Single-agent Ifosfamide Research Articles

Randomised phase 2 study comparing the efficacy and safety of the oral tyrosine kinase inhibitor nintedanib with single agent ifosfamide in patients with advanced, inoperable, metastatic soft tissue sarcoma after failure of first-line chemotherapy: EORTC-1506-STBSG “ANITA”

PurposeEORTC-1506-STBSG was a prospective, multicentric, randomised, open-label phase 2 trial to assess the efficacy and safety of second-line nintedanib versus ifosfamide in patients with advanced, inoperable metastatic soft tissue sarcoma (STS). The primary end-point was progression-free survival. Patients/methodsPatients with a variety of STS subtypes were randomised 1:1 to nintedanib (200 mg b.i.d. p.o. until disease progression) or ifosfamide (3 g/m2 i.v. days 1–3, every 21 days for ≤6 cycles). A Korn design was applied aiming to detect an improvement in median progression-free survival (mPFS) from 3 to 4.5 months (HR = 0.667). An interim look was incorporated to stop the trial for futility if <19 of the first 36 patients treated with nintedanib were progression-free at week 12. ResultsAt the interim analysis, among the first 36 eligible and evaluable patients randomised for nintedanib, only 13 (36%) were progression-free at week 12. The trial was closed for further accrual as per protocol. In total, 80 patients were randomised (40 per treatment group). The mPFS was 2.5 months (95% CI: 1.5–3.4) for nintedanib and 4.4 months (95% CI: 2.9–6.7) on ifosfamide (adjusted HR = 1.56 [80% CI: 1.14–2.13], p = 0.070). The median overall survival was 13.7 months (95% CI: 9.4–23.4) on nintedanib and 24.1 months (95% CI: 10.9–NE) on ifosfamide (adjusted HR = 1.65 [95%CI:0.89–3.06], p = 0.111). The clinical benefit rate for nintedanib and ifosfamide was 50% versus 62.5% (p = 0.368), respectively. Common treatment-related adverse events (all grades) were diarrhoea (35.9% of patients), fatigue (25.6%) and nausea (20.5%) for nintedanib; and fatigue (52.6%), nausea (44.7%) and vomiting, anorexia and alopecia (28.9% each) for ifosfamide. ConclusionThe trial was stopped for futility. The activity of nintedanib did not warrant further exploration in non-selected, advanced STSs.

Guidelines for the diagnosis and management of primary central nervous system diffuse large B-cell lymphoma.

Guidelines for the diagnosis and management of primary central nervous system diffuse large B-cell lymphoma.

Adjuvant radiotherapy and/or chemotherapy after surgery for uterine carcinosarcoma

Uterine carcinosarcomas are uncommon with about 35% not confined to the uterus at diagnosis. The survival of women with advanced uterine carcinosarcoma is poor with a pattern of failure indicating greater likelihood of upper abdominal and distant metastatic recurrence. To evaluate the effectiveness and safety of adjuvant radiotherapy and/or systemic chemotherapy in the management of uterine carcinosarcoma. We searched the Cochrane Gynaecological Cancer Group Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL), 2012, Issue 10, MEDLINE and EMBASE up to November 2012. We also searched registers of clinical trials, abstracts of scientific meetings, reference lists of included studies and contacted experts in the field. Randomised controlled trials (RCTs) comparing adjuvant radiotherapy and/or chemotherapy in women with uterine carcinosarcoma. Two review authors independently abstracted data and assessed risk of bias. Hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) and risk ratios (RRs) comparing adverse events in women who received radiotherapy and/or chemotherapy were pooled in random-effects meta-analyses. Three trials met the inclusion criteria and these randomised 579 women, of whom all were assessed at the end of the trials. Two trials assessing 373 participants with stage III to IV persistent or recurrent disease, found that women who received combination therapy had a significantly lower risk of death and disease progression than women who received single agent ifosfamide, after adjustment for performance status (HR = 0.75, 95% confidence interval (CI): 0.60 to 0.94 and HR = 0.72, 95% CI: 0.58 to 0.90 for OS and PFS respectively). There was no statistically significant difference in all reported adverse events, with the exception of nausea and vomiting, where significantly more women experienced these ailments in the combination therapy group than the Ifosamide group (RR = 3.53, 95% CI: 1.33 to 9.37).In one trial there was no statistically significant difference in the risk of death and disease progression in women who received whole body irradiation and chemotherapy, after adjustment for age and FIGO stage (HR = 0.71, 95% CI: 0.48 to 1.05 and HR = 0.79, 95% CI: 0.53 to 1.18 for OS and PFS respectively). There was no statistically significant difference in all reported adverse events, with the exception of haematological and neuropathy morbidities, where significantly less women experienced these morbidities in the whole body irradiation group than the chemotherapy group (RR= 0.02, 95% CI: 0.00 to 0.16) for haematological morbidity and all nine women in the trial experiencing neuropathy morbidity were in the chemotherapy group). In advanced stage metastatic uterine carcinosarcoma as well as recurrent disease adjuvant combination, chemotherapy with ifosfamide should be considered. Combination chemotherapy with ifosfamide and paclitaxel is associated with lower risk of death compared with ifosfamide alone. In addition, radiotherapy to the abdomen is not associated with improved survival.

