Bacille Calmette-Guérin (BCG)

Cancer Immunotherapy: BCG is useful in the treatment of superficial forms of bladder cancer. Since the late 1980s evidence has become available that instillation of BCG into the bladder is an effective form of immunotherapy in this disease. While the mechanism is unclear, it appears that a local immune reaction is mounted against the tumor. Immunotherapy with BCG prevents recurrence in up to ? of cases of superficial bladder cancer. BCG also finds use for immunotherapy of colorectal cancer

BCG

BCG is the most studied and most commonly prescribed immunotherapeutic agent for use in bladder cancer treatment. For more detailed BCG treatment information, see Dr. DL Lamms protocol, research and extensive list of referenced studies, including his latest findings about the efficacy of maintenance therapy.

A recent professional meeting slide presentation with transcript: Dr. Lamm’s latest, Dec. 2002 click here; Dr. Lamm has a website as of 2005 where you can leave questions and get a second opinion: http://www.bcgoncology.com

Bacillus Calmette-Guerin has been in use since the 1980′s, and is the most proven and effective form of immunotherapy at this point in time. Immunotherapy has a mechanism of action different from that of chemotherapy. It uses materials made by your own body or made in a laboratory to boost, direct, or restore your body’s natural defenses against disease.

Bacillus Calmette-Guerin (BCG), which is an inactivated form of the bacterium Mycobacterium tuberculosis, is given both intravesically mixed in a saline solution and instilled directly into the bladder via a catheter, as well as in the form of a percutaneous vaccine. Although it is not yet totally understood why BCG and other immunotherapies work against cancer, they are thought to elicit an immune response.

It’s been shown that BCG induces a variety of cytokines into the urine of patients with superficial TCC, and that some cytokines have antiangiogenic activity. One study demonstrated that interferon- inducible protein 10 (IP-10) and its inducing antiangiogenic cytokines, interferon-gamma (IFN-gamma) and interleukin-12 (IL-12), are increased during intravesical BCG immunotherapy of bladder TCC. These data suggest that, in addition to a cellular immune response, BCG may induce a cytokine- mediated antiangiogenic environment that aids in inhibiting future tumor growth and progression.

BCG has resulted in complete tumor regression in one half or more of treated patients with papillary tumors, and in more than 70% of those with CIS. Controlled studies have demmonstrated a significant reduction in tumor recurrence, protection from which has been observed to persist for 5 years or more. Dr. Lamm’s studies have also shown statistically significant reductions in the rate of disease progression and a significant reduction in the mortality rate, after treatment with BCG immunotherapy.

The proven effectivenes of BCG in treating carcinoma in situ has made it the treatment of choice for CIS. Although European studies have reported less spectacular results after a long term study of comparing BCG to Mitomycin C, the reported studies used a less than optimal protocol according to Dr. Lamm’s recommendations. Still, the superiority of BCG over chemotherapeutic agents in treating high risk tumors and CIS is acknowledged.

BCG is usually reserved for higher grade tumors or recurrences, while solitary, superficial papillary tumors are most often treated (if treated at all) with an intravesical chemo as first line of attack. Once a tumor has shown signs of muscle invasion (T2), BCG is no longer considered a viable option.

Though side effects vary with the individual, the great majority of people find BCG treatments tolerable with side effects being temporay, and some have no adverse reactions at all. Dysuria (pain or difficulty upon urination) and urinary frequency are expected as a consequence of the inflammatory response, and cystitis is the most frequent adverse reaction-occurring in up to 90% of cases. Blood in the urine may occur with cystitis and is seen in one-third of patients. Irritative bladder symptoms are unlikely in the week after the first intravesical BCG. Side effects of BCG are cumulatory, and generally increase with successive treatments. Some people complain of flu like symptoms including fatigue, joint pain and muscle ache.

Treatment

For maximum effect the solution should be instilled when the bladder is completely empty and remain in direct bladder contact for 2 hours. Patients are recommended to limit fluid intake for 8-12 hours, and to have no fluid intake for 4 hours before treatment is scheduled. Avoid direct skin contact during and after urinating as it may cause skin rash and irritation. You are advised to sit while urinating and to empty the bladder completely. Thorough cleansing of genital area and hands is advised.

