(UroToday.com) In anticipation of the 2021 American Urological Association (AUA) Annual Meeting which is being held, in a delayed fashion, in September, the AUA hosted a “May Kick-Off Weekend” which highlighted a variety of important topics in both benign urology and urologic oncology. Saturday afternoon, Adam Feldman led a course entitled “Trimodality Therapy (TMT) for Management of Muscle Invasive Bladder Cancer” along with faculty Richard Lee and Jason Efstathiou.
Leading on from talks from Dr. Feldman providing the rationale for TMT and from Dr. Efstathiou describing the radiotherapy components of the TMT paradigm, Dr. Lee presented on the role and questions regarding chemotherapy in TMT. He began by highlighting that the use of concurrent chemotherapy is important to success of TMT and that it is very rare that patients can’t get chemotherapy.
He then discussed the large number of active radiosensitizing drugs that may be used including cisplatin, paclitaxel, 5-fluorouracil (5-FU), mitomycin C, low-dose gemcitabine, and carbogen/nicotinamide. Using data from the Erlangen experience, he suggested that the combination of 5-FU and cisplatin may enhance complete response rates.
Building on this, he highlighted a number of seminal studies in trimodal therapy for bladder cancer. The first highlighted study is BC2001, a UK-based phase III trial of radiotherapy alone versus radiotherapy plus mitomycin C and F-5U for patients with cT2-cT4a bladder cancer. Three hundred and sixty patients were accrued between 2001 and 2008 and followed for a median of nearly 70 months. While there was a later splitting of the curves, no statistically significant benefit was seen in terms of overall survival (hazard ratio 0.82, 95% confidence interval 0.63-1.09, p=0.16). However, for disease-specific survival, there was a significant benefit to the combination of radiotherapy with chemotherapy.
Dr. Lee then discussed the RTOG 0233 trial, a randomized phase II trial of twice daily radiotherapy with cisplatin and 5-FU versus twice daily radiotherapy with paclitaxel and cisplatin in patients with cT2-cT4a bladder cancer. The advantage of the paclitaxel and cisplatin approach is the ability to avoid a port-a-cath for prolonged 5-FU infusion. This study demonstrated near superimposition of the curves as highlighted below for survival with intact bladder, across a number of relevant outcomes.
Notably, in addition to comparable efficacy, toxicity was low and comparable in the two arms.
Dr. Lee then discussed phase I dose-finding studies of twice-weekly gemcitabine with daily radiotherapy performed at the University of Michigan. Dose-limiting toxicity was observed with gemcitabine doses above 27 mg/m2. However, this dosing, in this single armed study, was associated with promising efficacy data in terms of overall, disease-specific, and bladder-intact survival.
These data led to the launch of the RTOG 0712 trial, a phase II comparison of twice daily radiotherapy with cisplatin and 5-FU or daily radiotherapy with gemcitabine. Assessing their primary endpoint of three-year metastasis-free survival, this study demonstrated the comparability of the approaches.
Further, both regimes were generally well tolerated. As a result, Dr. Lee concluded that gemcitabine is a good choice for patients who can’t tolerate cisplatin due to renal function or hearing loss.
Dr. Lee then discussed the role of adjuvant chemotherapy. Following cystectomy, there are no level 1 evidence to support the use of this approach. Similarly, following TMT, the data do not support its use: in univariable but not multivariable analysis, adjuvant chemo was associated with disease-specific survival in the MGH cohort. He then discussed the potential for neoadjuvant chemo, an approach that is supported by level 1 data in the surgical setting. This has been assessed in the RTOG 8903 trial, a phase III study of two cycles of neoadjuvant MCV chemotherapy prior to daily radiotherapy with cisplatin chemosensitization. This study showed no difference in overall, disease-free, or metastasis-free survival. Beyond this one trial, the aggregation of available data fails to demonstrate a benefit to neoadjuvant chemotherapy. Thus, neither adjuvant nor neoadjuvant chemotherapy is routinely used. However, he emphasized that there is a role for neoadjuvant therapy, for example in patients with bulky lymphadenopathy prior to their definitive treatment.
He closed by highlighting his approach to the administration of chemotherapy in TMT. As is shown below, this approach is flexible on the patient of patient comorbidity and other considerations.
Presented by: Richard Lee, MD, MBA, Urologist, Weill Cornell Medicine, New York, NY
Written by: Christopher J.D. Wallis, Urologic Oncology Fellow, Vanderbilt University Medical Center, @WallisCJD on Twitter during the AUA2021 May Kick-off Weekend May 21-23