ИСПОЛЬЗОВАНИЕ ПАКЛИТАКСЕЛА В ХИМИОЛУЧЕВОЙ ТЕРАПИИ БОЛЬНЫХ ПЛОСКОКЛЕТОЧНЫМ РАКОМ АНАЛЬНОГО КАНАЛА: ПИЛОТНОЕ ИССЛЕДОВАНИЕ

Objectives: to assess the feasibility of a combination of the intensity-modulated radiation therapy (IMRT) with a triplet chemotherapy with paclitaxel, capecitabine, and mitomycin C in the treatment of patients with anal cancer, and to evaluate the toxicity of the proposed treatment regimen.Materials and methods. All patients included in the study had stage I–IIIB anal cancer. All patients underwent IMRT radiotherapy 52–58 Gy (the dosage is calculated according T symbol) by 1.8 to 2.2 Gy fractions daily. The proposed chemotherapy scheme includes mitomycin C 10 mg/m2 on day 1, paclitaxel 45 mg/m2 on days 3, 10, 17, 24, 31, capecitabine 625 mg/m2 during radiotherapy. A complete response to treatment after 26 weeks, and the compliance to the study protocol were the primary end points of the study.Results. The study included 38 patients. Among patients stage I anal cancer occurred in 1 (2.6 %) case, II – in 5 (13.2 %), IIIA – 15 (39.5 %) and IIIB – in 17 (44.7 %). A significant deviation from the protocol reported in 6 (15.8 %) patients, in 11 (28.9 %) patients a slight alteration from the treatment was documented, and 21 (55.3 %) patients completed the treatment of chemoradiotherapy with full compliance to the study protocol. The high profile of toxicity (grade III–IV) was recorded in 23 (60.5 %) patients. An incomplete clinical response at 26 weeks after treatment was reported in 5 (13.2 %) patients, one whom continued watchful waiting and achieved complete response at 9 months posttreatment. Median followup was 27 months. 1 patient developed a local recurrence 1 year posttreatment.Conclusions. The proposed triplet chemotherapy regimen using IMRT is feasible and has acceptable toxicity. For further assess the continuous research is needed. Целью исследования явилась оценка эффективности лучевой терапии с модулированной интенсивностью (intensity-modulated radiation therapy, IMRT) с трехкомпонентной химиотерапией паклитакселом, капецитабином и митомицином С в лечении пациентов, больных раком анального канала, а также изучение профиля токсичности предложенной схемы лечения.Материалы и методы. Все пациенты, включенные в исследование, имели I–IIIB стадии опухолевого процесса. Больным была проведена лучевая терапия по технологии IMRT последовательными фракциями от 1,8 до 2,2 Гр ежедневно до суммарной очаговой дозы 52–58 Гр (в зависимости от исходной стадии Т). Предложенная схема химиотерапии включала прием митомицина С 10 мг/м2 внутривенно (в/в) в 1-й день, паклитаксела 45 мг/м2 в/в в 3, 10, 17, 24 и 31-й дни, капецитабина 625 мг/м2 2 раза в сутки перорально в дни лучевой терапии. Полный ответ на лечение через 26 нед и соблюдение протокола исследования являлись основными оцениваемыми параметрами.Результаты. В исследование были включены 38 пациентов. Опухолевый процесс I стадии был выявлен у 1 (2,6 %), II – у 5 (13,2 %), IIIA – у 15 (39,5 %) и IIIB – у 17 (44,7 %) больных. Значительное отступление от протокола зарегистрировано у 6 (15,8 %) пациентов, у 11 (28,9 %) отмечено незначительное отступление от схемы лечения, 21 (55,3 %) больной завершил режим химиолучевой терапии в полном соответствии с протоколом исследования. Высокий профиль токсичности (III–IV степени тяжести) зарегистрирован у 23 (60,5 %) пациентов. Неполный клинический ответ через 26 нед после окончания лечения был отмечен у 5 (13,2 %) больных, из них 1 пациентке продолжено динамическое наблюдение, полный ответ достигнут через 9 мес, остальным 4 предложено хирургическое лечение. Медиана наблюдения составила 27 мес. У 1 больной развился рецидив заболевания через 1 год после завершения химиолучевой терапии.Выводы. Предложенный режим трехкомпонентной химиотерапии по протоколу IMRT имеет допустимую токсичность и позволяет достичь высоких результатов лечения у прогностически неблагоприятной группы пациентов. Для дальнейшей оценки необходимо продолжение исследований

Результаты комбинированного лечения резектабельного рака желудка в зависимости от статуса микросателлитной нестабильности

