Cardiac safety of trastuzumab in combination with epirubicin and cyclophosphamide in women with metastatic breast cancer: results of a phase I trial.

This prospective, parallel-group, dose-escalation study evaluated the cardiac safety of trastuzumab (Herceptin) plus epirubicin/cyclophosphamide (EC) in women with human epidermal growth factor receptor-2 (HER2)-positive metastatic breast cancer (MBC) and determined an epirubicin dose for further evaluation. HER2-positive patients received standard-dose trastuzumab plus epirubicin (60 or 90 mg/m(2))/cyclophosphamide (600 mg/m(2)) 3-weekly (EC60+H, n=26; EC90+H, n=25), for four to six cycles; 23 HER2-negative patients received EC alone (90/600 mg/m(2)) 3-weekly for six cycles (EC90). All patients underwent thorough cardiac evaluation. Two EC90+H-treated patients experienced symptomatic congestive heart failure 4.5 and 6 months after the end of chemotherapy. One EC60+H-treated patient experienced an asymptomatic decrease in left ventricular ejection fraction (LVEF) to <50% 6 months after the end of chemotherapy. No such events occurred in control patients. Asymptomatic LVEF decreases of >10% points were detected in 12 (48%), 14 (56%) and 5 (24%) patients treated with EC60+H, EC90+H, and EC90. Objective response rates with EC60+H and EC90+H were >60%, and 26% for EC90 alone. These results indicate that trastuzumab may be combined with EC with manageable cardiotoxicity and promising efficacy.

Anthracycline and trastuzumab in breast cancer treatment.

This study was designed to evaluate the cardiac safety of the combined treatment of HER2-positive metastatic breast cancer patients with trastuzumab (Herceptin) plus epirubicin and cyclophosphamide (EC) in comparison with EC alone in HER2-negative metastatic breast cancer patients. Patients included those with metastatic breast cancer without any prior anti-HER2 treatment, anthracycline therapy, or any other chemotherapy for metastatic disease. This was a nonrandomized, prospective, dose-escalating, multicenter, open-label, phase I study in Germany. A control group of 23 patients received EC 90/600 mg/m2 3-weekly for six cycles (EC90 alone). A total of 26 HER2-positive patients were treated with trastuzumab, or H (2 mg/kg weekly after an initial loading dose of 4 mg/kg), and EC 60/600 mg/m2 3-weekly for six cycles (EC60+H); another 25 HER2-positive patients received H and EC 90/600 mg/m2 3-weekly for six cycles. Asymptomatic reductions in left ventricular ejection fraction (LVEF) of more than 10% points were detected in 12 patients (48%) treated with EC60+H and in 14 patients (56%) treated with EC90+H vs 6 patients (26%) in the EC90 alone cohort. LVEF decreases to <50% occurred in one patient in the EC60+H cohort and in two patients in the EC90+H cohort during the H monotherapy. No cardiac event occurred in the cohort with EC90 alone. The overall response rates for EC60+H and EC90+H were >60%, vs 26% for EC90 alone. The interim results of this study approve the cardiac safety of the combination of H with EC, with low risk of cardiac toxicity. The combination regimen revealed promising efficacy.

[Management of Werlhof disease in pregnancy complicated by diabetes mellitus type I]. / Management eines M. Werlhof in der Schwangerschaft bei gleichzeitig bestehendem Diabetes mellitus Typ I.

We report on a 25-year old female in whom idiopathic thrombozytopenic purpura and diabetes type I existed at the same time in pregnancy. In this constellation we decided to treat her with intravenous immunoglobulins for five days and delivered her by caesarean after recovery of the maternal thrombozytes. While this proved to be an effective treatment for the mother with few adverse effects we saw severely low thrombozytopenia of the child requiring intensive postnatal care. A longterm treatment with immunoglobulins for about three weeks could be a possible treatment for the fetal as well as the maternal thrombozytopenia. Reports on this question do not yet exist.

Evaluation of neurotoxicity induced by paclitaxel second-line chemotherapy.

