First BCG Maintenance Started: Half Dose 40Mg

Hi Bills,

That is a great news that your father reaches the first milestone first.  And thank you for taking time to provide your feed back. 
Below are a few comments at random.

1.  The side effects more its indication that BCG is working the way it's should and more its effectiveness?  

There was a  clinical trial done in 2003.  Its conclusion says "Conclusions: While a correlation between BCG toxicity and efficacy  exists, this study does not confirm that BCG toxicity is actually responsible for an improved outcome."    I have also heard a similar comment by Dr. Kyrkreja of MD Anderson more recently when she and Dr. Kamat were answering to questions by patients.  Incidentally I know a patient who called the urologist because the patient got scared of seeing big clots of blood after BCG but the urologist told the patient it was because BCG was working.   

pubmed.ncbi.nlm.nih.gov/14499675/


2.  He drinks more water in morning that keeps his Urine clear till the evening. After 5pm urine becomes yellowish and he says its slightly burns ( tolerable and lasts few seconds)

This is just my opinion.
Yellow urine means more  salt concentration than when it is clear.   Your father's tumor was found at almost bottom of the bladder according to the description of you urologist on the first cystoscopy exam.  So, the area of TURBT is exposed to urine longer than other area in the bladder.  Irritation indicates that the bladder may not have been completely healed.  Salt stings open wound.  Have you considered suggesting your father drinking water more evenly through out the day?  

3.  May restart BCG even with 10 mg, which is almost 1/10th of initial dosage of 80mg.

Jack had posted in this regard. I have reviewed Jack's description of how Dr. Lamm might approach the side effects. He recommended 1/10th in the case.    Jacked had attached the protocol for BCG treatment  by Dr. O'Donnell.  (Thanks Jack).   Dr. O'Donnell states "the decision to retreat patients with BCG after they have developed severe BCG cystitis must be made with extreme caution. If you must, wait at least 6 months after all inflammation has subsided and restart BCG at a very low dose of 1/30 -1/100th with 100 MU of interferon-alpha".    So, he even reduces the dose to 1/30 to reduce the side effect  but it is supplemented with Interferon Alpha to keep the efficacy high.  Incidentally, reduced BCG + Interferon Alpha has been for BCG unresponsive patients with some success.   So, 10mg seems to be a good testing restart dosage.  


4. Intravesical BCG  vs Intravesical Chemotherapy for TaHG.

MD Anderson's published algorithm (2020) for treating TaHG is BCG induction course ( 6 weeks) plus maintenance for 3 years.  I was surprised to see it was different from AUA guidlines, which recommends just 6 weeks of induction course (BGC or Chemo).  But, the guideline says if TaHG > 3cm or multiples, it should be treated as high risk.   Since the side of your father's tumor was almost 3 cm, treating it as high risk NMIBC makes sense, so the induction plus 3 years of maintenance if possible is justified. Besides BCG has been working so far.

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www.mdanderson.org/documents/for-physicians/algorithms/cancer-treatment/ca-treatment-bladder-web-algorithm.pdf

5. Mitomycin

What your dad had was perioperative chemotherapy, which AUA guideline suggests to be administered within 24 hrs after the initial TURBT if a urologist who does cystoscopy thinks the tumor looks like low grade.  This is to kill fragments of the tumor which might  have have landed to other parts of the bladder, thus reducing the recurrence rate  by 10-15%.  I assume that  because low risk TaLG is usually treated with cystoscopy surveillance only, the protocol increases the recurrence rate, hence mitomycin is administered.  For intermediate or high risk, intravesical chemotherapy or BCG is administered anyway, Mitomycin becomes redundant. My urologist did not do this citing me when I asked the question before TURBT that it was done before but not anymore because it wasn't effective.  I  am still not happy about it after 3 years.  The reason I pointed out England was I think NA provides several treatment options for BCG unresponsive / Intolerable compared to UK, though in the last 2 years, I have seen posts which a patient in Arizona, and a patient in New Hampshire were put on Mitomycin when BCG became unavailable for maintenance.   Anyway, in your case,  we often say "If it ain't broke, don't fix it".  Since BCG has been working so far, it makes sense to continue with BCG, but carefully taking care of side effects.  


Best

Hi Joe,
 
Thanks and Thanks again for the concern which you showed in your reply. Respect . By the way  my dad will achieve first milestone this month 9th as he completes 1year without any recurrence. I hope this continues for all year to come.( Ameen)
I will answer your reply in phases
 
1)I am very concerned  with your father's health condition if the last two BCG doses of the maintenance course was the cause.   The dose was reduced from the induction treatment, but it triggered severe side effects again even giving  6 months rest.
 
