Impact of a surgeon on the relapse-free survival of patients with non-muscle-invasive bladder cancer

Background. The high rate of recurrences after visual complete transurethral resection (TUR) is a main problem in the treatment of nonmuscle-invasive bladder cancer (NMIBC). One of the factors influencing the long-term results of treatment for this pathology may be the quality of TUR, which depends on a surgeon’s experience.Objective: to evaluate the impact of a surgeon on relapse-free survival rates after radical treatment in patients with NMIBC and to search the optimal quality criteria for TUR in this disease.Materials and methods. The data of patients with primary or recurrent NMIBC treated using TUR with and without intravesical therapy at the N. N. Aleksandrov Republican Research and Practical Center for Oncology and Medical Radiology in 2004 to 2013 were retrospectively analyzed. The investigation included a total of 949 cases of performing organ-sparing treatment in 784 patients. The operations were made by 5 surgeons with comparable experience with TUR.Results. At a median follow-up of 64.3 (3–124) months, the 5-year relapse-free survival rates in 5 surgical groups were 62.9 (95 % confidence interval (CI) 56.2–69.7), 53.6 (95 % CI 47.4–59.9), 51.0 (95 % CI 39.6–62.4), 46.2 (95 % CI 36.4–56.0), and 44.2 % (95 % CI 36.8–51.7), respectively (p < 0.0001). According to the data of multivariate analysis including all potential factors, the prognostic role of a surgeon’s experience retained a high level of statistical significance (p = 0.0013). The differences between the surgeons were less pronounced after resection of tumors at a low risk for recurrence. Analysis of the distribution of the recurrence rates within the first 3, 6, and 12 months after TUR in relation to the surgeon, which were stratified according to recurrence risk groups, showed that the most differing rates were observed 12 months after TUR.Conclusion. An operating surgeon has a significant effect on the risk of recurrence after radical treatment in patients with NMIBC. In our investigation, this effect was observed in spite of the relative much experience with surgical treatment of this disease by all surgeons and the performance of operations in one highly specialized center. The differences between the surgeons are less pronounced after resection of tumors at low recurrence risk. The recurrence rates for primary single (below 10 %), recurrent or multiple (below 19 %), and for recurrent and multiple (below 32 %) tumors within the first year after surgery can be taken for the quality criteria of TUR

Эффективность трансуретральной резекции под контролем фотодинамической диагностики и внутрипузырных инстилляций бациллы Кальметта-Герена при низкодифференцированном раке мочевого пузыря без мышечной инвазии

