Oncology during the New Coronavirus Infection Pandemic.

The COVID-19 pandemic has served as a catalyst for a whole layer of scientific research, including in Russia, where, since 2020, international multicenter studies have been conducted on the impact of the coronavirus infection on the course of oncological diseases, as well as on the development and application of new clinical methods in oncology. In the years 2020-2022, new methods of nuclear medicine based on the targeted effect of ionizing radiation of radiopharmaceuticals began to be actively developed, in particular, new domestic radiopharmaceuticals (RPs) for diagnostics and therapy and methods of intra-arterial radioembolization developed by RPs with 90Y and 188Re of primary and metastatic tumors of various localization. New methods of radiation therapy have been introduced into clinical practice, including remote radiation therapy with "fast" neutrons, which makes it possible to overcome the resistance of a tumor to radiation and drug treatment. In addition, the search for and introduction into clinical practice of new approaches in the field of gene therapy and the use of oncolytic viruses continues. Platforms for complex pharmacogenomic analysis based on global knowledge and deep machine learning are being used in Russia, allowing for the precise selection of the most effective therapy. New multidisciplinary technologies are being developed. © Pleiades Publishing, Ltd. 2022, ISSN 1019-3316, Herald of the Russian Academy of Sciences, 2022, Vol. 92, No. 4, pp. 456–463. © Pleiades Publishing, Ltd., 2022.Russian Text

The new coronavirus infection COVID-19 pandemic that began in 2019 has significantly affected the work of healthcare authorities in all countries without exception, particularly in Russia. Governments and relevant ministries were forced to restructure urgently the work of medical organizations based on the rapidly changing epidemic situation. As of December 14, 2021, population losses from COVID-19 in the world were estimated at an average of 8000–9000 people per day [1]. The change in the system and procedure for providing medical care to one degree or another affected all branches of medicine, including oncology.

At the same time, the burden of cancer is steadily growing, with enormous physical, emotional, and financial consequences for populations and health systems around the world. According to the WHO, about 26 000 people die from malignant neoplasms every day in the world. That is why the work of the oncological service and scientific research in the development and implementation of modern methods for diagnosing and treating oncological diseases should not stop even in such a difficult time.

If we turn to Russian statistics, then with the growth of opportunities for early diagnosis and with the expansion of screening programs and medical examination programs for 2016–2019, the number of detected cases of malignant neoplasms has only increased [2]. However, in 2020, this trend did not continue: at the moment, a decrease in the number of detected oncological diseases has been recorded. The incidence rate of malignant neoplasms in Russia in 2020 decreased by 13.2% compared to 2019. A similar trend was observed, for example, in the Republic of Belarus, where the incidence in 2020 decreased by 20.18% compared to 2019. Obviously, this trend is associated with the pandemic of a new coronavirus infection, which caused the forced suspension of screening programs, early diagnosis, and medical examination of the population and, accordingly, led to a decrease in the detection of malignant neoplasms.

Studies have already emerged that confirm the inadvisability of suspending early cancer detection programs during the COVID-19 pandemic. Thus, the well-known British oncologist Professor K. Sikora believes that their delay every six months due to the pandemic will lead in subsequent years to an increase in the proportion of advanced forms of cancer and, as a result, an additional increase in mortality by about 50 000 patients per year [3]. Postponing preventive and screening interventions, for example, for breast cancer, cervical cancer, and tumors of the gastrointestinal tract by only a week can lead to a decrease in the detection of 400 cases of these diseases in the early stages, when effective radical treatment is highly likely. Thus, the oncological community should be prepared to see an increase the proportion of common (metastatic) forms of cancer and those resistant to traditional therapeutic approaches in the next few years. In addition, the new coronavirus infection directly affects the health and quality of life of cancer patients. According to studies by colleagues from China, published in the journal Lancet, cancer patients had a higher risk of severe complications compared to patients without this pathology [4].

In the context of the pandemic of the new coronavirus infection, starting in 2020, the oncological service faced the problem of a shortage of medical and scientific personnel. The outflow of personnel from oncological research institutes and universities, including graduate students and resident physicians, to practical healthcare due to better wage conditions (especially in departments of infectious diseases) cannot always be stopped by motivating professional and scientific growth. The problems of scientific management in the context of COVID infection are also associated with the difficulty of forming well-characterized and traced samples and databases of cancer patients due to interruptions in specialized treatment courses during scientific research, as well as difficulties in assessing the results of scientific research due to the additional impact of coronavirus infection on the results of treatment of the underlying disease and the quality of life of cancer patients and a reduction in funding for scientific projects not related to the study of infection.

