Treatment of metastatic Ewing's sarcoma or primitive neuroectodermal tumor of bone: evaluation of combination ifosfamide and etoposide--a Children's Cancer Group and Pediatric Oncology Group study.

PURPOSE: One hundred twenty patients with metastatic Ewing's sarcoma or primitive neuroectodermal tumor (PNET) of bone were entered onto a randomized trial evaluating whether the addition of ifosfamide and etoposide to vincristine, doxorubicin, cyclophosphamide, and dactinomycin improved outcomes. METHODS: Thirty-two patients had metastases to lungs only, 12 patients had metastases to bone marrow or bones only, 64 patients had metastases in multiple sites, and five patients had metastases in other sites; seven patients could not be assessed precisely. Treatment comprised 9 weeks of chemotherapy before local control and 42 weeks of chemotherapy; thereafter, regimen A consisted of vincristine 2 mg/m(2), cyclophosphamide 1,200 mg/m(2), and either doxorubicin 75 mg/m(2) or dactinomycin 1.25 mg/m(2). Regimen B consisted of regimen A alternating every 3 weeks with ifosfamide 1,800 mg/m(2)/d for 5 days and etoposide 100 mg/m(2)/d for 5 days. RESULTS: Patients treated on regimen B did not have significantly better survival than those treated on regimen A. The event-free survival (EFS) and survival (S) at 8 years were 20% (SE, 5%) and 32% (SE, 6%), respectively, for those treated on regimen A and 20% (SE, 6%) and 29% (SE, 6%), respectively, for those treated on regimen B. Patients who had only lung metastases had EFS and S of 32% (SE, 8%) and 41% (SE, 9%), respectively, at 8 years. There were six toxic deaths (5%), four from cardiac toxicity and two from sepsis (four treated on regimen B and two treated on regimen A). Two had second malignant neoplasms. CONCLUSION: Adding ifosfamide and etoposide to standard therapy does not improve outcomes of patients with Ewing's sarcoma or PNET of bone with metastases at diagnosis.     

Ifosfamide plus etoposide in newly diagnosed Ewing's sarcoma of bone.

PURPOSE: We assessed the activity of ifosfamide plus etoposide against newly diagnosed Ewing's sarcoma of bone by administering this drug pair before standard induction therapy (the upfront window approach). PATIENTS AND METHODS: Twenty-six children and adolescents with newly diagnosed, previously untreated Ewing's sarcoma of bone were enrolled onto this pilot study (EW-87). Eighteen were at a higher risk of treatment failure, with a primary tumor size of more than 8 cm or metastases at diagnosis. Window therapy with ifosfamide (1.6 g/m2/d with mesna uroprotection) and etoposide (100 mg/m2/d) was given in three 5-day cycles at 21-day intervals. Responses were evaluated clinically and radiologically. Subsequent induction therapy comprised three cycles of cyclophosphamide and doxorubicin. Radiation therapy was the primary local control modality; surgery was limited to biopsy or resection of expendable bones. After the local control phase, alternating courses of vincristine plus dactinomycin, ifosfamide plus etoposide, and cyclophosphamide plus doxorubicin were given as maintenance therapy. RESULTS: There were four complete responses and 21 partial responses to ifosfamide/etoposide window therapy (overall response rate 96%; 95% confidence interval [CI], 80% to 99%). Disease progression was observed in four patients during the cyclophosphamide/doxorubicin phase. Chemotherapy was well tolerated; only 16% (20 of 125) of all ifosfamide/etoposide window and maintenance cycles resulted in hospitalization for fever and neutropenia. Two patients developed chemotherapy-induced cystitis. CONCLUSIONS: The combination of ifosfamide and etoposide is highly active against previously untreated Ewing's sarcoma and generally is well tolerated. The ultimate impact of these two agents on outcome will be determined in randomized multicenter studies.     

