Prolonged Oral Etoposide Research Articles

Oral etoposide monotherapy for Chinese patients with metastatic breast cancer: Efficacy and tolerance regardless of heavy prior therapy.

1107 Background: Effective treatment options for metastatic breast cancer (MBC) patients heavily pretreated with chemotherapy are limited. Oral etopside 50mg/m2/daily for consecutive 21 days among 28 days has single-agent activity in these patients. However, the patients who have received heavy prior chemotherapy may have poor tolerance to prolonged oral etoposide for 21 days. Dosage and usage of oral etoposide remain uncertain. This study was designed as a prospective clinical trial to evaluate the efficacy and safety of short-term oral etoposide in Chinese patients with MBC who had received heavy prior therapy. Methods: Patients with measurable disease who had been previously treated with at least 2 chemotherapy regimens were treated with oral etoposide at 60 mg/m2 on day 1 to day 10 of a 21 day cycle. The primary end point was the progression free survival (PFS). The secondary end points were objective response rate (ORR), clinical benefit rate (CBR), overall survival (OS), and toxicity profiles. Results: Thirty-two patients received 230 cycles with a median of 6 cycles (range, 2 to 20 cycles) per patients. 8 patients (25%) had partial response (PR), 14 patients achieved stable disease (SD) and the ORR was 25%. 9 patients achieved SD for more than 24 weeks and CBR was 53%. Medium PFS was 5 months. The medium OS was 16 months (range, 3-51months). The patients achieved clinical benefit had longer survival time than those didn’t (25.0 verses 11.0 months, p<.01). Among the 16 patients who have received more than 4 previous regimens treatment, 4 patients got PR, and 4 patients achieved SD for more than 24 weeks, which lead to a CBR of 50%. The most common hematologic adverse events were anemia (43.8%) and neutropenia (38.5%), whereas nausea/vomiting (75.0%) and alopecia (62.5%) were the most frequent non-hematologic toxicity. Conclusions: These data demonstrate that oral etoposide given for 10 days of a 21-day cycle is effective and represents a well-tolerated treatment option for Chinese women with heavily pretreated MBC.

Complete remission with intraperitoneal cisplatin followed by prolonged oral etoposide in a stage IIIc primary leiomyosarcoma of the fallopian tube patient

Leiomyosarcoma (LMS) of the fallopian tube is exceedingly uncommon. So far as we investigated, only eighteen cases of LMS of the fallopian tube have been reported. Here we report a nineteenth case which was International Federation of Gynecology and Obstetrics stage IIIc LMS of the fallopian tube successfully treated with intraperitoneal cisplatin followed by prolonged oral etoposide. A 70-year-old female was introduced to our institute due to intrapelvic tumor and ascites. Because of elevated serum lactate dehydrogenase and CA125 as well as the findings of pelvic magnetic resonance imaging and computerized tomography, the patient was suspected to have ovarian cancer. In laparotomy, the large pelvic tumor was seemed to originate from the right fallopian tube. Pathologically, the patient was diagnosed as stage IIIc fallopian tube LMS. At the end of the operation, cisplatin was given intraperitoneally followed by prolonged oral etoposide. Although a lot of dissemination was noted throughout the peritoneal cavity, the patient is alive without any evidence of recurrence for more than 6 years since the initial operation. In this uncommon entity, a cisplatin- and etoposide-based regimen could be considered.

Sequential prolonged oral topotecan and prolonged oral etoposide as second-line therapy in ovarian or peritoneal carcinoma: A phase I Gynecologic Oncology Group study