The toilet must be neutralized of any live bacteria; this is done by pouring 2 cups of household bleach into the water and letting it stand for 15-20 minutes.

The bladder should be thoroughly flushed after BCG instillation by increasing fluid intake.

Call the doctorif you experience

Urinary problems

  • continued pain and burning
  • urgency
  • frequency
  • blood or blood clots in the urine

Flu like symptoms

  • fever
  • chills
  • joint pain

Increased fatigue
Frequent or persistent coughing
Skin rash(despite having taken precautions mentioned above)

For a more complete description about use, side effects and possible complications, drug interaction, etc, see RxMed’s Drug Reference for two commonly used strains of the vaccine: Pacis ImmuCyst . See also http://www.immucyst.com/ for more info.

It is not recommended to instill BCG until at least one-two weeks after resection of the tumor. BCG should not be given if irritative symptoms from the previous instillation are present, nor in the presence of undetermined fever or urinary tract infection. Fewer than one in 1000 people who use the BCG percutaneous vaccine develop significant local reactions, and potentially fatal disseminated disease develops in fewer than one in a million. Complications usually result from faulty technique, including the accidental intracutaneous injection of the stronger percutaneous vaccine, or poor selection of subjects for vaccination. BCG should never be given to people who are known to be infected with HIV.

The viability of BCG is crucial for induction of a local immune response and for effective therapy. Favorable results occur more frequently among patients who exhibit a granulomatous inflammatory response in the bladder and delayed hypersensitivity skin test response to purified protein derivative. Marked variability in viability of bacillus Calmette-Guerin organisms has been observed among different lots of BCG, and a direct relationship has been observed between vaccine viability and therapeutic efficacy. In one study, most patients who failed initial therapy with a low viability lot of bacillus Calmette-Guerin responded favorably to re-treatment with a higher viability lot.

Sex

Men having this treatment can pass on BCG during sex. To protect your partner from coming into contact with BCG, you should not have sex for 48 hours after each treatment. Use a condom if you have sex at other times during the six weeks of treatment. You should also use a condom for sex for six weeks after treatment has ended. http://www.accv.org.au/cancer1/patients/bladder/howtreated.htm

Drug interactions-Antibiotics

In case of BCG instillation therapy, the antibiotics in the class of quinolones, doxycycline and gentamycin should be avoided in concomitant urinary tract infections. In case of severe systemic complications, 5-quinolones might be used additionally if one of the anti-tuberculosis drugs including isoniazid, rifampicin or ethambutol is not tolerated. Cycloserine, previously proposed for the early treatment of BCG-sepsis is not recommended any more. Only the appropriate use of antibacterial drugs during intravesical BCG immunotherapy preserves the therapeutic safety and efficacy.

Quinolone *antibiotics:

Trovan (trovafloxain mesylate), Trovan IV (alsatrofloxacin mesylate, Ciloxan (ciprofloxacin hydrochloride), Zagam (sparfloxacin), Elequin (levofloxacin), Levaquin (levofloxacin), Cipro* (ciprofloxacin), Maxaquin (lomefloxacin), Noroxin (norfloxacin), Floxin (ofloxin)
*Cipro is an often used antibiotic, though not always without side effects. For more info on Cipro you can look here: http://prostatitis.org/ciproeffects.html

Doxycyclines–Antibiotic/tetracyclines:

Periostat (Doxycycline Hyclate), Atridox (doxycycline hyclate), Vibramycin Ca (doxycycline calcium), Doryx (doxycycline hyclate), Doxycycline (doxycycline hyclate), Vibra Tabs (doxycycline hyclate), Monodox (doxycycline monohydrate)

gentamycin:

Garamycin (gentamicin sulfate), Genoptic (gentamicin sulfate ophth), Gentacidin (gentamicin sulfate ophth), Gentak (gentamicin sulfate ophth)
http://www.rxlist.com/

Antibiotics For bladder cancer

2006: A randomized controlled clinical trial of 115 patients determined the impact of the antibiotic Ofloxacin on side effects of BCG therapy; the findings were interesting, showing 22% fewer ‘moderate’ side effects, a lessing of severe complications between instillations 1 and 9 (54% vs. 76% respectively), and a better adherence to therapy, with 81% of the antibiotic group completing the therapy vs. 66% of those who received placebos.

