Clinical trials corner issue 11(1)
Abstract:
Dear Readers,
In this issue, we highlight recently presented and published trials from ESMO 2024 Annual Meetings. In the future, please reach out to us directly in order to highlight any specific clinical trials at pkagarwal@uchicago.edu or cns9006@med.cornell.edu and/or at BLC@iospress.com.
Sincerely,
Piyush K. Agarwal, MD
Associate Editor, Bladder Cancer
Director, Bladder Cancer Program
The University of Chicago
Chicago, Illinois
Cora N. Sternberg, MD, FACP
Associate Editor, Bladder Cancer
Clinical Director, Englander Institute for Precision Medicine
Weill Cornell Medicine
New York, New York
Practice patterns and outcomes of conventional versus split-dose cisplatin in neoadjuvant ddMVAC in bladder cancer
Abstract:
Background
The practice patterns and efficacy of ddMVAC administered with split-dose cisplatin for patients with muscle-invasive bladder cancer (MIBC) remains largely undefined.
Objective
To characterize the application and overall survival (OS) in patients with MIBC receiving conventional ddMVAC versus split-dosed ddMVAC and to examine the predictive variables in those receiving split-dosed cisplatin.
Methods
Using data from the CancerLinQ Discovery database, we identified 626 patients with bladder cancer between 2000–2023 with receipt of ddMVAC. The primary outcome was OS by receipt of split-dose versus conventional ddMVAC. A secondary outcome of interest assessed predictors of receipt of split-dose ddMVAC. Use of split-dose versus conventional ddMVAC was compared using chi-square tests. Univariate and multivariable OS were estimated using Cox proportional hazards models. Predictors of receipt of split dose versus conventional ddMVAC were estimated using logistic regression models.
Results
Most patients with MIBC are treated with standard dose ddMVAC. In multivariate analysis, no statistically significant difference in OS was observed between split-dose and conventional ddMVAC (HR 1.3, CI 0.78–2.18, p = 0.316). We demonstrate a notable decline in the use of split-dose cisplatin over time. Baseline GFR and performance status were not predictors of split-dosing in this cohort.
Conclusions
Most patients with MIBC received conventional ddMVAC with decreasing frequency of split-dose cisplatin use over time. We did not observe a difference in OS between patients with MIBC who received standard versus split-dose cisplatin.
Standard vs extended lymphadenectomy for muscle invasive bladder cancer
Abstract:
Muscle invasive urothelial cancer of the bladder (MIBC) is often a lethal disease and its treatments, particularly radical cystectomy and urinary diversion, may cause considerable morbidity (including grade 5 = death), prolonged hospitalizations, high re-hospitalization rates, side effects (e.g., sexual dysfunction), complications (e.g., hydronephrosis), and significant long term body image issues. There have been attempts to improve efficacy (e.g., using neoadjuvant and adjuvant systemic therapy) and reduce short-term (e.g., enhanced recovery after surgery [ERAS] protocols, minimally invasive surgical approaches) and intermediate/ long-term (e.g., “nerve” and vaginal sparing cystectomies, continent urinary diversions) morbidity. Despite these efforts improvements in outcomes have only been modest and much of these attributable to improvements in perioperative and supportive care.
The recently published results of the SWOG S-1011 randomized trial of standard vs extended lymphadenectomy in patients with MIBC (stages T2-4a) undergoing cystectomy and urinary diversion adds to this literature.1
As background, a large population data base study reported that cancer specific survival was better in patients undergoing cystectomy who had pelvic lymph node dissection (LND) than in those who had no lymphadenectomy.2 Subsequently, data from several retrospective series3 and one prospective observational study4 indicated that extended LND resulted in survival benefits, and 5–15 years ago it became adopted by many high-volume centers as the appropriate approach with no randomized prospective evidence supporting it.5
In the SWOG S-1011 trial, 658 patients with MIBC (57% of whom had received neoadjuvant chemotherapy [NAC]) were registered and 592 eligible patients were randomized intraoperatively to undergo radical cystectomy and “standard” bilateral pelvic LND (external iliac, internal iliac and obturator nodes up to the iliac bifunction5) vs “extended” LND (the “standard” LND template + common iliac, presciatic and presacral nodes, and if considered appropriate the dissection could continue up to the inferior mesenteric artery). Oncologic outcomes including disease-free and overall survival, local and distant recurrence rates as well as morbidities (up to grade 5) and surgical staging, margins and node yields were monitored.
This surgical trial had serval methodological features worth noting which tried to overcome the variability inherent with many surgeons taking part in a cooperative group study looking at surgical (and oncologic) outcomes. These included:
1- Preoperative credentialing of participating surgeons by a committee of experienced cystectomy surgeons including having performed at least 50 cystectomies over the previous 3 years, and review of operative and pathology reports and of intraoperative photographs of operative fields from five recent cystectomies demonstrating the completeness of the surgeries.
2- The randomized assignment of extended or standard dissection was made intraoperatively, with neither the patient nor surgeon knowing the assignment preoperatively.
