Vol 22, No 3 (2020)

Chronic lymphocytic leukemia/small lymphocytic lymphoma. Clinical recommendations

Over the past two decades, many new variants of targeted therapy for metastatic colorectal cancer (mCRC) had appeared, and significantly increased patient survival. However, there were questions relating to the definition of the optimal sequence and the combination of different drugs. Cytotoxic agents, including irinotecan, oxaliplatin, 5-fluorouracil and capecitabine, are the basis of the treatment of mCRC. In addition, the arsenal of modern oncologist includes the group of drugs inhibiting the epidermal growth factors (for example, cetuximab and panitumumab) and inhibiting tumor angiogenesis factors (for example, bevacizumab and aflibercept). Moreover, the use of immuno-oncology drugs, trastuzumab or encorafenib is possible in case of knowing tumor-specific molecular signature. Unfortunately, these new indications can be used only in small proportion of patients. The multikinase inhibitor regorafenib takes a special place, it can be used in patients in spite of RAS mutation status. The increasing attention has been paid to the selection of the drugs for sequential therapy of mCRC, recently. This review discusses important clinical data on the direct role of targeted drugs in the treatment of mCRC in different subgroups of patients.

Young women with reproductive tract neoplasms who receive treatment leading to termination of ovarian function often suffer from menopause symptoms that contribute to dramatic drop in quality of life. Climacteric symptoms in women with iatrogenic menopause are more severe than in case of natural menopause, especially in women with reproductive tract neoplasms. They lead to dramatic drop in quality of life and are one of the main reasons to stop applying endocrine therapy in women with hormone-positive tumors, which leads to decrease in disease free survival and to decline the prognosis. The most effective treatment option for climacteric symptoms of moderate to severe degrees is menopause hormone therapy; however, such therapy is not suitable for patients with estrogen-dependent tumors in past medical history due to the likelihood risk of progression of cancer, as well as the risk of venous thrombosis, the frequency of which in cancer patients increases. Non-hormonal pharmacological and non-pharmacological correction methods are used as first-line therapy for menopause disorders in women with estrogen-dependent tumors of the reproductive system. Among non-hormonal non-pharmacological correction methods actively study such methods as acupuncture, yoga, exercise to control weight, and a diet rich in phytoestrogens. The most effective non-hormonal methods of correcting vasomotor symptoms are serotonin and norepinephrine reuptake inhibitors. However, currently in Russia these drugs can be prescribed only by a psychiatrist. The finding of effective and safe non-hormonal methods to correct menopause symptoms in women with hormone-positive reproductive tract tumors is the important task in practice among doctors in different specialties.

80–90%. The identification of gene mutation profile of non-small cell cancer allows to make a molecular portrait, which plays the crucial role in choosing the targeted therapy with tyrosine kinase inhibitors.

The aim is to study the frequency and spectrum of activating mutations in non-small cell lung cancer in Tambov region.

The study of the presence of mutations and the main driver gene mutation profile: EGFR, ALK, BRAF, ROS1 and PDL-1 using sections of paraffin-embedded after the surgery and biopsy in 238 patients with the help of polymerase chain reaction and immunohistochemistry. The age of patients ranged from 28 years to 82 years, with a mean age of 60.3 years.

Results. Adenocarcinoma was detected in 80.3% of patients, and squamous cell variant – in 19.7% of cases. The frequency of the driver gene activating mutations in non-small cell lung cancer was 29%, this index exceeded the frequency in the European population. Statistically significant predominance of female (63.6%) vs male (36.4%) was achieved. The mutation frequency increases with age. In this case, EGFR mutations were observed more often – 22.3%. This index was slightly higher than in the European population. Statistically significant predominance of female was achieved. The highest frequency of mutations was demonstrated in patients 65–70 years of age (24%). The deletion of exon 19 and single-nucleotide replacement L858R of exon 21 were observed in 54.5% and 45.5% of cases, respectively. The mutation of exon 19 was more often detected in male, at the same time the mutations of exons 19 and 21 in female were detected in almost the same frequency. Maximum frequency mutation rate (77.7%) in the EGFR gene was detected free from metastases to the regional lymph nodes. ALK mutations were found in 14.6% of patients, this index was slightly higher than the European level.

PDL-1 expression is found in 40% male patients.

Conclusion. The results of the study revealed some features of the profile of activating mutations in non-small cell lung cancer in the region. This data should be taken into account on planning and applying targeted therapy.

Aim. Comparison of the results of the use of dermatoscopic algorithms «Chaos and Clues», «Triage Amalgamated Dermoscopic Algorithm» (TADA) and BLINCK technique in the diagnosis of melanoma and other malignant skin tumors depending on the presence of previous dermatoscopy experience.

Materials and methods. Algorithms were tested on 85 patients with 85 skin formations who visited the polyclinic of Kursk Regional Clinical Oncology Clinic in 2017–2019. The average age of the patients was 54.8 years old. Dermatoscopy was performed by the non-polarized dermatoscope HEINE mini 3000, photo documentation by the Canon PowerShot SX540 HS camera. Immersion medium – ethyl alcohol (conc. 70%). Patients were carefully examined physiologically and clinically. A clinical and epiluminescence pattern of all neoplasms was obtained, their morphological examination was performed. For the research 2 groups of 3 participants were formed based on the criterion of previous dermatoscopy experience. Each algorithm was evaluated by objective (sensitivity, specificity) and subjective (speed, convenience) criteria. The dermatoscopic results obtained by the techniques used were compared to the histological findings.

