Efficacy and safety of CT-P6 versus reference trastuzumab in HER2-positive early breast cancer: updated results of a randomised phase 3 trial.

PURPOSE: Neoadjuvant CT-P6, a trastuzumab biosimilar, demonstrated equivalent efficacy to reference trastuzumab in a phase 3 trial of HER2-positive early-stage breast cancer (EBC) (NCT02162667). We report post hoc analyses evaluating pathological complete response (pCR) and breast pCR alongside additional efficacy and safety measures. METHODS: Following neoadjuvant treatment and surgery, patients received adjuvant CT-P6 or trastuzumab (6 mg/kg) every 3 weeks for ≤ 1 year. RESULTS: In total, 271 and 278 patients received CT-P6 and trastuzumab, respectively. pCR and breast pCR rates were comparable between treatment groups regardless of age, region, or clinical stage. Overall, 47.6% (CT-P6) and 52.2% (trastuzumab) of patients experienced study drug-related treatment-emergent adverse events (TEAEs), including 17 patients reporting heart failure (CT-P6: 10; trastuzumab: 7). Two CT-P6 and three trastuzumab patients discontinued adjuvant treatment due to TEAEs. CONCLUSION: Adjuvant CT-P6 demonstrated comparable efficacy and safety to trastuzumab at 1 year in patients with HER2-positive EBC, supporting CT-P6 and trastuzumab comparability.

[Interleukin-2 (Ronkoleykin) in the first-line chemotherapy for B-cell non-Hodgkin lymphoma].

In this paper we present the results of a randomized prospective study, in which we examined the influence of rIL-2 ("Ronkoleykin ") on the effectiveness of the R-CHOP combination in the first-line treatment of patients with B-cell non-Hodgkin lymphomas. From March 2006 to December 2009, the study included 109 newly diagnosed patients. Standard R-CHOP was used in 59 patients, in 50 patients rIL-2 was added, injected subcutaneously in a dose of 1 million IU per day during each course in 1-5th days. It was found that the inclusion of rIL-2 in the R-CHOP regimen increased the effectiveness of the treatment of B-cell NHL with a high-risk of poor disease's course.

The effect of cytostatics and hyperthermia on RAJI human lymphoma cells.

AIM: To evaluate the effect of hyperthermia on cytostatic activity of chemotherapeutic drugs carboplatin, cisplatin, oxaliplatin, carmustine, gemcitabine and etoposide in human lymphoma cell culture. METHODS: RAJI human lymphoma cells were incubated with cytostatics at 37 °C or 42 °C and evaluated for cell culture growth. RESULTS: The number of viable cells after incubation with the drugs (except for gemcitabine) at 42 °C for 30 min was significantly lower than at 37 °C. There were synergism of cytostatic effects of platinum drugs (carboplatin, cisplatin and oxaliplatin) with cytostatic effect of 42 °C and the summation of cytostatic effect of carmustine or etoposide with the action of hyperthermia. The thermal enhancement ratio was 3.0 for oxaliplatin, 2.0 for cisplatin, 1.8-2.4 for carboplatin. The combination of platinum drugs with gemcitabine resulted in a significant enhancement of cytostatic activity. CONCLUSION: Our findings suggest that a gain in sensitivity of RAJI human lymphoma cells to platinum drugs occurs at 42 °C.

[Use of LAK-cells and systemic chemotherapy with hyperthermia in the management of chemo-resistant tumors].

Tentative results of LAK-cell and whole-body hyperthermia (WBH) were evaluated in 19 children with advanced chemorefractory tumors. LAK-cells were obtained by extracorporeal incubation of peripheral blood lymphocytes: a germ-cell rhabdomyosarcoma was detected in 4, Askin's tumor--2--2, renal cell carcinoma--2 and miscellaneous--7. Autologous LAK-cells were infused twice: on completion of WBH as body temperature fell to as low as (+) 40 deg. C and on day after WBH. The latter was well tolerated. Complete or partial response to thermochemobiotherapy was reported in 8 patients. Overall 5-year survival was 43% (median follow-up--12.6 months).

Dose enhancement effect of anticaner drugs associated with increased temperature in vitro.

