ASCO GU 2018: Multimodality Approach to Locally Advanced Bladder Cancer

San Francisco, CA (  The treatment of patients with locally advanced bladder cancer (BC) can often be nuanced, and emerging evidence of improved therapies makes this space difficult to navigate. In this case panel discussion, Dr. Alison Birtle, Dr. Alfred Witjes, and Dr. Dean Bajorin addressed several difficult cases offering their expertise on the optimal management strategy for complex patients with locally advanced bladder cancer.

Case 1: Patient with cT2 BC with a positive pelvic node on CT. He received neoadjuvant chemotherapy (NAC) and his node responded from 4cm to 2cm after 4 cycles of gem/cis. 

Dr. Witjes: a response from 4cm to 2cm is suboptimal, so this patient should receive 2 more cycles of gem/cis to try and improve the response of his disease. He cited the EAU 2017 guidelines and evidence from Bhindi et al. showing that patients who have more thorough responses to NAC have better outcomes after surgery. Because the outcome for this patient is more likely determined by systemic disease rather than local disease, he would aggressively treat him systemically.

Dr. Birtle would also give 6 cycles of chemotherapy to try and downstage this patient, followed by chemoradiation. Because of his suboptimal response to 4 cycles, he is more likely to die of distant relapse, so one could argue that this patient would benefit from bladder preservation. She presented the BC2001 protocol for chemoradiation (5FU/MMC), where updated 10yr data shows excellent loco-regional control translating into an OS benefit at 10 yrs. Lastly, she would treat the bladder alone, not the whole pelvis, because of data suggesting no difference in survival between the two and increased toxicity with whole pelvis XRT.

Dr. Bajorin concurs with 6 cycles of chemotherapy. All of the trials for NAC have used patients that were either N0 or were N1 with LN <2cm. So, by these criteria, this patient would not have been considered for NAC in the aforementioned trials. This patient would, however, be eligible for immunotherapy (either single-agent immuo-oncologic (IO) agent or trials with combination IO/chemotherapy). 

The patient underwent radical cystectomy and was pT2N1M0 (1/23 nodes).

Dr. Birtle discussed the role of adjuvant XRT. In practice, many Radiation Oncologists in the community are using adjuvant XRT (ART) for high-risk patients after cystectomy, mostly for cases with positive margins. With only one risk factor, the benefit of ART in this patient is uncertain. 

Dr. Bajorin discussed how well we can assess the prognosis for N+ disease after NAC. Studies show these patients do quite poorly (survival ~2yrs). In limited data for patients receiving further chemo vs. observation, there may be a slight benefit to further chemo, but not significantly better. In an NCDB analysis, there was potential evidence that adjuvant chemotherapy in high risk patients after NAC may have some survival benefit, but prospective data would be needed to truly believe such data. In sum, he would not give more adjuvant therapy at this point in time. Specific biomarkers for sensitivity to platinum-based therapy may help differentiate patients who could benefit from further chemo in future trials.

Dr. Witjes argues that maybe this patient was cured with the surgery. In spite of all the limitations of such analyses, there may be an improved survival for extended-LND. In this context, he would just opt for surveillance for this patient.

Case 2: 74yo female with bulky bladder disease + right hydronephrosis.

Dr. Witjes showed data that 25% of patients with muscle-invasive BC will have hydronephrosis, but relieving obstruction will improve renal function in 15% of patients and make them eligible for NAC. Discussing role of JJ stent vs. nephrostomy tube for decompression, there are benefits and risks to both. Some new evidence suggests that placing a stent might increase risks of spread to the upper tract, so a nephrostomy tube may be the preferred option.

The patient had NAC followed by radical cystectomy/ileal conduit – pathology T3bN0, margin positive.

Dr. Birtle would observe this patient or put them in a clinical trial. No current evidence exists for adjuvant XRT.

Dr. Bajorin discussed trials with IO agents as adjuvant therapy for patients with high risk disease following NAC (3 studies ongoing with pembrolizumab, nivolumab, and atezolizumab). No evidence that adjuvant chemotherapy in this setting would be of use, so he would place this patient on a trial.

Dr. Witjes, given lack of evidence, would place this patient on surveillance. Positive ureteral margins should just be followed by serial upper tract imaging and urine cytology.

Case #3: 82yo cT2N0, GFR 43, frail, undergoes TURBT and chemoradiation. After 3 months, found to have T2 disease but no metastases.

Dr. Witjes would proceed to cystectomy if the patient could survive it. If he is too frail, he would consider repeating a maximal TURBT.

 Dr. Bajorin would consider carboplatin + gemcitabine or paclitaxel – patients receiving doublet therapy have a mOS of 9 months so the outcome is not excellent. This treatment regimen would also be hard in a frail patient. Single agent therapy could be considered for palliative purposes. IO agents are now available – atezolizumab and pembrolizumab are approved and available for cisplatin-ineligible patients. 

The same patient was presented, but this time with a history of brachytherapy for prostate cancer 5yrs earlier.

Dr. Birtle asks if there are any symptoms that we need to palliate? What is his current urinary symptom status? There is a need to balance local control vs. symptoms. One might consider doing a TURBT followed by treatment with an IO agent. If he gets XRT, she recommends using IMRT and avoiding the bladder base due to prior brachytherapy exposure. 

Dr. Witjes points out that at surgery, brachytherapy seeds are often found quite high in the bladder neck/bladder base, which can add some complexity to the procedure. However, if the patient can handle it, he would offer a radical cystectomy and consider cutaneous ureterostomies for palliative purposes and to avoid the morbidity associated with bowel surgery.

This panel presented a very insightful discussion on the complexities involved with treating patients with locally advanced bladder cancer. The myriad ongoing trials assessing the role of chemotherapy and IO agents in the adjuvant setting will hopefully help clarify the standard of care for these patients in the future.

Presented by: Alison Birtle, MD, Radiation Oncology, Alfred Witjes, MD, Urology, Dean Bajorin, MD, Medical Oncology

Written by: Shreyas Joshi, MD, Fox Chase Cancer Center, Philadelphia, PA at the 2018 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, February 8-10, 2018 - San Francisco, CA

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