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Article of the month: Better QOL with orthotopic neobladders

Every week the Editor-in-Chief selects the 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 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. Singh of orthotopic neobladder reconstruction by sigmoid colon.

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

Prospective comparison of quality-of-life outcomes between ileal conduit urinary diversion and orthotopic neobladder reconstruction after radical cystectomy: a statistical model

Vishwajeet Singh, Rahul Yadav, Rahul Janak Sinha and Dheeraj Kumar Gupta
Department of Urology, King George Medical University, Lucknow, Uttar Pradesh, India

OBJECTIVE

• To conduct a prospective comparison of quality-of-life (QoL) outcomes in patients who underwent ileal conduit (IC) urinary diversion with those who underwent orthotopic neobladder (ONB) reconstruction after radical cystectomy for invasive bladder cancers.

PATIENTS AND METHODS

• Between January 2007 and December 2012, 227 patients underwent radical cystectomy and either IC urinary diversion or ONB (sigmoid or ileal) reconstruction.

• Contraindications for ON were impaired renal function (serum creatinine >2 mg/dL), chronic inflammatory bowel disease, previous bowel resection and tumour involvement at the bladder neck/prostatic urethra. Patients who did not have these contraindications chose to undergo either IC or ONB reconstruction, after impartial counselling.

• Baseline characteristics, including demographic profile, body mass index, comorbidities, histopathology of the cystoprostatectomy (with lymph nodes) specimen, pathological tumour stage, postoperative complications, adjuvant therapy and relapse, were recorded and compared.

• The European Organization for Research and Treatment of Cancer QoL questionnaire C30 version 3 was used to analyse QoL before surgery and 6, 12 and 18 months after surgery.

RESULTS

• Of the 227 patients, 28 patients in the IC group and 35 in the ONB group were excluded. The final analysis included 80 patients in the IC and 84 in the ONB group.

• None of the baseline characteristics were significantly different between the groups, except for age, but none of the baseline QoL variables were found to be correlated with age.

• In the preoperative phase, there were no significant differences in any of the QoL domains between the IC or the ONB groups. At 6, 12 and 18 months in the postoperative period, physical functioning (P < 0.001, P < 0.001 and P = 0.001, respectively), role functioning (P = 0.01, P = 0.01 and P = 0.003, respectively), social functioning (P = 0.01, P = 0.01 and P = 0.01, respectively) and global health status/QoL (P < 0.001, P < 0.001 and P = 0.002, respectively) were better in patients in the ONB group than in those in the IC group and the differences were significant.

• The financial burden related to bladder cancer treatment was significantly lower in the ONB group than in the IC group at 6, 12 and 18 months of follow-up (P = 0.05, P = 0.05 and P = 0.005, respectively)

CONCLUSIONS

• ONB is better than IC in terms of physical functioning, role functioning, social functioning, global health status/QoL and financial expenditure.

• ONB reconstruction provides better QoL outcomes than does IC urinary diversion.

 

Video: Peri-operative blood transfusion: outcomes in patients with bladder cancer

Impact of peri-operative blood transfusion on the outcomes of patients undergoing radical cystectomy for urothelial carcinoma of the bladder

Luis A. Kluth1,3, Evanguelos Xylinas1,4, Malte Rieken1,5, Maya El Ghouayel1, Maxine Sun1, Pierre I. Karakiewicz6, Yair Lotan7, Felix K.-H. Chun3, Stephen A. Boorjian8, Richard K. Lee1, Alberto Briganti9, Morgan Rouprêt10, Margit Fisch3, Douglas S. Scherr1 and Shahrokh F. Shariat1,2,11

1Department of Urology and 2Division of Medical Oncology, Weill Cornell Medical College, New York Presbyterian Hospital, New York, NY, USA, 3Department of Urology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany, 4Department of Urology, Cochin Hospital, Assistance Publique-Hopitaux de Paris, Paris Descartes University, Paris, France, 5Department of Urology, University Hospital of Basel, Basel, Switzerland, 6Department of Urology, University of Montreal, Montreal, QC, Canada, 7Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA, 8Department of Urology, Mayo Medical School and Mayo Clinic, Rochester, MN, USA, 9Department of Urology, Vita-Salute University, Milan, Italy, 10Department of Urology of la Pitié-Salpétrière, Assistance Publique-Hôpitaux de Paris, University Paris VI, Faculté de Médicine Pierre et Marie Curie, Paris, France, and 11Department of Urology, Medical University of Vienna, Vienna, Austria

L.A.K. and E.X. contributed equally to this work

Read the full article
OBJECTIVE

• To determine the association between peri-operative blood transfusion (PBT) and oncological outcomes in a large multi-institutional cohort of patients undergoing radical cystectomy (RC) for urothelial carcinoma of the bladder (UCB).

