Continuous Infusion Etoposide Research Articles

DA-EPOCH-R: An alternative treatment for high-risk diffuse large B cell lymphoma?

Diffuse large B cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma with an annual incidence of 7–8 cases per 100,000 per year. With standard induction therapy comprising rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R/CHOP), 40% of all patients get cured. Patients relapsing or being refractory to R/CHOP have a poor prognosis with a 10 % cure rate. On the other hand, the prognosis for patients with an event-free survival of 24 months is excellent. Despite the possibility of identifying patients at high risk for R/CHOP failure at the time of diagnosis, to date, an adequate risk-adapted induction has not been established. Dose-adjusted application of rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (DA-EPOCH-R) is a pharmacodynamic approach to improve R/CHOP by the addition of etoposide, prolonged exposure to chemotherapy agents (continuous infusion of etoposide, vincristine, and doxorubicin over 96 h) and dose adjustment based on the absolute neutrophil count nadir. DA-EPOCH-R has shown promising results in retrospective analyses of various high-risk DLBCL cases. The following article reviews various approaches to define and to treat patients with high-risk DLBCL with a focus on treatment with DA-EPOCH-R.

Combination of gemcitabine, l-asparaginase, and oxaliplatin (GELOX) is superior to EPOCH or CHOP in the treatment of patients with stage IE/IIE extranodal natural killer/T cell lymphoma: a retrospective study in a cohort of 227 patients with long-term follow-up

Optimal treatment strategies for localized extranodal natural killer/T cell lymphoma (ENKTL) have not been fully defined. We retrospectively compared the efficacy and safety of combined gemcitabine, L-asparaginase, and oxaliplatin (GELOX) (n=38), continuous infusion of etoposide, vincristine and doxorubicin, with cyclophosphamide and prednisone (EPOCH) (n=54), or combined cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) (n=135) as induction chemotherapy in patients who were newly diagnosed with stage I/II ENKTL. After induction chemotherapy, the complete response (CR) rate and overall response rate (ORR) for the GELOX group were significantly higher than those in the EPOCH group (68.4 vs. 42.6%, P=0.011 for CR and 86.8 vs. 68.5%, P=0.038 for ORR). Both EPOCH and GELOX groups can attain much higher CR rates than CHOP group (CR rate was 31.8%, P<0.05). The 3-year overall survival (OS) and progression-free survival (PFS) rate were significantly better in GELOX group than in EPOCH or CHOP group (87.0 vs. 54.0 vs. 54.0% for OS, P<0.05; 72.0 vs. 50.0 vs. 43.0% for PFS, P<0.05). However, no significant differences were found between EPOCH and CHOP groups in OS or PFS (P=0.765 for OS, and 0.421 for PFS). The safety profiles were acceptable in all three groups. In conclusion, GELOX is superior to EPOCH or CHOP in the treatment of patients with stage I/II ENKTL. Further clinical trials of ENKTL should use asparaginase-based regimens as the standard chemotherapy.

Dose-Adjusted EPOCH-Rituximab Combined With Fludarabine Provides an Effective Bridge to Reduced-Intensity Allogeneic Hematopoietic Stem-Cell Transplantation in Patients With Lymphoid Malignancies

