Vol 25, No 2 (2023)

The results of several completed studies have led to a change in approaches to treating renal cell carcinoma (RCC) and are reflected in the clinical guidelines of the Ministry of Health of Russia and the practical guidelines of the Russian Society of Clinical Oncology (RUSSCO). The article presents the key points of these updates.

Pomalidomide is a third-generation immunomodulatory drug (IMiD) that has taken an important place in the management of relapsed/refractory multiple myeloma (RRMM) including in patients with resistance to lenalidomide (R). Synergism of antitumor activity was obtained by combining pomalidomide with dexamethasone (Pd), proteasome inhibitors (PIs), and monoclonal antibodies directed against CD38 and SLAMF7 receptors. The dose-limiting toxicity of pomalidomide is neutropenia (48–60% grade ≥3 for a dose of 4 mg/day). Overcoming resistance to lenalidomide is seen as a key benefit of pomalidomide in the development of triplets that can be used in 2nd and subsequent lines of RRMM treatment. In OPTIMISMM study (phase III), 70% of patients were lenalidomide resistant. Randomization was performed on VPd (bortezomib-Pd) and Vd (bortezomib, dexamethasone) therapy. Vd as control was implemented in two related phases III trials ENDEAVOR (carfilzomib, dexamethasone) and CASTOR (daratumumab-Vd). For patients with resistance to lenalidomide, the median progression-free survival (PFS) was 9.5 mon for VPd in OPTIMISMM; 9.3 mon in CASTOR (resistant to R 21%) for DVd, and 9.3 mon in ENDEAVOR (21%) for Kd - 8.6 mon. The ICARIA-MM study (phase 3; resistance to R – 94%) demonstrated the benefit of incorporating isutaximab into the triplet (median PFS 11.1 and 5.9 mon for Isa-Pd and Pd respectively; p<0.0001). Similar data were obtained in the ELOQUENT-3 study (phase II; resistance to R - 90%) for elotuzumab (10.3 and 4.7 mon for EPd and Pd respectively; p=0.008). In the APOLLO study (phase III; resistance - 80%), the efficacy of the triplet with daratumumab was confirmed (12.4 and 6.9 mon for DPd and Pd respectively; p = 0.0018). In the present review, the focus is on the consideration of treatment regimens that are of relevance to Russian clinical practice.

The neoplasm we refer to as diffuse large B-cell lymphoma (DLBCL) consists of many different subtypes that should not be subject to a single standardized treatment. Critical at the diagnostic stage is the identification of rare (5–10%) but extremely aggressive variants – high grade B-cell lymphomas with MYC and BCL2 and/or BCL6 double-hit (DH) or triple-hit (TH) rearrangement, in which intensive chemoimmunotherapy programs should be applied. The main and most frequent variant of the heterogeneous group of B-cell lymphomas discussed in this publication is diffuse large B-cell lymphoma, not otherwise specified (NOS). Two immunohistochemical subtypes of DLBCL NOS are distinguished, GCB and non-GCB. According to cell of origin, the DLBCL NOS is divided into GCB, ABC, and an unclassified (U) subtypes. In addition, DLBCL NOS includes MYC and BCL2 double-expressor lymphoma (DEL), which is not a unique biological entity, occurs in both GCB and non-GCB subtypes of DLBCL, and is associated with a worse prognosis. Over the past two decades, DLBCL NOS, which accounts for more than 80% of all cases, has been the subject of a growing number of molecular studies that have identified prognostic factors that are being actively introduced into real-world clinical practice. Since the turn of the century, the R-CHOP regimen has been considered the most frequent first line therapy approach for DLBCL NOS, achieving long-term remissions in 60–70% of patients. The worst outcomes when using R-CHOP are recorded in groups at high risk of progression according to the International Prognostic Index (IPI – 3–5), as well as in the presence of unfavorable molecular genetic characteristics of the tumor, such as DEL or ABC subtype of DLBCL NOS. These patient populations benefited the most from the inclusion of polatuzumab vedotin in the initial therapy regimen (Pola-R-CHP). This approach reduced the risk of progression and death in patients with high-risk DLBCL by 30%, reducing the need for second-line therapy by 34%, which can be considered a breakthrough in the last 20 years of searching for improving the "gold standard" of first-line therapy and potentially defining a new standard of therapy for primary patients with high-risk DLBCL.

Determination of cancer risk factors allow us to develop diagnostics tests that improved identification and reduced the rate of mortality of most frequent cancer diseases including breast cancer, prostate cancer, gastrointestinal tumors. Today individual risk of breast cancer considers personal genetics, medical history of patient, lifestyle, and a number of additional factors. Calculation of the first mathematical models for breast cancer risk assessment included anthropometric data, hormonal status, and family history of cancer. The discovery of BRCA1 and BRCA2 genes’ role in the development of breast cancer and the accumulation of data from population studies contributed to the introduction of the genetic component into mathematical models. The trend of the last decade is the integration of the polygenic component into the scheme for calculating the individual risk of breast cancer. In this review, we have analyzed existing models, assessed their relevance for certain groups of patients, studied the trends in the development of methods for molecular genetic diagnosis of breast cancer and determining the personal risk of developing the disease.

