Findings on Bacillus Calmette–Guérin (BCG) for Superficial Bladder Cancer

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Findings on Bacillus Calmette–Guérin (BCG) for Superficial Bladder Cancer

October 12, 2015 by Demet Sag, Ph.D., CRA, GCP

Findings on Bacillus Calmette–Guérin (BCG) for Superficial Bladder Cancer

Curator: Demet Sag, PhD, CRA, GCP

Bladder cancer is arising from the epithelial lining, specifically the urothelium of the urinary bladder with a five year survival rate. The common one is transitional cell carcinoma (90%) and the remaining 10% of bladder cancer are squamous cell carcinoma, adenocarcinoma, sarcoma, small cell carcinoma. This is a 9^th common disease in women and 4^th in men in the US. There is an increased bladder cancer death observed from 1990 to 2010. This disease is prevalent among men than women, ½ versus 1/3 of population due to higher androgen receptor expression in men.

https://en.wikipedia.org/wiki/File:Bladder_Cancer_Treatment_Guide_v4.png

The common symptoms are blood in the urine (hematuria), pain during urination, however, some of these symptoms may not be harmful or belong to other diseases such as non-cancerous conditions, including prostate infections, over-active bladder and cystitis. Hematuria may be caused by bladder or ureteric stones, infection, kidney disease, kidney cancers and vascular malformations.

https://upload.https://upload.wikimedia.org/wikipedia/commons/thumb/c/ce/Bladder_cancer_world_map_-_Death_-_WHO2004.svg/340px-Bladder_cancer_world_map_-_Death_-_WHO2004.svg.pngwikimedia.org/wikipedia/commons/thumb/c/ce/Bladder_cancer_world_map_-_Death_-_WHO2004.svg/340px-Bladder_cancer_world_map_-_Death_-_WHO2004.svg.png

The first use of bacterial toxins goes back to 1700s. A new York Bone Surgeon used as a source to cure inoperable cancer patients Thus, Coley’s toxins regarded as the first use of bacterial vaccine in cancer treatment. Today BCG is used to treat bladder cancer with the similar purpose to stimulate innate immune response to cure the disease. The Listeria monocytogenes based vaccine development for other types of cancer is underway. Removal of virulence factors is the key yet choosing right type of bacteria possibly the commensal microbiome can be an important approach. Now, in 20^th century especially after FDA approval of couple immunotherapies, a new wave in immunotherapy development is started.

figure-Semin Oncol. Author manuscript; available in PMC 2013 Jun 1.

There are 904 reported bladder cancer clinical trials, among them 272 are active with recent updates. (www.clinicaltrials.com)

https://upload.wikimedia.org/wikipedia/commons/thumb/7/75/Blasentumor.jpg/220px-Blasentumor.jpg

The common method for diagnosis is cystoscopy, yet they are not conclusive so supportive tests are required. Recently with the advent of bioinformatics and genomics there are biomarker development. Some of them are still include primary pathways like Notch, Wnt etc. However, associated somatic mutations at HRAS (190020), KRAS2 (190070), RB1 (614041), and FGFR3 (134934), HRAS, KRAS2, RB1, and FGFR3 thought to be important. Analysis of LOH at 11p13, a region containing the Wilms tumor suppressor gene (WT1; 607102), showed deletion at the CAT locus (115500) in 13 of 18 bladder cancers (72%), at the WT1 locus in 7 of 14 (50%), and at the FSHB locus (136530) in 6 of 16 (38%). Some are developing new specific biomarkers. In addition, there is another method based on microbiome in urine samples.

CATEGORY	FEATURES
GU	Transitional cell bladder carcinoma
Inheritance	Autosomal dominant (11p)

Age-standardized death from bladder cancer per 100,000 inhabitants in 2004.^[43]

no data

less than 1.5

1.5–3

3–4.5

4.5–6

6–7.5

7.5–9

9–10.5

10.5–12

12–13.5

(WHO Disease and injury country estimates”. World Health Organization. 2009. Retrieved 11 Nov 2009.)

