AUA 2024: Can I use Markers and Imaging to Avoid Local Consolidation for Patient who has cT0 stage after Neoadjuvant Chemo or IO?

(UroToday.com) The 2024 American Urological Association (AUA) annual meeting held in San Antonio, TX between May 3 and May 6, 2024, was host to the AUA-IBCG Bladder Cancer Forum. Drs. Stephen Williams, Arnulf Stenzl, and Petros Grivas discussed whether biomarkers and imaging can be used to avoid local consolidation for patients who are cT0 after neoadjuvant chemo-or-immunotherapy (IO)

Dr. Williams initiated the debate by presenting the case of a 75-year-old woman who has been experiencing gross hematuria for 6 months. She underwent TURBT and was found to have a 6cm T2 tumor of the bladder along with a 1cm TaHG and CIS, with no lymphovascular invasion, She opted for accelerated MVAC (with G-CSF) for 4 cycles followed by restaging to consider either radical cystectomy + pelvic lymph node dissection or trimodal therapy (TMT). Post-chemotherapy, there is no evidence of disease (cT0), as confirmed by negative cystoscopy, bladder biopsy, and cytology results. Dr. Williams posed the question to the audience whether they would employ biomarkers and imaging to avoid local consolidation for this patient exhibiting a complete response after neoadjuvant chemotherapy. Interestingly, 75% of the audience indicated they would proceed with radical cystectomy + pelvic lymph node dissection or radiotherapy if she opted for TMT. 

Dr. Arnulf Stenzl advocated for proceeding with consolidation radical cystectomy/radiotherapy (TMT). He began his presentation by emphasizing the advancements in assessing residual disease in patients with cT0 status post-neoadjuvant chemotherapy. He mentioned the utilization of photodynamic diagnosis (PDD) or multiparametric magnetic resonance imaging (mpMRI) in this clinical dilemma could be valuable. 

Dr. Stenzl explained that PDD involves the use of violet-blue light following intravesical instillation of 5-aminolaevulinic acid (ALA) or hexaminolevulinic acid (HAL). Current guidelines recommend PDD with blue-light cystoscopy in transurethral resection of bladder tumors (TURBTs) and guided bladder biopsy for the treatment and diagnosis of non-muscle-invasive bladder cancer (NMIBC). In a recent study comparing PDD versus white-light cystoscopy, PDD detected at least 1 additional CIS tumor in 46% of cases. However, the role of PDD in evaluating residual disease and CIS after neoadjuvant chemotherapy remains less clear. Furthermore, Dr. Stenzl highlighted that mpMRI utilizes VI-RADS generated from T2W, DWI, and DCE sequences to assess the probability of muscle invasion.

Dr. Stenzl mentioned that in patients with CIS, the response to cisplatin-based chemotherapy is poor, and up to 77% have residual CIS on final pathology of the cystectomy specimen. He then proceeded to discuss TURBT as monotherapy, so he looked at the placebo group compared to patients who received chemotherapy and radical cystectomy. The complete pathologic response after TURBT alone in different series is low and ranges from 5% to 15%.

He then moved on to discuss the role of three-dimensional (3D) organoids as potential biomarkers in bladder cancer. They can help identify bladder cancer lines through Raman microspectroscopy (RMS) and fluorescence lifetime imaging microscopy (FLIM). In a study by Becket et al., organoids were derived from a bladder cancer cell line, and immunofluorescence staining for the epithelial cell markers cytokeratin 5 and cytokeratin 7 and the transcription factor GATA3 was performed. Interestingly, he mentioned that all organoids expressed cytokeratin 7 and GATA3 and could potentially be used to identify residual disease in cT0 patients.²

So how do current biomarkers perform? Dr Stenzl discussed that using the current biomarkers available 46% of high-grade tumors and 42% of CIS are not detected. Mainly because there is a wide range of variability among different biomarkers and tests, and since this is also an operator-dependent assessment with variable results across different institutions.
Dr. Stenzl discussed the Xpert Bladder cancer test, a new mRNA-marker assay for follow-up after the primary diagnosis. This test measures the levels of five target mRNAs from a cleared urine sample using real-time RT-PCR. He mentioned the BIAS project, which enrolled 139 patients with T0 bladder cancer. At T0, 41% of patients had a negative test, and 36 (63.2%) continued to be in active surveillance (AS). All patients with a negative Xpert test did not have urothelial carcinoma after T0, and the failure-free rate differed significantly between patients who had a negative test and those who had one or two negative tests.  

Additionally, Dr. Stenzl mentioned that we now have better tools to assess our patients and select more appropriately those who would benefit from a cystectomy. He discussed the Frailty: G8 screening tool endorsed by the EAU guidelines, as shown below. Moreover, he stated that comprehensive geriatric assessment tools and prospective studies in older adults integrating comprehensive geriatric assessment can shed light on the optimal management of urologic malignancies in this population. Dr. Stenzl demonstrated how patients aged 65 years or older with good functional status and minimal comorbidities seem to enjoy similar survival benefits from therapy (treatment for urologic malignancies) as their younger counterparts. 
Dr Stenzl concluded his presentation with the following messages:

• Cisplatinum-based chemotherapy alone is no cure.
• We should consider cystectomy in our patients if:

• They have a life expectancy of at least 3 years.
  • Frailty score 1-2
  • Experienced perioperative management
  • cT0 – controversial but probably necessary

Dr. Petros Grivas defended why biomarkers and imaging should be used to avoid local consolidation for patients who have cT0 stage after neoadjuvant chemotherapy or IO. He began by saying that radical cystectomy and radiation therapy are associated with morbidity and quality of life implications. We should consider that a significant percentage of patients have a remarkable response to neoadjuvant/induction systemic therapy and that there is data that has shown favorable outcomes with TURBT + Chemotherapy in selected patients with cT0 after neoadjuvant systemic therapy.