Objective. Preclinical models suggest synergy when topoisomerase I and II inhibitors are given sequentially, but not simultaneously. A phase I study was conducted in previously treated ovarian or peritoneal carcinoma to determine the tolerability (maximum number of days) of sequential oral topotecan and oral etoposide. Methods. Topotecan (0.8 mg/m 2) was administered daily (days 1–5) followed by etoposide (50 mg/m 2) administered daily for up to 5 days (days 8–12). Patients on dose levels 3 and 4 repeated topotecan for up to 5 days starting on day 15 after the initial topotecan and etoposide sequence. Cycles were repeated every 28 days. Dose-limiting toxicities (DLT) were defined as: neutrophils <1000/μl or platelets <50,000/μl before completing administration of etoposide or topotecan; neutropenic fever; platelets <20,000/μl; or a delay greater than 2 weeks in starting cycle 2 due to hematologic toxicity (ANC <1500/μl or platelets <100,000/μl on scheduled day of treatment). Results. Nineteen patients were entered into this trial, and a total of 54 cycles (range 1–10) of therapy were administered. Dose-limiting toxicities, principally neutropenia, occurred when therapy was administered for 3 of 4 weeks. Conclusion. Oral topotecan and oral etoposide administered at these doses daily for 5 days sequentially for a maximum of three (out of every four) weeks of therapy are tolerable. In some cases, it may be necessary to hold therapy the third week. Based on the activity seen in this patient population, it is planned to take this regimen into a phase II setting.

Treatment With Oral Etoposide for Childhood Recurrent Ependymomas

In this study the authors retrospectively evaluated the feasibility and effectiveness of prolonged oral etoposide therapy in children with recurrent ependymoma. Twelve ependymoma patients with documented recurrent or persistent disease were treated between May 1998 and October 2003. All patients were treated monthly with oral VP-16 administered at a dose of 50 mg/m2/d for 21 days, with a 7-day interval between cycles, for a planned minimum number of six cycles. Response (complete plus partial) after two cycles occurred in 5 of the 12 patients (41.6%). Response plus stable disease occurred in 10 of the 12 (83.3%), with a median duration of response or stable disease of 7 months (range 4-30). The median survival was 7 months; the 2-year progression-free survival was 16.7%. These results emphasize that oral etoposide is an attractive option for childhood recurrent ependymomas in terms of administration, tolerability, and neuroradiologic response.

Developmental Chemotherapy and Management of Recurrent Ovarian Cancer

Despite improvements in median and overall survival using a combination of platinum and paclitaxel, long-term survival rates for patients with advanced epithelial ovarian carcinoma (EOC) remain disappointing, and the development of more effective primary therapies remains a priority. In particular, several nonplatinum agents have demonstrated activity in phase II trials among patients with recurrent platinum-resistant EOC. These agents include gemcitabine, topotecan, liposomal doxorubicin, and prolonged oral etoposide. Preclinical models have indicated a biologic basis for combinations of these agents with platinum, which has been attributed to inhibition of pathways involved in DNA repair. However, efforts to develop multidrug combinations with platinum and paclitaxel have encountered substantial bone marrow toxic effects, necessitating significant dose reductions and prompting exploration of alternative schedules and sequences of drug administration. In this regard, the Gynecologic Oncology Group (GOG) and other organizations have conducted pilot studies in previously untreated patients to define combinations that are suitable for group-wide phase III trials. With international collaboration, GOG has launched a five-arm trial that will compare four new combinations against carboplatin and paclitaxel. The selection of candidate regimens for this trial illustrates the challenges of drug development in EOC, emphasizing the role of phase II trials in patients with recurrent disease and indicating potential strategies to help evaluate newer biologic and molecular-targeted reagents.

Prolonged oral etoposide in recurrent or advanced non-squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study

