ASCO GU 2019: Multimodality Treatment in Challenging Cases of Urothelial Carcinoma: Case Panel Discussion

San Francisco, CA ( In this case panel discussion, 3 patient cases were reviewed highlighting important points in the management of bladder cancer. The text below includes a summary of each case presented and key points made by the panelists.

Case 1: Small Cell Bladder Cancer: 65-year-old man who presents feeling lethargic, 10 lb weight loss, poor appetite. He has microscopic hematuria. Cystoscopy and subsequent TURBT demonstrates small cell bladder cancer.

Q1: Would you do a PET scan for staging? - Audience response leaned towards yes.

Dr. Barchetti then reviewed current EAU guidelines, which do not find PET/CT indicated in nodal staging of bladder cancer.

- CT and PET/CT have similar sensitivity (~45%), specificity (~90%) and accuracy (~80%)
- VI-RADS (Panebianco et al. EU 2018) is a new MRI based staging system for bladder cancer lesions that have been introduced. Similar to PI-RADS MRI staging for prostate cancer.
  • Defines a standardized approach to imaging and reporting for bladder cancer
  • The scoring should be done, preferentially, in UNTREATED patients before TURBT or at least 2 weeks after TURBT
  • Below is the VIRADS scoring system for each of the phases
ASCO GU 2019 VIRADS scoring system

- This patient was VIRADS 2

Q2: How would you treat this patient? (chemo →RC, Chemo →RT, RC alone, RT alone, RC →adjuvant chemo)
- Audience response favored the first option, chemo →RC

Dr. Skinner then kicked off the discussion regarding management. Key point is that the general consensus is that chemotherapy should be the first line therapy. Local consolidation therapy is recommended –but there is no data to support either RT or surgery.
- She reviewed the USC (Quek et al. J Urol 2005) and the MDACC series (Siefer-Radtke et al. J Urol 2004) of men treated with RC without chemotherapy (USC) or with chemotherapy (MDACC)
- Patients treated with chemotherapy first had much better OS!

Dr. Huddart weighed in and agreed that chemotherapy up front is recommended. There is some NCDB data that demonstrates that RT or RC can be used as local consolidation, but chemotherapy is the mainstay of therapy.

Dr. Galsky then weights in on small cell bladder cancer biology. He noted that a recent study by Shen et al (Oncogene 2018) that looked at the genomics of small cell neuroendocrine bladder cancer vs. urothelial bladder cancer identified 3 key findings:
  1. Small cell bladder cancer shares a lot of genomic features and mutations with urothelial histology
  2. It has high MSI which can be targetable
  3. Many cases of small cell bladder cancer have TP53 and RB1 loss
A study by Kouba et al. (JAMA Oncology 2017) highlighted the variability in treatment paradigms for small cell bladder cancer –their review of all cases of published small cell bladder cancer treated demonstrated 8 pathways. This is visually demonstrated below:

ASCO GU 2019 management of small cell bladder cancer

There are few prospective studies of systemic chemotherapy in patients with small cell bladder cancer (Galsky et al. Urology 2007, Siefer-Radtke et al. JCO 2009), but they do support its use. More recently, in the lung cancer literature, there is evidence that immune checkpoint inhibitors (in isolation or combination ie nivo/ipi) may have clinical activity that can be leveraged in these bladder cancer patients.

Case 2: Upper Tract Urothelial Carcinoma: This is a case of a 78-year-old man with prior para-aortic RT in 1981 for testicular carcinoma. Presents with groin pain and hematuria. CT scan to rule out kidney stone identifies a mass in the left upper ureter/renal pelvis; however, this is a noncontrast scan.

First, Dr. Barchetti reviewed the appropriate imaging for upper tract staging. CT Urogram is still the standard of care, with high sensitivity. MR Urography should be reserved for patients who cannot undergo CT Urography, usually when radiation or iodinated contrast are contraindicated.
- He did not that split function testing may be indicated from a surgical planning standpoint
- VIRADS scoring is not yet appropriate for UTUC

Q1: How would you surgically manage this large lesion? (Options: Open, Laparoscopic, Robotic)
- Audience response: primary laparoscopic