Longe, Jacqueline L. 2005 showed staging of the bladder cancer as follows:

Diagram showing the T stages of bladder cancer

T (Primary tumour)

· TX Primary tumour cannot be assessed

· T0 No evidence of primary tumour

· Ta Non-invasive papillary carcinoma

· Tis Carcinoma in situ (‘flat tumour’)

· T1 Tumour invades subepithelial connective tissue

· T2a Tumour invades superficial muscle (inner half)

· T2b Tumour invades deep muscle (outer half)

· T3 Tumour invades perivesical tissue:

· T3a Microscopically

· T3b Macroscopically (extravesical mass)

· T4a Tumour invades prostate, uterus or vagina

· T4b Tumour invades pelvic wall or abdominal wall

N (Lymph nodes)

· NX Regional lymph nodes cannot be assessed

· N0 No regional lymph node metastasis

· N1 Metastasis in a single lymph node 2 cm or less in greatest dimension

· N2 Metastasis in a single lymph node more than 2 cm but not more than 5 cm in greatest dimension,or multiple lymph nodes, none more than 5 cm in greatest dimension

· N3 Metastasis in a lymph node more than 5 cm in greatest dimension

M (Distant metastasis)

· MX Distant metastasis cannot be assessed

· M0 No distant metastasis

· M1 Distant metastasis.

bacillus Calmette-Guerin BCG
Bacillus sp. BC1
Bacillus sp. BC3
Bacillus sp. BC6
Bacillus sp. BC

Mycobacterium bovis BCG

Taxonomy ID: 33892
Inherited blast name: high GC Gram+
Rank: no rank
Genetic code: Translation table 11 (Bacterial, Archaeal and Plant Plastid)
Other names:

synonym:	bacillus Calmette-Guerin BCG
synonym:	bacillus Calmette-Guerin
synonym:	Mycobacterium tuberculosis var. bovis BCG
acronym:	BCG

Lineage( full )

cellular organisms; Bacteria; Actinobacteria; Actinobacteria; Corynebacteriales; Mycobacteriaceae;Mycobacterium; Mycobacterium tuberculosis complex; Mycobacterium bovis

Taxonomy of Listeria monocytogenes

Taxonomy ID: 1639
Inherited blast name: firmicutes
Rank: species
Genetic code: Translation table 11 (Bacterial, Archaeal and Plant Plastid)
Other names:

synonym:	Listerella hepatolytica
synonym:	Erysipelothrix monocytogenes
synonym:	Corynebacterium parvulum
synonym:	Corynebacterium infantisepticum
synonym:	Bacterium monocytogenes hominis
synonym:	Bacterium monocytogenes
authority:	Listeria monocytogenes (Murray et al. 1926) Pirie 1940
authority:	“Listerella hepatolytica” Pirie 1927
authority:	“Erysipelothrix monocytogenes” (Murray et al. 1926) Wilson and Miles 1946
authority:	“Corynebacterium parvulum” Schultz et al. 1934
authority:	“Corynebacterium infantisepticum” Potel 1950
authority:	“Bacterium monocytogenes” Murray et al. 1926
authority:	“Bacterium monocytogenes hominis” Nyfeldt 1932
type material:	SLCC 53
type material:	NCTC 10357
type material:	DSM 20600
type material:	CIP 82.110
type material:	CCUG 15526
type material:	ATCC 15313

Lineage( full )

cellular organisms; Bacteria; Firmicutes; Bacilli; Bacillales; Listeriaceae; Listeria

Entrez records
Database name	Subtree links	Direct links
Nucleotide	52,614	34,526
Nucleotide GSS	51	51
Protein	1,062,786	834,212
Structure	189	70
Genome	1	1
Popset	350	350
Domains	1	1
GEO Datasets	964	649
PubMed Central	5,924	5,924
Gene	118,634	30,988
SRA Experiments	5,901	5,777
Probe	127	127
Assembly	372	274
Bio Project	355	123
Bio Sample	10,163	9,970
Bio Systems	7,240	814
PubChem BioAssay	362	322
Protein Clusters	3,885	1,204
Taxonomy	209	1

