Bacillus Calmette-Guerin

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Article of the week: Update on the guideline of guidelines: non‐muscle‐invasive bladder cancer

February 19, 2020/by Gary D. Steinberg

Every week, the Editor-in-Chief selects an Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to this post, there is also a video produced by the authors. Please use the comment buttons below to join the conversation.

If you only have time to read one article this week, we recommend this one.

Update on the guideline of guidelines: non‐muscle‐invasive bladder cancer

Jacob Taylor , Ezequiel Becher and Gary D. Steinberg

Department of Urology, NYU Langone Health, New York, NY, USA

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Abstract

Non‐muscle‐invasive bladder cancer (NMIBC) is the most common form of bladder cancer, with frequent recurrences and risk of progression. Risk‐stratified treatment and surveillance protocols are often used to guide management. In 2017, BJUI reviewed guidelines on NMIBC from four major organizations: the American Urological Association/Society of Urological Oncology, the European Association of Urology, the National Comprehensive Cancer Network, and the National Institute for Health and Care Excellence. The present update will review major changes in the guidelines and broadly summarize new recommendations for treatment of NMIBC in an era of bacillus Calmette‐Guérin shortage and immense novel therapy development.

Video: Update on the guideline of guidelines: non‐muscle‐invasive bladder cancer

February 19, 2020/by Jacob Taylor

Update on the guideline of guidelines: non‐muscle‐invasive bladder cancer

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Abstract

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Article of the Month: Effect of the Interval Between First and Second TUR on Outcomes in NMIBC

November 4, 2015/by admin Z.9

Every Month the Editor-in-Chief selects the Article of the Month from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an accompanying editorial written by a prominent member of the urological community. This blog is intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation.

Finally, the third post under the Article of the Week heading on the homepage will consist of additional material or media. This week we feature a video from Dr. Ilker Gökce, discussing his paper.

If you only have time to read one article this week, it should be this one.

Significance of time interval between first and second transurethral resection on recurrence and progression rates in patients with high risk non muscle invasive bladder cancer treated with maintenance intravesical Bacillus Calmette-Guerin

Sumer Baltacı, Murat Bozlu*, Asıf Yıldırım†, Mehmet Ilker Gokce, İlker Tinay‡, Guven Aslan§, Cavit Can¶, Levent Turkeri‡,Ugur Kuyumcuoglu** and Aydın Mungan††

Department of Urology, Ankara University School of Medicine, Ankara , *Department of Urology, University of Mersin School of Medicine, Mersin,†Department of Urology, Istanbul Medeniyet University School of Medicine, ‡Department of Urology, Marmara University School of Medicine, Istanbul, §Department of Urology, Dokuz Eylul University School of Medicine Inciralti, Izmir, ¶Department of Urology, Medical Faculty, Eskisehir Osmangazi University, Eskisehir, **Department of Urology, Trakya University School of Medicine, Edirne, and ††Department of Urology, Bulent Ecevit University School of Medicine, Zonguldak, Turkey

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OBJECTIVES

To evaluate the effect of the interval between the initial and second transurethral resection (TUR) on the outcome of patients with high-risk non-muscle-invasive bladder cancer (NMIBC) treated with maintenance intravesical Bacillus Calmette-Guérin (BCG) therapy.

PATIENTS AND METHODS

We reviewed the data of patients from 10 centres treated for high-risk NMIBC between 2005 and 2012. Patients without a diagnosis of muscle-invasive cancer on second TUR performed ≤90 days after a complete first TUR, and received at least 1 year of maintenance BCG were included in this study. The interval between first and second TUR in addition to other parameters were recorded. Multivariate logistic regression analysis was used to identify predictors of recurrence and progression.

RESULTS

In all, 242 patients were included. The mean (sd, range) follow-up was 29.4 (22.2, 12–96) months. The 3-year recurrence- and progression-free survival rates of patients who underwent second TUR between 14 and 42 days and 43–90 days were 73.6% vs 46.2% (P < 0.001) and 89.1% vs 79.1% (P = 0.006), respectively. On multivariate analysis, the interval to second TUR was found to be a predictor of both recurrence [odds ratio (OR) 3.598, 95% confidence interval (CI) 1.885–8.137; P = 0.001] and progression (OR 2.144, 95% CI 1.447–5.137; P = 0.003).

