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"Positional isomer of CYCLOPHOSPHAMIDE which is active as an alkylating agent and an immunosuppressive agent." (MeSH 2013)

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Web Resources: Ifosfamide
Recent Publications: Ifosfamide

Web Resources: Ifosfamide (6 links)

Recent Publications: Ifosfamide

Moon JY, Baek SW, Ryu H, et al.
VIP (etoposide, ifosfamide, and cisplatin) in patients with previously treated soft tissue sarcoma.
Medicine (Baltimore). 2017; 96(4):e5942 [PubMed] Free Access to Full Article Related Publications
We retrospectively reviewed outcomes of treatment with VIP (combination of etoposide, ifosfamide, and cisplatin) in patients with previously treated soft tissue sarcoma (STS).We analyzed the medical records of patients with advanced or relapsed STS who had undergone VIP treatment as second-line or more chemotherapy between January 2000 and December 2015. The patients were treated with a combination of etoposide (100 mg/m for 5 days), ifosfamide (2000 mg/m for 2 days), and cisplatin (20 mg/m for 5 days) once every 4 weeks. Treatment response, progression-free survival (PFS), and overall survival (OS) were analyzed in all patients and between responder and nonresponder groups (responders showed a tumor response to any prior systemic chemotherapy before VIP).Twenty-four patients with a median age of 50 years (range: 20-68 years) were treated with VIP. Eleven (45.8%) patients were male and 7 (29.2%) received 2 or more chemotherapy regimens before VIP. Median PFS was 3.7 months (95% confidence interval [CI], 1.3-6.1 months) and median OS was 10.0 months (95% CI, 6.6-13.5). The overall response rate was 37.5%, and the disease control rate was 50%. The responder group showed better PFS (7.7 months vs 3.0 months; P = 0.101) and significantly improved OS (11.0 months vs 8.8 months; P = 0.039) compared to those of nonresponders. All patients reported some grade of hematological toxicity. The most frequently encountered hematological toxicity was neutropenia (any grade, 77.7%; grade 3 or 4, 74.0%).VIP might be effective in patients with previously treated STS.

Kusaba H, Kumagai H, Inadomi K, et al.
Efficacy analysis of the aprepitant-combined antiemetic prophylaxis for non-round cell soft-tissue sarcoma patients received adriamycin and ifosfamide therapy.
Medicine (Baltimore). 2016; 95(49):e5460 [PubMed] Free Access to Full Article Related Publications
Appropriate antiemetic prophylaxis for moderately emetogenic chemotherapy in patients with non-round cell soft-tissue sarcomas (NRC-STS) remains unclear. We retrospectively investigated efficacy and safety of aprepitant-combined antiemetic prophylaxis in patients with NRC-STS receiving adriamycin plus ifosfamide (AI) therapy. Forty NRC-STS patients were enrolled, their median age was 50 years (range 18-74), and 13 (32.5%) were female. Median cycle number of AI therapy was 4. Twenty patients received the doublet antiemetic prophylaxis (5-hydroxytryptamine-3 receptor antagonist and dexamethasone), and 20 received triplet (5-hydroxytryptamine-3 receptor antagonist, dexamethasone, and aprepitant). In the overall period, complete response rate for nausea and emesis in the triplet group was significantly higher than that in the doublet group (70% vs 35%; P = 0.027). Patients with no-emesis in the overall period were more frequently observed in the triplet group than in the doublet group (90% vs 65%; P = 0.058). All toxicities other than emesis were almost equivalent in both the groups. These results suggest that a triplet antiemetic prophylaxis may be optimal in the treatment with AI therapy for NRC-STS.

Chhibar P, Zhu Z, Cheedella NK, et al.
Hepatitis B Reactivation After Ifosfamide Therapy for Retroperitoneal Sarcoma.
Am J Case Rep. 2016; 17:371-4 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Patients receiving cancer treatment are at risk for hepatitis B virus (HBV) reactivation. Ifosfamide is an alkylating agent and is considered to be one of the important drugs for the treatment of metastatic sarcoma. No association of ifosfamide and HBV reactivation has been reported so far.
CASE REPORT: We report a case of a 61-year-old Asian man with metastatic retroperitoneal liposarcoma who was HBcAb positive and was treated with ifosfamide and dacarbazine, developed HBV reactivation secondary to ifosfamide requiring treatment with tenofovir. To the best of our knowledge, this is the first report describing HBV reactivation in a patient with positive HBcAb who was treated with ifosfamide.
CONCLUSIONS: We recommend close surveillance of possible HBV reactivation while employing ifosfamide chemotherapy.