Background. microsatellite instability (MSI) is a prognostic marker of survival in many malignant diseases and show resistance to chemotherapy at early stages of colorectal cancer and show no benefits from chemotherapy at early stages of colorectal cancer. However, the role of MSI in resectable gastric cancer (GC) remains unknown.Aim. To study the results of treatment of resectable gastric cancer with microsatellite instability.Materials and methods. The study included 286 patients with resectable gC who received treatment at the N. N. Blokhin national medical Research Center of Oncology. All patients underwent PCR testing for MSI-H in 5 markers (BAT25, BAT26, NR21, NR24, NR27). Tumor regression grades (TRG) were evaluated according to the mandard tumour regression score, including disease-free survival and overall survival.Results. MSI indicated in 27 cases (9.44 %) out of 286 resectable gastric cancer. In group patients who received only surgical treatment, 2-year disease-free survival in patients with MSI-H was 77.80 % versus 88.29 % in MSS patients (hazard ratio (HR) 1.82, 95 % confidence interval (CI) 0.37–8.82, p = 0.45), 2-year overall survival in patients with MSI-H was 88.90 % versus 95.36 % in MSS patients (HR 2.03, 95 % CI 0.20–19.8, p = 0.54). In patients who received perioperative chemotherapy, 28.57 % (4 / 14) had progression in MSI-H tumor versus 3.61 % (6 / 166) in MSS tumor (p <0.001). In group patients who received treatment combined with chemotherapy, 2-year disease-free survival in patients with MSI-H was 59.60 % versus 67.36 % (HR 1.96, CI 95 % 0.88–4.35, p = 0.09), 2-year overall survival in patients with MSI-H was 67.30 % versus 85.86 % in MSS patients (HR 1.86, 95 % CI 0.64–5.41, p = 0.25)Conclusion. MSI-H is not a favorable prognosis factor in patients with resectable GC who are treated surgically combined with chemotherapy. The prevalence of progression in patients with MSI-H-status is higher than MSS-status with perioperative chemotherapy (FLOT / FOLFIRINOX).Введение. Микросателлитная нестабильность является прогностическим маркером выживаемости при многих злокачественных заболеваниях и не имеет преимуществ при химиотерапии на ранних стадиях рака толстой кишки. Однако роль микросателлитной нестабильности при резектабельном раке желудка остается неизвестной.Цель исследования – изучение влияния микросателлитной нестабильности на результаты лечения пациентов с резектабельным раком желудка.Материалы и методы. В исследуемой группе было 286 пациентов с резектабельным раком желудка, получивших лечение в ФГБУ «НМИЦ онкологии им. Н.Н. Блохина» Минздрава России. У всех больных проводился тест на микросателлитную нестабильность с помощью BAT25, BAT26, NR21, NR24, NR27. Оценивались степень патоморфологического регресса (TRG) по A. m. mandard, безрецидивная и общая выживаемость.Результаты. Микросателлитная нестабильность (MSI) выявлена у 27 (9,44 %) из 286 больных операбельным раком желудка. В группе пациентов, получивших только хирургическое лечение, 2-летняя безрецидивная выживаемость у больных с MSI-H-статусом по сравнению с MSS-статусом составила 77,80 % против 88,29 % (отношение рисков (ОР) 1,82, 95 % доверительный интервал (ДИ) 0,37–8,82, p = 0,45), 2-летняя общая выживаемость у больных с MSI-H-статусом по сравнению с MSS-статусом составила 88,90 % против 95,36 % (ОР 2,03, 95 % ДИ 0,20–19,8, p = 0,54). В группе пациентов, получивших периоперационную химиотерапию, у 28,57 % (4 / 14) пациентов с MSI-H-статусом прогрессировало заболевание против 3,61 % (6 / 166) пациентов с MSS-статусом (p <0,001). В группе пациентов, получивших комбинированное лечение с химиотерапией, 2-летняя безрецидивная выживаемость у больных с MSI-H-статусом по сравнению с MSS-статусом составила 59,60 % против 67,36 % (ОР 1,96, 95 % ДИ 0,88–4,35, p = 0,09), 2-летняя общая выживаемость у больных с MSI-H-статусом по сравнению с MSS-статусом составила 67,30 % против 85,86 % (ОР 1,86, 95 % ДИ 0,64–5,41, p = 0,25).Выводы. MSI-H является неблагоприятным фактором прогноза при хирургическом лечении с химиотерапией резектабельного рака желудка. Частота прогрессирования у больных РЖ с MSI-H-статусом опухоли выше, чем c MSS-статусом после периоперационной химиотерапии (FLOT / FOLFIRINOX)

Периоперационная химиотерапия в режиме FLOT у больных операбельной аденокарциномой желудка и кардиоэзофагеального перехода (I–III тип по классификации SIEWERT). Опыт НМИЦ онкологии им. Н.Н. Блохина

