Objective: to re-evaluate the efficacy and safety of lenvatinib with pembrolizumab in unselected Russian renal cell carcinoma (RCC) patients, included in the phase IV study, in a median follow-up extended to 17.1 months. The primary end point was progression-free survival (PFS), secondary end points were overall survival (OS), objective response rate (ORR) and duration of response (DOR), disease control rate (DCR) and its duration, as well as safety. Materials and methods. The study included medical data of 165 patients with verified advanced RCC who received lenvatinib with pembrolizumab in 36 centers of the Russian Federation from 05.02.2018 to 25.07.2024. The median age was 60 (20-76) years, the male to female ratio was 2.3:1. The majority of patients had Karnofsky performance status >= 80 % (74.6 %), clear cell RCC (93.3 %) without sarcomatoid differentiation (93.3 %), metachronous metastases (50.9 %) localized in >1 organ (75.2 %), were nephrectomized (63.0 %) and did not receive antitumor therapy (91.0 %). At the time of lenvatinib with pembrolizumab therapy start 40 patients (24.2 %) were classified into International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) favorable prognostic group, 92 (55.8 %) in the intermediate prognostic group, and 33 (20.0 %) in the poor prognostic group. The median follow-up was 17.1 (1.5-72.9) months. Results. The median PFS achieved 24.0 (18.7-29.3) months, 17-month PFS- 60.5%. The median OS was 48.9 (18.5- 79.2) months, 17-month OS - 76.1 %. Objective response was registered in 46.0 % of patients including 2.4 % complete responders; the DCR was 92.1 %. The median DOR was 16.6 (2.1-72.9) months, duration of disease control - 14.3 (2.1-72.9) months. Confirmed dynamics of change in the sum of tumor foci diameters was recorded in 152 patients, while the median change was -25 % (from -100 % to +29 %). Any decrease in the sum of tumor foci diameters occurred in 69.1 % of cases. The incidence of any adverse events (AE) was 78.2 %, severe AE - 24.2 %, and serious AE - 9.7 %. Immune-mediated AEs developed in 17.0 % of cases and AE grades 3-4 in 6.7 % of cases. Mortality from AEs was 1.2 %. Conclusion. Compared with the registration study, in real-world clinical practice in patients with advanced RCC the lenvatinib with pembrolizumab provides a lower ORR with comparable PFS and OS rates and demonstrates a satisfactory safety profile.

This article analyzes first results of the randomized phase III clinical trial CheckMate 274 that has demonstrated the advantage of adjuvant immunotherapy with nivolumab, a PD-1 inhibitor, over placebo in high-risk patients with muscle-invasive urothelial carcinoma after radical surgery

Objective. Evaluation of utility and safety of salvage cystectomy after organ preservation treatment in patients with muscle-invasive bladder cancer.Materials and methods. A retrospective study included data on 130 patients with transitional cell carcinoma treated at the N.N. Blokhin Russian Cancer Research Center in 1981-2016. The main group included 66 patients who underwent salvage cystectomy after unsuccessful organ preservation treatment based on beam radiation therapy. Lymph node dissection was performed in 42 (63.6 %) patients. For the purposes of urinary diversion 42 (63.6 %) patients received ileal conduit (Bricker procedure), 7 (10.6 %) - Studer deal neobladder, 17 (25.8 %) - other treatment. Bladder cancer was morphologically confirmed in 62 (93.9 %) samples (P1 stage - 6 (9.1 %), P2 - 21 (31.8 %), P3 - 25 (37.9 %), P4 - 18 (27.2 %)); lymph node metastases were discovered in 11 (16.6 %) cases. Anaplasia grade was G(3) in 35 (56.5 %) of the 62 samples containing tumor. Control group included 64 patients who underwent radical cystectomy without previous treatment. Rates of T3a-4b categories and G3 anaplasia grade were significantly higher in the main group (p < 0.0001).Results. Rate of intraoperative complications of salvage cystectomies was 10.6 %, postoperative - 42.7 % (28 of 65) (severity grade I-II in 27.3 % (18 of 28) of cases, severity grade III-V in 15.4 % (10 of 28) of cases). Five-year total, specific and relapse-free survival in the main group was 43.7, 58.6 and 54.7 %, respectively. Independent factors of favorable prognosis for survival were anaplasia grade G(1-2), hydronephrosis and lymph node dissection. Recurrences after salvage surgeries were less frequent than after cystectomies performed without previous treatment (19 (30.6 %) and 31 (48.4 %), respectively, p = 0.031). No other statistically significant differences between salvage and radical cystectomies were observed.Conclusion. Salvage cystectomy after unsuccessful organ preservation treatment in patients with muscle-invasive bladder cancer is associated with acceptable surgical risk and provides satisfactory long-term results comparable with radical cystectomy.

