Thickness uniformity measurements and damage threshold tests of large-area GaAs/AlGaAs crystalline coatings for precision interferometry.

Precision interferometry is the leading method for extremely sensitive measurements in gravitational wave astronomy. Thermal noise of dielectric coatings poses a limitation to the sensitivity of these interferometers. To decrease coating thermal noise, new crystalline GaAs/AlGaAs multilayer mirrors have been developed. To date, the surface figure and thickness uniformity of these alternative low-loss coatings has not been investigated. Surface figure errors, for example, cause small angle scattering and thereby limit the sensitivity of an interferometer. Here we measure the surface figure of highly reflective, substrate-transferred, crystalline GaAs/AlGaAs coatings with a custom scanning reflectance system. We exploit the fact that the reflectivity varies with the thickness of the coating. To increase penetration into the coating, we used a 1550 nm laser on a highly reflective coating designed for a center wavelength of 1064 nm. The RMS thickness variation of a two inch optic was measured to be 0.41 ± 0.05 nm. This result is within 10% of the thickness uniformity, of 0.37 nm RMS, achieved with ion-beam sputtered coatings for the aLIGO detector. We additionally measured a lower limit of the laser induced damage threshold of 64 MW/cm 2 for GaAs/AlGaAs coatings at a wavelength of 1064 nm.

Ten-year results of intense dose-dense chemotherapy show superior survival compared with a conventional schedule in high-risk primary breast cancer: final results of AGO phase III iddEPC trial.

Background: Primary breast cancer (BC) patients with extensive axillary lymph-node involvement have a limited prognosis. The Arbeitsgemeinschaft fuer Gynaekologische Onkologie (AGO) trial compared intense dose-dense (idd) adjuvant chemotherapy with conventionally scheduled chemotherapy in high-risk BC patients. Here we report the final, 10-year follow-up analysis. Patients and methods: Enrolment took place between December 1998 and April 2003. A total of 1284 patients with 4 or more involved axillary lymph nodes were randomly assigned to receive 3 courses each of idd sequential epirubicin, paclitaxel and cyclophosphamide (iddEPC) q2w or standard epirubicin/cyclophosphamide followed by paclitaxel (EC â†’ P) q3w. Event-free survival (EFS) was the primary end point. Results: A total of 658 patients were assigned to receive iddEPC and 626 patients were assigned to receive EC â†’ P. The median duration of follow-up was 122 months. EFS was 47% (95% CI 43% to 52%) in the standard group and 56% (95% CI 52% to 60%) in the iddEPC group [hazard ratio (HR) 0.74, 95% CI 0.63-0.87; log-rank P = 0.00014, one-sided]. This benefit was independent of menopausal, hormone receptor or HER2 status. Ten-year overall survival (OS) was 59% (95% CI 55% to 63%) for patients in the standard group and 69% (95% CI 65% to 73%) for patients in the iddEPC group (HR = 0.72, 95% CI 0.60-0.87; log-rank P = 0.0007, two-sided). Nine versus two cases of secondary myeloid leukemia/myelodysplastic syndrome were observed in the iddEPC and the EC â†’ P arm, respectively. Conclusion: The previously reported OS benefit of iddEPC in comparison to conventionally dosed EC â†’ P has been further increased and achieved an absolute difference of 10% after 10 years of follow-up.

Matrix heater in the gravitational wave observatory GEO 600.

Large scale laser interferometric gravitational wave detectors (GWDs), such as GEO 600 require high quality optics to reach their design sensitivity. The inevitable surface imperfections, inhomogeneities, and light-absorption induced thermal lensing in the optics, can convert laser light from the fundamental mode to unwanted higher order modes, and pose challenges to the operation and sensitivity of the GWDs. Here we demonstrate the practical implementation of a thermal projection system which reduces those unwanted effects via targeted spatial heating of the optics. The thermal projector consists of 108 individually addressable heating elements which are imaged onto the beam splitter of GEO 600. We describe the optimization of the spatial heating profile and present the obtained results.

German Adjuvant Intergroup Node-positive Study (GAIN): a phase III trial comparing two dose-dense regimens (iddEPC versus ddEC-PwX) in high-risk early breast cancer patients.