AIM: To evaluate in vitro the influence of elevated temperature (42 degrees C for 60 min) on the action of anticancer drugs doxorubicin, vinorelbine, carboplatin, ifosfamide, etoposide, oxaliplatin, docetaxel and gemcitabine. METHODS: HeLa tumor cell cultures, 24h after seeding, were incubated for 60 min with different concentrations of chemotherapeutical drugs at a temperature of 37 degrees C or 42 degrees C. 48 h later the number of viable cells in the flasks were counted using trypan-blue exclusion on a hemacytometer. RESULTS: Hyperthermia alone caused only 10-20% growth inhibition of cell culture. All the chemotherapeutic drugs used demonstrated a dose enhancement effect at elevated temperature. Thermal enhancement ratio for cell proliferation for oxaliplatin, vinorelbine, carboplatin and ifosfamide exceeded 4, for doxorubicin and gemcitabine exceeded 2. Thermal enhancement ratio for cell death did not exceed 1.4. CONCLUSION: Synergism of hyperthermia and chemotherapeutical drugs was clearly demonstrated for oxaliplatin, vinorelbine, carboplatin, ifosfamide and to a lesser extent for doxorubicin and gemcitabine. Enhancement of the cytostatic effect of anticancer drugs by hyperthermia was more prominent than their cytotoxic effect.

The effect of hypoxia on photocytotoxicity of TICS tricarbocyanine dye in vitro.

AIM: To evaluate the effect of cell oxygenation on photocytotoxicity of a novel tricarbocyanine indolenine dye covalently bound to glucose (TICS). METHODS: HeLa cells were incubated with 5 microM TICS, 2 h later irradiated by laser at 740 nm with a light dose of 10 J/cm(2), delivered at a power density of 10, 20, 25 or 30 mW/cm(2), in air or in argon atmosphere, and then scored for viability. RESULTS: The photocytotoxicity of TICS increased dramatically as the power density was reduced. Under hypoxia TICS-photosensitized cell death was determined but its value was lowered, compared to photoirradiation in the air. CONCLUSION: Photosensitizing effect of TICS is only partially dependent on the oxygenation of tumor cells.

Oxidative metabolism of rat blood in the course of alveolar hepatic carcinoma PC-1 growth.

AIM: To evaluate oxidative metabolism of rat blood in the course of alveolar hepatic cancer growth in vivo. METHODS: The oxidation imbalance was assessed by the rise in the values of the integral index of oxidation stress. The structural and functional state of erythrocyte membranes was investigated by spin electron paramagnetic resonance spectroscopy. RESULTS: The growth of alveolar carcinoma was found to be associated with intensification of lipid peroxidation processes with increased blood content of conjugated dienes, malonic dialdehyde against the background of decreased concentration of endogenous antioxidants tocopherol and retinol. Destabilization of the structural state of erythrocyte membranes of rat tumor hosts at the development of oxidation stress was studied, which was characterized by nonspecific structural changes of membrane sorption centres, reduction in specific capacity in the protein-lipid contact area and its increase in the phospholipid bilayer, rise in the degree of order and polarity. CONCLUSION: Alveolar carcinoma growth in rats resulted in intensification of free radical lipid peroxidation processes with a shift of the prooxidant-antioxidant balance to the left and development of oxidation stress.

[Salvage thermochemotherapy in advanced refractory malignant tumors in children]. / Termokhimioterapiia pri refrakternykh i daleko zashedshikh zlokachestvennykh opukholiakh u detei.

The data are presented on polychemotherapy given to 17 children with advanced refractory malignant tumors using whole body hyperthermia and hyperglycemia. All patients suffered tumor progression throughout treatment and afterwards. Adjuvant Roncoleukin (interleukin-2) was administered in 5. Such salvage therapy was followed by overall tumor regression in 29.3%. Overall 4-year survival in such cases was 19%. Immunological monitoring of adjuvant whole body hyperthermia and interleukin-2 was carried out.

[Role of high-dose BEAM-chemotherapy and autologous hemopoietic stem cell transplantation in the treatment of drug-resistant Hodgkin disease]. / Mesto vysokodoznoi BEAM-terapii i autologichnoi transplantatsii gemopoéticheskikh kletok u bol'nykh khimiorezistentnymi formami bolezni Khodzhkina.

In 1995-1999, 67 patients with relapsed Hodgkin's disease or refractory to chemotherapy (group A--first relapse, B--primary refractory disease, and C--repeated relapse) received cytoreductive (dexaBEAM, DHAP) therapy followed by high-dose BEAM chemotherapy and autologous bone marrow or blood cell transplantation. Early postoperative transplant-related mortality rate was 4.5%. At day 100, complete remission rates were: group A--95.6%; B--74.1%; and C--76.5%. Survival for all patients was: overall--61.9%; event-free--43.9%; disease-free--46%; and relapse-free survival--49.5%. Such factors as primary refractory disease, age over 30 years and response to cytoreductive therapy had significant influence on overall survival prognosis.

