Wood structural differences between northern and southern beech provenances growing at a moderate site.

Planting provenances originating from southern to northern locations has been discussed as a strategy to speed up species migration and mitigate negative effects of climate change on forest stability and productivity. Especially for drought-susceptible species such as European beech (Fagus sylvatica L.), the introduction of drought-tolerant provenances from the south could be an option. Yet, beech has been found to respond plastically to environmental conditions, suggesting that the climate on the plantation site might be more important for tree growth than the genetic predisposition of potentially drought-adapted provenances. In this study, we compared the radial growth, wood-anatomical traits and leaf phenology of four beech provenances originating from southern (Bulgaria, France) and northern locations (Sweden, the Netherlands) and planted in a provenance trial in the Netherlands. The distribution of precipitation largely differs between the sites of origin. The northern provenances experience a maximum and the southern provenances experience a minimum of rainfall in summer. We compared tree productivity and the anatomy of the water-conducting system for the period from 2000 to 2010, including the drought year 2003. In addition, tree mortality and the timing of leaf unfolding in spring were analysed for the years 2001, 2007 and 2012. Comparison of these traits in the four beech provenances indicates the influence of genetic predisposition and local environmental factors on the performance of these provenances under moderate site conditions. Variation in radial growth was controlled by environment, although the growth level slightly differed due to genetic background. The Bulgarian provenance had an efficient water-conducting system which was moreover unaffected by the drought in 2003, pointing to a high ability of this provenance to cope well with dry conditions. In addition, the Bulgarian provenance showed up as most productive in terms of height and radial growth. Altogether, we conclude that the similarity in ring-width variation among provenances points to environmental control of this trait, whereas the differences encountered in wood-anatomical traits between the well-performing Bulgarian provenance and the other three provenances, as well as the consistent differences in flushing pattern over 3 years under various environmental conditions, support the hypothesis of genetic control of these features.

Hydraulic adjustment of Scots pine across Europe.

* The variability of branch-level hydraulic properties was assessed across 12 Scots pine populations covering a wide range of environmental conditions, including some of the southernmost populations of the species. The aims were to relate this variability to differences in climate, and to study the potential tradeoffs between traits. * Traits measured included wood density, radial growth, xylem anatomy, sapwood- and leaf-specific hydraulic conductivity (K(S) and K(L)), vulnerability to embolism, leaf-to-sapwood area ratio (A(L) : A(S)), needle carbon isotope discrimination (Delta13C) and nitrogen content, and specific leaf area. * Between-population variability was high for most of the hydraulic traits studied, but it was directly associated with climate dryness (defined as a combination of atmospheric moisture demand and availability) only for A(L) : A(S), K(L) and Delta13C. Shoot radial growth and A(L) : A(S) declined with stand development, which is consistent with a strategy to avoid exceedingly low water potentials as tree size increases. In addition, we did not find evidence at the intraspecific level of some associations between hydraulic traits that have been commonly reported across species. * The adjustment of Scots pine's hydraulic system to local climatic conditions occurred primarily through modifications of A(L) : A(S) and direct stomatal control, whereas intraspecific variation in vulnerability to embolism and leaf physiology appears to be limited.

Ifosfamide-based drug combinations: preclinical evaluation of drug interactions and translation into the clinic.