Peripheral blood stem cell support reduces the toxicity of intensive chemotherapy for children and adolescents with metastatic sarcomas

BACKGROUND: To increase the dose intensity (DI) of chemotherapy for pediatric patients with metastatic sarcomas, including the Ewing sarcoma family of tumors (ESFT) and rhabdomyosarcoma (RMS), the authors tested the feasibility of an intensive regimen supported by granulocyte-colony stimulating factor (G-CSF) and peripheral blood stem cells (PBSC). METHODS: Twenty-three children and adolescents with metastatic sarcomas received vincristine, doxorubicin, cyclophosphamide, ifosfamide, sodium mercaptoethanesulfonate (mensa), and etoposide (VACIME) chemotherapy, consisting of 8 courses of vincristine 2 mg/m(2) on Day 0, doxorubicin 37.5 mg/m(2) per day on Days 0-1, cyclophosphamide 360 mg/m(2) per day on Days 0-4, ifosfamide 1800 mg/m(2) per day on Days 0-4, mesna 2400 mg/m(2) per day, and etoposide 100 mg/m(2) per day on Days 0-4. Doxorubicin was omitted in Courses 7 and 8. G-CSF was given after each course of therapy. Courses of therapy were repeated every 21 days or as soon as hematopoietic recovery permitted. PBSC were collected twice: first, after Course 2 (infused after Courses 3 and 4) and, second, after Course 4 (infused after Courses 5 and 6). Surgical resection followed Course 6, and radiotherapy followed Course 8. RESULTS: PBSC collections were adequate in 91% of all harvests. The mean DI was 82% (standard deviation, 14%) of the intended DI, which was greater than historic data without PBSC support. Seventeen patients (74%) achieved a complete response (CR), 12 patients with chemotherapy alone and 5 more patients after undergoing surgical resection. Fifteen patients developed progressive disease, with a 2-year event free survival (EFS) rate of 39% (95% confidence interval, 19-59%). Hematopoietic toxicity was severe and cumulative, although it was less than that seen previously without PBSC support. CONCLUSIONS: PBSC-supported multicycle chemotherapy is a feasible method to increase chemotherapy DI for pediatric patients with metastatic sarcomas. Although the CR rate compared favorably with previously reported response rates, the 2-year EFS rate was similar to that achieved with other intensive regimens.     

Randomized phase II evaluation of 6 g/m2 of ifosfamide plus doxorubicin and granulocyte colony-stimulating factor (G-CSF) compared with 12 g/m2 of ifosfamide plus doxorubicin and G-CSF in the treatment of poor-prognosis soft tissue sarcoma.

PURPOSE: The relative value of increasing ifosfamide dose in combination chemotherapy for patients with soft tissue sarcoma (STS) is unclear. The purpose of this study was to compare the efficacy and toxicity of doxorubicin with high-dose (HD) ifosfamide or standard-dose (SD) ifosfamide in patients with STS. PATIENTS AND METHODS: Chemotherapy-naive patients with STS were randomly assigned to receive doxorubicin 60 mg/m(2) and either SD ifosfamide (1.5 g/m(2)/d, days 1 through 4) or HD ifosfamide (3.0 g/m(2), days 1 through 4) every 21 days. Patients were stratified by the presence or absence of metastatic disease. End points were overall survival (OS), 1-year disease-free survival (DFS), and toxicity. RESULTS: The study group consisted of 79 patients (52 patients with localized disease and 27 patients with metastases). Both groups were well-balanced with respect to known prognostic factors. There was no significant difference in 1-year DFS comparing SD ifosfamide with HD ifosfamide (55% v 52%; P = .81). For SD ifosfamide, 2- and 3-year OS were 73% and 52% versus 57% and 49% for HD ifosfamide (P = .34). The incidence of grade 3/4 neutropenia, anemia, and thrombocytopenia were 49%, 23%, and 10%, respectively, on the SD ifosfamide arm, compared with 88%, 58%, and 63%, respectively, on the HD ifosfamide arm. There were five early deaths, all on the HD ifosfamide arm. CONCLUSION: When combined with doxorubicin, HD ifosfamide did not improve 1-year DFS and OS. Toxicity was clearly greater with the HD ifosfamide arm, and lack of outcome differences might be explained by toxicities with HD ifosfamide. These results suggest that HD ifosfamide combination regimens should not be used as first-line therapy for patients with STS.     

A phase III comparison of etoposide/cisplatin with or without added ifosfamide in small-cell lung cancer.