BACKGROUND: Dose-dense (dd) regimens are one of the preferred options for the adjuvant treatment of breast cancer patients with intermediate to high risk. The German Adjuvant Intergroup Node-positive trial aimed at optimizing intense dd (idd) strategies by evaluating drug combinations and the addition of capecitabine. PATIENTS AND METHODS: Women (aged 18 years and biologically <65 years) with histologically involved axillary lymph nodes were randomly assigned to receive three courses each of epirubicin (E) 150 mg/m2, paclitaxel (P) 225 mg/m2 and cyclophosphamide (C) 2500 mg/m2 (reduced to 2000 mg/m2 after recruitment of 1200 patients) q2w intravenously (i.v.) (iddEPC-regimen) or ddEC (E 112.5 mg/m2 + C 600 mg/m2, i.v. q2w for 4 cycles) followed by paclitaxel weekly (Pw 67.5 mg/m2 i.v. q8d for 10 weeks) plus capecitabine (X 2000 mg/m2 p.o. days 1-14, q22 for 4 cycles) (ddEC-PwX-regimen). Further randomization assigned patients to ibandronate for 2 years versus observation and to pegfilgrastim day 2 versus 4. RESULTS: From June 2004 to August 2008, 2994 patients were randomized to either iddEPC (N = 1498), or ddEC-PwX (N = 1496) and started treatment. Median age was 50 years; pN1 (37.8%), pN2 (35.3%); pN3 (26.9%); 46.4% were G3 tumors; 76.9% hormone receptor-positive and 22% HER2-positive. After a median follow-up of 74 months, 645 events and 383 deaths were recorded. Hematological adverse events grades 3-4 were more common with iddEPC (P < 0.001), nonhematological with ddEC-PwX (P = 0.04), even if the toxicity profile of the two regimens was different. At 5 years, estimated disease-free survival rates for ddEC-PwX and iddEPC were 81.7% [95% confidence interval (CI) 79.5-83.6] versus 80.2% (95% CI 78.0-82.2). Hazard ratio (HR)=0.95 (95% CI 0.81-1.11, log-rank P = 0.49). Five-year overall survival rates were 89.4% for ddEC-PwX (95% CI 87.7-91.0) and 89.0% for iddEPC (95% CI 87.2-90.6), HR = 0.85 (95% CI 0.69-1.04, log-rank P = 0.10). CONCLUSION: Adding capecitabine to ddEC-Pw did not improve outcome in comparison to iddEPC but increased toxicity and should not be recommended for further use.

The Patient's Anastrozole Compliance to Therapy (PACT) Program: a randomized, in-practice study on the impact of a standardized information program on persistence and compliance to adjuvant endocrine therapy in postmenopausal women with early breast cancer.

BACKGROUND: Compliance and persistence are often overlooked in adjuvant breast cancer treatment. PATIENTS AND METHODS: PACT was a prospective, multicenter, randomized, open, parallel-group study assessing whether educational materials (EMs) enhanced compliance with aromatase inhibitor (AI) therapy in postmenopausal women with early, hormone-receptor-positive (HR+) breast cancer. The primary end points were compliance (proportion taking ≥ 80% anastrozole) at 12 months and persistence (proportion reporting anastrozole intake during the study period). RESULTS: Four thousand eight hundred and forty-four patients were randomly assigned 1:1 to receive standard therapy or standard therapy with EMs. There was no difference between arms in compliance (N = 2740; 88.5%/88.8%, respectively, P = 0.81) or persistence rates (N = 2740; 40.5%/43.0%, respectively, P = 0.18). Modified end point analyses found no differences in compliance between arms based on the classification of: (i) patients with missing documentation or follow-up visit <9 months as non-compliant (N = 4397, P = 0.15); (ii) patients with early (≤ 292 days) 12-month follow-up documentation excluded (N = 4091, P = 0.19); (iii) patients reaching ≥ 80% compliance during individual follow-up as compliant (N = 4397, P = 0.26). Modified persistence analyses found no difference between arms (N = 4397, P = 0.37). CONCLUSIONS: Addition of EMs to standard therapy did not significantly affect compliance and persistence with adjuvant anastrozole. CLINICALTRIALS ID: NCT00555867.

Influence of zoledronic acid on disseminated tumor cells in primary breast cancer patients.