Ifosfamide is an alkylating antineoplastic agent with documented activity against a variety of solid tumor types, most notably lung cancer, testicular cancer, and sarcoma. Ifosfamide has been included in various drug combination protocols, usually on an empirical basis. To gather more insight into the mechanisms that underlie these drug interactions and to develop guidelines for further improvement of clinical combination protocols, we performed a broad preclinical evaluation program of ifosfamide-based combination regimens using isobologram analysis of drug interactions. In established cisplatin-sensitive and cisplatin-refractory ovarian carcinoma cell lines, a schedule-dependent drug interaction between paclitaxel and activated hydroperoxy-ifosfamide (4-OOH-IF) could be demonstrated. When both drugs were given for 2 hours, simultaneous exposure or the sequence of paclitaxel followed by 4-OOH-IF were additive or synergistic. In contrast, application of 4-OOH-IF before paclitaxel resulted in pronounced antagonism. Based on the sequence-dependent synergistic interactions a phase I trial was initiated with paclitaxel given on day 1 and ifosfamide given on days 2 to 5 in patients with cisplatin-refractory ovarian cancer. Four dose levels were evaluated in 18 patients. The maximum tolerated dose was paclitaxel 175 mg/m2 on day 1 and ifosfamide 2,000 mg/m2 on days 2 to 5, with central nervous system toxicity and nephrotoxicity being dose-limiting. The recommended dose for further evaluation of this combination was paclitaxel 175 mg/m2 on day 1 and ifosfamide 1,500 mg/m2 on days 2 to 5. Although all patients were heavily pretreated with multiple agents, nine of 18 patients achieved an objective response. Ifosfamide also has been shown to reduce cellular glutathione content; thus, a series of experiments evaluated the ability of activated cyclophosphamide or ifosfamide to deplete cellular glutathione in vitro. It was demonstrated that glutathione depletion is dose- and time-dependent, with 4-OOH-IF leading to a more pronounced suppression of cellular glutathione compared with 4-OOH-Cy. The decrease in cellular glutathione content was maximal at 2 hours after drug treatment; however, cellular glutathione levels returned to normal within 24 hours. When 4-OOH-IF was combined in vitro with cisplatin, schedule-dependent interactions again became obvious. The highest antitumor activity was seen when both drugs were given concurrently; sequential application with 4-OOH-IF given before cisplatin resulted in antagonism. Since adequate glutathione levels are necessary for multidrug resistance protein (MRP) function, glutathione depletion might lead to reversal of MRP-mediated drug resistance. Preliminary data showed that 4-OOH-IF significantly decreases glutathione concentrations in MRP-expressing human HT1080/DR4 sarcoma cells, leading to maximum steady-state reduction after a 90-min exposure to 4-OOH-IF. Taken together the data reported here demonstrate that in vitro ifosfamide may potentiate the antitumor activity of a variety of cytotoxic agents and therefore merits further clinical evaluation in drug combinations (eg, taxanes, anthracyclines).

Reversal of MDR1-associated resistance to topotecan by PAK-200S, a new dihydropyridine analogue, in human cancer cell lines.

Recent data suggest that expression of the membrane P170-glycoprotein (P-gp) may confer resistance to the topoisomerase-I-interactive agent topotecan. The present study describes the cellular effects of a new dihydropyridine analogue, PAK-200S, on P-gp-mediated resistance to topotecan in human breast and ovarian tumour cells. PAK-200S at a non-cytotoxic concentration of 2.0 microM completely reversed resistance to topotecan in P-gp-expressing MCF-7/adr (breast) and A2780/Dx5 (ovarian) tumour cells, respectively, with no effects on parental cells. Cellular pharmacokinetic studies by reversed-phase high-performance liquid chromatography analysis showed significantly lower cellular drug concentrations of the pharmacologically active closed-ring lactone of topotecan in multidrug-resistant cells than in parental cells. PAK-200S was effective in restoring the cellular lactone concentrations of topotecan in resistant MCF-7/adr cells to levels comparable to those obtained in parental cells. Furthermore, exposure of MCF-7/adr cells to topotecan in the presence of PAK-200S significantly increased the induction of protein-linked DNA breaks. PAK-200S did not alter nuclear topoisomerase I-mediated ex vivo pBR322 DNA plasmid unwinding activity and topoisomerase-I protein expression. These results suggest that reversal of P-gp-mediated resistance to topotecan by PAK-200S was related to the restoration of cellular drug concentrations of the active lactone form of topotecan rather than a direct effect on topoisomerase-I function.

Maintenance treatment with medroxyprogesterone acetate in patients with advanced breast cancer responding to chemotherapy: results of a randomized trial. Essen Breast Cancer Study Group.