PATIENTS AND METHODS

• We conducted a retrospective analysis of 2895 patients treated with RC for UCB.

• Univariable and multivariable Cox regression models were used to analyse the effect of PBT administration on disease recurrence, cancer-specific mortality, and any-cause mortality.

RESULTS

• Patients’ median (interquartile range [IQR]) age was 67 (60, 73) years and the median (IQR) follow-up was 36.1 (15, 84) months.

• Patients who received PBT were more likely to have advanced disease (P < 0.001), high grade tumours (P = 0.047) and nodal metastasis (P = 0.004).

• PBT was associated with a higher risk of disease recurrence (P = 0.003), cancer-specific mortality (P = 0.017), and any-cause mortality (P = 0.010) in univariable, but not multivariable, analyses (P > 0.05).

• In multivariable analyses, pathological tumour stage, pathological nodal stage, soft tissue surgical margin, lymphovascular invasion and administration of adjuvant chemotherapy were independent predictors of disease recurrence, cancer-specific mortality and any-cause mortality (all P values <0.002).

CONCLUSIONS

• Patients with UCB who underwent RC and received PBT had a greater risk of disease recurrence, cancer-specific mortality and any-cause mortality in univariable, but not multivariable, analysis.

• Although the greater need for PBT with more advanced disease is probably caused by a number of factors, including surgical and cancer-related factors, the present analysis showed that the disease characteristics rather than need for PBT led to worse outcomes.

 

Editorial: Diabetes mellitus and non-muscle-invasive bladder cancer: not just a coincidence?

Urologists are familiar with the plethora of comorbidities affecting patients with bladder cancer. Many are smoking-related, such as respiratory disease, ischaemic heart disease and peripheral vascular disease. Other conditions are associated with an ageing, increasingly obese population. Rieken et al. [1], present intriguing observations suggesting an association between diabetes mellitus (DM), its treatment and the prognosis of non-muscle-invasive bladder cancer (NMIBC). In a retrospective, multicentre cohort study of 1117 patients diagnosed with NMIBC, the authors conclude that patients taking metformin have better recurrence-free survival compared with patients with diabetes who did not take metformin. The Kaplan–Meier curves even hint at improved outcomes for patients taking metformin compared with the population without diabetes, although the difference did not reach statistical significance. Only 125 patients (out of 1117) had DM, of whom 43 were prescribed metformin. Outcome measures were recurrence and progression, with comparison of cancer-specific mortality not possible because of the low frequency of events. The study population was treated between 1996 and 2007, so re-resection was not routine, and rates of postoperative intravesical chemotherapy and adjuvant chemotherapy/immunotherapy were low. Treatment for some patients was therefore suboptimal by current standards, and there may have been differences between the multinational institutions.

The association between type 2 diabetes and the incidence of several cancer types (e.g. breast, colorectal and pancreatic) is well documented. The biological mechanisms responsible are unclear [2], and a causal relationship is debated. Postulated mechanisms include the effects of hyperinsulinaemia, hyperglycaemia and signalling pathways involving the IGF receptors. The protective effect of metformin is similarly unclear, although the authors cite studies indicating anti-proliferative properties.

A number of large cohort studies have endeavoured to show there is a higher risk of cancers in populations with diabetes. The challenge for such studies is the relatively low incident rate of bladder cancer in the population (17.1 per 100 000) [3]. Additionally, studies using general practice databases encounter problems obtaining data relating to bladder cancer characteristics. The increased detection of bladder cancer in the population with diabetes is a potential confounder, as monitoring using urine analysis is more likely.

Rieken et al. [1], in taking the opposite approach by identifying their cohorts on the basis of confirmed diagnosis of NMIBC, present accurate data regarding cancer characteristics but accept there is a potential for lack of accuracy in the recording of DM and treatment using chart review. We are not able to draw any conclusions regarding the severity of DM, its complications or compliance with prescribed medication. Future studies would be strengthened by incorporating tests such as HbA1c concentration as a marker for glycaemic control. Additionally, they do not specify the type of diabetes, although the reader can speculate that patients treated with metformin had type 2 DM. It is important to recognize that the pattern of cancer risk appears to be different for type 1 diabetes [4].

