Following Anne Calveresi’s talk on prostate cancer, Edouard Trabulsi discussed the treatment paradigm in bladder cancer. He began by highlighting the epidemiology of bladder cancer which accounts for more than 83,000 new cases annually, more than 17,000 deaths each year, and a prevalence of more than 600,000 individuals in the United States. Bladder cancer is the fourth most common malignancy in men.
Dr. Trabulsi then discussed the breakdown of bladder cancer including non-muscle invasive (NMIBC) and muscle-invasive disease (MIBC). Among patients with NMIBC, he highlighted AUA Risk Stratification which guides treatment decisions.
For patients with NMIBC, the mainstay of treatment is intravesical therapy. Dr. Trabulsi emphasized that this has formed the backbone of our treatment approach for decades. Perioperative chemotherapy, administered immediately following surgery with the rationale to decrease tumor implantation, is recommended for most patients following TURBT and is the only adjuvant therapy given for patients with low-risk NMIBC. Dr. Trabulsi briefly highlighted data from the SWOG S0337 trial, demonstrating that immediate post-operative instillation with gemcitabine significantly reduced the risk of disease recurrence among patients with suspected low-grade NIMBC.
For patients with intermediate or high-risk disease, further treatment is recommended, with BCG forming the backbone of guideline-recommended treatment. While the underlying biology of BCG is not entirely understood, it functions as a non-specific immune adjuvant and has shown benefit to reduce recurrence and, when used with a maintenance strategy, reduce progression.
Dr. Trabulsi highlighted the standard BCG treatment approach including a 6 weekly induction course followed by maintenance therapy. For patients who have significant toxicity and in the context of BCG shortages, reduced dosing may reduce, but doesn’t eliminate, the efficacy of BCG.
In the context of the current BCG shortage, he highlighted guidance from the AUA regarding treatment alternatives and approaches to maximize benefit from available BCG resources.
While many patients respond well to BCG, a not insignificant proportion will have recurrent or progressive disease. Dr. Trabulsi emphasized the FDA guidance regarding adequate BCG, comprising two induction courses or one induction course plus one maintenance course, before defining treatment failure. As highlighted below, there are a variety of definitions of BCG failure.
While there are alternatives for patients with BCG-unresponsive disease, many patients wish to attempt further intravesical therapy. There are a number of available options though Dr. Trabulsi emphasized that their preferred approach at Thomas Jefferson is gemcitabine and docetaxel.
In addition to these intravesical approaches and the option of radical cystectomy, pembrolizumab was approved for the treatment of high-risk BCG-unresponsive NMIBC with CIS with or without papillary disease on the basis of data from the Keynote-057 trial which demonstrated a complete response rate of 41% and median duration of response of 16 months.
Dr. Trabulsi then transitioned to discussing the treatment of muscle-invasive bladder cancer. In his view, MIBC mandates cystectomy in patients who are able to undergo the procedure with consideration for chemoradiotherapy in patients who are not good surgical candidates. For patients undergoing radical cystectomy, he highlighted data from the Grossman trial demonstrating the benefit of neoadjuvant chemotherapy. This has now become the standard of care and, with the use of a dose-dense approach to MVAC as well as growth factor support, has become more tolerable.
In addition to these survival benefits, the use of neoadjuvant chemotherapy was associated with a much higher rate of pT0 disease (38% vs 15%).
He highlighted subsequent data from a phase II trial of accelerated (dose-dense) MVAC which allows for a median time to surgery of 9.7 weeks.
This trial similarly showed a pT0 rate of 38% with a further 16% of patients having T1, Ta, and CIS disease while the remainder had persistent muscle-invasive disease. Thus, compared with baseline, 65% of patients were downstaged while only 17.5% had upstaging.
In contrast to pre-operative neoadjuvant therapy, chemotherapy may be given in the adjuvant setting, with two notable advantages: local treatment is not delayed and pathologic staging can allow for better treatment selection, avoiding overtreatment. However, following cystectomy, 30% of patients will no longer be chemotherapy eligible and thus, there is a significant risk of undertreatment. However, for those who do not receive neoadjuvant chemotherapy, he highlighted data from the EORTC 30994 trial demonstrating that immediate chemotherapy is associated with statistically significantly improved progression-free survival and non-significantly improved overall survival compared to deferred treatment until the time of relapse, among patients with pT3-4 or pN+ disease at cystectomy.
Closing discussion of perioperative chemotherapy in MIBC, Dr. Trabulsi highlighted the ASCO endorsement of the European Association of Urology Guidelines which recommend cisplatin-based neoadjuvant therapy for patients with T2-T4a cN0M0 bladder cancer.