3- 3. Lymph node packets were identified by location and sent separately for counts of number of nodes identified by the pathologist and number of positive nodes, in part as a form of quality control.
4- There was a peer review quality control assessment of 100 randomly selected patients including at least one patient per surgeon and 50 patients from each group by two experienced urological oncology surgeons who were not associated with the study.
Patients undergoing extended dissection had more lymph nodes removed (median 39) than those with the standard LND (median 24), and if any nodal metastases, a greater number of positive nodes (median 2 [range 1–35]) vs (median 1 [range 1–16]). However, the percentage of patients in each group with any positive node was similar (26% for extended LND vs 24% for standard). Most importantly disease-free survival (5 year estimated 60% for standard vs 56% for extended) and overall survival (63% standard vs 59% extended) were similar in both groups.
Moreover, there was a higher proportion of patients with grade 3–5 complications who underwent extended dissection (54% vs 44%, p = 0.01), including 19 deaths over the first three months in the extended group vs 7 in the standard group.
A similar trial has been conducted in Germany, differing in that clinical stage T1 patients were included and those who received NAC were not, also showed no significant differences in recurrence-free, cancer specific on overall survivals.6 Additionally, randomized phase 3 trials of standard vs. extended LNDs in endometrial, gastric, and pancreatic cancers have not showed improved survival with extended dissections despite prior nonrandomized series and population-based data supporting extended dissections in those malignances.5–7 There was also increased morbidity with the extended dissections in patients with gastric cancer.7
So, what we have learned from the SWOG S-1011 trial is that rigorous surgical studies can be performed in the cooperative group setting with careful attention to the screening of the participating surgeons (as well as patients) and strict performance monitoring during the study. However, the outcome results reinforce the conclusions that when it comes to LND for MIBC (as well as other abdominal/pelvic malignancies), “bigger” is not always “better” and is associated with higher morbidity.
Platinum-based chemotherapy rechallenge or enfortumab vedotin after maintenance avelumab or pembrolizumab for locally advanced or metastatic urothelial carcinoma
Abstract:
Background:
In current clinical practice, the use of switch maintenance avelumab is recommended for patients with locally advanced and metastatic urothelial carcinoma who experience favorable responses to first-line chemotherapy.
Objective:
We aimed to evaluate the potential advantages of platinum-based chemotherapy (Pl-CT) rechallenge after maintenance avelumab.
Methods:
A retrospective analysis involving 383 patients treated with first-line Pl-CT between 2015 and 2023 was conducted. Subsequent treatment strategies included Pl-CT or enfortumab vedotin (EV) following maintenance avelumab or pembrolizumab, and their benefit was evaluated.
Results:
Pl-CT rechallenge following maintenance avelumab did not show significant benefits, demonstrating lower response rates and shorter progression-free survival compared to EV. Conversely, both Pl-CT and EV following pembrolizumab showed similar efficacy.
Conclusions:
These findings suggest that in the current clinical landscape, EV might be a more preferable option than Pl-CT rechallenge subsequent to avelumab maintenance therapy, thereby influencing treatment decisions for metastatic urothelial carcinoma.
Impact of DNA repair deficiency on sensitivity to antibody-drug conjugate (ADC) payloads in bladder cancer
Abstract:
Background
Enfortumab vedotin (EV) and Sacituzumab govitecan (SG) are antibody-drug conjugates (ADCs) with demonstrated activity in advanced bladder cancer. A subset of bladder tumors harbors a DNA repair deficiency in either the homologous recombination (HR) or nucleotide excision repair (NER) pathway that has the potential to impact sensitivity to specific classes of therapeutics.
Objective
Define the impact of HR or NER deficiency on sensitivity to ADC payloads alone or in combination with DNA repair targeted agents in bladder cancer.
Methods
Isogenic cell pairs with versus without HR or NER deficiency were profiled using DNA repair and drug sensitivity assays. Sensitivity to the ADC payloads monomethyl auristatin E (MMAE) and SN-38 alone or in combination with small molecule inhibitors of poly(ADP-ribose) polymerase (PARP), ATR, or USP1 were measured using cell viability assays.
Results
BRCA2 loss was sufficient to confer an HR deficient phenotype and increase sensitivity to cisplatin and PARP inhibition in bladder cancer cell lines. HR deficiency, but not NER deficiency, increased sensitivity to MMAE and SN-38 in bladder cancer cells. The combination of SN-38 and PARP inhibition displayed synergistic cell killing independent of HR or NER status.
Conclusion
HR and NER deficiency have distinct impacts on sensitivity to cisplatin and ADC payloads in bladder cancer preclinical models.
Summary from the NCI clinical trials planning meeting on next generation of clinical trials in non-muscle invasive bladder cancer
Abstract:
The National Cancer Institute organized a virtual Clinical Trials Planning Meeting (CTPM) on ‘Defining the next generation of clinical trials with combination therapies in non-muscle invasive bladder cancer (NMIBC)’ led by the Bladder Cancer Task Force of the NCI Genitourinary Cancers Steering Committee. The purpose of this meeting was to accelerate advances in clinical trials for patients with high-risk NMIBC. The meeting delivered a multidisciplinary expert consensus on optimal strategies for next-generation clinical trial designs in NMIBC with prioritization of combination therapies. Two clinical trial concepts were developed for potential implementation within the National Clinical Trials Network.
