H. G. Meerpohl

Surgery in Recurrent Ovarian Cancer: The Arbeitsgemeinschaft Gynaekologische Onkologie (AGO) DESKTOP OVAR Trial

BackgroundThe role of cytoreductive surgery in relapsed ovarian cancer is not clearly defined. Therefore, patient selection remains arbitrary and depends on the center’s preference rather than on established selection criteria. The Descriptive Evaluation of preoperative Selection KriTeria for OPerability in recurrent OVARian cancer (DESKTOP OVAR) trial was undertaken to form a hypothesis for a panel of criteria for selecting patients who might benefit from surgery in relapsed ovarian cancer.MethodsThe DESKTOP trial was an exploratory study based on data from a retrospective analysis of hospital records. Twenty-five member institutions of the Arbeitsgemeinschaft Gynaekologische Onkologie Ovarian Committee (AGO OC) and AGO-OVAR boards collected data on their patients with cytoreductive surgery for relapsed invasive epithelial ovarian cancer performed in 2000–2003.ResultsTwo hundred and sixty-seven patients were included. Complete resection was associated with significantly longer survival compared with surgery leaving any postoperative residuals [median 45.2 vs. 19.7 months; hazard ratio (HR) 3.71; 95% confidence interval (CI) 2.27–6.05; P < .0001]. Variables associated with complete resection were performance status (PS) [Eastern Cooperative Oncology Group (ECOG) 0 vs. > 0; P < .001], International Federation of Gynecology and Obstetrics (FIGO) stage at initial diagnosis (FIGO I/II vs. III/IV, P = .036), residual tumor after primary surgery (none vs. present, P <.001), and absence of ascites > 500 ml (P < .001). A combination of PS, early FIGO stage initially or no residual tumor after first surgery, and absence of ascites could predict complete resection in 79% of patients.ConclusionsOnly complete resection was associated with prolonged survival in recurrent ovarian cancer. The identified criteria panel will be verified in a prospective trial (AGO-DESKTOP II) evaluating whether it will render a useful tool for selecting the right patients for cytoreductive surgery in recurrent ovarian cancer.

Topotecan Weekly Versus Conventional 5-Day Schedule in Patients With Platinum-Resistant Ovarian Cancer: A Randomized Multicenter Phase II Trial of the North-Eastern German Society of Gynecological Oncology Ovarian Cancer Study Group

PURPOSE Weekly administration of topotecan (Tw) is less toxic and widely considered a better treatment option than conventional 5-day therapy (Tc) in women with platinum-resistant recurrent ovarian cancer. We conducted a randomized phase II trial (TOWER [Topotecan Weekly Versus Conventional 5-Day Schedule in Patients With Platinum-Resistant Ovarian Cancer]) to better define the ratio between benefits and risks with either treatment approach. PATIENTS AND METHODS Patients were randomly assigned to two independent two-stage protocols of Tw (4 mg/m(2)/wk administered on days 1, 8, and 15) or Tc (1.25 mg/m(2)/d on days 1 to 5). We evaluated risk ratios (RRs) for the primary end point of clinical benefit (complete response, partial response, and stable disease), the duration of progression-free survival (PFS) and overall survival (OS), associated hazard ratios (HRs), and RRs of toxicity with 95% CIs. RESULTS In total, 194 patients were randomly assigned at 54 centers to Tw (n = 97) or Tc (n = 97). Clinical benefit was observed in 36 of 76 (47%; 95% CI, 36% to 59%) Tw and 46 of 80 (58%; 95% CI, 46% to 68%) Tc patients (RR, 1.21; 95% CI, 0.90 to 1.64; P = .205). Patients in the Tw group had a slightly shorter PFS (HR, 1.29; 95% CI, 0.96 to 1.76) but similar OS (HR, 1.04; 95% CI, 0.74 to 1.45) compared with Tc. Tw was associated with significantly lower risks of anemia (RR, 0.35; 95% CI, 0.16 to 0.79), neutropenia (RR, 0.38; 95% CI, 0.23 to 0.65), and thrombocytopenia (RR, 0.23; 95% CI, 0.09 to 0.57). CONCLUSION With regard to effectiveness in terms of response and PFS, Tc remains the standard of care in patients with platinum-resistant recurrent ovarian cancer. However, comparable OS rates and a favorable toxicity profile make Tw another viable treatment option in this setting.