The purpose of this randomized phase III trial was to study whether medroxyprogesterone acetate (MPA) maintenance treatment prolongs the time to progression in advanced breast cancer patients responding to an induction chemotherapy. Patients with progressive advanced breast cancer previously untreated with anthracylines and progestins were given epirubicin (30 mg/m2) and ifosfamide (2 g/m2) on days 1 and 8 at 3-weekly intervals. Patients without disease progression after 6 cycles of chemotherapy were randomly assigned to receive, until progression, either no treatment or MPA at a daily total dose of 500 mg. Ninety patients were randomized: 46 to the MPA arm and 44 to the observation arm. Median time to progression was longer in the MPA arm: 4.9 months versus 3.7 months in the intent-to-treat analysis (p = 0.02), and 4.9 months versus 3.0 months in the secondary efficacy analysis (p = 0.012). Seven patients were removed from MPA due to side effects. The changes in patient-rated quality of life scores were similar in both groups. The median length of survival from randomization was 17.4 months for patients receiving MPA and 18.3 months for patients randomized to observation (p = 0.39). In conclusion, in patients with advanced breast cancer achieving remission or non-progression with 6 cycles of epirubicin and ifosfamide chemotherapy, MPA maintenance treatment led to a significant, though modest, prolongation of the time to progression without affecting overall survival of the study patients.

Paclitaxel and UFT plus oral calcium folinate in pretreated metastatic breast cancer.

This phase I study was designed to determine the maximum tolerated dose (MTD) and dose-limiting side effects of combination treatment with paclitaxel (Taxol) and UFT (uracil and tegafur in a 4:1 molar ratio) plus oral calcium folinate (Orzel) for advanced metastatic breast cancer. After premedication, patients received paclitaxel as a 3-hour IV infusion (175 mg/m2) on day 1; UFT was administered orally at 300 mg/day (dose level 1), 400 mg/day (dose level 2), 500 mg/day (dose level 3), or 600 mg/day (dose level 4) in combination with 90 mg/day of calcium folinate in three divided doses for 14 days. Twenty patients with pretreated metastatic breast cancer have entered the trial so far. The main toxicity was neutropenia, occurring in 68% of patients. World Health Organization grades 1 and 2 peripheral neuropathy, arthralgia, and myalgia were common but not dose-limiting. All patients had grade 3 alopecia due to paclitaxel. One of six patients treated at dose level 4 experienced a dose-limiting toxicity with neutropenic fever. But within four dose levels MTD was not reached, and the study will continue to accrue patients to dose level 5. Objective responses were observed at all dose levels. In conclusion, the combination of paclitaxel and UFT plus oral calcium folinate seems to be a convenient and effective regimen for patients with pretreated metastatic breast cancer. Phase I is ongoing in order to determine MTD and the recommended dose for phase II testing.

Phase I study of a weekly 1 h infusion of paclitaxel in patients with unresectable hepatocellular carcinoma.

The majority of patients with hepatocellular carcinoma will develop either unresectable or metastatic disease and, therefore, are candidates for systemic chemotherapy. Only a few chemotherapeutic agents have shown documented activity in the treatment of advanced hepatocellular carcinoma and there is clearly a need for the evaluation of new active drugs. Therefore, we performed a phase I trial with a weekly schedule of paclitaxel in patients with advanced hepatocellular carcinoma. 16 patients with documented progression of unresectable hepatocellular carcinoma were included. After premedication, paclitaxel was given as a 1 h infusion on days 1, 8, 15, 22, 29 and 36 representing one treatment cycle. The cycle was repeated every 50 days. The starting dose was 70 mg/m2 and the doses were escalated in steps of 10 mg/m2/week. A minimum of 3 patients were treated at each dose level. All treatment was given on an out-patient basis. Dose-limiting toxicity was reached at a dose of 100 mg/m2/week with 2 of 6 patients treated at that dose level having WHO grade 4 neutropenia. Other toxic side-effects were only mild. 1 partial response and 9 cases with disease stabilisation were observed in 16 patients with initially progressive disease. We, therefore, conclude that the recommended dose for a further phase II trial in patients with hepatocellular carcinoma is 90 mg/m2/week. These data indicate that paclitaxel given at this dose and schedule might have activity in hepatocellular carcinoma and further investigation in phase II trials is warranted.

