Intravenous Etoposide Research Articles

Superior Survival in Non-Hodgkin Lymphoma Following Autologous Stem Cell Transplantation with Intravenous Busulfan, Cyclophosphamide, and Etoposide.

Preparative regimens for autologous stem cell transplantation (ASCT) are distinguished mainly by their toxicities, not differences in their antitumor efficacy. Erratic gastrointestinal absorption confers a narrow therapeutic range for oral busulfan-based regimens, whereas the bioavailability and pharmacokinetic (PK) profile of intravenous (IV) busulfan are highly predictable. In a pilot study, we observed better relapse-free survival among lymphoma patients over 50 years old who underwent ASCT after high-dose busulfan, cyclophosphamide, and etoposide (BuCyVP) with IV busulfan in place of oral busulfan. This analysis describes outcomes of ASCT for 604 adult patients with non-Hodgkin lymphoma (NHL) who received IV busulfan (N=136) or oral busulfan (N=468) as part of conditioning with BuCyVP from 1996 through 2007 at the Cleveland Clinic. Oral busulfan was used in the preparative regimen through 10/2004 in patients older than 50 years and through 5/2006 in patients age 50 years or younger; after these dates, IV busulfan was used. The regimen consisted of busulfan (1 mg/kg PO or 0.8 mg/kg IV) Q6 hours x 14 doses; etoposide 60 mg/kg IV over 36 hours; and cyclophosphamide 60 mg/kg IV daily for 2 consecutive days. Busulfan levels were not measured. Patients who received IV rather than oral busulfan were older (median 58 vs. 51 years), had less advanced stage, had diffuse large B-cell NHL (DLBCL) or high-risk IPI scores less frequently, were more heavily pretreated (3 or more regimens in 40% vs. 25%), and received chemotherapy for stem cell mobilization more frequently. Prior radiotherapy, disease status at transplant, and CD34+ cell dose were similar between groups. Mean scores using the Oral Mucositis Assessment Scale (OMAS) during ASCT indicated more severe mucositis with oral busulfan than with IV busulfan (0.90 versus 0.54, P<0.001). Although the times to neutrophil and platelet engraftment were equivalent, median length of stay was 1 day shorter for IV versus oral busulfan (P<0.001). Median follow-up was 69 months versus 15 months for oral and IV busulfan recipients, respectively. Overall survival (OS) and relapse-free survival (RFS) were superior in patients receiving IV versus oral busulfan (median OS not observed versus 72 months, P=0.03; median RFS not observed compared with 31 months, P=0.005). Nonrelapse causes accounted for 65/225 deaths (29%) among oral busulfan recipients and 3/24 deaths (12.5%) among IV busulfan recipients. In multivariable Cox proportional hazards analysis using stepwise selection, IV versus oral busulfan was associated with superior OS (P=0.002) and RFS (P=0.001), and a lower risk of relapse (P=0.013). Other factors significantly associated with improved OS and RFS in multivariable analysis included younger age (OS: P<0.001; RFS: P=0.004), B-cell versus T-cell NHL histology (OS and RFS: P<0.001), less extensive prior therapy (OS and RFS: P<0.001), and chemotherapy-sensitive disease before ASCT (OS and RFS: P<0.001). Relapse was also associated with NHL subtype (T-cell versus others, P<0.001), extent of prior therapy (P<0.001), and disease status (P<0.001). In summary, IV busulfan in conditioning with BuCyVP for ASCT is associated with superior non-relapse mortality, RFS, and OS compared with oral busulfan in patients with NHL. These findings suggest that IV busulfan is not only less toxic but also a more effective anticancer agent than oral busulfan. Alternate dosing schedules and PK-directed dosing may enable the activity of IV busulfan to be optimized further in ASCT for NHL. [Display omitted]