First-Line Trastuzumab Plus Epirubicin and Cyclophosphamide Therapy in Patients With Human Epidermal Growth Factor Receptor 2–Positive Metastatic Breast Cancer: Cardiac Safety and Efficacy Data From the Herceptin, Cyclophosphamide, and Epirubicin (HERCULES) Trial

PURPOSE A high incidence of congestive heart failure (CHF) has been observed in patients with metastatic breast cancer (MBC) receiving doxorubicin-based chemotherapy and trastuzumab. The Herceptin, Cyclophosphamide, and Epirubicin (HERCULES) trial evaluated trastuzumab plus cyclophosphamide and the less cardiotoxic anthracycline epirubicin. PATIENTS AND METHODS This prospective trial combined a phase I dose-finding stage with a phase II randomized stage. In total, 120 patients with human epidermal growth factor receptor 2 (HER2) -positive MBC and adequate cardiac function received first-line trastuzumab (4 mg/kg intravenous loading dose, then 2 mg/kg every week) plus cyclophosphamide (600 mg/m(2)) and either epirubicin 60 mg/m(2) (HEC-60) or 90 mg/m(2) (HEC-90) for six cycles, followed by trastuzumab monotherapy until progression. Sixty patients with HER2-negative disease received epirubicin (90 mg/m(2)) and cyclophosphamide (EC-90) alone. The primary end point was dose-limiting cardiotoxicity (DLC). RESULTS Incidence of DLC was 5.0%, 1.7%, and 0% in the HEC-90, HEC-60, and EC-90 arms, respectively. All DLC events were manageable. There were no cardiac-related deaths. Other adverse-event profiles were comparable across the three arms, except febrile neutropenia, which was reported in 10% of the HEC-90 arm compared with 3% of the other arms. Tumor response rates were 57%, 60%, and 25% in the HEC-60, HEC-90, and EC-90 arms, respectively; median time to progression was 12.5, 10.1, and 7.6 months, respectively. CONCLUSION The HEC regimen is a promising treatment option for patients with HER2-positive MBC. The lower incidence of DLC with HEC, compared with the historic incidence associated with trastuzumab plus doxorubicin, supports further evaluation of the regimen, especially in adjuvant or neoadjuvant settings.

Course, patterns, and risk-factors for chemotherapy-induced emesis in cisplatin-pretreated patients: a study with ondansetron

Vomiting and nausea are the most distressing side-effects of cancer chemotherapy. With standard antiemetic regimens (e.g. metoclopramide based combinations) sufficient antiemetic control is achieved in 50-70% of cisplatin treated patients. Ondansetron, a selective 5-HT3-receptor antagonist has shown efficacy in cisplatin-induced emesis. In the present study, we evaluated the safety and efficacy of ondansetron in cisplatin pretreated patients who had suffered from severe emesis in spite of antiemetic prophylaxis. Complete antiemetic control was reached in 43.5% on the day of treatment and in 27.2% of the patients regarding a worst day analysis. 25% of the patients suffered from severe cisplatin-induced emesis (greater than 5 emetic episodes per 24 h). We try to characterise risk-factors for cisplatin-induced emesis by performing a multivariate analysis. Sex, cisplatin dose, and combination therapy with cisplatin plus anthracyclines seem to be independent risk-factors for vomiting on day 1 and on worst day. Delayed emesis occurred less often when sufficient antiemetic protection from acute vomiting had been obtained. Female sex, cisplatin dose and recurrent disease seem to influence the probability for occurrence of delayed vomiting.

