First-line bevacizumab plus taxane-based chemotherapy for locally recurrent or metastatic breast cancer: safety and efficacy in an open-label study in 2,251 patients.

BACKGROUND: First-line bevacizumab combined with chemotherapy significantly improves efficacy versus chemotherapy alone in human epidermal growth factor receptor 2 (HER2)-negative locally recurrent or metastatic breast cancer (LR/mBC). This large, open-label study further assesses first-line bevacizumab with taxane-based chemotherapy in routine oncology practice. PATIENTS AND METHODS: Patients with HER2-negative LR/mBC, Eastern Cooperative Oncology Group (ECOG) performance status (PS) of zero to two and no prior chemotherapy for LR/mBC received bevacizumab 10 mg/kg every 2 weeks or 15 mg/kg every 3 weeks plus taxane-based chemotherapy (or other non-anthracycline chemotherapy) until disease progression, unacceptable toxicity or patient withdrawal. The primary end point was safety; time to progression (TtP) was a secondary end point. RESULTS: Median follow-up in 2251 treated patients was 12.7 months. Median age was 53 years and 94% of patients had ECOG PS of zero or one. Bevacizumab was most commonly administered with single-agent paclitaxel (35%), single-agent docetaxel (33%) or taxane-based combination therapy (10%). The most frequent grade ≥3 adverse event (AE) was neutropenia (5.4%). Grade ≥3 AEs previously associated with bevacizumab included hypertension (4.4%), arterial/venous thromboembolism (3.2%), proteinuria (1.7%) and bleeding (1.4%). No new bevacizumab safety signals were observed. Median TtP was 9.5 months (95% confidence interval 9.1-9.9). CONCLUSIONS: The study population in ATHENA was more representative of general oncology practice than populations enrolled into randomised trials, although there may have been some bias towards younger, fitter patients. The safety and efficacy of bevacizumab-taxane therapy in this large study were consistent with results from randomised first-line trials.

Gemcitabine and carboplatin treatment in patients with relapsing ovarian cancer.

Despite progress in primary treatment of patients with advanced ovarian cancer, the majority develop recurrence of the disease. A platinum salt treatment, either as monotherapy or in combination with another cytostatic agent, is indicated for patients who have relapsed 6 or more months after primary treatment and thus have platinum-sensitive relapse. Because repeated use of paclitaxel treatment may lead to substantial neurotoxicity, the combination of gemcitabine with carboplatin represents a suitable treatment option, which is widely used in common clinical practice in the Czech Republic and Slovakia. This non-interventional, prospective study observed the effectiveness and tolerability of second-line treatment with gemcitabine and carboplatin in patients with platinum-sensitive relapse of ovarian cancer in routine clinical practice. The primary endpoint was to evaluate the survival and secondary endpoints were to evaluate time to disease progression, objective tumor response rate, and treatment toxicity. Patients were enrolled to planned second-line treatment with gemcitabine and carboplatin (gemcitabine 1000 mg/m2 and carboplatin AUC 5 on Day 1, and gemcitabine 1000 mg/m2 on Day 8 of a 21-day cycle) for platinum-sensitive relapse of ovarian cancer as a part of routine clinical practice and followed for 12 months. The events (death, tumor progression), tumor response, and maximal grades of toxicity were recorded according to common clinical practice. Survival time (using Kaplan-Meier analysis) and objective tumor response rate were calculated using data forms, and a subgroup analysis was performed using log rank tests for time-to-event endpoints; p-values were also calculated. Response rates were calculated for the whole population; for the subgroups, the Fisher's exact test was performed and only p-values were calculated. Between January 2004 and June 2005, 53 patients were enrolled in the study. The median age was 57 years and 96% of patients had an Eastern Cooperative Oncology Group Performance Status (ECOG-PS) of 0 and 1 at baseline. Approximately 91% of patients were originally diagnosed with stage III or IV; 60% of patients had disease free intervals (DFIs) of 12 or more months from previous therapy, and the additional 40% less than 12 months. The 1-year survival rate was 83%. Median survival time was not determined within the 12-month period following the start of the treatment study due to the limited duration of follow-up. Objective tumour response rate was 67.3%. Most common reasons for discontinuation of therapy were "Planned treatment completed" (53%) and "Tumor progression" (11%). Most common toxicities were leukopenia, anaemia, neutropenia, and thrombocytopenia; grades 3 and 4 of these toxicity types did not exceed 30%. Febrile neutropenia was recorded in two patients. Most common non-haematological toxicities were nausea and vomiting, fatigue, and neuropathy; grades 3 and 4 of these were below 6%. Results on time to disease progression are not published due to inconsistent statistical analysis of reported data. Based on this observation from routine clinical practice, which corresponds with previously published results from controlled clinical trials, the gemcitabine and carboplatin combination seems to be a suitable therapeutic option for patients with platinum-sensitive relapse of ovarian cancer.