Progress in Small-Cell Lung Cancer: The Lowest Common Denominator

Progress in the therapy of small-cell lung cancer (SCLC), commonly viewed at initial presentation as one of the most highly chemotherapy-sensitive solid tumors, has been painfully slow. In fact, it could be argued that little to no therapeutic advances have been made for extensive stage patients in more than 20 years. In a disease uniquely positioned from its causal biology and growth kinetics to be vulnerable to both new chemotherapeutic drug classes and the wealth of targeted therapeutic agents which have entered clinical development within the last decade, why has so little progress been made? In this issue of Journal of Clinical Oncology, Hermes et al present a randomized trial in extensive SCLC comparing oral etoposide plus carboplatin (EC) to a newer chemotherapeutic regimen of considerable interest: irinotecan and carboplatin (IC). The authors conclude that IC prolongs survival over EC, without compromising quality of life, supporting the use of this regimen as a new standard in SCLC. Viewed from a North American perspective, the Hermes et al trial clearly raises as many questions as it answers. Are the conclusions warranted? Does the regimen share a common denominator with other recent reports in the literature, or is it a one-of-a-kind experience? Finally, does this study truly represent progress in SCLC? To address these questions, we first must consider current treatment perspectives for extensive-stage SCLC. Although regional differences exist, in North America and worldwide, first-line chemotherapy for extensive stage SCLC most commonly consists of a platinum agent (cisplatin or carboplatin) combined with multiday intravenous etoposide. Attempting to build on this platform, several randomized phase III trials, all published in JCO, have disappointingly shown no survival advantage with the addition of topotecan consolidation, paclitaxel, Bec-2 vaccination, or thalidomide to a platinum-etoposide backbone. However, in 2002, the Japan Clinical Oncology Group published the striking results of J9511, a small phase III trial demonstrating the superiority of irinotecan and cisplatin (IP) over etoposide and cisplatin (EP) in response rate, progression-free survival (PFS) and survival, both overall and at 1 and 2 years. Was this the advance we had been waiting for? In view of pharmacogenomic considerations for irinotecan in Japanese populations and the limited patient sample size in J9511 due to Data Safety Monitoring Board–mandated early closure, confirmatory studies were launched. Using a modified dose schedule of IP, Hanna et al were unable to demonstrate superiority over EP. Most recently, at the 2008 Annual Meeting of the American Society of Clinical Oncology, the Southwest Oncology Group reported results of S0124, a large phase III study comparing IP to EP, in which the treatment regimens utilized in J9511 were exactly duplicated. While there were no significant efficacy differences observed between IP and EP in this North American population, a patient-level toxicity comparison of S0124 and J9511 confirmed greater toxicity in the Japanese study. Table 1 compares key parameters regarding patient demographics and end points of the four phase III trials comparing irinotecan and platinum to etoposide and platinum regimens. Clearly, the study by Hermes et al stands out in several ways: eligibility criteria (performance status [PS] 0 to 4 and brain metastases), use of oral etoposide, dose of carboplatin (area under the curve, 4), and age-mandated cycle 1 dose reductions, to name some of the most obvious. These differences in study design and patient characteristics may explain differences in survival outcomes; the Hermes et al trial reports the shortest overall survival times; response rates and PFS were not reported. Moreover, arbitrary dose reductions for patients older than age 70 may also have adversely affected survival times in the Hermes et al study. More than half of all new lung cancer patients are older than 70 years of age. The rationale for empiric age-related dose reductions in the Hermes et al study is unclear because older patients appear to tolerate chemotherapy as equally well as younger patients with similar PS and equal degrees of comorbidities. Potential pharmacogenomic variability in irinotecan metabolism due to genetic polymorphisms of uridine diphosphateglucuronosyltransferase is another dimension worth considering. Both interindividual and population-related differences are well recognized. While this factor was not assessed in the Hermes et al trial, other recent studies suggest it is of clinical significance in predicting the therapeutic index of this agent, including a preliminary report from the S0124 study. In addition, the treatment regimens selected for the Hermes et al trial may have contributed to reduced efficacy in both arms of the study. For example, despite initial enthusiasm, use of oral etoposide has fallen substantially in the United States. This is in part due to interpatient differences in bioavailability and pharmacodynamics, JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 26 NUMBER 26 SEPTEMBER 1

Primary meningeal CNS lymphoma treated with intra-arterial chemotherapy and blood-brain barrier disruption

Diffuse large B-cell lymphoma of the meninges is a particularly rare form of primary CNS lymphoma. We report a case of a 63-year-old woman found to have primary meningeal lymphoma (PML) with dural and leptomeningeal involvement whom we treated with multiple cycles of intra-arterial (IA) methotrexate, intravenous (IV) etoposide phosphate, and IV cyclophosphamide after reversible osmotic blood-brain barrier disruption (BBBD). Improvement was evident on gadolinium-enhanced brain MRI one month into therapy. At 67 months post-diagnosis there is no evidence of CNS disease. After completing her therapy regimen, she remained disease-free for 34 months, when stage IV diffuse large B-cell lymphoma was discovered in her left adrenal gland and right thigh. Following six cycles of rituximab and CHOP treatment, she is presently in complete remission. IA methotrexate and reversible osmotic BBBD without radiation therapy may be an effective therapy for treating PML.

The Effect of Rituximab on Mobilization with AMD3100 Plus G-CSF in Patients with Relapsed or Refractory NHL or HD.

