[Joe]

In October 2024, Canadian Agency for Drugs and Technologies in Health (CADTH) – issued Reimbursement Recommendation with Conditions (Draft) for the Padev + Keytruda combo treatment.  The details of the recommendation is available from Canada’s Drug Agency site.

“www.cda-amc.ca/sites/default/files/DRR/2024/PC0353-Padcev_DRAFT_REC.pdf”

I think the next step is the price negotiation.  According to the report, based upon submitted price by suppliers, the combo treatment costs $24,547 per 28 days, or roughly  $300,000 per year.  A price deduction of 78% for both drugs would be required to meet the Canada’s price expectation.

It is noted that in September 3, 2024, European Commission approved the combo treatment.  On October 8, 2024 UK approved the combo treatment.    Their approvals do not mean that the combo treatment is accessible to patients right away.  Each European Union (EU) country must conduct its own health technology assessment (HTA) similar to CADTH to decide if the drug will be covered by public health insurance.  Germany may take the treatment available within 6 months.

In UK, National Institute for Health and Care Excellence (NICE) has started the appraisal the clinical and cost effectiveness of Keytruda with PADCEV within its marketing authorisation for treating untreated locally advanced or metastatic urothelial cancer.  The expected reporting by NICE is 04 June 2025.

[Joe]

Hi Ruth,

Thank you for updating us the progress.   As you may know already, the adjuvant treatment after TURBT depends upon several factors.  I am guessing that the fact your urologist is saying that the TURBT will probably be followed by BCG indicates tumours are likely non muscle invasive (NMIBC).    Canadian Urological Association (CUA)’s guidelines for NMIBC state that the only time that does not require some sort of intravesical treatment, i.e. BCG or chemotherapy, is if it is low risk NMIBC.   It is low risk if it is the first time, a solitary, papillary type, less than 3 cm, the stage is Ta and it is low grade (LG).   Ta is when the tumour is within the epithelial tissue layer and not progressed to the lamina propria/connective tissue layer (T1).    The CUA guidelines classify any high grade (HG) as high risk.   Intermediate risk for low grade NMIBC, either multiple, greater than 3 cm, or recurrence.   Typically, low risk NMIBC is surveillance only.  Intermediate risk is either intravesical BCG or intravesical chemotherapy, typically for one year.  High risk NMIBC is usually treated with intravesical BCG for up to 3 years.   But the guidelines are guidelines and ultimately I think the urologist will recommend treatment based upon various factors, including the urologist’s clinical experience.

Cytology – The Paris Reporting  System (TPS) will only report high grade NMIBC , basically a) Negative for High Grade Urothelial Carcinoma, b) Suspicious for High Grade Urothelial Carcinoma, and c) High Grade Urothelial Carcinoma.  There are other reporting categories in TPS, but not mentioned here. I think cytology will help the urologist validate the result of the pathology report.    I do not think those masses are determined to be malignant yet.

 

 

[Joe]

Hi Ruth,

How is everything going?  I am curious to know what led you to have the CT scan done.   Your questions are something you want to ask to your doctors. Meanwhile for entertainment sake, I will try to answer your questions as you requested.    I usually get the CT scan images from the hospital and try to view it myself, but I find it interesting but difficult to understand it well.   I was able to locate the image of a 2 mm kidney stone which the report said, ha.

Anyway, I was checking a few articles on CT scan imaging and medical terminology.  A lesion is  considered polypoid if it protruded into the bladder lumen and is attached to the bladder wall by a narrow stack.  The mass can be benign like papilloma  or cancer.  Papilloma tends to be found at single site and tends to be small.    The right ureterovesicular junction (UVJ) is just where the right ureter meets bladder.  So, the largest tumour encases seems to mean that the right ureter is covered by the tumour of 3.9 x 3.4 cm.  Yet, the report does not say hydronephrosis of the right kidney, which is a condition where the right kidney becomes stretched and swollen as the result of a build-up of urine inside them due to the blockage of urine.  Also, the report does not say that the right ureter is dilated meaning that the right ureter is stretched or widened.  So, it sounds like urine from the right kidney seems to be coming out to the bladder normally even if the tumour is covering up the right UVJ.    Incidentally, I don’t think the tumor has not spread beyond the bladder wall or even invaded the muscle layer of the bladder wall because the report should say so if that is the case.  I have looked at CTC images of transitional carcinoma and it is obvious to me.   You can look at sample of images of bladder cancer in American Journal of Roentgenology (Radiology) – see the following link.  I think most images are by MRI, but CT scan should give equivalent images.

“ajronline.org/doi/10.2214/AJR.17.17798”

Fig. 1A -Non muscle invasive T1HG, papillary type tumour.

Fig. 2A –  T3HG, muscle invasive bladder cancer.

Fig. 3A –  T2HG , muscle invasive bladder cancer at two sites 5 weeks after initial TURBT.   The second TURBT was done to resect those two tumours.

 

• This reply was modified 1 month, 3 weeks ago by Joe.

[Joe]

Please read the following with a big grain of salt.  There may be errors, especially in numbers.  Please pose any question.

