EFFICIENCY AND CARDIOTOXICITY OF IMMUNE CHECKPOINT INHIBITORS (CLINICAL CASE)

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Introduction.

The cardiotoxicity of cytotoxic drugs has always been an urgent problem in oncology. The most significant from this point of view were the drugs of the anthracycline series, as evidenced by the emergence of the concept (term) "anthracycline cardiomyopathy" [1]. Their cardiotoxicity is determined by a direct damaging effect on cardiomyocytes (CMC) and largely depends on the total dose [2]. For example, the recommended total doses are: Doxorubicin 360 mg/m2, Idarubicin 150 mg/m2, Epirubicin 720 mg/m2, Daunorubicin 800 mg/m2. The localizations in which they are used and the age of patients are varied [3, 4].

Trastuzumab was the next drug that appeared in medical oncology practice, making a breakthrough in the treatment of Her2/neu positive breast cancer and having a damaging effect on CMC. Currently, many treatment regimens for patients with various histological forms of lung cancer have been replenished with the so-called checkpoint inhibitors (CPTs). These drugs potentiate the body's immune response by blocking the connection between the programmed cell death receptor PD-1 and its ligands [5].

The use of ICT has made it possible to significantly improve the results of treatment of patients with lung cancer. At the same time, it turned out that ICTs cause a wide variety of immune-mediated adverse events (iAEs) with a frequency of up to 70% [6]. A significant part of them affects the vital organs with a violation of their function and possible death.

All complications have one thing in common - the mechanism of their development: an autoreactive immune response against healthy tissues due to excessive stimulation of immunological reactivity. In addition to PD-1 receptors and their corresponding ligands, there are also PD-L2 ligands. They are located on healthy cells. Immunological drugs also break these bonds, which is why the immune system perceives its organs and tissues as foreign and begins to fight against them. Thus, there are complications that are similar in their mechanism of development to autoimmune diseases [7].

ICT cardiotoxicity manifests itself in the form of myocarditis, Takotsubo syndrome, acute coronary syndrome, and pericarditis. Myocarditis is recorded in 46% of cases of death during therapy with immune response checkpoint inhibitors. The diagnosis of immune-mediated cardiotoxicity is the same as that of anthracycline [8]. Treatment is the abolition of immunotherapy, the use of glucocorticosteroids, the use of immunosuppressive drugs, according to indications, the treatment of acute coronary syndrome, pericardiocentesis, and the use of plasmapheresis is possible. The issue of resuming TKI therapy is considered individually [9].

When using ICT, monitoring the state of cardiac activity is standard. The studied indicators include: 1) ECHO-KG with the determination of the ejection fraction (a decrease is considered to be a decrease by more than 10% from the initial value or a decrease below 50%); 2) NaPro-BNP is a laboratory indicator, rather non-specific; 3) Troponin I — cardiospecific laboratory indicator; 4) ECG monitoring (dynamics, rhythm disturbances, conduction, acute coronary pathology, etc.) [10]. The frequency of all control measures, except for the ECG, before the course of special drug treatment and in case of suspected EI. ECG is monitored before each course of immunotherapy (IT) [11].

Purpose of the study. To study the effectiveness of treatment with Nivolumab and the cause of death when using it in a patient with non-small cell lung cancer.

Methods. The study of histological preparations of a malignant lung tumor with the determination of the degree of therapeutic pathomorphosis according to Lavnikova G.A. [12], as well as cardiac and lung tissues with an assessment of their pathological changes.

Results.

     In August 2018, in a 65-year-old patient S., computed tomography (CT) of the chest organs (CT) revealed peripheral focal lesions in both lungs, mediastinal lymphadenopathy. A transthoracic puncture biopsy of a focal mass in the right lung was performed. Histological conclusion: metastasis of adenocarcinoma. On PET-CT in October 2018, tumor tissue was found in the S2, S6 segments of the right lung, focal changes in the lungs.

The medical-advisory commission made a diagnosis: peripheral cancer of the right lung stage IV T4NxM1 (pulm). In November 2018, an operation was performed: atypical resection of S2 and S6 segments of the right lung. Histological diagnosis by immunohistochemical examination: solid adenocarcinoma of the lung, without germination of the visceral pleura. There is no EGFR mutation.

In February 2019, the medical advisory commission recommended chemotherapy courses according to the scheme: Pemetrexed 500 mg/m2 IV 1 day, Cisplatin 75 mg/m2 IV 1 day, every 3 weeks. Until May 2019, 4 courses of chemotherapy were carried out according to this scheme. At the CT of the WGC in May 2019, the stabilization of the process was stated. In July 2019, CT scan of the chest revealed continued tumor growth.

Second-line chemotherapy was prescribed according to the scheme: Paclitaxel 175 mg/m2 intravenously. 1 day, Carboplatin AUC5 IV cap. 1 d, cycle 21d. Until September 2019, 3 courses of chemotherapy of the 2nd line were carried out. At the CT scan of the WGC dated October 2019, the progression of the process was established. The third line of chemotherapy with Gemcitabine in mono mode (1000 mg/m2 IV cap 1.8d, cycle 21d) in the amount of 2 courses led to the stabilization of the process (CT of the WGC from December 2019: compared with CT from October 2019 without significant dynamics of the process ).