Figure from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3574585/

Figure: Pivotal events in the development of Lm-based vaccines for tumor immunotherapy. (From PMCID-PMC4026700 Attenuated Listeria monocytogenes for current and future immunotherapies)

Clinical Evaluation of Lm-Based Immunotherapies

From http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3574585/

Strategy	Description	Indication	Clinical Status	References
Deletion of virulence genes	ΔactA/ΔplcB NP (BMB72) attenuated Lm administered orally	Healthy volunteers	Phase I	PMID: 2065500; PMID: 1338384
	ΔactA/ΔinlB NP (BMB54) attenuated Lm administered orally	Healthy volunteers	Phase I	PMID: 1338384
	ΔactA/ΔinlB (ANZ-100); administered intravenously	Subjects with metastatic disease to the liver	Phase I
	ΔactA/ΔinlB mesothelin (CRS-207); administered intravenously	Subjects with cancer to the ovary and pancreas, non-small cell lung cancer and mesothelioma	Phase I
		Subjects with metastatic pancreatic cancer	Phase II (ongoing)
Aberrant expression of PrfA	Lm-LLO-E7 (ADXS11-001; Lovaxin C); administered intravenously	Subjects with advanced cervical carcinoma	Phase I	PMID:15699154 PMID:19785060
		Subjects with cervical intraepithelial neoplasia grade 2/3	Phase II (ongoing)
		Subjects with recurrent squamous or non-squamous cell carcinoma of the cervix	Phase II (ongoing)

Lm-based vaccines in development that target clinically-relevant tumor-associated antigens.

(from PMCID-PMC4026700 Attenuated Listeria monocytogenes for current and future immunotherapies)

Target	Target antigen	Lm-based Vaccine	Lm-strain	Lm-expressed Antigen	References
Cervical cancer	HPV16 E7	Lm-E7	10403S (wt)	LLO signal sequence fused to HPV16 E7	Gunn et al.,2001
	HPV16 E7	Lm-LLO-E7 (ADXS-HPV)	XFL-7 (prfA-)	dtLLO fused to HPV16 E7	Gunn et al.,2001
	HPV16 E7	rLm-E7	10403S (wt)	HPV16 E7 fused at the N-terminus with the LLO signal sequence and at the C-terminus with E. coliPhoA	Lin et al.,2002
	HPV16 E7	Lm-ActA-E7	XFL-7 (prfA-)	ActA a.a. 1-420 fused to HPV16 E7	Sewell et al., 2004a
	HPV16 E7	Lm-PEST-E7	XFL-7 (prfA-)	LLO a.a. 1-50 fused to HPV16 E7	Sewell et al., 2004b
	HPV16 E7	Lm-v1 and v2	Lmdd (dal- dat-)	dtLLO fused to HPV16 E7 expressed from a pCMV-driven plasmid delivered by Lm	Souders et al., 2006
	CRPV E1	E1-rLm	10403S (wt)	CRPVE1 fused at the N-terminus with the LLO signal sequence and at the C-terminus with E. coilPhoA	Jensen et al., 1997
Breast cancer	Rat Her2/neu	Lm-LLO-EC1, EC2, EC3, IC1, and IC2	XFL-7 (prfA-)	dtLLO fused to selected regions of rat Her2/neu	Singh et al., 2005
	Human Her2/neu	Lm-hHer2/neu chimera	XFL-7 (prfA-)	dtLLO fused to chimeric protein containing epitopes from human Her2/neu	Seavey et al., 2009b
	Human Her2/neu	Lm-cHer2 (ADXS-cHER2)	LmddA (dal- dat- actA-)	dtLLO fused to chimeric protein containing epitopes from human Her2/neu	Shahabi et al., 2011
	Mouse ISG15	Lm-LLO-ISG15	XFL-7 (prfA-)	dtLLO fused to mouse ISG15	Wood et al., 2012
	Mouse MAGE-b	Lm LLO Mage-b_311-660	XFL-7 (prfA-)	dtLLO fused to mouse Mage-b a.a. 311-600	Kim et al.,2008
	Human p53	LmddA-LLO-p53	LmddA (dal- dat- actA-)	dtLLO fused to human p53	Ishizaki et al., 2010
Tumor-associated vasculature	Mouse VEGFR-2 (Flk-1)	Lm-LLO-Flk-E1, E2, and l1	XFL-7 (prfA-)	dtLLO fused to selected regions of mouse VEGFR-2 (Flk-1)	Seavey et al., 2009a
	Human HMW-MAA	Lm-LLO-HMWMAA-C	XFL-7 (prfA-)	dtLLO fused to human HMW-MAA a.a. 2160-2258	Maciag et al., 2008
	Mouse CD105 (endoglin)	Lm-LLO-CD105A and B	XFL-7 (prfA-)	dtLLO fused to selected regions of mouse CD105 (endoglin)	Wood et al., 2011
Melanoma	Mouse TRP2, LCMV NP	Lm-TRP2-NP	10403S (wt)	Mouse TRP2 a.a. 24-191 fused at the N-terminus with the LLO signal sequence and at the C-terminus with LCMV NP a.a. 177-191 followed byE. coli PhoA	Bruhn et al., 2005
	Mouse TRP2	Lm-TRP2	10403S (wt)	Mouse TRP2 a.a. 24-191 fused at the N-terminus with the LLO signal sequence and at the C-terminus with E. coli PhoA	Bruhn et al., 2005
	Human HMW-MAA	Lm-LLO-HMWMAA-C	XFL-7 (prfA-)	dtLLO fused to human HMW-MAA a.a. 2160-2258	Maciag et al., 2008
Prostate cancer	Human PSA	Lm-LLO-PSA	XFL-7 (prfA-)	dtLLO fused to human PSA	Shahabi et al., 2008
Prostate cancer	Human PSA	ADVX-31-142 (ADXS-PSA)	LmddA (dal- dat- actA-)	dtLLO fused to human PSA	Wallecha et al., 2009
Hepatocellular carcinoma	HBc, HBV-X, Human alpha-Fetoprotein, and Human MAGE-A	Lm-MPFG	Lmdd (dal- dat-)	dtLLO fused to a fusion peptide containing full-length HBc, HBx a.a. 52-60, HBx a.a 140-148, AFP a.a 158-166, MAGE a.a. 271-279 and a flag tag	Chen et al.,2012