Paclitaxel, bleomycin, etoposide, and cisplatin (T-BEP) as initial treatment in patients with poor-prognosis germ cell tumors (GCT): a phase II study.

First line treatment of patients pts with poor-prognosis GCT, using BEP, is unsatisfactory. T-BEP (paclitaxel followed by BEP) demonstrated promising efficacy in the group of pts with intermediate and poor prognosis GCT. We present the results achieved with 1st line T-BEP in pts with poor-prognosis CGT. Twenty-four pts received T-BEP as initial therapy. Three pts (12.5%) had primary mediastinal GCT. Four cycles of T-BEP were given 21 days apart. Paclitaxel 175 mg/m2 was administered on day 1 before administration of BEP. The administration of G-CSF was not scheduled. Surgical resection of all radiographic residua was considered. All pts were assessable for response. Complete or partial response with negative tumor markers was achieved in 13 pts (54.2%; CI 95%: 34.3-74.1%). Median follow-up is 35.6 months. Median survival was not achieved and median time-to-progression is 9.5 months. Myelosuppression was the major toxicity with Gr3-4 granulocytopenia experienced in 52.1% of all courses. There were two treatment-related deaths due to sepsis. Patients treated with 1st line T-BEP didn't achieve higher response rate or time to progression. However, the overall survival observed in our study is surprisingly long. We do not recommend using this regimen without G-CSF support due to substantial toxicity.

Gemcitabine plus cisplatine and paclitaxel (GCP) in second-line treatment of germ cell tumors (GCT): a phase II study.

The aim of the study was to determine the efficacy and toxicity of gemcitabine, cisplatin and paclitaxel (GCP) combination as a first salvage treatment of patients with relapsed GCT. Four courses of paclitaxel 175 mg/m(2) and cisplatin 50 mg/m(2), both on day 1, and gemcitabine 1000 mg/m(2), on days 1 and 8, every 3 weeks, were given to 12 consecutive patients who had failed standard 1st line treatment. Six patients (50%; 95% CI 21-79%) achieved favourable response and two of them are maintained 38+ and 29+ months. Median survival time was 16 months (range, 0.77-38+). All, but two patients had hematological toxicity Gr3-4 with infectious complication seen only in 6 courses of therapy. GCP is an active second-line combination regimen for relapsed GCTs with acceptable toxicity profile. However the results of this study did not show expected treatment efficacy and we raise the idea of cisplatin dosage relevance in this combination.

Prevention of febrile neutropenia in cancer patients by probiotic strain Enterococcus faecium M-74. Pilot study phase I.

Febrile neutropenia (FN) remains a potentially life-threatening complication of anticancer chemotherapy. Bacterial translocation via intestinal mucosa is a significant mechanism of FN development. Competitive inhibition of bowel colonization by pathogenic microorganisms by lactic acid bacteria could be a useful prevention of FN. The aim of the study was the evaluation of dose and safety of probiotic strain Enterococcus faecium M-74 enriched with organic selenium in patients with solid and hematological malignancies. Eleven (9 M/2F) patients were included in the study. In the first phase six patients with germ cell tumors treated by chemotherapy were included. They received prophylaxis by nonpathogenic strain E. faecium M-74 during 2 cycles of chemotherapy. The planned daily dose was 6 x 10(9) bacteria. Regarding the insufficient colonization of the gut, the dose was further increased up to 18 x 10(9) tid. After safety evaluation, five patients were included with relapse of acute leukemia. In patients with germ cell cancer, severe neutropenia G3/4 was noted in 10 of 12 cycles of chemotherapy. The febrile episode was not observed in any of the patients. The gut colonization by enterococci reaches 10(6) CFU/g stool. In 5 patients with acute leukemia during 127 days of severe neutropenia 12 febrile episodes occurred. There was not noted any febrile episode or infection provoked by the tested strain. Tolerance of therapy was excellent without significant undesirable effects. Optimal dose was assessed and safety of probiotic strain was evaluated in neutropenic patients with solid, or hematological malignancies. Based on these results we plan phase II study to evaluate the effectiveness of this strain in FN prophylaxis.

