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Initial experience of intravesical gemcitabine for patients with high-risk superficial transitional cell carcinoma of the bladder following BCG failure.

This study reports the use of intravesical gemcitabine in managing patients with high-risk bladder cancer, refractory to Bacillus Calmette-Guerin (BCG). Patients were given gemcitibine; treatment response was evaluated by fluorescence-cystoscopy, biopsy, and urine cytology. Time to reoccurrence increased with instillation time.

Key Words: Gemcitabine; bladder, carcinoma, bacillus calmette-guerin BCG) failure.

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Worldwide, bladder cancer is the sixth most common cancer, with an estimated 382,660 new cases diagnosed in 2008 (Ferlay et al., 2010). In 2010, there were 10,335 new bladder cancers diagnosed in the United Kingdom (UK), ranking bladder cancer as the fourth most common cancer in males (7,390 cases) and the 11th most common cancer for females (2,945 cases) (Office for National Statistics, 2012).

Approximately 80% to 90% are superficial bladder cancer (SBC) (Ta, T1, or carcinoma in situ [CIS]) (Cancer Research UK, 2013). Low-grade (Grade 1) superficial bladder cancer can be cured by resection or intravesical mitomycin (Gudjonsson et al., 2009; Sylvester, Oosterlinck, & van der Meijden, 2004). Moderate or high-grade SBC (Grades 2, 3, or CIS) will progress to invasive cancer in up to 50% of cases. There is evidence that moderate or high-grade SBC is best treated with resection and intravesical Bacillus Calmette-Guerin (BCG) treatment (Cancer Research UK, 2013; Duchek et al., 2010; Gan, Mostafid, Khan, & Lewis, 2013).

Intravesical BCG reduces the risk of recurrence and delays disease progression for intermediate and high-grade superficial transitional cell carcinoma (TCC) and CIS (Gan et al., 2013; Huncharek & Kupelnick, 2003; Konety & Williams, 2004). However, ap proximately 30% of patients who have been treated with intravesical BCG will progress to muscleinvasive disease (Burger et ah, 2012; Gan et ah, 2013; van Rhijn et al., 2009). Moreover, patients for whom BCG is not effective in preventing recurrence typically have a poor prognosis.

The gold-standard treatment for patients with recurrent, high-risk SBC following intravesical BCG is radical cystectomy (Babjuk et al., 2013; van Rhijn et ah, 2009). However, for many patients, factors such as co-morbidity and reduced life expectancy mean such a treatment is clinically inappropriate. Some patients who are fit for cystectomy do not want major surgery and its consequent morbidity. It is, therefore, necessary and desirable to develop new chemotherapeutic agents as effective alternatives to surgery. This need has most recently led the bladder cancer community to investigate the role of intravesical over intravenous gemcitabine as an agent for bladder preservation.

Gemcitabine, 2', 2'-difluorodeoxycytidine, is an analogue of deoxycytidine, a nuclesoside compound, which has antitumor activity against several solid tumors (Priami, 2009; Veltkamp et al., 2008). It is a pro-drug analogue of cytidine that when transported into cells, is phosphorylated by deoxycytidine kinase to its active diphosphate and triphosphate forms--dFdCDP and dFdCTP. The mechanism of action of the gemcitabine metabolites is to enhance inhibitors of cell growth, resulting in the failure of DNA repair and induction of cellular apoptosis (Veltkamp et al., 2008).

Gemcitabine has been used previously with promising results as systemic chemotherapy in conjunction with cisplatin in the treatment of advanced bladder cancer. Few side effects and good tolerance of the treatment have been demonstrated in patients for whom cystectomy is not appropriate and those with metastatic disease (Shelley, Cleves, Wilt, & Mason, 2011). A recent systematic review of gemcitabine in the management of patients with highgrade SBC, refractory to BCG, has suggested the treatment to be effective and well-tolerated (Shelley et al., 2012). Gemcitabine is particularly suitable for regional therapy because of its high total body clearance and low rate of systemic absorption (Shelley et al., 2011; Ueno, Kiyosawa, & Kaniwa, 2007).

Problem Statement

High-grade SBC, refractory to BCG, is difficult to manage. Intravesical gemcitabine is an experimental but promising alternative to radical surgery in patients with SBC refractory to BCG treatment.

Purpose of the Study

The aim of this study was to assess the acceptability, tolerance, and durability of intravesical gemcitabine in the management of patients with high-risk bladder cancer refractory to BCG therapy.

