[Evolution and revolutionary events in oncology in the end of XX - beginning of XXI century].

This review highlights major achievements of the Russian oncology in the past decades, such as works of N.N. Petrov, L.A. Zilber, N.N. Blokhin, E.E. Pogosyants. Revolutionary shift in the understanding of the malignization process have become possible after decoding of human genome, as well as genome of several tumors such as breast cancer, acute myeloblastic leukemia, several brain tumors, testicular cancer and other neoplasms. The issue of stem cells being possible ancestors of tumor cells is also discussed in the review. Also the author observes main modern therapeutic approaches towards cancer treatment. It is specially highlighted that XXI century molecular biology achievements made it possible to start personal tumor treatment based on its' specific genotype.

A prognostic model in patients treated for metastatic gastric cancer with second-line chemotherapy.

BACKGROUND: This retrospective study was carried out to evaluate the prognostic significance of clinical factors in patients treated for metastatic gastric cancer with second-line chemotherapy. PATIENTS AND METHODS: We evaluated the prognostic significance of various clinical factors in 126 patients, who were treated with second-line chemotherapy. RESULTS: Median progression-free and overall survival (OS) for second-line chemotherapy were 3.3 and 5.3 months, respectively, with an overall response rate of 11.1%. Multivariate analysis identified three independent prognostic factors: performance status: Eastern Cooperative Oncology Group zero to one [hazard ratio (HR) 2.3, 95% confidence interval (CI) 1.7-5.4], hemoglobin (Hb) level: >/=10 g/dl (HR 2.2, 95% CI 2.1-2.4) and time-to-progression (TTP) under first-line therapy: >/=5 months (HR 0.5, 95% CI 0.3-0.8). From the obtained data, a prognostic index was constructed, dividing the patients into three risk groups: good (n = 40), intermediate (n = 36) and poor risk group (n = 56). The median survival for good, intermediate and poor risk groups were 13.5, 6.0 and 2.9 months, respectively, whereas the 1-year OS rates were 50.2%, 14.2% and 2.6%, respectively (P = 0.00001). CONCLUSIONS: With inadequate data from randomized controlled trials at the moment, our report indicates that second-line chemotherapy is effective and beneficial in patients with good performance status, higher Hb level along with higher TTP under first-line therapy.

[Targeted drugs for the treatment of disseminated colonic cancer].

5-Fluorouramcil has been the medicine of choice for systemic treatment of metastatic colonic cancer for the last 35 years. Objective positive results of this therapy were documented in 30% of the cases, it delayed the development of active disease by 4 months, and ensured a 6 month survival. Introduction of irinotecan, oxaliplatin, capecitabine, S = 1, and other drugs into clinical practice improved overall efficiency of therapy to 40-50%, increased time till progression of the disease to 6 months and survival to 15 months. Targeted drugs (bevacizumab, cetuximab) combined with the known chemotherapeutic programs (FOLFOX, FOLFIRI, XELIRI, XELFOX, etc.) showed even higher therapeutic effect, i.e. overall efficiency 50-60%, time to progression 10 months and survival of more than 1.5 years. Panitumumab is an active agent to be used in the third-line therapy.

[Docetaxel in the treatment of metastatic gastric cancer].

Since the late 1990s, docetaxel (Dtx), an antitubular drug, has been studied as a tool for the treatment of GC. Maximum effectiveness of docetaxel as monotherapy amounted to 24%, with a median survival of 7 months. Two-drug combinations were developed containing docetaxel with 5-fluorouracil (DF) and docetaxel with cisplatin (DC). They proved effective in 43 and 33% of the cases respectively and ensured a similar median survival of 9-10 months. Clinical studies of a three-component combination containing docetaxel, 5-fluorouracil and cisplatin (DCF) as first-line therapy of metastatic GC were carried out in the XXIst century and showed its efficacy in 50% of the cases with a median survival of 10-12 months. The DCF regimen may be considered as a new standard for the treatment of patients with metastatic GC and satisfactory health status (ECOG 0-1). The combination is being modified to improve its toxicity profile by substituting oxaliplatin for cisplatin and oral fluoropyrimidines for i.v. 5-fluorouracil.

Long term results of treatment in patients with extragonadal germ cell tumours.

From 1979 to 1991 56 patients with extragonadal germ cell tumours (EGCT) received cisplatin based chemotherapy. From 16 patients with seminomatous EGCT 13 achieved complete remission (CR) with chemotherapy alone, 2 with additional radiotherapy with final CR rate of 94%. 5 (31%) patients developed relapses and at a median follow-up of 38 (5-103) months 11 (69%) are alive and 10 (62%) have no evidence of disease (NED). Only 7 patients with non-seminomatous EGCT reached CR with chemotherapy alone and 8 more with additional chemotherapy or surgery. Overall CR was 37% and 3 (20%) relapses have been observed. At a median follow-up of 26 (3-114) months 14 (35%) are alive and remain free of disease, 26 (65%) have died. By univariate analysis seminomatous EGCT patients had a significantly greater likelihood of achieving a CR, for non-seminomatous EGCT BEP induction chemotherapy was superior to VAB-6, and NSEGCT patients with serum levels > 2000 ng/ml had worse prognosis. Current staging systems are insufficient to predict the treatment outcome in EGCT.