Paclitaxel plus ifosfamide and cisplatin in second-line treatment of germ cell tumors: a phase II study.

The aim of this study was to determine efficacy and toxicity of TIP combination (paclitaxel, ifosfamid, cisplatin) as first salvage treatment in patients with relapsed germ cell tumours (GCTs). Excellent results were achieved from TIP combination with a dose 250 mg/m(2) of paclitaxel [5]. Our hypothesis was that comparable efficacy with less toxicity could be achieved even with a lower dose of 175 mg/m(2) paclitaxel in TIP. In 17 consecutive patients with failed standard 1st line treatment, we used four to six courses of paclitaxel 175 mg/m(2) on day 1 and ifosfamide 1,200 mg/m(2) plus cisplatin 20 mg/m(2), both on day 1 through 5, every 3 weeks. Eleven patients achieved favorable response (65%; 95% confidence interval, 42 to 87%) with 7 complete responses (41%). Estimated 2-year disease free survival is 47% (95% CI, 23-71%). Treatment combination was well tolerated and myelosupression was major toxicity. Granulocytopenia Gr3-4 was observed in 8% and febrile neutropenia in 7% of the courses. No case of severe neurotoxicity or treatment-related death was observed. In our study, TIP combination had good toxicity profile. The results however, did not show expected treatment efficacy and we raise the idea of paclitaxel dosage relevance in TIP.

Sequential development of chronic lymphocytic leukemia in a patient with polycythemia vera.

A patient with a seven-year history of polycythemia vera treated by repeated phlebotomies and intermittent busulfan administration developed gradually lymphocytosis accompanied by thrombocytopenia in peripheral blood and in the bone marrow. A marked pathological monoclonal proliferation of the B-cell population was detected. The sequential development of chronic lymphocytic leukemia in the patient with polycythemia vera could be considered as a coincidence because there is no reliable explanation of this event at present.

Therapy of P388 leukemia with benzaldehyde.

Optimal schedules of benzaldehyde (50-100 mg kg-1 intraperitoneally) on day 1 or on several days after inoculation of 10(5) P388 leukemia cells to DBA 2J mice increased survival by 70-100%. No significant prolongation of survival was observed between the various schedules of benzaldehyde treatment. Significantly longer survival was observed on day 30 after benzaldehyde treatment with 100 mg kg-1 on day 1 or 50 mg kg-1 on days 1-4 as compared to untreated controls, but no cure was achieved with any schedule and dose of benzaldehyde. No or minimal activity of benzaldehyde on L1210 and L5178Y leukemias, Ehrlich adenocarcinoma and Yoshida sarcoma was observed.

Single versus combination chemotherapy of L1210 leukemia.

Thirteen anticancer agents, ten dual-agent combinations and five three-drug combinations were tested for treatment of L1210 leukemia in dBA/2-J mice. Data obtained form each three-drug regimen were compared with those obtained after administration of each drug alone and each two-drug combination. Cure (greater than 60 days survival) was observed in most of animals treated with VP-16 213 and VM-26. Certain regimens produced 90-100% cure rates (cyclophosphamide plus VP-16 213 or cytosine arabinoside). Inclusion of second or third agent in the treatment schedules produced improvement, deterioration or no effect on median survival time and cure rates, depending on the choice and sequences of evaluated agents. Eighty per cent of mice inoculated even with 10(7) L1210 can be cured by administration of modified schedule of VP-16 213 plus cyclophosphamide.

Combined chemoimmunotherapy of L5178Y lymphoma.