Fernandez-Garayzabal JF et al. (1996)

Fernandez-Garayzabal, J.F., Suarez, G., Blanco, M.M., Gibello, A., and Dominguez, L. “Taxonomic note: a proposal for reviewing the interpretation of the CAMP reaction between Listeria monocytogenes and Rhodococcus equi.” Int. J. Syst. Bacteriol. (1996) 46:832-834.

Jones D & Seeliger HPR (1983)

Jones, D., and Seeliger, H.P.R. “Designation of a new type strain for Listeria monocytogenes. Request for an opinion.” Int. J. Syst. Bacteriol. (1983) 33:429. [No PubMed record available.]

Kathariou S & Pine L (1991)

Kathariou, S., and Pine, L. “The type strain(s) of Listeria monocytogenes: a source of continuing difficulties.” Int. J. Syst Bacteriol. (1991) 41:328-330.

JCICSB (1987)

Judicial Commission of the International Committee on Systematic Bacteriology “Minutes of the Meeting, 5 September 1986, Manchester, United Kingdom.” Int. J. Syst. Bacteriol. (1987) 37:85-87. (Note: rejection of proposal by Jones & Seeliger (1983) for new type strain)

Murray EGD et al. (1926)

Murray, E.G.D., Webb, A.A., and Swann, M.B.R. “A disease of rabbits characterized by a large mononuclear leucocytosis caused by a hitherto underscribed bacillus Bacterium monocytogenes n. sp.” J. Pathol. Bacteriol. (1926) 29: 407-439. [No PubMed record available.]

Pirie JHH (1940)

Pirie, J.H.H. “The genus Listerella Pirie.” Science (Washington) (1940) 91:383. [No abstract available.]