The most important cytotoxic drugs for the treatment of ovarian cancer, platinum compounds and paclitaxel, are known to induce neurotoxicity, which is dose limiting when higher paclitaxel doses are used or platinum-pretreated patients are treated. The absolute dose of paclitaxel per course has been demonstrated to be an important risk factor for the development of neurotoxicity. The role of cumulative dose, treatment duration and infusion schedule as additional risk factors are still in debate, and are therefore evaluated in this study. This study evaluates paclitaxel induced neurotoxicity in 38 patients, most of whom had already received platinum treatment, receiving either 135 or 175 mg/m2 as 3-h or 24-h infusion. Patients were compared with an age-matched control group. A detailed questionnaire and neurophysiological measurements including vibration perception threshold were used. Overall, the majority of patients (76%) developed some degree of neurotoxicity, but symptoms were usually mild or moderate with no grade 3/4 neurotoxicity observed. Age has been demonstrated to be an important risk factor for the development of neurotoxicity. Furthermore, the higher dose per course showed a significant impact on neurotoxicity, while the different infusion schedules were of minor importance. Vibration threshold perception, 2-point discrimination, a walking-the-line test, and reports of paresthesias were shown to be the most sensitive and useful parameters for neurotoxicity evaluation. Neurotoxicity is a common adverse event during paclitaxel chemotherapy in platinum-pretreated patients. A clinically useful test panel composed of a detailed history and the above three easily performed neurophysiological evaluations should be incorporated into future studies evaluating new drugs, treatment modifications, new combinations, and potential modulators of chemotherapy-induced neurotoxicity.

[Paclitaxel/carboplatin in first line treatment of advanced ovarian carcinoma]. / Paclitaxel/Carboplatin in der First-line-Behandlung fortgeschrittener Ovarialkarzinome.

Surgery and chemotherapy are the cornerstones of therapy for advanced ovarian cancer. Further improvement of treatment results can be expected from new drugs that act differently from cisplatin. Paclitaxel is one of those drugs. Evidence from several clinical trials has currently established two roles of paclitaxel: salvage therapy for patients who are clinically platinum resistant and front line therapy in combination with cisplatin in newly diagnosed patients with advanced disease. The efficacy of the paclitaxel dose and schedule used in the GOG trial 111 has not been proven and thus needs further evaluation before it should be used in common practice. Continued clinical research in Germany focuses on several questions including 1) the determination of the relative merits of carboplatin and cisplatin in combination with paclitaxel, and 2) the potential role of paclitaxel/platinum combinations in limited disease patients. Answering these questions may help to develop new meaningful approaches in the treatment of ovarian cancer.

Clinical phase I study with one-hour paclitaxel infusion.

BACKGROUND: Paclitaxel (PAC) is one of the major anti-cancer drugs, effective in different tumors. Studies with 24-hour infusion with 135 mg/m2 and a three-hour infusion with 175 mg/m2 showed a significant schedule-dependent toxicity. We evaluated a one-hour infusion schedule within a phase I study to determine the dose limiting toxicity (DLT), the maximum tolerated dose (MTD), and the anti-cancer efficacy. PATIENTS AND METHODS: Patients with advanced malignant tumors were treated within cohorts by one-hour infusional paclitaxel starting with 150 mg/m2 and stepwise escalation with 25 mg/m2 increments. Therapy was repeated in three-week intervals. Cycles were repeated until progression. Toxicity was closely monitored, anti-cancer efficacy was only evaluated in those patients who received at minimum two treatment cycles. RESULTS: Thirty-four patients entered the study (11 NSCLC, five SCLC, seven ovarian cancer, one cervix cancer, nine MBC, one HN cancer). The MTD was PAC 250 mg/m2. The DLT was central and peripheral neuropathy (WHO grade 3). Other significant toxicities were fatigue, myalgia/arthralgia and paraesthesia. No significant myelotoxicity was observed. Totally twentyone patients were evaluable for response. A partial response was observed in five (24%) patients (two NSCLC, two ovarian cancer, one head and neck cancer). Three (14%) patients had stable disease and in 13 (62%) patients progressive disease was observed. CONCLUSIONS: Paclitaxel 225 mg/m2 on day 1 administered as one-hour infusion and repeated every three weeks can be given safely, featured no relevant myelotoxicity, and is the recommended dose for phase II studies.