There is currently no standard chemotherapy regimen for patients with lymphoid malignancies being considered for reduced-intensity conditioning allogeneic hematopoietic stem-cell transplantation (RIC-alloHSCT). The ideal regimen would provide disease control and result in lymphocyte depletion to facilitate engraftment. To this end, we developed a novel regimen by adding fludarabine to dose-adjusted continuous-infusion etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin plus with or without rituximab (DA-EPOCH-F/R). One hundred forty-seven patients with lymphoid malignancy (median age, 50 years) who had heavily pretreated (median prior regimens, three) and chemo-refractory (47%) disease were treated with DA-EPOCH-F/R before RIC-alloHSCT. Patients received one to three consecutive cycles until achieving lymphocyte depletion (CD4(+) count < 200/μL) or progressive disease. Overall response rate was 41%; 39% of patients had stable disease. Toxicity included grade 4 neutropenia in 65% and thrombocytopenia in 25% of patients. DA-EPOCH-F/R resulted in lymphocyte depletion (P < .001), which was inversely associated with serum interleukin (IL) 7 and IL-15 levels. Of 147 patients, 143 patients proceeded to RIC-alloHSCT. Patients with lower CD3(+) (P < .001), CD4(+) (P < .001), and CD8(+) (P < .001) T-cell counts after DA-EPOCH-F/R were more likely to achieve full donor lymphoid chimerism by day +14 after transplant. Relative to nonresponders to DA-EPOCH-F/R, patients with complete and partial response had increased event-free survival (77.4 v 4.8 months; P < .001) and overall survival (98.5 v 16.2 months; P < .001). DA-EPOCH-F/R safely provides tumor cytoreduction and lymphocyte depletion, thereby offering a bridge to RIC-alloHSCT in patients with aggressive lymphoid malignancies.

EPOCH-FR: A novel salvage regimen for patients with lymphoid malignancies being considered for reduced-intensity allogeneic hematopoietic stem cell transplantation.

6536 Background: There is no standard chemotherapy regimen for patients (pts) with lymphoid malignancies being considered for reduced intensity allogeneic hematopoietic stem cell transplantation (RI-alloHSCT). The ideal regimen would result in disease control and recipient lymphocyte depletion and have limited toxicity. We developed a novel regimen consisting of continuous infusion etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin plus fludarabine ± rituximab, depending on CD20+ expression (EPOCH-FR). Methods: 147 pts, median age 50 yrs (range 21-71), with high-risk lymphoid malignancies (47% with chemo-resistant disease to last regimen, median 3 prior regimens [range 1-13]) were given EPOCH-FR (74% dose-adjusted) prior to RI-alloHSCT. Pts received 1 (48%), 2 (21%), or 3 (31%) cycles of EPOCH- FR until they were lymphodepleted (CD4+ count < 100/μl) or had progressive disease. Results: Overall response rate (RR) was 41% (16% CR, 25% PR); 39% had SD. RR of FCC/CLL>DLBCL/HL>TCL (p = 0.047). More EPOCH-FR cycles were associated with higher RR (17% vs. 33% vs. 84%) (p < 0.0001). 17% of pts with chemo-resistant disease had CR/PR. EPOCH- FR resulted in significant lymphodepletion (pretreatment median CD3+ = 574/μl, CD4+ = 244/μl, and CD8+ = 249/μl vs. posttreatment CD3+ = 184/μl, CD4+ = 97/μl and CD8+ = 68/μl (p < 0.0001). Pts with greater lymphodepletion of CD3+ (p=0.038) and CD4+ (p=0.017) were more likely to achieve CR/PR. Toxicity in 263 cycles included Grade 4 thrombocytopenia in 25%, neutropenia in 65%, and non-heme toxicity in 6%. Of 147 pts, 143 proceeded to RI-alloHSCT. Pts with greater lymphodepletion of CD3+ (p = 0.0007), CD4+ (p = 0.0004), and CD8+ (p = 0.0019) were more likely to achieve full donor lymphoid chimerism by Day +14 post-transplant. Following transplant, pts with CR/PR vs SD/PD to EPOCH-FR had median EFS = 77.4 vs. 4.8 mos (p < 0.0001) and OS = 98.5 vs. 16.2 mos (p = 0.0006) respectively. Conclusions: EPOCH-FR safely provides disease response and lymphodepletion in pts with lymphoid malignancies being considered for RI-alloHSCT. No significant financial relationships to disclose.

