FAST: a randomised phase II study of zolbetuximab (IMAB362) plus EOX versus EOX alone for first-line treatment of advanced CLDN18.2-positive gastric and gastro-oesophageal adenocarcinoma.

BACKGROUND: Claudin 18.2 (CLDN18.2) is contained within normal gastric mucosa epithelial tight junctions; upon malignant transformation, CLDN18.2 epitopes become exposed. Zolbetuximab, a chimeric monoclonal antibody, mediates specific killing of CLDN18.2-positive cells through immune effector mechanisms. PATIENTS AND METHODS: The FAST study enrolled advanced gastric/gastro-oesophageal junction and oesophageal adenocarcinoma patients (aged ≥18 years) with moderate-to-strong CLDN18.2 expression in ≥40% tumour cells. Patients received first-line epirubicin + oxaliplatin + capecitabine (EOX, arm 1, n = 84) every 3 weeks (Q3W), or zolbetuximab + EOX (loading dose, 800 mg/m2 then 600 mg/m2 Q3W) (arm 2, n = 77). Arm 3 (exploratory) was added after enrolment initiation (zolbetuximab + EOX 1000 mg/m2 Q3W, n = 85). The primary endpoint was progression-free survival (PFS) and overall survival (OS) was a secondary endpoint. RESULTS: In the overall population, both PFS [hazard ratio (HR) = 0.44; 95% confidence interval (CI), 0.29-0.67; P < 0.0005] and OS (HR = 0.55; 95% CI, 0.39-0.77; P < 0.0005) were significantly improved with zolbetuximab + EOX (arm 2) compared with EOX alone (arm 1). This significant PFS benefit was retained in patients with moderate-to-strong CLDN18.2 expression in ≥70% of tumour cells (HR = 0.38; 95% CI, 0.23-0.62; P < 0.0005). Significant improvement in PFS was also reported in the overall population of arm 3 versus arm 1 (HR = 0.58; 95% CI, 0.39-0.85; P = 0.0114) but not in high CLDN18.2-expressing patients; no significant improvement in OS was observed in either population. Most adverse events (AEs) related to zolbetuximab + EOX (nausea, vomiting, neutropenia, anaemia) were grade 1-2. Grade ≥3 AEs showed no substantial increases overall (zolbetuximab + EOX versus EOX alone). CONCLUSIONS: In advanced gastric/gastro-oesophageal junction and oesophageal adenocarcinoma patients expressing CLDN18.2, adding zolbetuximab to first-line EOX provided longer PFS and OS versus EOX alone. Zolbetuximab + EOX was generally tolerated and AEs were manageable. Zolbetuximab 800/600 mg/m2 is being evaluated in phase III studies based on clinical benefit observed in the overall population and in patients with moderate-to-strong CLDN18.2 expression in ≥70% of tumour cells.

[Case of restoration of reproductive function using the method of cryopreservation and autotransplantation of ovarian tissue in a Hodgkin's lymphoma patient].

Recent advances of cancer treatment resulted in the increase of patient survival rate. Treatment for Hodgkin's lymphoma (HL) may impair reproductive function, which leads to a decrease of the quality of life of cancer survival. Today different approaches have been developed for fertility preservation, one of which is the cryopreservation of ovarian tissue with subsequent orthotopic transplantation. We have described a recovery of reproductive function in patient of 28 years with acute ovarian failure, which was induced after cancer treatment. After the orthotopic transplantation cryopreserved ovarian tissue ongoing pregnancy was achieved in the natural cycle after IVF insemination. We have described the first live birth in Russia after the orthotopic transplantation cryopreserved ovarian tissue in cancer patient. This approach has resulted in the recovery of endocrine function without replacement hormonal therapy and possibility for a woman to have her own biological baby. It suggests that cryopreservation of ovarian tissue should be offered to all young women diagnosed with cancer.

Role of C-reactive protein concentration of blood plasma in assessment of the severity and the effectiveness of treatment in patients with squamous cell carcinoma of the oral cavity mucosa.

The purpose of this study was to determine the prognostic significance of dynamics of C-reactive protein concentration in blood plasma as a marker for the progression of squamous cell carcinoma of the oral cavity mucosa. From January 2014 to August 2014 there were under the observation 35 patients with squamous cell carcinoma of the oral cavity mucosa. All patients were divided into 2 groups: group 1 - primary patients who had been diagnosed with malignant lesions of the oral cavity mucosa for the first time (17 people); group 2 - patients with recurrent disease (18 people). All 17 patients of group 1 received induction polychemotherapy by PF scheme and 18 patients of group 2 - curative polychemotherapy by the following schemes: PF, DCF, TC. In all patients there was performed an assessment of the level of C-reactive protein in blood serum at the stage prior to drug treatment and before each subsequent cycle of chemotherapy. An assessment of the level of C-reactive protein before treatment showed that in 17 patients of group 1 its level was in the normal range. Patients of group 2 had an increased concentration of C-reactive protein in blood plasma. Analysis of obtained data allows concluding that the level of C-reactive protein may be effectively used as a prognostic marker in patients with this pathology.

