Evaluation of the effectiveness of transarterial chemoembolization irinotecan-loaded with drug-saturable microspheres for the treatment of patients with neuroendocrine tumors with liver metastases

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Background: Since 2021, transarterial chemoembolization of the hepatic arteries (TACE) has been included in the recommendations of professional communities for the treatment of metastases of neuroendocrine liver tumors (NEO). However, the heterogeneity of both this group of patients and types of chemoembolization with a limited range of cytostatics used in the treatment makes it difficult to analyze the data and introduce the method into the combination therapy regimens.

Aim: to study the effectiveness of transarterial chemoembolization with irinotecan-loaded drug-saturable microspheres for the treatment of patients with neuroendocrine tumors with liver metastases.

Methods: A retrospective, observational, uncontrolled study of 34 patients with liver metastases from neuroendocrine cancer who underwent 52 TACE with irinotecan-loaded drug-saturable microspheres. Group 1 consisted of 15 patients who already had liver metastases at the time of the primary focus detection, group 2 included 19 patients with liver metastases having appeared some time after the detection of the primary focus. To plan and evaluate the effectiveness of chemoembolization, computed tomography and magnetic resonance imaging were used every 10–15 weeks during the systemic treatment. All the patients received systemic NEO therapy before and after the embolization.

Results: An increase in the progression-free time from 101 [57; 120] and 145 [89; 263] days after chemotherapy up to 300 [134; 344] and 304 [240; 342] days after TACE in groups 1 and 2, respectively, with no difference between the groups (p=0.31 and p=0.57, respectively). We did not find a linear relationship between the doubling time of the tumor and the change in the volume of the tumor lesion (R2=0.1085 and R2=0.0265 in groups 1 and 2). When comparing the intragroup scores, there was a statistically significant difference (p=0.009, p=0.046) in the tumor volume reduction and progression-free time between the patients who underwent TACE immediately and those who underwent TACE after chemotherapy. The diagnostic and angiographic images of liver metastases varied within the same organ and depended on the size of metastases. There were no adverse events after TACE.

Conclusions: TACE with irinotecan-loaded drug-saturable microspheres is an effective method for the treatment of liver metastases of neuroendocrine cancer, allowing one to increase the time without progression.

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Contribution of the authors Zvezdkina E.A.: writing an article, performing all diagnostic studies, remote consultation of all diagnostic studies, analysis of results, analysis of literature, participation in a medical consultation. Kedrova A.G.: selection and examination of patients, surgery at the stages after chemoembolization, participation in a medical consultation, therapy at the stages before and after chemoembolization, analysis of the results; Lebedev D.P.: performer of the part of chemoembolizations for all presented patients, analysis of the results; Krasilnikov S.E. - retrospective selection of patients, analysis of the treatment; Krestyaninov O.V. - performer of chemoembolization of some of the presented patients, analysis of the results; Greyan T.A.: drug treatment of patients, analysis of the results; Panchenkov D.N.: surgery at the stages after chemoembolization; Stepanova Yu.A.: performance of diagnostic ultrasound studies. ORCID authors / ORCID of authors Е.А. Zvezdkina/E.A. Zvezdkina: https://orcid.org/0000-0002-0277-9455 Relevance Neuroendocrine tumors (NET) are malignant neoplasms that develop from cells of the APUD system. Their most common localization is the pancreas, stomach, small intestine, lungs, although other organs may be the source. Neuroendocrine cancers are slow-growing tumors, however, they are capable of metastasizing [1]. In this case, the liver becomes the main target organ. In 2012, the European Society for the Study of Neuroendocrine Tumors (ENETS) proposed a classification of liver metastases [2]. At the same time, the simple form, when the foci are localized in one lobe of the liver or adjacent segments and can be removed surgically, accounts for only 20-25% of cases. All other situations (complex form, diffuse form) are unresectable. In 2021, the European Society of Cardiovascular and Interventional Radiologists (CIRSE) issued recommendations for transarterial liver chemoembolization (TAChE), where neuroendocrine tumors were included as indications for surgery [3]. However, the situation is complicated by the fact that TACE is a heterogeneous group of methods (in the CIRSE recommendations alone, 5 options are indicated), which differ not only technically, but also in the mechanism of action. One of the options for TACE is the use of drug-saturable microspheres (DMS). These are polymer granules capable of absorbing cytostatic, increasing their volume tenfold. Once in the vessels of a malignant neoplasm, LNM clog them, and a cytostatic is released in the tumor for several weeks. The microspheres themselves decrease in size and leave the vascular bed [4, 5]. Thus, the treatment becomes multicomponent: 1) the tumor is ischemic due to blockage of arterial vessels; 2) cytostatic blocks the growth and reproduction of tumor cells. The second active component of TACE drug-saturated microspheres is a chemotherapy drug. However, to date, there are no unified recommendations for chemotherapy of neuroendocrine tumors due to the lack of statistical data and heterogeneity within the group. Available regimens for the treatment of G1/G2 pancreatic NET in the form of a combination of streptozocin with fluorouracil or adriamycin, as well as a regimen of cisplatin or oxaliplatin in combination with etoposide NSC-141540 for the treatment of G3 NET, show an efficiency of 35–40% [6, 7]. Therefore, we conducted a retrospective study to investigate the effectiveness of transarterial chemoembolization with drug-saturable microspheres with irinotecan for the treatment of liver metastases in neuroendocrine tumors of different locations at different stages of the disease. PATIENTS AND METHODS General characteristics of patients For the period from September 2015 to February 2022, he performed 52 operations of transarterial chemoembolization with drug-saturable microspheres with irinotecan at the Federal Research and Clinical Center for Specialized Types of Medical Care and Medical Technologies of the Federal Medical and Biological Agency of Russia, the dynamics of as of 31.10.2022. Characteristics of patients and follow-up data are shown in Table No. 1. Table No. 1. Characteristics of patients with liver metastases of neuroendocrine cancer. Age at the time of TACE, g. Stage of the primary focus Localization of the primary focus Time from the moment of diagnosis to the appearance of liver mts Time from the appearance of liver mts to TACE58.55±12.5 min 29max 82Т1 10% (n=5)Т235 % (n=12) T3 45% (n=14) T4 10% (n=3) Pancreas 40% (n=12) Small intestine 30% (n=11) Lung 20% ​​(n=8) Prostate 10% (n=3) Group 1 Immediately 35% (n=15) Group 2 First 6 months 15% (n=5) 6 months-1.5 years 15% (n=5) 1.5-6 years 35% (n=9) <2 weeks 35% (n=7) >3 months 65% (n=13) Most patients (n=25, 75%) had multiple focal bilobar liver disease, 7 patients (20%) had multiple lesions within the same lobe liver,