Outcome of patients with recurrent medulloblastoma or central nervous system germinoma treated with low dose continuous intravenous etoposide along with dose‐intensive chemotherapy followed by autologous hematopoietic stem cell rescue

Adults and children with recurrent malignant central nervous system (CNS) tumors have a poor prognosis despite high dose chemotherapy with a conventional stem cell rescue regimen. In this study we evaluated the results of low dose, continuous infusion etoposide over 21 days added to a conventional high-dose regimen of carboplatin and thiotepa in eight patients with relapsed pediatric CNS tumors. Patients with high risk CNS tumors were treated with etoposide 25 mg/m(2)/day by continuous intravenous (IV) infusion from day -22 to day -2, carboplatin 667 mg/m(2)/dose IV (or area under the curve = 9 mg/ml/min according to the Calvert formula on days -8, -7, and -6, and thiotepa 300 mg/m(2)/dose IV on days -5, -4, and -3, followed by autologous hematopoietic stem cell rescue on day 0. Eight adults and children, with a mean age of 12.9 years (age range 5.6-27.8 years), with relapsed primary CNS tumors (metastatic medulloblastoma (7), germinoma (1)), were enrolled. The mean survival post-transplant was 4.8+ years, (range 8-160+ months). The 2- and 5-year overall survival rates were 75% and 50% respectively. None of the survivors required additional salvage irradiation. The strategy of low dose chronic exposure to a topoisomerase inhibitor along with ablative carboplatin and thiotepa with stem cell rescue showed promising survival outcomes in these relapsed patients. This treatment strategy deserves further evaluation in a larger group of high-risk or relapsed primary CNS tumors.

Equitoxicity of bolus and infusional etoposide: results of a multicenter randomised trial of the German High-Grade Non-Hodgkins Lymphoma Study Group (DSHNHL) in elderly patients with refractory or relapsing aggressive non-Hodgkin lymphoma using the CEMP regimen (cisplatinum, etoposide, mitoxantrone and prednisone)

To compare toxicity of etoposide bolus with continuous infusion and to assess the efficacy of the CEMP (cisplatinum, etoposide, mitoxantrone, prednisone) regimen, 47 patients with refractory or relapsed aggressive non-Hodgkin's lymphoma older than 60 years (n=43) or not qualifying for high-dose chemotherapy (n=4) received five four-weekly CEMP cycles. Patients were randomised to start with bolus or continuous-infusion etoposide and then received bolus and infusional etoposide in an alternating fashion. The primary objective was the comparison of differences in the course of leukocytopenia and thrombocytopenia between the two application schedules. CEMP was well tolerated with little organ and moderate haematotoxicity. There was no difference in toxicity between bolus and continuous-infusion etoposide. Complete remission rate was 44% in patients relapsing >or=1 year, 27% in patients relapsing within the first year after achieving complete remission and 5% in primary refractory patients. Median event-free and overall survivals for all patients were 3 and 10 months, respectively. The observed equitoxicity and the more challenging logistics of a 60-h infusion make bolus injection the preferred application of etoposide. As the CEMP regimen is well tolerated and efficacious in elderly patients with relapsed or refractory aggressive non-Hodgkin's lymphoma for whom more aggressive therapies are not feasible, a three-weekly modification of CEMP should be tested in combination with rituximab.

Early Stem Cell Transplantation for Refractory Acute Leukemia after Salvage Therapy with High-Dose Etoposide and Cyclophosphamide