Galleri : Blood-based multi-cancer early detection (MCED) by  GRAIL

Illumina, Inc. is the largest and leading manufacturer of DNA sequencing equipment in the world.  Recently, Illumina spin off its DNA analysis division GRAIL as a separate company. GRAIL started in 2016 focusing detection of multiple cancers analyzing cell free DNA in blood. Later GRAIL named such blood-based multi-cancer early detection (MCED) as “Galleri”.

Though previously mentioned Signatera (tissue informed)ctDNA testing and Guardant 360 (tissue uninformed)ctDNA testing both analyze DNAs obtained from fragments of tumour in blood, Galleri analyses DNAs obtained from fragments of tumour and normal cells in blood. Also though Signatera and Guardant 360 ctDNA test analyze abnormal genes, Galleri compares pattern of DNA methylations to patterns of DNA methylations of persons with no cancer and persons with various cancers to determine if the client has cancer or not, and if cancer, it will tell what cancer it is.

I have thought that accumulation of abnormality in specific genes in DNA – genetic abnormality would cause cancer. This is true, but recently I learned that epigenetic abnormality can cause cancer also. I understand Epi means above or upon, so epigenetic means above genetic.  For example, even a tumour suppressor gene, i.e. TP53 is normal in DNA,  methylation can silence the gene from transcription resulting in not synthesizing p53 protein.  There are about 28 million sites in the human genome, where methylation can happen.  GRAIL has accumulated data of methylation from over 1 million sites in DNA from non cancer persons and persons with cancer, and analyzed patterns of methylation of various cancers and normal tissues.    Galleri will compare a client’s DNA methylation patterns vs GRAIL’s database of methylation patterns. Figures of methylation patterns of person with no cancer and with lung cancer are shown.  Blue indicates unmethylated sites and red indicates methylated sites. So, if Galleri test for the pattern of a client DNA methylation of the particular section of the DNA that is similar to the pattern of the lung cancer, Galleri can raise a red flag for that particular section of DNA as a possible sign of cancer.  Grail’s site says Galleri uses AI – machine learning for this pattern recognition process.

“tinyurl.com/bddfe8vf”

The Galleri test has not been cleared or approved by FDA.  The Galleri test received FDA Breakthrough Device Designation in 2019.   Based upon Grail’s own studies, the Galleri test has shown a low false-positive rate of 0.5% (detects a cancer signal when no cancer is present).  A true-positive rate ( detects cancer signal when a specific cancer is present) is about 50% in average for 50+ cancer types, but its accuracy goes up to 67% for 12 major cancers, including bladder cancer. The Galleri test data came from 20,000 participants at more than 140 clinical study sites.  UHN/UT and Princess Margaret Cancer Centre in Toronto was listed as the test site in Canada.   In November, 2023, the US Food and Drug Administration (FDA) approved an Investigational Device Exemption study to determine whether the Galleri blood test can reduce late-stage cancer diagnoses for cancers that don’t have traditional screening approaches. The blood test, which has been sold in the US since 2021, is not currently FDA approved, but Grail is hoping that interim data from its study will help the test secure premarketing authorization from the FDA. Note that the current price of Grail test is US$949.  The study will track outcomes in as many as 50,000 Medicare beneficiaries who will receive annual Galleri tests alongside routine medical care compared with a matched group who will only receive usual care. Participants will include individuals from racial and ethnic minorities, and seniors from historically underserved communities.

Furthermore, National Health Service (NHS) in UK and Grail has been conducting a very large three year study NHS-Galleri trial  to find out how Galleri MCED test for UK citizens between the ages over 50 and 77 years old will benefit  not only to UK citizen but also to UK healthcare system – NHS.  Already 140,000 UK citizens had participated.

NHS England has reviewed preliminary data from the first year of the NHS-Galleri trial and did not find them compelling enough to justify proceeding straight away with a large-scale pilot program of the test in NHS clinical practice, while we await the final results of the trial. Committing to accelerate implementation of the test in the NHS at scale would have been an exceptional step, requiring exceptional data after just one year, and while what we have seen is very promising, the data so far do not support moving at such a fast pace.

As planned at the outset of the trial, the results will be used by the UK National Screening Committee to consider whether the Galleri test could play a role in a national cancer screening program. We think that NHS patients should be the first to benefit from new technologies, and we want to be ready to make the test available to an increasing number of people rapidly if the final trial results show evidence of significant benefit for patients.

A similar study (PATHFINDER 2)  in the US with UHN in Toronto started in 2021 involving with 35,000 participants who are 50 years or older.  The primary completion date in Feb, 2026.

Referenced sites

Grail home site, Galleri home site, NHS site, various research papers on methylation and cancer,  Youtube on Methylation, ChatGTP, my daughters biology, bio-chemistry, cell biology text books.

 

• This reply was modified 1 month, 3 weeks ago by Nightingale.
• This reply was modified 1 month, 3 weeks ago by Nightingale.