A total of 92 patients with small-cell lung cancer (SCLC) were randomized to receive cisplatin (80 mg/m2, day 1)/etoposide (100 mg/m2, days 1, 3, 5) (PE) or cisplatin (80 mg/m2, day 1)/etoposide (100 mg/m2, days 1, 3, 5)/ifosfamide (2 g/m2, days 1, 2, 3) (PEI) combination chemotherapy. After 2 courses of chemotherapy, patients with limited disease (LD) received chest irradiation of 40-50 Gy. Of the 89 patients who could be wholly evaluated, the overall response rate was 78% for PE and 74% for PEI therapy (NS). For all patients the complete response (CR) rates were 14 versus 21%, respectively, and 22 versus 30% for LD. However, the median survival times for all patients were 55 weeks for PE therapy versus 56 weeks for PEI therapy (NS). The 2-year survival rates were 15 and 17%, respectively, for all patients (NS). There was no difference in the duration of response between PE and PEI therapy in cases with CR or partial response. However, severe leukopenia (< 2,000/mm3) occurred more often after PEI (73%) than after PE (44%) therapy (p < 0.05). These results suggest that PEI is not superior to PE chemotherapy in SCLC. The use of ifosfamide in multimodality treatment regimens needs to be studied further.     

Adjuvant bleomycin, vincristine and cisplatin (BOP) for high-risk stage I non-seminomatous germ cell tumours: a prospective trial (MRC TE17)

Adjuvant BEP (bleomycin, etoposide, cisplatin) is effective treatment for high-risk clinical stage I (HRCS1) non-seminomatous germ cell tumours (NSGCT), but the known toxicities of etoposide, and the expansion of the HR group to any patient with vascular invasion (50% of patients), led the Medical Research Council to pilot the BOP regimen. Patients received two courses of BOP 14 days apart: cisplatin 50 mg m(-2) days 1 and 2, vincristine 1.4 mg m(-2) (max. 2 mg) days 2 and 8, bleomycin 30,000 IU days 2 and 8. Primary outcome was relapse rate; quality of life, fertility, hearing and lung function were assessed pre- and post-treatment. In all, 100 patients were required. A total of 115 eligible patients were registered, all received two courses of chemotherapy. Median follow-up is 70 months; two relapses have occurred and the 5-year relapse-free rate is 98.3% (95% confidence interval (CI) 95.5%, 99.9%). As assessed by clinicians during treatment, complete (reversible) alopecia was present in 20% of patients; World Health Organization (WHO) grade 1/2 neurotoxicity was present in 41%/5% of patients during treatment and 22%/1% at 6 months. However, 12% of patients reported 'quite a bit' or 'very much' pain/numbness/tingling in hands/feet 2 years after chemotherapy. Mature follow-up confirms high efficacy for two courses of cisplatin-based adjuvant chemotherapy in HRCS1 NSGCT. Substituting vincristine for etoposide decreases alopecia, but gives a low incidence of significant neuropathy. There are no clearcut advantages to 2 x BOP over 2 x BEP, except for patients who wish to maximise the chance of avoiding significant alopecia.     

The efficacy of a combination of etoposide, ifosfamide, and cisplatin in the treatment of patients with soft tissue sarcoma

BACKGROUND: Successful chemotherapy for patients with soft tissue sarcoma (STS) has been limited by a lack of active drugs. The most effective single agents are doxorubicin, dacarbazine, and, more recently, ifosfamide. Previously the most widely used combination has been CYVADIC (cyclophosphamide, vincristine, doxorubicin, and dacarbazine). In one randomized trial, ifosfamide was superior to cyclophosphamide; two nonrandomized studies also reported favorable results. Etoposide monotherapy was successful in 8%; the effectiveness of cisplatin was 5-23%. In view of these findings, the authors treated STS patients with an etoposide, cisplatin, and ifosfamide (VIP) combination. METHODS: The eligibility criteria included histologically confirmed, inoperable, metastatic or locally recurrent STS; a World Health Organization (WHO) performance status of 0-2; a maximum age of 75 years; and progressive, measurable disease. A total of 104 patients were treated from January 1990 to June 1997. The median age of the patients was 42.4 years. The patients were treated with a combination of etoposide (100mg/m(2) for 5 days), ifosfamide (2000 mg/m(2) for 2 days), and cisplatin (20mg/m(2) for 5 days) once a month via a peripheral vein. The treatment response and the toxicity were assessed according to WHO criteria. RESULTS: Of 104 evaluable patients, 47 responded. The overall response rate was 46% (complete response: 10%; partial response: 36%). In 43 patients the disease remained stable (41%). Remission duration was 4.6 months. Toxicity was moderate. The main adverse events were alopecia (100%), nausea and vomiting (73%), and leukopenia (29%). CONCLUSIONS: This new combination is promising for the treatment of patients with advanced STS.     