Yes we reduced the dosage to half(40mg) as compared to induction (80mg) and we stopped BCG after 2 doses. Reason being :
a) We did not want him to have the same severe side effect which he has during his induction and took him 4 month to recover
b) Uro and we decided that we will monitor how his response will be @40mg and after 1st and 2nd dose and then continue to 3rd
dose.
c) I had earlier mentioned and its was suggested by Alan and you ( I suppose ) that my dad's case falls under intermediate risk , BUT I will consider him in High Risk and use the high risk protocol for BCG ( which is 3 yrs, but we will see how far we can go).
d) Although my dad's case is intermediate risk( TaHG) but  I don't want any chance go begging, so will make sure he will take BCG till 2 to 3 yrs.
 
2nd dose of BCG  Maintainace showed some side effects and he became weak and lost some weight with urine urgency & frequency, BUT they were not as severe as Induction course. Side effects are reduced to 80 to 90%. He drinks more water in morning that keeps his Urine clear till the evening. After 5pm urine becomes yellowish and he says its slightly burns ( tolerable and lasts few seconds)
 
2) So, I am concerned that he may experience severe side effects even the dose is reduced further.  I know it is something your urologist and oncologist decide with you and your father.   But one way is to wait and see.  Or, try intravesical chemotherapy. 
 
Yes, We have a plan to further reduce the dose to1/3th or more and I am keen the next BCG cycle he takes all 3 doses, even if I
have to start with 10mg BCG, I will , just to make sure he takes all three, becoz as per Dr. Kamat, dose does not matter , it’s the frequency that matters, so 2 is better than one and 3 is better than 2. 

I did not ask Uro about the Chemotherapy , but I will and I think he might have thought something else , otherwise he would have
suggested me Mitomycin. My dad has Mitomycin soon after the TURBT last year.
 
 
3) The initial diagnosis was TaHG.  TaHG is considered intermediate risk, and the standard protocol is one year BCG or one year intravesical chemotherapy.   I think the intravesical chemotherapy is mentioned because for TaHG, the efficacy is equivalent.  Though the side effects are reported with intravesical  chemotherapy, they say it is  milder than the side effects of BCG.  Mechanism of action to kill cancer cells are different between intravesical chemotherapy and BCG.   Chemo agent goes into cancer cells and stops
cancer cells to divide and lead it to death, where BCG elicits our immune system responses and the immune responses kill the cancer cells. 
 
We will see this till our next BCG cycle which is due in Dec2021-Jan 2022. By that time we will complete our second maintenance(
hopefully all 3 doses)
 
 
 
 4) If your dad's side effects are caused by too strong response from his immune system to BCG because it has been primed for BCG, alternative approach may be brought up to your doctors. 
 
I need to understand more on this as I don't know if it’s a good thing or bad. Is strong response from Immune system good indication
or bad? I heard from Sara and others in the forum that more the side effects more its indication that BCG is working the way it's should and more its effectiveness. Is this correct ? Please advise on this.
 
 
5) Incidentally, I sometimes check BCG treatment in UK.  For some reason, they do not talk about BCG dose reduction for BCG  intolerable patients.  They usually try Mitomycin intravesical treatment.   That seems to be the standard protocol for
BCG intolerable besides RC.   In US and in Canada, Gemcitabine and Docetaxel Sequential treatment seems to have gained the ground of becoming the first line treatment of BCG intolerable patients.  There are people who have been treated with GEM/DOC protocol in this forum. They can share their experience when and if you need to know about it. 

I would say that my father is not completely BCG intolerant as he has taken induction (4 doses) and maintenance (2 doses). I have many doc friends and they all say that we have cases where the patient even cannot take the 2nd dose of BCG induction and we have to look to some other options. So considering those cases , I see my father far better place and condition. Yes there are side effects which he experiences but we are still trying.
 
 
Final Thoughts: Currently my dad is doing better after 2 doses of40mg BCG although side effects( frequent urination) were there and he lost some 4 to 5 kgs. I am concentrating on his diet these days. Had an appointment with dietitian as well. We will continue next BCG and try our best to complete all 3 doses (even if we will start 10mg BCG) and increase it gradually to 20mg ( 3rd dose), that time will tell. We will wait and watch after each BCG dose in next BCG cycle.

Finally I thank you for your immense knowledge and  research which you are doing.

Respect and God Bless.
 