The COVID-19 pandemic has stimulated research in oncology on such a biological phenomenon as systemic inflammation. It is known that an unfavorable course of the coronavirus infection leads to the development of a systemic inflammatory response (SIR), which is expressed in a massive release of cytokines (“cytokine storm”) and acute phase proteins into the bloodstream [5]. Similar phenomena, expressed to varying degrees, can also be observed at the stages of development of a tumor disease. In oncology, SIR activation is initially recorded in about a third of patients with resectable tumors and in half of patients with inoperable tumors [6, 7]. An increased SIR level in cancer patients before treatment correlates with the spread of the tumor process, a shorter period of overall and recurrence-free survival after surgical, drug, and combined treatment, and with a poor response of the tumor to chemotherapy [8-12].

Biological markers of the systemic inflammatory response in cancer patients occur most often: the level of C-reactive protein (CRP) in the blood plasma, the synthesis of which in the liver is induced by pro-inflammatory cytokines entering the systemic circulation; the Glasgow Prognostic Score (GPS) index, which takes into account the ratio of the level of CRP and the content of albumin in the blood plasma; the ratio of neutrophils or platelets to lymphocytes (NLR and PLR, respectively), which indirectly reflects the ratio of inflammatory reactions and specific immunity reactions; and peripheral blood levels of pro-inflammatory mediators like interleukin IL-6, IL-8, IL-1β, IL-12, IL-17, and tumor necrosis factor (TNF) [13].

Systemic release of pro-inflammatory cytokines and SIR activation are observed in various types of anticancer therapy, including targeted and immunotherapy [14-16]. It is assumed that this may be due to the formation of tumor cell degradation products, reprogramming of tumor-associated macrophages and fibroblasts, and direct induction of cytokine synthesis in tumor cells under the action of cytostatics [17-20]. Experimental studies have established that the consequences of such reactions can provoke tumor metastasis, and the mechanisms of such a paradoxical effect of antitumor drug treatment are being actively studied [18-20]. Based on the data of experimental studies, a chain of events has been formed that can link the release of cytokines during antitumor therapy with the induction of metastasis (Fig. 1).

Fig. 1.

Proposed mechanism of the paradoxical stimulating effect of anticancer drug treatment on tumor progression (based on data from experimental studies) [18, 20]. * Cytokines as molecules of intercellular communication; ** tumor infiltration by macrophages; ***“cytokine storm”; **** circulating cytokines.

Currently the Herzen Moscow Research Institute of Oncology (MRIO, a branch of the National Medical Research Radiological Center of the Russian Ministry of Health) is conducting a study of SIR in patients receiving drug antitumor therapy, algorithms for its assessment, and the clinical significance. In the future, schemes for stopping the systemic inflammatory response will be proposed to improve treatment outcomes.

The Petrov National Medical Research Center of Oncology (NMRCO) of the Russian Ministry of Health is conducting a postregistration noninterventional cohort study of the effectiveness and safety of vaccine prevention of coronavirus infection COVID-19 with Sputnik V in patients with metastatic solid tumors against the background of systemic drug treatment. It is important to compare the level of virus-neutralizing antibodies IgA, IgM, and IgG to SARS-CoV-2 antigens (N-protein, RBD, and S1) in cancer patients relative to healthy individuals (medical personnel) in accordance with the hypothesis that the effectiveness of the vaccine when applied to cancer patients is not lower than in the case of healthy people (frequency difference is less than 20%). In addition, it becomes relevant to study the adverse effects of vaccination in cohorts of patients and in comparison with data from registration studies during various drug therapy regimens. It is assumed that adverse events do not increase after the second vaccination compared with the first vaccination. However, the level of virus-neutralizing IgG antibodies may be 30% lower in patients on chemotherapy with a high risk of developing hematological toxicity, which will require a third injection of the vaccine. In addition, the timing of revaccination with a decrease in the protective titer of virus-neutralizing IgG antibodies to the RBD domain of the spike protein (S) of SARS-CoV-2 below the reference values remains unexplored.

At the first stage, healthy individuals (n = 22) were included in the study, in whom the phagocytic activity of neutrophils and monocytes, the subpopulation composition and functional activity of immunocompetent peripheral blood cells (T-lymphocytes, T-helpers, cytotoxic T-lymphocytes, T-regulatory cells, B-lymphocytes, NK, and NKT cells), and the level of specific antibodies to the proteins of the SARS-CoV-2 virus were studied: nucleocapsid protein (N), receptor-binding domain (RBD), and S1 subunit of the spike protein. The level of antibodies was determined using the BD FACSDiva v8.0.1 software by the ratio of the median fluorescence intensity (MFI) of the antigen in comparison with the control.

The subpopulation composition of lymphocytes and the activity of phagocytic cells in all studied samples were within the range of reference values. When analyzing the level of antibodies, four cohorts were identified. The first cohort included those vaccinated after the coronavirus infection COVID-19 (n = 7); the second consisted of those unvaccinated but who had had a coronavirus infection (n = 2); the third consisted of vaccinated, not ill with COVID-19 (n = 4); the fourth included unvaccinated and not ill (n = 9) (Figs. 2, 3).