Research Question

The research question addressed was, "Does intravesical gemcitabine offer patients with moderate to high risk BCG refractory bladder cancer a bladder preserving treatment option?"

Significance

The significance of this study was to preserve the patient's bladder and prevent patients from having a radical cystectomy, or at the very least, provides patients the additional time created through the use of gemcitibine giving the nurse specialist the opportunity to prepare the patients physically and psychologically for radical cystectomy in the case of intravesical gemcitabine failure.

Methods

Research Design and Setting

This study was a prospective cohort study conducted through Barts Healthcare National Health Service (NHS) Trust in London, England. Barts Health, consisting of six hospitals, is the largest NHS trust in Britain and one of the country's leading health care providers. A multi-disciplinary bladder cancer team (MDT), consisting of oncologists, urologists, radiologists, pathologists, and specialist nurses, meet once a week.

Sampling Strategy

All patients failing intravesical BCG therapy between October 2005 and November 2012, with histological confirmation of high-grade (G3) superficial (Ta/T1) bladder cancer who had developed recurrent tumors despite having been treated with BCG for at least six weeks (induction course) were prospectively recruited and selected as part of the trial on the basis of Ta or T1 disease confirmed on magnetic resonance imaging (MRI). Patients were excluded on the basis of T2 disease demonstrated on CT scan, incontinence, or patient choice. Individual eligibility into the study was identified by the MDT and then vetted before enrollment by the clinical nurse specialist with responsibility for the BCG treatment program.

Procedures

Eligible participants were treated with intravesical gemcitabine once a week for six weeks. Each patient received a single dose of 1,500 mg of intravesical gemcitabine in 50 ml of normal saline on a once-weekly schedule for six consecutive weeks. All treatment was administered by a specialist nurse trained in the administration of intravesical chemotherapy and immunotherapy.

Instrumentation

Demographic data were collected on all patients, including age, gender, grading of disease, and co-morbidity. Data on the dwell time (duration of time patient tolerated intravesical gemcitabine) in minutes and any adverse events were recorded.

The response to treatment was evaluated by fluorescence cystoscopy, bladder biopsy, and urine cytology carried out by the local urology team between six and eight weeks after completing treatment. Patients went on to receive a check cystoscopy and biopsy approximately every three months with histology results prospectively gathered.

Results

Characteristics Of Participants

The sample consisted of 19 patients, 12 males (63.2%) and seven females (36.8%), ranging in age from 48 to 88 years (Md = 73, M = 69.79, SD = 12.85). The majority that had previously smoked cigarettes were now stopped (n = 11, 57.9%); one (5.3%) continued to smoke, and seven (36.8%) had never smoked. All participants had completed a full induction course of BCG, with eight completing further cycles of maintenance treatment. One patient stopped BCG due to symptoms, and the 18 others stopped due to recurrence of tumor. Thirteen of these patients developed recurrence of TCC after only six cycles of BCG (induction course). This group was classified as BCG-resistant.

Disease Treatment or Outcomes Following Gemcitabine

All patients completed the intravesical gemcitabine treatment course. The dwell time for the medication ranged from 20 to 120 minutes (M = 66.58, SD = 43.27). All 19 patients were followed up for a period of two to 62 months (M = 12 months) following completion of treatment, in most cases, until tumor recurrence was demonstrated. Most patients experienced a median of three check cystoscopies and biopsies (range 1 to 8). Table 1 provides a summary of disease treatment or outcomes.

At the time of analyzing the results, seven patients were free of recurrence. Overall, the median time to recurrence was eight months (range 2 to 62). At 12 months of follow up, eight patients were recurrence-free, and one patient had been downgraded. In total, 12 patients developed recurrence.

Of patients with a positive biopsy, two were downgraded to less-aggressive tumors. All patients with recurrence went on to receive best standard care with specific outcomes detailed in Table 2.

At the time of data analyses, four patients had undergone cystectomy, two were receiving intravesical interferon therapy, and one had been entered into the HYMN trial. One patient had died from unrelated lymphoma. The remaining patients with recurrence of tumor were receiving local endoscopic treatment. No major adverse events occurred as a result of treatment with gemcitabine; reported minor adverse events were limited to dysuria and urinary frequency.

Of note, of the 12 patients who suffered a recurrence of tumor, one patient was downgraded. Another patient who developed a recurrence of superficial tumor subsequently went into remission, and at the time of writing, had not experienced further recurrence.

Limitations

This study included only cases that had completed a full induction course of BCG treatment. This limited the number of patients deemed eligible for the study. Our study was almost certainly underpowered to detect possible links between time to recurrence and smoking status, age, sex, or original tumor histology. Larger studies, which are appropriately powered to detect the potential effects of such factors, are needed before any direct associations can be ruled out.

