SUO 2022: Intermediate Risk: New Trials and Horizons

( The 2022 Society of Urologic Oncology annual meeting featured a bladder cancer session, including a presentation by Dr. Sarah Psutka discussing new trials and horizons for intermediate risk bladder cancer. Dr. Psutka started her presentation by highlighting the need to hone definitions and increasing precision of guideline-based care. However, the problem is the need to reduce the therapeutic burden for intermediate risk non-muscle invasive bladder cancer and improve outcomes, and the solution may be to use strategies to de-escalate therapeutic burden and improving treatment efficacy. In 2022 there will be 81,180 new bladder cancer diagnoses, with 61,000 of these being non-muscle invasive bladder cancer (mostly low/intermediate risk). Although there is variability in the definition of intermediate risk non-muscle invasive bladder cancer among the AUA/SUO, NCCN, EAU, and IBCG, there is generally agreement on treatment recommendations:

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Dr. Psutka notes that the current treatment paradigm for intermediate risk non-muscle invasive bladder cancer is to perform transurethral resection followed by postoperative chemotherapy +/- adjuvant intravesical BCG or chemotherapy +/- maintenance for 1 year, with the cycle repeating itself over and over with each recurrence.

Recent work from the International Bladder Cancer Group has provided updated definitions and management recommendations for the treatment of intermediate risk non-muscle invasive bladder cancer.1 Among intermediate risk (low-grade tumors), the following risk factors should be assessed:

  • Tumor size >3 cm
  • Multiple tumors
  • Early recurrence (<1 year)
  • Frequent recurrence (>1/year)
  • Failure of previous intravesical treatment

Those patients with none of the above risk factors, they should be treated similarly to those with low-risk disease (no additional treatment). For patients with 1-2 risk factors, they should be treated as intermediate risk disease and thus treated with additional adjuvant induction intravesical chemotherapy (or BCG if prior chemotherapy has been used). For patients with >= 3 risk factors, they should be treated as high risk disease with BCG/chemotherapy for at least 1 year, with maintenance therapy:

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The current outcomes of intermediate risk non-muscle invasive bladder cancer are 1 and 5-year recurrence free survival rates with TURBT only 62% and ~40%, respectively, improving to 84.6% after induction BCG + 1 year of maintenance BCG. Importantly, Dr. Psutka notes that recurrence of low grade non-muscle invasive bladder cancer after TURBT is low grade in 90% of cases and is not life-threatening.

There are also problems with the current resection/adjuvant therapy paradigm, including morbidity and cost. With regards to morbidity, there is a 5.1% risk of 30-day complications, 1.5% rate of transfusion, 3.7% readmission rate, 1.5% reoperation rate, 0.8% mortality rate, 65% rate of post-operative delirium, and 10% rate of anesthesia related long-term cognitive decline. With regards to cost, surveillance and frequent TURBTs, as well as intravesical therapy (both induction and maintenance) are prohibitively expensive. Additionally, the financial toxicity to the patient is secondary to direct and indirect costs, as well out of pocket costs, all of which take their toll on the patient and their caregivers. In fact, the cumulative costs of care for intermediate risk non-muscle invasive bladder cancer over a 5-year period is estimated at $146,250.

So, how can we reduce the therapeutic burden of intermediate risk non-muscle invasive bladder cancer? Dr. Psutka discussed six strategies for doing so. 

Strategy #1: De-escalate Recurrence Treatment to the Outpatient Setting

In a study by Pedersen and colleagues,2 they compared 4 month recurrence-free survival after outpatient department diode laser coagulation of bladder tumors using local anesthesia versus the gold standard of transurethral resection of bladder tumor using general anesthesia among intermediate-risk Ta low-grade bladder tumors. Overall, 206 patients were randomized and 176 finished treatment and follow-up as per protocol. Four-month recurrence-free survival was 8% higher after photocoagulation of bladder tumor (95% CI -8% to 24%), and the predefined noninferiority criterion was met. Pain score (1-10) during photocoagulation of bladder tumor was 2.4 (interquartile range 0.8-3.3), and postoperative lower urinary tract symptom score (0-100) was 13.9 points higher (95% CI 6.9-21.0, p < 0.001) in the group with transurethral resection of the bladder. The frequency of minor complications was 8.1% higher after TURBT (95% CI 1.0-14.6%, p = 0.026), and 98% (95% CI 92-100%) of patients preferred photocoagulation of bladder tumor.