The optimal therapy for patients with chemotherapy sensitive relapsed or refractory lymphoma is high dose therapy followed by autologous hematopoietic stem cell rescue. Rituximab (R) has been added to salvage regimens to increase response rate, thereby making more patients eligible for high dose therapy. However, when R is used prior to the salvage regimen, it has been associated with a delay in platelet engraftment (Hoerr et al, J Clin Oncol. 2004 Nov 15;22:4561–6). We have previously noted in a retrospective review of 117 patients with lymphoma treated with high dose therapy and autologous HSC transplant that concurrent treatment with R did not impact stem cell collection or post transplant engraftment (Kaufman et al, BBMT, February 2005, Sup 1, [11.2] 6). AMD3100 (plerixafor) is a CXCR4 inhibitor that, when used with G-CSF, more effectively mobilizes stem cells than G-CSF alone. In order to test the hypothesis that R does not negatively impact stem cell collection or post-transplant engraftment when AMD3100 is used with G-CSF, we performed a prospective trial of the use of AMD3100, G-CSF and R for patients with CD20 (+) relapsed chemosensitive lymphoma versus the use of AMD3100 and G-CSF for patients with CD20 (−) relapsed chemosensitive lymphoma. Patients were treated with 2 cycles of ICE ± R depending on CD20 status of the malignant cell. Patients who had a response proceeded to mobilization with AMD3100 and G-CSF for the CD20 (−) group (Arm A) or AMD3100, G-CSF, and four weekly doses of R at 375 mg/m2 (two doses prior to G-CSF and AMD3100, and two doses after) for the CD20 (+) group (Arm B). After collection, patients were treated with high dose therapy with targeted intravenous busulfan, etoposide and cyclophosphamide followed by autologous HSC transplantation. Patient demographics, mobilization characteristics, graft yield, engraftment data, and toxicity were assessed. 21 patients have been accrued. 11 in Arm A (10 Hodgkin Lymphoma {HL} and 1 with Peripheral T Cell Lymphoma) and 10 in Arm B (2 HL and 7 NHL, and 1 with a composite HL/NHL). The median number of days of collection was 2 for each arm. The median CD34 (+) collected was 4.64 * 106 CD34+ cells/kg in Arm A compared to 5.25 * 106 CD34+ cells/kg in Arm B (p=0.6) The median number of CD34(+)/CD38(−) was similar for both arms. As expected from in vivo B-cell depletion, the percentage of CD19 (+) cells in the product was decreased in Arm B compared to Arm A (2.24% vs. 0.09%, p<0.002). R treated patients did not experience increased serious adverse events. All patients in both arms had durable and equivalent neutrophil and platelet engraftment (Table 1). In conclusion, rituximab can be administered safely to patients when AMD3100 and G-CSF are used for collection of hematopoietic stem cells. Importantly, no negative impact on graft characteristics or engraftment was perceived. Further trials are planned.Table 1:EngraftmentArm AArm Bp valueN1110CD 20 statusnegativepositiveMedian Day to Neutrophil Engraftment1211.50.39Median Day to Platelet Engraftment17170.72Median Day 100 Total WBC4.03.50.55Median Day 100 Platelet Count1791780.77

Multicenter study of intravenous busulfan, cyclophosphamide, and etoposide (i.v. Bu/Cy/E) as conditioning regimen for autologous stem cell transplantation in patients with non-Hodgkin's lymphoma

The current study aimed to evaluate the efficacy and toxicity of a combination of intravenous busulfan, cyclophosphamide and etoposide (i.v. Bu/Cy/E) as a conditioning regimen prior to autologous hematopoietic stem cell transplantation in patients with non-Hodgkin's lymphoma (NHL). Sixty-four patients with relapsed/refractory (n=36) or high-risk (n=28) lymphoma were enrolled. The high-dose chemotherapy consisted of i.v. Bu (0.8 mg kg(-1) i.v. q 6 h from day -7 to day -5), Cy (50 mg kg(-1) i.v. on day -3 and day -2) and E (400 mg m(-2) i.v. on day -5 and day -4). The median age was 43 (range 18-65) years, and 39 patients were male. Diffuse large B-cell lymphoma (40.6%) was the most common histological subtype. All evaluable patients achieved an engraftment of neutrophils (median, day 12) and platelets (median, day 13). Hepatic veno-occlusive disease was observed in four patients (three mild, one moderate grade), and two patients (3.1%) died from treatment-related complications. At a median follow-up of 16.4 months, 15 patients (23.4%) exhibited a relapse or progression, while 13 patients (20.3%) had died of disease. The estimated 3-year overall and progression-free survival for all patients was 72.1 and 70.1%, respectively. In conclusion, the conditioning regimen of i.v. Bu/Cy/E was well tolerated and seemed to be effective in patients with aggressive NHL.

Dose finding study of oral PSC 833 combined with weekly intravenous etoposide in children with relapsed or refractory solid tumours

PSC 833 is an effective MDR1 reversal agent in vitro, including studies with paediatric cancer cell lines such as neuroblastoma and rhabdomyosarcoma. This study was performed to determine the safety profile, dose limiting toxicity (DLT) and maximum tolerated dose (MTD) in children with solid tumours and to determine the influence of PSC 833 on the pharmacokinetics of co-administered etoposide. Each patient received one cycle of intravenous etoposide (100 mg/m 2 daily for 3 days on three consecutive weeks) to document baseline pharmacokinetics, and subsequently the same schedule using a dose of 50 mg/m 2 was given combined with PSC 833 given orally every 6 h at a starting dose of 4 mg/kg. Thirty two eligible patients (23 male, median age 8.3 years) were enrolled. Neuroblastoma and rhabdomyosarcoma were the common disease types. Brain tumours were excluded. DLT was defined as any non-haematological grade 3–4 toxicity (common toxicity criteria) and using a specific toxicity scale for cerebellar toxicity. The MDT was defined as the first dose below which 2 or more patients per dose level experienced DLT. Grade 1–2 ataxia occurred in cohorts 2 and 3 (4 and 5 mg/kg, respectively). Three patients developed grade 3 neurotoxicity in the 6 mg/kg cohort and this defined the MTD. Six responses were observed (2 CR, 4 PR). Pharmacokinetic studies indicated that the clearance of etoposide was reduced by approximately 50% when combined with PSC 833. It is concluded that the toxicity profile and MDT is similar in both children and adults, as is the effect on etoposide metabolism. The study demonstrated the feasibility and safety of carrying out a paediatric phase 1 trial across European boundaries and acts as a model for future cooperative studies in rare cancers among children.