Abu-Khalaf MM, Raza MA, Hatzis C, et al.
Efficacy and tolerability of combination cisplatin and ifosfamide chemotherapy with vaginal cuff brachytherapy in the first line treatment of uterine carcinosarcoma.
Eur J Gynaecol Oncol. 2016; 37(2):199-203 [PubMed] Related Publications
PURPOSE OF INVESTIGATION: A retrospective study to evaluate six cycles of cisplatin 40 mg/m2 on day 1 and ifosfamide 1,200 mg/m2 daily on days 1 to 4 with Mesna every four weeks as first line treatment for 29 patients with a diagnosis of uterine carcinosarcoma.
MATERIALS AND METHODS: A total of 23 of 29 patients received high dose rate intracavitary vaginal cuff brachytherapy (VCBT) with two fractions of seven Gy each. Median age was 65 years (range 40-82); 13 (44.8%) had Stage I disease, three (10.3%) had Stage II, eight (27.6%) had Stage III, and five (17.2%) patients had Stage IV disease.
RESULTS: Most common toxicities were anemia grade 1 (35%)/grade 2 (45%), and neutropenia grade 3 (17%)/grade 4 (6.9%). Eleven dose modifications, four treatment discontinuations, and one patient withdrawal occurred. At a median follow up of 45 months (range 9 to 144), Progression free survival (PFS) was 20% and overall survival (OS) was 40% for Stage IV, PFS 75% and OS 62.5% for Stage III, compared to a PFS 75% and OS 72.2% for Stages I-II. Median OS for the entire group was 12.43 years (95% CI 3.69 to inf); for Stage I-III 12.4 years (6.1 to inf), and for Stage IV 15.6 months (95% CI 9.4 to inf).
CONCLUSIONS: Cisplatin and ifosfamide chemotherapy with VCBT was well tolerated and has promising activity in uterine carcinosarcoma.

Sasada S, Kodaira M, Shimoi T, et al.
Ifosfamide and Etoposide Chemotherapy in the Treatment of Recurrent/Refractory Rhabdomyosarcoma in Adults.
Anticancer Res. 2016; 36(5):2429-32 [PubMed] Related Publications
BACKGROUND: No standard chemotherapy for adults with recurrent/refractory rhabdomyosarcoma (RMS) has yet been established. The present study aimed to assess the effect of ifosfamide and etoposide (IE) chemotherapy on previously treated RMS.
PATIENTS AND METHODS: Adults with recurrent/refractory RMS were treated with ifosfamide (1,800 g/m(2)/day), etoposide (100 mg/m(2)/day) and mesna (1,080 mg/m(2)/day) for 5 days. The effect and toxicity were evaluated by chart review.
RESULTS: Fifteen patients, with a median age of 33 years (range=25-67 years), were treated with IE chemotherapy. A median of six cycles of chemotherapy were administered and an objective response was obtained in eight patients. The median progression-free survival was 5.2 months (95% confidence interval=2.3-6.7 months) and overall survival was 14.4 months (95% confidence interval=4.6-28.3 months). Toxicity greater than grade 3 was as follows: neutropenia in all patients, anemia in seven, thrombocytopenia in seven and febrile neutropenia in eight.
CONCLUSION: IE chemotherapy could be an alternative optional treatment method in adults with recurrent/refractory RMS.