Results. Using algorithms by a group having previous dermatoscopy experience, the following results were obtained: in the method «Chaos and Clues» sensitivity – 93.75±3.3%, specificity – 77.4±4.6%, speed – 3 points, convenience – 3 points. TADA sensitivity – 96.8±2.2%, specificity – 79.2±4.8%, speed – 4 points, convenience – 5 points. BLINCK sensitivity – 96.8±2.2% specificity – 77.4±4.6%, speed – 4 points, convenience – 5 points. In the group with no previous dermatoscopy experience, the results were as follows: in the «Chaos and Clues» algorithm, sensitivity – 93.75±3.3%, specificity – 62.3±5.7%, speed – 3 points, convenience – 3 points. TADA sensitivity – 84.4±4.6%, specificity – 64.2±5.8%, speed – 4 points, convenience – 5 points; BLINCK sensitivity – 80.6±4.4%, specificity – 77.4±4.6%, speed – 5 points, convenience – 4 points. Thus, these algorithms can be used in the diagnosis of malignant skin neoplasms. At the same time, individuals with no experience of dermatoscopy are encouraged to use the «Chaos and Clues» algorithm. In a group having experience in dermatoscopy, both the TADA and the BLINCK technique can be used equally.

The method of liquid biopsy allows detection of circulating tumor DNA (ctDNA) in patient blood, but the clinical significance of this approach in pancreatic cancer is still unclear. In this regard, we have carried out a meta-analysis of the studies dedicated to the predictive significance of ctDNA in pancreatic cancer.

Materials and methods. We carried out the search for the articles and abstracts in PubMed, ASCO and ESMO databases published before February 2020, containing data about the connection between ctDNA and the prognosis of pancreatic cancer. The exclusion criteria were the studies including 10 or less participating patients, absence of the data about the relative risk of mortality and/or progression, and the 95% confidence interval. The meta-analysis was carried out by using the Review Manager software (RevMan), Version 5.3.

Results. There were no significant systematic errors associated with the publications. The presence of ctDNA in patient blood showed poor overall survival of patients (odds ratio – OR 2.21, 95% confidence interval – CI 1.35-3.33, p=0.001) regardless of the prevalence of the disease. In case of the resectable process, the detection of ctDNA in patient blood both before and after surgery was a factor of worse progression-free survival (OR 2.32, 95% CI 1.54–3.5, p<0.001 and OR 3.06, 95% CI 1.63–5.76, р=0.0005 and overall survival (OR 2.01, 95% CI 1.12–3.63, р=0,02 and OR 3.39, 95% CI 2.12–5.44, р<0.00001, respectively).

Conclusions. The detection of ctDNA in the bloodstream in pancreatic cancer patients is a factor of poor prognosis in both localized and advanced cancer. It is very important to make further prospective studies to develop the optimal protocol for detecting ctDNA in patient bloodstream.

The huge global burden of oncological diseases is growing and measures to counter this complex challenge are high on national health agendas. The Russian National Long-Term Oncology Strategy 2030 defines priorities, goals and directions in the fight against cancer. It also contains action plans for more effective prevention, earlier and more specific diagnosis and more effective treatment options. Against this backdrop, experts now suggest to complement standard oncology treatment strategies by adding Patient Blood Management (PBM). For many clinical disciplines where a low blood count and considerable blood loss are commonly encountered, this bundle of care is the new standard. Based on clinical and scientific evidence, it aims to optimise medical and surgical patient outcomes by clinically managing and preserving a patient’s blood. The principles of this comprehensive concept can and must be transferred to oncology, thus offering value in improving cancer care and the efficacy of medical institutions. Accumulating evidence demonstrates that anaemia and iron deficiency, but also thrombocytopenia, blood loss and coagulopathy are independent risk factors for adverse patient outcomes including morbidity, mortality, reduced quality of life and prolonged average length of hospital stay in both surgical and medical patients. For the timely and effective detection and correction of these risk factors, an international network of multi-disciplinary clinicians and researchers has developed PBM. The rapidly growing body of evidence for PBM not only shows improved patient outcomes, but also reduced resource utilisation including the use of allogeneic blood components. The reduction of allogeneic blood transfusion further improves patient safety and outcomes, since transfusion is another independent risk factor for adverse outcomes. Supported by WHO endorsements and following the recommendations of an increasing number of state or national health authorities, PBM is about to become a new standard of care. However, even though the aforementioned risk factors are highly prevalent in oncology settings due to chemo-/radiotherapy and the pathology of the disease, the integration of PBM in standard oncology treatment pathways is lagging behind. Thus, and in support of the Russian National Long-Term Oncology Strategy 2030 to improve quality of oncological care, with the support of the National Association of Specialists in PBM (NASPBM), the PBM Oncology Working Group of the Russian Federation was created, consisting of national and international experts in oncology and PBM. On July 9, 2020, the Working Group met to discuss the rationale for PBM in oncology and to assess the need to implement PBM in Russian oncology care. As a result, the Group recommended to include PBM as an integral part of standard oncology treatment pathways, delineated the action required from facilitating stakeholders in the Russian Federation, determined a roadmap for implementation and developed a national resolution as a call to action on the matter. Presented herein, this resolution acknowledges the global and local impetus to reduce cancer mortality, and the rationale for PBM interventions to improve patient outcomes and alleviate the social and economic burden of cancer on the healthcare system.