Discussion

Data collected in this study suggest the use of intravesical gemcitabine can prolong the interval between BCG failure and the need for cystectomy, which is consistent with a recent systematic review of intravesical gemcitabine (Shelley et al., 2012). The median time from completion of treatment to recurrence was eight months, which is both clinically and psychologically significant for patients in whom there is no other option. The research team found that even for patients experiencing recurrence after only a few months, this interval was useful in preparing patients psychologically for the need for cystectomy, helping them adjust to the implications of body image change and implications of adjusting to of life with a stoma (Singh, Yadav, Sinha, & Gupta, 2013). This traumatic event should not be underestimated considering its association with significant changes in urinary and sexual function, interpersonal relationships, and psychosocial stress. These factors all contribute to the impact factor on the patient's perceived quality of life (Porter & Penson, 2005). The results also suggested that increased gemcitibine dwell time helped to reduce the rate of tumor recurrence, although larger prospective trials are needed to investigate these associations more thoroughly, to establish a causative relationship.

An important part of the consent process in patients undergoing cystectomy involves informed decision making. We found that the increased period of time afforded by gemcitibine gave the nurse specialist time to thoroughly inform patients of the benefits, risks, alternatives, and recovery following radical cystectomy. Matching a patient's decisions to their individual values, preferences, and expectations is often one of the most difficult things to achieve (Vasdev, Phillai, Snowdon, & Thorpe, 2012).

There is an increasing drive to improve and enhance patient recovery during the perioperative period for radical cystectomy. The preoperative workup of patients, such as health optimization and preoperative feeding, are the key to achieving this goal. The additional time created through the use of gemcitibine allows a longer term view of this perioperative period.

Only half of the patients with an ileal conduit care for their urostomy independently. One reason highlighted in other research has been better patient education and early proficiency in stoma care. Research suggests an association exists between self-stomal care and improved quality of life (Tal et al., 2011); having additional time to appropriately prepare patients for life with a stoma is part of this process and is achievable while on gemcitibine.

Conclusions

The results of our initial experience of the use of intravesical gemcitabine in the treatment of patients with superficial high-grade bladder cancer that has recurred despite previous BCG treatment are encouraging. Our results suggest that in this patient group, intravesical gemcitabine is safe and well-tolerated, and a proportion of patients will respond to the treatment and remain free from recurrence in the short to medium term. Even where treatment might fail in a shorter time frame, it appears that this additional time may be useful to prepare patients physically and psychological for radical cystectomy.

Prospective studies are needed to establish the efficacy of intravesical gemcitabine in those patients with BCG refractory disease and in those for whom BCG is not tolerable. Further studies with a larger cohort of patients and use of stricter, established definitions will be essential to fully determine its place in the management of high-grade superficial bladder cancer, particularly in patients considered high risk for general anaesthetic or who do not want surgery. Its role may well be deemed in the future to be most important as a holding mechanism while patients assimilate themselves to the need for cystectomy, its impact in terms of body image, and preparation time for managing a stoma.

Implications for Urologic Nursing

The physical and psychological impact of cystectomy is well-documented. The spotlight on nursing communication skills could not be brighter than in patients undergoing radical surgery with potential life-changing consequences. Having adequate time to prepare patients for radical surgery is paramount in this group, with the holistic needs assessment an integral part of this process, ensuring a thorough assessment of the patient's pre- and post-surgery needs.

Research Summary

Background

High-grade superficial bladder carcinoma, refractory to Bacillus Calmette-Guerin (BCG), is difficult to manage. Intravesical gemcitabine is an experimental but promising alternative to radical surgery in patients with superficial bladder cancer (SBC) refractory to BCG treatment.

Purpose

The aim of this study was to assess the acceptability, tolerance, and durability of intravesical gemcitabine in the management of patients with high-risk bladder cancer refractory to BCG therapy.

Methods

Patients with recurrent high-grade superficial bladder cancer following treatment with intravesical BCG were treated with intravesical gemcitabine once weekly for six weeks. Response to treatment was evaluated by fluorescence cystoscopy, bladder biopsy, and urine cytology approximately every three months.

Results

Nineteen patients were included. Time to recurrence was eight months; increase in time to recurrence was associated with increased dwell time. Treatment for recurrence included cystectomy, intravesical interferon therapy, hyperthermia and mitomycin (HYMN) trial, and local endoscopic treatment.