PMID: 20806452

Skerman VBD et al. (1980)Skerman, V.B.D., McGowan, V., and Sneath, P.H.A. (editors). “Approved lists of bacterial names.” Int. J. Syst. Bacteriol. (1980) 30:225-420

Wayne LG (1986)

Wayne, L.G. “Actions of the Judicial Commission of the International Committee on Systematic Bacteriology on requests for opinions published in1983 and 1984.” Int. J. Syst. Bacteriol. (1986) 36:357-358. [No PubMed record available.]

PMID: 12065500

H, Loock K, Sisul D, Jensen E, Miller JF, Hohmann EL. “Safety and shedding of an attenuated strain of Listeria monocytogenes with a deletion of actA/plcB in adult volunteers: a dose escalation study of oral inoculation”. Infect Immun. 2002;70:3592–601.

PMID:21338384

Johnson PV, Blair BM, Zeller S, Kotton CN, Hohmann EL. “Attenuated Listeria monocytogenes vaccine vectors expressing Influenza A nucleoprotein: preclinical evaluation and oral inoculation of volunteers”. Microbiol Immunol. 2011;55:304–17.

PMID:15699154

Mathew A, Terajima M, West K, et al. “Identification of murine poxvirus-specific CD8⁺ CTL epitopes with distinct functional profiles”. J Immunol. 2005;174:2212–9.

PMID:19785060

Radulovic S, Brankovic-Magic M, Malisic E, et al. “Therapeutic cancer vaccines in cervical cancer: phase I study of Lovaxin-C. J Buon”. 2009;14(Suppl 1):S165–8.

PMCID:PMC4026700

Laurence M. Wood and Yvonne Paterson ”Attenuated Listeria monocytogenes: a powerful and versatile vector for the future of tumor immunotherapy”. Front Cell Infect Microbiol. 2014; 4: 51. Published online 2014 May 12. http://dx.doi.org:/10.3389/fcimb.2014.00051

PMID:7724661

Wiemann B¹, Starnes CO. “Coley’s toxins, tumor necrosis factor and cancer research: a historical perspective”. Pharmacol Ther. 1994;64(3):529-64.

PMID: 7751885

Herr HW¹, Schwalb DM, Zhang ZF, Sogani PC, Fair WR, Whitmore WF Jr, Oettgen HF.

“Intravesical bacillus Calmette-Guérin therapy prevents tumor progression and death from superficial bladder cancer: ten-year follow-up of a prospective randomized trial”. J Clin Oncol. 1995 Jun; 13(6):1404-8.

Front Cell Infect Microbiol. 2013; 3: 41. Copyright/License ►Request permission to reuse

Table listing all bacteria identified in this study that can be routinely cultivated and identified individually by standard methods described by the Health Protection Agency in routine investigations of urine (“Health Protection Agency, 2012”).

Genus	Aerobe or Anaerobe	Gram status
Actinomyces	Anaerobe	Positive
Aerococcus	Anaerobe	Positive
Anaerococcus	Anaerobe	Positive
Arcanobacterium	Anaerobe	Positive
Arthrobacter	Anaerobe	Positive
Brevibacterium	Aerobe	Positive
Campylobacter	Anaerobe	Negative
Corynebacterium	Anaerobe	Positive
Enterobacter	Anaerobe	Negative
Enterococcus	Anaerobe	Positive
Eubacterium	Anaerobe	Positive
Finegoldia	Anaerobe	Positive
Fusobacterium	Anaerobe	Negative
Gardnerella	Anaerobe	Variable
Gemella	Anaerobe	Positive
Lactobacillus	Anaerobe	Positive
Mobiluncus	Anaerobe	Positive
Mycobacterium	Aerobe	Positive
Neisseria	Aerobe	Negative
Nocardioides	Aerobe	Positive
Paraprevotella	Anaerobe	Negative
Peptococcus	Anaerobe	Positive
Peptostreptococcus	Anerobe	Positive
Porphyromonas	Anaerobe	Negative
Prevotella	Anaerobe	Negative
Propionimicrobium	Anaerobe	Positive
Pseudomonas	Aerobe	Negative
Rhodococcus	Aerobe	Positive
Staphylococcus	Anaerobe	Positive
Stenotrophomonas	Aerobe	Negative
Streptococcus	Anerobe	Positive

Table detailing the genera identified within each defined age group for females only.