BACKGROUND: The presence of disseminated tumor cells (DTCs) in bone marrow of patients with early breast cancer (EBC) has been correlated with increased risk of metastatic disease or locoregional relapse. Zoledronic acid (ZOL) treatment has reduced DTCs in the bone marrow of patients with EBC in several studies. This controlled study sought to confirm these observations. PATIENTS AND METHODS: Patients with EBC and DTC-positive bone marrow were randomized (N = 96) to treatment with ZOL plus adjuvant systemic therapy or adjuvant systemic therapy alone. The change in DTC numbers at 12 months versus baseline was measured. RESULTS: DTC-positive patients treated with ZOL were more likely to become DTC-negative after 12 months of treatment compared with the controls (67% versus 35%; P = 0.009). At 12 months, DTC counts decreased to a mean of 0.5 ± 0.8 DTCs in the ZOL group and to 0.9 ± 0.8 DTCs in the control group. In addition, ZOL was generally well tolerated. CONCLUSIONS: Treatment with ZOL improves elimination of DTCs. Further studies are needed to determine whether the reduction in DTCs by ZOL provides clinical benefit.

PREPARE trial: a randomized phase III trial comparing preoperative, dose-dense, dose-intensified chemotherapy with epirubicin, paclitaxel and CMF versus a standard-dosed epirubicin/cyclophosphamide followed by paclitaxel ± darbepoetin alfa in primary breast cancer--results at the time of surgery.

BACKGROUND: Preoperative chemotherapy is a recommended treatment of both primary operable and locally advanced breast cancer. Strategies to improve efficacy include the use of anthracyclines, taxanes, and intensified dose with bone marrow support. PATIENTS AND METHODS: Patients received neoadjuvant epirubicin 90 mg/m(2) plus cyclophosphamide 600 mg/m(2) followed by paclitaxel 175 mg/m(2) (EC→T), each 3-weekly for four cycles (n = 370), or epirubicin 150 mg/m(2) followed by paclitaxel 225 mg/m(2) with pegfilgrastim followed by CMF (cyclophosphamide 500 mg/m(2), methotrexate 40 mg/m(2), fluorouracil 600 mg/m(2)) on days 1 and 8 (E(dd)→T(dd)→CMF), each 2-weekly and for three cycles (n = 363). Patients were randomly allocated to either simultaneous darbepoetin alfa (DA) (n = 356) or none (n = 377). RESULTS: Pathological complete response (pCR) rate (breast) was higher with E(dd)→T(dd)→CMF, 18.7% versus 13.2% with EC→T; P = 0.043, ypT0/Tis; ypN0 was reported in 20.9% versus 14.3% respectively; P = 0.019. Patients with grade 3 tumors and negative hormone receptor status had a significantly higher pCR rate. Mean hemoglobin values maintained higher with DA (13.6 versus 12.6 g/dl). E(dd)→T(dd)→CMF regimen showed more grade 3-4 mucositis, sensory neuropathy, and neurological complaints. Thromboembolic events were more frequent on DA (3% versus 6%; P = 0.055). CONCLUSION: Dose-dense and -intensified neoadjuvant chemotherapy with E(dd)→T(dd)→CMF was potentially superior to EC→T in terms of pCR. Primary use of DA did not affect pCR.

PREPARE trial: a randomized phase III trial comparing preoperative, dose-dense, dose-intensified chemotherapy with epirubicin, paclitaxel, and CMF versus a standard-dosed epirubicin-cyclophosphamide followed by paclitaxel with or without darbepoetin alfa in primary breast cancer--outcome on prognosis.

BACKGROUND: The objective of this study was to compare the effect of dose-intensified neoadjuvant chemotherapy with that of standard epirubicin plus cyclophosphamide followed by paclitaxel in combination with or without darbepoetin on survival in primary breast cancer. PATIENTS AND METHODS: A total of 733 patients received either four cycles of neoadjuvant epirubicin 90 mg/m(2) plus cyclophosphamide 600 mg/m(2) every 3 weeks followed by four cycles of paclitaxel 175 mg/m(2) every 3 weeks (EC→T), or three cycles of epirubicin 150 mg/m(2) every 2 weeks followed by three cycles of paclitaxel 225 mg/m(2) every 2 weeks followed by three cycles of combination chemotherapy with cyclophosphamide, methotrexate, and fluorouracil (E(dd)→T(dd)→CMF). The patients were randomly assigned to receive darbepoetin or none. The primary objective was to demonstrate a superior disease-free survival (DFS) of E(dd)→T(dd)→CMF compared with EC→T. RESULTS: Estimated 3-year DFS was 75.8% with EC→T versus 78.8% with E(dd)→T(dd)→CMF [hazard ratio (HR) 1.14; P = 0.37] and overall survival (OS) 88.4% versus 91.5% (HR 1.26; P = 0.237). Three-year DFS was 74.3% with darbepoetin versus 80.0% without (HR 1.31; P = 0.061) and OS 88.0% versus 91.8% (HR 1.33; P = 0.139). Patients with a pathologically documented complete response [pathological complete response (pCR)] had a significantly better DFS compared with those without achieving a pCR (estimated 3-year DFS: 89.2% versus 74.9%; HR 2.27; P = 0.001). CONCLUSION: Neoadjuvant dose-intensified chemotherapy compared with standard chemotherapy did not improve DFS, whereas the addition of darbepoetin might have detrimental effects on DFS.

