Vol 26, No 3 (2024)

On May 20, 2024, the Expert Panel discussed key issues of the diagnosis of alterations of the AKT signaling pathway, the effectiveness and safety of targeted therapy for hormone-positive (HR+) HER2-negative metastatic breast cancer (BC) concerning the emergence of a new selective AKT inhibitor capivasertib. The results of the CAPItello-291 study are presented. The experts concluded that a new effective treatment line has become available for patients with hormone-resistant advanced hormone-positive HER2-negative BC with genetic alterations in the AKT signaling pathway and relapse on previous adjuvant endocrine therapy with aromatase inhibitors or within the first year after the therapy or with progression during previous therapy with aromatase inhibitors for metastatic BC. Modern genetic testing methods for the alterations in the AKT signaling pathway can confirm the presence of this key biological target in the tumor for tailoring effective targeted therapy.

Aim. To analyze the treatment (8 cycle FLOT + surgery) to search for predictors of tumor pathomorphosis, assess the impact of chemotherapy on treatment results, and identify other factors that significantly influence treatment results.

Materials and methods. Included 119 patients who underwent perioperative chemotherapy (FLOT) in combination with surgery in 2023 on the basis of the Nizhny Novgorod Regional Clinical Oncological Dispensary. This study consisted of two blocks: Identification of relationships between the analyzed parameters and the pathomorphological response, the development of postoperative complications. Analysis of overall and disease-free survival (DFS). In the analysis of nominal indicators, the first step was to use χ2 Pearson and Fisher's exact test. At the second stage, when statistical significance was achieved, the strength of the relationship was calculated for variables with two levels of the factor – Cramer’s V on the Rea & Parker scale, odds ratio (OR) with a 95% confidence interval (CI), for variables with more than two factors, post-hoc analysis was performed with Benjamini–Hochberg correction for multiple comparisons. All quantitative indicators in the published sample have a distribution other than normal. The measure of central tendency is the median with 25th and 75th percentiles. When comparing two groups of quantitative indicators, the Mann–Whitney test was used; when comparing a larger number of groups, the Kruskal–Wallis test was used with post-hoc analysis using the Dunn test (if statistically significant differences were achieved at the first stage).

Results. Analyzing the relationship between neo-adjuvant chemotherapy according to the FLOT regimen and the presence of response (TRG I–II), there was a lack of respondents in the subgroup who received neo-adjuvant chemotherapy according to regimens other than FLOT (p=0.019). Patients with stage I disease have a comparatively higher response rate to treatment compared with patients with ≥ stage III disease (post-hoc p-value=0.006). In the group of respondents there are fewer patients with positive lymph nodes compared to the group that did not respond to treatment (8.7% and 91%), the result is statistically significant (p-value <0.001). The presence of a response (TRG I–II) statistically significantly reduces the chance of positive tests by 7.30 times – OR 0.137 (95% CI 0.044–0.421). When conducting a subgroup analysis, the median age of patients with complications of types I–IIIa by Clavien–Dindo is statistically significantly lower compared to complications of types IIIb–V. There was no statistically significant relationship between tumor differentiation and response to treatment (p=0.3). When analyzing overall survival, there was a statistically significant increase in the risk of death with an increase in the number of postoperative days by 1 by 1.134 times or 13.4% (p=0.004). An increase in the number of metastatic lymph nodes by 1 increased the risk of death by 1.091 times or 9.1% (p=0.017). When analyzing DFS, a statistically significant increase in the risk of progression was revealed with an increase in the degree of pathomorphosis according to Mandard by 1 degree (starting from I) by 1.423 times or by 42.3% (p=0.042), an increase in the degree of pN-status by 1 (starting from N1) by 1.290 times or by 29.0% (p=0.011), an increase in the number of postoperative days by 1 by 1.099 times or by 9.9% (p=0.025). When analyzing the overall survival of the subgroup who received adjuvant chemo, there was a statistically significant increase in the risk of death in the subgroup of patients with adjuvant cgemo with an increase in the number of metastatic nodes by 1 by 1.087 times or by 8.7% (95% CI 1.009–1.172; p=0.029). When analyzing DFS of the subgroup who received adjuvant chemo, there was a statistically significant increase in the risk of progression in the subgroup of patients who received adjuvant chemo with an increase in the degree of pN status by 1 (starting from N1) by 1.252 times or 25.2% (p=0.040). When determining the effect of adjuvant chemo on overall survival and DFS using the Cox regression method, no statistically significant results were obtained. However, taking into account the p-value close to 0.05, the regression coefficient and most of the 95% CI (less than 1), it can be assumed that conducting adjuvant chemo reduces the risks of death and disease progression, and to achieve statistically significant results, a larger number of and observation time, number of outcomes.