[COMBINATION OF VESSEL EMBOLIZATION AND CRYOTHERAPY IN SURGICAL TREATMENT OF SOFT TISSUE SARCOMAS].

The article analyzed the results of surgical treatment of 153 patients with soft tissue sarcomas. The surgery was complemented by preoperative embolization of vessels, which supplied the tumor, cryotherapy on the tumor and postoperative wound in 72 patients of main group. The control group consisted of 81 patients and there weren't any perioperative actions. It was shown, that more than 80% of soft tissue sarcomas had the main and mixed type of tumor blood supply. Partial and full reduction of blood flow could be obtained by embolization of the tumor in more than 50% patients. Combination of surgical and preoperative embolization of vessels and cryotherapy decreased the rate of local recurrence and increased the quantity of organosafe interventions.

[Laparoscopic surgery in treatment for colon cancer].

There are presented results of treatment of 347 patients with colorectal cancer. Laparoscopic surgery had been planned for 92 (26.5%) patients (study group). In 79 (85.9%) patients surgery was performed completely by laparoscopy, 13 (14.1%) patients underwent conversion. In 255 (73.5%) patients surgery was carried out from an open access (control group). The authors showed the effectiveness of the use of minimally invasive techniques in treatment for colorectal cancer.

[Influence of nutritive support on surgery outcomes in elderly patients with colon cancer].

The article presents the results of surgery outcomes in 127 elderly patients with colon cancer. The patients were divided into two groups: the main group (prospective, n = 52) and control group (retrospective, n = 75). The combined preoperative nutritive status assessment by BMI and a prognostic hypotrophy index were used. It included the optimization of nutritive support on all stages and an early tube removal, an enteral feeding during postoperative period. It was stated, that it significantly reduced the level of complications, period of intensive care unit stay on 2 days and a hospital stay on 4 days in main group. All the patients of the main group improved the quality of life during 7 days (EORTC QIQ CR29). Proposed nutritive support program allowed improvement of the quality of life and positive treatment outcomes in elderly patients with colon cancer.

Phase I, dose-finding study of AZD8931, an inhibitor of EGFR (erbB1), HER2 (erbB2) and HER3 (erbB3) signaling, in patients with advanced solid tumors.

AIM: AZD8931 is an oral equipotent inhibitor of EGFR (erbB1), HER2 (erbB2) and HER3 (erbB3) signaling. This Phase I, open-label study evaluated the safety, tolerability, and pharmacokinetics of multiple ascending doses of AZD8931 in patients with advanced solid tumors (NCT00637039). METHODS: Patients received AZD8931 as a single oral dose followed by 4 days of observation, then twice-daily dosing for 21 consecutive days. Using a standard 3 + 3 design, AZD8931 doses were escalated from 40 mg bid until the maximum tolerated dose (MTD) was established. RESULTS: Twenty-eight patients received AZD8931 (n = 5, 40 mg bid; n = 8, 80 mg bid; n = 6, 160 mg bid; n = 6, 240 mg bid; n = 3, 300 mg bid). Ovary (n = 8) and breast (n = 5) were the most common primary tumor types. The most frequent adverse events were treatment-emergent cutaneous (n = 27) and diarrhea (n = 21). Dose-limiting toxicities (DLTs) were identified in one patient in the 240 mg bid cohort (Grade 3 rash) and two patients in the 300 mg bid cohort (Grade 3 and 4 diarrhea). The pharmacokinetic profile of AZD8931 supported twice-daily dosing. AZD8931 was rapidly absorbed (median tmax 1-3 h), was well distributed and had moderate to high clearance with an elimination half-life of approximately 11 h. Exposure appeared to increase approximately proportionally with dose up to 160 mg. Of 21 patients evaluable for response at day 21, 12 had stable disease and nine had disease progression. CONCLUSION: The MTD of AZD8931 determined from the 21-day DLT period was 240 mg bid, although more long-term data are needed to confirm a dose of AZD8931 suitable for chronic treatment.

A randomised, double-blind, placebo-controlled phase 2 study of trebananib (AMG 386) in combination with FOLFIRI in patients with previously treated metastatic colorectal carcinoma.