Strategy #2: Chemoablation

In a prospective, single-center, nonrandomized study, Racioppi et al.3 evaluated the ablative power and patient safety of a short-term intensive schedule of intravesical Mitomycin C in patients with recurrent non-muscle-invasive bladder cancer. There were 47 patients (group 1) with a history of low- to intermediate-risk non-muscle-invasive bladder cancer with long free-recurrence intervals, recurrence of ≤1cm in maximum diameter, and negative cytology compared to 47 consecutive patients with the same baseline characteristics (group 2). Intravesical Mitomycin C was given three times per week for 2 weeks to group 1, and TURBT and early instillation and a weekly schedule of intravesical Mitomycin C was given to group 2. The complete response rate at 39 months was 61.7% in group 1 and 70.2% in group 2 (p = 0.38). Kaplan-Mayer analysis revealed no difference in cancer-free survival rates overall (log-rank <3.84):

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No cases of systemic toxicity were observed. Local toxicities did not differ between the groups (p = 0.32) and resolved on treatment of symptoms, and no patient discontinued their treatment. Thus, Dr. Psutka noted that >70% of TURBTs could have been avoided following recurrence of low/intermediate risk non-muscle invasive bladder cancer.

Strategy #3: Enhanced Drug Delivery to Improve Pharmacokinetic Absorption

The two main methods for improving pharmacokinetic absorption are electromotive drug administration or chemohyperthermia, increasing the permeability of the urothelium to intravesical agents. The HIVEC-II trial was a phase 2, open-label randomized clinical trial designed to assess the efficacy and safety of adjuvant intravesical chemohyperthermia for intermediate-risk non-muscle invasive bladder cancer.4 Patients were randomly assigned (1:1) to adjuvant chemohyperthermia with mitomycin C at 43°C or to room-temperature mitomycin C (control). Of note, both treatment arms received six weekly instillations of 40 mg of mitomycin C lasting for 60 min. A total of 131 patients were in the chemohyperthermia group and 128 patients in the control group. At 24 months, 42 patients (32%) in the chemohyperthermia group and 49 (38%) in the control group had experienced recurrence. Disease-free survival at 24 months was 61% (95% CI 51-69%) in the chemohyperthermia arm and 60% (95% CI 50-68%) in the control arm (HR 0.92, 95% CI 0.62-1.37; log-rank p = 0.8). 

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Progression-free survival was higher in the control arm (HR 3.44, 95% CI 1.09-10.82; log-rank p = 0.02) on intention-to-treat analysis but was not significantly higher on per-protocol analysis (HR 2.87, 95% CI 0.83-9.98; log-rank p = 0.06). Additionally, overall survival was similar (HR 2.55, 95% CI 0.77-8.40; log-rank p = 0.09). Adverse events were reported by 164 patients (87 chemohyperthermia vs 77 control), although major (grade III) adverse events were rare (13 chemohyperthermia vs 7 control). Based on these results, Dr. Psutka emphasized that the data does not support the use of HIVEC for intermediate-risk non-muscle invasive bladder cancer. 

Strategy #4: Enhance Length of Contact Between Therapeutic Agent and Tumor

The Optima-II trial was a phase 2b single-arm study in patients with low grade intermediate risk non-muscle invasive bladder cancer, in which 41/63 (65%) patients achieved the primary endpoint of complete response at 3 months, and 25/41 (61%) patients had a durable complete response at 12 months after the start of treatment. The probability of durable response 9 months after complete response was estimated to be 73% by Kaplan-Meier analysis.5 This study has set the stage for the ENVISION trial, which is a phase 3 single-arm study of UGN-102 as primary chemoablative therapy in patients with low grade intermediate risk non-muscle invasive bladder cancer. This trial will accrue approximately 220 patients with a history of low grade non-muscle invasive bladder cancer and prior TURBT who meet intermediate risk disease criteria and who will receive 6 once-weekly intravesical instillations of UGN-102 (75 mg mitomycin). The primary endpoint is complete response rate at 3 months after the start of treatment. Secondary endpoints include:

  • Duration of response (key secondary)
  • Durable complete response rate at scheduled disease assessment time points
  • Disease-free survival
  • Safety/tolerability

Strategy #5: Targeted Therapy to Improve Treatment Efficacy

Recent molecular work suggests that activating mutations in FGFR3 are present in 60% of low grade tumors. As such, a phase 2 window of opportunity study of pemigatinib (PO FGFR-1, 2, 3-inhibitor) is being tested as primary treatment in non-muscle invasive bladder cancer patients with recurrent low- or intermediate-risk tumors. The trial design is as follows: 