The antitumoral effect of chemotherapy and immunotherapy with BCG and/or irradiated L5178Y cells has been compared to antitumoral effect of chemotherapy alone. Significantly better results were noted in a transplantable L5178Y lymphoma grafted on DBA/2-J mice treated with methotrexate and BCG than in any other group which was not treated with BCG. The effect of irradiated lymphoma cells was similar to effectivity of methotrexate alone.

Determination of suramin in clinical samples using HPLC.

High-performance liquid chromatography (HPLC) was applied for the determination of suramin levels in serum samples from cancer patients treated with this drug. Ion-pair chromatography in combination with the deproteination procedure extraction and hydrolysis of complex serum proteins-suramin were recommended. Extraction recoveries and linearity for wide concentration range were evaluated. Detection limit of suramin in serum samples was determined (0.5 micrograms/ml), and concentration curves as the dependences of suramin concentration levels and time have been illustrated. Chromatographic conditions were optimized for minimal analysis time (max. 10 min) and suitable chromatographic resolution (Rij greater than 1.25).

Treatment of acute lymphoblastic leukemia in children. Long-term results of two trials.

Eighty-eight children younger than 15 years with acute lymphoblastic leukemia were treated with two similar protocols. Both regimens consist of multidrug combinations, with CNS prophylaxis. Sixty-four patients were enrolled on first protocol 0171 with vincristine and prednisone induction therapy. After remission induction patients were randomized on two arms: regimen A which consists of intensive courses of methotrexate with vincristine and prednisone reinductions and administration of cyclophosphamide. Regimen B is similar to regimen A, only courses of methotrexate are alternated with courses of 6-mercaptopurine during consolidation and intensification therapy. In maintenance phase both regimens have daily administration of 6-mercaptopurine and twice weekly administration of methotrexate, with vincristine and prednisone reinductions. The second protocol 0276/A is similar to regimen B of protocol 0171, but L-asparaginase is administered in the end of induction phase and total duration of therapy since induction of complete remission is prolonged from 2.5 to 4 years. Complete remission rate ranged from 92 to 96% in the patients achieving complete remission. In protocol 0171 actuarial proportion of children alive in complete remission for more than 10 years is 60% at present. The actual median survival of all children treated with protocol 0171 is 46+ months and actual median duration of complete remission is 43+ months. There was no significant difference between patients treated with methotrexate alone and those treated with combination of methotrexate and 6-mercaptopurine during consolidation and intensification phase. In protocol 0171 the relapse rate was 28% and the death rate in complete remission was 15%. More than 70% of complete responders in protocol 0276 is in continuous complete remission from 2+ to 57+ months, relapse rate is only 4% at present and the death rate in complete remission is 9% in this protocol.

Adjuvant clodronate therapy in patients with locally advanced breast cancer--long term results of a double blind randomized trial. Slovak Clodronate Collaborative Group.

Between March 1990 and May 1993 seventy three patients with previously untreated breast cancer, Stage III or IV without osseal metastases were randomized to sodium clodronate 1600 mg daily p.o.(arm A = 37 patients) or placebo (arm B = 36 patients) over 2 years, additionally to standard therapy. Ten patients were not evaluable for response because of short duration of therapy (less than 2 months). Bone metastases developed in 30% of patients in arm A and 23% patients in arm B. Median time to appearance of bone metastases was 13 months in arm A and 28 months in arm B. Non-bone metastases appeared in 48% patients in arm A and in 48% patients in arm B. Time to development of non-bone metastases was 20 months in arm A and 16 months in arm B. Five-year survival was 41% in arm A and 39% in arm B. There were no significant differences between the treated and control arms.

Treatment of advanced Hodgkin's disease with modified MOPP regimens. A long-term observation.