Dr. Skinner addressed this question. First, she referred to Dr. Matin’s excellent talk earlier today of difficulties with diagnosis and management of UTUC –in particular, endoscopic management. However, this patient warrants radical nephroureterectomy. In terms of approach, there is evidence that laparoscopic NUx has equal results compared to open NUx.
- Main issue is the bladder cuff management, which is more problematic with laparoscopic surgery
- Open surgery warrants either one long incision or two separate incisions, which entails longer recover
- Robotic nephroureterectomy is appealing–shorter recovery, no need to reposition patient, enables complete LND

Q2: Can this patient get consolidative radiation?
Dr. Huddart addressed this question. A prior study of consolidative radiation for patients with metastatic UC after resection of primary tumor demonstrated that patients with single node positive did best. Of 22 patients, 8 had long-term survival (4 with nodal disease only, 2 with lung mets).

Q3: Neoadjuvant or adjuvant chemotherapy for this patient?
- Audience response favored neoadjuvant therapy

Dr. Galsky addressed this question. The POUT trial data is the only Level 1 evidence in this field and supports adjuvant therapy. But, the same arguments that existed for NAC vs. AC for bladder cancer exist for UTUC. Yet, his main take home point is patient eligibility for chemotherapy before and after NUx:

ASCO GU 2019 cisplatin eligible patients

Unfortunately, on 15% of patients after NUx is still eligible for cisplatin chemotherapy. But 58% are eligible prior to NUx. So, if perioperative chemotherapy is recommended, NAC would be better. Yet, Level 1 evidence is still pending. There is some perspective (non-randomized trials) that demonstrate good pCR and downstaging rates (~14-40% and ~62-75%, respectively).

Case 3: The Co-Morbid Patient: This is a 66-year-old man with recurrent NMIBC. However, he has a history of a heart transplant in 1996 for idiopathic cardiomyopathy (<10% survival past 20 years), HTN, hyperlipidemia, and Type 2 DM.
He had a prior left partial nephrectomy in 2002 for pT1a ccRCC, FG3, SM(-) disease.
He has ESRD on hemodialysis now.

He developed gross hematuria (2012) and cystoscopy identified a 2 cm papillary lesion. CT Urogram without evidence of upper tract disease or metastases. TURBT demonstrated HG Ta disease with muscle present. He was treated with 6 cycles of gemcitabine induction and maintenance.

Q1: Which intravesical therapy would you use in an immunocompromised patient? (ie immunotherapy such as BCG or chemotherapy such as MMC/gemcitabine)
- Audience response: Chemotherapy

The panel generally agreed. Dr. Skinner did not that there were some studies that demonstrated that BCG could be used safely in some patients on chronic steroids, but shouldn’t be used in patients on active treatments blocking TNF blockers or stronger immunosuppressants. The patient then had a recurrence in 2013 –HG Ta. But right retrograde pyelogram demonstrated filling defects. Ureteroscopy demonstrated multiple papillary lesions. He underwent a right laparoscopic nephroureterectomy –pTaN0 multifocal HG urothelial carcinoma. They attempted BCG at this time, but he had to stop due to pain, and refused further treatments. One year later, he developed a bladder recurrence –LG Ta lesion this time, but now the left retrograde pyelogram demonstrated filling defects and URS showed a papillary lesion in the renal pelvis.

- He is readmitted frequently for V-tach arrhythmia’s indicated his poor medical health

Q2: What would you do now? (Options: URS+laser ablation, above and nephrostomy BCG, left NUx, left NUx and cystectomy)
- While the audience favored the last option, he actually had a left NUx alone.

His Left NUx pathology was pTaN0 multifocal HG urothelial carcinoma. His cystoscopic surveillance becomes more difficult due to smaller bladder capacity ---and his PSA is noted to be rising. He is then found to have 6 cores Gleason 7 prostate cancer on prostate biopsy.

Q3: Is there a role for chemoradiation for T1 HG bladder cancer? Options: Yes (equivalent to cystectomy), Yes (but only in select cases), and No. -Audience and panel agreed that the answer was Yes (but only in select cases)If this patient were healthy, the optimal management would have radical cystoprostatectomy. But due to his significant comorbidities, any reason to avoid a surgery is recommended.
- Weiss et al. (JCO 2006) previously noted an 88% CR rate in 141 patients with HG T1 disease treated with RT or cRT. 80% of those patients had bladders preserved.