Background. For a long time, interest in the HLA peptide complex is unabated, the clinical significance of which in cancer is still the subject of intense debate. Through the presentation of HLA antigens, tumor cells become available for recognition and destruction by effector cells of the immune system. A detailed analysis of the expression status of HLA molecules by breast cancer cells is of both scientific and important practical value. It can provide additional information about the immune system to determine a further strategy for treating breast cancer.

Aim. To evaluate the frequency of expression of HLA-I and class II molecules by breast cancer cells and to determine its relationship with the morphological and clinical characteristics of the tumor.

Materials and methods. This study included 82 patients with breast cancer who received treatment at the Blokhin National Medical Research Center of Oncology. Immunophenotyping of the primary tumor was performed by the immunohistochemical method (immunofluorescent staining) on cryostat sections. The reaction was evaluated using a ZEISS luminescent microscope (AXIOSKOP, Germany). The frequency of expression of HLA-I and class II molecules was studied depending on the clinical and morphological characteristics of breast cancer.

Results. It was found that the frequency of expression of HLA I and II class molecules by breast cancer cells differed. HLA class I antigens are preserved in almost half of the cases 54.5%, while HLA class II antigens are preserved in 22.0%. Associations of molecules of the major histocompatibility complex with clinical and morphological signs of breast cancer were revealed. The frequency of HLA-DR negative cases increases in the stage advanсed (p=0.029). The frequency of monomorphic expression of HLA class II with T1 tumor was 50% versus 0% at T4 tumor (p=0.032). Estrogen receptor-negative tumors in most cases did not express HLA-II class (85.2% vs 64%; p=0.034). No connection with other clinical and morphological features of the tumor has been established.

Conclusion. In most cases of breast cancer, the expression of HLA class II molecules is lost, while the expression of HLA class I is preserved in half of the cases. Monomorphic expression of HLA class II is characteristic of the early stage of breast cancer development and predominantly of receptor-positive tumors.

Aim. To assess the safety and to analyze an influence of cabozantinib monotherapy toxicity on treatment efficacy in unselected Russian patients with metastatic renal cell carcinoma (mRCC).

Materials and methods. Medical data of 92 patients with verified mRCC were included in the study. The median age of the patients was 56 (19–79) years, most of them - 60 (65.2%) were of male gender. Twenty five (27.2%) persons had Eastern Cooperative Oncology Group performance status (ECOG PS). At the time of cabozantinib monotherapy start 5 (5.4%) patients had favorable, 54 (58.7%) – intermediate, and 33 (35.9%) – unfavorable prognosis by International Metastatic Renal Cancer Database Consortium (IMDC) model. Eighty-three (90.2%) patients were pretreated, including 76 (82.6%) patients who previously received anti-angiogenic agents. All patients were administered with cabozantinib monotherapy (60 mg/day); dose adjustment was performed according to the instruction.

Results. Adverse events (AEs) were reported in 81 (88.0%) of 92 patients; 30 (32.6%) AEs were grade 3–4. Toxicity-related dose reduction of cabozantinib was required in 28 (30.4%), treatment interruption in 15 (16.3%), and discontinuation in 2 (2.2%) patients. The most common AEs were hypertension (69 patients, 75.0%), asthenia (47 patients, 51.1%), diarrhea (43 patients, 46.7%), and palmar-plantar erythrodysesthesia (43 patients, 46.7%). The most common severe AEs were: arterial hypertension (17 patients, 18.5%), diarrhea (6 patients, 6.5%), and palmar-plantar erythrodysesthesia (2 patients, 2.2%). The most frequent laboratory abnormalities during therapy were elevated serum transaminases (33 patients, 35.9%), anemia (13 patients, 14.1%), and thrombocytopenia (10 patients, 10.9%). No previously unreported AEs or laboratory abnormalities were observed. There was a significant increase in progression-free survival (hazard ratio 2.5; 95% confidence interval 1.0–5.9; p=0.046) and overall survival (hazard ratio 3.0; 95% confidence interval 1.2–8.3; p<0.025) in patients with treatment-related arterial hypertension.

Conclusion. The observational study confirmed the acceptable safety profile of cabozantinib in the first and subsequent lines of treatment in mRCC patients. No new safety signals were identified. Treatment-related arterial hypertension may be a favorable predictor of survival.

Background. Epithelial forms of ovarian cancer account for up to 90% of all ovarian malignancies. Epithelial forms of ovarian cancer are classified according to the WHO criteria of 2014 into several types: the most common are serous carcinomas (70%), mucinous carcinomas (3%), endometrioid tumors (10%), light cell cancer, transitional cell cancer, mixed and undifferentiated carcinomas are rare.

Aim. To study the overall survival and progression-free survival depending on the stage of the disease, the pathological type of tumor and the degree of differentiation of tumor cells.