BACKGROUND: This phase 2 study evaluated trebananib (AMG 386), an investigational peptide-Fc fusion protein that neutralises the interaction between angiopoietins-1/2 and the Tie2 receptor, plus FOLFIRI as second-line treatment for patients with metastatic colorectal cancer. METHODS: Patients had adenocarcinoma of the colon or rectum with progression within 6 months of receiving only one prior fluoropyrimidine/oxaliplatin-based chemotherapy regimen for metastatic disease. All patients received FOLFIRI and were randomised 2:1 to also receive intravenous trebananib 10 mg kg(-1) once weekly (QW) (Arm A) or placebo QW (Arm B). The primary end point was investigator-assessed progression-free survival (PFS). RESULTS: One hundred and forty-four patients were randomised (Arms A/B, n=95/49). Median PFS in Arms A and B was 3.5 and 5.2 months (hazard ratio (HR) 1.23; 95% CI, 0.81-1.86; P=0.33) and median overall survival (OS) was 11.9 and 8.8 months, respectively (HR 0.90; 95% CI; 0.53-1.54; P=0.70). Objective response rate (ORR) was 14% and 0% in Arms A and B, respectively. Incidence of grade ≥3 adverse events was similar between treatment arms (Arm A, 61%; Arm B, 65%) and included pulmonary embolism (1%/4%), deep vein thrombosis (5%/2%), and hypertension (1%/0%). CONCLUSION: Administration of trebananib plus FOLFIRI did not prolong PFS compared with placebo plus FOLFIRI. Toxicities were manageable and consistent with those known for FOLFIRI and trebananib.

[Clinical recommendations on treatment of the elderly colorectal cancer patients].

Colorectal cancer (CRC) is one of the commonest malignancies of Western countries, with approximately half the incidence occurring in patients > 70 years of age. Elderly CRC patients, however, are insufficient to fully examined, therefore, they receive inadequate treatment and underrepresented in clinical trials. The International Society of Geriatric Oncology created a task force with a view to assessing potential for developing guidelines for the treatment of elderly (geriatric) patients. A review of the evidence presented by the task force members confirmed the paucity of clinical trial data in elderly people and the lack of evidence-based guidelines. However, recommendations have been proposed on the basis of the available data and on the emerging evidence that treatment outcomes for fit, elderly CRC patients can be similar to those of younger patients. This gives hoped that such efforts will pave the way for formal treatment guidelines based upon solid scientific evidence in the future.

[Quality of life of patients with locally advanced operated gastric cancer during the period of chemotherapy].

The comparative analysis of the main life quality parameters for patients with locally advanced operated gastric cancer was carried out using the EORTC QLQ-C30, STO-22 version 3.0. at stages of chemotherapeutic treatment. All patients (n = 47) have been divided into 2 groups depending on application of chemotherapy (cisplatin + 5-fluorouracil) prevention by hemo-immunostimulation ("Glutoxim"). The changes in functional state, symptoms and general health status of patients were evaluated. It is revealed that application of Glutoxim significantly improves functional state and insignificantly influences disease symptoms.

Effect of trabectedin on the QT interval in patients with advanced solid tumor malignancies.

PURPOSE: The primary objective of this study was to access the potential effects of trabectedin on the QT/QTc interval in patients with locally advanced or metastatic solid tumors. METHODS: Patients (n = 75) who had received ≤3 previous lines of chemotherapy and had either relapsed or had progressive disease were enrolled. Patients were administered 3-h intravenous infusions of placebo (saline) on day 1 and trabectedin (1.3 mg/m(2)) on day 2. Time-matched serial triplicate ECG recordings and pharmacokinetic blood samples were collected over 24 h on both days. Heart rate corrected mean QT intervals and changes from predose baseline in QTc (ΔQTc) were assessed. The difference in ΔQTc between trabectedin and placebo was calculated at each time point (ΔΔQTc). RESULTS: The upper limits of the 90% confidence interval for ΔΔQTcF and ΔΔQTcB at all time points were less than the prespecified noninferiority margin of 10 ms (≤6.65 ms). No patient had a QTc > 500 ms or a time-matched increase from baseline in QTc > 60 ms at any time point. Regression analyses indicated ΔΔQTc was poorly correlated with trabectedin concentration. No adverse events suggestive of proarrhythmic potential were reported. CONCLUSION: Trabectedin did not prolong the QTc interval. Safety and pharmacokinetic profiles of trabectedin were similar to that observed in other ovarian and breast cancer studies.

[Features of hemocomponental therapy in oncological patients].