[Joe]

Re: bladder preservation

In general,  bladder preservation therapy is called Trimodal Therapy (TMT), which consists of a)  another resection as much as possible, b. chemotherapy and C radiation.  The patient selection is the key for  a successful TMT to have similar efficacy as RC in terms of recurrence free survival, progression free survival and over all survival rate.  University of Toronto and its affiliated hospitals have been most active on TMT and I understand UBC/VGH is also offering TMT.   In the US, Massachusetts General Hospital(MGH) has been proponent of TMT.    Optimum patient criteria for TMT has been described by Dr. Girish Kulkarni, MD, PHD, FRCSC Head, Department of Surgical Oncology, University Health Network (UHN) / University of Toronto.  Actually, there is a TMT clinic in UHN patient goes and get a consultation if TMT is a good fit or not.  I understand you are already the 2nd round of neoadjuvant chemotherapy.  That is okay as neoadjuvant chemotherapy is recommended for TMT anyway.  So, I think you will still time to make the decision.    Dr. Alexandre Zlotta of UT is also involved in TMT and presented the result of the clinical study of TMT vs RC by Canada and US at AUA 2023 meeting.   I will list the link to the presentation by Dr. Zlotta and Dr. Kulkarni.  If you have questions, please post your question.

Tumours < 5cm
Single tumour
Minimum to no carcinoma in-situ (CIS)
Good bladder function/capacity
Able to frequent follow up
Good kidney function
Links to videos

Dr. Zlotta’s summary of the US/CANADA clinical study TMT/RC

“www.youtube.com/watch?v=48A5BztM_aU”

Dr. Dr. Kulkarni presentation of TMT vs RC

“www.youtube.com/watch?v=P_Yzo8rri4Q”

Dr. Peter Black’s presentation of bladder preservation

“www.youtube.com/watch?v=YEtO5_WFPyQ”

 

Re:  Ilial Conduit IC vs Neobladder

There is another urinary diversion called Indiana Pouch (IP).   Because IP requires additional surgery training, limited number surgeons are experienced with IP in Canada  In British Columbia, Dr. Peter Black of UBC/VGH and another surgeon in Vancouver Island are who have experience with IP as per my knowledge 4 years ago.  IP makes a pouch using intestine and that is where urine is stored.  From the pouch to belly button or near abdomen, a stoma is built just like IC but instead of collecting by an external bag, an catheter is inserted through stoma and urine is removed through the catheter.   There are a few female – younger patients who had chosen IP instead of IC or Neobladder.  I also heard that Neobladder can be more programmatic for female than male because of anatomic differences.  But I do not know detail now but these female patients opted for IP rather Neobladder are because of some issues of Neobladder for female.  Note that I am aware of a female patient who was successful with neobladder also.

[Joe]

Incidentally, I think  UBC/VGH is an centre of excellence/expertise for bladder cancer in Canada.     If I remember correctly, in the past,  I heard Dr. Alan So, an associate professor at UBC urology department talking about accessibility of a second opinion and mentioned that a bladder cancer patient from Vancouver Island visited to UBC/VGH for a second opinion.  I think  Dr. Peter Black – professor in UBC urology department and Dr. Alan So – associate professor are specializing especially in bladder cancers at UBC/VGH.  Perhaps, you can contact their urology clinic and find out about a second opinion.   Also, I have listed the link to second opinion in BC.   Hope it helps.

“urology.med.ubc.ca/bladder-care-centre”

Urology Clinic Contact

Tel 604 875 5003
Fax 604 875 5604

“www.healthlinkbc.ca/health-topics/getting-second-opinion”

[Joe]

I only know a urologist in  Vancouver Island.

John Kinahan MD

Address: 1503 Hillside Ave, Victoria, BC V8T 2C1

Hours: Closed ⋅ Opens 9 a.m. Thu

Phone: (250) 384-8515

I do not him personally, but he is the owner of a company called Silverado Research Inc., who does clinical studies in the urology field. In  recent years, Selverado Research Inc recruited BCG unresponsive patients for Merck’s global clinical trial of BCG (Merck Onco-Tice)  + Pembrolizumab(Keytruda) for BCG unresponsiveness. Note that Silverad completed is clinical trial and not longer recruiting patients.  Anyway, I presume that Dr. Kinaha should be familiar with the topic on BCG unresponsive, which you seem to be interested in.  Incidentally, the official clinical trial number is NCT03711032 and you can do search at Clinicaltrials.gov site.

[Joe]

I cannot speak from my own experience as I was diagnosed as intermediate risk TaG2, but I can share what I have learned on Papillary urothelial neoplasm of low malignant potential (PUNLMP).   To answer the question on treatment for PUNLMP, the short answer is it will likely be treated as low risk TaLG, i.e. typically if it is a single site and less than 3 cm, TURBT followed by regularly scheduled cystoscopy.  Below are the rationale for the treatment protocol.