Definitive radiotherapy and Single-Agent radiosensitizing Ifosfamide in Patients with localized, irresectable Soft Tissue Sarcoma: A retrospective analysis

Background and PurposeStandard therapy for soft-tissue sarcomas remains complete resection. For primary radiotherapy local control rates of 30-45% have been reported. We analyzed retrospectively 11 cases of radiochemotherapy with single-agent ifosfamide in patients with macroscopic soft-tissue sarcomas.Patients and MethodsThe patients were treated in irresectable high risk situations. Radiation therapy was performed with median 60 Gy. During the first and fifth week the concomitant chemotherapy with ifosfamide was added. Two patients received trimodal therapy with additional regional hyperthermia.ResultsThe therapy was completed in 73% of the patients. Average local control time was 91 months, median disease-free-survival/overall-survival was 8/26 months. Five-year rates for local control/disease free survival/overall survival were 70%/34%/34%. The limited prognosis is mainly caused by systemic treatment failure.ConclusionsThe data strongly suggest a better outcome of radiochemotherapy with ifosfamide compared to radiotherapy alone and radiotherapy in combination with other radiosensitizers.

Trabectedin in advanced, pretreated soft tissue sarcoma: The Hospital Sírio-Libanês experience in a compassionate use program.

e20511 Background: There is no established standard therapy for patients (pts) who had disease progression after an anthracycline-based chemotherapy, although some antitumor activity has been reported with single agent ifosfamide and chemotherapy combinations including gemcitabine with docetaxel, and vinorelbine and dacarbazine. Trabectedin is the first compound of a new class of antineoplastic agent with a mechanism of action that involves the transcription-dependent nucleotide excision repair system, approved for use in metastatic sarcomas only in Europe. Methods: We reviewed the clinical data from all pts with metastatic soft tissue sarcoma treated in a Trabectedin Compassionate Use Program. All pts had to have prior therapy with at least one line of an anthracycline-based regimen. Trabectedin was administered in a 24-hour infusion at 1.2–1.5mg/m2 (at the attending physician's discretion), repeated q3 weeks. Results: A total of 35 pts (20 M, 15F), with several soft-tissue sarcoma histologies were included. Five received 1 prior line of chemotherapy; 17 received 2 lines and 13 received 3 or more lines of prior chemotherapy. Three pts have not yet been treated and 5 died before receiving trabectedin. Performance status, according to ECOG criteria, was: zero, 3 pts; one, 16 pts; two, 8 pts; three, 2pts; four, 6pts. Response was evaluated according to RECIST. Among the 26 evaluable patients there were 2 PRs, 13 SD, 11 PD. Median TTP was 128 days (range 2-393). Fourteen patients (54%) had TTP > 120 days and nine patients (35%) > 180 days. Toxicity was manageable, and most frequent events were neutropenia, protracted nausea and fatigue. One patient had severe AST/ALT elevation and 3 patients had G2/3 CPK elevation. Three patients died within 30 days after the first cycle and were labeled as PD. Conclusions: According to EORTC criteria to consider activity of a drug in sarcoma therapy (TTP in 3 months >39% and TTP in 6 months>14%; Van Glabbeke et al.), our data suggest that trabectedin is active, with acceptable toxicity, even in a heavily pretreated patient population. No significant financial relationships to disclose.

