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.

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.

[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.

[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.

[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.

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.

[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.

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.

[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.

[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.

[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.

[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.

An open randomised trial of second-line endocrine therapy in advanced breast cancer. comparison of the aromatase inhibitors letrozole and anastrozole.

It was previously shown that letrozole (Femara) was significantly more potent than anastrozole (Arimidex) in inhibiting aromatase activity in vitro and in inhibiting total body aromatisation in patients with breast cancer. The objective of this study was to compare letrozole (2.5 mg per day) and anastrozole (1 mg per day) as endocrine therapy in postmenopausal women with advanced breast cancer previously treated with an anti-oestrogen. This randomised, multicentre and multinational open-label phase IIIb/IV study enrolled 713 patients. Treatment was for advanced breast cancer that had progressed either during anti-oestrogen therapy or within 12 months of completing that therapy. Patients had tumours that were either positive for oestrogen and/or progesterone receptors (48%) or of unknown receptor status (52%). The primary efficacy endpoint was time to progression (TTP). Secondary endpoints included objective response, duration of response, rate and duration of overall clinical benefit (responses and long-term stable disease), time to treatment failure, and overall survival, as well as general safety. There was no difference between the treatment arms in TTP; median times were the same for both treatments. Letrozole was significantly superior to anastrozole in the overall response rate (ORR) (19.1% versus 12.3%, P=0.013), including in predefined subgroups (receptor status-unknown, and soft-tissue- and viscera-dominant site of disease). There were no significant differences between the treatment arms in the rate of clinical benefit, median duration of response, duration of clinical benefit, time to treatment failure or overall survival. Both agents were well tolerated and there were no significant differences in safety. These results support previous data documenting the greater aromatase-inhibiting activity of letrozole and indicate that advanced breast cancer is more responsive to letrozole than to anastrozole as second-line endocrine therapy.

[The use of Neupogen in prevention of purulent septic complications after radical surgery for esophageal cancer]. / Neipogen v profilaktike gnoino-septicheskikh oslozhnenii pri radikal'nykh operatsiiakh na pishchevode po povody raka.

To prevent purulent complications, a granulocyte-colony stimulating factor--filgrastim-neupogen (200 or 480 mg) was injected during radical surgery and for the following 6 weeks in 26 patients with esophageal tumors and gastric cancer disseminated to the esophagus. A significant rise in leukocyte levels which potentiated antibacterial therapy was recorded in all patients. Purulent septic complication was registered in one case.

[The role of cardioxane (ICRF-187) in the prevention of cardiotoxicity of anthracyclines in the combined drug therapy of extensive ovarian cancer]. / Mesto kardioksana (ICRF-187) v profilaktike kardiotoksichnosti antratsiklinov pri kombinirovannoi khimioterapii rasprostranennogo raka iaichnikov.

The investigation was concerned with clinical application of cardioxane (dexrazoxan, ICRF-187) which is intended to counteract the cardiotoxic effect of anthracycline drugs. It was tested in 24 courses of combination chemotherapy (CAP) in 48 cases of extended ovarian tumor. The "threshold" total dose of doxorubin (500 mg/m2) which caused persistent cardiomyopathy in such patients as well as cases of relapse was practically never reached due to the absence of therapeutic effect. The total dose of doxorubicin of 120 mg/m2 raised the likelihood of acute cardiac intoxication. With prophylactic administration of cardioxane, clinical signs of acute cardiointoxication were slight; irreversible intoxication was recorded in 0.8%. The drug improved tolerance; it neither increased the overall toxicity of combination chemotherapy nor affected the results.