2 vs 3 BCG Maintenance Treatments

Greetings.  Well, my husband just had a f/u cystoscopy and he needed a biopsy.  There is a velvety like lesion (sounds like CIS) in one of the areas of scar tissue from his original TURBT. 80% it is inflammation but that leaves 20% that it is a recurrence.  MSK would NOT give him a 3rd dose, so he only had 2 last round.  Which begs the question "is full dose better than half dose at a reduced frequency?" I guess this remains to be seen.  I can tell you this, however...if this IS a recurrence, I will always wonder if it is because he only had 5 induction followed by 3 maintenance and then down to 2 at the 6 month mark. I am hopeful we will get urine cytology back by tomorrow. Mayo tends to move quickly and they drop results into the portal immediately. This is not the news we were hoping for today, but we won't know for sure until path comes back. 

Clinical trial was brought up as a next step.  I hate to see him pushed into a trial when he was not given the frequency and duration that both the EU and American guidelines state is appropriate to begin with. 

Sorry, I got a bad cold from my granddaughter.  It lasted nearly three weeks.  

How did your call to MSK to get the 3rd dose go?    What is the status now?

Thank you for your detailed response. Much appreciated!  I have read a plethora of review articles and clinical trial data, and although Mayo did do blue light cystos on him, they will not be doing them moving forward, as Karl Storz has had issues with the flexible version and now only the rigid version is available. I guess they are working on a new flexible scope, but it probably won't be available in this country for some time. 

I think I will call MSK again tomorrow and see if they will take him for dose #3. I do understand the definition of BCG unresponsive, however, this is not my husband, and I would like to keep it that way.

I agree that Mayo seems to have come up with their own protocol. Who knows if this is ok or not, as there are no data on the schedule my husband is on.  This makes me incredibly uncomfortable.  My husband is leaning toward not messaging the uro onc and do a wait and see approach to find out if he will potentially get more doses at the 9 month mark.  I really don't like uncertainty and feel this is not the best route.

Suggestions welcome.....

A very good question. 

I think it is best to ask to Mayo AZ why they chose  5 weeks + 3 week, then 2 wks for remaining maintenance.   I am very interested to know why Mayo AZ did not follow a consensus statement published in 2019, which recommended dose reduction to 1/2, 1/3 which several academic hospitals seemed to have followed.    The current BCG shortage started when Sanofi abandoned  the most popular intravesical BCG product business in 2016, peaked at 2019-2021 when MERCK took over Sanofi's customer with Onco-Tice.  Mayo AZ must have accumulated their data with their own protocol and reason to continue with their  protocol.  

Tice BCG shortage

The BCG production facility in Durham, NC can produce maximum of 700-800K vials a year. The demand exceeds more than 1M vials.  The reason the shortage subsided is because  a) many academic hospitals implemented dose reduction & use of intravesical chemotherapy for intermediate risk NMIBC , b) several European countries switched from Tice to BCG-MEDAC which is manufactured by Medac Corp. in Germany as the main supplier, c)  a few countries like Australia and New Zealand supplemented Tice with other BCGs.   US and the UK are the only countries who decided to use only Tice BCG.  US chose dose reduction and prioritized BCG for high risk. To UK, MERCK guaranteed 90% supply if Tice BCG remains sole source of BCG.  Initially, UK recommended reduction of BCG treatment frequency, which later stopped the recommendation due to the result of NIMBUS clinical trial.

SWOG clinical trial (2000) led by Dr. Lamm
The clinical trial was to compare BCG treatment  with 6 weeks induction course only vs  6 weeks + 3 weeks ( 7 times) maintenance (in total 27 instillations).  It is difficult to compare SWOG protocol and Mayo AZ protocol.
 As Allan mentioned only 16% were able complete the whole treatment mainly due to side effects.  

NIMBUS clinical trial (2023-2019) led by European 
The clinical trial was see if side effects could be reduced without affecting efficacy by reducing number of BCG instillations.   
The standard BCG schedule was 6 wks of induction followed by 3 wks of maintenances at 3,6 and 12 month ( 15 installations).  The reduced frequency BCG schedule was the induction at wks 1,2 and 6 followed by 2 wk (wks 1 and 3) of maintenance at 3,6, and 12 months (in total 9 instillation).   

Result   After 12 month of median follow-up, 46/170  or  27%  of (reduced frequency group) versus 21/175  or 12%  of (standard treatment group) had recurrence, hence it was determined that reduced frequency was inferior to standard frequency, and the trial was terminated at that point.

Note that the NIMBUS protocol is different from Mayo AZ.   

Incidentally, in 2015, FDA and AUA got together and came up the definition of BCG Unresponsibe.    Patient is considered as BCG unresponsive if there is recurrence in spite of the patient having received Adequate BCG treatment.   FDA/AUA defined Adequate BCG treatment is when a patient receives (5 or 6) weeks induction and  a (2 - 6) weeks maintenance treatment.   

Mayo AZ sounds like a good place for NMIBC patients to be treated as they used flexible blue light cystoscopy after 5 weeks BCG treatment, then after the first 3 weeks maintenance treatment for your husband.    I do understand the dilemma. 

According to SWOG protocol and the results of the NIMBUS trial (Safety analysis showed that the reduced frequency schedule of BCG was inferior to the standard frequency schedule for time to first recurrence according to the previously defined stop criterion. Recruitment of patients was stopped immediately.  Clinical trial information: NTR4011. ), current data do not recommend 2 inductions unless there is early recurrence of disease. Frequency and duration are critical. I am so glad that you are NED after all this time, but I do feel my husband (a physician) should follow what clinical trial data support. He has HG disease and although it is NMIBC, his chance of recurrence is not 0. He is at Mayo and with a respected uro onc, but for whatever reason, Mayo AZ does not have the supply of BCG that the east coast has. I am not sure about the mother ship in Rochester because we have not explored that as an option. It seems that the west in general struggles with supply more than the east. Perhaps MSK has more because they are a cancer only institution and there are some pretty big names there. Whatever the reason it is very frustrating.  I believe in the science and have poured through the data. It is clear that the SWOG protocol should be followed if you can find supply.