Development Of Therapeutic Bcg For Bladder Cancer
The anti-tumor potential of BCG was first noted in 1929 when an autopsy series by Pearl noted a lower rate of cancer in patients who had tuberculosis . Around the same time, Holmgren also published a description of the anti-neoplastic nature of BCG. Further studies of BCG revealed its ability to retard transplanted tumor growth, first in mice systemically infected with BCG and later with direct injection of BCG into the tumor . This work also specifically found that close contact between BCG and the tumor was needed for efficacy. A later study by Bast determined that a lower tumor burden led to improved treatment efficacy . With these studies in mind, Morales surmised that instilling BCG into the bladder via a catheter, the same route utilized for thiotepa, after TURBT, would allow for similar BCG-tumor direct contact. He began recruiting patients for his research in 1972.
Highlighting The Value Of Genetic Modeling Of Bladder Cancer
Is genetic modeling of bladder cancer still useful in the postHuman Genome Project era? The answer is a resounding yes, according to NYU Langones Xue-Ru Wu, MD, the Bruce and Cynthia Sherman Professor of Urological Research and Innovation and vice chair of urological research, in a special supplement on bladder cancer published in 2020 in Clinical Cancer Research by the American Association for Cancer Research.
We need genetically tractable experimental systems more than ever to validate the biologic potential of combinatorial bladder tumor drivers, says Dr. Wu, whose research has helped illuminate how non-muscle-invasive bladder tumors form along the receptor tyrosine kinase RAS-PI3K signaling pathway. By interrogating the effects in mice of systematically deleting individual genes residing on chromosome 9p21, Dr. Wu demonstrated that common mutations must be accompanied by certain collaborative events in order for tumors to arise.
Genetic modeling is also key to better understanding the effects of lifestyle-associated carcinogens, such as tobacco and e-cigarette smoke, and environmental factors, including industrial chemicals found in many manufactured products, he says. In addition, scientists have an ongoing need for tools to evaluate novel diagnostic, treatment, and preventive strategies.
Critical Shortage In Bcg Immunotherapy: How Did We Get Here And Where Will It Take Us
Intravesical Bacillus Calmette-Guérin vaccine, one of the most successful bio-therapies to date, has been the gold standard treatment for non-muscle invasive bladder cancer for 44 years. International shortages have necessitated rationing this life-saving medication with deleterious effects on the primary treatment of high-grade non-muscle invasive bladder cancer. Understanding the history of intravesical Bacillus Calmette-Guérin gives us insight into the current shortages and future perspectives for novel immunotherapy opportunities against this deadly disease.
Urologic oncology. 2021 Nov 05
Michael Harvey, Bodie Chislett, Marlon Perera, Nathan Lawrentschuk, Damien Bolton, Gregory Jack
Department of Urology, Olivia Newton-John Cancer Centre at Austin Health, University of Melbourne, Melbourne, Australia Department of Urology, Western Health, Melbourne, Australia. Electronic address: ., Department of Urology, Olivia Newton-John Cancer Centre at Austin Health, University of Melbourne, Melbourne, Australia., Department of Urology, Olivia Newton-John Cancer Centre at Austin Health, University of Melbourne, Melbourne, Australia Department of Urology, Western Health, Melbourne, Australia., Uro-Oncology Service, Peter MacCallum Cancer Centre, Victoria Comprehensive Cancer Centre, Melbourne, Australia.
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Adverse Effects Of Bcg
Common adverse effects include cystitis, dysuria, malaise, fatigue, and a low fever . These can be managed by NSAIDS, phenazopyridine, and anticholinergics. If symptoms become intense or last longer than 24 hours, consider either delaying additional instillations until symptoms improve or reducing the dose.
In a review including 2602 patients treated with intravesical BCG instillation , the most common side effects were fever > 103ºF, hematuria, granulomatous prostatitis, pneumonitis and/or hepatitis, arthralgia, epididymitis, sepsis, rash, ureteral obstruction, bladder contracture, renal abscess, and cytopenia.
