Targeted therapy in the treatment of solid tumors: practice contradicts theory.

The basic principle of targeted therapy formulated about ten years ago consists in the design and application of drugs specifically directed against well-defined targets that are critical for tumor survival and not compromising for normal organs and tissues. The past decade has been marked by the appearance of an immense diversity of novel antitumor agents with claimed targeted action. Unfortunately, despite indisputable progress in clinical settings, some popular drugs against solid tumors (e.g. bevacizumab, trastuzumab, erlotinib, gefitinib) nominally assigned to targeted-action drugs, cannot actually be classified with this group being nonconforming to a priori stated goals of targeted therapy. The state-of-the-art and current problems in targeted therapy of solid tumors are reviewed.

[Efficacy of moxifloxacin (Avelox) in prophylaxis of infection in patients with profound neutropenia]. / Effektivnost' ispol'zovaniia moksifloksatsina (Aveloks) dlia profilaktiki infektsii u bol'nykh s glubokoi neitropeniei.

Comparative efficacy of moxifloxacin and ciprofloxacin as prophylactics of infection in cancer patients with severe neutropenia after the chemotherapy was studied. The study included 40 patients with malignant lymphomas and solid tumore who received 52 courses of the aggressive chemotherapy. Twenty four patients (30 courses) received oral moxifloxacin in a dose of 400 mg once a day from the first day of the neutrophil count decrease below 1.0 x 10(9)/l until its recovery to > 1.0 x 10(9)/l or when the signs of infection appeared. In the control group 16 patients (22 courses) received oral ciprofloxacin in a dose of 500 mg twice a day. The patients in both the groups were compatible by the diagnosis, age and neutropenia duration. The median of the days of the febrile neutropenia duration in the patients prophylactically treated with moxifloxacin was statistically lower (2.1 vs 3.6 in the control group, p < 0.05). The incidence of febrile neutropenia in the moxifloxacin group was significantly lower than that in the control group (73 and 100% respectively, p = 0.01). The incidence of bacteriologically confirmed infection in the moxifloxacin group was also lower (6% vs 27.2%, p = 0.04). Therefore, moxifloxacin proved to be a more efficient agent vs ciprofloxacin (standard prophylactic) in prevention of febrile neutropenia and neutropenic infection in cancer patients, which is likely due to its higher activity against grampositive organisms.

[Prophylaxis of fungal infection in patients with hematologic neoplasms and severe neutropenia after high-dose chemotherapy]. / Profilaktika gribkovoi infektsii u bol'nykh s gematologicheskimi novoobrazovaniiami i glubokoi neitropeniei, razvivsheisia posle provedeniia vysokodoznoi khimioterapii.

Infection is one of the main causes of death in patients with hemoblastoses. Within the last years there was observed an increase in the ratio of fungal infections in the structure of mortality among hematologic patients with neutropenia. The present study was aimed at comparative estimation of the efficacy of the prophylactic use of various azole antifungal agents in patients with hematologic neoplasms and severe neutropenia. The trial enrolled 88 patients comparable by the diagnosis and chemotherapy characteristics, in whom severe neutropenia developed after intensive therapy. Antifungal drugs were used prophylactically when the neutrophil count lowered below 1.0 x 10(9)/l until its increasing above 1.0 x 10(9)/l or when the signs of fungal infection were evident. Itraconazole was used in cyclodextrin solution in 30 patients in a dose of 0.2 g orally twice a day and fluconazole was used in capsules in 24 patients in a dose of 0.2 g orally once a day. The results were compared with those of the ketoconazole use in a dose of 0.2 g orally twice a day (n = 34). The frequency of fungal infection proved by the clinical documentation was 20.5% in the ketoconazole group (k) (7 out of 34 patients), 8.3% in the fluconazole group (f) (2 out of 24 patients) and 6.6% in the itraconazole group (i) (2 out of 30 patients), p (k-f) = 0.21, p (k-i) = 0.11 and p (f-i) = 0.74. The frequency of fungal infection proved by the microbiological documentation was statistically much higher in the ketoconazole group (38.2%) vs. the fluconazole group (8.3%) (p = 0.013) and the itraconazole group (6.6%) (p = 0.004). The prophylactic use of itraconazole and fluconazole was efficient in preventing development of invasive mycoses in the patients with hemoblastoses and severe neutropenia. Their efficacy was much higher than that of ketoconazole.

Expression of Flt-1 and Flk-1 receptors for vascular endothelial growth factor on tumor cells as a new prognostic criterion for locally advanced breast cancer.