Dr. Grivas presented a study by Herr et al., which is a single institution experience of surgical candidates that received MVAC x 4 cycles (n=111). After chemotherapy, 54% were cT0 and of these patients, 28 underwent TURBT only. After 10 years, 61% of the patients who did not undergo cystectomy had the bladder intact.⁴
He then presented the Mazza study, a multicentric cohort study including 148 patients treated with chemotherapy: 28% MVAC, 68% Gem/Cis, and 4% other, who had a clinical complete response (cT0) on TURBT + cytology + CT scan. Of the patients who elected surveillance, 10% died from urothelial carcinoma (71 had a local recurrence and 4 had a distant recurrence). However, at the time of analysis, 73 (49%) were free of recurrence, which is almost half of the population. The bladder was intact in 76% of the patients at 5 years.

However, in a SWOG 0219 trial neoadjuvant paclitaxel, carboplatin, and gemcitabine had a promising 46% cT0 rate (n=34). but the study failed to meet the primary objective as there was an unacceptably high rate (60%) of persistent cancer at cystectomy in patients presumed to have cT0 who underwent immediate cystectomy.⁶
Dr. Grivas then mentioned that the question we should ask ourselves is if we can predict who will respond to neoadjuvant cisplatin-based chemotherapy. He discussed several biomarkers associated with a pT0 response, such as ERBB2 mutations and ATM/RB1/FANCC mutations. Subsequently, he presented the results of the HCRN GU 16-257 study, a phase II, investigator-initiated, multicenter study. In this trial, patients who underwent neoadjuvant treatment with gemcitabine, cisplatin, plus nivolumab after transurethral resection of bladder tumor (TURBT) and achieved a complete response were offered bladder sparing based on their clinical characteristics. The study design is outlined below.
In the HCRN GU 16-257 study, clinical complete response was defined as no abnormalities post cycle #4 on imaging or urine cytology and <= Ta LG on post cycle #4 on bladder biopsies. The clinical complete response (cCR) was 43%, and 32 patients did not undergo immediate cystectomy.⁷  
Dr. Grivas showed the plot below which demonstrates the outcomes of patients achieving a clinical CR (n=33), with 9 patients eventually undergoing a delayed radical cystectomy, often after evidence of local recurrence, with 2/33 patients developing metastases.
  
The median follow-up for these patients with a clinical CR was 30 months (range: 18 to 42 months). The bladder-intact MFS in this patient cohort is demonstrated below in the Kaplan Meier graphic.  
Patients with a cCR had significantly better MFS and OS as demonstrated in the KM curves below. cCR predicted treatment benefit with an appositive predictive value of 0.96 (95% CI: 0.89 – 1.0).  
Our objective should prioritize standardizing the definition of complete clinical response (cCR) and its associated outcomes with neoadjuvant immune checkpoint blockade (IO). Dr. Grivas presented compelling data indicating that utilizing MRI, particularly VI-RADS, to predict pathological response to neoadjuvant IO exhibits high accuracy. For instance, in the PURE-01 trial, MRI demonstrated an AUC of 0.92 for predicting pT ≤1 post-Pembrolizumab and an AUC of 0.74-0.76 for predicting pT0.⁸

Additionally, Necchi et al. reported that in the same study, patients with VI-RADS 0-3 post-Pembrolizumab exhibited improved event-free survival compared to those with VI-RADS 4-5 (p=0.0008).⁸
Dr. Grivas highlighted the significant prognostic value of circulating tumor DNA (ctDNA) following neoadjuvant chemotherapy (NAC). He emphasized that ctDNA clearance after neoadjuvant Atezolizumab was notably associated with improved disease-free survival (DFS) (HR 0.26) and overall survival (OS) (HR 0.14). Furthermore, post-radical cystectomy, the presence of ctDNA positivity was linked to the benefits of adjuvant immune checkpoint blockade in terms of OS (HR 0.59, 95% CI 0.41-0.86).

To wrap up his presentation he asked the audience a question:

If you were the patient and you have cT0 – clinical CR (negative cystoscopy, bladder biopsy, cytology, CT, mpMRI, ctDNA) after neoadjuvant systemic therapy. Would you consider combining excellent long-term oncology outcomes and quality of life?

Presented by:

• Arnulf Stenzl, MD, Chairman and Professor in the Department of Urology, Eberhard Karls University of Tuebingen Medical School, Tübingen, Germany
• Stephen Williams, MD, MBA, MS, FACS, FACHE Chief Division of Urology at the University of Texas Medical Branch, Galveston, TX
• Petros Grivas, MD, PhD, Medical Oncologist, University of Washington, Seattle, WA

Written by: Julian Chavarriaga, MD - Society of Urologic Oncology (SUO) Clinical Fellow at The University of Toronto, @chavarriagaj on Twitter during the 2024 American Urological Association (AUA) annual meeting held in San Antonio, TX between May 3^rd and May 6^th, 2024

References:

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