ASCO 2018: Challenges of Perioperative Systemic Therapy of Localized Urothelial Cancer

Chicago, IL ( Dr. Aragon-Ching started off this multi-disciplinary session on the management of bladder cancer. She, and the two other speakers, addressed 3 specific cases, highlighted below, in an effort to make their points. The 3 cases were:  

1. 67 year old medically fit male patient who presented with hematuria. Cysto and TURBT demonstrates MIBC, new diagnosis. CT scan shows diffusely irregular bladder thickening and asymmetry in the posterior wall. No known family history. PS 0. Adequate organ function. 

2. 65 year old man with prior HG pTa bladder cancer treated with BCG (induction + maintenance) who presents 4 years later with CT Urogram demonstrating right hydronephrosis, lobulated right bladder mass and pelvic adenopathy 2.5 cm (node-positive). TURBT shows HG MIBC with squamous differentiation. Right sided stent placed, creatinine improves significantly. Gem/Cis 4 cycles completed, good response – hydro resolves, node < 1cm.  

3. 84 year old elderly cachectic male presents with 2 months gross hematuria. CT Urogram with 6 cm bladder mass. TURBT with MIBC, new diagnosis. Creatinine 1.2, ECOG worsens to 1, lives with daughter now. Frail. 

Dr. Aragon-Ching’s focus was on challenges in perioperative systemic therapy for localized urothelial cancer (MIBC in particular). She started by quickly reviewing the current literature and where we stand from a systemic chemotherapy standpoint in MIBC. Her main points were as follows: 

1. Level 1 evidence exists for neoadjuvant chemotherapy (NAC) in MIBC – primarily from classic MVAC and CMV clinical trials and the International Bladder Cancer Trialists Group meta-analysis.  
2. Gem-Cis regimen developed to help reduce toxicity from MVAC; found to be non-inferior.  
3. More recently dose dense or accelerated MVAC (ddMVAC or aMVAC) has been developed to reduce adverse effect profile, but still has same oncologic outcomes. 
4. GC and MVAC appear to relatively equivalent in achieving pT0 (complete response) – no clinically significant difference. Most recent study by Zargar et al. (J. Urol 2018) suggests that maybe GC may be slightly inferior to MVAC.  
5. pT0 (pathologic CR) is an excellent surrogate for survival, demonstrated in multiple studies. 

Compared to pTis/pT1+, pT0 patients have much better OS (HR 0.45, p<0.0001) 

Adjuvant chemotherapy – on this topic, she was brief but noted the following: 

1. Meta-analyses (2005 & 2017) have seemed to support the survival benefit with AC – but most of the included studies are underpowered, so the results must be taken cautiously 

2. Should be offered to patients with high-risk disease (pT3+ or N1/N2 disease on cystectomy) who were unable to get NAC 

Cisplatin remains the backbone of systemic chemotherapy. Carboplatin is insufficient – not enough oncologic efficacy to warrant delaying definitive cystectomy.  

Yet, all patients who are candidates for cisplatin-based chemotherapy will not benefit from therapy. Can we better predict responders? There are suggestions that may eventually lead to selection criteria – but at this time, no. 

1. DNA repair gene mutations (ERCC1, ERCC2,ERBB2, ATM, RB1, FANCC mutations) may predict for better chemotherapy response 

2. Patients with basal molecular subtype of MIBC may represent chemotherapy sensitive disease 

Colleagues are currently initiating and running a Phase II clinical study to assess this already – A031701 trial #. Phase II study which offers bladder preservation to patients with DNA-repair gene mutations who have excellent clinical response to dose-dense Gem-Cis chemotherapy (cT0 or cTis). All other patients go on to radical cystectomy. 

In node-positive patients (patient #2), she notes that many people would not technically consider chemotherapy as neoadjuvant chemotherapy. As this patient has metastatic disease already, many would treat this patient as metastatic UC – and if they have good response, consider consolidation with radical cystectomy. Yet, metastatic UC warrants 6 cycles of chemotherapy, while NAC is usually 4 cycles. So, many medical oncologists currently treat with 4 cycles and assess pathologic response.  

She did note that staging changes have impacted management. Previously, node positive patients were consider stage IV disease. However, more stratification has resulted in node positive patients being considered Stage IIIA or IIIb. Even patients with non-visceral nodal mets outside of regional nodes are now considered Stage IVA – as there is evidence they do better than patients with visceral metastases (Stage IVB).  

As we saw above, regardless of nodal mets, if there is clinical response, patients who receive chemo and go on to cystectomy and have pT0N0 response have very good prognosis. Hence, it is worthwhile to consider consolidation if they have good response to chemotherapy. 

With regards to the squamous differentiation in the pathology of patient #2, she noted briefly that while variant histology does have worse prognosis, it is primarily pure variants that are treated differently. At this time, if the primary histology is urothelial, they should be treated the same way. In the SWOG 8710 study, patients with variant histology/mixed tumors actually had a higher rate of CR with chemotherapy! 

The last case highlights the frail, elderly patient – which is not uncommon in the bladder cancer field! First, she reviewed the criteria for cisplatin eligibility – unfortunately, while age alone is not a limitation, many of the contraindications are more common in the elderly – worse performance status (PS 2+), Creatinine clearance < 60, grade 2+ hearing loss, grade 2+ peripheral neuropathy, and NYHA class III heart failure. Recent ASCO guidelines updates actually strongly recommend geriatric evaluation / geriatric assessment in all patients older than 65 who are receiving chemotherapy! There are tools available, including a Comprehensive Geriatric Assessment Tool and G8 questionnaire.  

She briefly touched on the role of chemoradiation and trimodal therapy as an option (alternative) to elderly patients who may not tolerate cystectomy – but deferred to Dr. Zietman’s talk on the topic for details. 

She reiterated that NAC is not recommended for cisplatin-ineligible patients. She would therefore recommend definitive local therapy – ideally with radical cystectomy.  

She briefly noted that immunotherapy may help fill this void – cisplatin ineligible patients may be candidates for neoadjuvant immune checkpoint inhibitors, if these studies are positive. There are numerous such trials ongoing at this time, and may help elderly patients be better candidates for neoadjuvant therapy. 
  • One of those studies is presenting their results at ASCO – Abstract 4507. Pathologic CR with pembrolizumab in neoadjuvant setting was ~40%.  
She provided a great overview of the topic, and then handed it over to Dr. Steinberg to discuss surgical considerations for these 3 patients. 

Presented By: Jenny Aragon-Ching 

Read the Corresponding Case-based Discussions:
Gary Steinberg, Nuances of Surgical Management of Localized/Locally Advanced Urothelial Cancer
Anthony Zietman, Bladder-Sparing Strategies in Bladder Cancer

Written by: Thenappan Chandrasekar, MD, Clinical Fellow, University of Toronto, Twitter: @tchandra_uromd at the 2018 ASCO Annual Meeting - June 1-5, 2018 – Chicago, IL USA

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