Management of bladder cancer in kidney transplant recipients: A narrative review
Abstract:
Background
Bladder cancer in the setting of previous a kidney transplant (KT) is challenging to manage due to complex medical and surgical considerations.
Objective
To provide a comprehensive evaluation of the scope of management of bladder cancer in KT patients, and describe the controversies surrounding these management options.
Methods
A systematic review of studies reporting management of KT patients with bladder cancer and involving ≥3 patients was performed. A narrative review was also performed for various aspects of management such as pathophysiology, surgical considerations, intravesical therapy, immunosuppression and oncological surveillance.
Results
Bladder cancer incidence in KT recipients is 2.8–4.1 times higher than the general population, and there is a notable association with aristolochic acid nephropathy as well as BK virus oncogenesis. Regarding surgical treatment, transurethral resection is preferred for non-muscle invasive tumors, and intravesical BCG for intermediate- and high-risk patients appears to be underutilized despite its safety and associated reduction in recurrence. Radical cystectomy with limited pelvic lymph node dissection, urinary diversion, and consideration of bilateral nephroureterectomy appears to be the safest method of oncological control in muscle-invasive tumors. A switch in immunosuppressive regimens to mTOR inhibitors may be considered in lieu of its antitumor effects. Routine surveillance in KT patients with risk factors for bladder cancer is challenging and may be warranted especially in the Asian population which has a higher rate of urothelial malignancy.
Conclusions
This review provides a thorough summary of management strategies for bladder cancer in the setting of previous KT.
Single-cell RNA sequencing and spatial transcriptome analysis in bladder cancer: Current status and future perspectives
Abstract:
Background
Bladder cancer is one of the most prevalent malignancies, and the mechanisms underlying its progression and the role of the tumor microenvironment (TME) are unclear. Recent advancements in single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics (ST) enable detailed analysis of the cellular heterogeneity, gene expression, and cell–cell interactions in bladder diseases.
Methodology
We conducted a comprehensive search for recent articles that have investigated bladder diseases using scRNA-seq and ST.
Results
scRNA-seq and ST have led to significant discoveries in bladder disease research. These technologies have enabled the identification of multiple molecular subtypes within individual tumors and of the mechanisms of treatment resistance. Additionally, molecular differences based on gender have been explored, explaining the heterogeneity of the incidence and progression of bladder cancer. These findings deepen our understanding of the pathology of bladder diseases and highlight the transformative potential of scRNA-seq and ST in identifying novel biomarkers and therapeutic targets.
Conclusions
Integrating scRNA-seq and ST has considerably enhanced our understanding of tumor heterogeneity and the tumor microenvironment within tissues. These insights may lead to the development of personalized therapies and the improvement of patient outcomes. Several challenges, such as technical limitations and access difficulties, need to be addressed for the future clinical application of these technologies.
Serum metabolomic analysis identified serum biomarkers predicting tumour recurrence after Bacillus Calmette–Guérin therapy in patients with non-muscle invasive bladder cancer
Abstract:
Background
Metabolomic research and metabolomics-based biomarkers predicting treatment outcomes in bladder cancer remain limited.
Objective
We explored the serum metabolites potentially associated with the risk of recurrence after intravesical Bacillus Calmette–Guérin (BCG) therapy.
Methods
Two independent cohorts, a discovery cohort (n = 23) and a validation cohort (n = 40), were included in this study. Blood was collected before the induction of BCG therapy (pre-BCG blood; both discovery and validation cohorts) and after six doses of BCG (post-BCG blood; only discovery cohort). Metabolome analysis of serum samples was conducted using capillary electrophoresis time-of-flight mass spectrometry. The endpoint was intravesical recurrence-free survival, which was analysed using Kaplan–Meier estimates, the log-rank test, and the Cox proportional hazard model.
Results
Of the 353 metabolites quantified, nine (2.5%) and four (1.1%) were significantly upregulated and downregulated, respectively. The heatmap of hierarchical clustering analysis and principal coordinate analysis for the fold changes and in serum metabolites differentiated 10 recurrent cases and 13 non-recurrent cases in the discovery cohort. A metabolome response-based scoring model using 16 metabolites, including threonine and N6,N6,N6-trimethyl-lysine effectively stratified the risk of post-BCG recurrence. Additionally, pre-BCG metabolome-based score models using six metabolites, octanoylcarnitine, S-methylcysteine-S-oxide, theobromine, carnitine, indole-3-acetic acid, and valeric acid, were developed from the discovery cohort. Univariate and multivariate analyses confirmed a high predictive accuracy in the validation and combination cohorts.
Conclusions
We demonstrated that numerous types of serum metabolites were altered in response to intravesical BCG and developed high-performance score models which might effectively differentiated the risk of post-BCG tumour recurrence.