Conclusion. Neo-adjuvant FLOT is associated with a large number of TRG I–II in patients with an early stage of the disease in comparison with advanced forms of the disease. There was no effect of tumor differentiation or its histological subtype on the degree of TRG. Perioperative chemotherapy does not increase the incidence or severity of postoperative complications. Metastatic lesions of the lymph nodes significantly worsen overall survival and DFS; in the group of patients with TRG grade I–II, the frequency of metastatic lymph node lesions is lower compared to patients with TRG III–V. There is no significant data on the need for adjuvant chemo in the presence or absence of pathomorphosis, however, it can be assumed that performing adjuvant chemo reduces the risks of death and disease progression.

Background. The choice of the optimal scheme of perioperative chemotherapy of locally advanced gastric cancer is an urgent problem in real clinical practice.

Aim. To analyze therapy tolerability in this cohort of patients.

Materials and methods. Perioperative chemotherapy of gastric cancer was performed in 90 patients in the Chemotherapy Department of the Oncology Center №1 of the Yudin City Clinical Hospital from January 2021 to February 2024.

Results. The incidence of severe complications at the preoperative stage was 41.9% for the FOLFOX regimen and 40.7% for the FLOT regimen, at the adjuvant stage – 17.4 and 43.2%, respectively. Operative treatment was successfully performed in 79 (87.8%) patients, and the full scope of combined treatment of locally advanced gastric cancer was completed in 59 (65%) patients. 80.8% of pathomorphologic responses in the FOLFOX group and 67.9% in the FLOT group were TRG3-4, with complete response noted in only one patient.

Conclusion. High toxicity rates in elderly and comorbid patients on the FOLFOX regimen require the development of an individualized approach to the treatment of this group of patients.

Background. HIV infection and its consequences remain one of the dramatic problems of our time. Currently, for people receiving antiretroviral therapy, non-AIDS-related diseases are becoming relevant, among which malignant tumors are steadily coming to the fore. International data show that HIV-infected patients with cancer are significantly less likely to receive full anti-tumor treatment than patients without HIV.

Aim. To obtain objective data on the incidence, clinical course, and effectiveness of the most common therapies for patients with malignancies and HIV in real-world practice in Russia.

Materials and methods. The study was supported by the All-Russian National Union "Association of Oncologists of Russia." The questionnaire was sent to 1000 oncologists in all regions of the Russian Federation, of which 366 (36%) participated in the anonymous survey. The study did not imply any material award for the respondents. The questionnaire was developed with the direct collaboration of leading oncology experts in malignancies in HIV patients. It included questions about the frequency of follow-up of oncological patients with HIV, awareness of oncologists about the features of the malignancies in HIV patients, and treatment and supportive therapy of cancer patients with HIV infection. The key points of the analysis were the frequency and conditions of the standard anti-tumor treatment program for patients with cancer and HIV.

Results. Lack of knowledge among oncologists, low oncological alertness among infectious disease doctors, and lack of specific guidelines for the management of this complex cohort of patients are the main reasons why patients with cancer and HIV fail to receive standard treatment for cancer in Russia.

Conclusion. The urgency of the issue of treatment of patients with cancer and HIV warranted the study. This is due to the global trend of an increase in malignancies in HIV-infected people. Conducting educational activities, valid population studies, and creating a national register of these patients will form the basis for developing special clinical guidelines approved by the Ministry of Health of Russia.

Background. One of the main adverse events that significantly reduce the quality of life of patients and limit the total focal dose is radiation-induced skin reactions (RISR). Their timely diagnosis, prevention, and treatment remain urgent tasks of modern radiotherapy.

Aim. To improve the effectiveness of total skin irradiation (TSI) in patients with primary skin lymphomas by reducing the clinical manifestations of RISR by using additional therapy with a hydrogel containing active components with vasoprotective and anti-inflammatory action.

Materials and methods. A comparative randomized prospective study was conducted, including data from 52 patients who received electron TSI by conventional fractionation at a total focal dose of 14 to 30 Gy for primary cutaneous lymphomas at the Granov Russian Research Center of Radiology and Surgical Technologies from September 2021 to January 2024. Before the first TSI session, during treatment and 2 weeks after the end of radiation therapy, all patients underwent assessment for RISR, quantitative assessment of various degrees of severity of radiodermatitis using instrumental methods and assessment scales; for the observation group, a therapeutic regimen for the prevention and treatment of RISR was used, including a hydrogel with troxerutin (2%) and trolamine (0.07%), and in the control group, basic skin care using moisturizers.

