Characterization and cloning of a 37.6-kb plasmid carried by Legionella pneumophila recovered from patients and hospital water over a 12-year period

High-dose chemotherapy is associated with a high complete response rate and possibly some survival advantage in patients with metastatic breast cancer. We designed a clinical trial consisting of a two-step high-dose chemotherapy regimen followed by posttransplantation doxorubicin as the first chemotherapy treatment for metastatic disease. Twenty-one patients with metastatic breast cancer and no previous chemotherapy for metastatic disease were treated with high-dose cyclophosphamide (Cy; 5000 mg/m2), followed by granulocyte colony-stimulating factor. Peripheral blood stem cells were collected. Subsequently, patients received Cy (6000 mg/m2), thiotepa (500 mg/m2), and carboplatin (800 mg/m2) (CTCb) with hematopoietic rescue. Upon recovery of hematopoietic and gastrointestinal toxicity, three cycles of doxorubicin (Dox; 60 mg/m2) were delivered. After Cy, nine patients (45%) developed neutropenic fevers. There were no episodes of bacteremia. Patients received CTCb 37 days after starting Cy and had a hospital stay of 19 days. After CTCb, the median number of days to an absolute neutrophil count >5 x 10(9)/liter was 8, and the median number of days to a platelet count >20 x 10(9)/liter was 9. Neutropenic fevers occurred in 12 patients. There were no hemorrhagic complications. Fifty-five of the 63 planned courses of Dox were delivered. The median time from peripheral blood stem cell infusion to the first Dox cycle was 38 days. The median time to the second Dox cycle was 28 days, and to the last cycle was 30 days. Three episodes of neutropenic fevers were observed. Two patients developed herpes zoster. This regimen is feasible, with acceptable toxicity.     

DIZE (dexamethasone, idarubicin, and continuous infusion of ifosfamide and etoposide): an effective and well-tolerated new regimen for patients with relapsed lymphoma

We performed a phase II study of dexamethasone, ifosfamide, idarubicin and etoposide (DIZE) in patients with relapsed or refractory Hodgkin's (HL) and non-Hodgkin's lymphoma (NHL). The regimen consisted of dexamethasone (20 mg i.v. days 1-4), idarubicin (8 mg/m2 i.v. days 1+2), continuous infusion (c.i.) of ifosfamide (1,000 mg/m2 days 1-4), and c.i. etoposide (60 mg/m2 days 1-4). G-CSF (5 microg/kg) was used to support neutrophil recovery from day 5. In older patients (> 60 years) the dosage of idarubicin and ifosfamide was reduced to 75% in the initial cycle. Fourty six patients (pts) were treated with a total of 131 cycles. Sixteen pts were primary resistant and 30 were relapsed. Median age was 54.3 years (range 22-75). The median number of different prior chemotherapies was 1.7 (range 1 to 5). 31/46 (67.4%) pts had advanced disease (stage III or IV); 19/46 had B symptoms. Of 43 evaluable pts the response rate was 58.1% including 11 complete remissions (CR) and 14 partial remissions (PR). Mean duration of response was 8 months (1-30+). DIZE was more effective in relapsed than in refractory high-grade NHL (74 % vs 16.6%; p < 0.001). Of four heavily pretreated pts with HL, one obtained CR and two PR (response rate 75%). Myelosuppression was generally moderate with a mean duration of leukocytopenia < 1,000/microl of 2.5 days (range 0-18) and of thrombocytopenia < 25,000/microl 1.5 days (range 0-17). One patient died of uncontrollable infection in treatment related neutropenia. No other serious toxicities apart from alopecia were observed. We conclude that DIZE is safe and effective in heavily pretreated pts with relapsed lymphoma. The continuous infusion of cytostatic drugs such as that used in the new DIZE protocol might reduce hematotoxicity.     

Molecular and cellular mechanism of angiotensin II-mediated apoptosis

We hypothesized that the conventional ProMACE-CytaBOM regimen could be improved by administering all drugs on d1 with the S-phase agents first in the sequence, prednisone d2-6 only, increasing doxorubicin to 50 mg/m2, and adding G-CSF d2-13 to ameliorate neutropenia. This regimen was tested in a Phase I study of 20 patients (pt) with non-Hodgkin's lymphoma (NHL). The median age was 61 yrs (range, 29-79). Four pt had low grade and 16 intermediate/high NHL. The International Prognostic Index was low in 6 cases, low-intermediate in 12, and high-intermediate in 2. Twelve pt received > or =6 cycles; 4 had 5 cycles, 3 had 4 cycles, and 1 received only 1 cycle. Sixteen pt received subsequent cycles without delay. The response rate was 95% (19/20) with 12 CR and 7 PR; one pt progressed during treatment. After a median follow-up of 30 months, 85% (17/20) remain alive. This higher dose ProMACECytaBOM regimen can be given to older adult patients in an outpatient setting. Phase III studies would be required to determine if it produces a superior overall survival compared to other regimens.     

