ASCO GU 2018: Best of Journals: Urothelial Carcinoma
Syn3 is a polyamide surfactant that enhances the adenoviral transduction of the bladder lining. 40 patients with HG BCG-refractory or relapsed disease were enrolled and were randomized to one of two different dosage groups of the intravesical treatment. If patients showed an initial response, they were then given maintenance treatments at 4,7, and 10 months. The primary endpoint was HG recurrence-free survival at 1 year. 35% of all patients enrolled met this endpoint. Secondary endpoint included toxicity, and 39 of the 40 patients did experience adverse effects, the most common of which were urinary urgency, and dysuria. No patients experienced grade 4 or 5 AEs. The importance of this study is that it shows patients can have a durable response with this treatment which is better than the current standard of care. Dr. Chang cautioned, however, that we need to wait for results of the ongoing phase III trial before we can be more certain about efficacy. He feels that this trial represents a promising intravesical treatment option for patients who are BCG unresponsive who need therapy options other than radical cystectomy.
Dr. Chang next highlighted the combined AUA/ASCO/ASTRO/SUO guidelines that were published regarding the treatment of non-metastatic muscle-invasive urothelial carcinoma of the bladder (MIBC). The importance of these guidelines is that they are the first guidelines that were developed and endorsed by a multidisciplinary committee. The key points brought up in the new guidelines include the need for multidisciplinary treatment for patients with MIBC, cisplatin based chemotherapy should be offered prior to cystectomy, and bladder preservation therapies should be discussed with the patient as an option. Radiotherapy alone should not be offered with a curative intent, nor should partial cystectomy. Furthermore, the guidelines highlighted the importance of concurrent pelvic lymphadenectomy in patients undergoing cystectomy. A limitation of these guidelines is the fact that they are still not uniformly adopted by physicians, particularly in the United States. Dr. Chang stated that the guidelines are a good starting point, but need to be better distributed and understood by physicians who treat patients with bladder cancer.
The next article discussed was a meta-analysis of patients undergoing radical cystectomy who were placed on an enhanced recovery after surgery (ERAS) protocol post-operatively. This EAU publication from Dr. Mark Tyson was a pooled analysis of 13 studies and included nearly 1500 patients. Key findings from this analysis showed that there is decrease in the length of hospital stay post-operatively, and a shorter return of bowel function. Dr. Chang felt that the important take home message from this study is that standardization of care and the utilization of post-operative protocols is clearly on the horizon and will represent an important change in how we take care of post-surgical patients. Dynamic and continuous reassessment of all aspects of perioperative care is essential.
Dr. Chang next highlighted an EAU paper that evaluated the impact that molecular subtypes in MIBC have on response and survival in patients who receive neoadjuvant chemotherapy. This article by Seiler et al, used tissue microaray data to sub-classify patients with MIBC into four distinct categories based on gene expression. They found that certain sub-groups of MIBC, particularly the basal group, tend to have a much more impressive and durable response to neoadjuvant chemotherapy than do the other sub-groups. This study represents what is on the horizon in terms of personalized cancer treatment based on tumor molecular and genetic analysis. He acknowledged that prospective validation is still required before this will become standard of care.
The next study looked at was the Cancer of the Bladder Risk Assessment (COBRA) Score Estimating Mortality After Radical Cystectomy. This was published in December, 2017 from the group at UC San Francisco. The goal of this study was to develop a simple risk stratification tool for cancer-specific survival after radical cystectomy based on a patients clinical and pathologic features. SEER and NCDB databases were used to gather data and for study validation. Using three simple features including patients age, tumor stage, and lymph node density, patients were assigned a COBRA score from 0-7, which were found to correlate directly with the risk of cancer-specific mortality after cystectomy. For every one increased point on the COBRA scale, there was an increase in cancer-specific mortality by 1.6x. Dr. Chang acknowledged that population based cohorts are subject to error, however he feels that this is a quick and simple tool to help counsel patients regarding prognosis following radical cystectomy.
Finally, Dr. Chang reviewed the data from a randomized phase II trial that compared adjuvant sandwich chemotherapy plus radiotherapy to adjuvant chemotherapy alone in patients with locally advanced bladder cancer after radical cystectomy. Patients were enrolled if they were >70 years of age and had either T3b bladder cancer or node-positive disease. 75 patients received 2 cycles of gemcitabine/cisplatin (Gem/Cis) prior to radiotherapy (4500 Gy over 3 weeks, followed by 2 cycles of Gem/Cis, while 45 patients received adjuvant chemotherapy alone (4 cycles Gem/Cis). They found that the patients who underwent combination chemotherapy and radiotherapy had a significantly increased local recurrence-free survival at 2 years (96% versus 69%). The combination group also was found to have an improved disease-free survival at 2 years (68% versus 56%). There were slightly higher rates of adverse effects in the combination therapy group. Dr. Chang found this study to be compelling because it is the first randomized trial the supports the use of combination chemotherapy and radiotherapy in patients with high risk disease after radical cystectomy. He noted, however, that this is a phase II study within a phase III study, and so is not a game-changer quite yet.
Speaker: Sam Chang, MD, MBA, Vanderbilt University Medical Center
Written by: Brian Kadow, MD, Fox Chase Cancer Center, at the 2018 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, February 8-10, 2018 - San Francisco, CA