CONCLUSIONS

The interval between first and second TUR should be ≤42 days in order to attain lower recurrence and progression rates. To our knowledge, this is the first study demonstrating the effect of the interval between first and second TUR on patient outcomes.

Editorial: Is 42 days the ‘magic number’ for repeat TURBT?

November 4, 2015/by Eila Skinner

Gökçe et al. [1] have evaluated a group of 242 patients from 10 centres with high-risk non-muscle-invasive bladder cancer (NMIBC) who underwent repeat resection and subsequent follow-up treatment, including induction and maintenance BCG for at least 1 year. They included patients who had repeat transurethral resection (TUR) within 90 days and excluded anyone who was upstaged to T2 or who did not complete 1 year of maintenance BCG. They divided patients into two groups according to time to second TUR, Group A (14–42 days) and Group B (43–90 days). The groups were similar in terms of patient age and gender, tumour multifocality, presence of carcinoma in situ (CIS), and stage and grade. The only factors on multivariable analysis that were statistically significant predictors of recurrence were grade, associated CIS, and time to second TUR. Only grade and time to second TUR were significant predictors of progression.

Figures 1 and 2 in the paper show an enormous difference in both recurrence-free survival and progression-free survival according to time to second TUR. For both outcomes, 42 days seemed to be the ‘magic number’, since re-TUR after 42 days was associated with much worse outcome. Patients who had repeat TUR at >42 days had nearly double the rate of both recurrence and progression than those who had repeat TUR within 6 weeks.

This is quite a dramatic result, and it is hard to imagine biologically how such an effect could be explained. Second TUR has two primary objectives, to identify occult muscle-invasive disease, and to remove tumour that was inadvertently left behind at the first resection. Both of these goals have been shown to be important and to result in better outcomes compared with no repeat TUR [2]. However, in this study [1], patients who had repeat TUR at >6 weeks after the initial resection had a progression rate similar to those in prior studies who had no second TUR at all [2]. What could be occurring that would cause a delay of just a few weeks in second TUR to double the risk of subsequent progression of disease?

This is a retrospective study without centralised pathology review, and no information is available about the reasons that patients had repeat TUR at an earlier or later interval, nor about the pathological findings at the repeat TUR. One must be wary that there is significant selection bias involved. There is a hint of this in the fact that the rate of residual tumour at repeat TUR in the two groups is very different (35% vs 53%). Perhaps the later group also had a higher rate of residual invasive components on the repeat resection? Herr et al. [3] have shown that residual T1 disease on repeat TUR is highly predictive of subsequent progression. Or alternatively, perhaps it is the delay in administration of BCG that really results in the worse outcome? Patients with a longer delay to repeat TUR by definition also have at least an equivalent delay in starting BCG.

Although high-risk NMIBC can certainly be aggressive, it seems highly unlikely that a week or two-one way or another in terms of treatment would make such a huge difference in the outcome. However, this is a provocative study that remains to be validated. It will be useful to see if other groups with similar patient populations can duplicate these findings. For the time being, as a routine practice it makes sense to repeat the TUR sooner rather than later whenever possible.

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Eila C. Skinner

Thomas A. Stamey Research Professor of Urology, Chair, Department of Urology, Stanford University, Stanford, CA, USA

References

1 Gokce MI, Baltaci S, Bozlu M et al. Signiﬁcance of the interval between ﬁrst and second transurethral resection on recurrence and progression rates in patients with high-risk non-muscle-invasive bladder cancer treated with maintenance intravesical Bacillus Calmette-Guerin. BJU Int 2015; 116: 721–6

2 Divrik RT, Sahin AF, Yildirim U, Altok M, Zorlu F. Impact of routine second transurethral resection on the long-term outcome of patients with newly diagnosed pT1 urothelial carcinoma with respect to recurrence, progression rate, and disease-speciﬁc survival: a prospective randomized clinical trial. Eur Urol 2010; 58: 185–90

3 Herr HW, Donat SM, Dalbagni G. Can restaging transurethral resection of T1 bladder cancer select patients for immediate cystectomy? J Urol 2007; 177: 75

Video: Significance of time interval between first and second TUR on recurrence and progression rates in BCG-treated NMIBC

November 4, 2015/by admin Z.9

Significance of time interval between first and second transurethral resection on recurrence and progression rates in patients with high risk non muscle invasive bladder cancer treated with maintenance intravesical Bacillus Calmette-Guerin

Sumer Baltacı, Murat Bozlu*, Asıf Yıldırım†, Mehmet Ilker Gokce, İlker Tinay‡, Guven Aslan§, Cavit Can¶, Levent Turkeri‡,Ugur Kuyumcuoglu** and Aydın Mungan††

Read the full article

OBJECTIVES

PATIENTS AND METHODS

RESULTS

CONCLUSIONS

Granulomatous Cholangitis as a Complication of Intravesical BCG Administration for Bladder Cancer

October 26, 2011/by admin Z.9

We describe a patient who presented with findings suggestive of acute cholecystitis and cholangitis.