Modifying effect of organocobalt complexes on the tumour response to anticancer treatments.

A new type of agents are proposed for combined cancer therapy. They are organocobalt (III) chelates containing a sigma-bounded organyl group and a mixed tridentate ligand derived from a Schiff base. These complexes generate free radicals due to the action of protons in physiological ranges of pH and temperature, and hence are conceivably capable of selectively attacking a malignant neoplasm that is slightly acidic and can be made even more so by introducing some means intensifying glycolysis. An in vivo examination was performed using transplanted rat tumours (Guerin and Walker 256 carcinomas, Sarcoma 45). The modifying effect of one of these complexes on the tumour response to cis-DDP, radiation and/or local hyperthermia was tested by means of tumour growth delay assay and local tumour control. The potentiating effect of the complex was maximal when it was administered 60-90 minutes prior to other agents (cisDDP, X-irradiation heat). The enhancement ratio was found to be ca. 2.0-4.0 for cisDDP and 2.0 for radiation. In conclusion, in our tumour models, an increase of the antitumour effect was obtained for conventional antitumour agents when they were supplemented with organocobalt complex. It can be hypothesised that DNA in tumour cells may be considered to be the main target for organocobalt complexes.

[Effect of chemoradiotherapy on the pituitary-thyroid system in children with Hodgkin's disease]. / Vliianie khimioluchevogo lecheniia na sostoianie gipofiz-tireidnoi sistemy u detei, bol'nykh limfogranulematozom.

The functional status of the thyroid gland was evaluated in 63 children with Hodgkin's disease, aged 4-15 years, before, in the course of and 5 years after chemoradiation therapy. Thyroxin (T4), triiodothyronine (T3) and thyroid-stimulating hormone (TSH) in the blood were assayed. The disease was shown to disrupt the pituitary-thyroid system leading to hypothyroidism development which progressed as the disease advanced. While chemotherapy brought the balance between the peripheral thyroid hormone levels and TSH back to normal, thyroid function decreased again following radiotherapy of the neck. The most pronounced and persistent failure of the pituitary-thyroid system was registered with the total target dose of 30 Gy and higher. Irradiation in a dose of 20 Gy caused less disruption and the function was spontaneously restored within 12 months after the treatment.

Experimental grounds for using chlorin e6 in the photodynamic therapy of malignant tumors.

The toxicity, pharmacokinetics and antitumour effect of chlorin e6 after light irradiation were studied. The LD50 value of chlorin e6 in C3H mice is 189 +/- 9 mg kg-1 and in Wistar white rats is 113 +/- 18 mg kg-1 14 days after intraperitoneal injection. The concentration of chlorin e6 in blood, liver, kidney, spleen and tumors (sarcoma M-1 and sarcoma 45) of the rats was determined by a fluorescence method, 3, 6, 12, 18, 24, 48 and 72 h after administration at a dose of 10 mg kg-1. For this purpose, chlorin e6 was extracted from tissues by the detergent Triton X-100. The depth of necrosis in sarcoma 45, the regression rate of sarcoma M-1 and the animal cure rate were evaluated after chlorin e6 administration at doses of 1-10 mg kg-1 and subsequent irradiation with krypton laser light. Depending on the dose and the time interval between chlorin e6 injection and irradiation, the depth of necrosis in sarcoma 45 varied from 5.0 to 15.0 mm. The cure rate of the animals with sarcoma M-1 varied from 10% to 60%. The antitumor effect was directly proportional to the chlorin e6 dose and light energy exposure and inversely proportional to the time interval between photosensitizer injection and irradiation.

Sensitivity of different rat tumour strains to photodynamic treatment with chlorin e6.

Transplantable rat tumours (sarcoma M-1, sarcoma 45, alveolar liver cancer PC-1 and Pliss' lymphosarcoma) were used to study chlorin e6 accumulation in tumours and its photodynamic effect. Tumours were irradiated by krypton ion laser light (647 and 676 nm; 90 J cm-2) 15 min and 24 h after chlorin e6 injection at doses of 5 and 10 mg kg-1. The relationship between some morphological peculiarities of these tumour strains, photosensitizer accumulation in tumours and their response to the photodynamic treatment is discussed.

Photodynamic therapy with chlorin e6. A morphologic study of tumor damage efficiency in experiment.