Pilot trial of infusional cyclophosphamide, doxorubicin, and etoposide plus didanosine and filgrastim in patients with human immunodeficiency virus-associated non-Hodgkin's lymphoma

PURPOSE: To determine the following: (1) the feasibility of combining the antiretroviral didanosine (ddl) with a 96-hour continuous intravenous (IV) infusion of cyclophosphamide (800 mg/m2), doxorubicin (50 mg/m2), and etoposide (240 mg/m2) (CDE) plus filgrastim in patients with non-Hodgkin's lymphoma (NHL) associated with human immunodeficiency virus (HIV) infection; (2) the effect of ddl on CDE-induced myelosuppression and CD4 lymphopenia; and (3) the effect of CDE on serum p24 antigen and quantitative HIV blood cultures. METHODS: Twenty-five patients with HIV-related NHL received CDE every 28 or more days. Consecutive patients were assigned in an alternating fashion to group A (ddl given at a standard dose during cycles one, two, five, and six) or group B (ddl given during cycles three, four, five, and six). RESULTS: ddl use was associated with less leukopenia (mean nadir, 3.33 v 1.49 x 10(3)/microL; p = .03), neutropenia (2.38 v 1.07 x 10(3)/microL; p = .03), and thrombocytopenia (76 v 48 x 10(3)/microL; p = .059), and fewer RBC (1.6 v 3.1 per cycle; p < .01) and platelet transfusions (0.7 v 1.5 per cycle; p < .01), but had no significant effect on CD4 lymphopenia. Furthermore, lymphomatous bone marrow involvement and low CD4 count were associated with significantly greater myelosuppression. Although there was no substantial change in serum p24 antigen, the HIV blood culture became quantitatively more positive or converted from negative to positive in seven patients (64%). Complete response (CR) occurred in 58% of patients (95% confidence interval, 38% to 78%), median CR duration exceeded 18 months, tumor-related mortality was 20%, and median survival was 18.4 months. CONCLUSION: Our results suggest that the CDE and filgrastim regimen is tolerable and effective for patients with HIV-associated NHL, and that combination with ddl is feasible and may result in less myelosuppression.     

Epirubicin cardiotoxicity: an analysis of 469 patients with metastatic breast cancer

PURPOSE: To evaluate the influence of cumulative dose, dose-intensity, single-dose level, and schedule of epirubicin on the risk of developing congestive heart failure (CHF) in patients with advanced breast cancer. PATIENTS AND METHODS: Four hundred sixty-nine consecutive anthracyline-naive patients with metastatic breast cancer were included. Only patients with cardiac failure according to New York Heart Association (NYHA) function class II or more were recorded as having CHF. For each patient, the following were calculated: the cumulative dose of epirubicin, mean dose-intensity (cumulative dose of epirubicin/duration of treatment), and single-dose level (cumulative dose of epirubicin/number of injections). RESULTS: Thirty-four patients (7.2%) developed CHF. The cumulative risk of cardiotoxicity was 4% at 900 mg/m2 and increased exponentially to 15% at 1,000 mg/m2. Irradiation against the mediastinum and thoracic spine increased the risk of CHF (P=.025), but dose-intensity, single-dose level, and schedule had no influence on the risk of developing CHF. Age, previous adjuvant irradiation (to the left or right hemithorax), and previous chemotherapy (cyclophosphamide, methotrexate, and fluorouracil [CMF]) were not risk factors. The median time to onset of CHF following the last dose of epirubicin was 57 days (range, 0 to 853). Among patients with CHF, 13 (38.2%) died of cardiac failure. The median survival time for all patients with CHF was 162 days (range, 0 to +1,957). Previous irradiation directly against the heart increased the risk of death due to cardiac failure and decreased the median survival time to 125 days (range, 0 to 336). CONCLUSION: The present large retrospective study of 469 patients substantiates previous results concerning the cardiotoxicity of epirubicin. A significantly increasing risk of CHF in patients who receive cumulative doses greater than 950 mg/m2 was established. The future recommended maximum cumulative dose of epirubicin should be 900 mg/m2 in patients with metastatic breast cancer. Previous irradiation against the heart leads to an increased risk of developing CHF with an accelerated course to death, which indicates an additive cardiotoxic effect of irradiation and epirubicin.     