Phase III Trial of Two Investigational Schedules of Ifosfamide Compared With Standard-Dose Doxorubicin in Advanced or Metastatic Soft Tissue Sarcoma: A European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group Study

Single-agent doxorubicin remains the standard treatment for advanced soft tissue sarcomas. Combining doxorubicin with standard-dose ifosfamide has not been shown to improve survival and is associated with a significantly increased toxicity; it is not known whether higher dose single-agent ifosfamide is superior to doxorubicin. This randomized prospective multicenter phase III trial was designed to compare progression-free survival of patients with advanced soft tissue sarcoma receiving either regimen of standard doxorubicin 75 mg/m2 every 21 days, ifosfamide 9 g/m2 over 3 days continuous infusion, or ifosfamide 3 g/m2 per day in 3 hours over 3 days. The primary end point was progression-free survival. Secondary end points included overall survival, response rate, and toxicity. The study included 326 patients. Grade 4 leukopenia, neutropenia, febrile neutropenia, and encephalopathy were more frequent in the ifosfamide arms. Progression-free survival, overall survival, and response rates were not significantly different between the three arms. An independent data monitoring committee reviewed the interim data and recommended early closure of the trial for futility (ie, no significant difference would be shown). Single-agent doxorubicin remains the treatment of choice for patients with advanced soft tissue sarcoma.

Metastatic Secondary Fibrosarcoma of Bone Responsive to RepeatedCourses of Ifosfamide and Associated With Hypoglycemia

We present a case of a 40-year-old man with secondary fibrosarcoma of bone, arising from a non-ossifying fibroma. He subsequently developed metastatic disease that responded to four successive chemotherapy courses, the last three using the same dose/schedule of single agent ifosfamide. Eventual rapid progression of a huge intra-abdominal mass was associated with the syndrome of extrapancreatic tumour hypoglycemia (EPTH). The clinicopathological behaviour of fibrosarcoma of bone, and the mechanism of EPTH are discussed.

Population pharmacokinetics of ifosfamide and its dechloroethylated and hydroxylated metabolites in children with malignant disease: a sparse sampling approach.

To assess the feasibility of a sparse sampling approach for the determination of the population pharmacokinetics of ifosfamide, 2- and 3-dechloroethyl-ifosfamide and 4-hydroxy-ifosfamide in children treated with single-agent ifosfamide against various malignant tumours. Pharmacokinetic assessment followed by model fitting. The analysis included 32 patients aged between 1 and 18 years receiving a total of 45 courses of ifosfamide 1.2, 2 or 3 g/m2 in 1 or 3 hours on 1, 2 or 3 days. A total of 133 blood samples (median of 3 per patient) were collected. Plasma concentrations of ifosfamide and its dechloroethylated metabolites were determined by gas chromatography. Plasma concentrations of 4-hydroxy-ifosfamide were measured by high-performance liquid chromatography. The models were fitted to the data using a nonlinear mixed effects model as implemented in the NONMEM program. A cross-validation was performed. Population values (mean +/- standard error) for the initial clearance and volume of distribution of ifosfamide were estimated at 2.36 +/- 0.33 L/h/m2 and 20.6 +/- 1.6 L/m2 with an interindividual variability of 43 and 32%, respectively. The enzyme induction constant was estimated at 0.0493 +/- 0.0104 L/h2/m2. The ratio of the fraction of ifosfamide metabolised to each metabolite to the volume of distribution of that metabolite, and the elimination rate constant, of 2- and 3-dechloroethyl-ifosfamide and 4-hydroxy-ifosfamide were 0.0976 +/- 0.0556, 0.0328 +/- 0.0102 and 0.0230 +/- 0.0083 m2/L and 3.64 +/- 2.04, 0.445 +/- 0.174 and 7.67 +/- 2.87 h(-1), respectively. Interindividual variability of the first parameter was 23, 34 and 53%, respectively. Cross-validation indicated no bias and minor imprecision (12.5 +/- 5.1%) for 4-hydroxy-ifosfamide only. We have developed and validated a model to estimate ifosfamide and metabolite concentrations in a paediatric population by using sparse sampling.

Combined etoposide, ifosfamide, and cisplatin in the treatment of patients with advanced thymoma and thymic carcinoma

Patients with thymic tumors (thymoma and thymic carcinoma) are known to respond to a variety of chemotherapeutic agents, including single-agent ifosfamide and cisplatin with etoposide. The purpose of this trial was to evaluate the response rate, progression free survival, overall survival, and toxicity of combined etoposide, ifosfamide, and cisplatin (VIP) in patients with advanced thymoma and thymic carcinoma. From July 1995 through February 1997, 34 patients with advanced thymoma or thymic carcinoma were entered on trial to receive etoposide (75 mg/m2 on Days 1-4) ifosfamide (1.2 g/m2 on Days 1-4), and cisplatin (20 mg/m2 on Days 1-4). Cycles were repeated every 3 weeks for four total cycles. Among 28 evaluable patients (pathology review excluded 6 patients), there were no complete responses and 9 partial responses (complete and partial responses combined, 32%; 95% confidence interval, 16-52%). The median follow-up was 43 months (range, 12.8-52.3 months), the median duration of response was 11.9 months (range, < 1-26 months), and the median overall survival was 31.6 months. Based on Kaplan-Meier estimates, the 1-year and 2-year survival rates were 89% and 70%, respectively. The toxicity was predominantly myelosuppression. The VIP regimen has moderate activity in patients with advanced thymic malignancies. However, with limited follow-up, the results of this trial appear to be inferior to other chemotherapy regimens reported in large Phase II trials performed in patients with this disease.