PUNLMP classification was first  introduced in 1998 and added in WHO 2004 grade classification for NMIBC (PUNLMP, LG and HG).  At that time, PUNLMP was considered to have better prognosis than LG and because there was a tendency that younger adult patients tend to have PUNLMP, they did not want to label as cancer to avoid mental stress and financial stress.
The result of a large study(*1)  involving urologists and pathologists from major European countries, including University of Toronto affiliated hospitals revealed that the usage of PUNLMP has drastically reduced in recent years compared to when it was first introduced, i.e.  1990-2000  PUNLMP (31.3%),  LG (46.2%), HG(21.5%)  to 2010-2018  PUNLMP (1.1%),   LG (70.6%), HG (28.3%).  Also, PUNLMP and LG  have shown similar trend in time to recurrence, i.e. close to 50% chance of experiencing a recurrence in the first 5 years, and time to progression between PUNLMP and LG were also similar which were less than 3% at 5 years.
The study concluded in stating that  , our results do not support the continued use of PUNLMP as a separate grade category in noninvasive papillary bladder tumors because, even if the
incidence of PUN-LMP is low, the prognosis of PUN-LMP and TaLG carcinomas was similar.
The study was published in 2019.  WHO 2022 grade classification still included PUNLMP.
Ref

*1 Papillary urothelial neoplasm of low malignant potential (PUN-LMP): Still a meaningful histo-pathological grade category for Ta, noninvasive bladder tumors in 2019?

“forums.bladdercancercanada.org/forums/topic/punlmp”

[Joe]

Hi Alestiri,

Not for PADCEV (EV) and Keytruda (Pembrolizumab)  combo treatment, but I had heard of a patient who exhausted the treatment, at that time it was chemotherapy,  for advanced bladder cancer, managed to access a bladder cancer treatment which was approved by FDA but not accessible in BC.   It was the patient’s oncologist who had arranged the treatment for the patient.  So, I think the oncologist of your father is the right channel.    Please google “Health Canada’s special access programs”. It leads to the Health Canada’s site on Special Access Programs. which the oncologist can fill out the form.      I expect that the oncologist is knowledgeable the process.

I have noticed that Health Canada’s special access programs has a few requirements that the request must be for treating a patient with a serious or life-threatening condition where conventional treatments: have failed, are unsuitable for, are not available in Canada.  Because chemotherapy which is accessible first line treatment (conventional) for locally advanced and metastatic bladder cancer after RC, which seems to have been arranged by the oncologist, I am not sure the special access program could apply.   The oncologist should be able to answer the question too.

FYI,  the conventional & accessible treatment for patients in BC after chemotherapy is  immunotherapy either by Avelumab if the chemotherapy is working  or Keytruda if the chemotherapy does not work well.  If immunotherapy  does not work, PADCEV is approved drug for this situation.   Anyway,  the oncologist is the right person about the treatment path and its effectiveness for what if scenario if the combo treatment is not accessible.

In terms of financing the combo treatment, I do no think BC Health Care System reimburse the combo treatment yet.  It has not gone through the necessary processes, including the economic evaluation of the combo treatment by Canada Drug Agency,  price negotiation by the pan-Canadian Pharmaceutical Alliance on be half of all government drug plans, then after that province must to decide to reimburse  the treatment.   It will be awhile. So, essentially,  the drug companies, in this case, Astellas for PADCEV and MERCK for Keytruda must agree to provide the drug free or at specially discounted price.     I looked up the contact information of the manufacturer of PADCEV – Astellas and Keytruda – Merck.   They may be able to give  you more information on the subject.

Astellas Pharma Canada , Markham, Ontario.    Phone 905-470-7990 or 1-800-575-1382     Customer Service  1-800-668-8641

Merck Canada Inc.   Quebec, H9H 4M7      Phone 514-428-7920  or 1-800-361-7031      Customer Service 1-800-463-7251   email  montreal.orderdesk@merck.com

[Joe]

Hi Marysue,

Verity-BCG on CIS

A large study which involved department of urology from 25 different countries, mostly Europe, a few American, and Japan was published in 2023.  The title of the  publication is “Efficacy of Different Bacillus of Calmette-Guérin (BCG) Strains on Recurrence Rates among Intermediate/High-Risk Non-Muscle Invasive Bladder Cancers (NMIBCs): Single-Arm Study Systematic Review, Cumulative and Network Meta-Analysis”.   In conclusion, the study says Our results do not support any clear advantage of one specific BCG strain over another.   Future research could be oriented toward BCG Tokyo 172, RIVM, and Tice, which showed possible insights into efficacy profiling. A 2020 single clinical study of SII Onco-BCG was listed in the article.   Note that Verity Pharmaceutical buys SII Onco-BCG from SII in India and markets as Verity-BCG in Canada.

In terms on CIS,  in Cancer journal January 2024,  UT team published an article titled “Carcinoma In Situ (CIS): Is There a Difference in Efficacy between Various BCG Strains? A Comprehensive Review of the Literature”.  The conclusion says  this review suggests that the clinical efficacy of the various BCG strains appears similar, irrespective of CIS characteristics. However, based on the weak level of evidence available and underpowered studies, randomized studies in this space should be encouraged as no definitive conclusion can be drawn at this stage.

