bcg and bladder cancer - pbworksnewenglandtb.pbworks.com/f/friedman+bcg+and... · bcg and bladder...

BCG and Bladder Cancer

Lloyd Friedman, M.D.

Yale University

Milford Hospital

Outline

• Bladder Cancer

• History of BCG

• Use of BCG as an Immunomodulator in Cancer

• Efficacy of BCG in Bladder Cancer

• Dose and Schedule of BCG

• Clinical BCGitis

• Treatment of BCGitis

• Mitigation of BCGitis

• Summary

Bladder Cancer

Rates

• 16,000 cases per year in the USA

– Usually transitional cell

• 13,000 deaths per year

TURBT is Not Curative

• TURBT is the primary treatment for

nonmuscle-invasive transitional cell cancer

• 45% of patients will have tumor recurrence

within 12 months of TURBT alone

• 3%-15% will progress to muscle invasion

and/or metastatic bladder cancer

Hall (AUA). J Urol 2007; 178:2314-30.

Camille Guerin (left) and Albert Calmette (c 1921)

Bacille Calmette-Guerin (BCG)

• Created after subculturing a strain of Mycobacterium bovis 231 times over 13 years in a special medium containing ox bile, potatoes and glycerin

• BCG used for the first time in humans in 1921

• It could not be stored until 1960 when it was transformed into lyophilized seed lots. Therefore, 1,000 additional passages occurred until that time with multiple daughter strains.

– Danish, Dutch, Glaxo (Evans/United Kingdom), Chicago (Tice), Montreal (Frappier), Toronto (Connaught), Tokyo (most frequently used for bladder cancer)

Use of BCG for Cancer

• 1950’s: Lloyd Old (Sloan Kettering) was

the first to investigate its use in cancer

– Mice infected with BCG were resistant to

transplantable tumors

• Macrophages with tumerocidal activity were

activated

• Old discovered tumor necrosis factor

Old LJ. Nature 1959; 184:291


• Zbar established that direct contact of the tumor with BCG in guinea pigs allowed for the destruction of tumor cells

– The effect was related to a local delayed-type hypersensitivity response and not to a direct effect of BCG

– It is the reason that BCG is instilled into the bladder so that it is in direct contact with the superficial bladder cancer

Zbar. J Natl Cancer Inst 1971;46:831.


• 1969: Mathe (France) Acute lymphoblastic leukemia

• 1970: Morton (USA) Regression of melanoma with intralesional BCG

• 1972: Alvaro Morales (Canada) first use of intravesicular BCG in superficial bladder cancer

• 1975: deKernion: Regression of bladder melanoma with cystoscopic infusion of BCG

• 1980: 2 studies demonstrated efficacy in bladder cancer

• 1990: FDA approved for bladder cancer, and it remains the recommended treatment for high grade noninvasive bladder cancer

Intravesicular BCG

Mechanism of Action

• Mononuclear cell infiltrate

– CD4 cells and macrophages

• IFN-gamma production

– Induces HLA-DR and ICAM-1 production

– Sensitizes tumor cells as targets for lymphokine-activated killer (LAK) cells

• Increased cytokine levels – IL1, IL-2, IL-6, IL-8, IL-12, IFN-gamma, TNF-alpha

Intravesicular BCG

Persistence of effect

• Immune activation my persist for months

• Ribosomal DNA was detected in bladder

wall biopsy specimens up to 24 months later

Rationale for the Use of BCG for

Bladder Cancer

Hall (AUA). J Urol 2007; 178:2314-30.


Induction

• Theracys (81 mg) in 50 ml saline or

• TICE BCG (50 mg) in 50 ml saline

– 1 to 8 x 108 CFU’s per vial

• Once a week for 6 weeks

– Instilled into bladder and retained for 2 hours

In What Circumstances Should

Maintenance BCG be Used

Bladder Cancer

Risk of Recurrence and Progression

Babjuk (EUA). E Urol 2008; 54:303-14.

Bladder Cancer

Recurrence and Progression Scores

Babjuk (EUA). E Urol 2008; 54:303-14.


Maintenance

• The American Urological Association

recommends induction followed by

maintenance BCG in patients with higher-

risk nonmuscle-invasive bladder tumors.

• 3-week maintenance therapy at 3, 6, 12, 18,

24, 30, and 36 months

Hall (AUA). J Urol 2007; 178:2314-30.


Maintenance Therapy

• EUA bladder cancer guidelines:

– At least a year of BCG maintenance therapy for

all high-risk patients who initiate therapy with

BCG

Babjuk (EUA). E Urol 2008; 54:303-14.