Phase II study with cisplatin and paclitaxel in combination with weekly high-dose 24 h infusional 5-fluorouracil/leucovorin for first-line treatment of metastatic breast cancer.

Results from our previous phase II study demonstrating high efficacy and low toxicity for a weekly schedule of 5-fluorouracil (5-FU)/leucovorin in intensively pretreated patients with metastatic breast cancer prompted addition of paclitaxel and cisplatin to this regimen for a phase II study of outpatient first-line treatment of metastatic breast cancer. (MBC). Twenty-eight patients with metastatic breast cancer have been evaluated. Pretreatment comprised adjuvant CTX in 24 out of 28 patients, but no prior CTX for MBC. Patients were treated with 5-FU 2 g/m2 (24 h infusion) plus leucovorin 500 mg/m2 (2 h infusion prior to 5-FU) weekly for 6 weeks (days 1, 8, 15, 22, 29 and 36); in addition, paclitaxel 175 mg/m2 (3 h infusion) was administered on days 0 and 21, and cisplatin 50 mg/m2 (1 h infusion) on days 1 and 22 prior to 5-FU/leucovorin, repeated every 50 days. All patients were treated as outpatients using Port-a-Cath systems and portable pumps. Aside from common total alopecia, neutropenia was common but only of short duration. No episodes of febrile neutropenia occurred. Non-hematologic toxicities (NCl CTC grade, percent of patients) consisted of mild to moderate diarrhea (2+3, 47%), mucositis (2, 14%), and nausea and vomiting (2+3, 60%). Out of 28 patients with bidimensionally measurable disease 25% (seven out of 28) achieved a CR, 57% (16 out of 28) achieved a PR, 11% (three out of 28) had a SD and 7% (two out of 28) had a PD. Overall RR was 82% (95% confidence interval 66-100%). Median remission duration was 8 months, median time to progression 9 months and median survival time 28 months with a median follow-up of 21 months. We conclude that the combination of paclitaxel, cisplatin and 5-FU/leucovorin is an effective non-anthracycline-containing regimen for the first-line treatment of MBC.

Paclitaxel plus ifosfamide in advanced ovarian cancer: results of a phase I study.

Patients with advanced ovarian carcinoma and an inadequate response to first-line platinum-based combination chemotherapy (CTX) have a very poor prognosis and effective salvage regimens are clearly needed. This phase I study was performed in order to determine the maximum tolerable dose (MTD) and dose-limiting toxicity (DLT) of the combination paclitaxel (P) and ifosfamide (IFO). After premedication, patients received P as a 3 h i.v. infusion on day 1; IFO was given as 1 h i.v. infusion with the standard dose of mesna i.v. on days 2-5, q day 22. The following dose levels (dl) were investigated: (mg/m2/day) dl1, P 135/IFO 1500; dl2, P 135/IFO 2000; dl3, P 175/IFO 2000; and dl4, P 175/ IFO 1500. Eighteen patients with advanced ovarian cancer entered this trial. In eight patients treated with an IFO dose of 2000 mg/m2 during dl2 and 3, two required treatment interruptions because of CNS toxicity CTC grade 3 and one patient experienced nephrotoxicity CTC grade 3, Therefore the MTD of IFO used in combination with P and given over 4 days is reached with 2000 mg/m2/day. In the fourth dl we escalated the P dose up to 175 mg/m2, reduced the IFO dose to 1500 mg/m2 and treated an additional five patients. No DLT occurred at that dl. Objective responses were observed at all dls. The combination of P and IFO is feasible and active in pretreated advanced ovarian carcinoma. dl4 is the recommended dose for phase II trials.

Paclitaxel in combination with weekly 24-hour infusional 5-fluorouracil plus leucovorin in the second-line treatment of metastatic breast cancer: results of a phase II study.