SII Onco-BCG from SII has been sold in several lower income countries but during BCG shortage,  it has been supplied to higher income countries such as New Zealand to supplement the shortage of their approved BCG such as ONCO-TICE or MEDAC-BCG (RIVM strain) by MEDAC in Germany.   Those countries executed special provisions to allow unapproved drug, in this case BCG, only during BCG shortage.  In those countries, it is allowed to use SII Onco-BCG for CIS or Papillary tumor such as HG.   Canada did not execute such provision though it does exist.  Instead, Verity Pharmaceutical came in and took an approach to market SII ONCO-BCG  as its own brand name Verity-BCG.   The point is SII Onco-BCG has been used for many years.  And if I borrow the words of the 2024 article of UT team, the clinical efficacy of the various BCG strains appears similar, in respective of CIS characteristics.   Your question is how does Verity-BCG perform compared to Merck Onco-Tice BCG which is also available (not sure about accessibility which seems to differ according to different authority, different hospital) to patients in Canada.  Health Canada imposed this comparison clinical trial to Verity Pharmaceutical to perform within a reasonable time for the  conditional release of Verity BCG.   Accordingly, Verity registered to FDA a randomized clinical trial (NCT05037279) in September, 2021 to compare Verity-BCG and Merck Onco-Tice BCG with expected start date January 1, 2023 recruiting over 500 patients and expected completion date January 1, 2026.  But it has not started yet, and I do not think it ever will if Merck actually completes a new BCG production line with 3 time more production capacity which is scheduled to be completed at the end of 2025 or 2026.    So, we would not know which BCG (Verity-BCG or Onco-Tice BCG) performs better in terms of efficacy and side effects and by how much for CIS.   I assume that urologists who used to prescribe Onco-Tice BCG but now prescribing Verity BCG would have sense how they are different in terms of efficacy and side effects on CIS.   Incidentally,  the clinical trial  SWOG 1602 (PRIME) was completed in the US.   The report should be ready by the end of 2024 according to Dr. Joshua Meek, one of three coordinators of the trial.   SWOG 1602 was to test if receiving BCG vaccine on your arm will improve the outcome of BCG treatment for NMIBC, and also to do randomized comparison test between Merck Onco-Tice BCG and Tokyo-172 strain BCG by Japan BCG Lab.  The trial recruited over 900 patients it has taken 7 years form the start of recruitment in 2017 till the result is ready to be reported. Dr. Meek also mentioned during 2024 ASCO meeting that FDA agreed to review Tokyo-172 BCG for CIS.   We should be able to learn more about insight of the performance of two different BCG once the report is published.

You may want to watch BCC recorded webinar on CIS by Dr. Peter black.  If I understand correctly, he mentions that he assumes that CIS exist in other parts of bladder unless small CIS is found closed to small papillary tumor and CIS can be completely resected, so it needs treatment such as BCG.  Also, CIS’ behavior is unpredictable such that though it is within epithelial layer it can progress to muscle tissue, so it is treated as high risk with BCG induction plus 3 years of maintenance.  On the other hand,  BCG is known to be highly effective to CIS and  BCG can eradicate CIS.   BCG has shown durability to CIS such that after 6 weeks induction, complete response rate is 55%, then without additional the complete response rate increase to 65% if we wait for 3 months.  If the first 3 weeks maintenance is completed, it has shown that the complete response rate increases to 85%.

[Joe]

Hi Marysue,

Your TNM is Tis because CIS.  The TNM system uses Ta for low grade papillary type NMIBC.   T0 means there are no primary tumours.  T1 means it has invaded lamina propria.    CIS does not grow into lumen of the bladder like papillary tumor, and has not crossed over the basement/basal layer of urothelial tissue into lamina propria.  By definition,  CIS is flat.   What did urologist say about  yellow/brown sea kelp – a field of little fingerling floaty things?  Besides its color it looks papillary type tumor.

 

• invasion not identified  : no cancer cells found in  lamina propria (T1) or in muscularis propria (T2 ..)
• negative for lymphvascular invasion : I find this expression is found often when the tumor has invaded  into lamina propria (T1) as there are lymphatic channels and blood vessels in lamina propria.  When lymphvascular invasion is positive, it is classified as very high risk and early cystectomy is discussed.
• muscularis propria is sampled and uninvolved  :  CUA Guidelines state on TURBT that all visible tumors should be completely resected, and ideal depth should include the detrusor muscle (muscularis propria) to allow for optimal  staging.
• Urothelial carcinoma in situ : TNM system was created and is updated by the American Joint Committee on Cancer (AJCC) and the International Union Against Cancer (UICC).  Carcinoma In-situ is TiS.
• With small component of adenocarcinoma in situ :  Yes, this is odd.    Like you said variant subtypes of NMIBC are considered aggressive not because we fully understand why they are aggressive but because clinically it is often found in advanced stage at the time of diagnosis.   There are only a few articles on adenocarcinoma in situ.    A 2001 study on adenocarcinoma in-situ by  The department of Pathology, Johns Hopkins, Maryland USA is summarized below.   It may explain yellow/brown sea kelp – a field of little fingerling floaty things.  Johns Hopkins Pathology Department is well known for providing second opinion on pathology result including for NMIBC.