Hi Bills,

I am very concerned  with your father's health condition if the last two BCG doses of the maintenance course was the cause.   The dose was reduced from the induction treatment, but it triggered severe side effects again even giving  6 months rest.  So, I am concerned that he may experience severe side effects even the dose is reduced further.  I know it is something your urologist and oncologist decide with you and your father.   But one way is to wait and see.  Or, try intravesical chemotherapy.   The initial diagnosis was TaHG.  TaHG is considered intermediate risk, and the standard protocol is one year BCG or one year intravesical chemotherapy.   I think the intravesical chemotherapy is mentioned because for TaHG, the efficacy is equivalent.  Though the side effects are reported with intravesical chemotherapy, they say it is  milder than the side effects of BCG.  Mechanism of action to kill cancer cells are different between intravesical chemotherapy and BCG.   Chemo agent goes into cancer cells and stops cancer cells to divide and lead it to death, where BCG elicits our immune system responses and the immune responses kill the cancer cells.   If your dad's side effects are caused by too strong response from his immune system to BCG because it has been primed for BCG, alternative approach may be brought up to your doctors.   Incidentally, I sometimes check BCG treatment in UK.  For some reason, they do not talk about BCG dose reduction for BCG intolerable patients.  They usually try Mitomycin intravesical treatment.   That seems to be the standard protocol for BCG intolerable besides RC.   In US and in Canada, Gemcitabine and Docetaxel Sequential treatment seems to have gained the ground of  becoming the first line treatment of BCG intolerable patients.   There are people who have been treated with GEM/DOC protocol in this forum. They can share their experience when and if you need to know about it. 

best

Surprise.  I just received a reply from Dr. Lamm regarding different CFU on each BCG production batch. Below is the reply.   

"Yours is a good question, and your suggestion is logical.  The dose is based on weight of the organisms, and the colony forming units is the best estimate of the number of viable bacteria. Unfortunately BCG clumps and does not separate like most bacteria.  The number of bacterioa in the colony forming units varies widely, hence the variation in CFU per batch.

We and others have demonstrated efficacy of non-viable BCG.  Once immunity is established, heat-killed organisms can elicit a response similar to live organisms.  Studies trying to look at CFU and response (CFU based on, for example, length of time since production) have not been very successful.

With the shortage, especially, I think it is best to keep the standard we have established."

So, if I understand correctly, in theory, CFU gives the best estimate of the number of viable bacteria but in practice, there are other factors which affect efficacy and side effects of BCG treatment.  In clinical environment, the treatment is based upon the evidence which requires studies involving many patients.  CFU related studies for BCG treatment have not successful to prove that it should be used as a measure its effects to the efficacy and the side effect, so we should continue to use the standard (dose based approach).

It is very interesting Dr. Lamm mentions even dead( killed by heating them)  BCG bacteria can elicit immune responses similar to by live BCG bacteria once immunity is established.   I am not sure what is its' implication to BCG treatment.  A Spanish team reported - Feb,2021 that heat killed BCG bacteria initiated NK cells (natural killer) anti tumor activities.   In the study report, they counted how many live+dead bacteria in a Merck  Onco-Tice vail.   OncoTICE® contains 2–8 x 10⁸ viable BCG per vial, according to the manufacturer’s information but the total number of mycobacteria measured by flow cytometry was 5.95x 10⁹, thus, only around 10% of mycobacteria present in the vial were alive after reconstitution in buffer.  So, they have found 10 times more dead BCG bacteria than live bacteria  in a  Onco-Tice vail.  Also the study reported that heat killed BCG bacteria invokes our immune system.  If dead bacteria invokes our immune system, CFU alone is not enough to determine the expected efficacy and the side effects.    

best

www.frontiersin.org/articles/10.3389/fimmu.2021.622995/full#T1

Re:  Dose reduction and CFU

I did not get a reply but I got a reply from another well known urologist.  I am afraid that I cannot disclose the name as it was a private email exchange.  Below is his response.

"There is wide variety in the number of bacteria (ie CFU) in each batch – but the bottom line is that it appears to work well regardless of that variability. There is probably a minimum number of BCG needed for effect – but that minimum lies below 1/3 of what is in a regular vial. I would not get hung up on theoretical possibilities of numbers – but would stick to clinical trial evidence.
 
We know that full dose is slightly better than 1/3 dose for intermediate and high risk NMIBC. And we know that 3 years of that full dose is better than 1 year for high risk patients but not intermediate risk patients. We know also from the important trials that dose reduction does not actually reduce side effects – so it is something we do despite dubious evidence.
 