Intraperitoneal treatment with the trifunctional bispecific antibody Catumaxomab in patients with platinum-resistant epithelial ovarian cancer: a phase IIa study of the AGO Study Group.

OBJECTIVE: The aim of this study was to select the best catumaxomab regimen for further investigation in ovarian cancer based on confirmed tumour response. METHODS: Randomised open-label phase IIa study in women with platinum-resistant or -refractory epithelial ovarian cancer. Catumaxomab (6-hour intraperitoneal infusion on days 0, 3, 7 and 10) was administered at a low (10, 10, 10 and 10 µg) or high dose (10, 20, 50 and 100 µg). Responders were patients with either a complete (CR) or partial (PR) response. RESULTS: Forty-five patients were randomised to receive either low dose (23) or high dose (22). There were no responders in the low-dose versus one patient (5%) in the high-dose group with a PR. In the low-dose group, two patients (9%) had stable disease compared with five patients (23%) in the high-dose group. Catumaxomab was well tolerated and there was no difference between the dose groups in the incidence of treatment-induced adverse events, the most common of which were gastrointestinal and injection-site reactions. CONCLUSION: Catumaxomab had modest activity in platinum-resistant ovarian cancer. The high-dose regimen was associated with a slightly better therapeutic index than the low dose regimen.

Huddle test measurement of a near Johnson noise limited geophone.

In this paper, the sensor noise of two geophone configurations (L-22D and L-4C geophones from Sercel with custom built amplifiers) was measured by performing two huddle tests. It is shown that the accuracy of the results can be significantly improved by performing the huddle test in a seismically quiet environment and by using a large number of reference sensors to remove the seismic foreground signal from the data. Using these two techniques, the measured sensor noise of the two geophone configurations matched the calculated predictions remarkably well in the bandwidth of interest (0.01 Hz-100 Hz). Low noise operational amplifiers OPA188 were utilized to amplify the L-4C geophone to give a sensor that was characterized to be near Johnson noise limited in the bandwidth of interest with a noise value of 10-11 m/Hz at 1 Hz.

ABC3 Consensus Commented from the Perspective of the German Guidelines: Third International Consensus Conference for Advanced Breast Cancer (ABC3), Lisbon, 07. 11. 2015.

The Third International Consensus Conference for Advanced Breast Cancer ABC3 on the diagnosis and treatment of advanced breast cancer was held in Lisbon from 5 to 7 November 2015. This year the focus was the treatment of metastatic breast cancer (stage IV) - including the patient perspectives. Important topics were questions relating to quality of life, the care for long-term survivors as well as the management of disease-related symptoms and treatment-based side effects. The use of standardised tools to assess individual treatment success and the benefits of new substances were important points for discussion. The diagnosis and treatment of inoperable locally advanced breast cancer were discussed two years ago during the ABC2 consensus 1. A working group of German breast cancer experts commented on the results of the ABC panellists, paying particular attention to the German guidelines (AGO, S3, DGHO) on the diagnosis and treatment of breast cancer 2, 3, 4, 5 in Germany.

First-line chemotherapy with epirubicin, paclitaxel, and carboplatin for advanced ovarian cancer: a phase I/II study of the Arbeitsgemeinschaft Gynäkologische Onkologie Ovarian Cancer Study Group.

PURPOSE: Despite the progress that has been achieved over the years, survival rates in patients with advanced ovarian cancer are still disappointing. New methods to improve the efficiency of first-line chemotherapy are warranted. One method to improve results is to add more non-cross-resistant drugs to platinum-paclitaxel combination regimens. Anthracyclines are among the candidates for incorporation as the "third drug" into first-line regimens for advanced ovarian cancer. PATIENTS AND METHODS: We performed a phase I/II trial with escalating doses of epirubicin (60, 75, and 90 mg/m2) combined with fixed doses of paclitaxel and carboplatin in 27 previously untreated patients with advanced gynecologic malignancies. RESULTS: Dose-limiting toxicity occurred at dose level 2 (75 mg/m2 epirubicin) and consisted of myelosuppression (neutropenia, thrombocytopenia). No dose-limiting, nonhematologic toxicities were observed. The maximum tolerable dose was epirubicin 60 mg/m2 (E) combined with a 3-hour infusion of paclitaxel 175 mg/m2 (T) and carboplatin AUC 5 (Carbo). Preliminary analysis indicated promising activity against ovarian cancer. CONCLUSION: The three-drug combination ET-Carbo, given according to the outlined dose and schedule, should be considered for further phase III evaluation. A randomized German-French intergroup trial comparing ET-Carbo with carboplatin-paclitaxel has already been initiated.