Primary refractory acute leukemia (AL) has a poor prognosis, although some patients can be salvaged with allogeneic stem cell transplantation (SCT). Induction of complete remission (CR) with conventional chemotherapy before SCT may improve outcome in this patient population. Between March 1991 and October 2003, 59 adults with primary refractory AL were treated with continuous-infusion etoposide (VP) 2.4 to 3.0 g/m 2 followed by cyclophosphamide (Cy) 6.0-7.2 g/m 2 intravenously over 3 to 4 days with the intention of proceeding to SCT in CR1. Forty-two patients had acute myelogenous leukemia (AML), 13 patients had acute lymphoblastic leukemia (ALL), and 4 patients had acute biphenotypic leukemia. The most frequent nonhematologic toxicities were oral mucosal, gastrointestinal, and hepatic toxicities (44%, 20%, and 15% of patients, respectively). Thirty-two (57%) of 56 evaluable patients entered CR1 with a median time to platelet and neutrophil recovery of 22 and 26 days, respectively. CR1 rates were similar in AML (54%) and ALL/acute biphenotypic leukemia (67%; P = .52), and analysis of baseline characteristics did not reveal any predictors of response to VP/Cy. Twenty-nine of 32 CR1 patients subsequently underwent SCT (24 allogeneic and 5 autologous). Estimated 5-year event-free survival (EFS) and overall survival for the entire cohort are 23% and 26%, respectively. In the allogeneic SCT group, 5-year EFS was 52% for AML patients and 14% for ALL patients ( P = .04), and only male sex was predictive of a favorable outcome ( P = .03). VP/Cy is able to induce CR1 in most patients with primary refractory AL with an acceptable toxicity profile. Subsequent allogeneic SCT can lead to long-term EFS in a significant proportion of patients.

Treatment of acute leukemia with idarubicin, etoposide and cytarabine (IDEA). A randomized study of etoposide schedule

The differences in toxicity of etoposide following continuous or bolus infusion are unknown. We studied the schedule-dependent toxicity of high-dose etoposide when combined with high-dose cytarabine and idarubicin (IDEA) in 138 patients with acute leukemia. Four groups of patients were studied: group I, relapse; group II, secondary acute myeloid leukemia (AML); group III, de novo AML, age >60 years; and group IV, induction failure or blast crisis of myeloproliferative syndrome. Treatment for groups I-III was idarubicin 8 mg/m(2) per day days 1-3, cytarabine 2000 mg/m(2) once a day days 1-6, and etoposide 1600 mg/m(2) total dose. Group IV treatment differed by cytarabine given twice daily days 1-6. Patients were randomized to etoposide as a continuous infusion days 1-6 or as a bolus infusion over 10 h on day 7. Continuous infusion etoposide produced significantly more oral mucositis than bolus etoposide. In groups I-III, comparing continuous and bolus etoposide, there was a median of 3 vs 0 days of grade 2 or more oral mucositis (P<0.0001) and 13.5 vs 0 days of total parenteral nutrition (TPN) (P=0.0003). Group IV patients had a median 7 vs 0 days of grade 2 or more oral mucositis (P<0.01) and 21 vs 7 days of TPN (P<0.003), respectively. There were no differences in hematologic recovery, length of hospital stay, complete remission rate or overall survival between the two etoposide schedules. Of groups I-III patients, 51% achieved complete remission, and 11% died from treatment-related complications. The toxicity profile of high-dose etoposide is schedule-dependent with prolonged exposure producing significantly more non-hematologic toxicity.

Chemotherapy in soft tissue sarcoma. The Scandinavian Sarcoma Group experience.

The Scandinavian Sarcoma Group (SSG) started its first chemotherapy study in soft tissue sarcoma (STS) in 1981 (SSG I). This study evaluated single agent doxorubicin given adjuvant in a prospective randomized trial in patients with high-grade STS. Neither overall survival nor disease-free survival was improved. Combination chemotherapy was hereafter studied in a phase II study (1991-1994) combining ifosfamide and continuous infusion etoposide with growth factor support (SSG X). The response rate in previously untreated patients was high (42%), but complete remissions were few. Analysis made on patients operated after chemotherapy indicated improved survival in this subgroup. Meta-analyses of adjuvant chemotherapy for localised resectable STS in adults, including the SSG I trial, has indicated improved disease-free survival and a trend towards improved overall survival. Presently, SSG is testing whether such a benefit can be found for adjuvant ifosfamide and doxorubicin treatment given after primary surgery in selected patients with high-grade STS and other well defined unfavourable prognostic factors (SSG XIII).