PURPOSE: To evaluate the antitumor activity in terms of response rate (RR), time to progression (TTP) and survival of paclitaxel in combination with weekly 24-hour infusional 5-fluorouracil (5-FU)/leucovorin in pretreated metastatic breast cancer (MBC). PATIENTS AND METHODS: Fifty-four patients with bidimensionally measureable disease were included during phase II. Thirty-two had anthracycline resistant disease. Treatment consisted of 5-FU (24-hour i.v. infusion) 2.0 g/m2, leucovorin (two-hour i.v. infusion prior to 5-FU) 500 mg/m2, weekly for six weeks (day 1, 8, 15, 22, 29, 36) and paclitaxel (three-hour i.v. infusion) 175 mg/m2 was administered additionally on days 1 and 22, q 50 days. RESULTS: We observed complete remissions in 4% of patients (2 of 54), partial remissions in 55% (30 of 54), stable disease in 37% (20 of 54) and progressive disease in 4% (2 of 54). The overall RR was 59% (95% CI 48%-72%). The RR in 32 patients with anthracycline resistant disease was 59% (19 of 32). The median duration of response was 12 months (3-22), median TTP eight months (2-22) and median survival time 15 months (2-28). Neutropenia was common, but of CTC grade 2 or 3 in most patients. Nonhematologic toxicities mostly consisted of CTC grade 1 and 2 myalgia, diarrhea, mucositis, nausea and vomiting. CONCLUSIONS: Paclitaxel combined with weekly 24-hour infusional 5-FU/leucovorin is well tolerated in the second line treatment of MBC. High efficacy was documented even in the treatment of anthracycline resistant disease, which warrants further evaluations.

Fluorouracil-based combinations in the treatment of metastatic breast cancer.

Although combination chemotherapy regimens may prolong survival for selected patients with metastatic breast cancer, few, if any, are cured. The standard regimens used in treatment, e.g., CMF (cyclophosphamide, methotrexate, and fluorouracil [5-FU]), FAC (5-FU, Adriamycin, and cyclophosphamide), and FEC (5-FU, epirubicin, and cyclophosphamide), were developed over a decade ago. Current efforts to improve therapeutic efficacy have concentrated on decreasing drug toxicity and increasing drug doses (e.g., high-dose chemotherapy with peripheral stem-cell support). An important alternative approach to increasing therapeutic efficacy focuses on altering the administration schedules of well-known chemotherapeutic agents and introducing active new agents. One of the most frequently used cytotoxic drugs, fluorouracil (5-FU), has documented activity in a variety of malignancies, most notably, breast cancer and gastrointestinal tract cancers. However, despite broad clinical experience with 5-FU, our knowledge about the mechanisms of resistance to the various administration schedules used is limited. In vitro data and clinical experience show that resistance to one schedule of 5-FU can be overcome by using alternative schedules, in particular, a protracted infusion. This article discusses our clinical experience with weekly high-dose 24-hour infusions of 5-FU in combination with folinic acid (leucovorin) alone and together with paclitaxel (Taxol) for the treatment of advanced breast cancer.

Infusional 5-fluorouracil/leucovorin plus paclitaxel and cisplatin in the first-line treatment of metastatic breast cancer: results of a phase II study.