CT scan of the chest in February 2020 revealed continued tumor growth. The medical commission recommended treatment with Nivolumab 240 mg intravenously every 2 weeks. Until April 2020, 6 courses of immunotherapy were carried out with the achievement of a partial regression of the process. The patient continued to receive similar courses of immunotherapy in a stable general condition. There were no significant complaints from the cardiovascular system. In September 2020, he was hospitalized for 12 courses of immunotherapy.

Upon admission, the general condition was satisfactory, there were no special complaints. ECHO-KG from 07/02/2020: the contractility of the left ventricular myocardium is good (ejection fraction EF 64% according to Teicholz), local contractility disorders were not detected. On the ECG from 09/14/2020, sinus tachycardia. On September 18, 2020, Nivolumab was administered, which the patient tolerated satisfactorily. A sharp deterioration in the general condition on the night of September 19, 2020 with a drop in blood pressure. Despite resuscitation measures, biological death was declared.

The study of histological preparations of tumor tissue, lung and heart tissue obtained after pathoanatomical autopsy revealed the presence of a keloid scar in the tumor bed with tumor cells with signs of therapeutic pathomorphosis of the 3rd degree. Hemorrhagic edema, a large number of siderophages were found in the lung tissue, which was recognized as reliable signs of acute and chronic left ventricular failure. In the myocardium, the phenomena of edema, CMC lysis, multiple foci of necrosis of varying degrees of prescription were found: from organized and organizing to "fresh" in the absence of significant coronary sclerosis, infiltration of the stroma with lymphoid elements.

The state of the myocardium was regarded as serous myocarditis with a predominant alternative component. Signs of fibrillation of the myocardium of the left ventricle of the heart were found.

On the basis of microscopic data, a pathoanatomical diagnosis was made:

Primary disease: G3 solid adenocarcinoma of the right lung, stage IV T4NxM1a. Operation in the Healthcare Institution of Higher Education "VOKB No. 1" dated November 20, 2018: atypical resection of S2 and S6 of the right lung, after 4 courses of chemotherapy until May 2019; progression on 07.2019, after 3 cycles of second-line chemotherapy; progression on 10.2019, after 2 cycles of 3rd-line chemotherapy until 11.2019; negative dynamics on 02.2020, after 12 courses of immune therapy, partial regression (tumor remnant in the lower lobe of the right lung with symptoms of stage III therapeutic pathomorphosis).

Complications of the underlying disease: subacute serous myocarditis, myocardial dystrophy; pulmonary edema, acute general venous plethora.

Concomitant diseases: ischemic heart disease, stenosing atherosclerosis of the coronary arteries (2nd degree, stage IV, stenosis by 30-50%); stenosing atherosclerosis of the cerebral arteries (grade 2, stage IV, stenosis by 30-40%); aortic atherosclerosis (grade 2, stage IV).

Findings:

1. ICT immunotherapy is quite effective even in multitreated patients with lung adenocarcinoma.

2. The drugs of this group have immune-mediated cardiotoxicity, which can be determined by the damaging effect on CMC of lymphoid elements. However, a direct adverse effect on the heart muscle cannot be completely excluded. This issue needs further research.

3. Ultrasound of the heart and ECG are not able to reliably control the state of the myocardium during immunotherapy. Even in the absence of significant clinical manifestations and reasonable suspicion of changes in the cardiovascular system, it is necessary to study additional relevant laboratory parameters.

About the authors

Tatyana Vladimirovna Galvas

Воронежский Государственный Медицинский Университет им. Н.Н. Бурденко

Email: galvas.tatyana@yandex.ru

ординатор кафедры онкологии ФГБОУ ВО «Воронежский Государственный Медицинский Университет им. Н.Н. Бурденко»

Russian Federation

Elena Andreevna Shitova

Воронежский Государственный Медицинский Университет им. Н.Н. Бурденко

Email: alyona_shhh@mail.ru

ординатор кафедры онкологии ФГБОУ ВО «Воронежский Государственный Медицинский Университет им. Н.Н. Бурденко» Минздрава России

Russian Federation, 394036, г. Воронеж, ул. Студенческая, 10

Ivan Petrovich Moshurov

Воронежский Государственный Медицинский Университет им. Н.Н. Бурденко

Email: ipmoshurov@vrngmu.ru

доктор медицинских наук, профессор, заведующий кафедрой онкологии ФГБОУ ВО «Воронежский Государственный Медицинский Университет им. Н.Н. Бурденко»

394036, г. Воронеж, ул. Студенческая, 10

Yuri Nikolaevich Potapov

Воронежский Государственный Медицинский Университет им. Н.Н. Бурденко

Author for correspondence.
Email: potapov@vokod.vrn.ru

доктор медицинских наук, профессор, профессор кафедры онкологии ФГБОУ ВО «Воронежский Государственный Медицинский Университет им. Н.Н. Бурденко»

Russian Federation, 394036, г. Воронеж, ул. Студенческая, 10

References

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