Objective Previous studies by the Gynecologic Oncology Group have demonstrated a 7% response rate with bolus etoposide as second-line therapy in nonsquamous cell carcinoma of the cervix. Prolonged oral etoposide, which exploits the schedule dependency of this agent, has demonstrated increased activity in squamous carcinoma of the cervix compared with bolus administration. To evaluate prolonged oral etoposide in nonsquamous cell carcinoma of the cervix, the current phase II trial was conducted. Methods Eligibility included nonsquamous cell cancer of the cervix, measurable disease, no more than one prior chemotherapy regimen no prior etoposide, WBC ≥ 3000/μl, platelets ≥ 100,000/μl, serum creatinine ≤ 2 mg%, and adequate hepatic function. The starting dose was 50 mg/m 2/day (40 mg/m 2/day for prior radiotherapy) for 21 days, every 28 days. Based on toxicity, dose escalation to a maximum dose of 60 mg/m 2/day was prescribed. Results Fifty-two patients were entered on this study, with 47 evaluable for toxicity and 42 evaluable for response. A median of three (range: 1–12) courses were given. Thirty-four patients received prior radiation therapy and 15 received prior chemotherapy. Oral etoposide was well tolerated, with grade 4 neutropenia occurring in 29.8% and grade 4 thrombocytopenia occurring in 8.5% of patients. Three complete (7.1%) and two partial (4.8%) responses were observed. All of the responses were seen in chemotherapy-naïve patients (5/27); four of five had disease in nonirradiated sites. Conclusion Prior radiation therapy significantly limited our ability to deliver prolonged oral etoposide. At this dose, this regimen is moderately active in chemotherapy-naïve patients with nonsquamous cell carcinoma of the cervix.

A Phase I Trial of Prolonged Oral Etoposide and Liposomal Doxorubicin in Ovarian, Peritoneal, and Tubal Carcinoma: A Gynecologic Oncology Group Study

Objectives. In an effort to explore second-line therapy in ovarian, peritoneal, and tubal carcinoma, a phase I trial combining prolonged oral etoposide and liposomal doxorubicin was conducted by the Gynecologic Oncology Group.Methods. Liposomal doxorubicin (20 mg/m2) was administered intravenously over 1 h followed by oral etoposide at 50 mg/m2/day beginning on day 2. In the first phase of accrual, the number of days of oral etoposide was increased until its maximum tolerated dose (MTD) was determined based on hematologic toxicity. In the second phase, etoposide was given at the MTD while the dose of liposomal doxorubicin was escalated until its maximum tolerated dose was reached based on hematologic or nonhematologic toxicity. Cycles were repeated every 28 days for a maximum of 12 courses. Dose-limiting toxicity was defined as neutropenic sepsis, grade 4 thrombocytopenia, absolute neutrophil count <1000/μl or platelets <50,000 during treatment with etoposide, or ≥grade 3 mucositis/stomatitis, palmar–plantar erythrodyesthesia, or rash.Results. Fifteen patients were accrued to the study's first phase, and 3 were accrued to the second phase. Dose-limiting hematologic toxicity occurred with 14 days of oral etoposide in combination with liposomal doxorubicin at 20 mg/m2. Efforts to escalate the dose of liposomal doxorubicin to 30 mg/m2 in combination with 12 days of oral etoposide at 50 mg/m2 resulted in dose-limiting hematologic toxicity. Five of 17 (29%; 95% CI: 13–53%) evaluable patients experienced a response.Conclusion. The regimen of oral etoposide at 50 mg/m2/day for 12 days in combination with liposomal doxorubicin at a dose of 20 mg/m2 is tolerable without supportive therapy. While this dose of oral etoposide has demonstrated activity as a single agent in ovarian cancer, liposomal doxorubicin has only been effective in ovarian cancer at higher doses. There are no immediate plans to study this combination further.

Developmental chemotherapy in advanced ovarian cancer: Incorporation of newer cytotoxic agents in a phase III randomized trial of the Gynecologic Oncology Group (GOG-0182)

Despite improvements in median and overall survival using a combination of platinum and paclitaxel, long-term survival rates for patients with advanced epithelial ovarian carcinoma (EOC) remain disappointing, and the development of more effective primary therapy remains a priority. In particular, several interesting chemotherapy agents have demonstrated activity individually in patients with recurrent EOC. Among these are gemcitabine, topotecan, liposomal doxorubicin, and prolonged oral etoposide. Preclinical models have suggested an advantage for combinations of these agents with platinum, which has been attributed to inhibition of DNA synthetic pathways involved in the repair of platinum-DNA adducts. However, efforts to develop multidrug combinations with platinum and paclitaxel have encountered substantial bone marrow toxicity, prompting exploration of alternative schedules and sequences of drug administration. In this regard, the Gynecologic Oncology Group (GOG) and other organizations have conducted a series of phase I pilot studies in previously untreated patients to define combinations that are suitable for group-wide phase III trials. With international collaboration, GOG has launched a five-arm trial (GOG-0182) that will compare these combinations against carboplatin-paclitaxel. The selection of candidate regimens for this trial illustrates the challenges of drug development in EOC. Semin Oncol 29 (suppl 1):20-31. Copyright © 2002 by W.B. Saunders Company.

