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The New England Journal of Medicine Feb 2003Ewing's sarcoma and primitive neuroectodermal tumor of bone are closely related, highly malignant tumors of children, adolescents, and young adults. A new drug... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
BACKGROUND
Ewing's sarcoma and primitive neuroectodermal tumor of bone are closely related, highly malignant tumors of children, adolescents, and young adults. A new drug combination, ifosfamide and etoposide, was highly effective in patients with Ewing's sarcoma or primitive neuroectodermal tumor of bone who had a relapse after standard therapy. We designed a study to test whether the addition of these drugs to a standard regimen would improve the survival of patients with newly diagnosed disease.
METHODS
Patients 30 years old or younger with Ewing's sarcoma, primitive neuroectodermal tumor of bone, or primitive sarcoma of bone were eligible. The patients were randomly assigned to receive 49 weeks of standard chemotherapy with doxorubicin, vincristine, cyclophosphamide, and dactinomycin or experimental therapy with these four drugs alternating with courses of ifosfamide and etoposide.
RESULTS
A total of 518 patients met the eligibility requirements. Of 120 patients with metastatic disease, 62 were randomly assigned to the standard-therapy group and 58 to the experimental-therapy group. There was no significant difference in five-year event-free survival between the treatment groups (P=0.81). Among the 398 patients with nonmetastatic disease, the mean (+/-SE) five-year event-free survival among the 198 patients in the experimental-therapy group was 69+/-3 percent, as compared with 54+/-4 percent among the 200 patients in the standard-therapy group (P=0.005). Overall survival was also significantly better among patients in the experimental-therapy group (72+/-3.4 percent vs. 61+/-3.6 percent in the standard-therapy group, P=0.01).
CONCLUSIONS
The addition of ifosfamide and etoposide to a standard regimen does not affect the outcome for patients with metastatic disease, but it significantly improves the outcome for patients with nonmetastatic Ewing's sarcoma, primitive neuroectodermal tumor of bone, or primitive sarcoma of bone.
Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Child; Cyclophosphamide; Dactinomycin; Disease Progression; Disease-Free Survival; Doxorubicin; Drug Administration Schedule; Etoposide; Female; Humans; Ifosfamide; Male; Neuroectodermal Tumors, Primitive; Prognosis; Sarcoma; Sarcoma, Ewing; Survival Rate; Treatment Failure; Vincristine
PubMed: 12594313
DOI: 10.1056/NEJMoa020890 -
Journal of Clinical Oncology : Official... Mar 2022This phase III randomized trial (NCT00954174) tested the null hypothesis that paclitaxel and carboplatin (PC) is inferior to paclitaxel and ifosfamide (PI) for treating... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
This phase III randomized trial (NCT00954174) tested the null hypothesis that paclitaxel and carboplatin (PC) is inferior to paclitaxel and ifosfamide (PI) for treating uterine carcinosarcoma (UCS).
PATIENTS AND METHODS
Adults with chemotherapy-naïve UCS or ovarian carcinosarcoma (OCS) were randomly assigned to PC or PI with 3-week cycles for 6-10 cycles. With 264 events in patients with UCS, the power for an overall survival (OS) hybrid noninferiority design was 80% for a null hazard ratio (HR) of 1.2 against a 13% greater death rate on PI with a type I error of 5% for a one-tailed test.
RESULTS
The study enrolled 536 patients with UCS and 101 patients with OCS, with 449 and 90 eligible, respectively. Primary analysis was on patients with UCS, distributed as follows: 40% stage I, 6% stage II, 31% stage III, 15% stage IV, and 8% recurrent. Among eligible patients with UCS, PC was assigned to 228 and PI to 221. PC was not inferior to PI. The median OS was 37 versus 29 months (HR = 0.87; 90% CI, 0.70 to 1.075; < .01 for noninferiority, > .1 for superiority). The median progression-free survival was 16 versus 12 months (HR = 0.73; = < 0.01 for noninferiority, < .01 for superiority). Toxicities were similar, except that more patients in the PC arm had hematologic toxicity and more patients in the PI arm had confusion and genitourinary hemorrhage. Among 90 eligible patients with OCS, those in the PC arm had longer OS (30 25 months) and progression-free survival (15 10 months) than those in the PI arm, but with limited precision, these differences were not statistically significant.
CONCLUSION
PC was not inferior to the active regimen PI and should be standard treatment for UCS.
Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinosarcoma; Disease-Free Survival; Female; Humans; Ifosfamide; Ovarian Neoplasms; Paclitaxel; Uterine Neoplasms
PubMed: 35007153
DOI: 10.1200/JCO.21.02050 -
Cancer Jun 2020The optimal treatment for advanced leiomyosarcoma is still debated. Given histotype-specific prospective controlled data lacking, this study retrospectively evaluated...
Doxorubicin plus dacarbazine, doxorubicin plus ifosfamide, or doxorubicin alone as a first-line treatment for advanced leiomyosarcoma: A propensity score matching analysis from the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group.
BACKGROUND
The optimal treatment for advanced leiomyosarcoma is still debated. Given histotype-specific prospective controlled data lacking, this study retrospectively evaluated doxorubicin plus dacarbazine, doxorubicin plus ifosfamide, and doxorubicin alone as first-line treatments for advanced/metastatic leiomyosarcoma treated at European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group (EORTC-STBSG) sites.
METHODS
The inclusion criteria were a confirmed histological diagnosis, treatment between January 2010 and December 2015, measurable disease (Response Evaluation Criteria in Solid Tumors 1.1), an Eastern Cooperative Oncology Group performance status ≤2, and an age ≥ 18 years. The endpoints were progression-free survival (PFS), overall survival (OS), and overall response rate (ORR). PFS was analyzed with methods for interval-censored data. Patients were matched according to their propensity scores, which were estimated with a logistic regression model accounting for histology, grade, age, sex, performance status, tumor site, and tumor extent.
RESULTS
Three hundred three patients from 18 EORTC-STBSG sites were identified. One hundred seventeen (39%) received doxorubicin plus dacarbazine, 71 (23%) received doxorubicin plus ifosfamide, and 115 (38%) received doxorubicin. In the 2:1:2 propensity score-matched population (205 patients), the estimated median PFS was 9.2 months (95% confidence interval [CI], 5.2-9.7 months), 8.2 months (95% CI, 5.2-10.1 months), and 4.8 months (95% CI, 2.3-6.0 months) with ORRs of 30.9%, 19.5%, and 25.6% for doxorubicin plus dacarbazine, doxorubicin plus ifosfamide, and doxorubicin alone, respectively. PFS was significantly longer with doxorubicin plus dacarbazine versus doxorubicin (hazard ratio [HR], 0.72; 95% CI, 0.52-0.99). Doxorubicin plus dacarbazine was associated with longer OS (median, 36.8 months; 95% CI, 27.9-47.2 months) in comparison with both doxorubicin plus ifosfamide (median, 21.9 months; 95% CI, 16.7-33.4 months; HR, 0.65; 95% CI, 0.40-1.06) and doxorubicin (median, 30.3 months; 95% CI, 21.0-36.3 months; HR, 0.66; 95% CI, 0.43-0.99). Adjusted analyses retained an effect for PFS but not for OS. None of the factors selected for multivariate analysis had a significant interaction with the received treatment for both PFS and OS.
CONCLUSIONS
This is the largest retrospective study of first-line treatment for advanced leiomyosarcoma. In the propensity score-matched population, doxorubicin and dacarbazine showed favorable activity in terms of both ORR and PFS and warrants further evaluation in prospective trials.
Topics: Adult; Aged; Aged, 80 and over; Bone Neoplasms; Dacarbazine; Doxorubicin; Female; Humans; Ifosfamide; Leiomyosarcoma; Male; Middle Aged; Propensity Score; Retrospective Studies; Sarcoma
PubMed: 32129883
DOI: 10.1002/cncr.32795 -
JAMA Oncology May 2023To our knowledge, this is the first clinical trial designed to investigate concurrent treatment with a checkpoint inhibitor and conventional chemotherapy in relapsed or... (Clinical Trial)
Clinical Trial
Pembrolizumab Added to Ifosfamide, Carboplatin, and Etoposide Chemotherapy for Relapsed or Refractory Classic Hodgkin Lymphoma: A Multi-institutional Phase 2 Investigator-Initiated Nonrandomized Clinical Trial.
IMPORTANCE
To our knowledge, this is the first clinical trial designed to investigate concurrent treatment with a checkpoint inhibitor and conventional chemotherapy in relapsed or refractory classic Hodgkin lymphoma in patients destined for an autologous stem cell transplant.
OBJECTIVE
To evaluate the complete response rate as assessed by 18F-fluorodeoxyglucose-positron emission tomography with computed tomography (FDG-PET/CT) after salvage therapy for patients with relapsed or refractory classic Hodgkin lymphoma.