Characterization of human soft-tissue sarcoma xenografts for use in secondary drug screening.

We have established ten transplantable human soft-tissue sarcoma (STS) xenografts grown as subcutaneous tumours in the nude mouse. Nine xenografts originated from patients that needed chemotherapy in the course of their disease. The xenografts were tested for their sensitivity to maximum tolerated doses of five anti-cancer agents. Growth of treated tumours was expressed as a percentage of control tumour growth and a growth inhibition > 75% was measured for doxorubicin in 20% of the STS xenografts, for cyclophosphamide in 30%, for ifosfamide in 20%, for vincristine in 20%, whereas etoposide was not effective in the STS xenografts. In three out of ten STS xenografts MDR1 mRNA was detectable, but this was not related to the resistance against doxorubicin, vincristine or etoposide. Topoisomerase IIalpha mRNA expression levels did not reflect sensitivity to doxorubicin or etoposide. In all STS tissues, however, these levels were lower than topoisomerase IIalpha mRNA in a drug-sensitive human ovarian cancer xenograft. Glutathione concentrations and the activities of glutathione S-transferase, glutathione peroxidase and glutathione reductase were not related to resistance against the alkylating agents or doxorubicin. Of interest, in all STS tissues, glutathione S-transferase pi was the predominant isoenzyme present. In conclusion, chemosensitivity of the STS xenografts reflects clinical response rates in phase II trials on the same compounds in adult STS patients. Relatively low levels of topoisomerase IIalpha mRNA may partly account for intrinsic resistance against, for example, doxorubicin. Additional factors must contribute to moderate responsiveness to alkylating agents.     

Ifosfamide, cisplatin and etoposide combination in locally advanced inoperable non-small-cell lung cancer: a phase II study

From March 1993 to February 1997, 43 eligible patients with inoperable stage IIIA (ten patients) and stage IIIB (33 patients), histologically confirmed NSCLC received 3 courses of the ICE combination (ifosfamide 1.5 g m(-2) and mesna 750 mg m(-2) two times a day, cisplatin 25 mg m(-2) and etoposide 100 mg m(-2), all administered intravenously (i.v.) on days 1-3 every 3 weeks) with G-CSF support. After three cycles, patients were submitted to radical surgery or received two additional courses of the ICE regimen and/or curative radiotherapy. Grade 3-4 neutropenia occurred in 21% of 114 evaluable courses, but was of short duration, leading to neutropenic fever in 5% of the courses. Severe thrombocytopenia and anaemia were observed in 13% and 3% of the courses respectively. Non-haematological toxicity was generally mild with only two episodes of reversible renal impairment. The overall response rate after three chemotherapy courses was 69% (28 partial responses, one complete response). Ten patients (8/10 patients in stage IIIA, 2/33 patients in stage IIIB) underwent radical surgery. Median TTP for patients not undergoing surgery (n = 33) was 8 months (range 3-34+); median DFS for patients rendered NED by surgery (n = 10) was 26 months (range 1-54+). Median OS for the entire group was 12.5 months (range 2-57+). The ICE regimen is active in locally advanced NSCLC with acceptable toxicity and warrants further exploration as induction chemotherapy in larger series.     

Salvage therapy with high-dose chemotherapy and autologous bone marrow support in the treatment of primary nonseminomatous mediastinal germ cell tumors.

The authors reported their experience with the use of high-dose chemotherapy and autologous bone marrow rescue (ABMR) as salvage therapy in the treatment of patients with recurrent and refractory primary nonseminomatous mediastinal germ cell tumors (PMGCT). Since 1987, the authors have treated 12 patients with PMGCT with high-dose carboplatin (1500 mg/m2 to 1800 mg/m2) and etoposide (1200 mg/m2 to 1350 mg/m2) (in two patients ifosfamide [10 g/m2] was added) with ABMR. Patients were either in second relapse or cisplatin refractory (progression within 4 weeks of last cisplatin dosing). They had received a median of two prior chemotherapy regimens (range, one to three), all had had prior cisplatin therapy, and most had failed ifosfamide-based therapy. Six patients were cisplatin refractory and of these only one achieved a partial response (PR) that was of short duration. It was planned that all patients would undergo two rounds of therapy; however, only 5 of 12 patients received two courses. The remainder had only one round of therapy either because of inadequate response (three patients) or excessive toxicity (four patients). There were four patients who died in the peritransplant period due to sepsis (two patients) or bleeding (two patients). The median survival of the group was 107 days (range, 14 days to 347 days). No patient achieved a complete remission, but there were six partial remissions, four with stable disease, and two with progressive disease. The use of high-dose carboplatin and etoposide with or without ifosfamide and ABMR was not effective in the treatment of this group of patients with PMGCT who were in second relapse or cisplatin refractory.     