Phase II trial of paclitaxel and cisplatin in women with advanced breast cancer: an active regimen with limiting neurotoxicity

PURPOSE: A phase II study of paclitaxel and cisplatin in patients with advanced breast cancer was performed to determine the objective response rate and make further observations about the toxicity of this regimen. PATIENTS AND METHODS: Patients were required to have histologically proven adenocarcinoma of the breast with no more than one chemotherapeutic treatment for advanced disease. Treatment consisted of paclitaxel 200 mg/m2 administered as a 24-hour intravenous (i.v.) infusion followed by cisplatin 75 mg/m2 i.v. Patients received granulocyte colony-stimulating factor (G-CSF) 5 micrograms/kg subcutaneously on day 3 until WBC recovery. Cycles were repeated every 21 days. Patients continued to receive therapy until disease progression or unacceptable toxicity. RESULTS: Forty-four patients entered the trial. Forty-two patients were assessable for response. Nineteen patients (43%) had no prior chemotherapy and 41 had no chemotherapy for metastatic disease. The median number of cycles administered per patient was five (range, one to seven). There were five complete responses (CRs) (11.9%) and 17 partial responses (PRs) (40.5%), with an overall response rate of 52.4% (95% confidence interval [CI], 36.4% to 68.0%). Nine patients had stage III disease. The response rate for this group was 66.7% (95% CI, 33.0% to 92.5%), with three CRs and three PRs. Among 35 patients with stage IV disease, there were two CRs and 14 PRs, with an overall response rate of 48.5% (95% CI, 30.8% to 66.5%). Overall, the median response duration was 10.6 months. Thirty patients (68%) developed transient grade 4 neutropenia. Cumulative neuropathy was the major dose-limiting toxicity. After five cycles of chemotherapy, 96% of patients had at least grade 1 neurotoxicity and 52% had at least grade 2 neurotoxicity. One patient had a toxic death after cycle 1 of therapy. CONCLUSION: The combination of paclitaxel and cisplatin as first-line chemotherapy for women with advanced breast cancer is an active regimen. However, the cumulative neurotoxicity was significant and dose-limiting in the majority of patients.     

Effect of biphosphonates on abnormal mandibular growth of rats intoxicated with uranium

The North Central Cancer Treatment Group designed a phase II trial to assess the efficacy and toxicity of topotecan in patients with unresectable malignant pleural mesothelioma. Twenty-two previously untreated patients with unresectable pleural mesothelioma and good performance status (Eastern Cooperative Oncology Group performance status 0, 1, or 2) were enrolled on this trial from October 1993 through July 1994. Nineteen men and three women, median age 66 years (range, 44-78 years), were treated with topotecan 1.5 mg/m2 intravenously over 30 minutes daily for 5 days at 3-week intervals until toxicity, progression of disease, or a patient decided to discontinue treatment. There were seven patients with measurable disease and 15 with evaluable disease; all were assessable for response and toxicity. A total of 113 cycles of treatment were given, for a median of three cycles (range, 1-26 cycles). Myelosuppression was the most frequent toxicity. Eighteen of 21 patients (86%) experienced grade 3 or 4 neutropenia during the initial treatment cycle. The median neutrophil nadir was 0.5 x 10(3)/microl (range, 0.1-1.6 x 10(3)/microl), and the median platelet nadir was 127 x 10(3)/microl (range, 18-460 x 10(3)/microl). Other toxicities more than grade 2 included malaise (two patients), and anorexia, infection, fever, pulmonary, and cardiac in one patient each. There were no objective responses, and 18 patients had stable disease for a median of 74 days. The median survival for all patients was 230 days, with 23% alive at 1 year. Topotecan as administered in this trial is reasonably well tolerated; however, the response rate was insufficient to warrant additional study in pleural mesothelioma.     

Final report of a phase II study of chemotherapy with bleomycin, epirubicin, and cisplatin for locally advanced and metastatic/recurrent undifferentiated carcinoma of the nasopharyngeal type

PURPOSE: This article presents an assessment of the combination of bleomycin, epirubicin, and cisplatin as induction chemotherapy before radiotherapy in the treatment of undifferentiated carcinoma of the nasopharyngeal type in patients with recurrent/metastatic disease (group A), and in previously untreated patients with locoregionally advanced disease (UICC-AJCC 87, N2-3, M0) (group B) in terms of toxicity, antitumoral activity, and therapeutic efficacy. PATIENTS AND METHODS: From January 1987 to September 1990, 111 consecutive patients with histologically proven UCNT were treated with six cycles of intravenous cisplatin (100 mg/m2 day 1) epirubicin (80 mg/m2 day 1), and bleomycin (15 mg bolus day 1), followed by 16 mg/m2/day continuous infusion for 5 days, repeated every 21 days for three cycles. Three further cycles without bleomycin were given to 44 patients in group A. In group B (67 patients), only three cycles of the same protocol were given, with a slightly lower dose of epirubicin (70 mg/m2), followed by conventional radiotherapy (70 Gy/7 weeks). RESULTS: Of 44 patients entered in group A, 38 were evaluable for response. We observed 9 (20%) complete responses and 11 (25%) partial responses, for a 45% overall response rate. In 12 patients not previously given chemotherapy, there were 4 complete responses, compared to 5 complete responses in 32 patients previously treated with chemotherapy. Four patients are alive with no evidence of disease after 53+, 60+, 61+, and 72+ months. In group B the overall response rate to chemotherapy was 98% with 42 complete (62%) and 24 partial responses (36%). Three months after the end of radiotherapy, the overall complete response rate was 94% (63 patients). After a median follow-up time of 77 months (range, 53-94), the 4-year overall survival and disease-free survival rates for this group are 66% and 60%, respectively. The median disease-free survival has not been reached at 90 months. CONCLUSION: The results of the BEC combination trial are very encouraging in metastatic and recurrrent UCNT, with durable remissions in this poor-prognosis population. The results in patients with locally advanced disease have motivated prospective phase III testing of the neoadjuvant chemotherapy approach to evaluate its impact on locoregionally advanced disease (> or =N2MO UICC-AJCC 87).     