Objective: to estimate overall survival (OS) rates in patients with metastatic castration-resistant prostate cancer (mCRPC), who have received currently available drugs and to identify the predictors of OS.Subjects and methods. The case histories of 112 patients with mCRPC treated at the N.N. Blokhin Russian Cancer Research Center in 2005 to 2014 were retrospectively analyzed. All the patients had received standard regimens based on docetaxel, cabazitaxel, abiraterone acetate in combination with prednisolone.Results. Whatever the treatment option was, three-year OS rate was 32.0 ± 5.44 %; median survival was 24.3 months. The following poor prognostic factors for OS were pain syndrome; an ECOG performance status score of 2; the levels of prostate-specific antigen ≥ 288 ng/ml, lactate dehydrogenase ≥ 450 U/l, alkaline phosphatase ≥ 250 U/l, calcium < 2.28 mmol/l, and hemoglobin < 11.5 g/dl; as well as < 24 months’ duration of a response to hormonal therapy.Conclusion. The use of standard drug treatment regimen for mCRPC may increase survival in this category of patients to achieve 3-years OV; and the identified factors of OV may aid in choosing treatment policy.

Objective: to assess the role of palliative nephrectomy in disseminated kidney cancer patients planned to undergo targeted antiangiogenic treatment.Subjects and methods. The investigation included data on 83 patients with T1-4N0 / +M1 disseminated renal cell carcinoma (RCC) who had received at least 2 targeted therapy cycles in 2009 to 2011. In 48 (57.8 %) patients, the treatment was preceded by palliative nephrectomy that was not carried out in 35 (42.2 %). Before starting targeted therapy, all the cases were confirmed to be diagnosed with clear cell RCC, with a sarcomatoid component being in 7 (8.4 %) patients. The median follow-up of all the patients was 21 (12–36) months.Results. The unremoved affected kidney in disseminated kidney cancer patients receiving targeted antiangiogenic therapy is an independent factor for the poor prognosis of progression-free (odds ratio (OR), 2.4; 95 % confidence interval (CI), 1.2–4.7) and overall (OR, 2.8; 95 % CI, 1.3–6.3) survival. Palliative nephrectomy does not improve the prognosis in patients with a low somatic status, the N+ category, and metastases into the bones and nonregional lymph nodes.Conclusion. Palliative nephrectomy in the selected patients with disseminated kidney cancer on targeted antiangiogenic therapy increases progression-free and overall survival.

Fluorescence in situ hybridization is a current technique to detect chromosomal specific genetic disorders specific to urinary bladder cancer (UBC). This technique may be used to diagnose UBC, to follow up patients after surgical treatment, to evaluate the efficiency of adjuvant therapy in these patients, and to predict the development of disease recurrence.