Authors: Hani M. Babiker, MD¹, Robyn E. Stiefeld¹, MD, and Holenarasipur R. Vikram², MD

1Department of Hospital Internal Medicine, and

2 Division of Infectious Diseases, Mayo Clinic, Phoenix, Arizona

Corresponding Author: Holenarasipur R. Vikram, MD, Division of Infectious Diseases, 5777 E. Mayo Blvd., Phoenix, AZ 85054. Phone: (480) 342-0115 E-mail: [email protected]

Abstract

Intravesical instillation of Bacillus Calmette-Guerin (BCG) remains a first-line treatment for superficial transitional cell carcinoma of the bladder. Although uncommon, clinicians should be aware of major adverse effects and complications resulting from intravesical BCG therapy in order to promptly arrive at the diagnosis and initiate therapeutic measures.

Herein, we describe a patient who presented with findings suggestive of acute cholecystitis and cholangitis. He was started on antibiotics and underwent Endoscopic Retrograde Cholangiopancreatography (ERCP) with sphincterectomy and stent placement. However, his liver function tests remained abnormal. Further inquiry delineated a history of bladder cancer treated with intravesical BCG instillation. A liver biopsy obtained during laparoscopic cholecystectomy confirmed granulomatous cholangitis. The patient received anti-tuberculous therapy and a tapering course of corticosteroids with a successful outcome.

Introduction

Bacillus Calmette-Guerin (BCG) is a live attenuated vaccine containing Mycobacterium bovis that is administered in many countries to prevent childhood tuberculous meningitis and military tuberculosis. BCG is not utilized in the United States because of the low risk of infection with M. tuberculosis and questionable efficacy. Intravesical BCG administration has been found to be very effective in the treatment in superficial bladder cancer. However, treatment with BCG can be associated with local or systemic complications. Herein, we present a case of granulomatous cholangitis and hepatitis following intravesical BCG therapy. Timely diagnosis and prompt initiation of therapy is essential for ensuring a favorable outcome.

List of Abbreviations

ALT Alanine Aminotransferase

ALK Alkaline Phosphatase

AST Aspartate Aminotransferase

BCG Bacillus Calmette-Guerin

ERCP Endoscopic Retrograde Cholangiopancreatography

LFTs Liver Function Tests

Tbili Total Bilirubin

Dbili Direct Bilirubin

Case Report

A 65 year-old-male with an underlying history of coronary artery disease, hypertension, obstructive airway disease, and bladder cancer presented to our Emergency Department with abdominal discomfort. Computed tomography (CT) of the abdomen was within normal limits. He was discharged once his symptoms abated.

Two weeks later, he presented with fever, jaundice, hypotension, abdominal pain, and jaundice. Abdominal examination revealed normal bowel sounds and mild right upper quadrant tenderness. There was no hepatosplenomegaly, guarding, rebound tenderness, or rigidity. His labs revealed a white blood cell count of 7.8 x 109/L, aspartate aminotransferase (AST) of 278 U/L, alanine aminotransferase (ALT) 305 U/L, alkaline phosphatase (ALK) 227 U/L, total bilirubin (Tbili) of 6.3 mg/dl, direct bilirubin (Dbili) of 3.6 mg/dl, lipase of 30 U/L, and ammonia of 36 mcg/dl. His Hepatitis A, B, and C serologies were negative. Abdominal ultrasound revealed gallbladder wall thickening, biliary sludge, and a normal calibre common bile duct.