Adenocarcinomas of the bladder are uncommon tumors, accounting for 0.5%-2% of all bladder malignancies.  In situ adenocarcinoma of the bladder is rarely reported.   It is noted that the definition of in-situ adenocarcinoma is different from urothelial carcinoma in-situ.   Urothelial carcinoma in-situ (CIS) is defined as flat, not growing into lumen like papillary tumor and not invading into lamina propria (T1).  CIS looks patchy red spots or often non visible in armature eyes.   In situ adenocarcinoma is defined as glandular looking cells not associated with infiltrating adenocarcinoma of bladder.  In situ adenocarcinoma can be papillary, cribriform or flat.    Adeno cis will be  used for in situ adenocarcinoma of bladder .

19 biopsies of adeno CIS were identified from the surgical pathology files of the Johns Hopkins Hospital between May 1984 and July 2000.  The cases accounted for 0.61% of all carcinomas seen on bladder biopsy, including both consulting (2nd opinion) and in-house material and 0.14% of all carcinomas seen on bladder biopsy from Johns Hopkins Hospital only.  In the US, many patients send tissue samples (slides)  to Johns Hopkins for 2nd opinion when pathology report is unsure such as your case.  So, majority of 19 cases seemed to have been sent for the 2nd opinion because they were diagnosed as adeno cis.  Anyway adeno CIS is very rare.

• All cases of adeno cis showed atypia diagnostic of malignancy in cytology, with hyperchromasia and some degree of pleomorphism.
• Mitoses were present in 89% of cases
• The component of in situ adenocarcinoma was categorized as focal(<10% of the total in situ lesion), moderate (10–50%), and predominant (>50%).   Your pathology said small component of adeno CIS.   It indicates the portion of adeno CIS is < 10% of urothelial CIS in your case.
• Urothelial CIS and/or TaLG were commonly identified with adeno CIS (79% of cases).  In 53% of these cases, the adeno CIS was predominant component.  In your case, Urothelial CIS was predominant.
• Ten (52%) of 19 patients were treated with BCG.
• Papillary architecture was most commonly seen (84%), followed by cribriform (63%) and flat (37%).     I am wondering if yellow/brown sea kelp – a field of little fingerling floaty things was  papillary type of adeno CIS because Urothelial CIS is flat.

[Joe]

Hi Marysue,

That’s true.   I think the current format of pathology report is still meant to be  a communication tool only for pathologist and urologist.  College of American Pathologists publishes Protocol for Examination of Specimens From Patients With Carcinoma of Urinary Bladder.  The protocol has checklist what needs to be reported for specimens from TURBT.  There three pages full of check list for specimens from TURBT.  According to Cancer Ontario site,  The Canadian Association of Pathologists has endorsed the College of American Pathologists (CAP) checklists as the pan-Canadian standard for synoptic pathology reporting, as of July 2009.   So, it is likely  that pathologists in Canada are using the checklist also.   But the pathology report is a synopsis which is a structured, standardized, and concise summary of key pathological findings for urologist.     Below is an example of synopsis from a presentation, 2017 BCAN, by Dr. Donna E. Hansel – the chief of anatomic pathology at the UC San Diego School of Medicine

Example of a CAP synoptic TUR report  * This isa templated report with fields required by CAP to ensure all parts of the diagnosis are capture.

Urinary Bladder : Biopsy and Transurethral Resection of Bladder Tumor (TURBT)

• Procedure : TURBT
• Tumor Type: Invasive carcinoma
• Histologic Type: Urothelial (transitional cell) carcinoma
• Associated Epithelial Lesions  Non identified
• Histologic Grade: Urothelial carcinoma,  High-grade
• Adequacy of Material for Determining Muscularis Propria Invasion:  Muscularis propria (detrusor muscle) present
• Lymph-Vascular Invasion : Not identified
• Microscopic Tumor Extension: Tumor invades subepithelial connective tissue (lamina propria)

I do not know how much a new patient can understand this example  pathology report.    Because the report uses the word like “invasive” carcinoma and “high grade”,  it may cause more anxiety than simply waiting for the urologist to explain it.   I see that it is a trend in our healthcare system to allow patient to have access the result of diagnosis including pathology report.  This has a plus side as patient get to see the report and  prepare questions prior to the meeting with urologist. A negative side is when patient does not understand fully what it meant, it can cause some anxiety.   I think the pathology report should state that the report  is meant for urologist and uses certain terminology required by regulatory and also say “Please ask your urologist if you have any question regarding to the report.”   Or, a sperate more patient centric pathology report can be added.    Incidentally, I think  the report indicates T1HG NMIBC without CIS.