Primary Therapy of Patients with Early Breast Cancer: Evidence, Controversies, Consensus: Opinions of German Specialists to the 14th St. Gallen International Breast Cancer Conference 2015 (Vienna 2015).

For the first time, this year's St. Gallen International Consensus Conference on the treatment of patients with primary breast cancer, which takes place every two years, was held not in St. Gallen (Switzerland) but - for logistical reasons - in Vienna (Austria) under its usual name. The 2015 St. Gallen International Consensus Conference was the 14th of its kind. As the international panel of the St. Gallen conference consists of experts from different countries, the consensus mirrors an international cross-section of opinions. From a German perspective, it was considered useful to translate the results of the votes of the St. Gallen conference into practical suggestions, particularly in light of the recently updated treatment guideline of the Gynecologic Oncology Group (AGO-Mamma 2015) in Germany. A German group consisting of 14 breast cancer experts, three of whom are members of the international St. Gallen panel, has therefore provided comments on the results of this year's votes at the 2015 St. Gallen Consensus Conference and their impact on clinical care in Germany. The 14th St. Gallen conference once again focused on surgery of the breast and the axilla, radio-oncologic and systemic treatment options for primary breast cancer depending on tumor biology, and the clinical use of multigene assays. The conference also considered targeted therapies for older and for younger patients, including the diagnosis/treatment of breast cancer during and after pregnancy and the preservation of fertility.

Cell genealogies in a plant meristem deduced with the aid of a 'bootstrap' L-system.

The primary root meristem of maize (Zea mays L.) contains longitudinal files of cells arranged in groups of familial descent (sisters, cousins, etc.). These groups, or packets, show ordered sequences of cell division which are transverse with respect to the apico-basal axis of the root. The sequences have been analysed in three zones of the meristem during the course of the first four cell generations following germination. In this period, the number of cells in the packets increases from one to 16. Theoretically, there are 48 possible division pathways that lead to the eight-cell stage, and nearly 2 x 10(6) that lead to the 16-cell stage. However, analysis shows that only a few of all the possible pathways are used in any particular zone of the root. This restriction of pathways results from inherited sequences of asymmetric cell divisions which lead to sister cells of unequal length. All possible division pathways can be generated by deterministic 'bootstrap' L-systems which assign different lifespans to sister cells of successive generations and hence specify their subsequent sequence of divisions. These systems simulate propagating patterns of cell divisions which agree with those actually found within the growing packets that comprise the root meristem. The patterns of division are specific to cells originating in various regions of the meristem of the germinating root. The importance of such systems is that they simulate patterns of cellular proliferation where there is ancestral dependency. They can therefore be applied in other growing and proliferating systems where this is suspected.

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.

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.