DESIGN, SETTING, AND PARTICIPANTS
A single-group, phase 2, multi-institutional nonrandomized clinical trial to evaluate the addition of pembrolizumab to ifosfamide, carboplatin, and etoposide (ICE) chemotherapy was conducted from April 20, 2017, to October 29, 2020, at 5 US sites. The 42 patients were aged 18 years or older, with an Eastern Cooperative Oncology Group Performance Status Scale score of 0 or 1 and biopsy-proven relapsed or refractory classic Hodgkin lymphoma after 1 or 2 prior lines of chemotherapy. Patients were required to be appropriate candidates for transplant, with measurable lesions detected by FDG-PET/CT.
INTERVENTIONS
Two cycles of pembrolizumab (200 mg intravenously on day 1) with ICE chemotherapy every 21 days, followed by stem cell mobilization and collection, and then 1 cycle of pembrolizumab monotherapy followed by FDG-PET/CT response assessment.
MAIN OUTCOMES AND MEASURES
The primary end point was complete response rate detected by FDG-PET/CT, defined as a Deauville score of 3 or lower. Patients with a complete response proceeded to an autologous stem cell transplant. Secondary end points included progression-free survival, overall survival, stem cell mobilization, and neutrophil and platelet engraftment. Adverse events were monitored to assess safety.
RESULTS
Forty-two patients were enrolled, with 37 evaluable for the primary end point. The median age was 34 years (range, 19-70 years), 25 patients were female (68%), 6 were African American (16%), and 26 were White (70%). The complete response rate for the 37 patients assessed by FDG-PET/CT imaging was 86.5% (95% CI, 71.2%-95.5%); the overall response rate was 97.3% (36 patients), with 10.8% partial responses (4 patients). New areas of FDG-PET positivity in 2 patients were biopsied, showing noncaseating granuloma in 1 case and a reactive lymph node in a second. Progression-free survival and overall survival 2-year estimates were 87.2% (32 patients; 95% CI, 77.3%-98.3%) and 95.1% (95% CI, 88.8%-100%), respectively. The addition of pembrolizumab to ICE chemotherapy did not negatively affect stem cell mobilization or collection or engraftment, similar to prior experience in this patient population and setting.
CONCLUSIONS AND RELEVANCE
Results suggest that the addition of pembrolizumab to ICE chemotherapy was well tolerated and highly effective in comparison with prior reports of chemotherapy-only regimens, supporting further investigation in patients with relapsed or refractory classic Hodgkin lymphoma eligible for an autologous stem cell transplant.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT03077828.
Topics: Humans; Female; Adult; Male; Hodgkin Disease; Ifosfamide; Carboplatin; Etoposide; Positron Emission Tomography Computed Tomography; Fluorodeoxyglucose F18; Antineoplastic Combined Chemotherapy Protocols; Salvage Therapy
PubMed: 36928527
DOI: 10.1001/jamaoncol.2022.7975 -
Human Vaccines & Immunotherapeutics May 2021Osteosarcoma (OS) is the most common malignant bone tumor and often occurs in children. Chemotherapy with methotrexate, cisplatin, doxorubicin, and ifosfamide has...
Osteosarcoma (OS) is the most common malignant bone tumor and often occurs in children. Chemotherapy with methotrexate, cisplatin, doxorubicin, and ifosfamide has greatly improved the prognosis of patients with OS, and most patients have been able to preserve their limbs. However, no progress has been made in the treatment for OS in the past few decades, and the prognosis of patients with metastasis and/or local recurrence remains poor. Therefore, studies aimed at developing new treatment methods for OS are urgently required. Here, we discuss the current status of immunotherapies for OS as well as the current limitations in the field.In recent years, immunotherapy has been shown to be effective for treating several cancers, and its indication is continually increasing. Immunotherapy is also expected to be widely used for treating OS, however, the efficacy of immunotherapy for OS has not been established.
Topics: Antineoplastic Combined Chemotherapy Protocols; Child; Cisplatin; Humans; Ifosfamide; Immunotherapy; Neoplasm Recurrence, Local; Osteosarcoma
PubMed: 33356848
DOI: 10.1080/21645515.2020.1824499 -
Annals of Oncology : Official Journal... Nov 2004The purpose of this study was to retrospectively analyze the relationship between neo-adjuvant chemotherapy (NAC) and outcome in patients with high-grade extremity... (Clinical Trial)
Clinical Trial
BACKGROUND
The purpose of this study was to retrospectively analyze the relationship between neo-adjuvant chemotherapy (NAC) and outcome in patients with high-grade extremity sarcomas.