Pharmacokinetic comparison of oral and intravenous etoposide in patients treated with the CHOEP-regimen for malignant lymphomas

The addition of etoposide to the CHOP protocol (CHOEP) has been shown to improve outcome in patients with aggressive non-Hodgkin's lymphoma. The intravenous administration of etoposide on three consecutive days represents a logistic problem and needs resources particular in the outpatient setting. This could be avoided by using etoposide capsules on days 2 and 3. However, the oral administration of cytotoxic agents is often affected by variable absorption and drug interactions. We investigated the pharmacokinetic equivalency of oral and intravenous etoposide in ten patients (male, n=7; female, n=3; median age 56 years) with aggressive lymphomas. Treatment consisted of standard CHOP plus etoposide 100 mg/m2 given intravenously on day 1, and 200 mg/m2 orally on days 3 and 4. Samples from blood and urine were taken on days 1 (i.v. study) and 3 (p.o. study) before and after etoposide administration. Etoposide levels were determined by high-performance liquid chromatography (HPLC), and pharmacokinetic parameters were calculated with the TOPFIT computer program. Mean peak plasma level after intravenous etoposide was significantly higher compared to oral administration (16.3+/-3.7 vs. 12.0+/-4.2 microg/ml; P=0.015). The mean bioavailability of oral etoposide was 58+/-15% with an interpatient variability of 26%. Significant differences of bioavailability of oral etoposide between the used dose levels (350, 400 and 450 mg) were not observed. Mean AUC after a 100 mg/m2 intravenous and a 200 mg/m2 oral dose of etoposide were 74.0+/-18.3 and 84.9+/-29.6 microg h/ml (P=0.481). Interpatient variability of AUC was 25% for the intravenous route and 35% after oral intake. Urinary etoposide excretion as percentage of administered dose was 39.4+/-10.6% after intravenous infusion versus 35.4+/-9.4% after oral intake (P=0.422). Renal clearance was also very similar with intravenous and oral route (18.5+/-7.4 vs. 16.7+/-6.6 ml/min; P=0.546). The equivalency of AUC after 200 mg/m2 of oral and 100 mg/m2 of intravenous etoposide support the use of the oral preparation in patients treated with the CHOEP regimen, which makes the chemotherapy more convenient for the patients and help to reduce costs.

Topotecan and etoposide as salvage chemotherapy in patients with irinotecan- and platinum-failed small-cell lung cancer: A phase II study

18177 Background: The efficacy and safety of a combined regimen of topotecan and etoposide was tested in patients with relapsed or refractory small-cell lung cancer. Methods: From October 2003 to May 2005, 23 patients who have failed to the previous irinotecan and platinum chemotherapy received intravenous topotecan 1mg/m2 (day 1–5) followed by intravenous etoposide 80mg/m2 (day 1–3). Treatment was repeated every 21 days for a maximum of 6 cycles. Results: Twelve patients were refractory to first-line chemotherapy. Seventeen patients (73.9%) were male and the median age was 63 years. ECOG performance status was 0–1 in 13 (56.5%) patients. The median cycles of chemotherapy was 3. Twenty one patients were assessable for response evaluation. The overall response rate was 17.4% (0 CR, 4 PR, 7 SD, 10 PD) under the intent-to-treat analysis. After a median follow- up of 20.8 months, median progression free survival was 4.7 months and median overall survival was 9.5 months. The estimated 1-year survival rate was 38.7%. In sensitive relapsed patients, 2 achieved tumor response and median progression free survival and overall survival were 5.5 months and 14.5 months. All patients were assessable for toxicity and major toxicities were myelosuppression. Grade 3/4 neutropenia and thrombocytopenia occurred in 18 (78.3%) and 12 (52.2%) patients, respectively. Grade 3/4 febrile neutropenia occurred in 2 patients (8.7 %) and infection in 3 patients (13.0%). There was one treatment-related death due to pneumonia. Conclusions: This salvage regimen failed to demonstrate a considerable response rate compared with monotherapy for relapsed or refractory SCLC. However, the combination of topotecan and etoposide could be further studied for sensitive relapsed patients pretreated with irinotecan and platinum No significant financial relationships to disclose.