Q4: If chemoradiation can be done, can the bladder and prostate be radiated at the same time?
- Both the panel and the audience agreed that radiation to the prostate and the bladder is safe

Case 4: Micropapillary Bladder Cancer: 76-year-old male patient presents with gross hematuria, his CXR is negative and CT Urogram demonstrates a 3cm bladder mass. Cystoscopy demonstrated a papillary tumor, and TURBT demonstrated HG T1 micropapillary histology.

Q1: In general, for high-grade T1 micropapillary bladder cancer, what would be your next step?
(Options: Repeat TURBT, intravesical BCG, Immediate cystectomy and NAC+RC)
- Audience: Repeat TURBT and immediate cystectomy
- Panel: Agreed those are the two most common options.

Dr. Skinner stated that she would repeat a TURBT. But, this is a moving target!
- Linder et al. (J Urol 2013) demonstrated that ~33% of cystectomy pathology specimens had variant histology
- Dr. Skinner notes that Stanford pathologists note variant histology on ~40% of TURBT specimens, sometimes with multiple patterns in the same specimen
- Importantly, while prior data has demonstrated that patients with micropapillary cancer are often higher stage and more aggressive when matched stage for stage, they do NOT have significantly different outcomes compared to urothelial carcinoma
- MSKCC –of patients with <= T1 micropapillary bladder cancer, 15 had initial cystectomy (5 year CSS 83%) while 21 re-TURBT and BCG (5-year CSS 75%).

Her conclusions:
  1. Repeat TURBT mandatory
  2. Consider PET imaging to identify microscopic nodal disease
  3. CIS, deep LP invasion, LVI may predict upstaging
  4. Early cystectomy should be considered in healthy patients
This patient underwent repeat TURBT and found to have HG Ta urothelial histology. Managed with BCG induction and 2 rounds maintenance before choosing to stop.

6 years later he returns with gross hematuria (now aged 82). He had been clear on cysto for 5 years. CT obtained at this time –demonstrated obvious mass in the bladder. TURBT demonstrates HG MIBC with micropapillary features. 4 cm mass that was maximally debulked. PET/CT demonstrated no evidence of metastatic disease.

They did note that micropapillary bladder cancer clusters with luminal type bladder cancers. While a meta-analysis of NAC for micropapillary bladder cancer, Dr. Galsky notes that pooled suboptimal data yields limited conclusions ... trash in means trash out. As such, he treats these patients similar to their urothelial counterparts and gives NAC.

As for chemotherapy and radiotherapy, the long-term 2016 follow-up of the BC2001 trial (James ND NEJM 2012) demonstrated that adding chemotherapy to RT yields much better PFS. Dr. Huddart’s group has demonstrated that patients who received NAC followed by RT+Chemo do the best, particularly in the setting of maximal TURBT.

- The HYBRID trial demonstrated that hypofractionated RT provides similar outcomes compared to standard RT protocols in patients with multiple comorbidities and may not be able to tolerate standard RT therapy

The take-home message from the case discussion is that bladder cancer requires a multidisciplinary approach, even from the earliest stages. The high degree of variability in audience responses highlights the variability in clinical practice. Additionally, recent treatment advances are leading to significant changes in treatment paradigms.

Presented by:
Moderators: Ananya Choudhury, MA, Ph.D., MRCP, FRCR, The Christie NHS Foundation Trust and University of Manchester, Manchester, United Kingdom, and Brant Inman, MD, Duke University Medical Center, Durham, North Carolina

Panel Members: Robert A. Huddart, MBBS, MRCP, FRCR, PhD, Radiation Oncologist, The Institute of Cancer Research and the Royal Marsden NHS Foundation Trust, London, United Kingdom; Matt D. Galsky, MD, FASC, Medical Oncologist, Icahn School of Medicine at Mount Sinai, New York, New York ; Eila C. Skinner, MD, Urologist, Stanford University, Stanford, California ; Giovanni Barchetti, MD, Radiologist, Sapienza University of Rome, Rome, Italy

Written by: Thenappan Chandrasekar, MD (Clinical Instructor, Thomas Jefferson University) (twitter: @tchandra_uromd, @JEFFUrology) at the 2019 American Society of Clinical Oncology Genitourinary Cancers Symposium, (ASCO GU) #GU19, February 14-16, 2019 - San Francisco, CA

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