Objective: to identify the predictors of perioperative complications and deaths in surgically treated patients with kidney cancer complicated by venous tumor thrombosis.Subjects and methods. The investigation included data on 463 kidney cancer patients with venous tumor thrombosis. The patients, median age was 57 years. The male / female ratio was 2.5:1. Perirenal, subhepatic, retrohepatic, and supradiaphragmatic tumor thrombi were diagnosed in 161 (34.8 %), 135 (29.2 %), 82 (17.7 %), and 85 (18.3 %) patients, respectively. Regional and distant metastases occurred in 90 (19.4 %) and 145 (31.3 %) cases, respectively. All the patients underwent thrombectomy, retroperitoneal lymphadenectomy; a tumor-affected kidney was removed in 452 (97.6 %) patients.Results. Median surgery duration was 259 (30–580) min; median blood loss was 3500 (100–27 000) ml. The incidence of intraoperative complications was 24.6 % (114 / 463); mortality was 0.9 % (4 / 463). The independent risk factors of intraoperative complications were cranial margin of a tumor thrombus (odds ratio (OR) 1.9; 95 % CI 1.4–2.6; p < 0.0001) and circular resection of the inferior vena cava (OR 5.8; 95 % CI 1.2–27.8; p < 0.0001). The incidence of postoperative complications was 25.7 % (118 / 459);mortality was 6.0 % (28 / 459). Resurgery was required in 31 (6.8 %) cases. Regression analysis identified the risk factors of postoperative complications (highly located cranial thrombus margin (OR 2.6; 95 % CI 1.1–6.4; p = 0.037) and lactate acidosis (OR27.1; 95 % CI 1.2–613.1; p = 0.038), postoperative death (hepatic vein thrombosis (OR 15.6; 95 % CI 4.5–54.3; p < 0.0001),lactate acidosis (OR 23.1; 95 % CI 3.4–158.4; p = 0.001) thrombus removal from the heart (OR 5.0; 95 % CI 2.1–12.2; p < 0.0001)),perioperative death (cranial thrombus margin (OR 1.9; 95 % CI 1.2–3.2); р = 0.007), contralateral renal vein thrombosis (O R 4.4;95 % CI 1.2–15.8; p = 0.025), lactate acidosis (OR 28.4; 95 % CI 4.9–165.1; p < 0.0001), and low creatinine clearance (OR 4.6;95 % CI 1.9–24.9; p = 0.017).Conclusion. Thrombectomy in patients with T3a–cNxMx kidney cancer is a technically difficult intervention associated with the high incidence of complications and death, which must be performed only in specialized centers. The identified risk factors may serve as criteria for predicting the results of thrombectomy.

In a recent randomized, double-blind, phase III clinical trials among patients with metastatic castration-resistant prostate cancer (CRPC) progressing on androgen-deprivation therapy or after docetaxel chemotherapy, abiraterone acetate was shown to significantly prolong radiographic progression free survival and overall survival compared with prednisone alone, even in symptomatic patients and patients having visceral metastases and high level of prostate specific antigen at baseline. Here we present our own experience with abiraterone acetate in patients who represent negative prognostic factors of castration-resistant prostate cancer outside of clinical trials. 25 metastatic CRPC patients were treated with abiraterone acetate from 2012 to 2014.

Objective: to study the prognostic value of alterations in the VHL gene and the plasma markers hVEGF, hVEGFR2, and hVEGFR3 in patients with metastatic kidney cancer (KC) who receive targeted therapy.Subjects and methods. Paraffin blocks from 22 patients with metastatic KC who received targeted therapy were analyzed for VHL gene mutation/methylation. Polymerase chain reaction (PCR) products were sequenced using a BigDye® Terminator v 3.1, a Cycle Sequencing Kit, and an ABI3100 genetic analyzer in accordance with the Applied Biosystems protocols. VHL gene methylation was determined by methyl-sensitive PCR. The markers hVEGF, hVEGFR2, and hVEGFR3 were measured in the plasma of 43 patients before, during, and after targeted therapy, by applying the commercial DuoSet® ELISA kits (RnDSystems, USA). The results obtained were analyzed by known statistical methods, by using the package of statistical programs SPSS 13.0 for Windows. Survival was estimated by the Kaplan-Meier method. Survival differences were found by the log-rank test in the patient groups. Cox uni- and multi-factorial regression analyses were used to identify factors that were prognostically significant for survival.Results. Out of 22 patients, 10 (45.5 %) and 1 (4.5 %) were found to have VHL gene mutations or methylation, respectively. VHL gene inactivation did not affect prognosis in patients and the results of antiangiogenic therapy. Correlation analysis revealed no relationship between the concentrations of hVEGF and hVEGFR2 before and during therapy or absolute increases in hVEGF and hVEGFR2 concentrations during treatment with the frequency of progression during targeted therapy, with progression-free survival, and total life expectancy. No correlation was either found between the hVEGFR3 concentration and its changes and the results of antiangiogenic therapy. There was an inverse correlation between the pretreatment plasma hVEGFR3 level and lifetime without progression during antiangiogenic therapy (r = – 0.477, p = 0.039).Conclusion. VHL gene alterations and plasma hVEGF and hVEGFR2 levels are not predictors of a response to antiangiogenic therapy. The pretreatment plasma hVEGFR3 level correlates with progression-free survival in KC patients receiving targeted therapy.

