BCG Complications for Bladder Cancer: Who, What, When and How to Treat?

Bacillus Calmette-Guérin (BCG) immunotherapy currently remains the most effective treatment for intermediate and high risk non-muscle-invasive bladder cancer, but has side effects that range from bothersome to life-threatening. To learn more about BCG treatment, please see our prior blog on the "Success Rates for Intravesical BCG Treatments for Bladder Cancer."

Here we review the common BCG side effects, the prevention and treatment of these effects.

Common BCG Side Effects:

• Mild Urinary Symptoms (5-90%) [1,2]
• Frequency
• Dysuria
• Hematuria (1-34%) [2]
• Malaise (Fatigue)
• Fever (3-17%) [3-5]

BCG works through a local immune response, therefore some side effects and indicative of BCG effectiveness.  In fact, fever has been reported to correlate with a reduction in the risk of recurrence; however, many patients have no symptoms from BCG and remain tumor free.

Patients should be instructed to expect mild urinary frequency and dysuria beginning after the second or third instillation. These symptoms should last only a few days and should not be disabling. Mild malaise, fatigue, and “flu-like” symptoms similar to those following a vaccination are seen less frequently, likely a consequence of immune stimulation and not generally of concern.

Unexpected or severe symptoms are often associated with increasing symptoms with successive instillations.

How to treat mild symptoms & side effects:

• Treatment for mild symptoms can include:
• phenazopyridine hydrochloride
• acetaminophen 
• nonsteroidal anti-inflammatory drugs
• If the side effects are tolerable (not increasing and not requiring medication), simply postponing treatment until all symptoms have resolved is the most appropriate approach. 
• While 6 weekly instillations are the optimal induction course for BCG, this is an arbitrary schedule that does not necessarily fit everyone. 
• Consider dose reduction.
• The recommended logarithmic reduction to 1/3, 1/10, 1/30 and 1/100th dose, for decades has shown that most symptoms can be managed with no observable reduction in efficacy. [6,7]
• Consider prophylactic antibiotics.
• Standard dose BCG plus ofloxacin 200 milligrams (mg) at 6 hours post instillation and the following morning has been demonstrated to have a significant reduction in local side effects with no reduction in efficacy. [8]
• Isoniazid prophylaxis did not reduce the side effects of BCG in a large EORTC study. [9] 

How to treat moderate symptoms or BCG cystitis:

Moderate symptoms are often characterized by prolonged malaise, loss of appetite, night sweats and low grade fever which suggest a systemic infection. BCG cystitis is characterized by persistent severe frequency, urgency and dysuria, characteristic of BCG cystitis. The response to fluoroquinolones often occurs more promptly than the response to other types of antibiotics but should not be given for significant BCG infection as a single antibiotic.

• A two-drug combination is generally sufficient for milder reactions treated early. 
• Fluoroquinolone 
• ofloxacin (200 to 400 mg every 12 hours)
• ciprofloxacin (500 mg every 12 hours) 
• levofloxacin (500 mg every 24 hours) 
• Isoniazid 300 mg daily
• For more intense or prolonged symptoms, a three drug combination is needed:
• Rifampin 600 mg daily and/or 
• Ethambutol 1200 mg daily 
• Monthly eye examinations are recommended to optic neuritis (6%). [10]
• Treatment is recommended for 3 to 6 months and symptoms may not even begin to improve for months after initiation of appropriate antibiotic therapy. 
• Prednisone (30-60 mg daily, gradual taper) may be used in addition to antimicrobials if symptoms are unresponsive and intolerable.
• Bladder contracture can occur is the rare circumstance that frequency and dysuria are not treated effectively.  

How to treat severe BCG-related symptoms and BCG-sepsis:

BCG sepsis is a rare complication (0.4%) [2] and is defined by high-fever and chills following BCG instillation.  The treatment of BCG sepsis includes:

• Prompt hospital admission 
• Broad-spectrum antibiotic coverage (triple antitubercular antibiotics)

Even with appropriate antibiotic treatment, hypotension followed by multisystem organ failure can occur. Due to an overwhelming immune response, steroid administration to suppress this immune hypersensitivity response (methylprednisolone 60-100 mg or more IV daily) can be life-saving. 

Patients with severe BCG reactions should not receive BCG in the future.Primates injected with one gram of BCG intravenously uniformly survive the infection, but a second intravenous injection in primates (like a second intraperitoneal BCG injection in rodents) is universally fatal.