Bottom line: dose reduction represents a slight compromise in efficacy, but is likely better than scrapping BCG all together."

best

Hi Sara, thank you very much for providing very detail recollection of your journey with BCG treatment. It is very good data to compare for other patients to compare wit their experience 

Thanks Alan for sharing your own BCG experience.   I often see the name of Dr. Lamm pops up here and then as the guru of BCG treatment.  So, sounds like you had a good urologist.   So, I was reviewing again what Dr. Kamat said in his 2019 webinar - "Predicting Response to Intravesical Immunotherapy with BCG".   One of rationales of  6 weeks + 3 weeks  rather than 6 weeks  + 6 weeks is based upon Dr. Lamm's study on immune responses, i.e. IL2 protein in urine during BCG treatment.  The number of IL2 gradually increases and it peaks at the 6th dose.  Then wait 3 months, which I assume it was, another 6 weeks BCGs were administered. They found out that IL 2 counts gradually increases from till the 3rd dose, then it drops at the 4 dose and continue to drop till the 6 dose.  I have heard another urologist saying that our immune system get exhausted if BCG is given more than 6 weeks straight.  BCG for bladder cancer was first attempted early 1970s by Dr. Molares of Queens' University in Toronto, Canada.  He said that the reason why he administered for 6 weeks was simply because when he ordered BCG vaccines from a BCG vaccine lab, it was delivered 6 vial as a set, and later on some study showed that 6 weeks gave the best result.   

In terms of side effects, majority of those who have to stop BCG happen in the induction course, and if patients can get through the induction and the first maintenance (3 weeks), they usually will complete the full 3 years BCG.  So, urologists should pay attention especially the induction course and the first maintenance course and manage the side effects so their patients can get through it, so another urologist (associate professor) explained to other urologists and residents in a university hospital.  The urologist mentioned Fluoroquinolone antibiotics are a class of medicines that kill bacteria and fight infections. Ofloxacin which belongs to Fluoroquinolone group was mentioned as mentioned to treat rather severe BCG side effect, citing a study done in France in 2006. 

The study compared BCG only group and BCG+Ofloxacin group.  Ofloxacin was given 6 hrs  and 12 after BCG instillation.  It did not reduce minor side effects (grade I symtoms), but reduced Grade 3-4 symptoms.   Greater number of patients were able to compete the treatment with BCG+Ofloxacin.  There were no effect on efficacy.  It is a bit counter effective because Ofloxacin kill bacteria and BCG is bacteria, which we need to infect the cancer cells for immune system to kill cancer cells.  But the study says it will reduce severe side effects, yet the efficacy is not affected.   The speaker is Dr. Alan So, associate professor of department of urological science of University of British Columbia, Canada and he is a clinical urologist at Vancouver General Hospital.   
    
In terms of how many patients can actually complete 3 years BCG treatment.  Alan was correct in saying that only 16% of the patients completed a fully three year course of BCG.  But that was before, now is different, so Dr. Kamat says.  

Dr. Kamat says " This is important because urologist will often just stop BCG at a arbitrary time point claiming that the patient cannot finish the course of BCG,. This was true in 1990s because we weren’t smart enough actually recognize little things we can help our patients, like using aspirin for example or using anti-spasma or stretching out the interval between bcg, So back when the trials were done the SWOG protocol for example,  only 16% of the patients completed a fully three year course of BCG. Today however, less than 10% patients discontinued due to toxicity because urologists got smarter.  They know how to manage side-effects, there are more drugs available for us to use, and patients have gotten a little bit more smarter as well, so they are motivated to get the complete the full treatment."   But also, I think there are about 15% of patients who have to halt the BCG treatment because of side effects. Dr. Kamat was referring  EORTC study 30962.

In terms of reduction of the dose vs reduction of side effects,  EORTC study 30962  was launched in 1996 in intermediate and high risk non-muscle invasive bladder cancer patients to determine if one third dose is as effective as full dose BCG, if one year of treatment is as effective as three years of treatment and if one third dose and one year of treatment are associated with less toxicity. After the accrual of 1355 patients and a median follow up of seven years, it was found that one third dose BCG was not less toxic than full dose and that three years of maintenance was not appreciably more toxic than one year of maintenance.   

Sara mentioned 1/3 eased her side effects to the extent that she was able to continue the BCG.  The large study showed 1/3 did not reduce the side effects,  not as much as 1/3 for sure.  I recall that Dr. Lamm mentioned 1/10 or even 1/100 is okay if it helps the patient continue BCG treatment.  But 1/100 will have the same efficacy.  1/3 will according to the study.  In this context, Dr. Kamat showed the result of another study, testing the efficacy of 1/3 and 1/6 and mitomycin.   1/3 gave the best efficacy, 1/6 gave lower efficacy, but better than mitomycin.   This study indicates that reducing the  dosage even to 1/6 is better than changing to intravesical chemotherapy to deal with the side effects.    

Hi Billes,
I have not received a reply from Dr.  Lamm regarding dose vs CFU, which one we should use to accurately measure the intended reduction of the side effects.  Its been more than a week, so I do not expect to receive the reply.  
I am sorry to hear that your dad has not fully recovered from the last BCG treatment.  I hope your dad gets full strength back soon.
best