Complications

Lamm. CID 2000; 31:S86-90.


Complications

• Average from 585 patients in multiple studies

• Frequency 71%

• Cystitis 67%

• Fever 25%

• Hematuria 23%

• Flu-like 15%

• Malaise 14%

• Nausea 8%

Shelley. Cochrane review 2000; CD001986


Complications

• Currently, serious side effects are

encountered in fewer than 5% of patients

because we understand the risks better.


Risks for Complications

• Traumatic catheterization

• Active cystitis/concurrent UTI

• Gross hematuria following TURBT!

• Advanced age: >70 (half developed

complications

• Administration too early after TURBT (i.e.,

within 2 weeks)


Localized disease

• BCG cystitis: symptoms occur within 2-4 hours in the majority of patients with or without low grade fever – usually resolves within 48 hours

• Granulomatous prostatitis – as high as 75% on biopsy, usually asymptomatic

• Epididymoorchitis, even years after administration


Sepsis

• Sepsis syndrome can occur with fever,

rigors, hypotension at a rate of 1/15,000

cases – probably due to cytokine release


Hepatitis

• Granulomatous hepatitis is rare and can

occur early or late in the course

• Symptoms include fever, anorexia and

jaundice.


Pneumonitis

• There is controversy about whether pneumonitis represents infection or a hypersensitivity reaction.

– There are cases where granulomas are identified without organisms on stain or culture.

• Clinical findings

– Miliary or nodular pattern in the lungs most often associated with a sepsis-like syndrome with dyspnea, fever and malaise.

– Respiratory compromise is possible.

• Glucocorticoids are often necessary


Osteomyelitis

• Very rare – usually involving the spine

• Vertebral body involvement can cause back pain

and neurologic manifestations as well as psoas

abscesses

• Joints can be affected at a rate of 0.5-1.0%, but are

not necessarily infected. Arthralgias are common

and the differential includes septic versus reactive

arthritis. Monoarthritis favors an infection


Noninfectious Arthritis

Clavel. Joint Bone Spine 2006; 73:24-8.


Other Manifestations

• Fever of unknown origin

• Mycotic aneurysms

• Psoas abscess

• Endophthalmitis

BCGitis

When Is Treatment Necessary

• Usually acute symptoms such as cystitis and

fever resolve within 48 hours

• The cardinal signs of BCG infection is a

relapsing fever with night sweats persisting

beyond 48 hours.

• Sometimes a bacterial cystitis occurs which

can confuse the picture

BCG Cystitis

Treatment

• Moderate to severe cystitis

– fluoroquinolone (levofloxacin 500 mg/day)

– isoniazid (300 mg/day).

• If symptoms persist for a week or more, add

rifampin. If it responds quickly, treat another 2

weeks. If slow response, treat 3 months. Can add a

short course of tapering steroids for 2-3 weeks.

BCG Dissemination

Treatment

• Full therapy with isoniazid, rifampin and

ethambutol initially (BCG is uniformly

resistant to pyrazinamide)

• Total duration of therapy: 3-6 months.

BCG Dissemination

Glucocorticoids

• Steroids are helpful in cases where

hypersensitivity is believed to be a

component. They are usually added where

the patient is very symptomatic, and tapered

once symptoms have resolved.

BCGitis

Prevention

• There is no benefit to giving INH to prevent

infection.

• There may be some benefit to the use of

fluoroquinolones.

– In one study, ofloxocin at 6 and 18 hours after

each BCG administration reduced the incidence

of severe local reactions and the need for

antituberculous therapy

Van Der Meijden. J Urol 2001; 166:476

Colombel. J Urol 2006; 176:935.

BCGitis

Lower dose

• The dose can be lowered to one half to one

quarter of the usual dose

– There is some concern that a lower dose can

reduce efficacy

• Reduce the dwell time to 30 minutes

• Schedule every other week.

Morales. J Urol 1992; 147:1256.

Mycobacterial Cell Wall-DNA

Complex in Patients Who Did Not

Respond to BCG

Morales. J Urol 2009; 181:1040.

Summary

• Bladder cancer is an indolent, but recurrent disease

• No therapy has been shown to be better than BCG

• Consideration for antibiotic treatment of BCGitis should occur after 48 hours post instillation

• Reactions might reflect true infection or an immune response

• If infection is likely, start with isoniazid or levofloxacin for cystitis, and isoniazid, rifampin, and ethambutol with or without steroids for disseminated disease.

bcg and bladder cancer - pbworksnewenglandtb.pbworks.com/f/friedman+bcg+and... · bcg and bladder...

Documents