Phase I Study of a Weekly Infusion of Irinotecan Hydrochloride (CPT-11) and a 14-day Continuous Infusion of Etoposide in Patients with Lung Cancer: Japan Clinical Oncology Group 9408

Background: To determine the maximum-tolerated dose (MTD) and acceptable dose level of CPT-11 in combination with a 14-day continuous infusion of etoposide in patients with refractory advanced lung cancer (LC), especially small cell lung cancer (SCLC). Methods: Etoposide was administered continuously at 25 mg/m2/day for 14 days. The initial dose of CPT-11 was 40 mg/m2 given as a 90-min intravenous infusion on days 1, 8 and 15 and the dose escalation of CPT-11 was planned in increments of 20 mg/m2 until severe or life-threatening toxic effects were observed. Results: Eight refractory advanced LC patients entered this study, of whom two were not assessable for toxicity because of patient’s refusal and progressive disease. One treatment-related death due to pulmonary toxicity and one patient with hypotension who needed catechol­amine for more than 48 h were observed at a CPT-11 dose of 40 mg/m2. The MTD of CPT-11 was 40 mg/m2. Therapeutic efficacy could be assessed in six patients, of whom two achieved a partial response. Conclusions: This regimen was too toxic and the recommended dose was outside this study. One has to consider pulmonary toxicity when using CPT-11, especially for patients previously treated with cytotoxic agents for which pulmonary toxicity has been reported.

High Dose Chemotherapy Without Hematopoietic Cell Support for the Treatment of Refractory Lymphoma

Conventional dose combination chemotherapy for patients with relapsed or refractory lymphoma is rarely curative. High dose chemotherapy followed by hematopoietic progenitor cell transplant (HPCT) has a clearly defined role in patients who have first relapsed after standard CHOP chemotherapy for lymphoma. However, the role of HPCT is less well defined for patients with chemo-resistant, or chemo-refractory disease. Sixteen patients (15 Non-Hodgkin's, 1 Hodgkin's Disease) were entered into a phase II study to determine if a dose intensive induction regimen in heavily pre-treated refractory lymphoma patients could permit further consolidation with HPCT. The primary endpoints were survival, response, tox-icity, and resource utilization. The regimen consisted of continuous infusion etoposide I or 2 gm/m2/72 hours, idarubicin 12mg/m2/d for 3 days followed by cytarabine 2gm/m2/72 hours on days 8,9, and 10 (VIC). Fifteen patients were evaluable for objective response. The overall response rate was 53% with 7 patients achieving a partial response and 1 patient achieving a complete response. Of the 8 responders, 6 patients subsequently received high dose chemotherapy followed by HPCT (4 autologous, 2 allogeneic). The median survival was 176 days for the non-responders contrasted with 722 days for the responders. The average duration of hospitalization was 38 days. Toxicity was mainfest primarily as mucositis with a median grade of 3 among the first 13 patients, and a median grade of 2 in three subsequent patients who received an etoposide dose of lgm/m2/72 hours. All patients had an episode of neutro-penic fever and 5 patients developed clinically significant pneumonitis during therapy.The VIC regimen is active in the treatment of chemo-refractory lymphoma with clinically significant differences in survival for patients who respond to therapy. Further modifications to the regimen could include the addition of a topoisomerase I inhibitor for synergy with etoposide, and using VIC as part of a tandem transplant regimen where response to VIC would allow further therapy with a myeloablative induction followed by HPCT.