All ages (n = 23)	Age 20–49 (n = 13)	Age 50–69 (n = 9)	Age 70+ (n = 11)	Age 20–49 and 50–69 (n = 4)	Age 50–69 and 70+ (n= 1)	Age 20–49 and 70+ (n = 9)
Actinobaculum	*Azospira*	Brevibacterium	Actinomyces	Aerococcus	Enterobacter	*Anaerovorax*
Anaerococcus	*Butyricicoccus*	*Catonella*	Arthrobacter	Arcanobacterium		*Flavonifractor*
Anaerosphaera	*Coriobacterium*	*Caulobacter*	*Gulosibacter*	*Brooklawnia*		*Gallicola*
Atopobium	*Friedmanniella*	*Methylovirgula*	*Jonquetella*	*Fastidiosipila*		*Helcococcus*
Campylobacter	Gardnerella	*Pelomonas*	*Lachnospiracea_incertae_sedis*			*Howardella*
Corynebacterium	*Microvirgula*	Peptostreptococcus	*Modestobacter*			Peptococcus
Dialister	Neisseria	*Sneathia*	*Oligella*			*Soehngenia*
Enterobacter	Paraprevotella	*Streptophyta*	*Parvimonas*			Staphylococcus
Enterocococcus	*Rhodopila*	*Thermoleophilum*	*Proteiniphilum*			Stenotrophomonas
Facklamia	*Sutterella*		Rhodococcus
Finegoldia	*Tepidimonas*		*Saccharofermentans*
Fusobacterium	*Tessaracoccus*
Lactobacillus	*TM7_genera_incertae_sedis*
Mobiluncus
Murdochiella
Negativicoccus
Peptoniphilus
Porphyromonas
Prevotella
Propionimicrobium
Sporanaerobacter
Streptococcus
Varibaculum

Those highlighted in bold are not routinely cultivated and/or reported individually by standard methods described the

UK Health Protection Agency in routine investigations of urine (Health Protection Agency,2012).

Table 3:

Table detailing the genera identified within each defined age group for males only.

All ages (n = 1)	Age 70+ (n = 48)		Age 20–49 and 50–69 (n = 1)
Staphylococcus	Aerococcus	*Kocuria*	Pseudomonas
	*Aminobacterium*	*Lactonifactor*
	Anaerococcus	*Marixanthomonas*
	*Anaerophaga*	*Megasphaera*
	*Anaerosphaera*	*Microvirgula*
	*Anaerotruncus*	Mobiluncus
	*Atopobium*	*Murdochiella*
	*Atopostipes*	*Mycoplasma*
	*Azospira*	*Parvimonas*	Age 20 and 70+ (n = 2)
	*Butyricicoccus*	Peptococcus	*Actinobaculum*
	Campylobacter	*Peptoniphilus*	Lactobacillus
	*Catonella*	Peptostreptococcus
	Corynebacterium	Porphyromonas
	*Dialister*	Prevotella
	Eubacterium	*Proteiniphilum*
	*Filifactor*	*Pseudoramibacter*
	Finegoldia	*Rikenella*
	Fusobacterium	*Saccharofermentans*
	Gardnerella	*Sediminitomix*
	Gemella	*Sneathia*
	*Gordonibacter*	*Soehngenia*

Those highlighted in bold are not routinely cultivated and/ or reported individually by standard methods described the UK Health Protection Agency in routine investigations of urine (Health Protection Agency,2012).

The Notch signaling is also play a main role in bladder cancer development

Bacillus Calmette–Guérin (BCG) for superficial bladder cancer

Larry H. Bernstein, MD, FCAP, Curator

LPBI

Intravesical therapy for bladder cancer

http://www.cancercenter.com/bladder-cancer/intravesical-therapy/

Intravesical therapy is usually an option for people with noninvasive (stage 0) or minimally invasive (stage I) bladder cancer. With intravesical therapy for bladder cancer, drugs are put directly into the bladder through a catheter, instead of being injected into a vein or swallowed. Both immunotherapy and chemotherapy drugs can be given this way.