Paclitaxel and cisplatin as salvage treatment in patients with non-seminomatous germ cell tumour who failed to achieve a complete remission on induction chemotherapy.

The purpose of this study was to evaluate the efficacy and toxicity of paclitaxel and cisplatin combination chemotherapy as salvage treatment in patients with non-seminomatous germ cell tumour. Sixteen patients with histologically proven germ cell tumour, measurable disease and/or elevated serum tumour markers were eligible for the protocol. All patients had previously not achieved a complete remission (CR) to platinum-based induction chemotherapy and cytoreductive surgery. The treatment consisted of paclitaxel 175-225 mg/m2 as a 3-hour infusion, followed by cisplatin 100 mg/m2, repeated every 3 weeks for up to four cycles. Seven patients achieved a marker-positive partial remission (PR) by the end of the cisplatin-based induction chemotherapy; the remainder had disease progression at the start of the paclitaxel plus cisplatin treatment. One (6%) CR and 3 (19%) PRs were achieved, with an overall response rate of 25% (90% confidence interval 7-43). The duration of the CR is currently 9+ months; two PRs lasted 2 months. One patient with a PR has been lost to follow-up. During a median follow-up of 8 months (range 1-11), 12 patients died from the disease progression. The median survival for the whole group was 7 months. Toxicity was moderate, with neutropenia grade 3 occurring in 29% of patients, thrombocytopenia grade 1-3 in 29%, creatinine > 130 mmol/l in 36%, peripheral neuropathy grade 1-2 in 50%, and nausea and vomiting in 43%. Paclitaxel plus cisplatin showed modest activity, with an overall response rate of 31% in patients with poor prognosis who had not achieved a CR on induction chemotherapy.

Efficacy of combination chemotherapy including Platidiam in the treatment of malignant testicular tumors.

Thirty-seven patients were treated for advanced malignant testicular tumors with combined chemotherapy including cis-platinum (Platidiam). A complete regression was achieved in 23 patients (62%). No severe side effects were observed. Also in this study the effectivity of cis-platinum in the treatment of testicular tumors was proved.

Drug dose delivery and treatment outcome relationship in standard bleomycin, etoposide and cisplatin combination chemotherapy in nonseminomatous germ cell tumor patients.

This study retrospectively evaluated the influence of drug dose delivery components (DDDC) of bleomycin, etoposide and cisplatin chemotherapy for metastatic nonseminomatous germ cell tumors on treatment outcome (NSGCT). Between December 1987 and January 1995, 75 NSGCT patients were treated with a median of 4 cycles (range 3-8) of cisplatin 120 mg/m2 on day 1, etoposide 100 mg/m2 on days 1 through 5 and bleomycin 30 U on days 1, 3, and 5 every 3 weeks. DDDC, such as cumulative dose, cumulative dose in mg/m2, dose intensity (DI), relative dose intensity (RDI), dose intensity products, and relative dose intensity products by drug, were calculated and tested as possible predictors of treatment outcome in patients classified according to Indiana University (IU), and International Germ Cell Cancer Cooperative Group (IGCCCG) classifications. Overall complete response (CR) rate was 64%, and 3-year progression-free survival (PFS) was 59%. By IU classification there were statistical differences in CR and survival between moderate (89-81%) and advanced disease (42-40%) (p < 0.005), while for patients classified according to IGCCCG criteria, statistical differences in CR and PFS there were not registered. DI (mg/m2/week) and RDI values for the entire group were: cisplatin 33-0.82; etoposide 133-0.80 and bleomycin 11-0.37. We did not observe a statistically significant difference in drug dose delivery components for treatment outcome between patients who achieved a CR and incomplete response when analyzed by either extent of disease or whole group. Extent of disease was the most important predictor of treatment outcome.

Phase I/II trial of carboplatin dose escalation in combination chemotherapy with etoposide, bleomycin and GM-CSF support for poor prognosis nonseminomatous germ cell tumors patients.