Aurer I, Nemet D, Mitrović Z, et al.
High-dose ifosfamide and mitoxantrone (HDIM) in patients with relapsed or refractory Hodgkin's lymphoma.
Ann Hematol. 2016; 95(7):1129-36 [PubMed] Related Publications
Relapsed/refractory Hodgkin's lymphoma (HL) is treated with salvage chemotherapy and autologous stem cell transplantation (ASCT). Optimal chemotherapy is unknown. We retrospectively analyzed outcomes of 58 patients treated with 2 cycles of high-dose ifosfamide and mitoxantrone (HDIM). HDIM consisted of ifosfamide 5 g/m(2)/day and MESNA 5 g/m(2)/day in continuous 24-h infusion (days 1 and 2), MESNA 2.5 g/m(2) over 12 h (day 3), and mitoxantrone 20 mg/m(2) (day 1) administered every 2 weeks. Stem cells were collected after the first cycle. Responding patients proceeded to ASCT. Toxicity was acceptable. Stem cell mobilization was successful in 96 % of patients. Overall response rate was 74 % (89 % in relapsing and 45 % in refractory patients) with 31 % complete remissions. After a median follow-up of 54 months, 5-year event-free survival was 56 % (69 % for relapsing and 35 % for refractory patients), and 5-year overall survival was 67 % (73 % for relapsing and 55 % for refractory patients). Significant adverse prognostic factors were refractoriness to previous therapy and HDIM failure. No differences in outcomes were noted between patients with early and late relapses or between complete and partial responders. HDIM is a well-tolerated and effective regimen for relapsed and refractory HL with excellent stem cell mobilizing properties. Patients failing HDIM may still benefit from other salvage options.

Schorb E, Finke J, Ferreri AJ, et al.
High-dose chemotherapy and autologous stem cell transplant compared with conventional chemotherapy for consolidation in newly diagnosed primary CNS lymphoma--a randomized phase III trial (MATRix).
BMC Cancer. 2016; 16:282 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Primary central nervous system lymphoma (PCNSL) is a highly aggressive Non-Hodgkin lymphoma (NHL) with rising incidence over the past 30 years in immunocompetent patients. Although outcomes have improved, PCNSL is still associated with inferior prognosis compared to systemic NHL. Many questions regarding the optimal therapeutic approach remain unanswered.
METHODS/DESIGN: This is a randomized, open-label, international phase III trial with two parallel arms. We will recruit 250 patients with newly diagnosed PCNSL from approximately 35 centers within the networks of the German Cooperative PCNSL study group and the International Extranodal Lymphoma Study Group. All enrolled patients will undergo induction chemotherapy consisting of 4 cycles of rituximab 375 mg/m(2)/d (days 0 & 5), methotrexate 3.5 g/m(2) (d1), cytarabine 2 × 2 g/m(2)/d (d2-3), and thiotepa 30 mg/m(2) (d4) every 21 days. All patients will undergo stem-cell harvest after the second cycle. After 4 cycles of induction chemotherapy, patients achieving partial or complete response will be centrally randomized to 2 different consolidation treatments: (A) conventional-dose immuno chemotherapy with rituximab 375 mg/m(2) (d0), dexamethasone 40 mg/d (d1-3), etoposide 100 mg/m(2)/d (d1-3), ifosfamide 1500 mg/m(2)/d (d1-3) and carboplatin 300 mg/m(2) (d1) (R-DeVIC) or (B) high-dose chemotherapy with BCNU (or busulfan) and thiotepa followed by autologous stem cell transplantation (HCT-ASCT). The objective is to demonstrate superiority of HCT-ASCT compared to R-DeVIC with respect to progression-free survival (PFS, primary endpoint). Secondary endpoints include overall survival (OS), treatment response and treatment-related morbidities. Minimal follow-up after treatment completion is 24 months.
DISCUSSION: The rationale for consolidation treatment in PCNSL is to eliminate residual lymphoma cells and to decrease the risk for relapse. This can be achieved by agents crossing the blood brain barrier either applied at conventional doses or at high doses requiring autologous stem cell support. HCT-ASCT has been shown to be feasible and highly effective in patients with newly-diagnosed PCNSL. However, it is unclear whether HCT-ASCT is really superior compared to conventional-dose chemotherapy after an intensified antimetabolites-based immunochemotherapy in patients with newly-diagnosed PCNSL. To answer this question, we designed this investigator initiated randomized phase III trial.
TRIAL REGISTRATION: German clinical trials registry DRKS00005503 registered 22 April 2014 and ClinicalTrials.gov NCT02531841 registered 24 August 2015.

