The Optimal Treatment of Muscle Invasive Urothelial Bladder Cancer with Neoadjuvant Chemotherapy with Cystectomy

Lisbon, Portugal ( Dr. Brausi moderated this SIU-SUO/ESOU debate between Dr. Black and Dr. Khochikar on the topic of neoadjuvant chemotherapy (NAC) in an elderly patient with muscle invasive bladder cancer (MIBC). This was an excellent debate with important points by both debaters – there may not be a right answer, but it was educational nonetheless. Below are the highlights and main points of the discussion.

As context, Dr. Brausi presented the following case: 83 year old male, heavy active smoker, history of hypertension. Presented to the emergency room with gross hematuria, pelvic pain and clot retention. After catheter placement and irrigation, his urine cleared within 2 days. He has normal serum creatinine (1.8 mg/mL), but is anemic (Hgb 9.9). Cystoscopy reveals a large 5 cm lesion in the left trigone, invading the left orifice and left bladder wall; complete TURBT was completed. He has evidence of left hydroureteronephrosis prior to his TURBT on ultrasound evaluation. Pathology: HG pT2 MIBC, with 10% squamous differentiation. cT3 due to hydronephrosis. 

The question to the debaters: Should this patient get NAC prior to RC?

Dr. Black: Yes

1. Bladder cancer is a disease of the elderly – the mean age of bladder cancer diagnosis is 73. The oldest of any malignancy. With an aging population, it is not uncommon to treat elderly patients with bladder cancer.

2. In a paper by Noon et al (BJC 2013), when cancer-specific and overall mortality was graphed for patients stratified by low-risk NMIBC, high-risk NMIBC and MIBC by decade at the time of diagnosis, it was important to note that in patients > 80 with MIBC, cancer-specific mortality was still the primary cause of death in that population, more than other-cause mortality.

3. Concept of elder neglect and undertreatment – In a paper by Gray et al (Eur Urol 2013), there was clear evidence that the proportion of patients >70 who underwent no intervention steadily increased to almost 50% in patients older than 80, and 75% in patients older than 90.

4. There is level 1 evidence to support the use of NAC prior to cystectomy – there is very little Level 1 evidence of any other treatment.

5. Galsky et al (JCO 2011) created a checklist of patients unfit for chemotherapy – while performance status, hearing loss and peripheral neuropathy are included, age is not.

6. In a study in Annals of Oncology (2005), there was no difference in response to platinum based therapy in patients older or younger than 70 – older patients tolerate therapy well and derive the same oncologic benefit.

7.  The key questions to ask:
      - Do we need to treat this cancer – who will die of disease or of other causes? With advanced bladder cancer, it is often death from bladder cancer!
      - If we treat, who is vulnerable to toxicity?
      - How do you modify therapy based on organ status, functional status, cognitive status, and functional status?
         * Age alone is not the determinant

8. Integrating geriatrics into oncology – this is becoming more established throughout
        - Geriatrics assessment can help fully evaluate a patient’s ability to tolerate therapy
        - Specifically assesses factors other than age that may affect morbidity and mortality

9. Hurria et al (JCO 2011) identified 11 risk factors of chemotherapy toxicity – age >72 was just one of the factors

        - Total score correlated significantly with toxicity
        - Patients with low score may still benefit from therapy

Ultimately, as with all other areas of oncology, risk stratification is important. But age alone should not be a cutoff.

Dr. Khochikar: No

Dr. Khochikar’s primary focus was on the goals of treatment. Often times the goals of patient care are not just oncologic cure – the entire patient must be considered.

1. Main goals of care in all patients, but particularly the elderly:
            - Oncologic Cure
            - Minimal morbidity and toxicity
            - Good quality of life
            - Meaningful and respectful remaining days
            - Are they ready for the intervention? Socially? Mentally?

2. Effectiveness of therapy is not established in the elderly patient in Level 1 evidence
            - There is no subset analysis of 80+ year old patients in any of the trials included in the ABC meta-analysis 
            - In the Annals of Oncology (2005) study, the age cutoff was 70, not 80. That cutoff is actually younger than the median age of diagnosis!
            - A 2005 paper by Clark et al (ACS) demonstrated worsening 5-year CSS and OS with age after RC – even absent NAC
                - Patients over 80 had a 45% 5-year CSS and 33% 5-year OS
            - Bladder cancer patients >80 also tended to have higher stage and higher grade disease, 72% were locally advanced
            - Hence, cure is much less likely even with RC in this population

3. Morbidity in the elderly
             - Again, ignoring the NAC, morbidity from a RC in the elderly carries more risk – higher morbidity and mortality

4. Eligibility
             - Thompson et al (2014) demonstrated that 50% of patients undergoing RC were eligible for NAC; only 39% in patients > 65. In patients > 80, that number is even less.

5. Going back to the stratification concept, he mentioned a “Staging the Aging” concept
            - Treatment needs to be tailored to the patient
            - Fit patients warrant full discussion prior to NAC + RC (limited node dissection, simple diversion)
            - Unfit patients – If unfit for surgery, consider TMT. If unfit for chemo – RC alone. If unfit for both – care rather than cure. 

Presented by: Peter Black, Makarand Khochikar 

Written by: Thenappan Chandrasekar, MD, Clinical Fellow, University of Toronto, Twitter: @tchandra_uromd at the 37th Congress of Société Internationale d’Urologie - October 19-22, 2017- Lisbon, Portugal 
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