High dose chemotherapy with G-CSF in refractory Hodgkin's disease

This study analyzed the long-term results in patients with Hodgkin's disease (HD) who were resistant or refractory to conventional chemotherapy and who were treated with intensive, non-myeloablative chemotherapy with granulocyte colony-stimulating factor (G-CSF) as hematological support. The study population included 86 patients who were treated with combination chemotherapy with high doses: BCNU, 300 mg/m2, on day 1, vincristine 1.4 mg/m2, and bleomycin 10 mg/m2 on days 1, 7, 14 and 21; etoposide 500 mg/m2, i.v., on days 14 and 15; and ifosfamide 4 g/m2, and epirubicin 180 mg/m2, on day 29. G-CSF 5 ug/kg/day, was used to ameliorate severe myelosuppression on days 3 to 13, 16 and 26 and 29 to 38. If a complete response was observed, two cycles of IOPP (ifosfamide 1.5 g/m2, i.v., on days 1 and 8; vincristine 1.4 mg/m2, i.v. on days 1 and 8; prednisone 60 mg/m2, p.o., daily, days 1 to 14 and procarbazine 100 ng/m2, p.o., daily, days 1 to 14 vere given as consolidation therapy. At 8-years, the overall survival rate vas 58% (50 out of 86 patients) being 38 and 76% in patients whose initial complete response was shorter or longer that 12 months, respectively or in 44% of induction failures. Hematological toxicity grade III or IV was observed in all cycles. However hematological recovery was already evident (median on day 13). Only transitory delay in continuing therapy was observed (median 3.9 days). Twenty-two patients developed infection-related granulocytopenia but no therapy related deaths were observed. G-CSF was well tolerated. This study indicates that the hematopoetic growth factor, G-CSF, was sufficient to act as hematological support in patients who received intensive, but non-myeloablative chemotherapy. In our opinion intensive chemotherapy without autologous transplant procedures can be considered in patients with refractory Hodgkin's disease because complete response rate and overall survival times are similar to more aggressive but more toxic regimens.     

Cisplatin etoposide versus cisplatin/etoposide/ifosfamide combination chemotherapy in small-cell lung cancer: a multicenter randomized controlled study. Hokkaido Study Group of Treatment for Small-Cell Lung Cancer]

Ninety-two patients with small-cell lung cancer (SCLC) were randomized to receive cisplatin (80 mg/m2, day 1)/etoposide (100 mg/m2, day 1, 3, 5) (PE) or cisplatin (80 mg/m2, day 1)/etoposide (100 mg/m2 1, 3, 5)/ifosfamide (2 g/m2, day 1, 2, 3) (PEI) combination chemotherapy. After 2 courses of chemotherapy, patients with limited disease (LD) received chest irradiation with 40-50 Gr. Of the 89 patients evaluable, the overall response rate was 77.8% in PE therapy, and 73.7% in PEI therapy (NS). The complete response rate (CR) of PE v PEI was 13.9% v 21.2% for all patients (NS), 22.2% v 30.4% for LD. Median survival times of PE v PEI for all patients were 55 weeks v 56 weeks (NS). The 2-year survival rate of PE v PEI was 15.4% v 16.5% for all patients (NS). There was no difference of the duration of response in cases with CR or PR between PE and PEI therapy. Leucopenia occurred more often after PEI than after PE therapy (p less than 0.01). These results suggest that PEI is not superior to PE chemotherapy in SCLC.     

Multiagent chemotherapy and deferred radiotherapy in infants with malignant brain tumors: a report from the Children's Cancer Group.