Chemotherapy with etoposide, vincristine, doxorubicin, bolus cyclophosphamide, and oral prednisone in patients with refractory cutaneous T-cell lymphoma

This Phase II study was undertaken to assess the efficacy and toxicity of chemotherapy with etoposide, vincristine, doxorubicin, bolus cyclophosphamide, and oral prednisone (EPOCH regimen) in patients with advanced, refractory cutaneous T-cell lymphoma (CTCL). Fifteen patients were treated with a 96-hour continuous infusion of etoposide, vincristine, doxorubicin, bolus cyclophosphamide, and oral prednisone, followed by granulocyte-colony stimulating factor support and trimethoprim/sulfamethoxazole prophylaxis. The median age of the patients was 53 years (range, 17-82 years). Six patients had Sézary syndrome (SS), four patients had visceral involvement, and four patients had anaplastic large cell morphology, three with Ki-1 (CD30) positivity. All patients had disease that was refractory to prior chemotherapy or electron beam irradiation and eight of these patients had received cyclophosphamide, doxorubicin, vincristine, and prednisone. Seven patients had received prior interferon therapy and nine patients had received fludarabine and/or 2-CDA. After a median of 5 cycles (range, 1-9 cycles), 4 patients achieved a complete response (27%) and 8 patients achieved a partial response (53%) for an overall response rate of 80% (95% confidence interval, 52-96%). Three patients with visceral involvement, two of three patients with anaplastic large cell morphology, and one patient with human T-cell lymphoma virus leukemia/lymphoma did not respond. All 12 responders had improvement in skin disease; 2 of 6 patients with SS had complete disappearance of circulating Sézary cells. The median progression free survival was 8.0 months (range, 3-22 months). After a median follow-up of 11.4 months (range, 2-56+ months), the median patient survival was 13.5 months. Grade 3 or 4 hematologic toxicity occurred in 8 patients (61%); 5 of these 8 patients had febrile neutropenia. Six patients developed staphylococcal bacteremia, two patients had disseminated herpes infection, and one patient had Pneumocystis carinii pneumonia. Grade 3 neurotoxicity occurred in one patient. Two patients had a significant decrease in left ventricular ejection fraction and one patient had supraventricular tachycardia. EPOCH chemotherapy has a high response rate with acceptable toxicity in patients with advanced and refractory CTCL.

Chemotherapy in soft tissue sarcoma. The Scandinavian Sarcoma Group experience.

The first chemotherapy study of soft tissue sarcoma (STS) by the Scandinavian Sarcoma Group was started in 1981 (SSG I). It evaluated the single agent adjuvant doxorubicin in a randomized setting in patients with high-grade STS. No improvement was noted in the overall survival or disease-free survival rate. More intense chemotherapy was thereafter (1991-1994) evaluated in a phase 2 study, introducing ifosfamide and a continuous infusion of etoposide with growth factor (SSG X). The response rate of previously untreated patients was high (42%), but complete remissions were few. Analysis of patients undergoing surgery after preoperative chemotherapy suggested an increased survival. A recent meta-analysis of adjuvant chemotherapy for localized resectable STS in adults, including the SSG I trial, indicated a better disease-free survival and possibly improved overall survival (Thierny et al. 1997). At present, we are studying whether such a benefit can be shown in patients with high-risk prognostic criteria by giving adjuvant ifosfamide and doxorubicin treatment after primary surgery (SSG XIII). In the latter SSG study, started on July 1, 1998, the adjuvant therapy is evaluated in a phase 2 study in selected patients with high-grade STS and other unfavorable prognostic factors.

Protracted Results of Dose-Intensive Therapy using Cyclophosphamide, Carmustine, and Continuous Infusion Etoposide with Autologous Stem Cell Support in Patients with Relapse or Refractory Hodgkin's Disease: A Phase II Study from the North American Marrow Transplant Group