Throughout the last 10 years, liver cancer mortality rate in the Russian Federation consistently exceeded the morbidity rate, which is related to the complexity of early diagnostics, absence of effective screening and oncological alertness of allied-profession doctors. In the situation when late disease intelligence does not frequently allow radical treatment, palliative methods remain the only option of survivability enhancement and improving the patients’ quality of life. Lenvatinib was approved as the first-line drug in the treatment of unresectable hepatocellular carcinoma based on the data of the REFLECT trial, in which the drug demonstrated achieving the patients’ overall survival (OS) comparable to the activity of sorafenib (13.6 months for lenvatinib vs 12.3 months for sorafenib; hazard ratio – HR 0.92; 95% confidence interval – CI 0.79–1.06). At the same time, significant inferiority of lenvatinib was observed for secondary endpoints: progression-free survival – PFS (7.4 months for lenvatinib vs 3.7 months for sorafenib; HR 0.66; 95% CI 0.57–0.77; р<0.0001), time to progression (8.9 months for lenvatinib vs 3.7 months for sorafenib; HR 0.63; 95% CI 0.53–0.73; р<0.0001) and objective response rate – ORR (24.1% for lenvatinib vs 9.2% for sorafenib). The further analysis of the results of the REFLECT study revealed the additional factors impacting patients’ survival, such as the level of a-fetoprotein (AFP) before treatment, treatment ORR, performance of subsequent antitumor therapy and procedures after completion of the target first-line therapy. In patients responding to lenvatinib in the first line and further receiving any second-line therapy, the mOS was 25.7 months as compared with the median overall survival (mOS) of 22.3 months in patients responding to sorafenib and receiving further second-line therapy. Additionally, in “responders” switching from lenvatinib to sorafenib, the mOS was 26.2 months. In the recently published comparative study of lenvatinib and transarterial chemoembolization on the BCLC B stage, inferiority of lenvatinib was demonstrated in terms of OS, PFS and ORR in certain patient categories. Considering the data obtained in the REFLECT population, where in patients achieving the RR to the first-line treatment with lenvatinib and further receiving the local antitumor procedures the mOS increased to 27.2 months (95% CI 20.7–29.8), prescribing target and locoregional therapy in certain cases in this very sequence is possible. The recently published data about administration of lenvatinib outside of the inclusion criteria for the REFLECT trial, have proved the efficacy and safety of this drug administration in real clinical practice, thus significantly expanding our understanding of the key role of lenvatinib in the first-line treatment of unresectable hepatocellular carcinoma.

Renal cell cancer metastases without evidence of a primary tumor are extremely rare. These variants are usually showed as a spontaneous description of single clinical cases.

Aim. This contribution is a clinical follow-up of synchronous renal cell cancer metastases of unknown primary site.

Results. A 52-year-old patient U. with a history of increased blood pressure, up to 170/100 mmHg for the last 5 years, who had undergone many instrumental examinations, including ultrasound examination, because of this disease. The computed tomography of the abdomen showed a 49×75 mm heterogeneous tumor in the right adrenal gland in October 2017. The combined positron emission and X-ray computed tomography showed a 79×54×41 mm mass in the right adrenal gland, associated with elevated fluorodeoxyglucose metabolic activity SUVmax 7.25. Focal accumulation of the radiopharmaceutical SUVmax 4.31 in a 17×11×24 mm mass was detected in the space of bifurcation in the mediastinum. The lytic lesion (10×15 mm) was found in right superior L3 articular process. The patient underwent retroperitoneoscopic adrenalectomy and thoracoscopic removal of mediastinal tumor in November 2017 because of the oligometastatic nature of the process. The histological study identified clear-cell carcinoma with areas of papillary structure in the right adrenal gland. The immunohistochemical study showed carcinoma cells intensively expressing CD10, and some other cells – RCC. The immune phenotype of the tumor was identified as clear-cell renal cell carcinoma. The immunohistological and immunohistochemical analysis reviled the metastases of the same variant of renal cell carcinoma in one of 9 lymph nodes. The patient was treated with pazopanib. The primary renal tumor was not detected during the dynamic observation, including the application of annual combined positron emission and X-ray computed tomography. The patient is alive without disease progression with a follow-up of 32 months.

Conclusion. Metastases of clear-cell renal cell carcinoma, including adrenal gland, without evidence of a primary site are extremely rare. The main method of treatment is a combination of surgery and targeted therapy, providing long-term local control of the course of the disease.