Results. Analysis of the physiological parameters of the skin showed statistically significant differences between the study groups: patients of the study group (group I; 30 subjects receiving the above-mentioned therapeutic regimen) compared with the control group (group II; 28 subjects who did not receive specific treatment for radiodermatitis) reported significantly lower rates of erythema (386±12.3 and 572±14.4; p=0.005), transepidermal water loss (25±0.3 and 38±0.4 g/m²/h; p<0.001) and a decrease in peak endothelial-dependent vasodilation of microvasculature and blood flow in the skin. A lower proportion of severe radiodermatitis (86.3 and 73.3%; p<0.05) and a statistically significant difference in the subjective quality of life scores by the 29-point Skindex-29 scale by an average of 22.2% were also found.

Conclusion. A comparative analysis of the quantitative indicators of radiodermatitis in the study group and the control group showed that the topical application of the hydrocolloid gel containing troxerutin and trolamine reduces the clinical manifestations of RISR concerning objectively measured physiological parameters of the skin and blood flow parameters of the microvasculature measured by high-frequency ultrasound, thus improving the quality of life of patients during and after the course of radiation therapy.

Background. The main approach in the treatment of patients with uterine leiomyosarcoma is surgery followed by chemotherapy, which is the basis of treatment. Febrile neutropenia (FN) is a life-threatening condition, so the use of granulocyte colony-stimulating factor (G-CSF) after each cycle of chemotherapy in this category of patients remains an integral part.

Aim. To evaluate the pharmacoeconomic efficacy of the use of short and long-acting G-CSF forms in a round-the-clock inpatient facility (RIF).

Materials and methods. A retrospective analysis of economic expenditures was performed at the Chelyabinsk Regional Clinical Center of Oncology and Nuclear Medicine in the RIF setting for the period from January 2018 to December 2023 for the treatment of 62 patients with high-grade uterine leiomyosarcomas of stage IB–IVA according to the classification of the International Federation of Gynecology and Obstetrics (2009). All patients underwent surgical treatment, complete hysterectomy with appendages, followed by antitumor drug therapy with a high risk of FN. In the economic cost analysis, the treatment regimens gemcitabine 900 mg/m² on day 1 and day 8 + docetaxel 100 mg/m² + empegfilgrastim (regimen code sh1207.1) and gemcitabine 900 mg/m² on day 1 and day 8 + docetaxel 100 mg/m² + filgrastim (regimen code sh1070) were compared. The costs of clinical blood tests and staying in RIF were also considered.

Results. The stay in the RIF was 9 bed days with a long-acting G-CSF regimen and 15 days with a short-acting G-CSF regimen. When using a treatment regimen with filgrastim in 6 patients, the number of bed days increased to 18 due to persistent neutropenia. No FN events were reported. The calculations consisted of the cost of a bed day in the RIF (1,660 rubles) and purchasing of short- and long-acting G-CSF, without the cost of the main therapy. The costs of treating patients with short-acting G-CSF were comparable to those with long-acting G-CSF.

Conclusion. The regimen with long-acting G-CSF is effective, easy to use, and cost-effective in RIF settings.

Improvement of the multidisciplinary approach to the treatment of rectal cancer over recent years has led to the fact that in specialized high-volume oncology clinics it is possible to achieve a complete pathomorphological response to neoadjuvant therapy in a third of patients. The emergence of new knowledge about the development of tumor complete response and the accumulation of clinical experience opens up possibility for the wider use of an organ-sparing approach. Undoubtedly, making such a critical strategic decision requires reliable and effective tools for complete response predicting. This review is devoted to methods for assessing tumor response in patients diagnosed with rectal cancer. A look at the problem is presented from the perspective of modern methods of medical imaging, molecular and genetic studies, the study of the characteristics of the immune response, and a new look at clinical data. New data can form the basis for new patient selection algorithms for personalized treatment protocols for rectal cancer, thereby improving long-term results and quality of life for patients.

Background. Combination therapy is the standard of care for intermediate and poor prognosis metastatic renal cell carcinoma. In the IMDC prognostic classification, tumor stage and histological type are not considered due to the lack of independent impact on overall survival. The CLEAR study demonstrated the efficacy of lenvatinib and pembrolizumab combination in long-term treatment outcomes, including overall survival in poor prognosis compared to sunitinib. The KEYNOTE-B61 study demonstrated high efficacy of this combination in patients with non-clear cell renal cell carcinoma.

Aim. To evaluate the efficacy of the combination of lenvatinib and pembrolizumab in patients with high tumor burden and non-clear cell histotypes.

Materials and methods. This prospective observational study included 54 patients with metastatic renal cell carcinoma who received a combination of lenvatinib and pemrolizumab in the first line between 2022 and May 2024 in oncology clinics of the Moscow Department of Health. Clear cell histotype was represented in 79.6% of cases, 14.8% had papillary cancer, and 5.6% of patients had chromophobe cancer. The primary endpoint was the objective response rate.