To determine the long-term results of high-dose chemotherapy and stem cell support in relapsed or primary refractory Hcdgkin disease patients. One hundred and thirty-one patients with relapsed or primary refractory Hodgkin's disease were treated with a dose-intensive therapy protocol consisting of etoposide (2400 mg/m2 continuous intravenous infusion) cyclophosphamide (7200 mg/m2 intravenously), and carmustine (3o(Moo mg/m2 intravenously) CBVi. All patients had previously failed conventional chemoradiotherapy. Severe toxicities were related to infectious, hepatic, and pulmonary complications. Fatal, regimen-related tox-icity was 19%; liver and lung dysfunction, as well as infection, were the most frequent problems. Ninety-one (69%) of the patients achieved a complete response (CR) (95% CI = 59% to 75%) after CBVi and autologous stem cell infusion. With a median follow-up of 5.1 years (range 3.0 to 9.5 years), overall and event-free survival are 44% (95% CI = 33% to 47%) and 38% (95% CI = 28% to 46%) respectively. While univariate analysis did not reveal a statistically significant variable to predict a better response, responsiveness to therapy demonstrated a trend. We conclude that CBVi is an effective therapy for relapsed or refractory Hodgkin's disease, producing long-term, durable remissions.

A randomised, concentration-controlled, comparison of standard (5-day) vs. prolonged (15-day) infusions of etoposide phosphate in small-cell lung cancer

This randomised trial was designed to investigate the activity and toxicity of continuous infusion etoposide phosphate (EP), targeting a plasma etoposide concentration of either 3 micrograms/ml for five days (5d) or 1 microgram/ml for 15 days (15d), in previously untreated SCLC patients with extensive disease. EP was used as a single agent. Plasma etoposide concentration was monitored on days 2 and 4 in patients receiving 5d EP and on days 2, 5, 8 and 11 in patients receiving 15d EP, with infusion modification to ensure target concentrations were achieved. Treatment was repeated every 21 days for up to six cycles, with a 25% reduction in target concentration in patients with toxicity. The study has closed early after entry of 29 patients (14 with 5d EP, 15 with 15d EP). Objective responses were seen in seven of 12 (58%, confidence interval (CI): 27%-85%) evaluable patients after 5d EP, and two of 14 (14%, CI: 4%-42%) evaluable patients after 15d EP (P = 0.038). Grade 3 or 4 neutropenia or leucopenia during the first cycle of treatment was observed in six of 12 patients after 5d EP and 0/14 patients after 15d EP (P = 0.004), with median nadir WBC count of 2.6 x 10(9)/1 after 5d and 5.0 x 10(9)/1 after 15d EP (P = 0.017). Only one of 49 cycles of 15d EP was associated with grade 3 or worse haematological toxicity, compared to 14 of 61 cycles of 5d EP. Although the number of patients entered into this trial was small, the low activity seen at 1 microgram/ml in the 15d arm suggests that this concentration is below the therapeutic window in this setting. Further concentration-controlled studies with prolonged EP infusions are required.

Phase II study of 96-hr continuous-infusion etoposide and doxorubicin with bolus cyclophosphamide in refractory epithelial ovarian cancer: Fleming G.F.; Waggoner S.E.; Rotmensch J.; Skoog L.A.; Langhauser C. USA Gynecol Oncol 1997 65/1 (42–45)

International Journal of Gynecology & ObstetricsVolume 59, Issue 1 p. 92-92 Citations from the literature oncology Phase II study of 96-hr continuous-infusion etoposide and doxorubicin with bolus cyclophosphamide in refractory epithelial ovarian cancer Fleming G.F.; Waggoner S.E.; Rotmensch J.; Skoog L.A.; Langhauser C. USA Gynecol Oncol 1997 65/1 (42–45) First published: 11 May 2004 https://doi.org/10.1016/S0020-7292(97)90186-7AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume59, Issue1October 1997Pages 92-92 RelatedInformation

Phase II Study of 96-hr Continuous-Infusion Etoposide and Doxorubicin with Bolus Cyclophosphamide in Refractory Epithelial Ovarian Cancer