To date, gastric cancer patients still have a poor prognosis. Current endoscopic or surgical treatment modalities are radical only for early gastric cancer (T1). Curability dramatically declines as tumor invasion progresses and lymph node metastasеs appear. In Europe and North America, the 5-year overall survival rate of patients with stage T2–4 cancer is 20 % [1]. Combination therapy for gastric cancer is being extensively studied to improve the treatment outcomes [2–6]. Currently, perioperative chemotherapy with FLOT regimen is the mainstay of resectable gastric cancer treatment in Europe. FLOT4-AIO randomized study has shown that the FLOT regimen was associated with significant increase in the median overall survival (50 versus 35 months), disease-free survival (18 versus 30 months) and R0 resection rate compared to ECF / ECХ regimen.In this work we evaluated the efficacy and toxicity of perioperative FLOT regimen in patients with gastric cancer and gastroesophageal junction cancer type I–III cT4aN0M0, cT1–4N + M0, using a prospective database of patients treated at the N. N. Blokhin Russian Cancer Research Center.На сегодняшний день прогноз больных раком желудка остаётся неблагоприятным. Для улучшения результатов терапии рака желудка активно изучается комбинированное лечение [2–6]. На сегодняшний день в Европе общепринятым подходом к лечению больных операбельным раком желудка является проведение периоперационной химиотерапии по схеме FLOT. В рандомизированном исследовании FLOT4‑AIO было показано, что назначение режима FLOT в сравнении с ECF/ECХ позволяет значимо увеличить медиану общей выживаемости c 35 до 50 месяцев, безрецидивной выживаемости с 18 до 30 месяцев и частоту достижения R0 резекций.В данной работе мы, используя проспективную базу данных пациентов, получивших терапию в НМИЦ онкологии им. Н.Н. Блохина, провели анализ эффективности и токсичности химиотерапии по схеме FLOT в периоперационном режиме у больных операбельным раком желудка и кардиоэзофагеальным раком I–III типа T2N0M0, TN+M0

Российский консенсус по профилактике, диагностике и лечению рака желудка

The Russian consensus on prevention, diagnostic and treatment of gastric cancer was prepared on the initiative of the Moscow clinical scientific center named after A. S. Loginov according to the Delphi method. Its aim was to clarify and consolidate the opinions of specialists on the most relevant issues of prevention, diagnosis and treatment of gastric cancer. An interdisciplinary approach was provided by the participation of leading gastroenterologists, oncologists and surgeons.Российский консенсус по профилактике, диагностике и лечению рака желудка подготовлен по инициативе Московского клинического научного центра им А. С. Логинова ДЗМ по Дельфийской системе. Его целью явилась консолидация мнений отечественных специалистов по наиболее актуальным вопросам профилактики, скрининга, диагностики и лечения рака желудка. Междисциплинарный подход обеспечен участием ведущих гастроэнтерологов, онкологов и хирургов.Цель статьи: представить положения Российского консенсуса по профилактике, диагностике и лечению рака желудка

Abemaciclib as an original inhibitor of cyclin-dependent kinase for the treatment of luminal HER2-negative disseminated breast cancer

Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, namely palbociclib, ribociclib and abemaciclib, have become a new standard of treatment of patients with hormone receptor-positive, HER2-negative disseminated or metastatic breast cancer (HR+ HER2- MBC), regardless of the line of therapy, menopause status and other individual characteristics. Short-term CDK4/6 inhibition leads to reversible arrest in the G1 phase of the cell cycle with restoration of Rb-1 phosphorylation and the complete cell cycle after termination of inhibition. The drugs have individual characteristics despite the similar mechanism of action described in the article. Abemaciclib, which differs from palbociclib and ribociclib in chemical structure, shows higher selectivity for CDK4, less myelosuppressive effect, which makes it possible to take it continuously, greater lipophilicity, and interacts more actively with ATP, resulting in its ability to interact with other kinases as well. Abemaciclib, the only one of all CDK4/6 inhibitors, has been proven effective in the treatment of refractory HR+ HER2-MBC: the proportion of patients with objective effect (OE) was 19.7%, that with disease control was 42.4%, median progression-free survival (PFS) was 5.95 months, median overall survival (OS) was 22.32 months. Abemaciclib combined with fulvestrant in the second-line therapy increases the effectiveness of treatment compared with endocrinotherapy (ET) alone: median PFS increased to 16.9 months from 9.3 (p < 0.001), OE to 35 from 16% (p < 0.001) in the ITT population, median OS to 46.7 from 37.3 months (p = 0.01) for abemaciclib in combination with fulvestrant. The use of abemaciclib in combination with nonsteroidal aromatase inhibitors (NSAIs) compared with aromatase inhibitors (AI) alone in the first-line therapy demonstrated increased median PFS from 14.76 to 28.18 months (p = 0.000002) and increased OE (from 37 to 49.7% (p = 0.005) in the ITT population. Diarrhea is the common adverse event of abemaciclib, which develops in 82–90% of patients. It does not exceed severity level 3, the frequency of the latter does not exceed 13%, diarrhea is reversible, and can be stopped by using antidiarrheal drugs. ET in combination with abemaciclib makes it possible to improve the effectiveness of treatment in the most prognostically unfavourable patient population