Fifty-three patients with advanced Hodgkin's disease, most of them previously treated, received 8 to 16 courses of modified MOPP regimens (nitrogen mustard replaced by trichlormethine in arm A, with addition of vinblastine to the 4-drug regimen in arm B, and alternation of three drugs--trichlormethine, vincristine, and prednisone--with probably non-cross resistant two drugs--vinblastine and procarbazine in arm C). Thirty patients (57%) achieved complete remission. Higher complete remission rate and longer survival was recorded in patients treated with 5-drug regimens (arms B and C) as compared to the 4-drug regimen (arm A), but the differences were not significant. Higher complete remission rates were observed in asymptomatic patients, females, and patients with lymphocyte predominance and nodular sclerosis subtypes of Hodgkin's disease. Besides expected short-term toxicity, 4 out of 30 complete responders developed secondary malignancies (two acute myeloblastic leukemias, one hepatocellular carcinoma, and one cerebellar astrocytoma). Several other patients had serious toxicity which could be attributed to chemotherapy. Twenty-eight percent of the patients has been alive 15 to 18 years since the start of this study.

Carboplatin and cyclophosphamide in the treatment of metastatic seminoma.

Cisplatin-based chemotherapy is highly effective in advanced seminoma, but at the cost of a considerable toxicity. The response rate of carboplatin is comparable with cisplatin combinations but the relapse rate is higher. Our study assesses the efficacy and the toxicity of the combination of carboplatin and cyclophosphamide in patients with advanced seminoma. Nineteen consecutive patients received 6 cycles of intravenous cyclophosphamide 750 mg/m2 and carboplatin 350 mg/m2, repeated every 21 days. The overall objective response rate was 100%, 11 patients (58%) achieved a complete response and 8 patients (42%) showed a partial response. At median follow up of 4.2 years 3 patients (15%) relapsed. The 2-year disease-free survival and the overall survival are 72 and 94%, respectively. This outpatient treatment was well tolerated and the toxicity was mild. One patient had granulocytopenic fever and one patient had grade 3 cystitis. The combination therapy with carboplatin and cyclophosphamide is an effective and tolerable regimen in advanced seminoma.

Treatment of adult acute lymphoblastic leukemia: results of two trials.

Thirty eight patients with acute lymphoblastic leukemia were treated protocol 0171 (VCR, PRED, MTX, cyclophosphamide +/- +/- 6-MP) and protocol 0276/A (VRC, PRED, L-ASP, MTX, 6-MP, cyclophosphamide). Overall complete remission rate in both studies was 84--85%, and additional treatment in protocol 0171 resulted in complete remission rate of 92%. Median duration of complete remission in protocol 0171 was 23 months and median survival of all patients was 33 months. Six patients randomized to regimen "A" (without 6-MP in intensification) had median duration of complete remission 8 months and media survival was 13 months. Seventeen patients treated with regimen "B" (with 6-MP in intensification) had median duration of complete remission 25 months and median survival was 39 months. Median survival of patients allocated on protocol 0276/A in 21+ months and median duration of complete remission is 23 months at present. Twelve percent of patients treated with the best regimen have survived more than 66 months in continuous complete remission. The incidence of drug related death in complete responders was 6%. The relapses were most frequent during the first two years of remission. Extramedullary leukemia as the initial site of relapse was observed in 9% of patients.

Comparison of two non-cross-resistant combinations (ABVP/LOPP) with COPP plus bleomycin in the treatment of advanced Hodgkin's disease.

Eighty patients with advanced Hodgkin's disease were randomized either to treatment with combination of doxorubicin, bleomycin, vinblastine, and prednisone (ABVP), alternating with lomustine, vincristine, procarbazine, and prednisone (LOPP)--Group A, or to combination of cyclophosphamide, vincristine, procarbazine, prednisone, and low dose of bleomycin (COPP-Bleo)--Group B. Thirty-nine out of 41 patients (95%) in Group A achieved complete remission (CR) as compared to 25 CR in 39 patients (64%) in Group B. Patients with systemic symptoms, bulky disease, and nodular sclerosis achieved significantly more CR after treatment with ABVP/LOPP regimen than with COPP-Bleo regimen. Ninety percent of patients are alive in Group A (median observation time 97+ months) as compared to 58% in Group B (median observation time 97+ months). Ninety-two percent of complete responders are in CR in Group A as compared to 53% of complete responders in Group B. These differences between both groups are significant. More serious (WHO grade III and IV) myelosuppression as well as stomatitis and alopecia were observed in Group A. Gastrointestinal toxicity and neurotoxicity was more frequent in Group A. No patient died due to toxicity in Group A as compared to one patient in Group B. Non-cross-resistant alternating regimen ABVP/LOPP was more effective in the treatment of advanced Hodgkin's disease than the COPP-Bleo regimen, especially for patients with advanced Stage IVB Hodgkin's disease.