PATIENTS AND METHODS
Inclusion criteria were high-grade, deep, >5 cm extremity soft tissue sarcomas. Patients diagnosed between 1990 and 2001 were treated with surgery only (n=282) or NAC containing doxorubicin/ifosfamide/mesna (AIM) (n=74). The stratified Cox proportional hazards model was used to test the effect of NAC on disease-specific survival and recurrence while adjusting for known prognostic factors.
RESULTS
NAC was associated with improved disease-specific survival for this cohort of patients (P=0.02). This overall improvement appears to be driven by the benefit of NAC on disease-specific survival for patient with tumors >10 cm. The 3-year disease-specific survival for tumors >10 cm was 0.62 (95% CI: 0.53-0.71) for patients not receiving NAC and 0.83 (95% CI: 0.72-0.95) for patients receiving NAC.
CONCLUSION
NAC with AIM was associated with a significant improvement in disease-specific survival in patients with high-grade extremity soft tissue sarcomas >10 cm. These data emphasize the need for further prospective clinical studies of neo-adjuvant or adjuvant chemotherapy for patients with large high-grade extremity sarcomas.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Cohort Studies; Extremities; Humans; Ifosfamide; Mesna; Middle Aged; Proportional Hazards Models; Prospective Studies; Retrospective Studies; Sarcoma; Soft Tissue Neoplasms; Survival Analysis; Time Factors; Treatment Outcome
PubMed: 15520069
DOI: 10.1093/annonc/mdh431 -
Journal of Clinical Oncology : Official... Apr 2010We previously reported a dose-finding and phase II trial of the TI-CE regimen (paclitaxel [T] plus ifosfamide [I] followed by high-dose carboplatin [C] plus etoposide...
PURPOSE
We previously reported a dose-finding and phase II trial of the TI-CE regimen (paclitaxel [T] plus ifosfamide [I] followed by high-dose carboplatin [C] plus etoposide [E] with stem-cell support) in germ cell tumor (GCT) patients predicted to have a poor prognosis with conventional-dose salvage therapy. We now report the efficacy of TI-CE with prognostic factors for disease-free survival (DFS) and overall survival (OS) in our full data set of 107 patients.
PATIENTS AND METHODS
Eligible patients had advanced GCTs with progressive disease following chemotherapy and unfavorable prognostic features (extragonadal primary site, incomplete response [IR] to first-line therapy, or relapse/IR to ifosfamide-cisplatin-based conventional-dose salvage). Univariate and multivariate analyses (MVAs) of prognostic factors were performed. The predictive ability of the Einhorn and Beyer prognostic models was assessed.
RESULTS
Most patients were platinum refractory and had an IR to first-line chemotherapy. There were 54 (5%) complete and eight (8%) partial responses with negative markers; 5-year DFS was 47% and OS was 52% (median follow-up, 61 months). No relapses occurred after 2 years. Five (24%) of 21 primary mediastinal nonseminomatous GCTs are continuously disease free. On MVA, primary mediastinal site (P < .001), two or more lines of prior therapy (P < .001), baseline human chorionic gonadotropin > or = 1,000 U/L (P = .01), and lung metastases (P = .02) significantly predicted adverse DFS. Poor-risk patients did worse than good- or intermediate-risk patients according to both Beyer (P < .002) and Einhorn (P < .05) models.
CONCLUSION
TI-CE is effective salvage therapy for GCT patients with poor prognostic features. Mediastinal primary site and two or more lines of prior therapy were most predictive of adverse DFS. Beyer and Einhorn models can assist in predicting outcome.
Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Combined Modality Therapy; Disease-Free Survival; Etoposide; Female; Hematopoietic Stem Cell Transplantation; Humans; Ifosfamide; Male; Middle Aged; Neoplasms, Germ Cell and Embryonal; Paclitaxel; Prognosis; Retreatment; Salvage Therapy
PubMed: 20194867
DOI: 10.1200/JCO.2009.25.1561 -
Leukemia & Lymphoma Dec 2020A modification of the SMILE regimen with dexamethasone, methotrexate, ifosfamide, L-asparaginase, etoposide (mSMILE) followed by Intensity-Modulated Radiotherapy (IMRT)...