Fig. 2.

The level of virus-neutralizing IgG antibodies to SARS-CoV-2 antigens (S1, N-protein, RBD) relative to control values (Guava® SARS-CoV-2 Multi-Antigen Antibody Kit, Luminex (United States), BD FACS Canto™ II flow cytometer, BD Biosciences).

Fluorescence intensity (MFI) of IgG to SARS-CoV-2 antigens (S1, N-protein, RBD) relative to control values (Guava® SARS-CoV-2 Multi-Antigen Antibody Kit, Luminex (United States), BD FACS Canto™ flow cytometer II, BD Biosciences).

Comparative analysis of the level of virus-neutralizing antibodies IgG to SARS-CoV-2 antigens (S1, N-protein, RBD) in the studied cohorts of healthy individuals showed that, regardless of vaccination, IgG to the nucleocapsid N protein (cohorts 1 and 2) were detected in those who had been ill, in contrast to those vaccinated but not exposed to COVID-19 (cohort 3). Three months later, those vaccinated showed a high content of IgG to SARS-CoV-2 antigens RBD and S1 (cohorts 1 and 3). In unvaccinated and nonill patients, the level of the studied IgG antibodies to SARS-CoV-2 did not reach the control values (cohort 4). IgA and IgM to SARS-CoV-2 did not differ significantly in all cohorts. Thus, vaccination of coronavirus infection COVID-19 with Sputnik V leads to the formation of a high level of virus-neutralizing IgG antibodies to SARS-CoV-2 antigens (RBD and S1) in healthy individuals with reference values of immunological parameters.

NMRCO conducted a study of the parameters of the blood coagulation system of patients with breast cancer (BC) and who underwent COVID-19 of varying severity. BC patients (50 people) were divided into groups: the main group of 30 patients who had a new coronavirus infection; control group 1 of 20 patients without confirmed infection; and control group 2 of 20 women without oncopathology and with a history of COVID-19. Cancer patients received courses of chemotherapy according to the stage of the process. The following indicators were studied: activated partial thromboplastin time (APTT), prothrombin time (PT), international normalized ratio (INR), prothrombin index (PTI), fibrinogen, soluble fibrin-monomer complexes (SFMC), thrombin time (TI), antithrombin III, D-dimer and plasminogen, and fibrin degradation products. Blood for the study was taken 4–6 weeks after the infection and two negative PCR tests for COVID-19.

In patients of the main group after treatment, differences in INR parameters were obtained in the group with an asymptomatic course (Me = 1.24) and in the group with a mild course (Me = 0.97): U = 10, Z = 2.766, p = 0.0057; in the asymptomatic group (Me = 1.24) and in the group with moderate course (Me = 0.98): U = 26.5, Z = 2.199, p = 0.027; in terms of TB in the asymptomatic group (Me = 14.5) and in the group with moderate-to-severe course (Me = 16.5) U = 18.5, Z = –2.725, p = 0.0064. When comparing groups of patients who underwent COVID-19 before (Me = 0.83) and after treatment (Me = 0.4), differences in the D-dimer index in patients with moderate course were obtained: U = 6.5, Z = –2.2861, р = 0.022 in the direction of decreasing the latter after chemotherapy. Differences in APTT values were obtained in the main group (Me = 30.65) and control group 1 (Me = 27.85): U = 119, Z = 3.574, p = 0.00035; antithrombin values in the main group (Me = 94) and control group 1 (Me = 106): U = 112, Z = 3.713, p = 0.00021; and SFMC indicators in the main group (Me = 17) and control group 1 (Me = 8): U = 180.5, Z = 2.356, p = 0.018.

The authors conclude that determination of the plasminogen levels can become an independent factor in the detection of thrombotic risk in cancer patients who have recovered from COVID-19. It is advisable, if there is a past coronavirus infection in the history of a patient with malignant neoplasms, to take it into account as an additional risk factor for venous thromboembolic complications for these patients.

In recent years, there has been active development of nuclear medicine technologies in Russia and 2021 was no exception. The number of both new developments and clinical trials of domestic radiopharmaceuticals (RPs) for diagnostics and therapy has increased [21, 22]. PSMA-oriented radioligand therapy (PSMA-RLT) in patients with metastatic castration-resistant prostate cancer (mCRPC) has not yet been registered in the world, but is undergoing phase 2 and 3 clinical trials in Europe, the United States, and Canada, in which more than 2000 patients have been successfully treated [23, 24]. NRRC has developed three original domestic targeted RPs for the diagnosis and treatment of metastatic castration-resistant prostate cancer: 99mTc-HYNIC-PSMA, 177Lu-DOTA-PSMA, and 225Ac-DOTA-PSMA, the targets for which are the prostate-specific membrane antigen (Fig. 4).