Reduced Incidence of Severe Palmar-Plantar Erythrodysesthesia and Mucositis in a Prospective Multicenter Phase II Trial with Pegylated Liposomal Doxorubicin at 40 mg/m2 Every 4 Weeks in Previously Treated Patients with Metastatic Breast Cancer

Purpose: The aim of this study was to assess whether the reduction in the total dose of pegylated liposomal doxorubicin (PLD) per cycle from 50 mg/m2 every 4 weeks to 40 mg/m2 every 4 weeks can effectively lower the incidence of treatment-related palmar-plantar erythrodysesthesia (PPE) and mucositis. Methods: Patients received PLD 40 mg/m2 every 4 weeks, and were evaluated for toxicity prior to each treatment and for response every 8 weeks. Results: All patients were previously treated with at least one chemotherapy regimen for metastatic disease, and 72% of the patients had a prior exposure to an anthracycline. Forty-six evaluable patients received a median of four PLD cycles, with a median dose intensity of 10 mg/m2/week and a median cumulative dose of 160 mg/m2. No National Cancer Institute Common Toxicity Criteria (NCI-CTC) grade 3 or 4 PPE was observed in these patients. NCI-CTC grade 3 or 4 mucositis occurred in 4.3% of patients, only. Response rates and survival results observed here were comparable to those observed with PLD 50 mg/m2 every 4 weeks in a matched patient population. However, patients treated with PLD 40 mg/m2 every 4 weeks experienced less PPE and mucositis and required clearly less dose reductions and treatment delays. Conclusion: The favorable safety profile observed in this study leads us to recommend the use of PLD 40 mg/m2 every 4 weeks for patients with advanced breast cancer.

Evaluation of neurotoxicity induced by paclitaxel second-line chemotherapy

Abstract 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.

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

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.

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.

Phase II study of pirarubicin combined with cisplatin in recurrent ovarian cancer

Although 50%–80% of patients with advanced ovarian cancer demonstrate an objective response after platinum-based chemotherapy, a majority of these patients will ultimately experience a relapse of their disease. Effective second-line treatment for these patients is of the utmost importance. We performed a phase II study with cisplatin and pirarubicin (each drug 50 mg/m2 i.v. every 28 days) in 17 patients with relapsed or persistent ovarian carcinoma. All patients had received platinum-containing primary chemotherapy. Overall survival from the time of diagnosis was 38.3 months (45.3 months in relapsed ovarian carcinoma and 28.3 months in ovarian carcinoma persisting after primary chemotherapy). Survival from entrance into the study was 13.0 months (14.2 months in relapsed disease and 11.2 months in refractory disease). Time to progression was 10.3 months. An objective response was observed in 4 patients and another 3 patients had stable disease. Major toxicity consisted of emesis (grade III/IV in 60/64 courses) and myelosuppression WHO grade III/IV in 15 courses. Neurotoxicity occurred in 3 patients and nephrotoxicity in 1 patient. Alopecia occurred in 12 patients. Tachycardia and other low-grade heart toxicities were observed after 5 courses. Dose reduction was necessary because of severe myelosuppression in 4 courses and because of nephrotoxicity in 1 course. Delay of subsequent chemotherapy courses for more than 7 days was necessary after 13 courses and was always due to myelosuppression. The dose-limiting toxicity of combination chemotherapy with cisplatin and pirarubicin is myelosuppression. Response and survival rates are superior in patients with relapsed disease compared to patients with resistent ovarian carcinoma.

Therapierefraktäre Emesis unter Cisplatin

Emesis unter Cisplatin (DPP)-haltiger Chemotherapie ist ein noch ungelostes Problem und fuhrt in bis zu 10% der Falle zum Abbruch einer potentiell kurativen Therapie. Wir untersuchten die antiemetisch