Phase II study of single agent ifosfamide in non-small cell lung cancer

Phase II study of single agent ifosfamide in non-small cell lung cancer

Safety and Efficacy of Adjuvant Single-Agent Ifosfamide in Uterine Sarcoma

Purpose. The role of adjuvant therapy for completely resected uterine sarcoma continues to be debated. Previous chemotherapy trials have shown little, if any, advantage over surgery alone, with significant added toxicity. To our knowledge, the current study is the first to evaluate adjuvant ifosfamide in completely resected uterine sarcomas.Methods. Between 1992 and 1999, 13 consecutive patients with completely resected moderate- to high-grade uterine sarcoma received three cycles of adjuvant ifosfamide (1.5 g/m2/day × 3 days, repeated every 28 days). Mesna was given 30 min prior to infusion. Postinfusion mesna was administered to 10 of the patients in the outpatient setting utilizing a subcutaneous infusion pump. The remaining 3 patients received traditional intravenous mesna at 4 and 8 h after infusion.Results. The median follow-up of the patient population was 26 months. For early-stage patients (n = 10), the 2-year progression-free survival was 60%, with a median of 26 months. The 2-year overall survival was 100%, dropping to 67% at 3 years. Early-stage patients showed an advantage in both progression-free and overall survival. Early-stage patients with mixed müllerian tumor (MMT) had a significantly longer time to progression that those with leiomyosarcoma (LMS) (2-year progression-free survival of 100% versus 33%; P = 0.019). Three patients required dose reduction secondary to grade 2–3 toxicities (neutropenia ×2, nausea and vomiting ×1). All significant toxicity was eliminated with dose reduction.Conclusions. Adjuvant ifosfamide appears to be safe and well tolerated in patients with completely resected uterine sarcoma. It can easily be given in the outpatient setting if mesna is administered via a subcutaneous pump. Our data, consistent with previous studies in advanced sarcoma, suggest a potentially greater role for ifosfamide in MMT than in LMS.

Treatment of invasive thymoma with single-agent ifosfamide.

To evaluate single-agent ifosfamide in the treatment of invasive thymoma. Fifteen patients (eight male and seven female) with histologically confirmed invasive thymoma were treated. The median age was 48 years (range, 23 to 76 years). Four patients had stage III disease, seven patients had stage IVa disease, and four patients had stage IVb disease. The most common histologic type was lymphoepithelial. Seven patients had received prior treatment, including one patient who received chemotherapy. Ifosfamide 1.5 g/m(2) was given on days 1 to 5, with mesna as a uroprotector. Thirteen patients were assessable for response. Five complete responses (38.5%; 95% confidence interval [CI], 17.7% to 64.5%) and one partial response (7.7%; 95% CI, 1.4% to 33.3%) were seen. The median duration of complete response was 66+ months (range, 25 to 87 months), and the estimated survival rate 5 years after ifosfamide treatment was 57% (SE, 32% to 79%). The most frequent toxicities were nausea, vomiting, and leucopenia, but these were well tolerated. Single-agent ifosfamide possesses significant activity against invasive thymoma and is comparable to currently used combination regimens. The inclusion of ifosfamide in combination therapy, particularly in place of cyclophosphamide in regimens such as cisplatin, doxorubicin, and cyclophosphamide, needs to be evaluated.

The place of ifosfamide in chemotherapy of small cell lung cancer: The Eastern Cooperative Oncology Group experience and a selected literature update: Ettinger DS. Johns Hopkins Oncology Center, 600 N Wolfe St, Baltimore, MD 21287. Semin Oncol 1995;22:Suppl 2:23–27

In a randomized Eastern Cooperative Oncology Group study, single-agent ifosfamide used to treat extensive-disease small cell lung cancer patients produced a 49% response rate compared with 56% for patients receiving standard combination chemotherapy (cyclophosphamide/doxorubicin/vincristine). When the drug was combined with carboplatin and etoposide to treat extensive-disease small cell lung cancer patients, overall response rate was 83%, median survival time was 9 months, and 2-year survival rate was 14%. The major toxicity was myelosuppression. These results confirm those of other investigators who have shown the effectiveness of the ifosfamide/carboplatin/etoposide regimen in treating patients with small cell lung cancer.