Morphological changes in rat sarcoma M-1 after photodynamic treatment with chlorin e6 were studied. The frequency of necrosis appearance and the depth of its spreading in tumor tissue were evaluated after intraperitoneal injection of chlorin e6 in doses of 1-10 mg kg-1 and subsequent irradiation by a krypton laser with light energy density 22.5-135 J cm-2, using the method of vital staining with Evans blue. It was found that the antitumoral effect of photodynamic treatment was strengthened by increasing the dose of the agent and light and reduced by increasing the time interval between chlorin e6 injection and light irradiation. The treatment being given in the parameters mentioned produced a depth of tumor necrosis which varied from 4.0 mm to 16.6 mm. The mechanisms of tumor tissue damage after photodynamic treatment in vivo are discussed.

[Radionuclide studies on the hormonal manifestations of heat stress in cancer patients under controlled total hyperthermia]. / Radionuklidnye issledovaniia gormonal'nykh proiavlenii teplovogo stressa u onkologicheskikh bol'nykh pri obshchei upravliaemoi gipertermii.

The results of the investigations of ACTH, HGH, hydrocortisone, glucagon, C-peptide, insulin in 180 patients with advanced and metastatic melanomas, soft tissue sarcomas, lung cancers and renal cell carcinomas testify to the development of the syndrome of endocrine hyperfunction in patients under whole-body guided hyperthermia as well as of functional pancreas insufficiency. The data presented form a biochemical basis for working out measures to optimally carry out whole-body hyperthermia treatment, aimed at increasing the range of indications for its use in clinical oncology.

[Complex treatment of locally advanced soft tissue sarcoma of the limbs]. / Kompleksnoe lechenie mestno-rasprostranennykh sarkom miagkikh tkanei konechnostei.

The experience of treatment of 40 patients with locally-advanced soft tissue sarcoma of the limbs. Treatment included preoperative chemoradiotherapy in combination with electromagnetic hyperthermia. As a result, 38 (95%) patients showed marked response which allowed radical limb-saving surgery whereas in 2 (5%) amputation was performed. Adjuvant chemotherapy was used for anaplastic tumors. Five-year survival rate was 64.7 +/- 6.7%.

[The prevention of the hypercoagulation syndrome during the combined treatment of lung cancer patients using artificial hyperglycemia]. / Profilaktika giperkoaguliatsionnogo sindroma pri kombinirovannom lechenii bol'nykh rakom legkogo s ispol'zovaniem iskusstvennoi giperglikemii.

Status of hemostasis system and occurrence of postoperative thromboembolic complications were assessed in 246 lung cancer patients in whom combined treatment included artificial hyperglycemia. The latter condition contributed to higher blood coagulability resulting in lung artery thromboembolism in some cases. Administration of a combination of heparin, curantil and nicotinic acid was followed by a decrease in blood coagulability, increase in anticoagulation function, decrease in platelet aggregability, activation of fibrinolysis and regression of biochemical signs of DIC syndrome thereby assuring a drop in the occurrence of thromboembolic complications.

[General hyperthermia in the chemoradiotherapy of small-cell lung cancer]. / Obshchaia gipertermiia pri khimioluchevoi terapii melkokletochnogo raka legkogo.

Treatment results were compared in 2 groups of patients with advanced small-cell lung cancer. Group 1 (52 cases) received chemoradiation treatment alone whereas in group 2 (41 patients) it was combined with general hyperthermia (temperature 40-41.8 degrees C during 3-4 hours). Response was observed in 63.5% of patients of group 1 and 79.5% of those in group 2. Complete response rates did not differ significantly (23.1 and 28.2%, respectively). 40.6 +/- 8.2% of patients receiving chemoradiation treatment plus general hyperthermia survived over 1 year, 20.5 +/- 7.1%--over 1.5 years and 15.9 +/- 6.7%--over 2 years. In the control group, the respective rates were 22.2 +/- 5.8%, 5.1 +/- 3.4% and 5.1 +/- 3.4%.

[The effect of whole-body controlled hyperthermia on the energy resources of cancer patients]. / Vliianie obshchei upravliaemoi gipertermii na énergeticheskie resursy u onkologicheskikh bol'nykh.

The results of examination of 120 patients with advanced malignant melanoma, soft tissue sarcomas and lung and renal cancer suggest disturbance in mechanisms of energy supply during whole-body guided hyperthermia. Cell glucose uptake was inhibited in hyperglycemic patients. High energy loss in due to utilization of such alternative substrates as lipids and proteins which, in turn, potentiates peroxidation of lipids toxic to cell membranes. These data provide biochemical rationale for developing procedures aimed at managing biochemical dysbalance, increase in carbohydrate utilization included.