Our phase II study results demonstrating high efficacy and low toxicity for a weekly schedule of high-dose, 24-hour infusional 5-fluorouracil (5-FU)/leucovorin (LV) in intensively pretreated patients with metastatic breast cancer prompted the addition of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) to the regimen for a phase I/II study of outpatient second-line treatment of metastatic breast cancer. That study further prompted the addition of cisplatin to the regimen for first-line treatment. Twenty-eight patients with metastatic breast cancer have been evaluated. Pretreatment comprised adjuvant chemotherapy in 24 of 28 patients, but no prior chemotherapy for metastatic disease. Patients were treated with high-dose 5-FU 2 g/m2 (24-hour infusion) plus LV 500 mg/m2 (2-hour infusion before 5-FU) weekly for 6 weeks (days 1, 8, 15, 22, 29, and 36); in addition, paclitaxel 175 mg/m2 (3-hour infusion) was administered on days 0 and 21 and cisplatin 50 mg/m2 (1-hour infusion) on days 1 and 22 before high-dose 5-FU/LV, repeated every 50 days. Patients were treated as outpatients using Port-a-Cath systems (SIMS Deltec Inc, St Paul, MN) and portable pumps. Neutropenia was common but mild to moderate and of short duration in most patients. No hospitalizations were required because of febrile neutropenia, and no granulocyte colony-stimulating factor support was used. Aside from common total alopecia, nonhematologic toxicities consisted mainly of moderate myalgia, diarrhea, mucositis, and nausea and vomiting. Hand-foot syndrome and peripheral neuropathy were cumulative and occurred most commonly during the third treatment cycle with mild to moderate expression. In 28 patients with bidimensionally measurable disease, 25% (seven of 28) attained a complete response, 57% (16 of 28) achieved a partial response, 11% (three of 28) had stable disease, and 7% (two of 28) had disease progression. Overall response was 82% (95% confidence interval, 66% to 100%). We conclude that the combination of paclitaxel/cisplatin with weekly high-dose infusional 5-FU/LV appears to be effective in the first-line treatment of metastatic breast cancer. Preliminary results must be confirmed by the final analysis of response duration, time to progression, and survival.

Infusional 5-FU, folinic acid, paclitaxel, and cisplatin for metastatic breast cancer.

Our phase II study results demonstrating high efficacy and low toxicity for a weekly schedule of high-dose, 24-hour infusional 5-fluorouracil(5-FU)/folinic acid (HD5-FU/FA) in intensively pretreated patients with metastatic breast cancer prompted addition of paclitaxel (Taxol) to the regimen, for a phase I/II study of outpatient second-line treatment of metastatic breast cancer. That study further prompted the addition of cisplatin (Platinol) to the regimen for first-line treatment. So far, 28 patients with metastatic breast cancer have been evaluated. Pretreatment comprised adjuvant chemotherapy in 24 of 28 patients, but no prior chemotherapy for metastatic disease. Patients were treated with HD5-FU 2 g/m2 (24-hour infusion) plus FA 500 mg/m2 (2-hour infusion prior to FU) weekly for 6 weeks (days 1, 8, 15, 22, 29, and 36); in addition, paclitaxel 175 mg/m2 (3-hour infusion) was administered on days 0 and 21 and cisplatin 50 mg/m2 (1-hour infusion) on days 1 and 22 prior to HD5-FU/FA, repeated every 50 days. Patients were treated as outpatients using Port-a-Cath systems and portable pumps. Neutropenia was common (67% World Health Organization grade 3) but mild to moderate in most patients and was of short duration. No hospitalizations were required because of febrile neutropenia, and no granulocyte colony-stimulating factor support was used. Aside from common total alopecia, nonhematologic toxicities consisted mainly of moderate myalgia, diarrhea, mucositis, and nausea and vomiting. Hand-foot syndrome and peripheral neuropathy were cumulative and occurred most commonly during the third treatment cycle, with mild-to-moderate expression. In 28 patients with bidimensionally measurable disease, 25% (7/28) attained a complete response, 57% (16/28) achieved partial response, 11% (3/28) had stable disease, and 7% (2/28) had disease progression. Overall response was 82% (95% confidence interval, 66% to 100%). Eight of 28 patients are still receiving treatment. It is concluded that the combination of paclitaxel/cisplatin with weekly HD5-FU/FA appears to be effective in the first-line treatment of metastatic breast cancer. Preliminary results must be confirmed by the final analysis of response duration, time to progression, and survival.

Extended phase II study of paclitaxel as a 3-h infusion in patients with ovarian cancer previously treated with plantinum.