Early-onset BCG infection often presents as systemic manifestations. In contrast, delayed-onset infection presents as localized disease. Manifestations are as follows:
- Systemic manifestations occur when BCG disseminates outside of the genitourinary tract. They include sepsis syndrome, pulmonary issues from dyspnea, granulomatous hepatitis, osteomyelitis, reactive arthritis, monoarthritis, psoas abscess, and vascular complications due to mycotic aneurysms.
- Localized manifestations include cystitis, bladder contracture, granulomatous prostatitis, prostate abscess, epididymo-orchitis, testicular abscess, pyelonephritis, renal abscess, urethral stricture, and balanitis.
The AUA has noted the following with regard to BCG2:
Contributor Information and Disclosures
Fellow in Urologic Oncology and Minimally Invasive Surgery, University of Chicago Medical Center
Chemotherapy For Bladder Cancer
Chemotherapy uses anticancer drugs to destroy cancer cells. It is sometimes used to treat bladder cancer. Your healthcare team will consider your personal needs to plan the drugs, doses and schedules of chemotherapy. You may also receive other treatments.
Chemotherapy is given for different reasons. You may have chemotherapy to:
- destroy cancer cells in the body
- shrink a tumour before other treatments such as surgery or radiation therapy
- destroy cancer cells left behind after surgery and reduce the risk that the cancer will come back
- make cancer cells more sensitive to radiation therapy
- relieve pain or control the symptoms of advanced bladder cancer
Chemotherapy for bladder cancer that has not grown into the muscle of the bladder wall is given as intravesical therapy, which means that the drugs are placed directly into the bladder. Chemotherapy may also be a systemic therapy given through a needle into a vein. This means that the drugs travel through the bloodstream to reach and destroy cancer cells all over the body, including those that may have broken away from the primary tumour in the bladder.
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Are There Feasible Alternatives To Bcg For The Effective Treatment Of Bladder Cancer
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Click here to read the Cover Story, BCG: a real-world example of health care rationing.
Yes
The BCG shortage has caused significant concern among both patients and providers as they consider their options for the treatment of nonmuscle-invasive bladder cancer. Because low-risk patients do not need induction intravesical therapy, and AUA guidelines recommend either BCG or chemotherapy for intermediate-risk patients, those most at risk for undertreatment during a BCG shortage are high-risk patients, for whom BCG is the preferred treatment.
However, there are therapeutic alternatives. Mitomycin C appears to be the best option, with a recent meta-analysis finding no difference in disease recurrence compared with BCG . Although a sub-analysis restricted to studies with maintenance therapy favored BCG , the overall comparison may be more pertinent to the current crisis. Importantly, meta-analyses have found no difference in the critical endpoints of cancer progression, cancer-specific mortality or all-cause mortality between MMC and BCG.
Most head-to-head studies of BCG and MMC used lower doses of MMC than are recommended today without optimized delivery. The SWOG 8795 study, with induction plus 1 year of maintenance therapy, demonstrated that 50 mg of TICE BCG improved RFS over MMC, but this was a low MMC dose of 20 mg in 20 mL.
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Supply Chain Challenges: Lessons From Bcg
Experts say that shortages of Bacillus Calmette-Guérin , the treatment of choice for treating high-risk nonmuscle invasive bladder cancer , will not be ending any time soon, meaning clinicians need to understand and adhere to new guidelines that direct the drug to patients most in need.
Shortages have been an on-again, off-again problem for years. For a long time, two large companies, Merck and Sanofi Pasteur, were making it in the U.S., but since 2017, only one of them has been supplying it, explained Sam Chang, M.D., Patricia and Rodes Hart Professor of Urologic Surgery at Vanderbilt University Medical Center. Chang chaired development of the most recent national guidelines for bladder cancer which seek to risk-stratify NMIBC patients and improve BCG utilization.
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What To Expect During Bcg Treatment
First, make sure you havent had any fluids for four hours before the treatment. Right before you go into the treatment room your doctor or nurse will have you empty your bladder.
Youll lie on your back, and the medical professional will insert a catheter into your urethra and into your bladder, likely using some local numbing, and use this tube to infuse the treatment.
Once the treatment is infused, your doctor or nurse will remove the catheter. Theyll have you lie on your back, each side, and your stomach for 15 minutes each. The BCG mycobacteria needs to touch the bladder cancer cells to activate the immune system. Youll then be free to go but will need to hold off on peeing for another hour.