Results. The objective response was assessed in 50 patients. The objective response rate was 38%, including 2% complete response according to RECIST 1.1, disease progression was in 8% of patients. The median depth of response was -25% (from -100% to +28). The median time to response was 12.4 weeks (1.1–38.3).

Conclusion. The efficacy of the combination of lenvatinib and pembrolizumab in real-life clinical practice outside the inclusion criteria of the CLEAR study is clinically significant and allows us to expect improvement even in patients with a large volume of metastatic process and non-clear cell histotype, but the expected benefit in patients with unsatisfactory somatic status remains disputed.

Aim. To compare of efficacy and safety of combined immune therapy (dual immune-oncology – IO combination therapies, IO-IO) and immune targeted therapy (ITT) in the first line treatment of patients with advanced renal cell carcinoma (RCC) treated in real world clinical practice.

Materials and methods. The ambispective study enrolled patients with metastatic RCC aged ≥18 years, with measurable neoplastic lesions, who were treated with first-line IO-IO therapy or ITT. The primary endpoint was progression-free survival (PFS).

Results. The study included data from 126 patients treated with IO-IO [46 (36.5%) patients of the IMDC intermediate and poor prognostic groups] or ITT [80 (63.5%) patients of all IMDC prognostic groups]. In a median follow-up of all patients of 16.1 (0.1–44.9) months, the median PFS was 16.1 (10.9–21.3) months, the median overall survival (OS) was not reached; one-year OS was 83.0%; the objective response rate on the first line of therapy was 44.4% with a complete response rate of 3.2%. The rate of tumor control was 88.1%. In the overall population, ITT versus IO-IO provided a significant benefit in terms of ORR (51.2% vs 32.6%; p=0.032), PFS (median 22.9 months vs 8.0 months; p=0.004) and one-year OS (87.5% vs 65.2%; p=0.042). In the IPTW population, multivariate analysis confirmed the independent prognostic significance of the treatment regimen for PFS (hazard ratio, 2.3; 95% confidence interval, 1.1–4.8; p=0.037) and OS (hazard ratio, 2.3; 95% confidence interval 1.1–4.8; p=0.037). No difference in the safety profile of IO-IO and ITT was identified.

Conclusion. The results support the hypothesis that ITT is more effective than IO-IO in the first-line treatment of advanced RCC in patients of IMDC intermediate and poor prognostic groups.

Background. It is well known that adjuvant therapy for breast cancer (BC) with tamoxifen is associated with an increased risk of endometrial hyperplasia (EH). Currently, the problem of hyperplastic processes and endometrial cancer during long-term tamoxifen therapy is particularly relevant since the incidence of endometrial disorders has a direct correlation with the duration of tamoxifen therapy. Follow-up by a gynecologist should be tailored to consider the risk of endometrial cancer in women who survived BC to improve the early detection of endometrial cancer and avoid unnecessary invasive procedures.

Aim. To predict adverse drug reactions (ADRs) of tamoxifen, including EH, endometrial polyps, and abnormal uterine bleeding, based on mathematical modeling in relation to the carriage of polymorphic variants of cytochrome P450 enzyme genes and drug transporter proteins.

Materials and methods. A prospective pharmacogenetic study of 120 women with stage I–III luminal BC receiving tamoxifen was conducted. The polymerase chain reaction method was used to detect the presence of polymorphisms of cytochrome P450 genes, followed by an assessment of their associations with ADRs of tamoxifen, namely with local gynecological symptoms.

Results. Predictive models of ADR occurrence based on the logistic regression function have been created and validated by ROC analysis. We have developed a prognostic model to estimate the probability of developing a composite endpoint (polyp, EH, abnormal uterine bleeding) based on history and genetic risk factors. It was found that the predictors of the combination of local gynecological ADRs (EH, endometrial polyp, and abnormal uterine bleeding) include such factors as weight loss, the presence of asthenia, an increase in the number of births, carriage of the TT genotype of the ABCB1 3435 polymorphic variant and the GG genotype of the CYP2D6*4 polymorphic variant, GG of the CYP3A5 polymorphic variant. The relatively high incidence (43.3%) of local gynecological symptoms requires regular monitoring by obstetrician-gynecologists using instrumental methods (transvaginal ultrasound).

Conclusion. This prognostic model has demonstrated high diagnostic effectiveness, which allows it to be implemented in the routine clinical practice of an obstetrician-gynecologist.

This publication is the Russian translation of the Plain Language Summary (PLS) of the Cochrane Systematic Review: Molenaar CJL, van Rooijen SJ, Fokkenrood HJP, Roumen RMH, Janssen L, Slooter GD. Prehabilitation versus no prehabilitation to improve functional capacity, reduce postoperative complications and improve quality of life in colorectal cancer surgery. Cochrane Database of Systematic Reviews 2023, Issue 5. Art. No.: CD013259.