(UroToday.com) The 2023 American Urological Association (AUA) annual meeting held in Chicago, IL between April 28 and May 1st, 2023, was host to a late-breaking oncology abstract session. Dr. Ali Mouzannar presented the results of a matched cohort analysis comparing perioperative outcomes of patients receiving neoadjuvant gemcitabine, cisplatin, and atezolizumab to those receiving gemcitabine + cisplatin prior to radical cystectomy.
Cisplatin-based neoadjuvant chemotherapy prior to radical cystectomy for patients with muscle invasive bladder cancer (MIBC) remains standard of care treatment. Favorable pathologic responses (i.e., <pT2, pN0 disease), which occur in 36-46% of cases, have been demonstrated to be associated with improved survival outcomes.1-3
Over the last few years, we have witnessed the emergence of numerous phase II trials evaluating checkpoint inhibitors in the neoadjuvant setting. The PURE-01 trial of neoadjuvant pembrolizumab demonstrated pT0 rates of 42%, whereas patients in the ABACUS trial of neoadjuvant atezolizumab achieved a pT0 rate of 31% in the radical cystectomy specimens. In 2022, Funt et al. published the results of a single arm phase II trial that evaluated the neoadjuvant combination of atezolizumab + gemcitabine/cisplatin in patients with MIBC. The primary endpoint of this trial was pathologic downstaging to <ypT2N0, which occurred in 69% of patients. ypT0N0 disease was achieved in 41% of patients. Grade 3+ immune-related AEs were experienced by 11% of the cohort.6
However, concerns about the additive toxicity of combining atezolizumab with gemcitabine/cisplatin remain. As such, the objective of this study was to assess the surgical safety of this neoadjuvant combination. To this end, the authors performed a propensity score-matched analysis of 36 patients from the Funt cohort (atezo + gem/cis) matched to 72 patients from an MSKCC contemporary cohort who received neoadjuvant gem/cis only. Patients were matched 2:1 using the nearest neighbor matching using the following criteria:
- Age-adjusted Charlson comorbidity index (CCI)
- BMI
- Surgical approach
- ASA score
- Clinical T-stage
- Smoking status
Despite propensity score matching using the aforementioned variables, there were some differences in baseline characteristics between the two groups, which suggested that patients in the Funt trial receiving atezo + gemc/cis were at inherently higher “risk” of more favorable outcomes:
- Patients in the atezo + gem/cis arm had a lower frequency of prior abdominal surgery (14% versus 44%)
- Patients in the atezo + gem/cis arm had a lower frequency of prior pelvic radiation (3% versus 8%)
- Patients in the atezo + gem/cis underwent a robotic-assisted radical cystectomy in 36% of the cases, compared to 18% in the gem/cis group
With regards to the study objective of evaluating perioperative outcomes, patients in the atezo + gem/cis group had a lower proportion of readmissions within 30 days (17% versus 33% in the gem/cis group) and required less frequency postoperative transfusion (44% versus 64%, p=0.054). Otherwise, no significant differences in estimated blood loss, positive surgical margins, and grade 3+ complications were observed. A common concern with the use of neoadjuvant ICIs is the development of immune-related adhesions that can complicate subsequent surgical approaches. However, adhesions were noted less frequently in the atezo + gem/cis arm (25% versus 39%), which may be related to the lower frequency of prior abdominal surgery/pelvic radiation in this group. A post-treatment effect was observed in 11% of patients in the atezo + gem/cis group, compared to 4% in the gem/cis group.
On multivariable analysis adjusted for ASA and smoking status, no statistically significant differences in the odds of these events were observed between the two groups.
The most common complications in both groups were bleeding, infectious, and GU in nature. However, the overall rates were similar across the two groups.
Dr. Mouzannar acknowledged that this study is limited by its retrospective design, with lack of randomization and concerns regarding residual, unmeasured confounders. He concluded that the combination of atezo + gem/cis appears to be safe and does not adversely impact surgical outcomes or complications. Further evidence from multi-arm RCTs will be needed to further evaluate this.
Presented by: Ali Mouzannar, MD, Society of Urologic Oncology fellow, Memorial Sloan Kettering Cancer Center, New York, NY
Written by: Rashid K. Sayyid, MD, MSc – Society of Urologic Oncology (SUO) Clinical Fellow at The University of Toronto, @rksayyid on Twitter during the 2023 American Urological Association (AUA) Annual Meeting, Chicago, IL, April 27 – May 1, 2023
References:- Galsky et al. Comparative effectiveness of gemcitabine plus cisplatin versus methotrexate, vinblastine, doxorubicin, plus cisplatin as neoadjuvant therapy for muscle-invasive bladder cancer. Cancer, 2015.
- Zargar et al. Multicenter assessment of neoadjuvant chemotherapy for muscle-invasive bladder cancer. Eur Urol, 2015.
- Iyer et al. Neoadjuvant Gemcitabine-Cisplatin Plus Radical Cystectomy-Pelvic Lymph Node Dissection for Muscle-invasive Bladder Cancer: A 12-year Experience. Clin Genitourin Cancer, 2020.
- Necchi et al. Impact of Molecular Subtyping and Immune Infiltration on Pathological Response and Outcome Following Neoadjuvant Pembrolizumab in Muscle-invasive Bladder Cancer. Eur Urol, 2020.
- Powles et al. Clinical efficacy and biomarker analysis of neoadjuvant atezolizumab in operable urothelial carcinoma in the ABACUS trial. Nat Med, 2019.
- Funt et al. Neoadjuvant Atezolizumab With Gemcitabine and Cisplatin in Patients With Muscle-Invasive Bladder Cancer: A Multicenter, Single-Arm, Phase II Trial. J Clin Oncol, 2022.