He was fluid resuscitated and commenced on ciprofloxacin and metronidazole for a tentative diagnosis of cholangitis and cholecystitis. The next day, his Tbili increased to 7.3 mg/dl and his liver enzymes remained elevated. Repeat abdominal CT scan revealed mild thickening of the gallbladder wall, cholelithiasis, and heterogenous enhancement of the liver parenchyma. ERCP was performed with removal of biliary sludge, stent placement, and sphincterectomy. However, the next day, his Tbili and Dbili increased to 10.2 mg/dl and 8.5 mg/dl, respectively; liver enzymes remained abnormal. An intrahepatic process versus biliary stent stenosis was considered, and repeat ERCP and cholangiogram were planned along with cholecystectomy. Prior to surgery, his liver function remained abnormal with a TBili of 16.1 mg/dl, DBili 12.8 mg/dl, ALK 507 U/L, AST 135 U/L, and ALT 159 U/L. Further inquiry into his past medical history revealed that he had received a total of three courses of intravesical BCG for superficial bladder cancer within the past 7 months (the last administration was 2 months prior to his current hospitalisation).

A liver biopsy performed at the time of cholecystectomy revealed portal infiltration with non-caseating granulomas centered around the bile ducts. There was focal bile duct proliferation with neutrophilic infiltration consistent with bile duct outflow impairment. Histology of the gall bladder showed acute inflammation with Gram-negative and Gram-positive cocci; granulomas were not evident.

Figure 1. Liver Histopathology

Liver histology demonstrates a granuloma centered around a bile duct ( arrow) and a hepatocyte (arrowhead). Concurrent neutrophilic and eosionphilic infiltration, and bile ductular proliferation resulted in biliary obstruction. Mild fibrosis and marked cholestasis in the surrounding liver was also noted. (Hematoxylin-eosin; ~x400.)

Bacterial, fungal, and mycobacterial smears and cultures were all negative from the liver biopsy specimen. A diagnosis of Mycobacterium bovis granulomatous cholangitis secondary to intravesical BCG administration was entertained. He was commenced on a regimen of isoniazid, rifampin, ethambutol, and vitamin B6 for six months and a 3-week tapering course of corticosteroids. His bilirubin and liver enzymes pursued a downward trend. Isoniazid was discontinued after the first month for transient liver enzyme elevation. His liver enzymes and bilirubin completely normalized within 2 months, and he remained asymptomatic. He completed a 6-month course of rifampin and ethambutol; LFTs remained normal at follow-up 2 months after discontinuing antituberculous medications.

Discussion

Bacillus Calmette-Guerin (BCG) vaccine was introduced in 1910 for protection against tuberculosis (TB). It is a live, attenuated vaccine containing M. bovis. It is utilized in many countries with a high prevalence of TB to prevent childhood tuberculous meningitis and military TB. BCG is not recommended in the United States because of the low risk of infection with M. tuberculosis, its variable and questionable efficacy against adult pulmonary TB, and its interference with tuberculin skin test reactivity. In 1976 Morales and colleagues described a novel utility for BCG – anticancer immunotherapy by intravesical instillation for superficial bladder cancer. Several studies have subsequently demonstrated its efficacy in treating superficial bladder cancer.  This is now the adjuvant treatment of choice for high grade and recurrent superficial bladder cancer.   Its mechanism of action is incompletely understood; it triggers a local cellular immune response with induction of cytokines that have antiangiogenic activity.

Complications of intravesical BCG treatment can be either local (cystitis) or disseminated, with an early or late presentation. Early manifestations occurs 8 to 12 weeks after BCG instillation, while late manifestations can occur more than a year after BCG therapy.8 Cystitis following BCG administration presents with dysuria, urinary frequency, low-grade fever, and malaise. These symptoms occur in 70% of patients approximately 2 to 4 hours after BCG instillation and resolve within 48 hours. Symptomatic therapy is successful in most instances. For persistent or severe symptoms that last beyond 48 hours, isoniazid should be administered. Rarely, a sepsis-like syndrome can occur soon after BCG instillation; patients develop fever, hypotension, and respiratory failure. This is thought to represent a hypersensitivity reaction to BCG as opposed to true dissemination.9 Other local complications (<1% each) include hematuria, epididymitis, prostatitis, and ureteral obstruction. Disseminated infection (‘BCGosis’) may result in granulomatous hepatitis, pneumonitis, osteomyelitis, endophthalmitis and prostatitis and other organ involvement.2,5,9 These complications can occur weeks to months after BCG administration in approximately 1% of patients. The most serious complication following BCG therapy is sepsis with hypotension and multiorgan failure in 0.4% of cases and carries a high mortality.5 Other published complications of intravesical BCG therapy include testicular masses, peritonitis, psoas abscess, tuberculous spondylitis, chest wall mass, acute renal failure, rhabdomyolysis, pancytopenia secondary to bone marrow infiltration and ruptured mycotic abdominal aortic aneurysm. 10 In a large study involving 2602 patients who received intravesical BCG, granulomatous hepatitis occurred in 0.7% of patients.9