We studied expression of Flt-1 and Flk-1 receptors on tumor cells obtained from 83 patients with locally advanced breast cancer after neoadjuvant chemotherapy. The mean period of observations was 32.3 months. The median recurrence-free survival periods for Flt-1(+) and Flt-1(-) patients were 55 and 32 months, respectively (p=0.0064). The overall survival periods for Flt-1(-) and Flt-1(+) patients were 45 and 67.6 months, respectively (p=0.014). The mean recurrence-free survival periods for Flk-1(+) and Flk-1(-) patients were 40.8 and 60.9 months, respectively (p=0.035). Expression of VEGF had no prognostic value. Our results show that overexpression of Flk-1 on breast cancer cells in patients receiving neoadjuvant chemotherapy is associated with a poor prognosis. By contrast, overexpression of Flt-1 improves survival.

[Use of Mabtera (rituximab) in treating patients with refractory courses of B-cell lymphoma, along with high-dose chemotherapy and autologous transplantation of hematopoietic stem cells]. / Primenenie mabtery (rituksimab) u bol'nykh refrakternym techeniem B-kletochnym limfom, poluchaiushchikh vysokodoznuiu khimoterapiiu s autologichenoi transplanttatsiei kletok-predshestvennits gemopoéza.

AIM: To study efficacy of rituximab in patients with resistant B-cell lymphoma on high-dose chemotherapy. MATERIAL AND METHODS: From September 2000 to April 2002 we studied efficacy and tolerance of rituximab at different stages of high-dose chemotherapy. The treatment was given to 10 patients with histologically verified CD20+ non-Hodgkin's lymphoma: diffuse large-cell (n = 4), Berkitt's (n = 2), follicular (n = 3), mantle-cell (n = 1). Five patients with diffuse large-cell lymphoma and Berkitt's lymphoma had a primary resistant course of the disease, one patient with diffuse large-cell lymphoma had a refractory recurrence. Follicular and mantle-cell lymphomas were characterized by a resistant course and large tumor masses. The patients received 1-2 courses of induction chemotherapy with dexa-BEAM with collection of peripheral stem cells followed by high-dose chemotherapy (BEAM-9, CBV + mitoxantron-1) with transplantation of autologous stem blood cells. Rituximab infusion (375 mg/m2) was conducted before the collection of the stem cells, prior to high-dose chemotherapy and in posttransplantation period after recovery of hemopoiesis. RESULTS: 4 patients achieved complete remission, 3-partial remission, 2 had progression and 1-stabilization. In mean follow-up 11 (2-20) months 7 of 10 patients were alive, overall survival being 15 +/- 2.4 months (95% confidence interval 10-19.7), median was not reached. 5 patients are in complete remission: 2 of them without further treatment, 3-after progression and repeat therapy including rituximab and interferon-alpha or rotuximab and CHOP chemotherapy. CONCLUSION: The addition of rituximab can improve the results of high-dose chemotherapy of patients with non-Hodgkin's lymphoma resistant to standard doses of cytostatics. Repeat use of this drug can be effective in some patients with progression after high-dose chemotherapy with rituximab.

[Benzylpenicillin efficacy for neutropenic infection prophylaxis in patients with cancer and postcytostatic neutropenia]. / Effektivnost' naznacheniia benzilpenitsillina dlia profilaktiki neitropenicheskoi infektsii u bol'nykh s opukholevymi zabolevaniiami i posttsitostaticheskoi neitropeniei.

Evaluation of benzylpenicillin (penicillin G) effect for infection prophylaxis at the oncological patients with severe postcytostatic neutropenia was performed. All the patients with neutrophils levels lower than 0.5 x 10(9)/L were recommended to use antibiotics for infection prophylaxis. Test-group (n = 40) used ciprofloxacin (0.5 g twice daily, per os) combined with benzylpenicillin (1.0 g four times daily, i/v); control group was treated by ciprofloxacin in the same dose only. Combination with benzylpenicillin resulted in statistically significant reduction of infections frequency among oncological patients.

[The role of high-dose chemotherapy with hemopoietic stem cell transplantation in the treatment of breast cancer with unfavorable prognosis]. / Rol' vysokodoznoi khimioterapii s transplantatsiei kletok- predshestvennikov gemopoèza pri lechenii prognosticheski neblagopriiatnykh form raka molochnoi zhelezy.

High-dose chemotherapy using transplantation of hemopoietic precursor cells offers much advantage for treatment of prognostically unfavorable cancers of the breast. Both experimental and clinical evidence points to a potential of raising antitumor effect by increased dosage of chemical drugs. Clinical studies using high-dose chemotherapy for treating patients with stage II-III tumors or with greater than or equal to 10 positive axillary lymph nodes, and locally-advanced and disseminated tumor established a relative rise in overall and recurrence-free survival, as compared with standard treatment. Hazardous cytopenia and related complications can be significantly reduced when hemopoietic precursor cells are transplanted from peripheral blood.