ASCO GU 2020: Management Strategies in the Face of the Bacillus Calmette-Guérin Shortage

So, what do we do and what management strategies exist? We need to:

• Perform a quality TURBT
• Ration our BCG supplies
• Utilize current intravesical treatments as alternatives
• Proceed to initial radical cystectomy
• Enroll in clinical trials

But first, Dr. Chang notes that for every situation, for every patient, we must do a better job of counselling regarding smoking cessation. Certainly, smoking increases the risk of bladder cancer, with a duration, intensity, and pack-year effect gradient. However, it is also important to note that smoking cessation decreases bladder cancer risk. In a population-based survey among NMIBC patients, 48% of smokers quit after diagnoses of bladder cancer, and patients were more than 5x likely to quit than those without bladder cancer.¹ The reasons for smoking cessation were the diagnosis of bladder cancer (76%) and advice from their urologist (55%). But challenges do exist – according to the report of the Surgeon General, >40% of adult smokers do not receive advice to quit from a healthcare profession, and less than 1 in 10 US adults successfully quit smoking each year. 

When managing NMIBC it is important to perform a quality TURBT. Dr. Chang notes that currently we are performing a century old technique and we haven’t changed our TURBT much in the last 100 years. Performing a quality TURBT is a multi-pronged process that depends on many variables including experience, tumor characteristics, and equipment. TURBT versus cold-cup biopsy and re-TURBT are important. Furthermore, surgeon experience makes a difference in the quality of the TURBT. In a study assessing 566 patients and 473 NMIBC specimens, logistic regression multivariate analysis revealed that the absence of detrusor muscle was associated with a higher recurrence rate at the first follow up cystoscopy (OR 3.6, 95% CI 1.7-7.5, p < 0.001).² Senior surgeons were more likely to resect detrusor muscle (OR 4.9, 95% CI 2.3-10.7, p < 0.001) and senior surgeons were independently associated with a lower recurrence rate at the first follow up cystoscopy (OR 5.3, 95% CI 2.1-12.9, p < 0.001). Whether all specimens should be reviewed by an expert pathologist is somewhat controversial. In a study of 98 consecutive cases reviewed by GU specialist pathologists of outside referred cases, 35% of patients had significant changes, 12% “should” have had a radical cystectomy, and 2% should not have had cystectomy.³

There are many issues pathologists have to deal with, including poor orientation with tangential sectioning, thermal injury, intense inflammatory response, nested variant mimicking von Brunn’s nests, CIS in von Brunn’s nests, prominent muscularis mucosae looks like detrusor muscle, and lamina propria fat looks like perivesical fat. The AUA guidelines recommend the use of enhanced cystoscopy when available, as it may increase detection rates and decrease the risk of recurrence.  A new technique that has generated some interest is the en bloc resection technique. En bloc resection seeks complete tumor removal, without scattering of the tumor with the resection loop. The hypothesis is that this “no touch” technique would lead to improved resection results and decreased recurrence rates. Dr. Chang’s take-home messages for performing a quality TURBT include (i) use enhanced techniques and judicious use of technology, (ii) separate specimens for better evaluation of stage, (iii) use bi-polar resection for larger, extensive tumors, (iv) cold cup specimens can be used to avoid cautery artifact, (v) repeat TURBT 4-6 weeks for T1 and high-risk Ta, (vi) pathologic communication/experience review may be important if there are concerns, (vii) realize that there is no substitute for experience. 

BCG should be rationed according to Dr. Chang and the first practice change we can make is to not give BCG to low-risk patients. According to the EAU in the current BCG shortage, instillations can be safely terminated when the patient has completed one year of BCG, if supply exists for maintenance therapy every attempt should be made to use 1/3 dose BCG and limit dose to one year. In a true BCG shortage maintenance therapy should not be given and BCG-naïve patients with high-risk disease should be prioritized for BCG induction therapy. 

We should also look to utilize current intravesical treatments as an alternative to BCG. Indeed, there are many past and ongoing trials in BCG unresponsive disease, but now and in the future, agents for intermediate/high risk disease in the BCG naïve population are being evaluated. Optimized mitomycin C has been used, increasing the concentration to 40 mg/20mL of sterile water, dehydration and emptying the bladder, as well as alkalinizing the bladder with oral sodium bicarbonate 650 mg x2 tabs the night before treatment. More recently, combination therapy has been used for intravesical chemotherapy. Several studies have shown that the combination of gemcitabine + mitomycin C provides RFS at 12 month rates of 58-72%, and 24 month rates of 48-49%. Furthermore, the combination of gemcitabine + docetaxel data has demonstrated a 6 months RFS rate of 82%, 12 month rate of 76% and 24 month rate of 66%. Following six week induction therapy, patients should be considered for monthly maintenance instillation. In 2016, a European study randomized 190 patients with NMIBC to chemohyperthermia with mitomycin C vs BCG and found that the 24-month ITT RFS was 78.1% in the chemohyperthermia group compared with 64.8% in the BCG group (p=0.08). The 24-month RFS in the per-protocol analysis was 81.8% in the chemohyperthermia group compared with 64.8% in the BCG group (p=0.02).⁴ Overall, progression rates were <2% in both groups. 

Dr. Chang’s opinion for alternative intravesical therapy is as follows:

• Low grade, papillary and intermediate risk should have optimized mitomycin C
• High risk disease should have combination chemotherapy with either gemcitabine and mitomycin C or gemcitabine and docetaxel (preferred)
• Chemohyperthermia may be an effective therapy, but is not currently available in the United States. 

Appropriately selected patients may be able to proceed to initial radical cystectomy, which is included in the AUA guidelines. The outcomes of initial cystectomy are excellent with 92% overall survival for pathologic T1 disease, and 5-year recurrence free rate of 83% for pT1 disease. 

Dr. Chang provides the following simplified, effect nomogram for initial, timely cystectomy:

Finally, in the BCG shortage era, NMIBC patients should be considered for clinical trials. Currently, SWOG 1602 is randomizing patients to intravesical Tice BCG vs Tokyo-172 strain vs priming with intradermal BCG and subsequent intravesical Tokyo-172 strain. The primary objective is time to high-grade recurrence in BCG-naïve NMIBC patients:




Presented by: Sam S. Chang, MD, MBA, Vanderbilt University, Nashville, TN

Written By: Zachary Klaassen, MD, MSc – Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, Twitter: @zklaassen_md 

References:

1. Bassett JC, Gore JL, Chi AC, et al. Impact of a bladder cancer diagnosis on smoking behavior. J Clin Oncol2012 May 20;30(15):1871-1878.
2. Mariappan P, Finney SM, Head E, et al. Good quality white-light transurethral resection of bladder tumors (GC-WLTURBT) with experienced surgeons performing complete resections and obtaining detrusor muscle reduces early recurrence in a new non-muscle-invasive bladder cancer: validation across time and place and recommendation for benchmarking. BJU Int2012 Jun;109(11):1666-1673.
3. Traboulsi SL, Brimo F, Yang Y, et al. Pathology review impacts clinical management of patients with T1-T2 bladder cancer. Can Urol Assoc J2017 Jun;11(6):188-193.
4. Arends TJ, Nativ O, Maffezzini M, et al. Results of a randomized controlled trial comparing intravesical chemohyperthermia with mitomycin C versus Bacillus Calmette-Guerin for adjuvant treatment of patients with intermediate- and high-risk non-muscle-invasive bladder cancer. Eur Urol2016 Jun;69(6):1046-1052.