An extended phase II study was performed to evaluate single-agent paclitaxel as salvage chemotherapy for ovarian cancer. The aim of this study was to evaluate the 3-h infusion schedule of paclitaxel in terms of toxicity and antitumour efficacy. Furthermore, we analysed the impact on response and survival of the extent of prior chemotherapy and status of resistance against platinum. This study was an open, non-randomised, multicentre trial. The dose of paclitaxel used was 175 mg/m2 in patients who had received one or two prior therapies, and 135 mg/m2 in patients who had received three prior therapies. Paclitaxel was given as a 3-h infusion. Courses were repeated every 3 weeks. 114 patients with platinum-pretreated epithelial ovarian cancer were recruited of whom 112 were found eligible and evaluable for toxicity. 104 patients with bidimensionally measurable disease who received more than one course of chemotherapy were evaluable for response, progression-free (PFS) and survival. Toxicity was generally manageable. Main toxicities were non-cumulative neutropenia with 22.3% of courses with WHO grade 3/4 and peripheral neuropathy which occurred in more than half of the courses and was of WHO grade 2 and 3 in 20.1 and 1.3% of the courses, respectively. Neuropathy was associated with the higher dose per course and with cumulative paclitaxel dose. Objective responses were reported in 20% (21/104) of the patients (95% CI 13-29%) with a median response duration of 36.7 weeks. Survival and PFS for the whole group were 45.9 and 15.1 weeks, respectively. Performance status, number of tumour lesions and extent of prior chemotherapy were found to be prognostic factors for survival. Extent of prior chemotherapy was the only prognostic factor for PFS. Platinum resistance did not predict response to treatment. Paclitaxel 175 mg/m2 given as a 3-h infusion is an appropriate treatment for patients with platinum-resistant ovarian cancer who have not previously received more than two chemotherapy regimens. Paclitaxel did not show results superior to historical data for platinum retreatment in patients with platinum-sensitive, recurrent ovarian cancer.

Phase II trial of continuous oral trofosfamide in patients with advanced colorectal cancer refractory to 5-fluorouracil.

Fourteen patients with 5-fluorouracil (5-FU) refractory, progressive colorectal cancer metastatic to liver and/or lung were treated with continuous oral trofosfamide, an alkylating agent structurally related to cyclophosphamide and ifosfamide. Trofosfamide was given daily at 200 mg/day. No objective partial or complete responses were seen in 14 evaluable patients. There were four patients with stable disease or minor responses; the median duration of stable disease during trofosfamide treatment was 14 weeks, with of range of 12-36 weeks. Mild to moderate side effects were reported in seven patients including grade 1-2 nausea in four patients, grade 1 leukopenia in two patients and grade 1 anemia in one patient. Trofosfamide in this dose and schedule shows minor activity in 5-FU refractory colorectal cancer. Because of very little side effects, dose escalations appear to be possible.

Metastatic breast cancer: treatment with fluorouracil-based combinations.

During the 1990s, one in nine women in the western world will be diagnosed with breast cancer, and more than 58,000 will die of the disease each year in Europe alone. Recent changes in the primary therapy of operable breast cancer have not altered patient prognosis. Adjuvant therapy delays systemic recurrence and improves survival for only a fairly selected fraction of these patients. Therapy for metastatic breast cancer has not improved significantly in recent years. While combination chemotherapy may prolong survival in selected patients, few if any achieve cure. Standard chemotherapy regimens used to treat metastatic breast cancer, such as CMF (cyclophosphamide/methotrexate/fluorouracil), FAC (5-FU/Adriamycin/cyclophosphamide), and FEC (5-FU/epirubicin/cyclophosphamide), were developed over a decade ago. Current efforts to improve therapeutic efficacy have concentrated on decreasing drug toxicity and increasing drug doses (e.g., high-dose chemotherapy with peripheral stem cell support). An important alternative to increasing therapeutic efficacy by such approaches is altering the administration schedules of well-known chemotherapeutic agents and introducing active new cytotoxic agents. One of the most frequently used cytotoxic drugs, 5-FU has documented activity in a variety of malignancies, most notably in breast cancer and gastrointestinal tract cancers. However, despite broad clinical experience, our knowledge of mechanisms of resistance in relation to various 5-FU schedules is limited. In vitro data and clinical experience show that resistance to one schedule of 5-FU can be overcome by using an alternative schedule, most often a protracted infusion.

