Raisons de l’ajournement des instillations intravésicales dans le traitement adjuvant des tumeurs de vessie n’infiltrant pas le muscle : une étude prospective

25 février 2020

Auteurs : W. Khan, A.S. Zugail, E. Blanc, Y. Neuziller, T. Lebret
Référence : Prog Urol, 2020, 2, 30, 75-79




 




Introduction


Bladder cancer (BC) is the fourth most common cancer in France and the second most common urological cancer after prostate cancer [1]. At the time of diagnosis, 75-85% of BCs are non-muscle invasive (NMIBC). In NMIBC, 60-70% of lesions will relapse in the first year and 10-20% will progress to muscle invasive bladder cancer (MIBC) and/or metastatic tumours.


The first step of the BC treatment is a complete removal of the tumours through a transurethral resection of the bladder (TURB). Clinico-histopathological features of NMIBC [2] allow to establish the risk of recurrence and progression as low, intermediate, high or very high. Subsequent therapeutic strategies are then adapted to these risk classifications [3].


The objective of adjuvant intravesical treatments is to reduce the frequency of recurrence, and to reduce the risk of tumour progression. Instillations of MMC are recommended for intermediate risk tumours and for concern low grade pTa tumours that have a low risk of progression but a high risk of recurrence [4, 5, 6]. Between six and eight MMC instillations are usually performed, at a dose of 40mg per instillation [5]. The side-effects of these instillations include skin reactions and chemical cystitis that may contraindicate the use of this product either temporarily or permanently. Induction therapy with Bacillus Calmette-Guérin (BCG) normally involves 6 weekly instillations that start after bladder healing (4-6 weeks after TURB). Maintenance treatment involves three weekly instillations at 3, 6 and 12 months after resection for intermediate-risk tumours, continued every 6 months until the 36th month for high-risk tumours [6, 7]. There are four definitive contraindications for BCG use: severe innate or acquired immunodeficiency; active tuberculosis; a history of systemic BCG reaction (organ infection or BCG sepsis); and a history of radiotherapy of the bladder (radiation cystitis).


Good therapeutic practice in relation to instillations has an impact on the effectiveness of intravesical therapy [6]. Postponement or stopping instillations may have a deletory effect on NMIBC prognosis, increasing both recurrence and progression risks [7]. Causes of disturbance in instillation protocol need to be identified, aiming to reduce them. The aim of this study was to assess the frequency and reasons why planned intravesical instillations could not be performed during adjuvant treatment of NMIBC.


Materials and methods


Study population


One-hundred consecutive patients treated by intravesical instillations of MMC or BCG in the Urology department of a tertiary Hospital, between August 2016 and March 2017, were included in this prospective epidemiological study. Due to serious shortage regarding BCG during the study, only induction treatment was allowed by the National Agency for Medicines (ANSM). All patients gave their written informed consent before participating in the study.


The following data were recorded: age, gender, tumour stage and grade, presence or absence of carcinoma in situ , history of instillations and type of instillation.


Pre-installation information


Before instillations began, written and oral information and instructions were given to the patients by a urological endoscopy nurse. The written information and instructions included: the weekly calendar of appointments; the patient information sheet prepared by the French Association of Urology (AFU); and urine analysis and culture (UAC) to be carried out 1 week before the first instillation session. The nurse explained the instillation procedure and repeated the instructions and information on the AFU form including water restriction for 8h preceding the instillation and the need to alkalinise the urine in the case of MMC instillation.


Before beginning the instillation session, the nurse checked the results of the UAC, asked the patient about tolerance of previous instillations if applicable and if he/she had any symptoms of a urinary tract infection (UTI), haematuria or fever. The nurse performed a urine test strip (dipstick) to check for nitrite (if the nitrite result was positive, the urologist postponed the instillation and a new UAC was performed). Depending on the results of UAC, antibiotic treatment was started to permit installation during the following session.


Questionnaires


At each session and in the case of postponement of an instillation, the nurse completed a questionnaire (Appendix A). This questionnaire included the reason(s) why the session was cancelled. The following reasons were included: UAC not performed; untreated positive UAC; sterile UAC but a positive dipstick (i.e. positive nitrite); side-effects (pollakiuria, urgency); haematuria; traumatic catheterisation; and refusal/absence of the patient.


Statistical analysis


Microsoft Excel 2016 was used for the statistical analysis. Intergroup comparisons of quantitative variables were performed using the Student's t -test.