Whilst detailed discussion of the management of DM is outside the remit of a urological study, there are some important factors to be considered. Metformin is frequently recommended as a first-line agent in the management of type 2 DM [5]. It follows, therefore, that patients treated with metformin may be different from those requiring second- or third-line drugs and drug combinations; thus the cohort treated with metformin may be younger, exhibit better glycaemic control, and have improved renal function compared with those treated with other drugs and exogenous insulin. An important consideration is that rather than a protective effect being exerted by metformin, it may be that other hypoglycaemic agents have an adverse effect on NMIBC outcomes. Pioglitazone has recently been associated with an increased incidence of urothelial cancer when taken for >2 years, although effects on prognosis are not established [6]. Were the patients with diabetes not taking metformin in fact treated with hypoglycaemic agents implicated in the aetiology of bladder cancer? When considering the plausibility of biological mechanisms, the time-lag between exposure to carcinogen and the development of bladder cancer is pertinent. There is a prolonged time-lag between exposure to cigarette smoking and the development of bladder cancer, so are we ready to accept that drug exposure for a short time-scale is protective or causative? Finally, we must consider the clinical relevance of these findings. As metformin is the current first-line therapy, it may be contraindicated in those not prescribed it and conversion may not be possible.

Notwithstanding the above caveats, when treating patients with NMIBC we are often embarking on a lifelong process of treatment and surveillance. We are obliged as doctors to consider the implications of common comorbidities in order to tailor treatment. In much the same way that we now consider metabolic syndrome when evaluating erectile dysfunction, in the future we may need to consider NMIBC and DM together, and work collaboratively with other healthcare professionals to optimize the management of both conditions.

Joanne Cresswell
Department of Urology, James Cook University Hospital, Middlesbrough, UK

Read the full article

References

  1. Rieken M, Xylinas E, Kluth L et al. Association of diabetes mellitus and metformin use with oncological outcomes of patients with non-muscle-invasive bladder cancer. BJU Int 2013; 112: 1105–1112
  2. Johnson JA, Carstensen B, Witte D et al. Diabetes and cancer (1). Evaluating the temporal relationship between type 2 diabetes and cancer incidence. Diabetologica 2012; 55: 1607–1618
  3. Cancer Research UK. Bladder cancer, average number of new cases per year and age-specific incidence rates, 2006–2008. Cancer Research UK, 2012
  4. Zendehdel K, Nyren O, Ostenson CG, Adami HO, Ekbom A, Ye W. Cancer incidence in patients with type 1 diabetes mellitus: a population-based cohort study in Sweden. J Natl Cancer Inst 2003; 95: 1797–1800
  5. NICE. NICE Clinical Guideline, 66, 2008
  6. Azoulay L, Yin H, Filion K et al. The use of pioglitazone and the risk of bladder cancer in people with type 2 diabetes: nested case-control study. BMJ 2012; 344: e3645

Video: Upstage, downstage: the spotlight on FDG-PET/CT for managing bladder cancer

Impact of 18F-fluorodeoxyglucose (FDG)-positron-emission tomography/computed tomography (PET/CT) on management of patients with carcinoma invading bladder muscle

Laura S. Mertens, Annemarie Fioole-Bruining*, Erik Vegt, Wouter V. Vogel, Bas W. van Rhijn and Simon Horenblas

Departments of Urology, *Radiology and Nuclear Medicine, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands

Read the full article
OBJECTIVE

• To evaluate the clinical impact of 18F-fluorodeoxyglucose (FDG)-positron-emission tomography/computed tomography (PET/CT) scanning, compared with conventional staging with contrast-enhanced CT imaging (CECT).

PATIENTS AND METHODS

• The FDG-PET/CT results of 96 consecutive patients with bladder cancer were analysed. Patients included in this study underwent standard CECT imaging of the chest and abdomen/pelvis <4 weeks before FDG-PET/CT.

• Based on the original imaging reports and recorded tumour stage before and after FDG-PET/CT imaging, the preferred treatment strategies before FDG-PET/CT and after FDG-PET/CT were determined for each patient using an institutional multidisciplinary guideline. One of the following treatment strategies was chosen: (i) local curative treatment; (ii) neoadjuvant/induction chemotherapy; or (iii) palliation.

• The changes in management decisions before and after FDG-PET/CT were assessed.

RESULTS

• The median (range) interval between CECT and FDG-PET/CT was 0 (029) days.