Wang B, Yu X, Xu S, Xu M
Combination of Cisplatin, Ifosfamide, and Adriamycin as Neoadjuvant Chemotherapy for Extremity Soft Tissue Sarcoma: A Report of Twenty-Eight Patients.
Medicine (Baltimore). 2016; 95(4):e2611 [PubMed] Free Access to Full Article Related Publications
To investigate the clinical efficacy of neoadjuvant chemotherapy in the treatment of extremity soft tissue sarcomas (STSs). We retrospectively analyzed 28 patients with extremity STS that received 2 cycles of preoperative and 6 cycles of postoperative neoadjuvant chemotherapy between May 2009 and June 2012. Chemotherapy comprised intravenous cisplatin (DDP) (120  mg/m(2), for 1 day), followed 1 week later with 5 days 2  g/m(2) ifosfamide (IFO) and 3 days 30  mg/m(2) adriamycin (ADM). CT scans of the lungs and X-ray films of the lesion sites were reviewed. Eighteen patients were treated for primary tumor and 10 for tumor recurrence. Overall tumor diameter ranged from 8 to 30  cm based on body surface measurement. A total of 224 cycles of chemotherapy were carried out and patients were followed up for 12 to 59 months. Twenty-five patients underwent wide resection surgery (89.2%), and 3 underwent amputation (10.7%). Disease-free survival was realized in 20 patients and 3 patients survived with tumors. Two-year disease-free survival rate was 71.4%, and overall 2-year survival rate was 82.1%. Postoperative metastases were observed in 5 patients, and all died of lung metastases. Postoperative recurrence was observed in 4 patients (including 1 patient occurred metastases later). Tumor size was reduced by 30% ± 11.3% on average after the preoperative chemotherapy, and was reduced by 43% ± 7.8% in 22 patients with tumors >15  cm in the diameter. Twelve patients achieved partial remission, 14 stable disease and 2 experienced progressive disease. Objective response rate was 42.9%. Disease control rate was 92.9%. Chemotherapy was well tolerated in all the patients. Main adverse reactions were transient and resolved after chemotherapy. Neoadjuvant chemotherapy is effective in the treatment of extremity STS.

Ramirez MD, Mertens AC, Esiashvili N, et al.
Yield of Urinalysis Screening in Pediatric Cancer Survivors.
Pediatr Blood Cancer. 2016; 63(5):893-900 [PubMed] Article available free on PMC after 01/05/2017 Related Publications
BACKGROUND: The Children's Oncology Group (COG) publishes consensus guidelines with screening recommendations for early identification of treatment-related morbidities among childhood cancer survivors. We sought to estimate the yield of recommended yearly urinalysis screening for genitourinary complications as per Version 3.0 of the COG Long-Term Follow-Up Guidelines and identify possible risk factors for abnormal screening in a survivor population.
PROCEDURE: A database of pediatric cancer survivors evaluated between January 2008 and March 2012 at Children's Healthcare of Atlanta was queried for survivors at risk for genitourinary late effects. The frequency of abnormal urinalyses (protein ≥1+ and/or presence of glucose and/or ≥5 red blood cells per high power field) was estimated. Risk factors associated with abnormal screening were identified.
RESULTS: Chart review identified 773 survivors (57% male; 67% Caucasian; 60% leukemia/lymphoma survivors; mean age at diagnosis, 5.7 years [range: birth to 17.7 years]; time from diagnosis to initial screening, 7.6 years [range: 2.3 to 21.5 years]) who underwent urinalysis. Abnormal results were found in 78 (5.3%) of 1,484 total urinalyses. Multivariable analysis revealed higher dose ifosfamide (odds ratio [OR] = 6.8, 95% confidence interval [CI] 2.9-16.0) and total body irradiation (TBI, OR = 3.0, 95% CI 1.0-8.4) as significant risk factors for abnormal initial urinalysis screening.
CONCLUSIONS: Pediatric cancer survivors exposed to higher dose ifosfamide or TBI may be at higher risk of abnormal findings on urinalysis screening. Targeted screening of these higher risk patients should be considered.