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

Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), the first taxane used in routine clinical practice, has aroused considerable interest for its high single-agent activity against breast cancer and for its novel mechanism of action. Epirubicin, the 4' epimer of doxorubicin, is another agent with a high activity against breast cancer and is known for its lower rate of toxic side effects, especially toxic cardiac events, compared with its mother compound. The combination of paclitaxel and doxorubicin yielded response rates between 63% and 93% in phase I/II studies. In these studies, however, the investigators reported severe cardiac toxic events. The rationale for the current study was therefore to evaluate the combination of paclitaxel/epirubicin, focusing mainly on cardiac toxicity. In two groups, 85 patients with metastatic breast cancer entered the study. Approximately 20% of the patients had primary metastatic breast cancer with large tumors at the primary site. Half of the patients had received adjuvant chemotherapy. Study medication in group A consisted of epirubicin 60 mg/m2 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-blockers. In group B, epirubicin 90 mg/m2 was combined with paclitaxel 175 mg/m2, given in the same manner as in group A. Dose escalation to 225 mg/m2 paclitaxel was planned in both groups. The main toxicity in both groups was neutropenia (73% World Health Organization grade 3/4 in group A and 93% in group B). Other hematologic side effects were rare. No febrile neutropenia was reported in group A, but two episodes occurred in group B. Peripheral neuropathy, arthralgia, and myalgia were mild (only World Health Organization grades 1 and 2). Alopecia was universal. In group A, the paclitaxel dose could be escalated to 200 mg/m2 in 15 patients and to 225 mg/m2 in seven patients. Dose reduction due to severe neutropenia was necessary in 11 patients. No cardiac events were reported in group A. In group B, the paclitaxel dose could be escalated to 200 mg/m2 in only one patient, and no patient reached 225 mg/m2. Three patients needed a dose reduction. In this group, one patient had a greater than 10% decrease in the left ventricular ejection fraction with no clinical signs. In group A, 43 patients were evaluable for response; in group B, 25 patients were evaluable. Thirteen patients were out of protocol with only bone metastasis, and two patients had more than one prior chemotherapy for metastatic disease. The response rate was identical in both groups, with five complete remissions and 24 partial remissions in group A and three complete responses and 14 partial remissions in group B. The duration of response was 8.2 months in both groups. The median cumulative epirubicin dose was 420 mg/m2 in group A and 630 mg/m2 in group B. The combination of paclitaxel 175 mg/m2 and epirubicin 60 or 90 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 this combination-line treatment of metastatic breast cancer is warranted.

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.

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.

Carboplatin plus paclitaxel as first-line chemotherapy in previously untreated advanced ovarian cancer. German AGO Study Group Ovarian Cancer. Arbeitsgemeinschaft Gynäkologische Onkologie.

Since publication of the results of the Gynecologic Oncology Group (GOG) III study, the combination of cisplatin and paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) has been adopted widely as the new standard for treating advanced ovarian cancer. Further attempts to optimize first-line chemotherapy with platinum and taxanes include substituting carboplatin for cisplatin, individualizing the carboplatin dose by calculating it according to the area under the concentration-time curve, and reducing the length of the paclitaxel infusion. Attempts to optimize platinum/paclitaxel combinations have led to the initiation of several small phase I/II trials evaluating the carboplatin/paclitaxel combination. The promising results of these studies have prompted the initiation of three phase III trials comparing carboplatin/paclitaxel with the standard combination of cisplatin/paclitaxel. An interim analysis after 1 year's accrual to the prospectively randomized German Arbeitsgemeinschaft Gynäkologische Onkologie (AGO) study is presented. Treatment consists of paclitaxel 185 mg/m2 infused over 3 hours on day 1 followed directly by either cisplatin 75 mg/m2 (arm B) or carboplatin dosed to an area under the curve of 6 (arm A). Treatment is repeated every 3 weeks for six courses. Eligibility criteria are epithelial ovarian cancer International Federation of Gynecology and Obstetrics stage IIB through IV, age of consent, written informed consent, Eastern Cooperative Oncology Group performance status < or =2, life expectancy of more than 12 weeks, adequate bone marrow function defined as neutrophil count 1.5 x 10(9)/L and platelet count > or =100 x 10(9)/L, adequate renal function defined as glomerular filtration rate (GFR) > or =60 mL/min, and adequate liver function defined as serum bilirubin levels within 1.25 x upper limit of normal. From October 1995 to December 1996, 442 of 660 planned patients were recruited to the AGO study. The interim analysis is based on data from 353 patients who were enrolled within the first study year. These preliminary data indicate that hematologic toxicity occurred more frequently in arm A (carboplatin/paclitaxel), while nonhematologic toxicity occurred slightly more frequently in arm B. Dose-intensity analysis did not reveal cumulative dose reductions or increasing use of colony-stimulating factors over subsequent courses in either arm. In all, 44 patients with measurable disease following surgery completed chemotherapy and were evaluable for response. The data remain blinded at this time, and results are reported for the group as a whole. So far, there have been 18 (41%) complete responses and 15 (34%) partial responses, for an overall response rate of 75%. Retrospective comparison with the GOG results reveals no significant difference in response rates between patients in the cisplatin/paclitaxel arm of GOG III and those in the AGO study: the GOG study reported a 73% response rate, compared with a preliminary 75% response rate in the AGO study, resulting in a relative risk of 1.03 (95% confidence interval, 0.83 to 1.27). Overall, this interim analysis did not reveal any reason to terminate this study early. Accrual is ongoing and is expected to be completed in 1997.