Blocks of preparations from 22 patients with metastatic renal cell carcinoma on target therapy were studied. The patients were examined for mutations/methylation of VHL gene. The mutations were detected in 10 (45.5%) of 22 patients, VHL methylation was found in 1 (4.5%) patient. Overall survival was 36.4 and 66.7% in the groups of patients with and without gene VHL alteration, respectively. Progression-free survival was 47.6 and 57.1%, respectively (p = 0.619), relapse-free survival--63.6 and 45.5%, respectively (p = 0.682), progression was registered in 36.4 and 54.5%, respectively (p = 0.682). Gene VHL inactivation had no effect on prognosis of the disease and results of anti-angiogenic therapy.

To compare the results of radical prostatectomy and conformal radiotherapy in prostatic cancer T1-4N0-1M0, we made a retrospective study of 306 patients with prostatic cancer T1-4N0-1M0 of whom 144 (47.1%) were treated surgically (radical prostatectomy) while 162 (52.9%) were exposed to extracorporeal conformic radiotherapy. Follow-up median was 30.7 +/- 29.8 months. Five and 10-year overall, specific and PSA recurrence free survival in 306 patients was 94.0% and 90.1% (median was not achieved), 96.6% and 94.3% (median was not achieved), 66.1 and 49.2% (median was 84.0 +/- 4.4 months). In multifactorial analysis significant prognostic factors of PSA recurrence free survival were T category (p = 0.021) and Glison's sum (p = 0.002). In the subgroup of patients with local prostatic cancer there was a significant superiority of the operated patients by PSA recurrence free survival over irradiated group in baseline PSA < 10 ng/ ml (p = 0.015), Glison's index < 7 (p = 0.071) and combination of these factors (p = 0.018). A favourable prognosis factor of PSA recurrence free survival in operated patients was operative Glison's index < 7 (p = 0.001), among operated patients--nadir PSA < 1 ng/ ml (p = 0.003). Surgical and radiation treatment of local and locally advanced prostatic cancer provided satisfactory results. In the group of good prognosis (cT1-2N0, PSA < 10 ng/ml, Glison's sum < 7) radical prostatectomy gives advantage of PSA recurrence free survival. In patients with prostatic cancer cT > T2, N+, Glison's index > 7 and PSA > 10 ng/ml surgical treatment and remote radiotherapy are equally effective in respect to survival free of biochemical recurrence.

The data of preoperative diagnosis and morphological examination were compared for 144 patients with prostatic carcinoma T1-4N0-XM0 subjected to radical prostatectomy in 1997-2007. In assessment of prostatic capsule invasion, sensitivity of the rectal examination was 21.7%, specificity--89.8%, diagnostic efficacy--68.1%, PPV--50.0%, NPV--70.9%, AUC under ROC curve--0.558 +/- 0.053 (p = 0.348); sensitivity of transrectal ultrasonic investigation--21.7%, specificity--89.8%, diagnostic efficacy--68.8%, PPV--52.6%, NPV--71.2%, AUC under ROC curve--0.563 +/- 0.053 (p = 0.211). Factors of a poor prognosis of prostatic capsule invasion were PSA > 10 ng/ml (p = 0.028) and Gleason score > 7 (p = 0.052). Combined use of these two parameters raises quality of preoperative assessment of category T [sensitivity--80.0%, specificity--55.1%, diagnostic efficacy--56.3%, PPV--80.4%, NPV--44.9%, AUC under ROC curve--0.624 +/- 0.049 (p = 0.017)]. Sensitivity of clinical assessment of N category was 11.1% in 100% specificity, 94.4% diagnostic efficacy, 100% PPV, 94.4% NPV, 0.556 +/- 0.107 (p = 0.577) AUC under ROC curve. A single significant prognostic factor of pN+ category was PSA > 10 ng/ml (p = 0.014). Sensitivity of histological examination of biopsy material in relation to true Gleason's parameter (< 7 or > 7) was 59.4%, specificity 89.3%, diagnostic efficacy 82.6%, PPV 61.3%, NPV 88.5%, AUC under ROC curve 0.743 +/- 0.056 (p < 0.0001). Thus, combined use of a baseline PSA concentration with a borderline value > 10 ng/ml and biopsy Gleason score > 7 raises quality of preoperative evaluation of extraprostatic tumor extension and condition of regional lymph nodes.