PURPOSE: To evaluate response rate, event-free survival (EFS), and toxicity of two chemotherapeutic regimens for treatment of children younger than 36 months with malignant brain tumors and to estimate control intervals without irradiation in children with no residual tumor after initial surgery and induction chemotherapy and with delayed irradiation in patients with residual tumor or metastatic disease at diagnosis. PATIENTS AND METHODS: Patients were randomly assigned to one of two regimens of induction chemotherapy (vincristine, cisplatin, cyclophosphamide, and etoposide v vincristine, carboplatin, ifosfamide, and etoposide). Maintenance chemotherapy began after induction in children without progressive disease. Children with no residual tumors after induction therapy and no metastatic disease at diagnosis were not to receive radiation therapy unless their tumors progressed. RESULTS: Two hundred ninety-nine infants were enrolled. Forty-two percent of patients responded to induction chemotherapy. At 5 years from study entry, the EFS rate was 27% +/- 3%, and the survival rate was 43% +/- 3%. There was no significant difference between the two arms in terms of response rate or EFS. For medulloblastoma, supratentorial primitive neuroectodermal tumor, ependymoma, and rhabdoid tumors, 5-year EFS rates were 32% +/- 5%, 17% +/- 6%, and 32% +/- 6%, and 14% +/- 7%, respectively. Fifty-eight percent of patients who were alive 5 years after study entry had not received radiation therapy. CONCLUSION: Intensified induction chemotherapy resulted in a high response rate of malignant brain tumors in infants. Survival was comparable to that of previous studies, and most patients who survived did not receive radiation therapy.     

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) x 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 mug ml-(1) in all patients and in patients treated at >/= 600 mg m -(2) the mean steady-state level was 14.4 mug 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) x 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.     

Prognostic factors in localized Ewing's tumours and peripheral neuroectodermal tumours: the third study of the French Society of Paediatric Oncology (EW88 study).

PURPOSE: (1) To improve survival rates in patients with Ewing's sarcoma (ES) or peripheral neuroectodermal tumours (PNET) using semi-continuous chemotherapy and aiming to perform surgery in all; (2) To identify early prognostic factors to tailor therapy for future studies. PATIENTS AND METHODS: One hundred and forty-one patients were entered onto the trial between January 1988 and December 1991. Induction therapy consisted of five courses of Cytoxan, 150 mg/m(2) x 7 days, followed by Doxorubicin, 35 mg/m(2) i.v on day 8 given at short intervals. Surgery was recommended whenever possible. The delivery of radiation therapy was based on the quality of resection and the histological response to CT. Maintenance chemotherapy consisted of vincristine + actinomycin and cytoxan + doxorubicin. The total duration of therapy was 10 months. RESULTS: After a median follow-up of 8.5 years, the projected overall survival at 5 years was 66% and disease-free survival (DFS) was 58%. In patients treated by surgery, only the histological response to CT had an influence on survival: 75% DFS for patients with a good histological response (less than 5% of cells), 48% for intermediate responders and only 20% for poor responders (> or = 30% of cells), P < 0.0001. The initial tumor volume by itself had no influence on DFS in these patients. In contrast, the tumour volume had a strong impact on DFS in patients treated by radiation therapy alone. Age had no impact on outcome. CONCLUSION: Therapeutic trials for localized Ewing's sarcoma should be based on the histological response to chemotherapy or on the tumour volume according to the modality used for local therapy.     

Cisplatin/etoposide versus ifosfamide/etoposide combination chemotherapy in small-cell lung cancer: a multicenter German randomized trial