• In 21.9% of the patients, stage on FDG-PET/CT and CECT were different. Upstaging by FDG-PET/CT was more frequent than downstaging (19.8 vs 2.1%).

• Clinical management changed for 13.5% of patients as a result of FDG-PET/CT upstaging. In eight patients, FDG-PET/CT detected second primary tumours. This led to changes of bladder cancer treatment in another four of 96 patients (4.2%).

• All the management changes were validated by tissue confirmation of the additional lesions.

CONCLUSIONS

• FDG-PET/CT provides important additional staging information, which influences the treatment of carcinoma invading bladder muscle in almost 20% of cases.

• Patient selection for neoadjuvant/induction chemotherapy was improved and futile attempts at curative treatment in patients found to have metastases were avoided.

Bladder Cancer: a stagnant foe?

This month’s topic for the Twitter-based International Urology Journal Club #urojc was bladder cancer, with a paper titled Unaltered oncological outcomes of radical cystectomy with extended lymphadenectomy over three decades’ by Zehnder et al, published online in July 2013. Open access to the paper was kindly provided by the BJUI.

 Zehnder and colleagues undertook a retrospective analysis of the University of Southern California cohort and identified 1488 patients with muscle invasive bladder cancer who underwent radical cystectomy and extended pelvic lymph node dissection between 1998 and 2005. They also included 190 patients from the University of Bern cohort to determine outcomes in patients with clinical N0 disease who were upstaged on pathology to node positive disease. Analysis, performed based on decade of intervention, showed no significant difference in overall survival (OS) or recurrence free survival (RFS) over the three decades. 10-year RFS was 78-80% for organ confined, lymph node negative, 53-60% in locally advanced, LN –ve and 30% in LN positive patients.

 

 

Firstly, it has certainly been suggested that the overall survival and cancer free survival outcomes are not as good in broader population based studies (Ontario Cancer Registry). Why?

 

 

 

 

Analysis of the SEER database has shown that cancer specific survival and overall mortality has not improved for any clinical stage of bladder cancer and in fact suggests that the incidence is increasing in the United States.

 

 

And of course, we must always look at the study design and determine whether the outcomes are reflective of the patient populations that we see in practice.

 


 

The roles of neo- and adjuvant chemotherapy were discussed at length. Only 6% of patients received neoadjuvant chemotherapy, with worse OS and RFS in multivariate analysis. The use of adjuvant chemotherapy actually almost doubled from the 80’s to 90’s, stable in the 00’s at 29%.

 

  

 

 

 

 

 

If neoadjuvant chemotherapy is so widely recommended, why has its use failed to take off?

 

 

 

 

 

 

 

Jim Catto suggested an excellent clinical pathway for the implementation of neoadjuvant chemotherapy.

If indeed bladder cancer is the poor cousin of prostate cancer, why has progress stagnated and what can we change?

 

 

 

 

 

 

 

 

 

 

So what are my humble take home messages from the discussion surrounding this month’s #urojc paper?

  1. Current data suggests that we have made no significant progress in bladder cancer outcomes over the past 30 years
  2. Early referral and diagnosis coupled with timely intervention key; be wary of progression in context of high grade NMIBC
  3. Both surgeon volume and hospital volume are thought to be independent predictors of overall survival. Patie nts do best at a high volume facility under the care of a high-volume Uro-oncologist in a multidisciplinary context
  4. Neoadjuvant chemotherapy, despite randomized controlled trial evidence in favour of its use, has poor uptake in a real world setting. Advances in dense dose regimens (MVAC and Phase III GC underway) with resultant improvement in progression free survival, lower toxicity profile and fewer dose delays make for an attractive partner to radical cystectomy and extended pelvic lymph node dissection.

To finish with the words of the self-proclaimed Urology King of Twitter, Dr Ben Davies:

 

 

 

Winner of the best tweet prize for July’s #urojc was Mike Leveridge from Queens University, Canada – he was certainly a little frustrated with the apparent lack of progress we have made. The July #urojc Best Tweet Prize was kindly supported by the Nature Journal “Prostate Cancer Prostatic Diseases” which is edited by Dr Stephen Freedland and will be a complimentary 12 month online access to the journal.

 

 

 

 

 

 

Do join us for the August #urojc which commences on Sunday 4th/Monday 5th depending on your time zone.

Dr Helen Nicholson is an Australian Urology Trainee, currently based at The Sydney Adventist Hospital, NSW. Tweeted initially under duress, now a voluntary convert @DrHLN

 

Comments on this blog are now closed.