Fig. 4.

Dynamics of changes in the average tumor volume after a single intravenous injection of RP 177Lu-DOTA-PSMA (BALB/c nu/nu mice with transplanted prostate cancer).

RP 177Lu-DOTA-PSMA passed preclinical and entered clinical studies for its subsequent registration. In addition, NMRRC conducted the first treatment in Russia with procedure RP 177Lu-DOTA-PSMA for patients with mCRPC, and now patients are being treated routinely at the center within the framework of Orders of the Russian Ministry of Health no. 1218n, dated November 12, 2020, and no. 780n, dated July 31, 2020. Twenty-nine patients have already been treated with the 177Lu-DOTA-PSMA radiopharmaceutical. Its distribution in the body was in good agreement with the distribution of diagnostic preparations with 18F and 68Ga on PET of these patients. There was a stabilization or decrease in PSA levels in all patients after radioligand therapy, as well as a decrease in the size of metastatic foci [25] (Fig. 5).

Fig. 5.

Identity of pharmacokinetics of diagnostic RP 18F-PSMA-1007/RP 68Ga-PSMA-617 and therapeutic RP 177Lu-DOTA-PSMA.

In 2020–2021, the Academician Granov Russian Research Center for Radiology and Surgical Technologies of the Russian Ministry of Health (RRCRST) developed a technology for the synthesis of the 225Ac-PSMA radiopharmaceutical for the treatment of patients with mCRPC resistant to radioligand PSMA therapy with a 177Lu radiopharmaceutical. In June–November 2021, the center, within the framework of Order of the Russian Ministry of Health no. 1218n, dated November 12, 2020, treated three patients with the 225Ac-PSMA radiopharmaceutical: one received one course of radiotherapy, and the other two received three courses of radiotherapy with an interval of two months. The activity of the administered RP was 8 MBq [26] (Fig. 6).

Fig. 6.

Results of RLT RP 225AC-PSMA of a patient with mCRPC.

The radionuclide 225Ac (half-life 9.92 days; alpha particle energy 5.94 MeV) is an alpha-emitting isotope the physicochemical characteristics of which are ideal for nuclear medicine purposes, and its only drawback is its rarity. In the world, 225Ac is obtained in small quantities in only three centers: the Leipunskii Institute of Physics and Power Engineering (Obninsk, Russia), the OakRidge National Laboratory (Tennessee, United States), and the Institute for Transuranium Elements (Karlsruhe, Germany). RRCRST, as well as in NRRC, conducted research with domestic 225Ac. The introduction of radioactive microspheres into the hepatic artery—endovascular radioembolization of the liver (SIRT, RE)—is one of the most effective methods of treating unresectable liver cancer [27, 28]. For RE, microspheres with the 90Y radionuclide (Theraspheres, MDS Nordion, Canada; SIR-spheres, Sirtex Medical, Australia) and microspheres with 166Ho (QuiremSpheres, Quirem Medical BV, Deventer, the Netherlands) are approved for clinical use in the world [27-30]. NMRRC is conducting clinical trials of the original domestic RP hepatoren-MRRC based on human blood albumin microspheres with a diameter of 20–40 μm, labeled with 188Re, for the treatment of unresectable liver cancer.

* * *

Taking into account the facts described above, at present, oncological science is focusing its attention on the search for and development of technologies for early detection of oncological diseases and effective treatment of advanced (metastatic) forms of cancer. In 2019–2021, the following were actively being developed:

• methods of nuclear medicine based on the targeted effect of ionizing radiation of radiopharmaceuticals, including the development of new domestic diagnostic and therapeutic radiopharmaceuticals;

• methods of X-ray endovascular radioembolization of primary and metastatic tumors of various localization;

• development and implementation of new types of radiation therapy, including “fast” neutrons, which make it possible to overcome resistance to radiation and drug treatment;

• development and implementation of new approaches (gene therapy, use of oncological viruses);

• development and implementation of platforms for complex pharmacogenomic analysis based on world knowledge and deep machine learning, making it possible to select the most effective therapy with precision;

• development of new multidisciplinary surgical techniques;

• study of the fundamental mechanisms of the possible carcinogenic potential of COVID-19.

The COVID-19 pandemic has served as a catalyst for a number of scientific studies, including in Russian centers where international multicenter studies of COVID infection in oncology are being conducted. In addition, the need to find new solutions in the field of diagnostics and treatment of COVID-19 has led scientists to closer interdisciplinary cooperation and the use of off-label technologies, as well as flexible maneuvering of radiation, combined, and complex treatment regimens.