Results


Study population


A total of 541 instillations were performed in 100 patients (77% men and 23% women). There were 363 BCG instillations in 72 patients (67.1%) and 178 MMC instillations in 26 (32.9%). Mean (±SD) patient age was 68.4±9.1 years and this did not differ significantly according to the type of instillation (64.2±10.2 years for MMC vs. 70.3±7.4 years for BCG). Only one patient treated with MMC had a history of intravesical treatment with the same drug. All BCG-treated patients were naïve to this drug. The characteristics of the tumours differed according to the treatment received (Table 1) and according to their respective indications.


Instillation postponement


Of the total number of instillations planned during the study period, 24 (4.4%) were postponed in 19 patients (16 men (87%) and three women (13%)). Of these 19 patients, eight (80% men) were scheduled for MMC instillations. These comprised 10 (42%) instillations or 6% of all MMC instillations. For the other 11 patients (92% men), 14 (58%) BCG instillations were postponed (4% of all BCG instillations).


The causes of instillation postponement were untreated positive UAC in 13 (54%) cases, side-effects (pollakiuria, urgency) in four (16.7%), haematuria due to traumatic catheterisation in four (16.7%), refusal or absence of the patient in two (8.3%) cases and a sterile UAC but positive dipstick test (positive nitrite) in one (4.3%) case. The respective frequencies of the causes of cancellation did not differ significantly in relation to the type of instillation (Table 2).


The postponed instillations were the first in the therapeutic protocol in 26% of cases, the second in 17%, the third in 17%, the fourth in 17%, the fifth in 4% and the sixth in 17%. The number of instillations preceding those cancelled did not differ significantly according to the type of instillation (2.1±2.0 instillations for MMC vs. 1.5±1.6 for BCG; P =0.64).


After instillation postponement, the therapeutic protocol was resumed the following week with the approval of the urologist in 20 (87%) cases. This frequency did not differ significantly in relation to the type of instillation (80% for MMC vs. 92% for BCG). The reasons for not resuming instillations the following week were: limiting pollakiuria at the first MMC instillation; an allergic reaction to MMC during the third instillation; and recurrence of NMIBC during BCG treatment.


Discussion


We provisionally assumed that causes of instillation postponement could be divided in patient- and treatment- related. The first ones are due to lack of compliance from patients regarding the medical team instructions. The others are due to treatment side effect. The results of this study show good patient compliance with the instructions of the urologist and nurse as 100% of patients underwent an UAC 7 days prior to their instillation session. We also observed good compliance with treatment since only one patient did not show up for a session.


Four sessions could not take place because of side-effects of treatment. Two were not related to previous instillations or to the treatment type; one case was due to balanitis and one to pollakiuria related to benign prostatic hypertrophy after TURB. The two other side-effects were intense urinary symptoms (pollakiuria and a VAS pain score of 10) after the second instillation and one case of skin rash after the third session.


In clinical trials studying various intravesical adjuvant treatments, mild systemic toxicities including fever, chills and malaise were observed in 19% of patients treated with BCG and 12% of patients treated with MMC [8]. Severe side-effects occur in <5% of patients treated with BCG resulting in permanent discontinuation of treatment [8]. However, few studies show the proportion of patients who had to discontinue both adjuvant therapies. Consequently, it is advisable to carry out instillations respecting the formal contraindications of BCG therapy and rigorous hygiene, asepsis and atraumatic catheterisation because traumatic instillations are the source of the majority of serious systemic complications resulting in cancellation of treatment [9].


The new guidelines for intravesical instillations state that instillations should be cancelled in cases of macroscopic haematuria, traumatic urinary catheterisation or symptomatic urinary tract infection, in addition to contraindications relating to the type of treatment used and for BCG therapy during the first 2 weeks following TURB. It is imperative that these guidelines are followed and health professionals are trained to perform safe urinary catheterisation [10].


The side-effects related to instillations are unpredictable [9]. It is therefore important that during each appointment and instillation session the nurse reminds the patient of the telephone number of the service in which they are being treated so that they can inform the team about any adverse event and to also remind the patient about post-instillation instructions such as increasing their fluid intake to decrease the symptoms of cystitis. This will enable the nurse to determine whether the session should be postponed or cancelled completely.