Verywell / Alex Dos Diaz
For at least six hours after your infusion, youll need to disinfect your pee to ensure none of the mycobacteria spread to anyone else. Pour an equal amount of bleach into the toilet after you pee and let it sit for 15 minutes before flushing.
Also, people with a penis who undergo BCG treatment should avoid sex for 48 hours to ensure they dont pass the mycobacteria to their partners.
You will likely need multiple BCG treatments. They may be given weekly for a few weeks, then less often for months or years to prevent cancer from coming back.
Association Between Antibiotic Treatment And The Efficacy Of Intravesical Bcg Therapy In Patients With High
- 1Department of Urology, Center for Urologic Cancer, National Cancer Center, Goyang, South Korea
- 2Department of Urology, Hallym University Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul, South Korea
- 3Biometrics Research Branch, Research Institute, National Cancer Center, Goyang, South Korea
- 4Division of Tumor Immunology, Research Institute, National Cancer Center, Goyang, South Korea
- 5Department of Pathology, National Cancer Center, Goyang, South Korea
Objective: To investigate the association between antibiotic therapy and the efficacy of intravesical BCG therapy in patients with high-risk non-muscle invasive bladder cancer .
Methods: This study involved the retrospective review of medical records of patients who underwent transurethral resection of bladder tumors for high-risk NMIBC followed by intravesical BCG therapy between 2008 and 2017. Patients were categorized as none, short- , and long-course use based on the duration of antibiotic treatment concurrent with or initiated 30 days before BCG therapy. Oncologic outcomes, including recurrence-free survival and progression-free survival, were analyzed.
Long-course antibiotic treatment concurrently with or prior to intravesical BCG adversely influenced disease recurrence and progression outcomes in patients with high-risk NMIBC. Careful use of antibiotics may be required to enhance the efficacy of intravesical BCG therapy. Further mechanistic and prospective studies are warranted.
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When You Go Home
Some hospitals allow you to go home with the medicine in your bladder if you live close by and are okay with the treatment. Your team will let you know if you can do this. You should follow the advice on what to do when you pass urine.
You need to drink lots of fluid after this treatment for 24 hours. It helps clear your system of the BCG.
You should not have sex for 24 hours after each treatment. During your course of treatment and for a week afterwards, you should wear a condom during sex.
Having bladder cancer and its treatment can be difficult to cope with. Tell your doctor or nurse about any problems or side effects that you have. The nurse will give you telephone numbers to call if you have any problems at home.
Treatment In Times Of Covid19
The COVID19 pandemic presents an altogether new challenge in managing NMIBC patients as application of BCG might be delayed. Furthermore, many patients with bladder cancer share risk factors for adverse outcomes after COVID19 infection.16 Minimising these patients risk of acquiring COVID19 while maintaining BCG therapy is therefore of utmost importance. Strategies to reduce patient contact must be enforced with the construction of dedicated care pathways to minimise hospital visits.
A number of vaccines against COVID19 have been approved by regulatory bodies across the globe with many more in development, though their impact has yet to be felt. Early epidemiological data suggest that vaccination with BCG may be have a role to play in the COVID19 pandemic.17 Since the vaccine has shown protective effects against other respiratory tract infections ,18 it has been theorised that BCG vaccination might be a potent preventive measure against COVID19 infection and may reduce disease severity. The mechanism by which this may occur remains under active investigation, but it is likely due to longterm activation and reprogramming of innate immune cells .19
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Certain chemotherapies, such as gemcitabine or mitomycin, can be used in lieu of BCG. But their efficacy pales in comparison, said Dr. Robert Svatek, chief of urologic oncology at University of Texas San Antonio.
Theres no question that BCG is more effective, Svatek said. Multiple trials have compared BCG to chemo, and every time it wins. It beats the chemo.
Patients can also elect a more extreme route: complete bladder removal surgery, or the construction of a bladder-like pouch made out of intestine. The costs of these complex surgeries are in the tens of thousands of dollars, and require years of follow-up treatment.