Effective salvage chemotherapy for patients with ovarian cancer who have failed platinum- and taxane-based regimens has not been identified. It has been reported that prolonged infusions of chemotherapy may be active in some malignancies which have become refractory to bolus treatments. We evaluated a regimen of 96-hr continuous-infusion doxorubicin (10 mg/m2/24 hr), etoposide (50 mg/m2/24 hr), and bolus cyclophosphamide (750 mg/m2) administered every 21 days to patients with ovarian cancer who had previously been treated with paclitaxel and a platinum compound. Nineteen women were treated, 15 of whom had platinum-refractory cancer. Six of the first 9 experienced a neutropenic fever after the first treatment cycle, and therefore all subsequent patients received prophylactic granulocyte-colony-stimulating factor. Other significant toxicities included hand and foot syndrome (1 patient) and mucositis (4 patients). There was one partial response in a patient with platinum-sensitive disease. We conclude that this regimen causes significant myelosuppression and does not have major activity in heavily pretreated patients with ovarian cancer.

A Phase I/II Study of a 72‐h Continuous Infusion of Etoposide in Advanced Soft Tissue Sarcoma

Purpose. The study was performed to assess the antitumour activity and toxicity of a 72-h continuous infusion of single-agent etoposide as second-line treatment for patients with locally advanced or metastatic soft tissue sarcoma (STS), following reports of substantial activity using this schedule of etoposide administration as first-line treatment in combination with ifosfamide. Patients/method. This was an open phase I/II trial performed at a single institution in patients with metastatic or locally advanced STS who had failed first-line treatment with doxorubicin + ifosfamide combination chemotherapy or, less commonly, single-agent treatment with doxorubicin or ifosfamide. Etoposide was given as a continuous intravenous infusion over 72 h. The starting dose level was 200 mg m-2 day-1 × 3 escalating in 10% steps in cohorts of three patients until dose-limiting toxicity was encountered. Results. Seventeen patients were treated, median age 47 years (range 26–71 years). No responses were seen in 16 assessable patients despite etoposide levels in the cotoxic range. The steady-state plasma concentration exceeded 8 μg ml−1 in all patients and in patients treated at ≥ 600 mg m −2 the mean steady-state level was 14.4 μg ml −1. The median event-free survival was 6 weeks (95% confidence interval (CI) 3.31–8.69) and the overall survival 16 weeks (95% CI 9.28–22.72). The maximum tolerated dose in this pretreated patient group was 200 mg mm-2 day-1 × 3. The dose-limiting toxicity was myelosuppression. Discussion. Etoposide given by 72-h infusion is inactive as second-line chemotherapy in STS. It is associated with significant toxicity when given in these doses, in this patient group.

Concurrent 72-Hour Continuous Infusion of Etoposide and Cisplatin in Metastatic Breast Cancer

We conducted a multiinstitutional phase II clinical trial to determine the toxicity, response, and survival rate of concurrent 72-h continuous infusion of etoposide and cisplatin in patients with metastatic breast cancer. A total of 26 women were enrolled, 4 of whom received no prior chemotherapy for metastatic disease. All patients were evaluated for toxicity, response, and survival employing the National Cancer Institute (NCI) Common Toxicity Criteria and the Eastern Cooperative Oncology Group (ECOG) response criteria. A total of 84 cycles of therapy were administered, median 3 (range 1 to 6). Severe grade 3 and grade 4 neutropenia occurred in 22 cycles (26%), and there were only 11 episodes (11%) of similar grade thrombocytopenia. Nausea and vomiting were seen in one third of cycles. A single patient (4%) had a complete remission, and seven patients (27%) had partial remissions for an overall objective response rate of 31% (95% confidence interval, 13 to 49%). Three of four patients (75%) without prior therapy for metastatic disease had objective responses. Median survival was 7 months. This combination regimen is active in extensively treated patients with metastatic breast cancer. It is responsible to further investigate the role of etoposide-cisplatin combination chemotherapy as firstline therapy for patients with metastatic breast cancer.

Treatment of advanced, high-grade soft-tissue sarcoma with ifosfamide and continuous-infusion etoposide

Treatment of advanced, high-grade soft-tissue sarcoma with ifosfamide and continuous-infusion etoposide