Paclitaxel combined with weekly high-dose 5-fluorouracil/folinic acid and cisplatin in the treatment of advanced breast cancer.

Our phase II study results demonstrating high efficacy and low toxicity for a weekly schedule of high-dose 5-fluorouracil (5-FU)/folinic acid (FA) in intensively pretreated metastatic breast cancer patients prompted the addition of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) to this regimen in a phase I/ II outpatient study. Patients were treated with high-dose 5-FU (by 24-hour infusion) and FA (by 2-hour infusion prior to 5-FU) weekly for 6 weeks (day 1, 8, 15, 22, 29, and 36) repeated every 50 days; in addition, paclitaxel was administered by 3-hour infusion on days 1 and 22. The following dose levels were used in phase 1 of the study. In dose levels 1 through 4, FA was given at a fixed dose of 500 mg/m2, followed by escalating doses of high-dose 5-FU (24-hour infusions of 1.5 [dose level 1], 1.8 [dose level 2], and 2.0 g/m2 [dose levels 3 and 4]). The paclitaxel dose, given over 3 hours on days 1 and 22, was 135 mg/m2 for dose levels 1 through 3 and 175 mg/m2 at dose level 4. Dose level 4 was chosen for further evaluation in the phase II portion of the trial. Among the 46 patients who entered this part of the trial, the median age was 46 years (age range, 26 to 70 years), the World Health Organization performance status was 0 to 1, and the median number of metastatic sites was 2.5 (range, one to four). All patients had bidimensionally measurable disease. Nine patients previously had received adjuvant chemotherapy, 16 had received prior chemotherapy for metastasis, and 21 had been treated with both types of chemotherapy. Of 29 anthracycline-pretreated patients, 25 had anthracycline-resistant disease. Interim results in 35 evaluable patients show complete remission in one patient (3%), partial remissions in 18 (51%), stable disease in 14 (40%), and progressive disease in two (6%). The overall response rate was 54% (95% confidence interval, 36% to 76%). The median number of treatment cycles administered per patient was three (range, one to five), the median time to maximum response was 2 months (range, 1 to 5 months), and the median remission duration was 8+ months (range, 2 to 17 months). Median survival time has not yet been reached. The combination of paclitaxel with weekly high-dose 5-FU/FA was well tolerated in second-line treatment of metastatic breast cancer and results also indicate high efficacy against anthracycline-resistant disease. In an ongoing phase II study we are evaluating the addition of cisplatin to the regimen as first-line treatment of metastatic breast cancer.

Activity- and schedule-dependent interactions of paclitaxel, etoposide and hydroperoxy-ifosfamide in cisplatin-sensitive and -refractory human ovarian carcinoma cell lines.

Paclitaxel has demonstrated broad clinical activity in a variety of malignancies both alone and in combination with other chemotherapeutic agents. The in vitro cytotoxicity of a 2 h exposure to paclitaxel, hydroperoxy-ifosfamide and etoposide alone, in combination and in sequence, was evaluated against established cisplatin-sensitive and cisplatin-refractory human ovarian carcinoma cell lines using isobologram analysis. The combinations of either paclitaxel-hydroperoxy-ifosfamide or paclitaxel-etoposide were found to be additive or synergistic when the drugs were given simultaneously or when paclitaxel was given 24 h before hydroperoxy-ifosfamide or etoposide respectively. However, when etoposide or hydroperoxy-ifosfamide were given before paclitaxel, antagonistic interactions were observed. With regard to etoposide this antagonism was evident for up to 24 h. In agreement with our data with the schedule-dependent interactions of paclitaxel and cisplatin in human gastric and ovarian carcinoma cell lines, these data demonstrate that the interactions of paclitaxel, etoposide and hydroperoxy-ifosfamide are also highly schedule dependent and applications of etoposide or ifosfamide before paclitaxel may result in pronounced antagonism. These findings could have implications for the design of further clinical protocols.