ASCO 2017: Management Strategies for Nonurothelial Bladder Cancer

Chicago, IL ( Dr. Aragon-Ching is a Medical Oncologist at Inova Schar Cancer Institute in Falls Church, VA, USA, and provided an excellent overview of current literature and management of non-urothelial bladder cancers. She focused only on pure non-urothelial bladder cancers – discussion of urothelial variants and mixed bladder cancers are not included in this talk.

While the WHO recognizes 8 non-urothelial bladder cancers, there are 4 primary histologies that predominate. The talk focused on these four histologies: squamous cell carcinoma (SCC), neuroendocrine tumors, bladder adenocarcinoma (urachal adenocarcinoma), and glandular neoplasms. These non-urothelial bladder cancers are rare, but often are more aggressive and may present with non-specific / atypical symptoms, making them difficult to diagnose or treat. She highlighted some of her unpublished work using the SEER dataset to look at the incidence of these histologies over a 20-year period. Compared to 215,000 cases of urothelial carcinoma, the incidence of SCC (~3000), adenocarcinoma (<1000), and neuroendocrine (<1000) bladder cancer is very low, and their 5-year survival ranged from 0.07-0.78%. Unfortunately, due to rarity, there are no clear guidelines for many of them 

Next, we went into the clinical presentation and management of each of the major histologies. Below, I highlight the take-home points for each

1) Squamous cell carcinoma
a. Accounts for 3-5% of bladder cancer cancer
b. Risk factors: Chronic inflammation, infection, schistosomiasis, cyclophosphamide use
c. Two main types worldwide: Bilharzial (schistosomiasis) or non-bilharzial
        - Bilharzial: Middle East / Southeast Asia, 5th decade predominant, 19% lymph node metastases, more advanced stage (but lower grade)
        - Non-Bilharzial: Europe / North America, 7th decade predominant, 5-10% lymph node metastases, advanced stage (but also high grade)
d. Due aggressive disease, radical cystectomy + lymph node dissection is standard of care
        - Local failure is typical pattern of recurrence
e. No proven role for neoadjuvant (NAC) or adjuvant chemotherapy (AC), but not because of lack of trials
        - ITP (Ifosfamide, Paclitaxel, cisplatin) is the only prospectively assessed regimen1, but it was not specific for SCC, and it was a small study
        - Pre-operative radiation may improve survival, but adjuvant radiation (while improving recurrence risk) does not affect survival2

2) Small Cell Carcinoma / Neuroendocrine (NE)
a. <1 % of all bladder cancers, very rare
b. Predominantly male (5:1 risk)
c. Key to diagnosis is that any small amount of small cell carcinoma in the sample warrants classification as NE
d. Diagnosis is by immunohistochemistry (IHC) – chromogranin, synaptophysin, CD56
e. Classified as limited or extended – if its within one field of radiation therapy or not.
f. Chemotherapy is the main therapy as it is a systemic disease, RC or radiation only for local symptoms or control
      - Neoadjuvant chemotherapy results in a high rate of pathologic downstaging and higher survival
      - Regimens: Cisplatin/etoposide, carboplatin (if cisplatin ineligible) OR alternating ifosfamide/doxorubicin and cisplatin/etoposide
g. As the incidence of brain metastases is low, routine prophylactic brain irradiation is not recommended

3) Bladder Adenocarcinoma
a. <2% of all bladder cancers
b. Risk factors: infection, history of bladder exstrophy/repair, bladder augmentation with bowel
c. Key thing to remember – search for a non-bladder primary! Requires referral to gastroenterology for colonoscopy
d. Non-urachal: older, male, higher grade
e. Urachal adenocarcinoma (unique subset)
     - Younger patients, equal male:female distribution
     - Develops in the urachal remnant, but can present as a bladder tumor (dome)
     - Always has enteric-type histology
     - Treatment: One of the few cases of bladder cancer in which partial cystectomy is oncologically acceptable, but the key is to include en-bloc resection of        the urachus and umbilicus (umbilectomy) – if not done, local recurrence in the tract is a high risk
     - No clear role for NAC or AC
f. For recurrent disease, chemotherapy regimens are similar to adenocarcinoma or SCC
     - Gemcitabine+5FU+leucovorin+cisplatin (GEM-FLP)
     - 5FU+oxaliplatin (modified FOLFOX)
     - ITP (similar to SCC)

She briefly summarized findings from a molecular profiling standpoint for each of the histologies. However, as these are rare, the conclusions should be taken carefully. Some key points:

1) Bladder adenocarcinoma had high ERBB2 and EGFR and, from a drug resistance standpoint, high BRCP and MRP1

2) Urachal adenocarcinoma had an association with high microsatellite instability (MSI), and the genes most commonly mutated were KRAS, NRAS, BRAF

While series in small cell and SCC are increasing, the studies remain quite small. Early next-generation sequencing analysis have promising results (some of which being presented at this conference), but nothing definitive yet.

Lastly, she highlighted recent work using targeted immunotherapy. Abstract 293 (A. Apolo et al) demonstrates efficacy of cabozantinib + nivolumab +/- ipilimumab – but specific efficacy was noted in the nonurothelial subsets. Upcoming trials include the ALLIANCE trial and SWOG DART trial, both of which specifically target rare GU cancers.

Presented By: Jeanny B. Aragon-Ching, MD, FACP (Inova Schar Cancer Institute, Falls Church, VA)

Written By: Thenappan Chandrasekar, MD, Clinical Fellow, University of Toronto
Twitter: @tchandra_uromd

1. Galsky MD, Iasonos A, Mironov S, Scattergood J, Donat SM, Bochner BH, Herr HW, Russo P, Boyle MG, Bajorin DF. Prospective trial of ifosfamide, paclitaxel, and cisplatin in patients with advanced non-transitional cell carcinoma of the urothelial tract. Urology. 2007 Feb;69(2):255-9.
2. Martin JW, Carballido EM, Ahmed A, Farhan B, Dutta R, Smith C, Youssef RF.
Squamous cell carcinoma of the urinary bladder: Systematic review of clinical characteristics and therapeutic approaches. Arab J Urol. 2016 Aug 1;14(3):183-91. doi: 10.1016/j.aju.2016.07.001. eCollection 2016 Sep. Review.
3. Lynch SP, Shen Y, Kamat A, Grossman HB, Shah JB, Millikan RE, Dinney CP, Siefker-Radtke A.
Neoadjuvant chemotherapy in small cell urothelial cancer improves pathologic downstaging and long-term outcomes: results from a retrospective study at the MD Anderson Cancer Center. Eur Urol. 2013 Aug;64(2):307-13. doi: 10.1016/j.eururo.2012.04.020. Epub 2012 Apr 17.

at the 2017 ASCO Annual Meeting - June 2 - 6, 2017 - Chicago, Illinois, USA