How to treat patients who cannot tolerate BCG treatments:

Many patients would benefit from intravesical treatments but are unable to receive BCG due to side effects.  Options include dose-reduction and/or shortened course BCG treatments, radiation therapy,[11], heat-killed BCG [12] or other, novel BCG agents.  This will be the subject of a future blog.

Nilay M. Gandhi, MD

This entry was written by Nilay M. Gandhi, MD, senior assistant resident at the Brady Urological Institute at Johns Hopkins.  

Some of the data is extracted from the chapter Presentation and Management of Significant Side Effects from Bacillus Calmette-Guérin Bladder Instillation by Nilay M. Gandhi and Donald L. Lamm, which will appear in newest edition of The Textbook of Bladder Cancer.

[1] J.M. Molina, C. Rabian, M.F. D’Agay, J. Modai.  Hypersensitivity systemic reaction following intravesical bacillus Calmette-Guerin: successful treatment with steroids. J Urol, 147 (1992), p. 695
[2] D.L. Lamm, A.P.M. van der Meijden, A. Morales, S.A. Brosman, W.J. Catalona, H.W. Herr et al. Incidence and treatment of complications of bacillus Calmette-Guérin intravesical therapy in superficial bladder cancer.  J Urol, 147 (1992), p. 596
[3] P. Bassi, P. Nicola, R. Spinadin, R. Carando, F. Pagano, G.L. Papagallo. Low dose vs standard dose BCG therapy of superficial bladder cancer: final results of a phase 3 randomized trial. Eur Urol, 35 (1999), p. 152 suppl. abstract 
[4] J.A. Martínez-Piñeiro, J. Jiménez León, L. Martínez-Piñeiro Jr., L. Fiter, J.A. Mosteiro, J. Novarro et al.  Bacillus Calmette-Guerin versus doxorubicin versus thiotepa: a randomized prospective study in 202 patients with superficial bladder cancer. J Urol, 143 (1990), p. 502
[5] P.D. Vegt, A.P.M. van der Meijden, R. Sylvester, M. Brausi, W. Holtl, C. de Balincourt. Does isoniazid reduce side effects of intravesical bacillus Calmette-Guerin therapy in superficial bladder cancer? Interim results of the European Organization for Research and Treatment of Cancer protocol 30911. J Urol, 157 (1997), p. 1246
[6] J.A. Martinez-Pineiro, N. Flores, S. Isorna, E. Solsona, J.L. Sebastian, C. Pertusa et al.
Long-term follow-up of a randomized prospective trial comparing a standard 81 mg dose of intravesical bacilli Calmette-Guerin with a reduced dose of 27 mg in superficial bladder cancer
BJU Int, 89 (2002), p. 671
[7] P. Rivera, M. Orio, J. Hinostroza, P. Venegas, P. Pastor, M. Gorena et al.
Nuestra experiencia con instilaciones de 1 mg de vacuna BCG en cancer vesical etapa T1
Actas Urol Esp, 23 (1999), p. 757
[8] Colombel M, Saint F, Chopin D, Nicolas L, Rischmann P. The effect of ofloxacin on bacillus Calmette-Guérin induced toxicity in patients with superficial bladder cancer: Results of a randomized, prospective, double-blind, placebo controlled, multicenter study. J Urol 2006; 176: 935–9.
[9] Sylvester RJ, Brausi MA, Kirkels WJ, et al. Long-term efficacy results of EORTC genito-urinary group randomized phase 3 study 30911 comparing intravesical instillations of epirubicin, bacillus Calmette-Guérin, and bacillus Calmette-Guérin plus isoniazid in patients with intermediate- and high-risk stage Ta T1 urothelial carcinoma of the bladder. Eur Urol 2010; 57 (5): 766-73.
[10] Griffith DE, Brown-Elliott BA, Shepherd S, McLarty J, Griffith L, Wallace Jr, RJ. Ethambutol ocular toxicity in treatment regimens for Mycobacterium avium complex lung disease. Am J Respir Crit Care Med 2005; 172 (2): 250-3.

[11] Harland SJ, Kynaston H, Grigor K, Wallace DM, Beacock C, Kockelbergh R, Clawson S, Barlow T, Parmar MK, Griffiths GO. National Cancer Research Institute Bladder Clinical Studies Group: A randomized trial of radical radiotherapy for the management of pT1G3 NXM0 transitional cell carcinoma of the bladder. J Urol 2007; 178 (3): 807-13.

[12] Lamm DL, Gandhi NM, Iverson T, et al. Clinical experience with heat-inactivated bacillus Calmette-Guérin (BCG) immunotherapy. J Urol 2013; 4 (suppl): 733.