A modification of the SMILE regimen with dexamethasone, methotrexate, ifosfamide, L-asparaginase, etoposide (mSMILE) followed by Intensity-Modulated Radiotherapy (IMRT) at lower than usual dose, has been adopted as standard of care for extranodal NK-/T-cell lymphoma (ENKL) at our institution. mSMILE is a short course, intensive regimen incorporating pegylated asparaginase. Here, we describe clinical details, outcome and safety of patients receiving mSMILE. Among 28 patients with ENKL treated, response post-mSMILE was 93% (CR 68%), response post IMRT was 95% (CR 87.5%). Among early-stage patients/low PINK-E ( = 13), overall survival (OS) was 100% at the median follow-up of 31 months; progression-free survival (PFS) was 92%. Advanced-stage and intermediate/high PINK-E patients fared similarly (OS 43%, PFS 33.3% at the median follow-up). Thirty-two percent of the patients experienced G3-4 non-hematologic toxicity, all experienced hematologic toxicity. Most localized-stage patients achieved long-term disease control. Despite high response rates, most of the advanced stage patients relapsed quickly.
Topics: Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Dexamethasone; Humans; Ifosfamide; Lymphoma, Extranodal NK-T-Cell; Radiotherapy, Intensity-Modulated; Treatment Outcome
PubMed: 32844695
DOI: 10.1080/10428194.2020.1811864 -
Current Treatment Options in Oncology Mar 2018Synovial sarcoma (SS) is a rare, yet highly malignant, type of soft tissue sarcoma (STS), for which survival has not improved significantly during the past years. In... (Review)
Review
Synovial sarcoma (SS) is a rare, yet highly malignant, type of soft tissue sarcoma (STS), for which survival has not improved significantly during the past years. In this review, we focus on systemic treatment in adults. Compared to other STS, SS are relatively chemosensitive. Ifosfamide and ifosfamide combinations are active in different lines of treatment. In high-risk extremity and chest wall STS, neoadjuvant doxorubicin and ifosfamide has shown as much activity as high-dose ifosfamide. There are indications that combination chemotherapy with doxorubicin and ifosfamide in this setting improves outcome. In the first-line metastatic setting, combination treatment with doxorubicin and ifosfamide is a preferred option in fit patients, while in other patients, sequential doxorubicin and ifosfamide can be considered. In second and later lines, pazopanib and trabectedin have shown activity. Many new approaches to treat metastatic SS are currently under investigation, both preclinical as well as clinical, including other receptor tyrosine kinase inhibitors, epigenetic modulators, compounds interfering with DNA damage response (DDR), and immunotherapy.
Topics: Adult; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Doxorubicin; Humans; Ifosfamide; Indazoles; Pyrimidines; Sarcoma, Synovial; Sulfonamides; Trabectedin
PubMed: 29516254
DOI: 10.1007/s11864-018-0525-1 -
Drug Design, Development and Therapy 2015The efficacy of ifosfamide-based chemotherapy in the treatment of osteosarcoma has been investigated; however, results are inconsistent. Therefore, we reviewed the... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
The efficacy of ifosfamide-based chemotherapy in the treatment of osteosarcoma has been investigated; however, results are inconsistent. Therefore, we reviewed the relevant studies and conducted a meta-analysis to assess the efficacy of ifosfamide-based chemotherapy in patients with osteosarcoma.
METHODS
A systematic literature search on PubMed, Embase, and Web of Science databases was performed. Eligible studies were clinical trials of patients with osteosarcoma who received ifosfamide-based chemotherapy. Hazard ratios (HRs) were pooled to compare event-free survival (EFS) and overall survival (OS). Risk ratios (RRs) were pooled to compare good histologic response rates and adverse event incidence. Meta-analysis was performed using a fixed-effects model or a random-effects model according to heterogeneity.
RESULTS
A total of seven randomized controlled trials were included in this meta-analysis. Pooled results showed that ifosfamide-based chemotherapy significantly improved EFS (HR=0.72, 95% confidence interval [CI]: 0.63, 0.82; P=0.000) and OS (HR=0.83, 95% CI: 0.70, 0.99; P=0.034); furthermore, this form of chemotherapy increased good histologic response rate (RR=1.27, 95% CI: 1.10, 1.46; P=0.001). In addition, patients in the ifosfamide group exhibited a significantly higher incidence of fever (RR=2.23, 95% CI: 1.42, 3.50; P=0.000) and required more frequent platelet transfusion (RR=1.92, 95% CI: 1.23, 3.01; P=0.004).
CONCLUSION
This meta-analysis confirmed that ifosfamide-based chemotherapy can significantly improve EFS and OS; this chemotherapy can also increase good histologic response rate in patients with osteosarcoma. However, evidence may be limited by potential biases and confounders. Thus, large-scale well-designed randomized controlled trials are needed to verify current findings.
Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Disease-Free Survival; Humans; Ifosfamide; Osteosarcoma; Randomized Controlled Trials as Topic; Survival Rate
PubMed: 26604690
DOI: 10.2147/DDDT.S91217