Background. High-grade non-muscle-invasive bladder cancer (NMIBC) is characterized by a high rate of recurrence, progression, and mortality associated with this disease. Organ-preserving treatment by transurethral resection and immunotherapy with bacillus Calmette-Guerin (BCG) is an initial approach to therapy in these patients. However, the efficacy of such therapy is limited. This justifies the use of other methods of treatment, such as TUR under the control of photodynamic diagnosis (PDD). Aim of this study was to evaluate the effectiveness of therapeutic interventions in patients with high-grade NMIBC.Materials and methods. We have retrospectively analyzed results of follow-up of patients with primary or recurrent high-grade transitional cell NMIBC, treatment by TUR in conjunction with BCG or without it N.N. Alexandrov National Cancer Centre in the period from 2004 to 2013. In total, the study included 113 patients (27 women and 86 men), in the median age of 72 years. We have evaluated 5-year recurrence- and progression-free survival, analyzed an influence of prognostic factors and methods of treatment on the risk of recurrence and progression with Cox model and Kaplan–Meier method.Results. With a median of follow up of 59 (12–116) months the rates of 5-year recurrence- and progression-free survival were respectively 42.5 and 71.6 %. Statistically significant association with the risk of recurrence was observed in multivariate Cox regression analysis for recurrent tumors (hazard ratio (HR) 2.73; 95 % confidence interval (CI) 1.61–4.62) and immunotherapy with BCG (HR 0.56; 95 % CI 0.31–0.99). BCG significantly increased recurrence-free survival in patients with both primary tumors, and with recurrent ones. Significant factors in the multivariate analysis with regard to the risk of progression were suspicion for muscle-invasive tumors according to the cystoscopic picture (HR 3.36; 95 % CI 1.09–10.4), abnormal tumor-free bladder mucosa, suspicious for carcinoma in situ (HR 7.23; 95 % CI 2.64–19.8), localization of tumor in the bladder neck, orifice zone, prostatic urethra (HR 2.91; 95 % CI 1.17–7.25) and PDD-assisted TUR (HR 0.10; 95 % CI 0.01–0.78). TUR under the control of photodynamic diagnosis significantly increased the survival to progression, regardless of the risk of progression, while BCG did not significantly affect the progression-free survival.Conclusions. 6-week course of BCG therapy in patients with high-grade NMIBC significantly reduces the risk of recurrence and has no effect on the risk of tumor progression. PDD-assisted TUR provides a significant reduction in the risk of progression, but not recurrence. The findings justify the inclusion of both modalities in the treatment of high-grade NMIBC. ВВЕДЕНИЕ: Низкодифференцированный рак мочевого пузыря без мышечной инвазии (РМПБМИ) характеризуется высокой частотой рецидивирования, прогрессирования и смертности, связанной с данным заболеванием. Начальной тактикой лечения большинства таких пациентов является органосохраняющее лечение с использованием трансуретральной резекции (ТУР) и иммунотерапии бациллой Кальметта-Герена (БЦЖ), однако возможности такой терапии ограничены, что обосновывает использование дополнительных методов, например фотодинамической диагностики (ФДД). Целью данного исследования стала оценка эффективности лечебных воздействий у пациентов, страдающих низкодифференцированным РМПБМИ.МАТЕРИАЛ И МЕТОДЫ: Ретроспективно проанализированы результаты наблюдения за пациентами с первичным или рецидивным переходно-клеточным низкодифференцированным РМПБМИ, леченным с использованием ТУР ± БЦЖ в РНПЦ ОМР им. Н.Н. Александрова с 2005 по 2013 гг. Всего в исследование включено 113 пациентов (27 женщин и 86 мужчин), медиана возраста 72 года. Рассчитаны 5-летние безрецидивная выживаемость и выживаемость до прогрессирования данной группы пациентов, анализировано влияние факторов прогноза и методов лечения на риск рецидива и прогрессирования с использованием модели Кокса и метода Каплана-Мейера.РЕЗУЛЬТАТЫ: При медиане наблюдения 59 мес. (12-116 мес.) показатели 5-летней безрецидивной выживаемости и выживаемости до прогрессирования составили соответственно 42,5% и 71,6%.В мультивариантном регрессионном анализе Кокса статистически значимая связь с риском рецидива отмечалась для рецидивных опухолей (отношение рисков (ОР) 2,73; 95% ДИ 1,61-4,62) и проведения иммунотерапии БЦЖ (ОР 0,56; 95% ДИ 0,31-0,99). БЦЖ существенно увеличивало безрецидивную выживаемость как у пациентов с первичными опухолями, так и с рецидивными. В отношении риска прогрессирования значимыми факторами в мультивариантном анализе оказались подозрение на мышечно-инвазивную опухоль по данным цистоскопической картины (ОР 3,36; 95% ДИ 1,09-10,4), измененная свободная от опухоли слизистая мочевого пузыря, подозрительная на CIS (ОР 7,23; 95% ДИ 2,64-19,8), локализация опухоли в шейке, зоне устьев, простатической уретре (ОР 2,91; 95% ДИ 1,17-7,25) и проведение ТУР под контролем ФДД (ОР 0,10; 95% ДИ 0,01-0,78). Проведение ФДД статистически значимо повышало выживаемость до прогрессирования вне зависимости от риска прогрессирования, тогда как БЦЖ существенно не влияла на выживаемость до прогрессирования.ВЫВОДЫ: У пациентов, страдающих низкодифференцированным РМПБМИ, проведение 6-недельного курса БЦЖ существенно снижает риск рецидива и не влияет на риск прогрессирования опухоли. Проведение ТУР под контролем ФДД обеспечивает значимое снижение риска прогрессирования, но не рецидива. Результаты исследования обосновывают включение обеих воздействий в алгоритм органосохраняющего лечения низкодифференцированного РМПБМИ

Влияние хирурга на безрецидивную выживаемость пациентов, страдающих раком мочевого пузыря без мышечной инвазии