Phase II trial of paclitaxel by 24-hour continuous infusion for relapsed non-Hodgkin's lymphomas: Southwest Oncology Group trial 9246

PURPOSE: The Southwest Oncology Group (SWOG) recently conducted a multiinstitutional phase II trial to determine the complete response (CR) and partial response (PR) rates, toxicities, and progression-free and overall survivals of patients with relapsed non-Hodgkin's lymphomas (NHLs) treated with a 24-hour continuous infusion of paclitaxel at a dose of 175 mg/m2. PATIENTS AND METHODS: Sixty-six patients with relapsed NHL who had received minimal prior therapy (one prior chemotherapy regimen for intermediate- to high-grade NHL [44 patients] or one or two prior regimens for low-grade NHL [22 patients]) were premedicated with dexamethasone, diphenhydramine, and cimetidine and then treated with continuous intravenous infusion paclitaxel over 24 hours every 21 days. RESULTS: Eleven of 66 patients (17%) achieved rigorously documented objective remissions, including two CRs (3%) and nine PRs (14%). In addition, another five patients (8%) achieved apparent PRs on a single computed tomographic (CT) scan. Responses were brief, lasting a median of 3 months (5 months for indolent lymphomas and 3 months for intermediate- to high-grade lymphomas). Grade 4 or 5 granulocytopenia was the only common serious toxicity, and occurred in 42 of 66 patients (64%). CONCLUSION: Paclitaxel is generally well tolerated when given as a continuous infusion of 175 mg/m2 over 24 hours, despite predictable granulocytopenia. However, single-agent paclitaxel has modest clinical efficacy compared with other available treatments for relapsed NHL.     

Adjuvant treatment of high-risk breast cancer using multicycle high-dose chemotherapy and filgrastim-mobilized peripheral blood progenitor cells

Women with primary breast cancer associated with extensive axillary node involvement or large primary tumors have a very poor prognosis despite treatment with standard-dose adjuvant chemotherapy. In an attempt to improve the outlook of these patients, we investigated the safety and feasibility of delivering three cycles of high-dose epirubicin and cyclophosphamide supported with filgrastim-mobilized peripheral blood progenitor cells (PBPC). Fifteen previously untreated women, median age 50 (range, 30-58) years, with poor prognosis early stage breast cancer received filgrastim (12 microgram/kg daily for 6 days) prior to chemotherapy to mobilize progenitor cells. Patients were then given three cycles of epirubicin (200 mg/m2) and cyclophosphamide (4 g/m2) at planned 28-day intervals, each followed by infusion of one third of the PBPC collected and daily administration of filgrastim (5 microgram/kg s.c.). Three leukaphereses collected a median of 114.9 (range, 22.7-273.5) x 10(4) granulocyte-macrophage-colony-forming cells/kg body weight. Hemopoietic recovery was rapid after each cycle, and there was no correlation between the rate of recovery and the number of granulocyte-macrophage-colony-forming cells infused. There was a small but significant progressive delay in recovery from hematological and nonhematological toxicities across the three cycles. Left ventricular ejection fraction fell to below 50% in eight (53%) patients, but none developed congestive cardiac failure. Two patients did not complete three cycles because of insufficient PBPC for a third cycle (n = 1) and 2-mercaptoethane sodium sulfonate- related drug reaction during the second cycle (n = 1). There were no deaths during the study or during the follow-up period (median, 70 weeks; range, 50-85 weeks), and no late toxicities occurred. Therefore, we concluded that the delivery of multiple cycles of nonmyeloablative, dose-intensive chemotherapy supported by PBPC and filgrastim is safe, and may be widely applicable to a variety of common chemosensitive cancers with a poor prognosis. The efficacy of three cycles of high-dose epirubicin and cyclophosphamide is to be compared with standard-dose chemotherapy in a randomized trial in patients with high-risk, operable stage II and III breast cancer.     