Weekly cisplatin and oral etoposide as treatment for relapsed epithelial ovarian cancer

Response rates to chemotherapy in relapsed, platinum resistant epithelial ovarian cancer remain poor. We have explored the effectiveness of weekly cisplatin combined with prolonged oral etoposide in this patient group. Forty-two women with relapsed, advanced ovarian cancer were treated with cisplatin 60 mg/m2 on days 1, 8, 15, 29, 36 and 43 and oral etoposide 50 mg given from day 1-14 and day 29-43. In those who were responding and tolerating treatment (n = 13) oral etoposide 50 mg was continued for two further cycles (days 1-21 repeated every 28 days). The interval since last platinum containing chemotherapy was > 6 months in 28 patients and < 6 months in 16 patients. Thirty-six patients were evaluable for response according to CA 125 criteria giving an overall response rate of 44%. The response rate in evaluable patients declined with increasing numbers of previous treatments: 57% with one prior treatment, 42% with two, 40% with three or more. The response rate in patients who had received platinum chemotherapy within six months prior to treatment was 46%. The only significant non-haematological toxicity was nausea and vomiting in 4 patients who experienced greater than grade 2 toxicity. The number of patients experiencing haematological toxicity more than grade 2 was as follows: haemoglobin 3, white blood count 12, platelets 6. Sixteen patients had dose delays and two had dose reductions. We conclude that this short but intensive regimen provides worthwhile response rates, even in those patients who would ordinarily be considered refractory to platinum, and has an acceptable toxicity profile.

Developmental chemotherapy in advanced ovarian cancer: Incorporation of topoisomerase-I inhibitors and perspective of the Gynecologic Oncology Group

Despite improvements in median and overall survival using a combination of platinum and paclitaxel, long-term survival rates for patients with advanced epithelial ovarian carcinoma (EOC) remain disappointing, and the development of more effective primary therapy remains a priority. In particular, several interesting chemotherapy agents have demonstrated activity individually in patients with recurrent EOC. Among these are gemcitabine, topotecan, liposomal doxorubicin, and prolonged oral etoposide. Preclinical models have suggested an advantage for combinations of these agents with platinum, which has been attributed to inhibition of DNA synthetic pathways involved in the repair of platinum-DNA adducts. However, efforts to develop multidrug combinations with platinum and paclitaxel have encountered substantial bone marrow toxicity, prompting exploration of alternative schedules and sequences of drug administration. In this regard, the Gynecologic Oncology Group (GOG) has conducted a series of phase I pilot studies in previously untreated patients to define combinations that are suitable for group-wide phase III trials. With international collaboration, GOG has launched a five-arm trial (GOG-0182) that will compare these combinations against carboplatin-paclitaxel. The selection of candidate regimens for this trial illustrate the challenges of drug development in EOC.

Prolonged oral versus high-dose intravenous etoposide in combination with carboplatin for stage IV non-small-cell lung cancer (NSCLC): a randomized trial