Strategy #6: Enhance the Response Rate for Adjuvant Therapy

Nadofaragene firadenovec is a non-replicating recombinant type-5 adenovirus vector-based gene therapy that delivers a copy of the human IFNα2b gene. The Phase III trial of nadofaragene firadenovec for BCG unresponsive NMIBC was a multi-center study to investigate the safety and efficacy of intravesical nadofaragene firadenovec 75 mL once every 3 months in 157 patients with high-grade, BCG-unresponsive NMIBC.6 Cytology and cystoscopy (with biopsy if clinically indicated) were performed at 3, 6, and 9 months to evaluate for recurrence of high-grade disease. At 12 months, all patients underwent urine cytology, cystoscopy, and mandatory biopsy. Patients free from high-grade recurrence were eligible for retreatment at 3-month intervals while they remained high-grade recurrence free. The study met its primary endpoint with 53.4% of patients with CIS ±Ta/T1 achieving a complete response, all by 3 months, including 43.6% of these patients remaining free of high-grade recurrence at 15 months. 

Dr. Psutka emphasized that there are several meaningful endpoints in intermediate risk non-muscle invasive bladder cancer. With regards to oncologic/clinical outcomes, this includes the following:

  • Recurrence-free survival
  • Rate of reclassification from intermediate to high-risk disease
  • Toxicity, harms, and complications 

The following are more centered around patient related outcomes:

  • Patient reported quality of life
  • Treatment burden: decreasing surveillance cystoscopy and TURBT frequency
  • Financial toxicity, cost, and resource utilization

Dr. Psutka concluded her presentation discussing new trials and horizons for intermediate risk bladder cancer with the following take home messages:

  • Some non-muscle invasive bladder cancer will chronically relapse, but are not life-threatening
  • Traditional treatment paradigms are likely leading to overtreatment, with unacceptable risks of harms, cost, and reduction in quality of life
  • The treatment paradigm for intermediate risk bladder cancer is evolving
    • Risk stratification is guiding treatment intensity
    • Treatment de-escalation
    • Resection vs primary ablation
    • Harnessing biology to improve treatment efficacy
    • Capturing endpoints that matter (ie. oncologic and patient centered)

Presented by: Sarah P. Psutka, MD, University of Washington, Seattle, WA

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 23rd Annual Meeting of the Society of Urologic Oncology (SUO), Nov 30 – Dec 2, 2022. San Diego, CA 


  1. Tan WS, Steinberg G, Witjes JA, et al. Intermediate-risk non-muscle invasive bladder cancer: Updated Consensus Definition and Management Recommendations from the International Bladder Cancer Group. Eur Urol Onc. 2022 Oct;5(5):505-516.
  2. Pedersen GL, Erikson MS, Mogensen K, et al. Outpatient photodynamic diagnosis-guided laser destruction of bladder tumors is as good as conventional inpatient photodynamic diagnosis-guided transurethral tumor resection in patients with recurrent intermediate-risk low-grade Ta bladder tumors. A prospective randomized non-inferiority trial. Eur Urol. 2022 Sep 1;S0302-2838(22)02564-7.
  3. Racioppi M, Di Gianfrancesco L, Ragonese M, et al. Chemoablation with intensive intravesical Mitomycin C treatment: A new approach for non-muscle invasive bladder cancer. Eur Urol Oncol. 2019 Sep;2(5):576-583.
  4. Tan WS, Prendergast A, Ackerman C, et al. Adjuvant intravesical chemohyperthermia versus passive chemotherapy in patients with intermediate-risk non-muscle-invasive bladder cancer (HIVEC-II): A phase 2, open-label, randomized controlled trial. Eur Urol. 2022 Aug 20;S0302-2838(22)02552-0.
  5. Chevli KK, Shore ND, Trainer A, et al. Primary Chemoablation of Low-Grade Intermediate-Risk Nonmuscle-Invasive Bladder Cancer Using UGN-102, a Mitomycin-Containing Reverse Thermal Gel (Optima II): A phase 2b, open-label, single-arm trial. J Urol. 2022 Jan;207(1):61-69.
  6. Boorjian SA, Alemozaffar M, Konety BR, et al. Intravesical nadofaragene firadenovec gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: A single-arm, open-label, repeat-dose clinical trial. Lancet Oncol. 2020 Nov 27:S1470-2045(20)30540-4.