EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Guidelines from the European Association of Urology (EAU) recommend adjuvant intravesical bacillus Calmette-Guérin (BCG) after transurethral resection of bladder in immunocompetent patient with intermediate- and high-risk nonmuscle invasive bladder cancer (NMIBC).¹

Bacillus Calmette-Guérin is a live attenuated form of Mycobacterium bovis; the precise mechanisms by which this form of immunotherapy works are complex.^2-4 It has been posited that BCG adheres to the urothelium and, once internalized, induces antigen-presenting cell-mediated induction of innate and adaptive immune responses, leading to decreased recurrence and progression rates of NMIBC.^2,4 However, intravesical BCG may have local and systemic toxicity. Local BCG toxicity, such as persistent irritative symptoms, may render succeeding treatments intolerable to the patient, and systemic BCG toxicity exposes patients to a life-threatening situation and prolonged antituberculosis drug administration.

With regard to NMIBC in kidney transplant (KT) recipients, this cancer is associated with a higher risk of recurrence compared with that shown in the nontransplant population affected by similar disease, probably because of underutilization of adjuvant endovesical treatment.^3,5 Furthermore, in cases of progression to muscle invasive bladder cancer (MIBC), radical cystectomy with pelvic lym-phadenectomy is the gold standard treatment.^6-8 In KT recipients, radical cystectomy with pelvic lymphadenectomy could be challenging, showing a high risk of vascular or graft injury and graft loss.^8,9 As such, a safe and effective adjuvant treatment to prevent recurrence and progression of NMIBC in these patients is an important need.¹⁰

Two main questions arise regarding the utilization of intravesical BCG in KT patients with high-risk NMIBC. First, does BCG have the same efficiency as that shown in the regular population, taking into consideration that immunosuppressive treatment after KT promotes an anti-inflammatory response? Second, is the morbidity of BCG instillations greater due to the immunocompromised status of KT recipients?

In a recent systematic review, Jue and colleagues⁶ reported that KT recipients treated with adjuvant intravesical BCG in NMIBC had significantly lower recurrence and progression to MIBC compared with patients who were not treated with BCG. Similarly, in 2017, Rodriguez Faba and colleagues⁷ reported the largest series of adjuvant endovesical treatment in KT recipients (88 patients) with a median follow-up of 126 months. Six patients had adjuvant intravesical BCG. The recurrence rate was 35% with a mean delay of 10 months. The investigators reported that 5.6% of patients progressed to MIBC and 16 recipients underwent radical cystectomy. As confirmed also by Roumeguere and colleagues, in a group of 8 KT recipients with NMIBC, local induction of immune response by BCG seemed to be effective even in immunocompromised patients.¹¹

The safety of intravesical BCG has been evaluated in nontransplant, immunocompromised patients with HIV and hematological malignancy.¹⁰ In HIV patients, use of adjuvant intravesical BCG was responsible for severe BCG toxicity, involving the need for prophylactic antitubercular therapy during the period of BCG instillation.^10,12 Herr and Dalgbani¹³ published the largest series, consisting of 45 immunosuppressed patients, who underwent BCG instillations for bladder cancer; the investigators confirmed the tolerability of the adjuvant treatment. Similarly, in KT patients, several reports have supported the safety of BCG instillation, with good tolerance and minimal side effects.^7,14-17 However, rare cases of subacute interstitial pneumonitis¹⁸ and fatal sepsis19 have been reported. In this context, prophylactic administration of antituberculous treatment to minimize BCG-induced toxicity^11,20,21 has been discussed. Al Khalifa and colleagues²² showed a reduction of local side effects when patients were given a 3-day course of isoniazid for each BCG instillation. However, other authors reported an increased rate of side effects, such as fever and malaise, in patients who received isoniazid.²³ Notably, tuberculostatic medication can cause changes in the metabolism of immunosup-pressive agents, requiring dose adjustments to avoid rejection of the graft.²¹ To date, no specific recommendations on peri-instillational prophylaxis have been made.

According to the literature, the efficacy and safety of BCG in KT recipients with NMIBC have only been evaluated in a limited number of case series. Although the available data have shown promising results, to date, sufficient levels of evidence on its effectiveness in KT recipients are not available, in contrast to available evidence in the general population.

With the considerations outlined here, a multicenter study may address the oncological benefits and harms of endovesical BCG treatments in KT recipients affected by NMIBC.

Volume: 20 Issue: 8 August 2022

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