Background. The high rate of recurrences after visual complete transurethral resection (TUR) is a main problem in the treatment of nonmuscle-invasive bladder cancer (NMIBC). One of the factors influencing the long-term results of treatment for this pathology may be the quality of TUR, which depends on a surgeon’s experience.Objective: to evaluate the impact of a surgeon on relapse-free survival rates after radical treatment in patients with NMIBC and to search the optimal quality criteria for TUR in this disease.Materials and methods. The data of patients with primary or recurrent NMIBC treated using TUR with and without intravesical therapy at the N. N. Aleksandrov Republican Research and Practical Center for Oncology and Medical Radiology in 2004 to 2013 were retrospectively analyzed. The investigation included a total of 949 cases of performing organ-sparing treatment in 784 patients. The operations were made by 5 surgeons with comparable experience with TUR.Results. At a median follow-up of 64.3 (3–124) months, the 5-year relapse-free survival rates in 5 surgical groups were 62.9 (95 % confidence interval (CI) 56.2–69.7), 53.6 (95 % CI 47.4–59.9), 51.0 (95 % CI 39.6–62.4), 46.2 (95 % CI 36.4–56.0), and 44.2 % (95 % CI 36.8–51.7), respectively (p < 0.0001). According to the data of multivariate analysis including all potential factors, the prognostic role of a surgeon’s experience retained a high level of statistical significance (p = 0.0013). The differences between the surgeons were less pronounced after resection of tumors at a low risk for recurrence. Analysis of the distribution of the recurrence rates within the first 3, 6, and 12 months after TUR in relation to the surgeon, which were stratified according to recurrence risk groups, showed that the most differing rates were observed 12 months after TUR.Conclusion. An operating surgeon has a significant effect on the risk of recurrence after radical treatment in patients with NMIBC. In our investigation, this effect was observed in spite of the relative much experience with surgical treatment of this disease by all surgeons and the performance of operations in one highly specialized center. The differences between the surgeons are less pronounced after resection of tumors at low recurrence risk. The recurrence rates for primary single (below 10 %), recurrent or multiple (below 19 %), and for recurrent and multiple (below 32 %) tumors within the first year after surgery can be taken for the quality criteria of TUR.Введение. Основной проблемой при лечении рака мочевого пузыря без мышечной инвазии (РМПБМИ) является высокая частота рецидивов после визуально полной трансуретральной резекции (ТУР). Одним из факторов, влияющих на отдаленные результаты лечения этой патологии, может быть качество выполнения ТУР, которое зависит от опыта хирурга.Цель работы – оценка влияния хирурга на безрецидивную выживаемость после радикального лечения пациентов с РМПБМИ, а также поиск оптимальных критериев качества выполнения ТУР мочевого пузыря при этом заболевании.Материалы и методы. Проведен ретроспективный анализ данных пациентов с первичным или рецидивным РМПБМИ, леченных с использованием ТУР с или без проведения внутрипузырной терапии на базе РНПЦ ОМР им. Н.Н. Александрова с 2004 по 2013 г. Всего в исследование включены 949 случаев проведения органосохраняющего лечения у 784 пациентов. Операции выполняли 5 хирургов со сравнимым опытом проведения ТУР.Результаты. При медиане наблюдения 64,3 (3–124) мес показатели 5-летней безрецидивной выживаемости в 5 хирургических группах составили 62,9 (95 % доверительный интервал (ДИ) 56,2–69,7), 53,6 (95 % ДИ 47,4–59,9), 51,0 (95 % ДИ 39,6–62,4), 46,2 (95 % ДИ 36,4–56,0) и 44,2 % (95 % ДИ 36,8–51,7) соответственно (p < 0,0001). По данным мультивариантного анализа с включением всех потенциальных факторов риска сохранялась прогностическая роль опыта хирурга с высокой степенью статистической значимости (р = 0,0013). Различия между хирургами были менее выражены при резекции опухолей с низким риском рецидива. Анализ распределения частоты рецидивов в первые 3, 6 и 12 мес после ТУР в зависимости от хирурга, стратифицированных по группам риска рецидива, показал, что наиболее различающиеся показатели наблюдались через 12 мес после ТУР.Выводы. Хирург-оператор оказывает существенное влияние на риск рецидива после радикального лечения пациентов с РМПБМИ. В нашем исследовании этот эффект наблюдался несмотря на относительно большой опыт оперативного лечения данной патологии всеми хирургами и выполнение операций в условиях одного высокоспециализированного центра. Различия между хирургами менее выражены при резекции опухолей с низким риском рецидива. За критерии качества выполнения ТУР можно принять частоту рецидивов в течение 1-го года после операции для первичных одиночных опухолей (до 10 %), для рецидивных или множественных опухолей (до 19 %) и для рецидивных и множественных (до 32 %)

FGFR3 and TP53 mutations in a prospective cohort of Belarusian bladder cancer patients