Docetaxel is the most effective chemical agent used in the treatment of hormone-resistant prostate cancer (HRPC). Three different docetaxel-based combinations were tested. The study included 30 patients with HRPC: 10 patients received chemotherapy as intravenous docetaxel, 75 mg/m2 once every 21 days with prednisolone, 10 mg/day (DP); other 10 patients had docetaxel, 75 mg/m2, estramustin, 300 mg/m2 daily, and prednisolone, 10 mg daily (DEP); 10 more patients received a combination of doxorubicin, 20 mg/m2 on day 1 of weeks 1, 3, and 5, ketoconazole, 1200 mg/day on days 1—7 of weeks 1, 3, and 5, docetaxel, 20 mg/m2 on day 1 of weeks 2, 4, and 6, estramustin, 420 mg/day on days 1—7 of weeks 2, 4, and 6, prednisolone, 10 mg daily (DEKP). The study revealed that all these three combinations have about the same efficacy; with their use, the clinical improvement rate was 70—80%. Thus, the use of docetaxel in different combinations is an effective treatment for HRPC.

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A total of 59 patients with hormone-resistent prostatic cancer (HDPC) treated in 1999-2004 entered the trial. Three schemes of first-line chemotherapy were examined for clinical efficacy and toxicity in the above patients. Anticancer combined treatment vinorelbin + cycloplatam was given to 23 patients, mitoxantron + prednisolone--to 23 patients, mitoxantron+cysplatin+prednisolone--to 13 patients. The latter scheme was most effect and toxic. Partial regression of metastases and a 50% decrease in the initial PCA level were seen in 23% cases. Vinorelbin+cycloplatam was less effective and toxic: partial regression of metastases--13%, PSA regression-- 17.4%. The least efficacy and toxicity were observed in the treatment with mitoxantron+prednisolone --.7%. Thus, the above first-line HDPC therapy was most effective but has the highest toxicity in using the scheme mitoxantron+cysplatin+prednisolone.

The purpose of the study was to reveal the most optimal treatment of hormone-resistant prostatic cancer (HRPC), by comparatively analyzing the efficiency and toxicity of 4 chemotherapy regimens: 1) mitoxantrone, 12 mg/m2, i.v. once 21 days; prednisolone, 10 mg/day (MP); 2) mitoxantrone, 12 mg/m2, i.v. on day 2; cisplatin, 60 mg/m2, i.v. on day 1; prednisolone, 10 mg/day (MCP); 3) docetaxel, 75 mg/m2; estramustine, 300 mg/m2 daily; prednisolone, 10 mg/day (DEP); 4) doxorubicin, 20 mg/m2, on day 1 of weeks 1, 3, and 5; ketoconasole, 1200 mg/day on days 1—7 of weeks 1, 3, and 5; docetaxel, 20 mg/m2 on day 1 of weeks 2, 4, and 6; estramustine, 420 mg/day, on days 1—7 of weeks 2, 4, and 6; prednisolone, 10 mg/day (DKDEP). The study covering 39 patients indicated the low efficiency of MR (8,6%) as first-line chemotherapy for HRPC and the high efficiency of the docetaxel-induced regimens used mainly as second-line chemotherapy: DEP (40%) and DKDEP (30%). Treatment of HRPC was most effective when the docetaxel-containing combinations were administered. The latter may be used as first-line chemotherapy and second-line one after application of mitoxantrone-containing regimens.