BCGosis is diagnosed by growth of M. bovis from tissue specimens, or by DNA hybridization. 11 However disseminated M. bovis infection is often paucibacillary, and it is difficult to isolate the pathogen in vitro. Many of the systemic manifestations of BCGosis can be attributed to a hypersensitivity reaction to mycobacterial antigens. Thus, a tentative diagnosis is often made based on the temporal relationship to intravesical BCG administration, clinical manifestations, histopathologic findings, and response to empiric antituberculous therapy. M. bovis is susceptible to first-line anti-tuberculous agents (except pyrazinamide). A 6 to 12 month course of therapy with isoniazid, rifampin, and ethambutol along with vitamin B6 supplementation has been widely utilised in published reports with an excellent response. A tapering dose of corticosteroids is usually included to combat the associated hypersensitivity reaction to mycobacterial antigens.2

Conclusion

We report a case of bacterial cholecystitis wherein liver enzyme and bilirubin levels remained abnormal despite cholecystectomy and antibiotic therapy. Concurrent liver biopsy demonstrated granulomatous cholangitis. LFT abnormalities completely resolved following a tapering course of prednisone and 6 months of antituberculous therapy aimed at M. bovis. This case highlights the importance of considering BCG-induced granulomatous hepatitis and cholangitis as a possible etiology in patients with LFT abnormalities following intravesical BCG administration. To the best of our knowledge, this is the first reported case of BCG-induced granulomatous cholangitis. Awareness of this entity, collection of tissue specimens for histopathologic and microbiologic examination, and prompt initiation of appropriate therapy led to a favorable outcome in our patient.

References

1. Morales A, Eidinger D, Bruce AW. Intracavitary bacillus Calmette-Guerin in the treatment of superficial bladder tumors. J Urol. 1976 Aug: 116:180-183

2. Lamm DL. Complications of bacillus Calmette-Guerin immunotherapy. Urol Clin North Am. 1992 Aug: 19:565-72.

3. Witjes JA, vd Meijden AP, Debruyne FM. Use of intravesical Bacillus Calmette-Guerin in the treatment of superficial transitional cell carcinoma of the bladder: an overview. Urol Int. 1990: 45(3):129-136.

4. Kamat AM, Lamm DL. Immunotherapy for bladder cancer. Curr Urol Rep 2001 Feb: 2(1):62-9.

5. Lamm DL. Efficacy and safety of bacillus Calmette-Guerin immunotherapy in superficial bladder cancer. Clin Infect Dis. 2000 Sep: 31(suppl 3):S86-90.

6. Shelley MD, Wilt TJ, Court J, Coles B, Kynaston H, Madson MD. Intravesical bacillus Calmette-Guerin is superior to mitomycin C in reducing tumor recurrence in high-risk superficial bladder cancer: a meta-analysis of randomized trials. BJU Int. 2004 Mar :93(4):485-90.

7. Bohle A. BCG’s mechanism of action–increasing our understanding. Eur Urol. 2000 :37:Suppl 1:1-8.

8. Gonzales OY, Musher DM, Brar I, et al. Spectrum of Bacille Calmette-Guerin (BCG) Infection after Intravesical BCG Immunotherapy. Clin Infect Dis. 2003 Jan: 36(2):140-8.

9. Lamm DL, van der Meijden PM, Morales A, et al. Incidence and treatment of complications of bacillus Calmette-Guerin intravesical therapy in superficial bladder cancer. J Urol. 1992 Mar:147(3):596-600.

10. Safdar N, Abad CL, KauL DR, Jarrard D, Saint S. Clinical problem-solving. An unintended consequence–a 79-year-old man with a 5-month history of fatigue and 20-lb (9-kg) weight loss presented to his local physician. N Engl J Med. 2008 Apr: 358(14):1496-1501.

11. Leebeek FW, Ouwendijk RJ, Kolk AH, et al. Granulomatous hepatitis caused by Bacillus Calmette-Guerin (BCG) infection after BCG bladder instillation. Gut. 1996 Apr: 38(4):616-618.

Date added to bjui.org: 26/10/2011

DOI: 10.1002/BJUIw-2011-093-web