To determine the maximum tolerated dose (MTD), and therapeutic efficacy of carboplatin (CBDCA) in combination with etoposide and bleomycin (CEB) as initial chemotherapy for poor prognosis germ cell tumors, a CBDCA dose escalation supported with GM-CSF had been performed. Twenty four untreated patients were treated with CBDCA 400 mg/m2 on day 1, etoposide 100 mg/m2 on days 1 to 5 and bleomycin 30 mg on days 1, 3, 5. Four cycles were scheduled at 21-day interval. The first cohort of 6 patients received only initial chemotherapy regimen. In the subsequent cohorts of six patients, the CBDCA dose was increased by 100 mg/m2. A fixed dose and schedule of GM-CSF at 5 micrograms/kg subcutaneously was given on days 6 through 15. Myelosuppression, with neutropenic fever and hemorrhages, was the dose-limiting toxicity at the 600 mg/m2 dose level. The recommended dose of CBDCA is 500 mg/m2. Overall complete response (CR) rate was 71% and with median follow up of 25 (16-34) months, 58% of patients are alive and have no evidence of disease (NED). A higher number of CR was achieved with CBDCA dose higher than 400 mg/m2 compared with CBDCA dose of 400 mg/m2 (92 vs. 50%, p = 0.03), as well as a higher proportion of patients who are alive and with NED (75 vs. 42%, p = 0.1). Despite GM-CSF support, the MTD of CBDCA could not be increased beyond 500 mg/m2 (50% of the dose escalation), due to severe myelosuppression. The treatment outcomes obtained with CEB in our study are no better than the standard cisplatin-based chemotherapy. Further studies of this regimen, where CBDCA dose should be calculated according to the patients glomerular filtration rate are warranted.

[Therapeutic effect of blastolysin in athymic mice with transplanted strains of human tumors]. / Terapevticheskii éffekt blastolizina u bestimusnykh myshei s perevivnymi shtammami opukholei cheloveka.

9 transplanted strains were used for the evaluation of antitumour effect of blastolysin. The short-term inhibition of the tumour growth was observed on the following models: breast cancer, stomach cancer, kidney cancer and chorionepithelioma.

[Enhanced antitumor action of 5-fluorouracil when used in combination with 4-methylmercaptopyrazolo[3,4-d]pyrimidine 1-nucleoside]. / Povyshenie protivoopukholevogo deistviia 5-ftoruratsila pri kombinirovannom primenenii s 1-nukleozidom 4-metilmerkaptopirazolo[3,4-d]pirimidina.

Mice BDF1 with L 1210 or mice BALB/c with plasmacytoma MOPS-406 after pretreatment with ineffective doses of 1-beta-D-ribofuranosyl-4-methylmercaptopyrazolo(3,4-d)pyramidin e (25 to 100 mg/kg per 5 days) were treated with 5-fluorouracil at the optimal dose 100 mg per day. This combination produced a 1.5-2-fold or 2 to 4 fold enhancement of the antitumour effect of 5-fluorouracil without simultaneous increase of lethal toxicity.

[Ribamidyl (ribavirin) as a modulator of the biological action of arabinosylcytosine and methotrexate]. / Ribamidil (ribavirin) kak moduliator biologicheskogo deistviia arabinoziltsitozina i metotreksata.

Administration of ribamidyl (Rb) prior to Ara-C to intact mice or mice with implanted tumours enhanced Ara-C toxicity. The growth of tumours (plasmacytoma MOPC-21, adenocarcinoma of the small intestine (strain AKATON), mammary adenocarcinoma 755 (Ca 755) resistant to Ara-C or Rb was inhibited after coadministration of these drugs. The augmentation of toxic and antitumour effects of Ara-C by Rb is similar to the described effect of high doses of thymidine. This is in accordance with the enhancement of the intracellular pool of thymidine phosphates under the action of Rb. The toxicity of methotrexate in vivo was increased by coadministration with Rb. This effect may be connected with a decrease in purine precursors pool under the action of Rb.

[Germ cell tumors of the testis: current status and future progress]. / Germinogennye opukholi iaichka: sostoianie problemy i nauchnyi progress.

The treatment of testicular cancer has undergone considerable evolution since the introduction of cisplatin and widespread recognition of its curative potentials at any stages of disease. This article provides an overview on statistical and epidemiological information, the latest developments in testicular cancer biology. Also, the results of treating 360 patients with nonseminomatous and 97 patients with seminomatous germ cell tumors are presented. A combined chemotherapy with cisplatin, etoposide and bleomycin demonstrates the highest rate of activity in nonseminomatous germ cell tumor patients. Surgical resection of residual masses after chemotherapy continues to be an important component of combined modality therapy in nonseminomatous testicular tumors. The needs for regular clinical examination during a follow-up have been underlined.

[The role of antitumor drugs in treating stomach cancer patients]. / Rol' protivoopukholevykh lekarstv v lechenii bol'nykh rakom zheludka.