Oxaliplatin, folinic acid and 5-fluorouracil (folfox) in pretreated patients with metastatic advanced cancer. The GERCOD

Preliminary studies suggest synergy between oxaliplatin and fluorouracil (5-FU). To assess this issue, we performed a study in pretreated patients with advanced colorectal cancer (CRC) resistant to leucovorin and 5-FU. Regimen consisted of oxaliplatin day 1, 130 mg/m2 every two cycles (folfox 1) or 100 mg/m2/cycle (folfox 2) or 85 mg/m2/cycle (folfox 3) and leucovorin 500 mg/m2 as a 2-hour infusion, followed by 5-FU 22 h infusion 1.5-2 g/m2 for two consecutive days every 2 weeks. One hundred and thirteen patients have been treated. One complete response (CR) and 32 partial responses (PRs) were observed for an overall response rate of 29.2%. Sixty-seven patients had prior documented progression while receiving the same schedule of leucovorin and 5-FU than the one used in the folfox regimens, among them 18 had PRs (26.9%). The best response rate was observed in patients treated with the folfox 2 regimen: 41.7%. From start of folfox, median progression-free survival was 6 months and median survival 13 months. Limiting toxicities were peripheral neuropathy and neutropenia. Fifty-four percent of the patients experienced WHO toxicity > or = grade 3 with the folfox1 regimen, 45% with the folfox2 and 40% with the folfox3. The folfox regimens achieve a high response rate in pretreated patients with CRC. Further studies are needed to determine the best oxaliplatin dose-intensity.     

Corticosteroids significantly delay the onset of docetaxel-induced fluid retention: final results of a randomized study of the European Organization for Research and Treatment of Cancer Investigational Drug Branch for Breast Cancer

PURPOSE: To confirm the efficacy of docetaxel in patients with breast cancer previously treated with one chemotherapy regimen for advanced or metastatic disease and to compare the incidence of fluid retention (FR) and skin toxicity when docetaxel is administered with and without prophylactic corticosteroids. PATIENTS AND METHODS: Eighty-three patients, pretreated with one chemotherapy regimen for metastatic breast cancer (MBC) with bidimensionally measurable and progressive disease, were eligible for this randomized trial. Docetaxel with prophylactic oral antihistamine was administered at a dose of 50 mg/m2 as a 1-hour infusion on days 1 and 8 every 21 days and patients were randomized to receive methylprednisolone (40 mg days -1, 0, 1, 7, 8, and 9 of each cycle) (arm A) or no methylprednisolone (arm B). RESULTS: Twenty-eight patients (34%, 95% confidence interval [CI], 23% to 45%) achieved on objective response. The median time to disease progression and median overall survival time were 5 and 13.5 months, respectively. In total, 415 cycles of docetaxel were administered (arm A: N = 219, median = six; arm B: N = 196, median = five). The most common toxicity observed was grade 3 or 4 neutropenia, which occurred in 79% of patients. Clinically significant nonhematologic side effects included skin reactions and asthenia. In an intent-to-treat analysis, patients who received methylprednisolone premedication had a delayed onset of FR (median time to onset of FR: arm A, 84 days; arm B, 62 days; P = .01) and received a higher median cumulative dose of docetaxel before the onset of FR (arm A, 333 mg/m2; arm B, 215 mg/m2; P = .001). There was no statistically significant difference in the incidence of skin toxicity between the two arms. CONCLUSION: Docetaxel, at this dose and schedule, has definite antitumor activity in pretreated MBC patients. Moreover, this is the first randomized trial to show that corticosteroids have a favorable impact on docetaxel-induced FR.     

Flow injection photometric determination of zinc and copper with zincon based on the variation of the stability of the complexes with pH