Intensive combination chemotherapy (TTL-I protocol) of large cell and immunoblastic lymphomas--long-term observation.

Fifty patients with advanced (Stage III and IV) large cell and immunoblastic lymphoma were treated with eight 4-week courses of chemotherapy. The first two identical A courses were composed of high dose cyclophosphamide, vincristine, 5-day administration of bleomycin, 2-week prednisone, and methotrexate with calcium leucovorin. The next two "B" courses were composed of vincristine, 3-day administration of doxorubicin together with bleomycin, and prednisone. The next two "C" courses were composed of cyclophosphamide, vincristine, bleomycin, prednisone, methotrexate, and calcium leucovorin. The last two "D" courses were the same as "B" courses. CNS prophylaxis was done with intrathecal methotrexate. Fourty-two patients (84%) achieved complete remission, 7 patients entered partial remission, and 1 patient failed to respond. The median survival of all groups was 80 + months (range 2-181 + months). Nine patients relapsed (21%), and seven patients died in complete remission, three of them died of toxicity. The most frequent toxicity was myelosuppression, mostly leukopenia, frequently followed by infection, sometimes severe. Neurotoxicity and stomatitis were frequent, but usually not severe. Two patients developed secondary malignancies. Most of the patients (54%) are alive without evidence of disease at present.

Sequential intermediate high-dose therapy with etoposide, ifosfamide and cisplatin for patients with germ cell tumors.

Intermediate high dose VIP (etoposide, ifosfamide, cisplatin) achieved comparable efficacy and improved tolerance in comparison with high-dose chemotherapy plus PBSC in poor risk germ cell tumors. The aim of this study was to confirm the effectivity and tolerance of this regimen in clinical practice. Twenty-five consecutive patients, 9 previously untreated with poor prognosis and 16 relapsed, were treated with 1.6 VIP or 1.9 VIP+PBSC. A relative dose intensity of 1.6 VIP was used in 14 patients and 11 patients received the intensity of 1.9 VIP. Clinical response was achieved in 56% of patients. Fifty-eight percent of patients have survived more than 1 year and 44% more than 2 years. No significant difference was noted between previously treated and untreated patients, as well as between the patients on 1.6 VIP and 1.9 VIP, with the exception of improved 1-year survival of patients on 1.9 VIP. One of four cisplatin-refractory patients achieved durable partial remission with a normal level of tumor markers. Serious non-hematological toxicity was rare. Myelotoxicity of 1.9 VIP was less serious in comparison with 1.6 VIP regimen, but the difference was not significant. Sequential intermediate high-dose therapy is an effective and tolerable regimen for patients with poor risk germ cell tumor as well as for relapsed patients.

[Effectiveness of cisplatin with continuous infusion of 5-fluorouracil in neoadjuvant chemotherapy of carcinoma of the oral cavity]. / Efektivita cisplatiny s kontinuálnou infúziou 5-fluorouracilu v neoadjuvantnej chemoterapii karcinómov ústnej dutiny.

The effect of neoadjuvant chemotherapy regimen utilizing cisdiaminodichloroplatinum (CDDP) with continuous 5-day infusion of 5-fluorouracil (5-FU) was analyzed during the treatment of 23 patients with histologically established epidermoid carcinoma of the oral cavity. All but four patients were in clinical stage III or IV of the disease and seven of them had an inoperable tumor. No one had been treated previously. Complete response after three courses of the chemotherapy was obtained in 13 patients (56.5%) and partial response in 8 (34.8%). The overall response amounted to 91.3%. Only two tumors showed no response to the therapy after one and two courses respectively. The former patient did not continue the chemotherapy due to toxicity and the latter because of its minimal effect. During therapy the disease did not progress in any of the patients studied. Neoadjuvant chemotherapy with CDDP and continuous 5-FU infusion lasting 120 hours was found to be both tolerable and an effective part of the complex management of oral cavity carcinoma without the risk of delaying subsequent definitive treatment. (Tab. 9, Ref. 18).