As alluded to above, pathologic down-staging, particularly to T0, is associated with improved long-term outcomes. While estimates differ somewhat between studies, approximately 25-35% of patients receiving neoadjuvant chemotherapy can expect to have pT0 disease while approximately 50% will be down-staged to NIMBC.
As will be described in more detail in the following paragraphs, there has been considerable development and utilization of immunotherapy in advanced bladder cancer. This approach has also been examined in the peri-operative setting in the PURE-01 study which examined pre-operative pembrolizumab. In keeping with rates from neoadjuvant chemotherapy, the pathologic CR rate in PURE-01 was 39.5%. In clinical practice, Dr. Trabulsi said that he typically uses neoadjuvant ddMVAC or gemcitabine-cisplatin though he has used neoadjuvant pembrolizumab selectively.
He then transitioned to discussing metastatic urothelial carcinoma. While chemotherapy remains the first-line treatment of choice for patients who are fit and eligible, immunotherapy now forms a key basis of the treatment of patients with metastatic urothelial carcinoma. Indeed, among patients who are cisplatin-ineligible, most preferred regimes involve treatment with immune checkpoint inhibitors.
Notably, since the February publication of these NCCN guidelines, atezolizumab has been withdrawn from this disease indication. When considering these guidelines, it’s important to understand what is meant by cisplatin-ineligible. Somewhat in parallel to definitions of BCG-unresponsive disease, this is not a strictly evidence-based approach, but rather an expert consensus. Notably, according to this definition, nearly half of all patients with metastatic urothelial carcinoma are cisplatin-ineligible.
Dr. Trabulsi then highlighted the rapid recent evolution of treatment options in advanced bladder cancer. While cisplatin became available in this space in 1978 followed by gemcitabine in 2008, there have been a subsequent 8 agents approved and available since 2016. Despite all these advances, cisplatin-based chemotherapy remains the first-line treatment of choice for patients who are eligible. However, alternative treatment approaches including immune checkpoint inhibitors may be the first-line treatment for other patients.
As highlighted in the figure above, avelumab maintenance is now recommended for patients with stable disease or response to initial chemotherapy on the basis of the JAVELIN Bladder 100 trial. This phase III trial showed significantly improved overall survival for patients receiving avelumab maintenance compared to best supportive care alone.
In terms of second-line treatment options, there are a variety of treatment approaches, most predicated on immune checkpoint inhibition though enrollment in clinical trials remains the recommended approach according to the NCCN.
Targeted therapies have become increasingly important in further lines of therapy including enfortumab vedotin (an antibody-drug conjugate that delivers cytostatic drugs to cell expressing nectin-4), erdafitinib (an oral FGFR inhibitor; indicated in patients with FGFR 2 or 3 alterations), and sacituzumab govitecan (an antibody-drug conjugate targeting the trophoblast cell-surface antigen (TROP-2)).
In spite of all of these treatment options, a vast majority of patients with advanced urothelial carcinoma do not benefit from these advances: less than half of all patients with newly diagnosed advanced bladder cancer receive first-line therapy and a much smaller proportion receive second or third-line therapy.
Circling back to previous aspects of his presentation, Dr. Trabulsi highlighted many ongoing trials of PD-1 or PD-L1 inhibitors in both monotherapy and combination therapy in the neoadjuvant setting.
Finally, in closing, Dr. Trabulsi briefly made mention of upper tract urothelial carcinoma. He highlighted that much of our treatment of this condition is extrapolated from the bladder cancer literature given the shared histology. While the ECOG-ACRIN 8141 assessed neoadjuvant ddMVAC in UTUC finding a 14% pathologic complete response rate and 60% down-staging to non-invasive disease, the randomized data in this disease space come from the POUT trial which examined adjuvant gemcitabine with cisplatin or carboplatin. POUT demonstrated significantly improved disease-free survival for those receiving adjuvant therapy.
Presented by: Edouard J. Trabulsi, MD, Professor, Co-Director, Multidisciplinary, Genitourinary Oncology Center, Co-Director, Prostate Diagnostic Center, Vice Chair of Research, Department of Urology, Director, Division of Urologic Oncology, Department of Urology, Jefferson University Hospitals
Written by: Christopher J.D. Wallis, Urologic Oncology Fellow, Vanderbilt University Medical Center Contact: @WallisCJD on Twitter during the AUA2021 May Kick-off Weekend, May 21-23, 2021