PURPOSE: The objective of this study was to determine the maximally tolerable doses (MTDs) of vinorelbine (VNR) and gemcitabine (GEM) when combined with a fixed dose of cisplatin (CDDP). PATIENTS AND METHODS: Chemotherapy-naive patients with stage IIIB-IV non-small-cell lung cancer (NSCLC) received a fixed dose of CDDP (50 mg/m2) and escalating doses of VNR (starting from 20 mg/m2) and GEM (starting from 800 mg/m2) on days 1 and 8, every three weeks. The single escalation of GEM alone, by 200 mg/m2 at each step, was initially planned up to a dose of 1,200 mg/m2, to be followed by increments of the VNR dose of 5 mg/m2 at each step. RESULTS: Thirty-one patients were enrolled at five different dose levels. The escalation was stopped at level 4 (GEM 1,200 mg/m2 and VNR 25 mg/m2) since two of six patients of this cohort showed dose-limiting neutropenia at treatment cycle 1. Two different dose levels, GEM 1,200 mg/m2 + VNR 20 mg/m2, and GEM 1,000 mg/m2 + VNR 25 mg/m2 were fairly well tolerated. No treatment-related deaths occurred. Neutropenia was the main toxic effect, occurring in 76% of the total of 116 cycles delivered, and in 24% of them was of grades 3 or 4. A total of eight patients (26%) experienced grade 4 neutropenia lasting more than seven days; in five of them it occurred in the first course. Neutropenic fever was observed in four cases. Grade 4 thrombocytopenia occurred in only two patients. Non-hematologic toxicity was a minor problem in all patients but was never dose-limiting. No complete responses were obtained, but sixteen out of 31 (52%) patients achieved partial responses. The median duration of response was 20 (range 6-56+) weeks, while at a nine-month median follow-up, the median survival time has not yet been reached. To date, 18 patients are still alive. The one-year projected survival for all patients was 51%. CONCLUSIONS: Our results show that CDDP, VNR and GEM can be safely given together without substantial reductions in their individual dose intensities. In our opinion, the dose level of GEM 1,000 mg/m2 + VNR 25 mg/m2 given in combination with CDDP 50 mg/m2 on days 1 and 8 of a three-week cycle can be recommended for phase II trials, since it provides a better balance in dose intensity of GEM and VNR. A phase II randomised study is underway to establish the activity of this new regimen (at the above-cited dose level) in chemo-naive NSCLC patients.     

Phase II study on cisplatin and ifosfamide in recurrent high grade gliomas

27 patients with recurrent high grade glioma following surgery and radiation therapy were treated with 100 mg/m2 cisplatin and 6 g/m2 ifosfamide per cycle, administered on days 1-3 in 4 week cycles, for a maximum of six cycles. Toxicity was assessed after every cycle. Response was assessed following every second cycle, and a 50% decrease of the largest cross-sectional tumour area on contrast enhanced magnetic resonance imaging or computed tomography scan was considered a partial response (PR). A total of 95 cycles was administered; 26 patients were evaluable for response. In 5 patients (19%), a PR was obtained (median time to progression (TTP): 34 weeks). Stable disease was observed in 6 patients (23%, median TTP: 22 weeks). The most frequent toxicity was haematological: 37% of cycles were complicated by a grade 3 or 4 leucopenia. 1 patients died, probably as a consequence of increased cerebral oedema induced by the cisplatin hydration schedule. Determination of the cisplatin concentration in this patient showed a 10-fold increase in the tumour concentration as compared with that in normal brain tissue, demonstrating the absence of a blood-brain barrier in the tumour. In conclusion, generally this schedule was well tolerated, but it is of moderate activity for recurrent glioma.     

Compomers and glass ionomers: bond strength to dentin and mechanical properties

Twenty-six patients with newly diagnosed ALL (age range 15-49 years, median 32 years) received treatment comprising: cycles 1 and 2: adriamycin 30 mg/m2 days 1-3, vincristine: 2 mg days 1, 8, and 15, with prednisolone 40 mg daily, given until complete remission (CR). L-asparaginase 10000 units/m2, days 1-14, was given only with the first cycle. Cycle 3 consisted of 100 mg/m2 etoposide orally, days 1-5, and 1 gm/m2 bd cytosine arabinoside (ara-C) days 1-5. Cycles 1-3 were then repeated. Intrathecal methotrexate (MTX) 12.5 mg was given on day 1 of each treatment cycle. The first 12 consecutive patients received this chemotherapy alone, the subsequent 14 received, in addition, 3 micrograms/kg GM-CSF subcutaneously, from day 4 of cycles 1,2,4 and 5 (and from day 6 of cycles 3 and 6) until the absolute neutrophil count had reached 0.5 x 10(9)/1. All patients in whom CR was achieved then received prophylactic cranial irradiation. With the exception of those with T-ALL, this was followed by oral maintenance therapy consisting of 6-mercaptopurine, MTX, and cyclophosphamide for 3 years. Patients receiving GM-CSF did not have shorter intercycle times or a lower incidence of documented infections than those who did not receive it. The CR rate was 89% overall-uninfluenced by GM-CSF, but higher than that achieved previously at St Bartholomew's Hospital in an equivalent age-group.     