Among the criteria for postponement studied here, dipstick positivity was found in one case; however this is not included in the guidelines for postponing instillations. Dipstick tests may therefore be unnecessary in order to avoid unnecessary postponement and extension of treatment to 7 weeks instead of 6 weeks.


The majority of cases of installation postponement were due to an untreated UAC. Two approaches can be proposed. On the one hand, managing the results of an UAC is a major problem. All of our patients had this test performed and 60% had their session postponed for an untreated UAC. Patients should therefore be more proactive at recovering their test results, contacting the service for an antibiotic prescription and making sure the results are received by the service. The UAC results should be sent to a single fax number or email address thereby concentrating all documents received by the service. A person, usually a health professional, should be responsible for reviewing all incoming UAC results several times a day. Positive UACs should be grouped together and shown to the urologist who will then decide whether the patient should take antibiotics or not and the patient should be contacted accordingly. In our opinion, this approach should help to decrease untreated UACs and/or UTIs. On the other hand, the CC-AFU 2018 recommendations state that UACs are optional. Symptomatic UTIs (symptoms of cystitis, fever, etc.) prevent instillations if they are not treated. Conversely, asymptomatic bacteriuria and leukocyturia do not postpone instillations [11].


A study conducted in the USA shows that routine UACs can be safely omitted prior to BCG instillations. Questioning a patient before their instillation session to ask about symptoms of a UTI is sufficient [12]. These recommendations are not yet followed widely. Urologists at the Foch hospital continue to perform UACs and cancel any instillations if the UAC is positive and the patient has not received antibiotics. A change in practice could consist of giving the patient a questionnaire, after each instillation, to ask them if they have any symptoms of a UTI instead of prescribing a UAC. Before each new session, the nurse will then recover this questionnaire and determine if the instillation can take place or not. One drawback is that not all patients are able to answer a questionnaire. Thus, performing a UAC effectively resolves this problem and protects the patient from a severe instillation reaction if they have a UTI.


To reduce instillations postponement, we believe patients should be more implicated in the management of theirs UAC. In a forensic analysis perspective, we suggest that the decision as to whether a UAC should be performed or not should be made on a case by case basis. The urologist should evaluate each patient and decide whether or not they should undergo an UAC before each instillation and forward the request to the nurse. The nurse should also assess the patient. At the end of these two appointments, the patient will leave with a prescription for an UAC if necessary and, if not, with a questionnaire to be completed and given to the nurse just before the instillation (Appendix A). This same questionnaire will be given to the patient after each session and retrieved by the nurse before the next session and so on. After analysis of the completed questionnaire, the nurse can decide whether or not to proceed with the instillation.


Conclusion


To our knowledge, this is the first in-depth study of the reasons for postponement of instillations during adjuvant treatment of NMIBC. Our results highlight the low proportion of postponed instillations (4.4%), but the main reasons for postponement, namely an untreated UAC and a positive dipstick test. These two factors are not included in the latest CC-AFU guidelines. To reduce instillations postponement, in both a medical and a forensic analysis perspectives, we suggest that patients should be more implicated in the management of theirs instillations. A modification of the conditions around instillation is in progress within our service. First, we have stopped doing pre-instillation dipstick tests for all treatments and reserve them for MMC instillations to determine the urinary pH. We also plan to give each patient a pre-instillation questionnaire (Appendix A), which will be analysed by the nurse before each session. Postponement of instillation sessions should therefore be reduced considerably.


Disclosure of interest


The authors declare that they have no competing interest.



Acknowledgments


We thank all nurses in our urology department who participated in this study.



Appendix A. Supplementary data


(36 Ko)
  




Table 1 - Summary of the intravesical treatments received according to the tumour characteristics.
Instilled drug  Stage 
WHO Grade 2016 
Carcinoma in situ  
  Ta  T1  Low  High   
MMC  9 (90)  1 (10)  9 (90)  1 (10)  1 (10) 
BCG  7 (50)  7 (50)  0 (0)  14 (100)  9 (69) 



Légende :
All values shown are n (%).



Table 2 - Summary of the reasons for postponement of intravesical instillations.
Instilled drug  Untreated positive UAC  Side-effects  Haematuria  Patient refusal/absence  Positive dipstick 
MMC  6 (60)  2 (20)  0 (0)  2 (20)  0 (0) 
BCG  7 (50)  2 (14)  4 (28)  0 (0)  1 (7) 



Légende :
All values shown are n (%). UAC: urine analysis and culture.


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