 

 

Article of the Week: Better fit than fat when it comes to radical cystectomy for bladder cancer

Every week the Editor-in-Chief selects the 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 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.

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

Obesity is associated with worse oncological outcomes in patients treated with radical cystectomy

Thomas F. Chromecki1,2*, Eugene K. Cha1*, Harun Fajkovic1,3, Michael Rink1,4, Behfar Ehdaie1, Robert S. Svatek5, Pierre I. Karakiewicz6, Yair Lotan7, Derya Tilki8, Patrick J. Bastian8, Siamak Daneshmand9,Wassim Kassouf10, Matthieu Durand1, Giacomo Novara11, Hans-Martin Fritsche12, Maximilian Burger12, Jonathan I. Izawa13, Antonin Brisuda14, Marek Babjuk14, Karl Pummer2 and Shahrokh F. Shariat1

1Weill Medical College of Cornell University, New York, NY, USA, 2Medical University Graz, Graz, Austria, 3Landeskrankenhaus St Poelten, St Poelten, Austria, 4University Medical Centre Hamburg-Eppendorf, Hamburg, Germany, 5University of Texas Health Science Center San Antonio, San Antonio, TX, USA, 6University of Montréal, Montréal, QC, Canada, 7University of Texas Southwestern Medical Center, Dallas, TX, USA, 8Ludwig-Maximilians-University Munich, Klinikum Grosshadern, Munich, Germany, 9University of Southern California Keck School of Medicine and Norris Comprehensive Cancer Center, Los Angeles, CA, USA, 10McGill University Health Centre, Montréal, QC, Canada, 11University of Padua, Padua, Italy, 12Caritas St Josef Medical Centre, University of Regensburg, Regensburg, Germany, 13University of Western Ontario, London, ON, Canada, and 14Hospital Motol, 2nd Faculty of Medicine, Charles University, Praha, Czech Republic
*These authors contributed equally.

Read the full article
OBJECTIVE

• To investigate the association between body mass index (BMI) and oncological outcomes in patients after radical cystectomy (RC) for urothelial carcinoma of the bladder (UCB) in a large multi-institutional series.

PATIENTS AND METHODS

• Data were collected from 4118 patients treated with RC and pelvic lymphadenectomy for UCB. Patients receiving preoperative chemotherapy or radiotherapy were excluded.

• Univariable and multivariable models tested the effect of BMI on disease recurrence, cancer-specific mortality and overall mortality.

• BMI was analysed as a continuous and categorical variable (<25 vs 25–29 vs 30 kg/m2).

RESULTS

• Median BMI was 28.8 kg/m2 (interquartile range 7.9); 25.3% had a BMI <25 kg/m2, 32.5% had a BMI between 25 and 29.9 kg/m2, and 42.2% had a BMI 30 kg/m2.

• Patients with a higher BMI were older (P < 0.001), had higher tumour grade (P < 0.001), and were more likely to have positive soft tissue surgical margins (P = 0.006) compared with patients with lower BMI.

• In multivariable analyses that adjusted for the effects of standard clinicopathological features, BMI >30 was associated with higher risk of disease recurrence (hazard ratio (HR) 1.67, 95% confidence interval (CI) 1.46–1.91, P < 0.001), cancer-specific mortality (HR 1.43, 95% CI 1.24–1.66, P < 0.001), and overall mortality (HR 1.81, CI 1.60–2.05, P < 0.001). The main limitation is the retrospective design of the study.

CONCLUSIONS

• Obesity is associated with worse cancer-specific outcomes in patients treated with RC for UCB.

• Focusing on patient-modifiable factors such as BMI may have significant individual and public health implications in patients with invasive UCB.

 

Read Previous Articles of the Week

Autologous cytotoxic T lymphocyte therapy was effective for M-VAC-refractory invasive bladder cancer

In the present study, we performed CTL therapy in a patient with metastatic bladder cancer, who had relapsed after M-VAC therapy.

 

Authors: Kogenta Nakamura MD, PhD1; Kazuhiro Yoshikawa PhD2; Yoshiaki Yamada MD, PhD1; Makoto Sumitomo MD, PhD1

1 Department of Urology, Aichi Medical University School of Medicine
2 Cell Therapy Center, Aichi Medical University Hospital

 
Corresponding Author: Kogenta Nakamura, MD, PhD, Department of Urology, Aichi Medical University School of Medicine. Nagakute-cho, Aichi 480-1195, Japan. Tel: +81-561-62-3311   E-mail address: [email protected]

 

Abstract
A report on the efficacy of CTL therapy for urogenital cancer already exists in the literature.1 In the present study, we performed CTL therapy in a patient with metastatic bladder cancer, who had relapsed after M-VAC therapy.