Aim: The aim of this study was to determine the frequencies of FGFR3 and TP53 mutations in a prospective cohort of 150 bladder cancer patients and to assess the relationship between their mutational status and clinicopathological variables. Materials and Methods: The FGFR3 and TP53 mutations were detected by the SNaPshot method and PCR-single-strand conformational polymorphism analysis followed by DNA sequencing. Results: The activating FGFR3 mutations were found in 71 (47.3%) whereas TP53 mutations were observed in 31 (20.7%) urothelial carcinomas. FGFR3-mutant tumors significantly correlated with lower tumor stage and grade, papillary form of bladder cancer and the absence of metastases while TP53-mutant tumors were strongly associated with higher tumor stage and grade as well as the presence of metastasis. We also found significant inverse correlation between FGFR3 mutations and TP53 alterations in urothelial carcinomas (p=0.03). Four possible genotypes were observed in the whole studied cohort, namely FGFR3mut/TP53wt (41.3%), FGFR3wt/TP53wt (38%), FGFR3wt/TP53mut (14.7%), and FGFR3mut/TP53mut (6%). Tumors with FGFR3wt/TP53wt genotype comprised the subgroup, in which all stages and grades were equally distributed. Conclusions: Our findings confirm the alternative role of FGFR3 and TP53 mutations in the development of bladder cancer. Together these two genetic markers are attributed to 62% of the tumors studied. Tumors with both wild type genes included urothelial carcinomas of all stages and grades and may develop through another genetic pathway. To elucidate complete molecular profile of bladder tumors further additional studies are needed. Key Words: bladder cancer, FGFR3 mutation, TP53 mutation, tumor genotype

Оценка риска рецидивирования и прогрессирования при раке мочевого пузыря без мышечной инвазии

A retrospective analysis of monitoring of patients with primary or recurrent non-muscle invasive bladder cancer (NMIBC) treated with transurethral resection (TUR) with or without restaging TUR or intravesical therapy in State Institution N.N. Alexandrov National Cancer Centre of Belarus in 2004–2012 was performed with an objective to develop a prognostic classification for NMIBC. The analysis included 921 patients. In the multivatiate analysis independent predictors of recurrence were recurrence rate, number of tumors, tumor size, grade, and tumor location in the trigone, anterior wall, dome, and prostatic urethra; predictors of progression were age, recurrence rate, tumor size, grade, and tumor location in the trigone and prostatic urethra. The patients were divided into 4 groups with low, intermediate, high and very high risk. Corrected C-index values for the developed classifications of recurrence and progression risks were 0.635 and 0.740 respectively, which were significantly higher than C-indices for the European Organization for Research and Treatment of Cancer tables.Для разработки прогностической классификации рака мочевого пузыря без мышечной инвазии (РМПБМИ) ретроспективно были проанализированы результаты наблюдения за пациентами с первичным или рецидивным РМПБМИ, леченными с использованием трансуретральной резекции (ТУР) с рестадирующей ТУР или без или внутрипузырной терапии в РНПЦ ОМР им. Н.Н. Александрова в период с 2004 по 2012 гг. В исследование включен 921 пациент. В мультивариантном анализе независимыми предикторами развития рецидива были частота рецидивирования, число опухолей, размер образования, степень дифференцировки и локализация опухоли в области треугольника, передней стенки, дна и простатической части уретры; предикторами прогрессирования – возраст, частота рецидивирования, размер опухоли, степень дифференцировки и локализация в области треугольника и простатической части уретры. Все пациенты были разделены на 4 группы: благоприятного, промежуточного, неблагоприятного и крайне неблагоприятного прогноза. Скорректированные показатели С-индексов для разработанных классификаций риска рецидивирования и прогрессирования составили 0,635 и 0,740 соответственно, что было существенно выше, чем С-индексы для таблиц Европейской организации по исследованию и лечению рака

The opposite association of HRAS and KRAS mutations with clinical variables of bladder cancer

HRAS, KRAS and NRAS gene products belong to the superfamily of small GTPases. These proteins regulate cellular response to extracellular stimuli by means of activation of different signaling pathways. Although the role of RAS gene mutations in the pathogenesis of various human cancers has been established, the clinical significance of these molecular alterations in bladder cancer remains unclear. The aim of this study was to determine the frequency and spectrum of HRAS, KRAS and NRAS mutations, to analyze their relationships with clinicopathological variables and to determine the prognostic value of these alterations in terms of recurrence, progression and mortality, in a prospective cohort of 249 bladder cancer patients. The frequency of RAS mutations detected by the SNaPshot method, was found to be 11.2 %, of which HRAS mutations accounted for 64.3 %, KRAS, for 28.6 % and NRAS, for 7.1 %. We failed to find any correlation between all RAS mutations and pathomorphological characteristics. However, when analyzed separately, HRAS and KRAS mutations were for the first time shown to be associated with the opposite clinical parameters of bladder cancer: HRAS mutations were significantly associated with low-stage low-grade papillary tumors of a small size (р < 0.05), whereas KRAS mutations were associated with non-papillary urothelial carcinomas and the presence of metastasis (р < 0.05). Analysis of the prognostic value of molecular alterations revealed an association of KRAS mutations with decreased cancer-specific survival in both the whole group of patients and the subgroup with non-muscle invasive disease. The data obtained suggest that HRAS and KRAS gene mutations may characterize alternative pathways of bladder cancer pathogenesis: HRAS mutations indicating benign and KRAS mutations, aggressive disease course