A total of 144 patients with small-cell lung cancer (SCLC) were randomized to receive cisplatin/etoposide (PE) or ifosfamide/etoposide (IE) combination chemotherapy. PE consisted of cisplatin, 80 mg/m2, intravenously (IV) on day 1, and etoposide, 150 mg/m2, IV on days 3 through 5. IE consisted of ifosfamide, 1,500 mg/m2, IV on days 1 through 5, and etoposide, 120 mg/m2, IV on days 3 through 5. Six cycles were administered in 3-week intervals. Nonresponders were switched immediately to CAV, consisting of cyclophosphamide, 600 mg/m2, IV on days 1 and 2, Adriamycin (Adria Laboratories, Columbus, OH), 50 mg/m2, IV on day 1, and vincristine, 2 mg, IV on day 1. Patients obtaining complete remission (CR) received prophylactic cranial irradiation with 30 Gy. After completion of chemotherapy, patients with limited disease received chest irradiation with 45 Gy. No maintenance therapy was given to patients in CR. Minimum follow-up was 2 years. Of the 141 patients evaluable, the overall response rate was 65% in PE therapy and 68% in IE therapy. The CR rate was 32% v 20% for all patients, 50% v 24% for limited disease, and 22% v 18% for extensive disease, all in favor of PE therapy. Median survival for all patients was 11.6 months v 9.4 months, for limited disease 14.8 months v 11.0 months, and for extensive disease 8.9 months v 7.5 months, all preferring PE therapy. The 2-year survival rate was higher in PE therapy than in IE therapy for all patients (12% v 9%) and for limited disease (23% v 10%), but not for extensive disease (5% v 9%). Median progression-free survival was 7.5 months v 6.0 months for all patients, 12.2 months v 8.8 months for limited disease, and 5.9 months v 4.4 months for extensive disease, all in favor of PE. Relapse in the area of the primary tumor was found less often after PE than after IE therapy (25% v 38%). Response to second-line CAV was seen in 30% of patients with prior PE and 43% with prior IE therapy, but was usually short lasting, and only one patient achieved CR. Toxicity included three lethal complications. Nausea, vomiting, diarrhea, and skin lesions occurred more often after PE than after IE therapy. These results suggest that PE is superior to IE chemotherapy in limited-stage, but not in extensive-stage SCLC, and that CAV is cross-resistant to PE, as well as to IE in the majority of patients.     

Long-term event-free survival after intensive chemotherapy for Ewing's family of tumors in children and young adults.

PURPOSE: To improve the long-term event-free survival of patients with Ewing's family of tumors (EFTs) using high-dose, short-term chemotherapy. PATIENTS AND METHODS: P6 was a prospective study of previously untreated patients with newly diagnosed EFTs. Patients received seven cycles of chemotherapy. Cycles 1, 2, 3, and 6 consisted of cyclophosphamide 2,100 mg/m2/d on days 1 and 2, and a 72-hour continuous infusion of doxorubicin 75 mg/m2 and vincristine 2 mg/m2 starting day 1. Cycles 4, 5, and 7 consisted of 5 consecutive days of ifosfamide 1,800 mg/m2/d and etoposide 100 mg/m2/d. RESULTS: Sixty-eight patients were enrolled from 1991 to 2001 (median age, 18.7 years; range, 3.7 to 39.9 years). At diagnosis, 44 patients had local-regional disease, and 24 had distant metastases. The 4-year event-free survival (EFS) rate for patients with local-regional disease is 82%; overall survival (OS) is 89%. The 4-year EFS rate for patients with distant metastases is 12%; the OS rate is 17.8%. All events occurred within 51 months of diagnosis. Four patients with distant metastases had progressive disease during therapy, and no patient with local-regional disease experienced disease progression during therapy. CONCLUSION: Sustained EFS and OS can be achieved with intensive chemotherapy in children and young adults with local-regional EFTs. This therapy is relatively ineffective in the treatment of metastatic EFTs.     

The IVADo regimen--a pilot study with ifosfamide, vincristine, actinomycin D, and doxorubicin in children with metastatic soft tissue sarcoma: a pilot study of behalf of the European pediatric Soft tissue sarcoma Study Group

BACKGROUND: The role of doxorubicin (Doxo) as part of multidrug regimens used to treat children with soft tissue sarcoma (STS) is controversial. To evaluate the feasibility of combining Doxo with the well established ifosfamide, vincristine, and actinomycin D (IVA) regimen, the Italian STS Committee performed a pilot study on a series of children with metastatic STS. METHODS: Between July 2002 and February 2004, 29 evaluable patients were enrolled in this study; 19 patients had rhabdomyosarcoma, 5 patients had peripheral neuroectodermal tumor, and 5 patients had other types of STS. The IVA-Doxo (IVADo) regimen included ifosfamide 3 g/m(2) on Days 1 and 2, vincristine 1.5 mg/m(2) on Day 1, actinomycin D 1.5 mg/m(2) on Day 1, and Doxo 30 mg/m(2) on Days 1 and 2. Three courses of IVADo were to be administered in the initial part of treatment and analyzed for toxicity and tumor response. RESULTS: Overall, 92 cycles were delivered. Major regimen-related toxicity was myelosuppression, with Grade 4 neutropenia in 67% of cycles and fever and neutropenia in 37% of cycles. Nonhematologic toxicity included Grade 3-4 mucositis (6.5% of cycles), constipation (9.7%), and peripheral neuropathy (6.5%). Other manifestations of major toxicity were venoocclusive disease and seizures, which occurred in one patient each. All but 1 patient with a malignant schwannoma showed some degree of tumor volume reduction; however, considering only complete and partial remissions, the response rate was 76% (+/- 7.9%). CONCLUSIONS: The intensive IVADo regimen was effective against pediatric STS with acceptable toxicity. This combination will be investigated in high-risk patients with rhabdomyosarcoma in a randomized trial launched by the European pediatric Soft tissue sarcoma Study Group.     