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About the authors

Elena A. Zvezdkina

The Skobelkin Research and Practical Centre for Laser Medicine

Author for correspondence.
Email: zvezdkina@yandex.ru
ORCID iD: 0000-0002-0277-9455
SPIN-code: 8428-4518

MD, PhD, research associate

Russian Federation, 40, Studentcheskaya street, Moscow, 121165

Anna G. Kedrova

Federal Scientific and Clinical Center for Specialized Medical Assistance and Medical Technologies of the Federal Medical Biological Agency; Academy of Postgraduate Education Federal Scientific and Clinical Center for Specialized Medical Assistance and Medical Technologies of the Federal Medical Biological Agency; E.N. Meshalkin National Medical Research Center

Email: kedrova.anna@gmail.com
ORCID iD: 0000-0003-1031-9376
SPIN-code: 3184-9760

MD, PhD, professor

Russian Federation, Moscow; Moscow; Novosibirsk

Dmitry P. Lebedev

Federal Scientific and Clinical Center for Specialized Medical Assistance and Medical Technologies of the Federal Medical Biological Agency

Email: lebedevdp@gmail.com
ORCID iD: 0000-0003-1551-3127
SPIN-code: 4770-5722

doctor for X-ray endovascular diagnostics and treatment

Russian Federation, Moscow

Sergey E. Krasilnicov

E.N. Meshalkin National Medical Research Center

Email: krasilnikov_s@meshalkin.ru
ORCID iD: 0000-0001-8366-6083

Director of the Institute of Oncology and Neurosurgery

Russian Federation, Novosibirsk

Oleg V. Krestyaninov

E.N. Meshalkin National Medical Research Center

Email: o_krestyaninov@meshalkin.ru
ORCID iD: 0000-0001-5214-8996

Head of the Research Department of Endovascular Surgery of the Institute of Oncology and Neurosurgery

Russian Federation, Novosibirsk

Tatevic A. Greyan

Federal Scientific and Clinical Center for Specialized Medical Assistance and Medical Technologies of the Federal Medical Biological Agency; Academy of Postgraduate Education Federal Scientific and Clinical Center for Specialized Medical Assistance and Medical Technologies of the Federal Medical Biological Agency

Email: tatev111@gmail.com
ORCID iD: 0000-0003-4118-3002
SPIN-code: 6952-4709

Oncologist of the oncology department, Senior Lecturer of the Department of Obstetrics and Gynecology

Russian Federation, Moscow; Moscow

Dmitry N. Panchenkov

Moscow State University of Medicine and Dentistry named after A.I. Evdokimov

Email: dnpanchenkov@mail.ru
ORCID iD: 0000-0001-8539-4392
SPIN-code: 4316-4651

Doctor of Medical Sciences, Professor, Head of the Laboratory of Minimally Invasive Surgery

Russian Federation, Moscow

Yulia A. Stepanova

A.V. Vishnevsky National Medical Research Center of Surgery

Email: stepanovaua@mail.ru
ORCID iD: 0000-0002-2348-4963
SPIN-code: 1288-6141

Doctor of Medical Sciences, Senior Researcher, Department of Radiation Methods of Diagnosis and Treatment

Russian Federation, Moscow

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2. Fig. 1. Study design. Note: ТАХЭ — transarterial chemoembolization of hepatic arteries; ХТ — chemotherapy.

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3. Fig. 2. Angiography (а): intense contrast of a metastasis with a diameter of 3 cm (white arrow); magnetic resonance imaging (б): the same metastasis with a diameter of 3 cm with slit necrosis in the structure (long arrow), an infiltrative metastasis with a diameter of 0.5 cm with a locally expanded bile duct in the center (3D arrow), the pancreatic tail tumor (triangular arrow); angiography of the pancreatic tumor (в): branched network of afferents (triangular arrows).

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4. Fig. 3. The same patient. Angiographic picture of another metastasis with a diameter of 3 cm (а): several thin recalibrated vessels (arrow) exiting in an atypical place; magnetic resonance imaging of the same metastasis (б): slit necrosis in the structure (arrow).

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