Tandem and triple high-dose chemotherapy with autologous stem cell rescue in metastatic breast cancer

The purpose of this phase II study was to evaluate the therapeutic efficacy and toxicity of a tandem or triple high-dose chemotherapy (HDC) with autologous peripheral blood stem cell transplantation (PBSCT) in patients with metastatic breast cancer (MBC) as first line chemotherapy. Conventional chemotherapy consisted of two cycles of epirubicin 120 mg/m2 and ifosfamide 7500 mg/m2 in the case of tandem HDC and one cycle of paclitaxel 135 mg/m2, epirubicin 90 mg/m2 and ifosfamide 6000 mg/m2 in the case of triple HDC. Tandem HDC was composed of two cycles of epirubicin 180 mg/m2, ifosfamide 12000 mg/m2 and carboplatin 900 mg/m2. In the case of triple HDC, paclitaxel 180 mg/m2, etoposide 1500 mg/m2 and thiotepa 600 mg/m2 was added as the third cycle. Patients with tandem HDC (n = 20) were evaluable for both survival and toxicity, and patients with triple HDC (n = 21) only for toxicity because of short-term follow-up. Both tandem and triple HDC were well tolerated and could be safely administered. Non-hematological WHO grade 3 or 4 toxicities were mucositis (8), temporary renal insufficiency (1), myocardial infarction (1), and neuropathy (1). No toxic death occurred. The Kaplan-Meier estimates for 44-months without progression and the overall survival were 12% and 38% respectively. The median survival was 22 months (95% CI: 7.4-51.7 months) and the median progression-free interval 14 months (95% CI: 5.1-43.7 months). In a population with an unfavorable prognosis, tandem HDC showed similar efficacy as to that described in other phase II studies. Triple HDC seems not to improve patient outcome compared to tandem HDC, but a long-term follow up is required.     

Passive immune globulin therapy in the SIV/macaque model: early intervention can alter disease profile

In this study, we investigated the impact of recombinant interleukin-2 (rIL-2) after high dose chemotherapy and autologous bone marrow transplantation (ABMT) in 25 patients with refractory or relapsed Hodgkin's disease (HD) (11 patients) and non Hodgkin's lymphoma (NHL) (14 patients). 48% of patients had resistant disease, 84% achieved complete remission after ABMT. rIL-2 was started at a median of 54 days post-transplant and consisted of a first cycle of 5 days followed by 4 cycles of 2 days every other week. Patients received a mean of 160 x 10(6) IU/m2 rIL-2 and hematological toxicity was moderate and transient. None of the 5 evaluable patients with measurable disease responded to rIL-2. After a 5 year median follow-up, the probability of survival and DFS is 72% (HD: 73% and NHL: 70%, p = NS) and 45% (HD: 36% and NHL: 48%, p = NS) respectively. These somewhat encouraging results warrant further evaluation of rIL-2 after ABMT in controlled studies, especially in NHL patients stratified for previous chemosensitivity.     

Treatment of patients with transitional-cell carcinoma of the urothelial tract with ifosfamide, paclitaxel, and cisplatin: a phase II trial

PURPOSE: A phase II trial of ifosfamide, paclitaxel, and cisplatin (ITP) was conducted in previously untreated patients with advanced transitional-cell carcinoma (TCC) to assess its efficacy and toxicity. PATIENTS AND METHODS: Thirty patients with metastatic or unresectable TCC were treated with ifosfamide 1.5 g/m2/d for 3 days with paclitaxel 200 mg/m2 over 3 hours and cisplatin 70 mg/m2 on day 1 of each 28-day treatment cycle. Therapy was continued for a maximum of six cycles. Prophylactic hematopoietic growth factor (recombinant human granulocyte colony-stimulating factor [rhG-CSF]) was given on days 6 to 17 of each cycle. RESULTS: Twenty-three of 29 assessable patients (79%; 95% confidence interval [CI], 60% to 92%) demonstrated a major response (six complete [CR] and 17 partial [PR]) with response durations that ranged from 5 to 24+ months. Five patients with T4 bladder primary tumors had a major response, two with pathologic CR. At a median follow-up duration of 17.9 months, nine (31%) patients remain disease-free (range, 10+ to 24+). Hematologic toxicity included anemia, thrombocytopenia, and neutropenia; febrile neutropenia was observed in 17% of patients and 4% of cycles. No grade 4 nonhematologic toxicity was observed. Grade 3 nonhematologic toxicity included alopecia, allergy (3%), renal insufficiency (13%), and neuropathy (10%). Dose reductions or drug omissions were necessary for adverse events in seven (23%) patients. CONCLUSION: ITP is an active, well-tolerated regimen in previously untreated patients with TCC of the urothelial tract. Further study of this regimen in patients with both TCC and non-transitional-cell urothelial tumors is ongoing.     