ВНУТРИПУЗЫРНАЯ ИММУНОТЕРАПИЯ ВАКЦИНОЙ БЦЖ И ИНТЕРФЕРОНОМ-Α2B ПРИ НЕИНВАЗИВНОМ РАКЕ МОЧЕВОГО ПУЗЫРЯ: РЕЗУЛЬТАТЫ ПРОСПЕКТИВНОГО РАНДОМИЗИРОВАННОГО ИССЛЕДОВАНИЯ

Background: Both bacillus Calmette-Gue’rin (BCG) and interferon-alpha (IFN-α) are active against urinary bladder cancer. In this studywe evaluate the therapeutic efficacy and toxicity of combined intravesical BCG plus IFN-α for treating non-invasive bladder cancer.Subjects and methods: A total of 149 patients (mean age 63.2 years) were enrolled for the study. The inclusion criteria were histologically verifiednon-invasive transitional cell carcinoma with intermediate and high risks of recurrence and progression. After transurethral tumor resection, all thepatients were randomized in three groups. Group 1 (n=60) was treated with a 6-week course of BCG, 125 mg, starting 14 to 21 days after TUR, Group2 (n=60) patients received 6-week instillations of BCG, 125 mg, plus IFN-α, 6 million units, Group 3 patients (n = 29) had 4-month courses ofintravesical IFN-α, 6 million units, twice daily during 3 consecutive days. A response was assessed by cystoscopy every 3 months after treatment.Results: A median follow-up of 30.9 months revealed recurrences in 26 (43.3%) patients in the BCG group, 8 (13.3%) patients in the BCG + IFN-αgroup and 18 (62.1%) patients in the IFN-α group. Progression to muscle invasion occurred in 12% and 7% in Groups 1 and 3, respectively, withno progression in Group 2 patients. Three-year relapse-free survival was higher in the BCG+IFN group (78.5% versus 62.6 and 40.2% in theBCG and IFN-α groups, respectively). There was no significant difference between the BCG groups in relapse-free survival. Monotherapy withIFN-α showed a significantly lower response rate than did BCG therapies (p = 0.007). Adverse reactions were observed in 25, 116, and 6.9% ofpatients from Groups 1, 2 and 3, respectively. Toxicity-related withdrawal and treatment delay were similar in both BCG groups. Comparison ofthe rate of adverse reactions revealed a significant difference between the BCG + IFN-α and BCG groups (p = 0.025). The respective rates ofmoderate-to-severe adverse reactions caused by treatment were 6.7 and 21.7% in the BCG+IFN-α and BCG groups, respectively (p = 0.013).Conclusions: Full-dose intravesical BCG plus IFN-α appears to be much effective than BCG and IFN-α monotherapies despite that there isno significant difference in this study. IFN-α monotherapy showed the lowest complication rate but a lower response rate than those withBCG therapies (p = 0.007). The co-administration of BCG and IFN-α displayed a significantly less complication rate and severe adversereactions (p = 0.025 and p = 0.013, respectively). Longer follow-up is required to validate these findings. Внутрипузырная иммунотерапия вакциной БЦЖ и интерфероном-α2b при неинвазивном раке мочевого пузыря: результаты проспективного рандомизированного исследовани

Результаты лечения больных раком мочевого пузыря с метастазами в регионарных лимфоузлах

The data of 668 radical cystectomies were used to study the results of treatment in 151 (22,6%) patients with urinary bladder cancer (UBC) metastasizing to the regional lymph nodes and to evaluate the impact of lymphodissection extent on the detection rate of metastases and on survival.In UBC, routine lymphodissection significantly increases the detection rate of regional metastases as compared with limited lymphodissection from 17,8 to 24,8% (p = 0,04). Expanded lymphodissection in patients with UBC with regional metastases could significantly increase overall 5-year survival (p = 0,006).In patients with UBC metastasizing to the regional lymph nodes, the survival rates found after cystectomy using the currently available urine derivation techniques suggest that orthotopic urine derivation may be used in this group of patients after radical operation. Among all factors influencing survival in such patients, the degree of involvement of regional lymph nodes (p = 0,04) and the extent of lymphodissection (p = 0,02) are of independent prognostic value.