This approach is useful for earlier stage cancers because the drugs kill malignant cells on the bladder lining only. Intravesical therapy does not reach the deeper layers of the bladder wall, the kidneys, ureters or urethra. If cancer has spread to other organs, those tumors would also not be treated with intravesical therapy.

There are a few types of intravesical immunotherapy:

Bacillus calmette-guerin (BCG) therapy: BCG is a type of intravesical immunotherapy, and can be an appropriate way to treat early-stage bladder cancer. BCG is a bacterium that does not cause any serious disease, but is related to the germ that causes tuberculosis. For bladder cancer treatment, BCG is inserted into the bladder through a catheter. The natural immune system becomes activated by the presence of the foreign bacteria, which then affects bladder cancer cells. BCG is usually given for one to six weeks, and may be given alongside transurethral resection. Less commonly, BCG is given as a long-term maintenance treatment.
Interferon: Several types of cells in the body produce substances called interferons, which help stimulate the immune system. These natural chemicals can also be made artificially for use as medications to treat various diseases. One application of synthesized interferon is as an intravesical immunotherapy treatment for early-stage bladder cancer.

Intravesical Chemotherapy

As described above, with intravesical chemotherapy, anticancer drugs that directly kill active cancer cells are inserted directly into the bladder through a catheter. This approach helps avoid many harsh side effects that occur as a result of the drugs harming normal cells.

The drugs most commonly used in intravesical chemotherapy are mitomycin and thiotepa. Other drugs used in this approach include valrubicin, doxorubucin and gemcitabine. Sometimes, mitomycin is given as “electromotive mitomycin therapy,” which means that the bladder is heated while the drug is inserted.

Complications of intravesical BCG immunotherapy

Author: Michael A O’Donnell, MD, FACS

Section Editor: Derek Raghavan, MD, PhD, FACP, FASCO

Deputy Editor: Michael E Ross, MD

INTRODUCTION

Intravesical administration of Bacillus Calmette-Guerin (BCG), a live attenuated strain of Mycobacterium bovis, has become a mainstay of adjunctive therapy for superficial bladder cancer. While generally well tolerated, both local and systemic infectious complications can arise. When disseminated BCG infection occurs, antituberculous therapy with or without glucocorticoids should be administered.

The infectious complications of BCG immunotherapy will be reviewed here. The clinical use of this agent for the treatment of superficial bladder cancer is discussed separately. Disseminated infection has also been rarely reported in patients receiving BCG vaccination for the prevention of tuberculosis [1]. (See “Treatment of non-muscle invasive bladder cancer” and “BCG vaccination”.)

PATHOGENESIS

The mechanism by which BCG leads to the development of infectious complications is not fully understood. Its mechanism of action as an immunotherapeutic agent in cancer is not fully known but recent evidence suggests that elaboration of a particular helper T cell cytokine profile known as the “Th1 response” is an integral part of its mechanism [2]. (See “Treatment of non-muscle invasive bladder cancer”, section on ‘Bacillus Calmette-Guerin’.)

Considerable debate exists in the literature about whether infectious complications due to BCG represent a hypersensitivity reaction or ongoing active infection. The hypersensitivity hypothesis gained early credence based upon the presence of granulomas and the absence of recoverable organisms. In a number of case reports, acid-fast bacilli have not been demonstrated and organisms have not grown despite a high clinical suspicion of BCG infection [3,4]. A response to glucocorticoids, administered along with antituberculous drugs, has also supported the notion of a hypersensitivity response.

In contrast, other case reports have demonstrated viable organisms in a variety of tissues, including lung [5], liver [6,7], pancreas [8], psoas abscess contents [9], mycotic aneurysm [10], bone marrow [11], vitreous fluid [12,13], and even the brain [14]. The fastidious growth nature of BCG in culture and a doubling time of 24 to 48 hours contribute to the difficulty in its isolation. M. bovis has also been demonstrated by PCR in some cases [15], although in other reports these studies have been negative [3]. Further compounding this story are several cases of delayed infection, months to even years after the original BCG administration [16,17].