Randomized study comparing carboplatin/cyclophosphamide and cisplatin/cyclophosphamide as first-line treatment in patients with stage III/IV epithelial ovarian cancer and small volume disease. German Ovarian Cancer Study Group (GOCA).

UNLABELLED: Several randomized studies in patients with advanced ovarian cancer have dealt with the comparison of cisplatin and carboplatin when given as either a single drug or in combination. The German Ovarian Cancer Study Group (GOCA) performed a prospective randomized trial in a subgroup of patients specified by a successful cytoreductive operation before the start of chemotherapy. From February 1987 to May 1990, 173 previously untreated patients with stage III and IV disease and limited tumor bulk of <2 cm postoperatively received either cyclophosphamide 600 mg/m2 plus carboplatin 350 mg/m2 or cyclophosphamide 1000 mg/m2 plus cisplatin 80 mg/m2. The drugs had to be administered on Day 1 every 28 days for six subsequent courses. RESULTS: In 158 assessable patients no significant differences in pathologically confirmed CR rates (pCR: 14% vs 16%), median time to progression (PFI: 19 months vs 26 months), and overall survival (OS: 35 months vs 37 months) were observed. Refusal of therapy due to toxicity was more frequent in the cisplatin arm, whereas patients with progressive disease predominated in the carboplatin arm. Nonhematologic adverse effects were more likely to occur with cisplatin whereas carboplatin patients experienced more myelosuppression. As prognostic factors associated with an increased risk of progressive disease and shorter overall survival time, stage of disease and amount of residual tumor after first surgery were determined. CONCLUSIONS: Carboplatin proved to be effective in patients with optimally debulked ovarian cancer. However, neither regimen used in this trial is sufficiently active to prevent tumor progression in the majority of patients.

Phase I/II study of the combination of carboplatin and paclitaxel as first-line chemotherapy in patients with advanced epithelial ovarian cancer.

PURPOSE: We performed a phase I/II study evaluating the combination of paclitaxel and carboplatin as first-line chemotherapy in patients with advanced ovarian cancer. The aim of this study was to define a feasible and safe combination regimen that could be recommended for future phase III studies. DESIGN: This study was a parallel two-arm, non-randomized, open trial. In a first step, carboplatin was administered at a fixed dose of AUC 5 and paclitaxel was escalated in 25 mg/ m2 steps starting at 135 mg/m2. Paclitaxel was given as a three-hour infusion. Carboplatin was administered on day 1 following paclitaxel in one study arm and 24 hours after paclitaxel infusion on day 2 in the other study arm. Carboplatin was escalated to AUC 6 and AUC 7.5 after the MTD for paclitaxel had been defined. Treatment was repeated every three weeks. PATIENTS: Sixty-one patients with untreated histologically confirmed epithelial ovarian cancer were recruited of whom 59 were found eligible and evaluable for toxicity. Thirty-three patients with bidimensionally measurable disease were evaluable for tumor response. RESULTS: We could not detect any advantage of the two-day schedule compared with the more convenient one-day schedule. Dose limiting toxicities were neutropenia, thrombocytopenia, and neurotoxicity. Except for two patients, toxicity was acceptable and clinically managable. One patient died of neutropenic sepsis and one further patient developed grade III peripheral neurotoxicity that did not resolve within two months after chemotherapy had been terminated. Overall objective response rate was 70%. The MTD for paclitaxel was 185 mg/m2 and AUC 6 for carboplatin, respectively. Secondary prophylaxis with G-CSF did not allow further dose escalation and therefore is not generally recommended. CONCLUSIONS: Paclitaxel 185 mg/m2 given as three-hour infusion followed by carboplatin AUC 6 is a feasible and safe regimen and can be recommended for phase III trials. Observed response rates justify further evaluation of this combination. A randomized phase III trial comparing a three-hour infusion of paclitaxel 185 mg/m2 combined with either carboplatin AUC 6 or cisplatin 75 mg/m2 as first-line chemotherapy of advanced ovarian cancer has recently been initiated by our group.

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.