The authors present an analysis of specific features of transfusions of erythrocyte containing media in oncological patients. Special attention was given to necessary selection of donor erythrocytes in performing operations with massive intraoperative blood loss. It considerably contributes to a decreased number of posttransfusional reactions and complications. For the recent five years transfusions of erythrocyte containing media to more than 15 thousand patients with surgical treatment were analyzed. Among them the individual selection of donor blood was fulfilled in 2047 cases. Compatible erythrocytes could not be selected in five cases only. In these patients infusions of Perftoran were used as an oxygen carrier both during operation and at the postoperative period.

[Complications of chemotherapy in combination with bevacizumab for treating metastatic colorectal cancer].

Ninety-six patients with unresectable or metastatic colorectal cancer received first-line chemotherapy plus bevacizumab. The purpose of our study was to evaluate the safety and efficacy of the therapy. Median relapse-free survival lasted 10.4 months. Addition of bevacizumab was well tolerated and may be recommended for clinical use.

[Improvement of drug therapy for advanced gastric cancer used at a municipal clinical dispensary].

Four categories of patients with advanced gastric cancer treated with different regimens of chemotherapy: (1) PF cisplatin 100 mg/m2/day+5-fluorouracil 1000 mg/m2/day intravenous infusion (100 hrs); (2) carboplatin (AUC5)+5-fluorouracil 500 mg/m2/day intravenous infusion (2 hrs), days 1-3; (3) DCF, and (4) bevacizumab+PF.

A randomized phase II study of bortezomib and pemetrexed, in combination or alone, in patients with previously treated advanced non-small-cell lung cancer.

BACKGROUND: This is a phase II randomized study to evaluate the efficacy and safety of bortezomib and pemetrexed alone or in combination, in patients with previously treated advanced non-small-cell lung cancer (NSCLC). The primary end point was assessment of response rate. METHODS: A total of 155 patients were randomized (1:1:1) to pemetrexed (500mg/m(2)) on day 1 plus bortezomib (1.6mg/m(2)) on days 1 and 8 (Arm A) or pemetrexed (500mg/m(2)) on day 1 (Arm B) or bortezomib (1.6mg/m(2)) on days 1 and 8 (Arm C) of a 21 day cycle. Response rate was assessed by investigators using Response Evaluation Criteria In Solid Tumors (RECIST) criteria and toxicity assessed by the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) grading system. RESULTS: Response rate was 7% in Arm A, 4% in Arm B, and 0% in Arm C; disease control rates were 73%, 62%, and 43%, respectively. Median overall survival was 8.6 months in Arm A, 12.7 months in Arm B, and 7.8 months in Arm C; time to progression was 4.0 months, 2.9 months, and 1.4 months, respectively. Most common reported adverse events >/=grade 3 were neutropenia (19%), thrombocytopenia (15%), and dyspnea (13%) in Arm A, neutropenia (10%) in Arm B, and dyspnea (13%) and fatigue (10%) in Arm C. CONCLUSION: In previously treated NSCLC the addition of bortezomib to pemetrexed was well tolerated but offered no statistically significant response or survival advantage versus pemetrexed alone, while bortezomib alone showed no clinically significant activity.

[Effect of enterosorption on immunologic parameters of patients with colorectal cancer in the postoperative period].

Our investigation was carried out on an assumption that end results among patients radically-treated for colorectal cancer might be improved by use of enteroabsorption. The study group included 17, controls--13 patients with diagnostically verified stage I-III tumors. Mixed sorbent (microcellulose + polysorb) (6g) was administered, once a week, on the average of 20 days after operation. Immunological vigor was assayed 3 weeks after surgery: immunoglobulin levels--by turbodimetric method, cellular profile of lymphocytes--monoclonal antibodies to cell markers CD3, CD4, CD8, CD16 and CD22. As a result of adjuvant treatment CD22 (B-lymphocytes) concentration increased significantly--from 17.70 to 21.66 (22%), while CD16 (innate killers) both in absolute numbers (19%) and by percentage points (9%). Circulating immunocomplex levels in the sorbent-treatment group were significantly lower (37.44 ths units) than in control (48 ths units) (average 28%). No relapse or metastases were reported in either group.

[The role of gap junction communication in metastatic B16 melanoma in C57BL mice].

The study is concerned with the effects of non-specific blocking gap junction communication with oleamide as well as genesis and spreading of melanoma B16 metastases to the lung in mice C57B1. The blocking exerted no distinct influence on primary tumorigenesis but had a marked effect on metastatic spread. Oleamide treatment during tumor growth led to an increase in area covered by metastases. A correlation was established between metastatic frequency and dosage: 1 mg/kg was followed by an upsurge in frequency of secondary lung tumors while 10 mg/kg--by a drop.