Enhanced chemotherapy delivery by intraarterial infusion and blood‐brain barrier disruption in the treatment of cerebral metastasis

Cerebral metastases are clinically significant in 10% to 30% of patients with neoplasia. Multiple cerebral metastases are typically treated with palliative radiotherapy. There is no consensus on the role of enhanced chemotherapy delivery as an adjuvant treatment modality in this disease. In this report, the authors detailed their experience with intraarterial (IA) chemotherapy infusion with and without blood-brain barrier disruption (BBBD) in patients with multiple cerebral metastases. From November 1999 to May 2005, 38 patients with multiple cerebral metastases were enrolled in a prospective study. Patients were treated with IA carboplatin, except for those with cerebral metastases of systemic lymphoma, who were administered IA methotrexate. Osmotic BBBD was offered to patients without the presence of a significant mass effect. These regimens were coupled with intravenous etoposide and cyclophosphamide. Cycles were repeated every 4 weeks. Survival was calculated from study entry and radiologic response was based on MacDonald criteria. Kaplan-Meier estimates were generated for all subgroups. Mean and median survival obtained was as follows: 34 and 29.6 months for the whole group; 33.6 and 42.3 months for ovarian carcinoma; 15.3 and 13.5 months for lung adenocarcinomas; 8.3 and 8.8 months for small cell lung carcinoma; 8.9 and 8.1 months for breast carcinoma; and 24.8 and 16.3 months, respectively, for cerebral metastasis from systemic lymphoma. Even with a small number of patients in each subgroup, the results obtained seem promising for multiple brain metastasis of ovarian carcinoma, adenocarcinoma of lung, small cell lung carcinoma, and systemic lymphoma.

Adult Langerhans Cell Histiocytosis with Independently Relapsing Lung and Liver Lesions That was Successfully Treated with Etoposide

A 35-year-old man initially presented with cough and fever. Computed tomography (CT) revealed diffuse small cysts in the lung, and multiple nodules in the liver. Lung and liver biopsies revealed that pathology was consistent with Langerhans cell histiocytosis. Lung shadows increased despite cessation of smoking, whereas the liver involvement improved. After initiating treatment with prednisolone, the chest CT findings improved. However, the liver nodules started to increase while tapering prednisolone. Intravenous etoposide was started, and the liver nodules decreased markedly. The difference in the clinical course between the lung and liver lesions might have been the result of differences in the clonality of these two organs.

Multiple Granulocytic Sarcomas in Essential Thrombocythemia

A 59-year-old woman was diagnosed with essential thrombocythemia in 1988 and had been treated with hydroxyurea, mitobronitol, busulfan, and ranimustine, in that order. Hepatosplenomegaly, low-grade fever, and body weight loss manifested, and a few blasts were noted in the peripheral blood studied in March 2002. A biopsied specimen of the bone marrow showed myelofibrosis but not a leukemia in August 2004. An abnormal karyotype with der(1; 13) appeared for the first time. She was treated with low-dose prednisolone. In January 2005, she experienced left hip joint pain, and magnetic resonance scanning showed a tumoral lesion in the femoral head. Histological diagnosis of the biopsied mass revealed that it was a granulocytic sarcoma, and radiotherapy was performed. In April 2005, bone scintigraphy showed multiple lesions. She became febrile and red blood cell transfusion-dependent with hepatosplenomegaly and a small number of circulating blasts. Intravenous cytarabine (low dose) and etoposide relieved the fever and hepatosplenomegaly; however, she developed a pathologic fracture of the right humerus. An additional karyotypic abnormality (7q22 deletion) was noted. She subsequently died of infection. Granulocytic sarcoma is very rare in essential thrombocythemia, and this patient may be the first reported case of essential thrombocythemia that developed multiple lesions and a pathologic fracture without transformation to overt leukemia.

Emetic potential of daily oral etoposide

Chemotherapeutic agents are classified by their degree of emetogenicity. Highly and moderately emetogenic agents require antiemetic prophylaxis for chemotherapy-induced nausea and vomiting. Intravenous etoposide is listed as having low emetic potential. However, oral etoposide is categorized as having moderate emetogenicity. Daily oral etoposide is used in refractory germ cell cancer patients. We prospectively evaluated the emetic potential of oral etoposide in this patient population. Between August 2003 and February 2006, 16 patients with refractory germ cell cancer received single-agent, daily oral etoposide 50 mg/M(2) for 21 consecutive days every 4 weeks. All patients had progressed after cisplatin combination chemotherapy and had received high-dose chemotherapy with carboplatin plus etoposide (intravenously) with peripheral blood stem cell transplant. No patient received prophylactic antiemetics. Patients completed a six-question Multinational Association of Supportive Care in Cancer (MASCC) antiemetic tool during each day of etoposide during the first 21-day course. Nausea intensity and duration were recorded. Number of emetic episodes and any antiemetic medications were recorded. All 16 patients completed the six-question MASCC form. Eleven of 16 had no nausea or vomiting and two other patients had only minimal nausea, despite absence of any prophylactic antiemetics. Only two patients required antiemetic support. Two patients experienced emesis for a single episode. One patient had nausea on days 9-20 with a MASCC rating of 3-6, and one patient had continued mild nausea (MASCC rating 1-3) for all 21 days. Daily oral etoposide has a low probability of producing chemotherapy-induced nausea and/or vomiting and, in our opinion, does not require prophylactic antiemetics.