Paclitaxel combined with carboplatin in the first-line treatment of advanced ovarian cancer: a phase I trial.

Recently, a randomized study conducted by the Gynecologic Oncology Group (GOG 111) demonstrated that, given by a 24-hour infusion, the combination of cisplatin and paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) is superior to combination cisplatin/cyclophosphamide in previously untreated patients with advanced ovarian cancer. This combination, however, necessitates hospitalization. Combination paclitaxel/carboplatin would be expected to induce fewer nonhematologic side effects but may be more myelotoxic. Thus, we started a phase I dose-escalation study to determine the maximal tolerated dose of paclitaxel given as a 3-hour infusion in combination with carboplatin, both drugs administered every 21 days. The paclitaxel dose was escalated by increments of 25 mg/m2, starting at 135 mg/m2 (level 1), 160 mg/m2 (level 2), 185 mg/m2 (level 3), and 210 mg/m2 (level 4). Carboplatin was administered to achieve an area under the concentration-time curve of 5, using the Calvert formula For study levels 5 and 6, the carboplatin dose was targeted at area under the concentration-time curves of 6 and 7.5, respectively, and was combined with a fixed paclitaxel dose of 185 mg/m2. Thirty previously untreated patients with stage IIC to IV ovarian cancer were enrolled. Nonhematologic toxicity, including nausea/vomiting and arthralgia/myalgia, was mild. Across all dose levels, a total of 16 patients developed peripheral neurotoxicity (World Health Organization grades 1 and 2). At dose level 5, one patient experienced reversible grade 4 neurotoxicity. Neutropenia was the principal dose-limiting hematologic toxicity. During 33 (31%) of 106 courses, World Health Organization grade 4 neutropenia was observed. Granulocyte colony-stimulating factor was required in only 7.6% of courses. Thrombocytopenia was less than that expected when carboplatin is given alone. Clinical responses were observed in eight of 14 patients, for an overall response rate of 57%. The combination of carboplatin plus paclitaxel was found to be an active regimen. This trial demonstrates that carboplatin dosed by the Calvert equation and 3-hour paclitaxel can be combined safely at full therapeutic doses for six or more courses in patients with advanced epithelial ovarian cancer.

Preliminary results of a phase II study of epirubicin and paclitaxel as first-line treatment in patients with metastatic breast cancer.

Preliminary results of this ongoing phase II study of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) plus epirubicin administered as first-line treatment to women with metastatic breast cancer indicate encouraging response rates and no severe toxicity. Among the 57 patients admitted to this study, 52% had received prior adjuvant chemotherapy (85% with cyclophosphamide/methotrexate/5-fluorouracil), 46% had received radiotherapy, and 30% had received both forms of therapy; 63% of patients were postmenopausal, mainly with poorly differentiated tumors, and 80% presented with > or = 2 metastatic sites. Epirubicin 60 mg/m2 was administered intravenously as a 1-hour infusion followed by paclitaxel 175 mg/m2 infused over 3 hours. Standard premedication was given. Granulocyte colony-stimulating factor support was not used. Neutropenia was evident in 72% of cycles but was not severe. Instances of anemia and thrombocytopenia were rare. Alopecia was universal. All nonhematologic toxicity observed was mild or moderate (peripheral neuropathy, myalgia, nausea, vomiting World Health Organization toxicity grade < 2). At this time, 41 patients are currently evaluable for response, complete and partial remission are evident in seven and 21 patients, respectively. The overall response rate so far is 68%. An additional 12 patients show evidence of stable disease, and one has shown disease progression. Paclitaxel is considered a promising new drug in the adjuvant treatment of patients with metastatic breast cancer. Combining it with epirubicin allows safe administration with no evidence of severe cardiotoxicity. The incidence of adverse cardiac events was much lower than that observed with combinations of paclitaxel and doxorubicin.

[Recurrent and 2nd line therapy in ovarian carcinoma: an overview of conventional systemic therapy modalities]. / Rezidiv- und 2nd-line-Therapie beim Ovarialkarzinom: eine Ubersicht der konventionellen systemischen Therapiemodalitäten.