Primary extracranial rhabdoid tumors. Clinicopathologic features and response to ifosfamide.

Malignant rhabdoid tumor (MRT) is an aggressive, invariably lethal tumor that is resistant to multimodal therapy. The authors reviewed the clinicopathologic features, treatment, and outcome of 13 children (7 boys and 6 girls) with diagnoses of primary extracranial MRT at St. Jude Children's Research Hospital between 1981 and 1990. The median age at diagnosis was 8 months (range, 10 weeks-18 years). Primary sites included the kidney (seven patients), liver (three patients), soft tissue of scapula, posterior mediastinum, and retroperitoneum. Seven patients had metastatic disease (lungs, six patients; cutaneous hemangioma, one patient). Ten patients had surgical resection of primary tumor (complete, nine patients; incomplete, one patient). Eleven patients had chemotherapy with multiple agents. Three of four chemotherapy responses observed were with regimens containing ifosfamide. Partial responses (PR, > 50% reduction in tumor size) were obtained in one patient who received single-agent ifosfamide during disease relapse (PR lasting 2 months), one patient who received a combination of ifosfamide, carboplatin, and etoposide at diagnosis (PR lasting 5 months), and one patient who was treated with bleomycin, cyclophosphamide, doxorubicin, and vincristine at diagnosis (PR lasting 5 months) and subsequently with ifosfamide in combination with carboplatin and etoposide during disease relapse (PR lasting 4 months). All patients died at a median period of 5 months (range, 0.5-30 months) after diagnosis. Based on this review, the authors recommend using ifosfamide alone or in combination with carboplatin and etoposide in front-line therapy for malignant rhabdoid tumor.

Ifosfamide alone and in combination in the treatment of refractory malignant gestational trophoblastic disease

We attempted to evaluate the use of ifosfamide either alone or in combination in patients with refractory malignant gestational trophoblastic disease. Our study comprised, in part, a phase II multiinstitutional trial of ifosfamide in refractory gynecologic malignancies and, in part, a review of institutional experience with ifosfamide in combination chemotherapy. Single-agent ifosfamide produced a significant response in titer in one of two patients with refractory choriocarcinoma. Ifosfamide with etoposide and cisplatin (also known as VIP) resulted in significant response in human chorionic gonadotropin titers in three patients with highly refractory metastatic gestational trophoblastic disease and one cure in this group of patients. Ifosfamide has activity in refractory choriocarcinoma and, when combined with etoposide and cisplatin (VIP), may be curative.

Ifosfamide and mesna in previously treated advanced epithelial ovarian cancer: activity in platinum-resistant disease.

There is a critical need to find new antineoplastic drugs that are active in platinum-refractory ovarian cancer. We conducted a phase II trial of single-agent ifosfamide with mesna uroprotection in patients with ovarian cancer previously treated with an organoplatinum compound to assess its activity in this clinical setting. Ifosfamide (1.0 or 1.2 g/m2/d for 5 days, delivered on a monthly schedule) was administered to the 57 patients entered onto this trial. Dose reductions were permitted for unacceptable toxicities. Toxicity included severe bone marrow suppression (WBC count less than 1,000/microL and/or platelet count less than 50,000/microL), renal dysfunction (serum creatinine level greater than 2.0 mg/dL), and reversible CNS dysfunction (disorientation, hallucinations, somnolence, and agitation), which occurred in 20%, 14%, and 12% of patients, respectively. Of 41 patients with strictly defined platinum-refractory ovarian cancer, five (12%) demonstrated a partial (four) or complete (one) response to this treatment program. Single-agent ifosfamide has modest but unequivocal activity in platinum-resistant ovarian cancer. Further studies of this drug used as a front-line agent along with an organoplatinum compound or as part of a dose-intensification program with bone marrow, peripheral stem cell, or colony-stimulating factor support are indicated. In addition, single-agent ifosfamide is a reasonable standard second-line treatment strategy in appropriately selected patients with platinum-refractory ovarian cancer.

Single agent ifosfamide (IFOS) therapy of ovarian cancer (OC) previously treated with cisplatin (CIS)

Single agent ifosfamide (IFOS) therapy of ovarian cancer (OC) previously treated with cisplatin (CIS)