Conclusions

Intravesical gemcitabine is a promising alternative to radical surgery in patients with superficial bladder cancer refractory to BCG treatment.

Level of Evidence--VI

(Polit & Beck, 2012)

doi: 10.7257/1053-816X.2014.34.2.95

Note: This study was funded by the Departments of Urology and Research at Barts Health National Health Service (NHS) Trust and Department of Oncology at Barts Health, London, United Kingdom.

References

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Polit, D.F., & Beck, C.T. (2012). Nursing research: Generating and assessing evidence for nursing practice (9th ed.). Philadelphia: Wolters Kluwer/ Lippincott, Williams & Wilkins.

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Sylvester, R.J., Oosterlinck, W., & van der Meijden, A.P. (2004). A single immediate postoperative instillation of chemotherapy decreases the risk of recurrence in patients with stage Ta T1 bladder cancer: A meta-analysis of published results of randomized clinical trials. Journal of Urology, 171(6, Pt. 1), 2186-2190.

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van Rhijn, B.W., Burger, M., Lotan, Y., Solsona, E., Stjef, C.G., Sylvester, R.J., ... Zlotta, A.R. (2009). Recurrence and progression of disease in non-muscle-invasive bladder cancer: From epidemiology to treatment strategy. European Urology, 56(3), 430-442. doi:10.1016/j.eururo. 2009.06.028

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Veltkamp, S.A., Pluim, D., van Eijndhoven, M.A.J., Bolijn, M.J., Ong, F.H.G., Govindarajan, R., ... Schellens, J.H. (2008). New insights into the pharmacology and cytotoxicity of gemcitabine and 2', 2'-difluorodeoxyuridine. Molecular Cancer Therapeutics, 7(8), 2415-2425. doi: 10.1158/1535-7163.MCT-08-0137

Paula Allchorne, MBA, Dip., RN, CNS, is a Uro-Oncoiogy Nurse Specialist, Department of Urology, Barts Health National Health Service (NHS) Trust, London, United Kingdom.

Benjamin W. Lamb, PhD, MA, MRCS, is a Urology Specialty Trainee, Department of Urology Barts Health National Health Service (NHS) Trust, and an Honorary Clinical Research Fellow, Department of Surgery and Cancer, Imperial College, London, United Kingdom.

Janette Kinsella, MSc, ANP, is an Advanced Nurse Practitioner, Department of Urology, Guys Hospital, London, United Kingdom.

Jonathan Shamash, MD, MRCP, MBChB, is a Consultant Medical Oncologist, Department of Oncology, Barts Health National Health Service (NHS) Trust, London, United Kingdom.

James S.A. Green, LLM, FRCS (Urol.), is a Consultant Urological Surgeon, Department of Urology Barts Health National Health Service (NHS) Trust, London, United Kingdom, and a Visiting Professor of Health Service Research, Department of Health and Social Care, London South Bank University, London, United Kingdom.
Table 1 Disease Treatment or Outcomes (N = 19)

Outcome                      n       %

Surveillance                 7     36.8
Interferon                   2     10.5
Local therapy                3     15.8
Cystectomy                   4 *   21.1
Poor surgical candidate      1     5.3
Hyperthermia and
  mitomycin (HYMN) trial     1     5.3
Died of unrelated lymphoma   1     5.3

* One patient treated with cystectomy later died.

Table 2.
Categories of Patients Who Had Tumor Recurrence following
BCG Treatment, Proportion, and Appropriate Treatment

Category     Definition             Proportion   Appropriate
                                                 Treatment

BCG-         Does not tolerate      Less         Alternative
intolerant   side effects of BCG    than 5%      intravesical
                                                 drug with
             Dysuria, fever,                     recurrence
             myalgia

             Full treatment not
             complete

             Did not receive
             sufficient therapy

BCG-         Tumor completely       20%          Further/
persistent   treated                to 40%       maintence
                                                 BCG
             Tumor recurs

             Has not failed
             initial therapy

             Treatment successful
             but recurrence
             occurs over time

BCG-         Biopsies/cytology do   60-%         Alternative
resistant    not normalize after    to 80%       intravesical
             BCG                                 drug with
                                                 recurrence
             Tumor recurs within
             six months of BCG
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Title Annotation:Research
Author:Allchorne, Paula; Lamb, Benjamin W.; Kinsella, Janette; Shamash, Jonathan; Green, James S.A.
Publication:Urologic Nursing
Article Type:Report
Geographic Code:4EUUK
Date:Mar 1, 2014
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