Multicenter study of intravenous busulfan, cyclophosphamide, and etoposide (IV Bu/Cy/VP-16) as conditioning regimen for autologous stem cell transplantation in patients with non-Hodgkin’s lymphoma

17544 Background: The current study aimed to evaluate the efficacy and toxicity of the combination of intravenous busulfan, cyclophosphamide, and etoposide (IV Bu/Cy/VP-16) as a preparative regimen prior to autologous hematopoietic stem cell transplantation (ASCT) in patients with non-Hodgkin’s lymphoma (NHL). Methods: Forty patients with relapsed (n = 24) or high-risk (n = 16) lymphoma were enrolled into the study. High-dose chemotherapy consisted of intravenous busulfan (0.8 mg/kg i.v. q 6 hr from day-7 to day-5), cyclophosphamide (50 mg/kg i.v. on day-3 and day-2), and etoposide (400 mg/m2 i.v. on day-5 and day-4). Results: The median age of patients was 34 years (range, 17–63 years), and 21 (52.5%) patients were male. Pathologic subtypes were as follows: diffuse large B cell (n = 20), peripheral T cell, unspecified (n = 8), extranodal NK/T cell (n = 4), angioimmunoblastic T cell (n = 3), anaplastic large cell (n = 4), nodal marginal zone B cell (n = 2), and lymphoblastic (n = 3). The median dose of infused CD34+ cells and MNC was 3.95 (range, 0.7–20.6) × 106 and 8.12 (range, 3.0–13.6) × 108, respectively. WBC and platelet were successfully engrafted after ASCT in all patients, and the median days of engraftment of WBC and platelet was 12 (range, 9–48) and 27 (range, 8–263) days, respectively. After the ASCT, 34 complete responses (CR; 85.0%) and 4 partial responses (PR; 10.0%) were confirmed. Thirty-three (82.5%) patients experienced a fever without documented infection, while 2 patient developed fungal infection. However, there was no treatment-related death. After median follow-up duration of 360 (range, 83–639) days, 33 patients are in continuous complete remission, 4 patients are alive in relapse, and 3 patients died of disease. The estimated event-free and overall survival rate at 1.5-year was 80.9 ± 10.0 % and 92.5 ± 5.7 %, respectively. Conclusions: IV Bu/Cy/VP-16 was found to be well-tolerated and effective as a conditioning regimen in patients with NHL. Accordingly, this regimen can be regarded as an alternative high-dose treatment option in the ASCT for NHL. No significant financial relationships to disclose.

Emetic potential of daily oral etoposide

18618 Background: Chemotherapy agents are classified by their degree of emetogenicity. Agents with high or moderate emetogenicity are treated with a 5HT3 antagonist + dexamethasone to mitigate acute and delayed chemotherapy-induced nausea and vomiting. Intravenous etoposide (E) has low probability of nausea and/or vomiting. However, at the 2004 Perugia International Antiemetic Consensus meeting, oral E was listed as a moderately emetogenic drug (Supp Care Cancer 13:80–84, 2005). Daily oral E has been used to treat refractory germ cell cancer. We prospectively evaluated the emetic potential of daily oral etoposide in this patient (pt.) population. Methods: Between 8/03 and 12/05, 13 male pts. with refractory germ cell cancer were treated with single agent daily oral E 50 mg/M2 day × 21 days every 4 weeks. All had progressed following cisplatin combination chemotherapy and had previously received high dose chemotherapy with carboplatin + E (intraveneously) with peripheral blood stem cell transplant. Median age was 35 (range 14 to 54). No pt. received prophylactic antiemetics. Pts. completed a 6 question Multinational Association Supportive Care Cancer (MASCC) antiemetic tool each day they received E. Intensity and duration of nausea were recorded, with 0 being none and 10 being most severe. Additionally, pts. were asked if they experienced vomiting. The number of vomiting episodes as well as any antiemetic medications were recorded. Data on 25 pts. will be presented and we currently have information on 13 pts. Results: 13 pts. completed the MASCC form. Only 2 pts. required antiemetic support. 1 pt. experienced emesis × 1 on day 1 and 1 pt. experienced emesis × 1 on day 11. 1 pt. experienced nausea on days 9 through 20 with a MASCC rating of 3–6. 1 pt. documented nausea day 1 through 21 with a MASCC rating of 1–3. 2 pts. experienced a MASCC rating of 1 of their nausea, 1 pt. on day 1 and 1 pt. on day 2. Overall, 8 of 13 pts. had no nausea or vomiting despite the absence of any antiemetics and 2 other patients had only minimal nausea for a single day. Conclusions: Daily oral E has only a low probability of emesis and does not require prophylactic antiemetics. [Table: see text]

Primary spinal yolk sac tumor with brain metastasis: case report and review of the literature