Remarkable improvements in primary surgery and chemotherapy for advanced ovarian cancer have been achieved in the last decades. Nevertheless, the majority of patients still develop recurrent disease and ultimately die from ovarian cancer. Evaluation of efficient second-line treatment is of clinical relevance. This review re-analyses the published data of conventional systemic treatment for recurrent and refractory ovarian cancer. Patients were grouped according to prior chemotherapy (with or without platinum; with or without paclitaxel) and according to clinical platinum resistance. Platinum resistance is defined as having progressed during platinum based chemotherapy or having relapsed within 6 months after completion of primary platinum containing treatment. The most favourable results in platinum sensitive ovarian cancer were reported for platinum containing re-induction chemotherapy. Results in platinum refractory ovarian cancer were different. Both hormonal treatment consisting of either tamoxifen or GnRH analogues, and chemotherapy with topoisomerase blocking agents, taxanes, or alkylating agents did show similar results. Unfortunately, there are only limited data from prospectively randomised trials in these patients. Therefore, recommendations remain inconclusive. Retrospective comparisons may help the clinician to chose the currently best available treatment for an individual patient, however, these treatments have to be evaluated in prospectively randomised trials. The protocols of the ongoing studies in refractory or recurrent ovarian cancer of the AGO Ovarian Cancer Study Group are outlined.

Phase I study of paclitaxel administered as a 1-hour infusion: toxicity and pharmacokinetics.

Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) is one of the most important new drugs used in the treatment of solid tumors. Use of paclitaxel, however, is associated with some toxicity. The main adverse side effects include myelotoxicity, neurotoxicity, hypersensitivity reactions, and asthenia. Toxicity seems to be schedule dependent. Currently, paclitaxel is routinely administered via 3- or 24-hour infusions. This study was performed to evaluate the toxicity and pharmacokinetics of a 1-hour infusion. Thirty-four patients with incurable solid tumors were included. Dose levels were escalated from 150 to 250 mg/m2. Thirty-four patients received a total of 105 courses of paclitaxel. The dose-limiting toxicity was World Health Organization grade 3 neuropathy at a dose of 250 mg/m2 in two of three patients. Two patients were not evaluable for dose-limiting toxicity because treatment was stopped after fewer than three courses due to disease progression. Neither had experienced a dose-limiting toxicity. Other toxicities were World Health Organization grade 1/2 neutropenia, asthenia, myalgia, arthralgia, and grade 1 hypersensitivity. Twenty-one patients were evaluable for preliminary anticancer efficacy. A partial response was observed in five patients (24%), stable disease in three (14%), and progressive disease in 13 (62%). The maximum tolerated dose was established at 250 mg/m2. A dose of 225 mg/m2 is recommended for further phase II trials. There was considerable interindividual and some intraindividual variability in pharmacokinetic parameters. Paclitaxel pharmacokinetics were linear up to 225 mg/m2, while a slightly overproportional increase in the peak plasma concentration and the area under the concentration-time curve was observed at 250 mg/m2, suggesting that paclitaxel's pharmacokinetic characteristics may be nonlinear at higher doses.

[Sequential course and prospective management of ifosfamide-induced multi-organ toxicity]. / Sequentieller Verlauf und prospektives Management bei Ifosfamid-induzierter Multiorgan-Toxizität.

We report on an 66-year old female in whom we diagnosed uterine carcinosarcoma and concurrent breast cancer. As first-line treatment the patient received ifosfamide 4.8 mg/m2 body surface. During her second course of chemotherapy she developed sequentially life-threatening toxicities; severe emesis followed by nephrotoxicity, neurotoxicity and myelosuppression. Early prophylactic administration of rhG-CSF (Filgrastim) helped to overcome severe, potentially fatal myelosuppression. The course of severe toxicities following high doses of ifosfamide might reflect a dependent sequence, where one organ failure causes a subsequent organ failure. Prophylactic treatment of anticipated toxicity should be considered for the management of severe ifosfamide-induced toxicity. Such treatment may consist of sufficient antiemesis, sufficient hydration, as well as a therapy with methylene blue in case of severe neurotoxicity.

Pathophysiology, severity, pattern, and risk factors for carboplatin-induced emesis.