Your pathology report must tell you if it is T0 or T1 directly or indirectly.  Mine said “non-invasive”.   It does not say non muscle invasive but just says non invasive.  Also said “No muscularis propria present”.  I had ask my urologist a few years later why tissue from muscle – muscularis propria was not sampled during TURBT.  My urologist said something like it was not necessary.   Then I understood “non-invasive” meant not muscle invasive and not invaded into lamina propria (T1) either.  So, I figured mine was T1HG.  Does your pathology says anywhere “non invasive” or Tumor invades lamina propria or Tumor invades muscularis propria?

 

 

 

[Joe]

Hi Chelsea,

I am glad to see Marysue and Nightingale giving their feedback.   You have done an excellent job by being a strong self advocate and I don’t know how you did it but you also managed to see two doctors for the second opinion in short time. Well Done!   What I have learned so far is that majority of urologists recommend BCG treatment for your NMIBC even if it is a small non invasive TaHG just because it is high grade. I don’t remember who said but a well known urologist mentioned that a small HG papillary tumor can be resected completely, but it can recur and progress, so treatment is necessary.  I will not dwell much on whether it is classified  as intermediate or  high-risk as both will receive BCG induction and maintenance, it will reduce the risk of recurrence and progression also equally. A case in point, the study (2016) in a Taiwan hospital showed the 13-15 doses group did little better than the 16-27 doses group for reducing the risk of recurrence by both groups almost by 30% compared to BCG induction only.

Treating like high-risk does not just mean adding more BCG treatment, but also making sure it is not missed by cystoscopy.  I have heard that Dr. Peter Black prescribes cytology (urine analysis) after every cystoscopy for high risk NMIBC patients.  Cytopathologist can look at cells in urine sample which came off from the lining of the bladder and say if Negative for High Grade Urothelial Carcinoma (UC), Suspicious or Positive for High Grade UC.  If Cytology says negative, it improves confidence level of cystoscopy negative.  If cytology is positive, urologist needs to find the cause.  Maybe cytology is already a part of follow up plan after one year of BCG treatment for intermediate-risk.  I think it can be discussed and requested later if regular cytology is not in plan.

I think the BCG treatment should be starting soon as it usually starts 4-6 weeks after the TURBT.  I think you had  TURBT 8 weeks so ago.  Incidentally, MD Andersons team and others checked 518 patients who had started BCG at a median (range) of 26 days (6-188) days after TURBT found that the rates of tolerability and response to adequate BCG are not predicated by the timing of induction BCG instillation after TURBT.  So, the data suggest your starting BCG  treatment now should not affect side effect or effectiveness of BCG treatment.   I also think cystoscopy will clarify discrepancy of ultrasound reports  but also it is almost time for cystoscopy, i.e. 3 months after TURBT anyway.

Anyway, thanks for sharing and updating your experiences so far.  I have learned so much myself for understanding my small TaG2 NMIBC.

 

 

• This reply was modified 5 months, 4 weeks ago by Joe. Reason: type

[Joe]

Hi Chelsea,

There is a publication in 2022 Aug  Journal of  Urology by MD Anderson team.  This article relates to your situation.  I do not have access to detail of the publication but the summary is enough.   MD Andersons Cancer Center in Texas is very well known cancer center and often publishes their studies on bladder cancers.   I think this was by now assistant professor during her clinical fellowship in urologic oncology at University of Texas MD Anderson Cancer Center, Houston, TX.   A co-author of the publication was Dr. Ashish Kamat, professor in Urology at MD Andersons, who is also  very well known in bladder caner world.   The study focused on risk of progression among intermediate-risk TaHG and high-risk TaHG.   The study says patients were risk stratified using EAU risk stratification method.    Patients were selected from 2,000-2018.   Because the risk of progression between the group of TaHG Intermediate and High risk were similar, EAU separating TaHG into intermediate risk and high risk did not change the outcome.  So, all TaHG should be treated as high-risk.   Perhaps, CUA guidelines incorporated the study by MD Andersons and recommended intermediate-risk TaHG to be treated as high-risk TaHG.  Note that the only difference between intermediate-risk TaHG and high-risk TaHG is the length of maintenance BCG  treatment, i.e. 1 year vs 3 year.

• TaLG  Intermediate-Risk   37 patients  (16%)    No progression
• TaHG Intermediate-Risk   92 patients (40%)     < 3cm, single, primary      5.9% progressed to T1  and 13% progressed T2 or higher
• TaHG High-Risk                 101 patients (44%)     6.5% progressed to T1 and 13% progressed to T2 or higher
• Rates of recurrence were similar in TaHG Intermediate or high risk groups
• Rates of BCG Unresponsive were similar in TaHG Intermediate or High risk groups.

Benefits of BCG maintenance treatment

2000 publication by Dr. Donald Lamm states the result of SWOG study on maintenance BCG resulted that with maintenance BCG (3 years), long-term (7 years) tumour recurrence in high-risk patients reduced from the expected 52% with a single 6-week course to only 25%.   The risk of progression at 4 years was reduced from 14% with induction only to 8% with induction and maintenance BCG.  How much improvement can 3 years maintenance BCG over 1 year BCG maintenance becomes fuzzy because not many studies done on that subject.  A study I saw in Taiwan resulted in finding that the total of 13-15 BCG treatments had equal efficacy compared 3 years (27 BCG treatment)  in terms of risk for recurrence.