Central nervous system primary germ cell tumors are typically pineal or suprasellar. Primary germ cell tumors of the spinal axis are very rare, with only a few case reports of germinomas and teratomas described in the literature. We present the unique case of a 25-year-old woman with an intradural, extramedullary primary yolk sac tumor (YST) at and below the level of the conus medullaris. The patient was treated with a subtotal resection and within a month had rapid regrowth of her YST. She was subsequently treated with four cycles of chemotherapy (intravenous cisplatin and etoposide), 40-Gy fractionated focal external beam radiation to the spine, and consolidation with four additional cycles of chemotherapy (intravenous carboplatin, vinblastine, etoposide, and bleomycin). Despite an initial reduction in tumor size and clinical improvement in her neurologic exam, she re-presented a year after surgery with gross enlargement of her spinal tumor and CSF dissemination with metastasis to her brain. Despite further chemotherapy and radiotherapy, the patient died from her disseminated YST. This case demonstrates that primary YSTs may occur in the spine, and like their intracranial counterparts, are associated with poor prognosis and dissemination through the neuroaxis. When feasible (no evidence of CSF dissemination, metastasis, or multifocal disease), optimal treatment includes as extensive resection of tumor as possible followed by adjuvant chemotherapy and radiation. The authors review the available literature on the treatment of intracranial malignant germ cell tumors, extrapolated to apply to the much rarer spinal lesions.

Open-Label, Multicenter, Randomized, Phase III Study Comparing Oral Topotecan/Cisplatin Versus Etoposide/Cisplatin As Treatment for Chemotherapy-Naive Patients With Extensive-Disease Small-Cell Lung Cancer

This open-label, randomized, multicenter phase III study compared oral topotecan/intravenous cisplatin (TC) with intravenous (IV) etoposide/cisplatin (PE) in patients with untreated extensive-disease small-cell lung cancer (ED-SCLC). A total of 784 patients were randomly assigned to either oral topotecan 1.7 mg/m2/d x 5 with IV cisplatin 60 mg/m2 on day 5 (n = 389) or IV etoposide 100 mg/m2/d x 3 with IV cisplatin 80 mg/m2 on day 1 (n = 395) every 21 days. Overall survival (primary end point) was similar between groups (P = .48; median: TC, 39.3 weeks v PE, 40.3 weeks). One-year survival was 31% (95% CI, 27% to 36%) in both groups and the difference of -0.03 (95% CI, -6.53 to 6.47) met the predefined criteria of < or = 10% absolute difference for noninferiority of TC relative to PE. Response rates were similar between groups (TC, 63% v PE, 69%). Time to progression was slightly but statistically longer with PE (log-rank P = .02; median: TC, 24.1 weeks v PE, 25.1 weeks). The regimens were similarly tolerable. Grade 3/4 neutropenia occurred more frequently with PE (84% v 59%), whereas grade 3/4 anemia and thrombocytopenia occurred more frequently with TC (38% v 21% and 38% v 23%, respectively). Lung Cancer Symptom Scale scores were statistically better with PE, but the differences were small and of debatable clinical significance. Oral topotecan with cisplatin provides similar efficacy and tolerability to the standard (etoposide with cisplatin) in untreated ED-SCLC and may provide greater patient convenience compared with intravenous etoposide and cisplatin.

Osmotic blood–brain barrier disruption chemotherapy for diffuse pontine gliomas

The prognosis for patients with diffuse pontine gliomas (DPG) remains poor. New aggressive innovative treatments are necessary to treat this disease. From 1984 to 1998, eight patients (4M/4F), median age 11 years, with DPG were treated with monthly osmotic blood-brain barrier disruption (BBBD) chemotherapy using intraarterial carboplatin or methotrexate and intravenous cytoxan and etoposide. Patients presented for a median duration of 6 weeks with increased intracranial pressure, long tract signs, diplopia, ataxia, and nausea/vomiting. DPG was demonstrated on magnetic resonance (MR) imaging in seven patients and on CT in one. Two patients had biopsies that showed an astrocytoma and an anaplastic astrocytoma. Three tumors enhanced on MR imaging after contrast administration. Three patients had radiation therapy before BBBD chemotherapy and four afterwards. Two patients had chemotherapy (tamoxifen, topotecan) before BBBD chemotherapy and two afterwards. In general, patients were evaluated with MR imaging every 3 months to monitor for a response to treatment. The median number of chemotherapy cycles that were administered by BBBD was 10, mean 10. Three patients also received one, two, or three cycles of intraarterial chemotherapy without BBBD. One patient that was started on carboplatin was converted to methotrexate, and five that were started on the methotrexate protocol were later converted over to carboplatin. One patient received monthly methotrexate followed by 14 days of procarbazine and one patient started on methotrexate was switched to navelbine. MR imaging demonstrated two partial responses, five patients with stable disease, and one with disease progression. The median time to tumor progression was 15 months with the range from <1 to 40 months. The median survival from the time of diagnosis was 27 months, ranging from 7 to 80 months. The median survival time from the first BBBD or intraarterial treatment was 16.5 months, ranging from 5 to 69 months. One patient was lost to follow-up with an unknown date of death. Although the sample size is small, the TTP and survival times are longer than those previously reported in other DPG series. In addition, the ability to demonstrate stable disease or partial responses in DPG on MR imaging argues for the therapeutic benefit of BBBD chemotherapy. The enhanced delivery of chemotherapy afforded by osmotic BBBD supports the further examination of this treatment modality for patients with DPG.