In order to investigate whether dose-intensive intravenous (i.v.) etoposide offers an advantage over prolonged oral administration of etoposide when combined with carboplatin (CBDCA), between January, 1991 and December, 1994, 171 patients with metastatic (stage IV) non-small cell lung cancer were randomized to receive CBDCA, 400 mg/m 2, day 1 with either oral etoposide, 50 mg/m 2, days 1–21 (group I) or i.v. etoposide, 200 mg/m 2, days 1–3 (group II), every 4 weeks for up to six cycles or until tumour progression. Of the patients 168 were fully assessable for response, survival and toxicity. There were three (4%) CR and 16 (19%) PR in group I, and the overall response rate was 23%. There were four (5%) CR and 12 (14%) PR in group II, and the overall response rate was 19% ( P=0.82). The median survival time (MST) in group I was 8 months, and 1- and 2-year survival rates were 35 and 9.5%, respectively, while the corresponding figures for group II were 7 months, and 31 and 7.1%, respectively ( P=0.40). Both haematological and non-haematological toxicity was significantly more frequent in group II with six (7%) patients in that group dying of treatment-related infection. Intensive i.v. etoposide combined with CBDCA was similar in efficacy to but more toxic than prolonged oral etoposide plus carboplatin and we do not recommend it for further investigation.

Prolonged oral etoposide in combination with intravenous cisplatin (oral EP) for non-small cell lung cancer (NSCLC)

Prolonged oral etoposide in combination with intravenous cisplatin (oral EP) for non-small cell lung cancer (NSCLC)

Prolonged Oral Etoposide in Recurrent or Advanced Squamous Cell Carcinoma of the Cervix: A Gynecologic Oncology Group Study

Objective.Previous studies by the Gynecologic Oncology Group have demonstrated no activity with bolus etoposide in squamous cell carcinoma of the cervix. Prolonged oral etoposide, which exploits the schedule dependency of this agent, has demonstrated activity in non-small cell carcinoma of the lung and has been studied in combination therapy with cisplatin. To evaluate prolonged oral etoposide in previously treated squamous cell carcinoma of the cervix, the current Phase II trial was conducted.Methods.Eligibility included squamous cell cancer of the cervix, measurable disease, allowed no more than one prior chemotherapy regimen which did not include etoposide, WBC ≥3000/μl, platelet count ≥100,000/μl, serum creatinine ≤2 mg%, and adequate hepatic function. The starting dose was 50 mg/m2/day (40 mg/m2/day for prior radiotherapy) as a single daily dose for 21 days, every 28 days. Based on toxicity, a dose escalation to a maximum dose of 60 mg/m2/day was prescribed.Results.Twenty-five patients were entered on this study; 24 were evaluable for toxicity. A median of 2 courses was given (range 1–8). All but one had received radiation therapy and 20 had received prior chemotherapy. Oral etoposide was not well tolerated with grade 4 neutropenia occurring in 33.3% and grade 4 thrombocytopenia occurring in 15%. Seven patients were unable to complete their first cycle due to toxicity and 8 patients received only one course of therapy. Of the remaining patients, 6 required dose reductions to 30 mg/m2/day. Only 3 patients were able to be dose-escalated to 50 mg/m2/day. Seventeen patients completed one course of therapy and were evaluable for response, of whom 16 had received prior radiotherapy and 15 prior chemotherapy. Two responses (11.8%) were observed, one complete response and one partial response. Both of these patients had disease in nonirradiated sites and one was chemotherapy-naive. Based on an intent-to-treat analysis, the response rate was 8.3%.Conclusion.Prior radiation therapy limited the ability to deliver prolonged oral etoposide. At the maximum tolerated dose, this regimen is not significantly active as second-line chemotherapy in squamous cell carcinoma of the cervix.

Prolonged Oral Etoposide in Recurrent or Advanced Leiomyosarcoma of the Uterus: A Gynecologic Oncology Group Study

Objective.In a previous study by the Gynecologic Oncology Group only modest activity was seen with bolus etoposide in leiomyosarcoma of the uterus (an 11% response rate). To exploit the schedule dependency of etoposide, which favors longer exposure, a Phase II trial of prolonged oral etoposide was conducted in this tumor.Methods.Eligibility included leiomyosarcoma of the uterus, measurable disease, one prior chemotherapy regimen which did not include etoposide, WBC ≥ 3000/μl, platelet count ≥100,000/μl, serum creatinine ≤2 mg%, and adequate hepatic function. The starting etoposide dose was 50 mg/m2/day (30–40 mg/m2/day for prior radiotherapy) as a single dose for 21 days, every 28 days. Based on toxicity, a dose escalation to a maximum etoposide dose of 60 mg/m2/day was prescribed.Results.Thirty-six patients were entered on this study; 34 were evaluable for toxicity and 29 were evaluable for response. A median of 2 courses were given (range 1–14). Grade 4 neutropenia occurred in 20.6% and grade 4 thrombocytopenia occurred in 5.8%. One patient developed acute myeloid leukemia 10 months after completing 7 cycles of therapy. Among the patients evaluable for response, 27 had received prior chemotherapy and 6 had received prior radiation therapy. Two partial responses (6.9%) were observed.Conclusion.This regimen has minimal activity as second-line chemotherapy in leiomyosarcoma of the uterus. No benefit to the chronic oral schedule is evident.