 

MD Anderson’s study

Title All High-Grade Ta Tumors Should Be Classified as High Risk: Bacillus Calmette-Guérin Response in High-Grade Ta Tumors

Purpose: There is variation amongst guidelines with respect to risk stratification of Ta tumors, specifically high-grade (HG) Ta tumors. We sought to investigate the response of all Ta tumors to bacillus Calmette-Guérin (BCG) and compare response rates based on European Association of Urology (EAU) classification as intermediate- (IR) or high-risk (HR).

Materials and methods: An institutional review of all patients who received adequate BCG from 2000-2018 was conducted. EAU 2021 prognostic risk groups were used to stratify patients including by the newly proposed adverse risk factors.

Results: When patient with Ta tumors were stratified into IR and HR, 37 (16%) had IR low-grade (LG) Ta, 92 (40%) had IR HG Ta and 101 (44%) had HR HG Ta tumors. BCG unresponsiveness developed in 13% of HR HG Ta tumors and 14% of IR HG Ta tumors compared to 0.0% of IR LG Ta tumors (p=0.003). While no patients with IR LG Ta tumors progressed, progression rates were similar in HR HG Ta and IR HG Ta tumors (≥T2: 5.9% and 6.5%; [Formula: see text]T1: 13% and 13%, respectively). Rates of recurrence, BCG unresponsiveness and progression were similar, irrespective of number of EAU risk factors present (p=0.9, p=0.8 and p=0.9, respectively).

Conclusions: All HG Ta tumors, regardless of EAU risk stratification, have inferior response to BCG and increased rates of progression compared to IR LG Ta tumors. EAU clinical risk factors did not improve prediction of oncologic outcomes among HG Ta patients who received adequate BCG. These data support consideration of all HG tumors as high risk.

Dr. Lamm’s publication on Preventing progression and improving survival with BCG maintenance

“pubmed.ncbi.nlm.nih.gov/10575266”

[Joe]

Hi Chelsea,

Clarification of  risk stratification of  TaHG and treatment.

The medical community seems to be aware that there is discrepancy between various guidelines in dealing with NMIBC  and discrepancy between guidelines and daily clinical practice in managing NMIBC.  *1     In case of TaHG, < 3cm , single , primary,  is classified as intermediate risk by EAU guidelines, AUA/Society of Urologic Oncology, CUA guidelines.  National Comprehensive Cancer Network (NCCN) 2024 puts TaHG into intermediate Risk if < 3cm and single referring  AUA risk stratification for NMIBC.  As mentioned before CUA guidelines classifies TaHG,<3cm, single, primary into intermediate-risk category but recommends (request to consider) to treat as high risk.  On the other hand, The French guidelines for NMIBC guidelines puts any HG into high-risk. The European Society for Medical Oncology (ESMO) – a leading professional for medical oncologist in Europe and globally classifies put any G3/HG into high risk category and TaG1,G2/LG into Intermediate if <3cm, single, primary.  A 2020 presentation by Dr. Eigl who is a medical oncologist specializing in urologic cancers put NIMBC (T1, CIS, or any high grade tumor) into high risk.    How 6 weekly induction + 1 year maintenance differ from 6 weekly induction + 3 year maintenance in terms of the risk of recurrence and progression is explored later.

Disparity of guidelines and clinical practice was published in 2017 in EAU. *1  Survey from 8 countries including France, Germany, UK, Italy, Poland, Chech Republic, Austria, Belgium and Netherlands were reviewed.  The summary (Europe) of disparity in treatment for intermediate risk and high risk NMIBC  is shown below.  498 physicians completed the questionnaire.   48 were uro-oncologists.

Intermediate-risk

Single instillation of chemotherapy < 24 hours   Intermediate-risk  60%   High-risk 53%
Adjuvant chemotherapy for 1 year   Intermediate-Risk  37%   High-risk 18%
Adjuvant BCG for 1 year :   Intermediate-risk 20%   High-risk 38%
Adjuvant BCG for 3 year :  Intermediate-risk  11%   High-risk 41%
No adjuvant treatment :    Intermediate-risk   11%   High-risk 5%
Others  :  Intermediate-risk (6 month chemo)  23%    High-risk cystectomy)  14%
The point is here that 89% of intermediate-risk NMIBC patients  received some sort of treatment 56% with chemo and 11% with BCG,  and 95% of high-risk NMIBC patients received some sort of treatment, mostly BCG.   The study did not reveal why 11% of intermediate-risk and 5% of high-risk did not receive any treatment.  But also, the study indicates that majority of urologists would have given some adjuvant treatment whether it is intermediate risk or high risk, which is your TaHG.

 

*1   Discrepancy Between European Association of Urology Guidelines and Daily Practice in the Management of Non-muscle-invasive Bladder Cancer: Results of a European Survey

“pubmed.ncbi.nlm.nih.gov/29074050”

• This reply was modified 6 months ago by Joe. Reason: typo

[Author]

Posts