 

Introduction
Standard chemotherapy for invasive bladder cancer with metastases includes M-VAC (methotrexate, vinblastine, doxorubicin, and cisplatin) and GC (gemcitabine and cisplatin).2 Many chemotherapeutic regimens have been used as second-line treatment, but no regimen surpasses M-VAC and GC.  There are high expectations for taxanes and other similar drugs, and the results of a large-scale, randomized trial are awaited.
Autologous cytotoxic T lymphocyte (CTL) therapy using autologous tumor tissue is a technique in which autologous lymphocytes collected from the peripheral blood and an autologous tumor irradiated with γ-rays are cultured in vitro in the presence of interleukin-2 (IL-2), and anti-CD3 for induction and proliferation of killer cells that are expected to be specific to the tumor, and then the killer cells are aseptically returned to the body.  For this therapy, it is essential that MHC-class I antigen is expressed on tumor cells.

 

Case report
We performed total cystectomy with periaortic and pelvic lymphadenectomy, and bilateral cutaneous ureterostomy in a 61 year old Japanese male patient with a diagnosis of T4N2M0 bladder cancer made 6 years previously.  We chose  to perform urinary diversion to cutaneous ureterostomy instead of ileal conduit, to avoid intestinal complications and also because we wished to start systemic chemotherapy as soon as possible. Pathological examination revealed urothelial carcinoma, grade G3, pT4. The right external iliac lymph nodes, bilateral obturator lymph nodes and aortocaval lymph nodes were positive.  Since the patient subsequently developed enlarged mediastinal, supraclavicular and para-aortic lymph nodes (Figure 1a), three courses of M-VAC therapy were performed in combination with mild hyperthermia, which is known to lead to fewer adverse reactions.3  The efficacy of the chemotherapy was evaluated using the Response Evaluation Criteria In Solid Tumor classification.  CT scan, after completion of three courses of M-VAC therapy, revealed that the mediastinal lymph nodes and the right supraclavicular lymph nodes had disappeared and the para-aortic lymph nodes were reduced in size.  Since CT scan subsequently showed enlarged para-aortic lymph nodes, two further courses of M-VAC therapy were performed.  However, the para-aortic lymph nodes remained unchanged (Figure 1b).
After approval was obtained from the institutional review board of our hospital (# 152), four courses of CTL therapy in combination with IFN-γ and IL-2 administration were initiated (at intervals of two weeks) after surgery.  Two days before administration, 200 mg/body of Endoxan was administered by intravenous infusion.  An average of 22.6  108 cells were administered.  During each course, blood was collected on the day after administration to examine whether the CD8 level had increased or not.  After completion of four courses of treatment, a CT scan was performed and revealed a partial response (PR) of the para-aortic lymph nodes (Figure 1 c).

 

Figure 1 (a) Computed tomography showing enlargement of para-aortic lymph nodes before M-VAC therapy.

 

(B) Computed tomography showing para-aortic lymph nodes remaining unchanged after M-VAC therapy.

 

(C) Computed tomography showing reduced para-aortic lymph node size after CTL therapy.  The lymph node size deceased from 15 to 8 mm.

 


 
At present, 71 months after completion of CTL therapy, the patient has had recurrence and has maintained his PR status.

 

Conclusion
Autologous CTL therapy did not cause any adverse reactions in our patient.  It is suggested that this therapy can be performed safely and should also be considered for cases of progressive bladder cancer with metastasis.

 

References
 
1 Kawai K, Saijo K, Oikawa T et al : Clinical course and immune response of a renal cell carcinoma patient to adoptive transfer of autologous cytotoxic T lymphocytes. Clin Exp Immunol 2003; 134: 264-269.
2 von der Maase H, Sengelov L, Roberts JT et al : Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J Clin Oncol 2005; 23: 4602-4608.
3 Yamada Y, Itoh Y, Aoki S et al. Preliminary results of M-VAC chemotherapy combined with mild hyperthermia, a new therapeutic strategy for advanced or metastatic transitional cell carcinoma of the urothelium. Cancer Chemother Pharmacol 2009; 64: 1079-1083.

 

Date added to bjui.org: 02/02/2012

DOI: 10.1002/BJUIw-2011-059-web
 

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

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

 

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