High-dose intensification therapy with autologous bone marrow support for limited small-cell bronchogenic carcinoma

The efficacy and toxicity of high-dose chemotherapy with autologous bone marrow transplantation (ABMT) was studied in 32 patients with untreated limited small-cell bronchogenic carcinoma (SCBC). Ten patients received three courses of induction therapy consisting of vincristine (VCR) (1.5 mg X 2), ifosfamide (5 g/m2), and Adriamycin (Ad; Adria Laboratories, Columbus, Ohio) (60 mg/m2). Patients then received two courses of intensification therapy with cyclophosphamide (CYT) (4.5 g/m2), 4' demethyl-epipodophyllotoxin-d-D-ethylidene glucoside (VP-16-213) (600 mg/m2) and VCR (2 mg) with ABMT. Another 22 patients received induction therapy with VCR, CYT (600 mg/m2), Ad (50 mg/m2), and VP-16-213 (180 mg/m2). All 22 patients also received intensification therapy of the same dose of CYT (4.5 g/m2) and VP-16-213 (600 mg/m2). Nine patients also received high-dose methotrexate (MTX), four patients received Ad (40 to 60 mg/m2), and two patients received both Ad and MTX. After intensification, patients received elective prophylactic brain irradiation (3,000 rad) and chest irradiation (5,000 rad). After induction therapy, there were 13 (41%) complete remissions (CR) and 17 (53%) partial remissions (PR). After intensification therapy, there were 22 CRs (69%) and 10 PRs (31%). Median survival for all patients was 14 months (range, 5 to 59+). Of the 13 patients who received intensification therapy in CR, five remain disease free (DF), four for 4 years or longer. Of the nine patients to achieve CR with intensification, only one is DF. No patient died during intensification. In conclusion, intensification with high-dose chemotherapy can increase the CR rate, and this approach is most likely to show long-term benefits in patients with minimal disease (CR) at the beginning of intensification therapy.     

Evaluation of intensive postremission chemotherapy for adults with acute nonlymphocytic leukemia using high-dose cytosine arabinoside with L-asparaginase and amsacrine with etoposide

In order to test the toxicity and efficacy of intensive postremission therapy with high-dose cytosine arabinoside with L-asparaginase and amsacrine with etoposide in adults with acute nonlymphocytic leukemia (ANL), 100 adults (ages 19 to 75) with previously untreated ANL were entered into a study using six sequential cycles of chemotherapy. Cycles 1 (induction), 3, and 5 included conventional doses of daunomycin, cytosine arabinoside, 6-thioguanine, vincristine (VCR), and prednisone. Cycle 2 was cytosine arabinoside 3 g/m2 intravenously (IV) every 12 hours for four doses, followed by L-asparaginase 10,000 U intramuscularly (IM) at hour 42; this combination was repeated 1 week later. Cycle 4 included amsacrine 120 mg/m2/d and etoposide 100 mg/m2/d, both IV for five days, and cycle 6 was three monthly courses of VCR on day 1, and prednisone, mercaptopurine, and methotrexate each for five days. Seventy-four patients (74%) achieved complete remission (CR) (51 with cycle 1 and 23 after cycle 2). The overall disease-free survival (DFS) for patients achieving CR is 27% at 3 years by Kaplan-Meier analysis, while for patients achieving CR with cycle 1 it is 34%. The actuarial probability of being free from relapse at 3 years for patients achieving CR is 34%. Sixteen of the 74 CR patients (22%) died in CR while continuing to receive intensive chemotherapy, including 12 (18%) who succumbed to infection (nine bacterial, three fungal). After a median follow-up of 20 months, 36 patients have relapsed and 21 remain alive in CR. Intensive consolidation with high-dose cytosine arabinoside, amsacrine, and etoposide can modestly prolong DFS compared with historical controls. However, relapse continued to be a major problem and, in addition, with more aggressive consolidation therapy, infection during marrow aplasia resulted in a significant number of deaths.