Ifosfamide and Etoposide Are Superior to Vincristine and Melphalan for Pediatric Metastatic Rhabdomyosarcoma When Administered With Irradiation and Combination Chemotherapy: A Report From the Intergroup Rhabdomyosarcoma Study Group
Philip P. BreitfeldElizabeth LydenR. Beverly RaneyLisa A. TeotMoody D. WharamThom E. LobeWilliam M. CristHarold M. MaurerSarah S. DonaldsonF. B. RuymannJames R. AndersonRichard J. AndrassyCarola A.S. ArndtK. Scott BakerFrederic G. BarrW. Archie BleyerPhilip P. BreitfeldJohn C. BrenemanJulia A. BridgeKenneth L. BrownHolcombe E. GrierDouglas S. HawkinsPeter J. HoughtonMichael J. LinkWilliam H. MeyerJeff M. MichalskiSharon MurphyCharles N. PaidasAlberto S. PappoDavid M. ParhamStephen J. QualmanLeslie L. RobisonEric SandlerLynn SmithPoul H. SorensenLisa A. TeotTimothy J. TricheTeresa J. ViettiDavid WalterhouseEugene S. WienerSuzanne L. WoldenRichard B. WomerJoan L. Leeson
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Purpose This study was designed to estimate the partial and complete response rates (CR and PR) of two novel drug pairs (vincristine and melphalan vs. ifosfamide and etoposide) and to improve overall survival of previously untreated patients with metastatic rhabdomyosarcoma. Patients and Methods One hundred twenty-eight patients were randomly assigned to phase II window therapy consisting of vincristine and melphalan (VM-containing regimen) or ifosfamide and etoposide (IE-containing regimen). Brief window therapy (12 wks) was immediately followed-up by vincristine, dactinomycin, and cyclophosphamide (VAC), chemotherapy, surgery, and irradiation, with continuation of either VM or IE in patients with initial response. Major endpoints were initial CR and PR rates after the phase II window phase of therapy, failure-free survival (FFS), and survival. Results Patients who received the VM-containing regimen experienced significantly more anemia, neutropenia, thrombocytopenia, and had more cyclophosphamide dose reductions. The initial PR and CR rates were not significantly different for patients treated with either regimen (VM, 74%; IE, 79%;P = 0.428). However, FFS and overall survival (OS) at 3 years were significantly better with the IE-containing regimen (FFS: 33% vs. 19%;P = 0.043; OS: 55% vs. 27%;P = 0.012). Conclusions Although the VM-containing regimen produced a high response rate, inclusion of melphalan appeared to limit the cyclophosphamide dose that could be administered, and ultimately, this regimen was associated with a significantly worse outcome than was the IE-containing regimen. Also, the IE-containing regimen was associated with a gratifyingly high survival rate at 3 years (55%), which is significantly higher than has been observed on any previous Intergroup Rhabdomyosarcoma Study Group regimen for similar patients. We believe that this promising outcome indicates that this drug pair merits further randomized testing in metastatic rhabdomyosarcoma.Keywords:
Melphalan
Nitrogen mustard
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The remission rates achieved with the combination of vincristine and etoposide are comparable with other frequently employed therapeutic regimens (ACO/EPICO, cisplatin/etoposide). The combination of etoposide with vincristine represents an alternative, in particular with respect to a merely palliative approach to treatment.
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Background. Children and adolescents with unresectable rhabdomyosarcoma fare poorly when treated with contemporary chemotherapeutic regimens. Evaluation of newly developed agents in these patients is important to improve their outcome. Based on a preclinical rhabdomyosarcoma xenograft model that accurately predicted the activity of new agents, the safety and efficacy of ifosfamide was evaluated as part of a Phase II clinical trial in previously untreated children with unresectable rhabdom yosarcoma. Methods. Twenty-two children and adolescents (median age, 9 years) with newly diagnosed unresectable rhabdomyosarcoma (Intergroup Rhabdomyosarcoma Study Group III [n = 15] or IV [n = 71] received two courses of ifosfamide at a dose of 1.6 g/m2 intravenously for 5 days over a 6-week period. Then the patients were evaluated for response, and additional treatment with surgery, radiation therapy, and multiagent chemotherapy (vincristine, cyclophosphamide, dactinomycin, and doxorubicin) was administered. Results. Nineteen of 22 patients (86%) had a partial response to ifosfamide given as a single agent. No complete responses to this agent alone were observed. After administration of additional chemotherapy and local control measures (radiation therapy and surgery), the estimated proportion of patients surviving progressionfree at 2 years was 63% (95% confidence interval, 37-80%). Ifosfamide was tolerated well; the most frequent toxicity was nondose-limiting myelosuppression. Transient mild renal toxicity infrequently was observed, and no central nervous system toxicity occurred in this group of patients. Conclusions. Ifosfamide appears to have significant clinical activity in untreated patients with unresectable rhabdomyosarcomas. These findings provide an accurate estimate of the response rate to single-agent ifosfamide in this group of previously untreated patients and thus provide a foundation for its rational incorporation into multiagent clinical trials. In addition, the potential benefits of this type of new drug development were demonstrated. Cancer 1993; 71:2119-25.
