Experience of organizing BCG therapy for localized bladder cancer in outpatient cancer care centers

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Introduction

According to the Global Cancer Observatory [1], in 2022, the number of patients with bladder can-cer (BC) exceeded 600 thousand worldwide, which accounted for 3% of all cancer patients. In 2022, 16,465 BC cases were registered in Russia [2]. In 75% of the cases, BC is represented by a non-muscle-invasive form of urothelial carcinoma. The standard of care for this BC is transurethral re-section (TUR) of the bladder followed by immediate intravesical instillation of an antitumor antibi-otic with or without subsequent adjuvant intravesical therapy. The typical features of non-muscle-invasive BC (NMIBC) are a high frequency of local recurrences and the ability to tumor progression with the muscle invasion associated with an inferior prognosis. The carcinoma in situ (CIS) of the urothelium stands out among NMIBC, has an aggressive course, and cannot be cured with TUR. De-pending on the risk of tumor recurrence/progression, NMIBC is classified into low, intermediate, and very high-risk groups [3, 4]. The most effective method of preventing recurrence and the only way to increase the time to tumor progression in intermediate- and high-risk groups, as well as virtu-ally no alternative method of treating CIS, is intravesical therapy with an antitumor vaccine based on attenuated Calmette-Guérin (BCG) tuberculosis bacilli. Several randomized trials have shown the benefits of the BCG vaccine compared to intravesical chemotherapy in intermediate- and high-risk patients [5–8]. Patients receiving BCG therapy need careful clinical, laboratory, and instrumental monitoring for the timely detection and correction of adverse events and assessment of the treat-ment’s effect. All of the above determines the high relevance of the development of medical and organizational approaches to provide effective and safe treatment, as well as adequate monitoring of the condition of patients with NMIBC receiving BCG therapy.

The objective of the study is to develop and test an organizational model for intravesical therapy with BCG antitumor vaccine in patients with NMIBC at the Outpatient Cancer Care Center (OCCC) using inpatient replacement technologies.

Materials and methods

From June 2023 to May 2024, at the Oncology Center No.1 of the Moscow City Clinical Hospital named after S.S. Yudin, NMIBC patients received intravesical BCG therapy covered by compulsory health insurance.

One hundred and eighty patients with intermediate- and high-risk NMIBCs without contraindica-tions to the use of attenuated tuberculous mycobacteria undergone bladder TUR and immediate in-travesical cytostatic instillation for verified Tis-T1N0M0 urothelial carcinoma received adjuvant BCG therapy at a standard regimen. All patients received an induction course of treatment, which started 3–4 weeks after TUR (6 weekly instillations), with subsequent monitoring of the effect of therapy and switch to the maintenance BCG therapy (monthly instillations for 1 year in the interme-diate group and 3 years for patients with poor prognosis) in case of achieving the complete response. Contraindications to subsequent instillations were gross hematuria, traumatic bladder catheteriza-tion, and symptoms of urinary infection. Routine monitoring included cystoscopy and microscopic examination of urine sediment every 3 months (for 2 years; then monitoring is planned every 6 months, then annually), as well as contrast-enhanced computed tomography of the abdomen and pelvis (every 6 months for 1 year, then every 12 months).

Intravesical BCG therapy is performed in a day hospital (DH) setting. To meet the safety require-ments of treatment with a vaccine based on live attenuated Mycobacterium tuberculosis, a single immunotherapy room has been established at the OCCC, where the urologic oncologist performs intravesical instillation of the BCG vaccine. Patients are then observed after intravesical instillation at the DH. In the absence of complications requiring further monitoring, patients are discharged from the DH on the day of instillation. If a more extended patient observation is necessary, they are admitted to the day-stay hospital. Patients with disease complications or recurrence receive treat-ment in a round-the-clock urological cancer hospital.

The results of the developed and introduced medical and organizational approaches to BCG thera-py were analyzed. The data were processed using Excel software packages (Microsoft, USA) and IBM SPSS Statistics ver. 20 (IBM, USA) with descriptive statistics methods.