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When receiving BCG it is especially important that your health care professional know if you are taking any of the following:

  • Amphotericin B by injection (e.g., Fungizone) or
  • Antineoplastics (cancer medicine) or
  • Antithyroid agents (medicine for overactive thyroid) or
  • Azathioprine (e.g., Imuran) or
  • Chlorambucil (e.g., Leukeran) or
  • Chloramphenicol (e.g., Chloromycetin) or
  • Colchicine or
  • Corticosteroids (cortisone-like medicine) or
  • Cyclophosphamide (e.g., Cytoxan) or
  • Cyclosporine (e.g., Sandimmune) or
  • Flucytosine (e.g., Ancobon) or
  • Ganciclovir (e.g., Cytovene) or
  • Interferon (e.g., Intron A, Roferon-A) or
  • Mercaptopurine (e.g., Purinethol) or
  • Methotrexate (e.g., Mexate) or
  • Muromonab-CD3 (e.g., Orthoclone OKT3) or
  • Plicamycin (e.g., Mithracin) or
  • Zidovudine (e.g., AZT, Retrovir)

Because these medicines reduce the body’s natural immunity, they may prevent BCG from stimulating the immune system and will cause it to be less effective. In addition, the risk of infection may be increased.

Other medical problems

The presence of other medical problems may affect the use of BCG. Make sure you tell your doctor if you have any other medical problems, especially:

Fever—Infection may be present and could cause problems
Immunity problems—BCG treatment is less effective and there is a risk of infection
Urinary tract infection—Infection and irritation of the bladder may occur

Concerns over high grade tumors – long term risk

Patients with high-risk superficial bladder tumors who retain their bladders owing to successful local BCG therapy have an increased risk of developing extravesical (outside the bladder) urothelial tumors.

One 2002 study involving 307 patients with mulitiple, recurrent Ta, T1 and CIS tumors were followed for a median of 12 years (range, 10–18 years). Extravesical tumors were detected during follow-up of positive urine cytology after no tumor was found in the bladder. Of the 307 patients, 78 (25%) developed tumors in the upper urinary tract (UTT). Of the 251 men 61 (24%) had tumors detected in the prostatic urethra or ducts (T4p). The median time to UTT and T4p was 56 and 11 months, respectively. UTT and T4p were diagnosed more frequently during the first 5 years, but such tumors occurred over 15 years of follow-up. The median time to UTT was 50 months among 246 patients with tumor recurrence in the bladder vs 114 months in 61 patients with no bladder recurrences. 88% of UTT occurred in patients with intact bladders and 12% after cystectomy. 32% of UTT and 44% of T4p relapses were lethal.

2005: Risk of understaging upon progression after BCG fails in high-risk superficial blc: “Five-year disease-specific survival rate was significantly lower in understaged (38%) as compared with not-understaged patients (90%) after a median follow-up of 40-months (range 1-142) (p=0.006). Overall five-year disease-specific survival was 79%. CONCLUSIONS: RC should be performed prior to progression in high risk superficial tumors that fail after TUR and BCG. In patients with clinical and pathological nonmuscle invasive disease,radical cystectomy (RC) provides an excellent disease-free survival. One third of patients with high-risk superficial bladder tumors who underwent RC after BCG failure were understaged and had a shorter survival. Tumor in the prostatic urethra at endoscopic staging was the only factor associated to understaging and shorter survival.

BCG and PSA

A study published in the November 2000 issue of the Journal of Urology showed that used of BCG can raise PSA (prostate specific antigen), and that intravesical BCG therapy is associated with significantly elevated PSA in up to 40% of cases. The authors state: “This effect is self-limited and PSA reverts to normal in 3 months. Therefore, we suggest that prostate biopsy be withheld in such patients and PSA monitored.” 2003: “Endovesical BCG administration produces an increase on serum PSA levels. This variation is higher in patients with history of TURP.”

Studies and trials are underway for other intravesical immunotherapeutic agents such as interferon alpha2b (or Intron A), which has shown activity against papillary tumors and CIS both as primary treatment and as secondary treatment after failure of other intravesical agents.

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