Carboplatin has proven efficacy in the treatment of ovarian cancer and has been proven to be less toxic compared to the parent compound cisplatin. Nevertheless, emesis is still a major problem associated with carboplatin-containing chemotherapy. Several investigators have focussed on the understanding of the pathophysiology and pattern of cisplatin-induced emesis. Data describing both the pathomechanisms and pattern of carboplatin-induced emesis are still lacking. This paper combines data from the literature with our own experience with the pattern and control of carboplatin-induced emesis, and presents data contributing to the understanding of the underlying pathomechanisms. Carboplatin induces a significant increase in urinary 5-HIAA excretion, the main metabolite of serotonin. 5-HIAA excretion levels remain elevated over 3 days following chemotherapy. Carboplatin-induced emesis is observed in about 40% of patients despite anti-emetic prophylaxis with 5-HT3 antagonists. Vomiting after carboplatin extends over days 1-3 with an equal distribution regarding the severity on each day. Analysis of the pattern of emesis revealed that delayed emesis (> 24 h after chemotherapy) is a major problem associated with carboplatin therapy. Description of the pattern of emesis as 'prolonged emesis' seems to be appropriate. 5-HT3 receptor antagonists such as ondansetron seem to be efficacious both in the control of acute and prolonged emesis following carboplatin chemotherapy, but randomly controlled data comparing ondansetron with other anti-emetic regimens have not yet been published. Univariate analysis reveals gender and combination therapy containing carboplatin and cyclophosphamide and/or anthracyclines as risk factors for emesis.

Positron emission tomography helps to diagnose tumor emboli and residual disease in choriocarcinoma.

BACKGROUND: Positron emission tomography (PET) has been shown capable of identifying malignant tissues. PATIENTS AND METHODS: WB-PET imaging in two women with metastatic choriocarcinoma is described. RESULTS: In a woman with tumor emboli secondary to a choriocarcinoma, WB-PET was the only noninvasive investigation to differentiate between tumor and blood clots. Moreover, PET helped to localize residual tumor tissue in another woman with persisting high beta-HCG serum levels after chemotherapy. CONCLUSIONS: WB-PET helps to localize tumor tissue in patients suffering from choriocarcinoma.

Interim Analysis of a Phase II study of epirubicin and paclitaxel as first-line therapy in patients with metastatic breast cancer.

Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), the first taxane to be used routinely in clinical practice, has aroused considerable interest for its high single-agent activity in breast cancer and its novel mechanism of action. The 4' epimer of doxorubicin, epirubicin is an agent with high activity against breast cancer but a lower rate of toxic side effects, especially cardiotoxic events, than its parent compound. Although the paclitaxel/doxorubicin combination has yielded response rates between 63% and 94% in phase I/II studies, some severe cardiotoxic events were reported. The rationale for our study was to evaluate the paclitaxel/epirubicin combination, focusing mainly on cardiotoxicity. In all, 57 patients with metastatic breast cancer entered the study, 28% of whom had primary metastatic breast cancer with large tumors at the primary site. Half of the patients had received adjuvant chemotherapy. Study medication consisted of 60 mg/m2 epirubicin given intravenously over 1 hour, followed by paclitaxel 175 mg/m2 administered as a 3-hour intravenous infusion after premedication with steroids, antihistamines, and H2 antagonists. The main toxicity was neutropenia (World Health Organization toxicity index grade 3/4, 72%). Other hematologic side effects were rare and no febrile neutropenia was reported. Peripheral neuropathy, arthralgia, and myalgia were mild (only World Health Organization grade 1 and 2). All patients had alopecia. The paclitaxel dose was escalated to 200 mg/m2 in eight patients, four of whom received a further escalation to 225 mg/m2. Severe neutropenia necessitated dose reductions in eight patients. No cardiac adverse events were reported. Of 41 patients evaluable for response, seven had complete remissions and 21 had partial remissions (68%). An additional 12 patients (29%) had stable disease. The combination of paclitaxel 175 mg/m2 and epirubicin 60 mg/m2 can be administered safely to patients with metastatic breast cancer. Although response was not the primary end point of this trial, the response data are nonetheless encouraging and suggest that further evaluation of the role of this combination in the first-line treatment of metastatic breast cancer is warranted.