A Phase II Study of Prolonged Oral Etoposide in Advanced or Recurrent Carcinoma of the Cervix

Objective.To evaluate the efficacy and toxicity of prolonged oral etoposide as single agent chemotherapy in patients with advanced or recurrent carcinoma of the cervix.Methods.Between May 1991 and February 1993, 44 patients with advanced or recurrent carcinoma of the cervix were entered onto this study. Patients were eligible if they had received no more than two prior cytotoxic regimens. The initial dose of etoposide was 37.5 mg/m2administered orally on a daily basis on days 1–21 of a 28-day cycle. Subsequent doses were unchanged, reduced, escalated, or omitted according to toxicity. Patients were evaluated for response and toxicity using standard Gynecologic Oncology Group criteria.Results.Forty-four patients were evaluable for response and toxicity. The overall response rate was 9.1% (2 CR, 2 PR). In patients with no prior chemotherapy the response rate was 4/25 compared to 0/19 for those who had prior therapy. The mean response duration was 2.7 months and the median survival from treatment for all patients was 7.7 months. The major toxicity was granulocytopenia, with 11% of patients having grade 3 or 4 toxicity. Gastrointestinal toxicity of some degree occurred in 11% of patients, and alopecia was universal.Conclusion.Prolonged oral etoposide has limited activity in advanced or recurrent carcinoma of the cervix. Its use as palliative therapy for this disease is not indicated.

Concurrent Cisplatin, Prolonged Oral Etoposide, and Vincristine plus Chest and Brain Irradiation for Limited Small Cell Lung Cancer: A Phase II Study of the Southwest Oncology Group (SWOG-9229)

Purpose: The primary objectives of the study were to evaluate the efficacy and safety of prolonged oral (PO) etoposide as part of cisplatin-based chemotherapy plus concurrent chest/brain irradiation induction, followed by CAV consolidation, in the treatment of patients with limited-stage small cell lung cancer (SCLC-LD) within a cooperative group setting. Methods and Materials: Fifty-six eligible patients with SCLC-LD received three 28-day cycles of cisplatin 50 mg/m 2 i.v. (days 1, 8; 29, 36; and 57, 64), PO etoposide 50 mg/m 2 (days 1–14, 29–42, and 57–70), and vincristine 2 mg i.v. (days 1, 29, and 57). Thoracic irradiation (TRT) was administered at 1.8 Gy in 25 daily fractions to a total dose of 45 Gy via an AP:PA arrangement, to begin concomitantly with induction chemotherapy. Prophylactic cranial irradiation (PCI) was started on day 15 of induction therapy. Fifteen daily fractions of 2.0 Gy were administered to the entire brain to a total dose of 30 Gy to finish at approximately the same time as TRT. Two 21-day cycles of consolidation cyclophosphamide 750 mg/m 2 i.v., doxorubicin 50 mg/m 2 i.v., and vincristine 2 mg i.v. (all on days 1 and 22), were given beginning on day 106 or week 16, from the start of induction therapy. Results: Among 56 eligible patients, 93% had SWOG performance status 0–1. All had adequate organ function and had not received prior therapy. The overall confirmed response rate was 46%, including 16% complete responders and 30% partial responders. After a minimun follow-up duration of 17 months, the Kaplan-Meier median progression-free (PFS) and overall survival (OS) were 10 and 15 months, respectively. Two-year survival is 28%. Only 28 of 56 patients (50%) completed chemotherapy per protocol, while 52 of 56 patients (93%) completed radiation per protocol. Eleven patients (20%) discontinued secondary to toxicity and two patients died from treatment. The major toxicity was hematologic. The two deaths were secondary to infection. Of the nonhematologic toxicities, there were 10 cases of pulmonary fibrosis (including one Grade 3) and six cases of pneumonitis (including one Grade 3). Conclusion: Concomitant chemoradiation with oral etoposide as part of a platinum-based chemotherapy and TRT induction regimen is toxic. The CR rate is not better than our prior best group-wide experience. The progression-free and overall survival are similar to published trials utilizing short-course i.v. etoposide. As in chemotherapy for extensive-stage SCLC, there is no apparent advantage to prolonged exposure to etoposide, and toxicity resulted in an inferior therapeutic index compared to programs with shortened exposure.