Results

The need for developing medical and organizational approaches to BCG therapy was analyzed based on the Unified Medical Information and Analytical System data. From 2018 to 2023, there was an 8.4% increase in the incidence of NMIBC in Moscow. In 2023, the number of patients with NMIBC reached 823 individuals. During the COVID-19 pandemic, there was a decrease in the inci-dence followed by a recovery growth (Table 1).

 

Table 1. Trend of the number of NMIBC patients in Moscow (2018 to 2023)

Years	Parameter (patient number, n)	Absolute in-crease/decrease	Growth/decline rate, %	1% growth value	Rank aggre-gation tech-nique	Moving aver-age method
2018	713	Нет	Нет	Нет	753,0	784,1
2019	793	80,0	11,2	7,1		686,3
2020	553	-240,0	-30,3	7,9	678,0	716,3
2021	803	250,0	45,2	5,5		705,0
2022	759	-44,0	-5,5	8,0	791,0	795,0
2023	823	64,0	8,4	7,.6		799,0

 

To analyze the incidence trend for 7 years of observation, considering the decrease in the detection of malignant tumors during the COVID-19 pandemic, the observation interval was extended for 2 years using the moving average method, and a moving trend curve was plotted (Fig. 1).

 

Fig. 1. Trends of NMIBC incidence using the moving average method.

 

There are no data on the distribution of patients with NMIBC in risk groups, which prevents direct calculation of the need for the BCG vaccine in Moscow. An indirect indicator of the need for BCG vaccination for 2023 was obtained by extrapolating the data on the characteristics of NMIBC pa-tients participating in international studies [9–11] to the population of Moscow patients, which amounted to 617 (95% confidence interval 594–640) individuals. The frequency of direct contrain-dications to BCG (tuberculosis, positive intradermal test) is unknown, precluding adjustment of the need based on this indicator. Considering the differences in the start/stop time of therapy, as well as the changing schedule of the frequency of BCG vaccine administration, prospective monitoring of the rate of therapy completion with the discontinuation rate due to adverse events, progression, and completion of the planned course of intravesical instillations, is crucial for further calculation of the needs for medical and organizational measures.

Routing of primary patients in Moscow is based on the provisions of the order of the Moscow De-partment of Health, “On the Organization of Oncology Medical Care in Medical Organizations of the Moscow State Health Care System” dated 14.01.2022 No.16 (as amended on 29.03.2023). Clari-fying diagnostics, oncological case conferences, referring patients to specialized treatment, and sub-sequent follow-up medical care are entrusted to OCCC. The Oncology Center No.1 of the Moscow City Clinical Hospital named after S.S. Yudin includes two OCCCs with outpatient urology cancer departments. According to the registration scheme [12], patients with suspected neoplasms of the genitourinary system from outpatient departments of the Central and North-Eastern administrative districts of Moscow are routed to these departments. The Center for Pathological and Molecular Ge-netic Diagnostics, the Radiology Department, urological cancer beds for round-the-clock stay, a day-stay hospital, and an oncological DH were established as part of the hospital. The interaction pattern of structural units is shown in Figure 2.

 

Fig. 2. Diagram of the interaction of the immunotherapy room in the structure of the cancer care center.

 

Of 180 patients, 103 (57.2%) completed the induction course of BCG therapy: 98 (54.4%) switched to maintenance therapy without progression or intolerable adverse events, 2 (1.1%) discon-tinued treatment due to intolerable toxicity, 3 (1.7%) underwent radical cystectomy due to disease progression; 77 (42.8%) patients still receive the induction course of treatment. Adverse events were reported in 25 (13.9%) patients: cystitis (25 [13.9%]), hematuria (9 [5.0%]), and prostatitis (1 [0.6%]). Two (1.1%) patients experienced grade 3 toxicity and discontinued BCG therapy. No seri-ous or fatal adverse events were reported. In all cases, patients were managed in the DH setting, 3 (1.7%) patients who underwent radical cystectomy due to the BC progression required elective hos-pitalization in a round-the-clock hospital after an additional examination. The follow-up period is insufficient for the final assessment of oncological outcomes.