Paclitaxel-induced "recall" soft tissue ulcerations occurring at the site of previous subcutaneous administration of paclitaxel in low doses.

The presented case reports a rare complication of paclitaxel misuse: recall soft tissue injury at the site of previous subcutaneous paclitaxel administration. Generally, paclitaxel extravasation causes only mild dermatologic toxicity and ulcerations are rare. We describe the third case of a so-called recall dermatitis following paclitaxel chemotherapy. In contrast to the previously reported cases, soft tissue damage arose at the abdominal wall at the injection sites of previously administered subcutaneous paclitaxel in homeopathic doses of 1.0 mg. The recall reaction continued to exacerbate after each course of systemic paclitaxel chemotherapy and finally led to surgical treatment. The course of the observed skin toxicity makes it probable that the pathomechanisms involved in these recall reactions are different from these responsible for the limited skin toxicity observed after paclitaxel extravasation.

Paclitaxel combined with carboplatin in the first-line treatment of advanced ovarian cancer.

In a phase I study to determine the maximum tolerated dose of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) given as a 3-hour infusion in combination with carboplatin administered every 21 days to women with advanced ovarian cancer, paclitaxel doses were escalated as follows: level 1, 135 mg/m2; level 2, 160 mg/m2; level 3, 185 mg/m2; and level 4,210 mg/m2. The fixed dose of carboplatin at levels 1 through 4 was given to achieve an area under the concentration-time curve (AUC) of 5 using the Calvert formula. In levels 5 and 6 the carboplatin dose was targeted at AUCs of 6 and 7.5, respectively, combined with a fixed paclitaxel dose of 185 mg/m2. To date, 30 previously untreated patients, all with a good performance status (Eastern Cooperative Oncology Group 0 to 2) have been entered into this ongoing study. The dose-limiting toxicity of the combination was myelosuppression (leukopenia, granulocytopenia, and thrombocytopenia). Neurotoxicity was largely moderate. So far, 14 patients are evaluable for response; of these, eight (57%) showed objective (complete or partial) response and disease stabilized in six patients. No patient had disease progression. We conclude that the combination of paclitaxel 185 mg/m2 administered as a 3-hour infusion followed immediately by a 1-hour infusion of carboplatin at an AUC of 6 can be administered safely in a 21-day schedule in the outpatient setting. The recommended dose for phase III studies is paclitaxel 185 mg/m2 and carboplatin AUC 6.

The role of serotonin as a mediator of emesis induced by different stimuli.

The aim of this work was to evaluate the impact of changes in serotonin metabolism on the pathophysiology of different types of emesis: pregnancy-induced emesis, emesis associated with inner-ear dysfunction, and cisplatin-induced emesis. The urinary excretion of 5-hydroxyindoleacetic acid (5-HIAA), the main metabolite of serotonin, was measured in 13 women with pregnancy-induced emesis, 12 patients who had nausea and vomiting following inner-ear dysfunctions, 27 patients with cisplatin-induced emesis and a control group of 21 women. 5-HIAA was measured with a fluorescence polarization immunoassay (Abbott) and corrected for varying urine concentrations. Both patients with emesis associated with inner-ear dysfunction and patients with pregnancy-associated emesis showed a similar 5-HIAA excretion pattern compared with the control group. No correlation between intensity of nausea or vomiting and changes in 5-HIAA excretion could be detected. In patients receiving cisplatin, the 5-HIAA excretion increased rapidly within the 12 h following cisplatin administration and returned to baseline levels after 24 h. There was a parallel increase of 5-HIAA excretion and numbers of emetic episodes in the first 12 h, but delayed emesis was not associated with elevated 5-HIAA excretion. Our results provide evidence that serotonin is involved in the pathophysiology of cisplatin-induced acute emesis. Cisplatin-induced delayed emesis, pregnancy-associated emesis, and emesis due to inner-ear dysfunction are not associated with elevated levels of 5-HIAA excretion. The serotonin pathway probably represents only one of many different afferent mechanisms capable of initiating the emesis cascade.