Mitomycin C, vinblastine, and carboplatin regimen in patients with nonsmall cell lung cancer. A phase II trial

BACKGROUND: The mitomycin C, vinblastine, and cisplatin (MVP) combination is one of the most frequently used in the palliative setting, but it produces considerable toxicity. Carboplatin and cisplatin have different patterns of toxicity. The goal of this study was to evaluate a combination similar to MVP, using carboplatin instead of cisplatin to render it more feasible in an outpatient setting. METHODS: Inclusion criteria for this study included: inoperable patients or patients relapsing after previous surgery, with nonsmall cell lung carcinoma (NSCLC), a performance status (PS) > 50%, and no previous chemotherapy. The chemotherapy regimen included carboplatin, 300 mg/m2 on Day 1; mitomycin, 8 mg/m2 on Day 1; and vinblastine, 4 mg/m2 on Days 1, 8, and 15 (on Day 15 vinblastine was delivered only in the first cycle) (MVC) every 3 weeks for at least 3 cycles. RESULTS: From August 1991 until August 1994, 70 patients entered the trial. All were evaluable for toxicity and response. The median age was 62 years (range, 40-73 years). The male/female ratio was 60:10 (86%:14%); the ratio of Stage III to Stage IV disease was 26:44 (37%:63%); and the ratio of PS > 70 to < or = 70 was 49:21. A total of 296 cycles (median, 4 [range, 1-6 cycles] per patient) were delivered, 280 of 296 (95%) in an outpatient setting with only 4 patients requiring hospitalization for treatment delivery. Overall response rate (RR) was 38.6% (95% confidence interval [CI], 27-51%) (1 complete response, 1.5%; 26 partial responses, 37.1%). Median duration of response was 9.8 months (range, 2-27 months). In Stage III patients the RR was 42% and in Stage IV patients it was 34%. Overall median survival was 9.5 months (95% CI, 6.8-15.3 months). Survival at 1 year was 39% (standard error [SE] 3.6%) and was 11% at 2 years (SE 3.6%). In Stage III patients median survival was 13 months and the 1-year survival rate was 54% (SE 10%); Stage IV patients had a median survival of 7.4 months and a 1-year survival rate of 28% (SE 7%). Delivered dose intensity was: carboplatin, 71%; vinblastine, 60%; and mitomycin C, 77% of the planned dose intensity. The back calculation of carboplatin area under the curve (AUC) with Calvert's formula and with the Cockcroft-Gault glomerular filtration rate estimation, showed a median AUC value of 4 (range, 2-8). Using the more precise Chatelut formula, AUC was again 4 (range, 2-7). Hematologic toxicity was the major side effect; Grades 3 and 4 leukopenia were observed in 34% and 6% of patients, respectively, and Grades 3 and 4 thrombocytopenia in 25% and 4% of patients, respectively. Grade 2 infection occurred in 10% of patients, with only 1 case of sepsis; severe constipation and Grade 2 alopecia occurred in only 1 patient; and no case of higher than Grade 1 nephrotoxicity was observed. No pulmonary toxicity was observed. Compliance with treatment was good with only one patient refusal after the first cycle. CONCLUSIONS: Chemotherapy for advanced NSCLS is still controversial, because effectiveness in terms of RR and symptom control must be weighed against treatment toxicity and costs. From our study it appears that MVC is easy to deliver in an outpatient setting, and has good patient compliance, low toxicity profile, and promising RR and response duration. The substitution of carboplatin for cisplatin in regimens for advanced NSCLC should be considered.     

Dose-dense therapy with weekly 1-hour paclitaxel infusions in the treatment of metastatic breast cancer

PURPOSE: To evaluate the efficacy and toxicity of paclitaxel administered as a 1-hour infusion on weekly basis, without interruption, to patients with metastatic breast cancer who had received prior therapy. PATIENTS AND METHODS: Thirty patients with metastatic breast cancer received sustained weekly paclitaxel therapy at an initial dose of 100 mg/m2 until disease progression. Prior therapy included adjuvant only (n=17), metastatic only (n=7), or both (n=6). Eighteen patients had received prior anthracycline therapy, 12 of whom had demonstrated progression of disease within 12 months of it. All patients were assessable for efficacy; 29 patients were assessable for toxicity. Pharmacokinetic studies of paclitaxel were also performed. RESULTS: A total of 469 weekly paclitaxel infusions were administered to 30 patients (median, 14 infusions/patient). The median delivered dose-intensity was 91 mg/m2/wk (range, 80 to 108). The overall response rate was 53% (95% confidence interval [CI], 34% to 72%), with 10% complete responses (CRs) and 43% partial responses (PRs). Median response duration was 7.5 months (range, 2 to 11+). Responses were observed in nine of 18 (50%) patients with prior anthracycline therapy, including six of 12 (50%) with disease progression on anthracycline within 1 year (three of four within 6 months). Therapy was well tolerated and remarkable for a lack of overall and cumulative myelosuppression. Grade 3/4 neutropenia occurred in four patients; febrile neutropenia was not observed. Peripheral neuropathy prohibited dose escalation above 100 mg/m2, and grade 3 neuropathy was observed in two of 21 patients at < or = 100 mg/m2. CONCLUSION: Weekly paclitaxel therapy is active and well tolerated in patients with metastatic breast cancer. Weekly therapy should be considered as a current clinical option for these patients and should be incorporated into future comparative clinical trials.