Materials and methods. A retrospective analysis of the treatment of 467 patients with stage IIIC–IVB ovarian cancer in the Primorsky Regional Oncological Dispensary for the period from 2003 to 2021 was carried out. The obtained parameters were processed using standard statistical analysis methods using the IBM SPSS Statistics 26 program.

Results. The overall results showed that the most favorable course of stage IIIC–IVB ovarian cancer has a serous type of ovarian cancer, probably due to its sensitivity to chemotherapy and aggressive surgical tactics. Patients with a mutation in the BRCA1/2 genes have a better prognosis in overall survival rates. BRCA1/2 mutations are associated with an improved response to chemotherapy with platinum-based drugs.

Conclusion. The analysis made it possible to determine the most favorable prognostic factors for advanced stages of ovarian cancer, when comparing the groups of high-grade and low-grade III–IV stage serous carcinoma, it was noted that the median overall survival, depending on the histological type, is better in the group of patients with low-grade III–IV stage serous carcinoma. When comparing, depending on the timing of the operation performed, it can be noted that the median overall survival and median progression-free survival rates are better in the group of patients who received primary cytoreductive surgery.

Background. Currently available data on the efficacy and indications for neoadjuvant chemotherapy in patients with primary resectable pancreatic cancer are contradictory and not clearly defined.

Aim. To conduct a comparative assessment of the effectiveness of neoadjuvant chemotherapy and primary surgical treatment followed by adjuvant chemotherapy in patients with primary resectable pancreatic cancer.

Materials and methods. In our study, the efficacy of neoadjuvant chemotherapy was retrospectively evaluated in 45 patients and in 153 patients with primary surgical treatment and subsequent adjuvant chemotherapy.

Results. With a median follow-up of 41.7 months. Both, recurrence free survival in the group of patients receiving neoadjuvant chemotherapy followed by surgical treatment (n=33; 73%) and in the group with surgical treatment and subsequent adjuvant chemotherapy (13.9 and 19.5 months; p=0.35) and overall survival (28.4 months vs 33.7 months; p=0.29) were no different. The CA level of 19.9>500 IU/ml in the neoadjuvant chemotherapy group was observed in 20 (44.4%) patients. At the same time, surgical treatment was performed only in 11 (55%) patients. At the same time, at the CA 19.9 level <500 IU/ml, at the end of neoadjuvant chemotherapy, surgical treatment was not performed in only 3 (12%) patients (p=0.005).

Conclusion. The long-term results of treatment of patients with primary resectable pancreatic cancer, whose first stage was neoadjuvant chemotherapy, practically do not differ from the group whose treatment began with surgery. Treatment of patients with an initially high (>500 IU/ml) level of CA 19.9 is preferable to start with neoadjuvant chemotherapy. Patients who may have doubts about the likelihood of adjuvant chemotherapy (general condition, social adaptation, place of residence), it is also preferable to start treatment with neoadjuvant chemotherapy. It is necessary to change the algorithm of examination of patients, especially those with a level of CA 19.9>500 IU/ml, to exclude a greater prevalence, for example, performing diagnostic laparoscopy to exclude metastases in the peritoneum.

Background. Solid organ transplantation recipients have a high risk of non-melanoma skin tumors. Patients after heart transplantation are prone to a higher incidence of malignant skin tumors due to intensive immunosuppressive therapy. The most common histological type is squamous cell carcinoma, followed by basal cell carcinoma. These tumors have a more aggressive clinical course, including the frequency of recurrence and metastasis, and a tendency to multifocal lesions.

Materials and methods. We present a clinical case of primary multiple squamous cell carcinoma with metastatic lesions of regional lymph nodes in a patient after heart transplantation.

Results. A 67-year-old patient underwent an orthotopic heart transplant in September 2018 for ischemic cardiomyopathy. Subsequently, triple immunosuppressive therapy was administered, including tacrolimus combined with mycophenolate mofetil and prednisolone. In May 2022, a solid tumor with ulceration occurred on the skin of the right scapular region. After some time, similar tumors appeared on the skin of the temporal region on the left, the posterior surface of the auricle and the parietal region on the left. The patient later found a solid, painless tumor on the left jaw angle. As a part of the examination in the oncology dispensary, a biopsy of the scapular skin tumor, scrapings from tumors, and aspiration biopsy of the submandibular lymph nodes were performed. Histological and cytological studies of all neoplasms showed squamous cell keratinizing cancer with metastases to the submandibular lymph nodes. Additional examination methods showed no signs of progression. The diagnosis was made: primary multiple synchronous skin cancer: right scapular area, stage III, cT3N0M0; left parietal area, stage II, cT2N0M0; occipital area, stage I, cT1N0M0; left auricle, stage IV, cT1N2M0. Considering the localization of tumors, surgical treatment was performed, including of excision of tumors in the scapular and parietal regions. Radiation therapy was performed on lymph nodes with metastases. After 6 months, a tumor recurrence was detected in the irradiation area.

Conclusion. After heart transplantation, squamous cell carcinoma of the skin is common. Usually, it affects the scalp and neck with metastases to the regional lymph nodes and is prone to recurrence. The primary treatment method is surgical and radiation therapy.