (n = 227), there was no significant difference between ddMVAC and GC for OS (HR 0.87, 95% CI 0.54-1.40; p = 0.57) or EFS (HR 0.86, 95% CI 0.59-1.26; p = 0.45). Among the 192 patients who underwent surgery, pathologic response (pT0 vs downstaging vs no response) was strongly correlated with superior postsurgical survival (5-yr OS 90%, 89% and 52%, respectively).

Conclusions: The COXEN GC score has prognostic value for patients receiving cisplatin-based neoadjuvant treatment. The randomized, prospective design provides estimates of OS and EFS for GC and ddMVAC in this population. Pathologic response (<pT2) performed well as an intermediate endpoint in this modern cohort. For expediency in evaluating new regimens, pathologic response should continue to be used in phase 2 trials.

Patient summary: In this study, we evaluated a biomarker to predict the response to chemotherapy. The results did not meet the preset study parameters, but our study provides information on clinical outcomes with the use of chemotherapy before surgery for bladder cancer.

Trial registration: ClinicalTrials.gov NCT02177695.

Keywords: Biomarkers; Cystectomy; Neoadjuvant chemotherapy; Urinary bladder cancer.

PubMed Disclaimer

Conflict of interest statement

Financial disclosures: Thomas W. Flaig certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Thomas W. Flaig has received institutional research funding from Novartis, Bavarian Nordic, Dendreon, GTx, Janssen Oncology, Medivation, Sanofi, Pfizer, Bristol-Myers Squibb, Roche/Genentech, Exelixis, Aragon Pharmaceuticals, Sotio, Tokai Pharmaceuticals, AstraZeneca/MedImmune, Lilly, Astellas Pharma, Agensys, Seattle Genetics, La Roche-Posay, Merck, Seagen, Myovant Science, and Criterium; serves on the board of directors for a University of Colorado-UCHealth AML joint venture; is am a founder of and holds intellectual property interests in Aurora Oncology; and is an inventor on two patents related to early-stage bladder cancer treatment and detection filed by The University of Colorado. Seth P. Lerner has participated in clinical trials run by Aura Bioscience, Endo, FKD, JBL (SWOG), Genentech (SWOG), Merck (Alliance), QED Therapeutics, Vaxiion, and Viventia; is a consultant/advisory board member for Aura Bioscience, BMS, C2i Genomics, Ferring, Incyte, Pfizer/EMD Serono, Protara, Stimit, Vaxiion, and Verity; holds a patent for a TCGA classifier; and has received honoraria from Grand Rounds Urology and UroToday. David James McConkey has received grant support from AstraZeneca and Rainier Pharmaceuticals, and serves on advisory boards for Janssen, H3 Biomedicine, and Rainier Pharmaceuticals. Ajjai Shivaram Alva is a consultant and/or advisor for AstraZeneca, Bristol-Myers Squibb, Merck, Pfizer, and EMD Serono; is a paid member of a data and safety monitoring board for Eisai; has received grants/research support from AstraZeneca, Bristol-Myers Squibb, and Merck; and has received other institutional financial or material support from Arcus Biosciences, Astellas Pharma, Celgene, Clovis Oncology, Pfizer, Prometheus Biosciences, and Seattle Genetics. Matthew I. Milowsky has received institutional research funding from Merck, Roche/Genentech, Bristol-Myers Squibb, Clovis Oncology, Mirati Therapeutics, Incyte, Seagen, G1 Therapeutics, Alliance Foundation Trials, Alliance for Clinical Trials in Oncology, Arvinas, ALX Oncology, Loxo, and the Hoosier Cancer Research Network; has a consulting role with Loxo/Lilly; and has financial relationships with Elsevier, Medscape, and Research to Practice. Bruno R. Bastos has received honoraria from Regeneron, Astellas, Seattle Genetics, and Sanofi Genzyme. Dan Theodorescu is a consultant/advisory board member for Machavert. Siamak Daneshmand is an advisory board member for Janssen, Ferring, Photocure, Spectrum, Pacific Edge, and Protara; has a consulting role with Janssen, Ferring, Photocure, and Pacific Edge; has received institutional research funding from QED, Photocure, Janssen, Ferring, and Pacific Edge; and has investment interests in Taris. The remaining authors have nothing to disclose.

Figures

Fig. 1 –
Fig. 1 –
Overall survival for favorable versus unfavorable COXEN scores in the pooled population (n = 167).
Fig. 2 –
Fig. 2 –
Comparison of (A) event-free survival and (B) overall survival by treatment arm in an intent-to-treat analysis of patients randomized to gemcitabine-cisplatin (GC) or dose-dense methotrexate-vinblastine-adriamycin-cisplatin (ddMVAC) treatment. RC = radical cystectomy.
Fig. 2 –
Fig. 2 –
Comparison of (A) event-free survival and (B) overall survival by treatment arm in an intent-to-treat analysis of patients randomized to gemcitabine-cisplatin (GC) or dose-dense methotrexate-vinblastine-adriamycin-cisplatin (ddMVAC) treatment. RC = radical cystectomy.
Fig. 3 –
Fig. 3 –
Overall survival by pathologic response at surgery, including a complete pathologic response (pT0) or improvement to non–muscle-invasive disease (pT0).
See this image and copyright information in PMC

Comment in

References

    1. Flaig TW, Spiess PE, Agarwal N, et al. Bladder cancer, version 3.2020, NCCN clinical practice guidelines in oncology. J Natl Compr Cancer Netw 2020;18:329–54. - PubMed
    1. Grossman HB, Natale RB, Tangen CM, et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med 2003;349:859–66. - PubMed
    1. Zaid HB, Patel SG, Stimson CJ, et al. Trends in the utilization of neoadjuvant chemotherapy in muscle-invasive bladder cancer: results from the National Cancer Database. Urology 2014;83:75–80. - PubMed
    1. Sternberg CN, de Mulder P, Schornagel JH, et al. Seven year update of an EORTC phase III trial of high-dose intensity M-VAC chemotherapy and G-CSF versus classic M-VAC in advanced urothelial tract tumours. Eur J Cancer 2006;42:50–4. - PubMed
    1. von der Maase H, Hansen SW, Roberts JT, et al. Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol 2000;18:3068–77. - PubMed

Publication types

Associated data