The treatment of advanced gastric carcinoma is a challenge to oncologists. Within the last 6-7 years several new regimens have been introduced: EAP, FAMTX, MEP, MVP, ELF. Overall response rate of these schemes is 30-40%, a complete response seldom reaching 10%. Anticancer drugs significantly improve quality of life. Chemotherapy of advanced cancer is the method of choice. New combinations and regimens may appear promising.

[Biological effects of leakadin]. / Biologicheskie éffekty leakadina.

57 patients with disseminated tumors of various sites received 10 daily doses of 600 mg/m2 leakadin intravenously. The immunostimulating effect was observed (OKT4/OKT8 normalization). The data on leakadin pharmacokinetics are discussed.

[The results of the use of bleomycin and its analogs in the VAB-6 protocol in treating testicular tumors]. / Rezul'taty primeneniia bleomitsina i ego analogov v kombinatsii VAB-6 pri lechenii opukholei iaichka.

Efficacy and toxicity of VAB-6 combinations with bleomycin, bleomycetin or peplomycin were studied in treatment of 77 patients with metastases of germ-cell tumors: testicle tumors in 71 patients and extragonadal tumors in 6 patients. After the chemotherapy complete regression was observed in 37 patients (48.7 per cent). In 44 patients (57.1 per cent) residual metastases after the chemotherapy were resected. The frequency of complete regression after using the VAB-6 combinations with bleomycin, bleomycetin and peplomycin amounted to 58.8, 61.5 and 47.1 per cent respectively. The treatment results depended on the disease extent. When the disease extent was minimal complete regression was observed in 87.5 per cent of the patients. The respective figures for the disease moderate and significant extents were 66.7 and 37.8 per cent. During the average observation period of 22.1 months (7-40 months) 39 patients survived and had no signs of the disease. The combinations markedly differed in their toxicity.

[Management and drug therapy of patients with disseminated testicular tumors]. / Opyt vedeniia i lekarstvennaia terapiia bol'nykh s disseminirovannymi testikuliarnymi opukholiami.

The experience gained in the treatment of 111 cases of testicular tumor is summarized in the paper. Methods of management of testicular cancer in the eighties differ significantly from those employed in the seventies. A set of drugs used is different. The share of cases of monochemotherapy has decreased markedly. PVB and VAB-6 schemes are highly effective inducing complete or partial remission in 80-90% of cases. Issues of treatment of patients with massive metastases in retroperitoneal lymph nodes and lungs remain unresolved. Timely diagnosis of dissemination will improve chemotherapy results.

[Rational combinations of hormonal and cytostatic agents in disseminated forms of breast cancer]. / O ratsional'nykh kombinatsiiakh gormonal'nykh i tsitostaticheskikh sredstv pri disseminirovannykh formakh raka molochnoo zhelezy.

The report deals with the results of chemotherapy of 25 cases of advanced breast cancer. The patients had received tamoxifen + diethylstilbestrol (or chlorotrianizen) to stimulate a short-term proliferation in tumor and to potentiate the effect of cytostatic drugs. Complete regression of tumor was observed in I case and partial regression--in 12 cases (overall response--52%). Tumor growth stimulation effect was assessed on the basis of changes in DNA synthesis rate and proliferative pool as evidenced by repeated biopsy of tumor.

[The use of aminoglutethimide (orimeten) in disseminated breast cancer]. / Primenenie aminogliutetimida (orimetena) pri disseminirovannom rake molochnoi zhelezy.

Administration of orimeten (aminoglutethimide), for disseminated breast cancer in 38 postmenopausal females, in whom other treatment modalities had failed, proved effective in 39%. Patients who had failed on tamoxifen responded to orimeten. Such side-effects as skin rash, drowsiness and cardiovascular disturbances were not pronounced. Limiting toxicity was 6%.

[Biochemical tests in the diagnosis of nephrotoxicity: assessment of the significance]. / Biokhimicheskie testy v diagnostike nefrotoksichnosti: otsenka znachimosti.

In order to identify early signs of nephrotoxicity in 38 patients with malignant tumors of the testicle, the data of 3 biochemical tests (measurements of gamma-glutamyltranspeptidase (gamma-GT) activity in the urine, of the content of creatinine and urea in blood serum) were compared. Activation of gamma-GT in the urine may be viewed as the first and early sign of nephrotoxicity, since the rise of creatinine and urea in the blood was observed later. The magnitude of gamma-GT activity (means + 2 sigma) - 5.9 Units/mmo le Cr may provide basis for the judgement about nephrotoxicity according to the scheme applied. The fall of gamma-GT activity without any further increase after multiple courses of chemotherapy is of prognostic significance for its evidences profound injury to the renal parenchyma and may serve as basis for correcting the doses of chemotherapeutic drugs. The reduction of gamma-GT activity to less than 3 Units/mmole creatinine (means - 2 sigma) may be regarded as indication for instituting disintoxication therapy.