Choice of adjuvant drug therapy on the basis of the molecular classification of breast cancer

Molecular genetic analysis identified some biological subtypes of breast cancer (BC): luminal A, luminal B, HER2 positive, and basal-like (including triple negative). The surrogate clinical and morphological criteria including the immunohistochemical determination of estrogen and progesterone receptors, the hyperexpression and/or amplification of HER2, Ki-67, or tumor grade (G) are used to identify the biological subtypes of BC in clinical practice. The biological subtypes are distinguished by their biological course and susceptibility to various systemic treatments, which requires different therapeutic tactics. The paper presents tactics of adjuvant therapy for BC in relation to its biological subtype according to the recommendations of the 12th St. Gallen International Breast Cancer Conference (2011) and considers the place of taxans

Clinical example of long-term control of disseminated signet-ring cell carcinoma of the stomach against the background of chemotherapy of the second line of treatment in combination with bevacizumab

The standard of treatment of the second line of disseminated stomach cancer is palliative chemotherapy with paclitaxel in combination with ramucirumab. Vascular endothelial growth factor A (VEGF-A) is a key regulator of blood vessel growth and its connection to the corresponding receptors of VEGFR1/2 leads to the activation of neoangiogenesis. In patients with disseminated stomach cancer, the level of VEGF-A rs25648 has a negative impact on both survival without progression of the disease and on overall survival. The antitumor activity of neoangiogenesis inhibitors in the second line of treatment may be related to a higher concentration of VEGF-A, the level of which, in turn, correlates with the volume of tumor tissue. In a small study of the second phase, the addition of bevacizumab to docetaxel in the second line of treatment of patients with disseminated stomach cancer allowed to achieve tumor growth control in 48% of patients. Meta-analysis of 7 studies (n = 905) showed that the use of two-component modes based on irinotecan in the second line in comparison with irinotecan monotherapy allows to increase significantly the survival rate without progression. This clinical observation illustrates this approach. Patients with signet-ring cell disseminated stomach cancer after rapid progression on the background of the first line of chemotherapy with docetaxel, oxaliplatin and 5-fluorouracil were prescribed chemotherapy of the second line in combination with bevacizumab. It is the second line of treatment that allowed to achieve long-term control of the disease, equal to 18 months, with a life expectancy of 30 months. When analyzing a clinical case, the justification of the patient’s treatment tactics, the choice of two-component mode of chemotherapy and the use of bevacizumab was carried out

Clinical example of enhancing efficacy of paclitaxel by combining it with ramuchirumabin in the second-line chemotherapy of disseminated gastric cancer

The low efficacy of cytostatic therapy in mGC led to an active study of the role of molecular targets in the carcinogenesis of GC. Ramucirumab is the only neoangiogenesis inhibitor, which demonstrated its antitumor activity both as monotherapy and in combination with paclitaxel in patients with mGC. A clinical case demonstrated an example of a long-term (26+ months) response to paclitaxel therapy after it was combined with ramucirumab with an acceptable toxicity profile, which allowed a patient to participate in social activities and maintain quality of life

A case of effective disease control of advanced gastric cancer following ramucirumab plus FOLFIRI in second line treatment in clinical practice

Ramucirumab is a human anti-vascular endothelial growth factor receptor 2(VEGFR-2)monoclonal antibodythat acts on vascular endothelial cells to inhibit angiogenesis. Ramucirumab in monotherapy or in combination with paclitaxel or FOLFIRI has proven to prolong overall survival in patients with pretreated metastatic gastric/gastrooesophageal junction adenocarcinoma. In clinical practice combination with ramucirumab showed promising efficacy with median overall survival in 9,6 months and manageable toxicities. Most common specific adverse events in ramucirumab were impaired wound healing, hypertension, bleeding and perforation. In several article describe dysphonia induced by anti-angiogenic compounds.Herein, we report on a case a high activity ramucirumab in combination with FOLFIRI. This report aims to present a long-term survivor of recurrent gastric cancer and describe dysphonia induced by ramucirumab