Long-term Visual Outcome Following Chemoreduction for Retinoblastoma

To evaluate long-term visual outcome following chemoreduction. Interventional case series evaluating 54 eyes of 40 children with retinoblastoma successfully treated with chemoreduction, consisting of a combination of intravenous carboplatin, etoposide phosphate, and vincristine sulfate plus focal therapy without external beam radiotherapy or enucleation. All patients were followed up for at least 5 years. Patient and tumor data were analyzed for their effect on the main outcome measures (final visual acuities of 20/40 or better and of 20/200 or better) using univariate and multivariate regression models. Patients who failed chemoreduction were excluded. There were 4 eyes in Reese-Ellsworth group I, 7 in group II, 3 in group III, 15 in group IV, and 25 in group V. The mean distance from the posterior tumor margin to the optic disc was 2 mm, and from the tumor margin to the foveola it was 3 mm. After a mean follow-up of 68 months, 27 eyes (50%) had a final visual acuity of 20/40 or better, and 36 eyes (67%) had final visual acuity of 20/200 or better. Of 33 eyes with macular tumor, only 8 (24%) had a final visual acuity of 20/40 or better, and 15 (45%) had a final visual acuity of 20/200 or better. Of 21 eyes with extramacular tumor, 19 (90%) had a final visual acuity of 20/40 or better, and all (100%) had a final visual acuity of 20/200 or better. The clinical factors that predicted visual acuity of 20/40 or better were a tumor margin at least 3 mm from the foveola and optic disc and an absence of subretinal fluid.

Clinical pharmacological profile of etoposide in elderly patients with lung cancer

AbstractTo clarify the clinical pharmacological profile of etoposide in the elderly, we carried out prospective therapeutic drug monitoring in 14 patients with advanced lung cancer aged 75 or more years. The patients received 50 mg etoposide as oral capsules for 21 consecutive days during the first course, and intravenous etoposide for 3 days during the second course of palliative treatment. Plasma and urine samples were collected on days 1 and 21 of the first course and day 1 of the second course, and etoposide concentrations were measured using high‐performance liquid chromatography. We compared these data with those obtained from 17 adult patients under 75 years old who participated in our previous study of combined oral etoposide/carboplatin chemotherapy. Within the elderly group, no significant differences in the area under the concentration‐versus‐time curve, elimination half‐life, plasma clearance, urinary excretion or bioavailability of oral etoposide were observed between day 1 and day 21. However, the mean (±SD) elimination half‐lives for elderly and adult patients were 10.3 ± 1.9 h and 5.8 ± 2.5 h, respectively, while the mean (±SD) bioavailabilities were 62.8 ± 27.5% and 37.4 ± 15.4%; both were significantly increased in the elderly patients. Our previously proposed limited sampling model was validated using the elderly data set and proved to be unbiased and precise. In conclusion, although no accumulation of oral etoposide was observed in elderly patients, there were age‐dependent changes in its pharmacokinetics, especially in bioavailability.

Topotecan and etoposide as first-line therapy for extensive disease small cell lung cancer: a phase II trial of a platinum-free regimen

In the treatment of extensive disease of small cell lung cancer (ED SCLC) there is an urgent need for more effective and better-tolerated drug regimens. We report on a prospective phase II trial performed to evaluate the efficacy and safety of a platinum-free regimen--containing topotecan and etoposide--in the first-line treatment of ED SCLC. Between December 1999 and July 2001, 28 chemotherapy-naive patients with ED SCLC were recruited; 9 patients had stage IIIB disease and 19 patients had stage IV disease. Based on phase I results, patients received treatment with intravenous topotecan 1 mg/m2 (days 1-5) followed by intravenous etoposide 75 mg/m2 (days 8-10). Treatment courses were repeated every 28 days for a maximum of 6 cycles. A confirmed response rate of 46.4% with 1 complete response (CR) and 12 partial responses (PR) (95% CI=27.5-66.1%) was observed. Stable disease (SD) was observed in 18% of patients. The median time to response was 7.9 weeks (range: 7.7-15.1 weeks) and median survival was 29.9 weeks (range from 3.3 to 91.4 weeks). Main toxicities encountered were haematological with Grade III/IV neutropenia in 2.6/1.5% of courses and Grade III/IV thrombocytopenia in 1.8%/0.7% of courses. These toxicities were manageable and were not associated with clinical sequels. Non-haematological toxicities were generally mild with no Grade III/IV toxicities reported apart from Grade III alopecia. The combination therapy of topotecan and etoposide is active in first-line chemotherapy for patients with ED SCLC. The regimen showed a tolerable safety profile. Since drug scheduling plays a critical role in the combination of topoisomerase I and II inhibitors, concurrent administration of topotecan and etoposide might increase the efficacy.