346 Cisplatin (P), ifosfamide (I), prolonged oral etoposide (E), and concurrent accelerated hyperfractionated thoracic radiotherapy (TRT) for patients with limited small cell lung cancer (LSCLC): Preliminary results of a phase II trial

346 Cisplatin (P), ifosfamide (I), prolonged oral etoposide (E), and concurrent accelerated hyperfractionated thoracic radiotherapy (TRT) for patients with limited small cell lung cancer (LSCLC): Preliminary results of a phase II trial

Etoposide for the treatment of paediatric tumours: what is the best way to give it?

Etoposide is one of the most important drugs available for the treatment of paediatric malignancies. Although there is evidence of schedule dependency for etoposide therapy in adults with small-cell lung cancer, the relevance of this observation to childhood cancers is uncertain. Prolonged parenteral or oral etoposide therapy has not yet shown a clear-cut advantage over intermittent treatment, and there are still no data to show that the administration of etoposide as a short intravenous (i.v.) daily infusion for 5 days does not represent acceptable therapy for primary disease. The pharmacokinetic variability seen with etoposide argues strongly for the use of pharmacologically guided dosing, and the introduction of etoposide phosphate will simplify both parenteral etoposide administration and the future evaluation of alternative etoposide schedules. Although the impact of molecular and cellular pharmacological investigations on the clinical use of etoposide has yet to be felt, the tools to perform these studies are now available and prospective trials can be designed. Such studies, performed in the setting of a pharmacologically guided trial to ensure control over pharmacokinetic variability, should identify the best way of treating children with etoposide.

A Phase II Trial of Prolonged Oral Etoposide (VP-16) as Second-Line Therapy for Advanced and Recurrent Endometrial Carcinoma: A Gynecologic Oncology Group Study

Prolonged oral etoposide is an active regimen in small and nonsmall cell carcinoma of the lung, carcinomas of the breast and ovary, germ cell tumors, and in lymphoma. A Phase II trial was conducted by the Gynecologic Oncology Group to determine its activity in endometrial carcinoma. Twenty-six patients with advanced or recurrent endometrial carcinoma were entered into study; one patient was ineligible because of an incorrect cell type. The remaining eligible patients were treated with etoposide at a starting dose of 50 mg/m2/day (30 mg/m2/day with prior radiotherapy) for 21 days. Based on hematologic toxicity, a dose escalation to a maximum dose of 60 mg/m2/day was prescribed. Twenty-two patients were evaluable for response and 25 were evaluable for toxicity. Fourteen had received prior radiotherapy and 24 had received prior chemotherapy. A median of two courses were given (range, 1–10). Grade 3 or 4 leukopenia occurring in 52% was the most common complication (grade 3, 36%; grade 4, 16%). Grade 4 thrombocytopenia occurred in 16% of patients. There were no objective responses including four patients with serous papillary carcinoma. This regimen is not significantly active as second-line therapy in endometrial carcinoma.

Pharmacokinetics and pharmacodynamics of prolonged oral etoposide in women with metastatic breast cancer

Pharmacokinetics and pharmacodynamics of prolonged oral etoposide in women with metastatic breast cancer