Nitrogen mustard
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Refractory (planetary science)
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Twelve FIGO stage III-IV ovarian cancer patients progressing or relapsing after primary cisplatin-containing combination chemotherapy were treated with ifosfamide and etoposide. Only patients with clinically evaluable disease entered the trial. The 12 patients received a median number of 3 courses (range 1-6). No complete or partial response and two disease stabilizations were observed. Ten patients progressed on therapy. The combination of ifosfamide and etoposide does not appear to be an effective salvage treatment for advanced ovarian cancer.
Salvage therapy
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Background. Ifosfamide has previously been shown to be active as a single agent and in combination with doxorubicin, etoposide, and teniposide in pediatric solid tumors and adult acute leukemia. The authors performed a dose-escalation trial of ifosfamide with a fixed dosage of etoposide, with mesna uroprotection, in children with multiply recurrent acute leukemia. Methods. Chemotherapy was administered daily for 5 days. Etoposide 100 mg/m2 was followed by ifosfamide at an initial dosage of 1.6 g/m2. The ifosfamide was escalated in 20% increments to the maximum tolerated dosage in cohorts of three patients. Mesna 400 mg/m2 was given immediately before the ifosfamide and then at 3 and 6 hours after ifosfamide in the initial patients. Subsequent patients were treated with mesna 400 mg/m2 just before ifosfamide, and then every 2 hours to a total dosage equal to the ifosfamide dosage. Results. Forty-four heavily pretreated patients were entered on study. Forty were evaluable for toxicity and 36 for response as well. The maximum tolerated dosage of ifosfamide was 4.0 g/m2/d for 5 days (20 g/m2/course). Overall, 10 patients achieved complete remission, and 3 achieved partial remission. Remissions were brief, although four patients went on to bone marrow transplant while in remission. One patient is still alive. Conclusions. The combination of etoposide and ifosfamide with mesna uroprotection showed promising activity in children with multiply recurrent acute leukemia.
Mesna
Nitrogen mustard
Refractory (planetary science)
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The result of a combination consisting of ifosfamide and etoposide was evaluated in 57 patients suffering from non‐Hodgkin's lymphoma (NHL) who had relapsed or were resistant to adriamycin‐containing combinations. Some of the patients (35%) also received methotrexate. 80% of the patients belonged to the histology group ‘high‐grade’ malignant NHL. 1times1 of the 57 patients (19%) obtained a remission, 5 of these were complete and 6 partial. The remission predominantly occurred in the group of patients with ‘high‐grade’ malignant histopathology who were treated at the first relapse after complete remission or when front‐line treatment induced a partial remission and ifosfamide and etoposide were added in direct connection with frontline treatment. It is concluded that the use of the combination of ifosfamide and etoposide should be limited to such patients.
Histopathology
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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.
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The remission rates achieved with the combination of vincristine and etoposide are comparable with other frequently employed therapeutic regimens (ACO/EPICO, cisplatin/etoposide). The combination of etoposide with vincristine represents an alternative, in particular with respect to a merely palliative approach to treatment.
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Phase II studies conducted in Europe and the USA on pediatric solid tumors have shown that ifosfamide, as a single agent, is an active drug against a variety of neoplasms – rhabdomyosarcoma (RMS), some non-RMS soft tissue sarcomas, Wilms’ tumor, bone sarcomas and neuroblastoma. Furthermore, an increase in tumor response rate has been observed when ifosfamide has been used in combination with other drugs. The usual dose of ifosfamide varies from 1.8 to 3 g/m<sup>2</sup>/day for 2–5 days according to the different regimens. Some controversies still exist on the modality of drug administration and more precisely on the time of infusion, however in pediatric practice, short infusion (e.g. 3 h) is usually preferred because of the reduced neurotoxicity in comparison to lengthier administration (e.g. 24 h). Ifosfamide is currently included in the standard therapy of pediatric bone and soft tissue sarcomas. It is also used in a selected high-risk group of patients with Wilms’ tumor, neuroblastoma and germ cell tumors.
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