As effective as BCG may be, creating a safe strain of a live tuberculosis bacteria is rife with complications. The process, start to finish, takes about three months beginning with two months of horticulture. BCG is grown on a specific variety of potato, and that alone takes two months to grow. Once harvested, its brewed in giant vats over the course of a month. And plenty can go wrong.
Sometimes entire batches of drugs like BCG can get ruined if someone just pushes the wrong switch, or throws one wrong chemical into a big vat of the drug.
Ive seen that happen just a big mistake, somebody puts in the wrong chemical, and several million dollars worth of a drug has to be discarded, said Dr. Otis Brawley, a physician at Johns Hopkins and until recently the chief medical and scientific officer at the American Cancer Society.
History Of Usage Of Bcg
Tuberculosis was noted to have an antitumour effect at the start of the 20th century. It was Pearl, who in an autopsy series at the Johns Hopkins Hospital in 1929 reported a lower frequency of cancer in patients with tuberculosis. In the 1930s the use of BCG as a cancer therapy was first raised, but enthusiasm for this did not mount until the 1950s and 1960s. In 1969, Mathe et al produced a paper on the treatment of lymphoblastoid leukaemia with BCG, which produced promising results, but unfortunately others could not reproduce their results. This coupled with the development of successful modern chemotherapy and radiotherapy meant enthusiasm for BCG as a treatment waned. Further research carried out by Coe and Feldman rekindled interest in BCG with the demonstration of a strong delayed hypersensitivity reaction to BCG in the guinea pig bladder. This knowledge aided Morales et al who in 1976 carried out the first clinical trial with intravesical BCG. They were able to demonstrate a remarkable decrease in the rates of recurrence of superficial bladder cancer in nine patients. A randomised prospective trial by Lamm et al in 1980 confirmed these earlier observations. Since this time it has been shown that BCG when used has inferred benefit to those with superficial bladder cancer in terms of decreased recurrence rate and increased time to recurrence.
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So Why The Shortage Of The Bcg Vaccine
In an article in the Washington Post, it appears that there is a nationwide shortage of the vaccine. As a result, many bladder cancer patients are facing the disease without one of the best treatments available.
According to the article,
Because of the BCG shortage, some patients are being undertreated, and some are going to have to undergo radical surgery and lose their bladders, said Bernard Bochner, a urologist at Memorial Sloan Kettering Cancer Center. Those patients will have to wear a urine-collection bag or undergo difficult surgery to make a new bladder out of their intestines life-altering changes, he said.
Fearful of such an outcome, patients are calling hospitals and clinics and scouring chat rooms looking for help. We are hearing from more and more desperate patients every day, said Stephanie Chisolm, director of education and research at the Bladder Cancer Advocacy Network, a patient group.
The shortage results from the relatively low price for the vaccine about $150 per dose, which is probably one of the least expensive cancer treatments on the market . The low price disincentivizes the sole manufacturer in the USA, Merck, from producing sufficient doses.
Here are some of the issues that are constraining the supply:
Mounting Drug Shortages Delay Treatments For Patients With Bladder Cancer
- BCG is one of more than a 100 drugs listed by the Food and Drug Administration as in shortage this year.
- The shortages started several years ago when Sanofi-Pasteur and Merck were making the drug.
- But after the FDA cited quality problems at a Sanofi plant in 2012, it left the market in 2016.
Karen Hay felt like she had the cleanest floors in all of Pittsburgh.
It was a miniscule bright side to the nightmare she was going through.
Her cancer diagnosis, two years ago, was hard enough. In her mid-50s, Hay didn’t fit the profile of someone typically diagnosed with bladder cancer. But the treatment she got seemed to work: a drug called BCG.
Then another bombshell: there was a shortage of that drug. The medicine she then received instead, a chemotherapy drug called gemcitabine, was so painful she said she couldn’t sit down. That’s how her floors got so clean.
“One of the things I could do was sweep,” Hay said in an interview at her home. “So you walk, you sweep, you walk, you sweep.”
BCG is one of more than a 100 drugs listed by the Food and Drug Administration as in shortage this year. It’s a persistent issue plaguing the U.S. health system, spanning everything from antibiotics to pain medicines to vaccines and therapies for childhood cancer.
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