Discussion

According to the Global Cancer Observatory [13], the incidence of malignancies is growing steadi-ly worldwide; from 2020 to 2040, their incidence is predicted to increase by 1.6 times from 19.3 million cases in 2020 to 30.2 million by 2040. A similar trend is predicted for mortality: an in-crease from 9.96 million cases in 2020 to 16.3 million cases in 2040 (also 1.6 times). These predic-tions determine the relevance of early detection and effective treatment of malignant neoplasms.

Despite the campaign against smoking, the number of NMIBC patients in Moscow is increasing, thus challenging clinicians and cancer care providers to ensure the accessibility of intravesical ther-apy with the BCG antitumor vaccine.

To meet the safety requirements of treatment with a vaccine based on live attenuated Mycobacte-rium tuberculosis, it is necessary to establish a single immunotherapy room at the OCCC. An outpa-tient urology cancer department provides initial examination of patients and follow-up medical care, including during the treatment. Inpatient-substituting technologies, including daycare beds or DH, can be used to monitor patients after a session of intravesical therapy. A one-day hospital, or DH, allows a patient to be discharged on the same day, followed by a visit to the oncologist. If it is neces-sary to monitor the patient by the attending physician, a day-stay hospital is more appropriate. Pa-tients with disease complications or recurrence should receive treatment in a round-the-clock uro-logical cancer hospital.

The experience of treating 180 patients with NMIBC for 12 months demonstrates the effectiveness of the proposed model of intravesical vaccine therapy in a real-world setting. Preliminary data on the efficacy and safety of treatment with the BCG antitumor vaccine are consistent with previously published results [13, 14].

Conclusion

The functioning of the BCG therapy room at OCCC makes it possible to introduce a highly effec-tive method of preventing NMIBC recurrence and progression into broad clinical practice. The combination of various inpatient replacement technologies and a round-the-clock urological cancer hospital on a functional basis within one medical organization allows for the necessary clinical and instrumental monitoring of patients receiving BCG therapy and ensures safety during diagnosis and treatment.

Disclosure of interest. The authors declare that they have no competing interests.

Authors’ contribution. The authors declare the compliance of their authorship according to the international ICMJE criteria. All authors made a substantial contribution to the conception of the work, acquisition, analysis, interpretation of data for the work, drafting and revising the work, final approval of the version to be published and agree to be accountable for all aspects of the work.

Funding source. The authors declare that there is no external funding for the exploration and analysis work.

About the authors

Sergey A. Parts

Yudin Moscow City Hospital

Author for correspondence.
Email: saparts@mail.ru
ORCID iD: 0009-0003-9954-4584
SPIN-code: 1350-6713

Cand. Sci. (Med.)

Russian Federation, Moscow

Yana V. Gridneva

Yudin Moscow City Hospital

Email: saparts@mail.ru
ORCID iD: 0000-0002-9015-2002
SPIN-code: 4189-6387

Cand. Sci. (Med.)

Russian Federation, Moscow

Maria I. Volkova

Yudin Moscow City Hospital; Russian Medical Academy of Continuous Professional Education

Email: saparts@mail.ru
ORCID iD: 0000-0001-7754-6624

D. Sci. (Med.)

Russian Federation, Moscow; Moscow

Albert V. Oskarev

Yudin Moscow City Hospital

Email: saparts@mail.ru
ORCID iD: 0000-0003-0847-4449

oncourologist, Department Head

Russian Federation, Moscow

Ogulshat R. Sinitsyna

Yudin Moscow City Hospital

Email: saparts@mail.ru
ORCID iD: 0009-0003-7184-0410

oncologist, Department Head

Russian Federation, Moscow

Evgeniya S. Kuzmina

Yudin Moscow City Hospital

Email: kuz011@mail.ru
ORCID iD: 0009-0007-2856-5176
SPIN-code: 9668-5733

oncologist, Department Head

Russian Federation, Moscow

Vsevolod N. Galkin

Yudin Moscow City Hospital

Email: gkob1@zdrav.mos.ru
ORCID iD: 0000-0002-6619-6179
SPIN-code: 3148-4843

D. Sci. (Med.), Prof.

Russian Federation, Moscow

Saida M. Gadzhieva

Moscow Healthcare Department

Email: zdrav@mos.ru
ORCID iD: 0009-0008-3455-493X

Cand. Sci. (Med.)

Russian Federation, Moscow

References

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