Fan XL, Cai GP, Zhu LL, Ding GM
Efficacy and safety of ifosfamide-based chemotherapy for osteosarcoma: a meta-analysis.
Drug Des Devel Ther. 2015; 9:5925-32 [PubMed] Article available free on PMC after 01/05/2017 Related Publications
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.

Torres LM, Rivera-Espinosa L, Chávez-Pacheco JL, et al.
A New Method to Quantify Ifosfamide Blood Levels Using Dried Blood Spots and UPLC-MS/MS in Paediatric Patients with Embryonic Solid Tumours.
PLoS One. 2015; 10(11):e0143421 [PubMed] Article available free on PMC after 01/05/2017 Related Publications
Ifosfamide blood concentrations are necessary to monitor its therapeutic response, avoiding any adverse effect. We developed and validated an analytical method by UPLC-MS/MS to quantify ifosfamide in dried blood spots (DBS). Blood samples were collected on Whatman 903® filter paper cards. Five 3 mm disks were punched out from each dried blood spot. Acetonitrile and ethyl acetate were used for drug extraction. Chromatographic separation was carried out in an Acquity UPLC equipment with a BEH-C18 column, 2.1 x 100 mm, 1.7 μm (Waters®). The mobile phase consisted in 5 mM ammonium formate and methanol:acetonitrile (40:48:12 v/v/v) at 0.2 mL/min. LC-MS/MS detection was done by ESI+ and multiple reaction mode monitoring, ionic transitions were m/z1+ 260.99 > 91.63 for ifosfamide and 261.00 > 139.90 for cyclophosphamide (internal standard). This method was linear within a 100-10000 ng/mL range and it was accurate, precise and selective. Ifosfamide samples in DBS were stable for up to 52 days at -80°C. The procedure was tested in 14 patients, ages 1 month to 17 years (9 males and 5 females), with embryonic tumours treated with ifosfamide, alone or combined, at a public tertiary referral hospital. Ifosfamide blood levels ranged from 11.1 to 39.7 μmol/L at 12 hours after the last infusion, while 24-hour levels ranged from 0.7-19.7 μmol/L. The median at 12 hours was 19.5 μmol/L (Q25 14.4-Q75 29.0) and 3.8 μmol/L (Q25 1.5-Q75 9.9) at 24 hours, p<0.001. This method is feasible to determine ifosfamide plasma levels in paediatric patients.

Okada N, Watanabe H, Kagami S, Ishizawa K
Ifosfamide and etoposide chemotherapy may interact with warfarin, enhancing the warfarin induced anticoagulant response.
Int J Clin Pharmacol Ther. 2016; 54(1):58-61 [PubMed] Related Publications
PURPOSE: To report a case of warfarin-response enhancement during administration of ifosfamide and etoposide chemotherapy.
CASE SUMMARY: A 15-yearold boy with rhabdomyosarcoma was treated with a regimen of alternating cycles of vincristine, doxorubicin, and cyclophosphamide (VDC) chemotherapy and ifosfamide and etoposide (IE) chemotherapy. During VDC chemotherapy, occlusion of the left middle cerebral artery occurred, and warfarin was started. On day 3 of IE chemotherapy, the patient's international normalized ratio (INR) transiently increased from baseline 2.61 to 5.45. The INR returned to normal within 3 days after warfarin discontinuation. An increase in INR was observed between days 1 and 3 of subsequent cycles of IE chemotherapy but not during VDC chemotherapy. This INR increase was also observed during concomitant use of aprepitant, an inducer of the CYP2C9.
DISCUSSION: There are no reports describing the interaction between warfarin and IE chemotherapy because coadministration of warfarin and IE chemotherapy is unusual. The Drug Interaction Probability Scale score of this interaction was 7, and it is probable that the enhancement of the warfarin response was caused by an interaction with IE chemotherapy. Moreover, in the present case, the enhancement of warfarin response was observed during concomitant use of aprepitant, which has been reported to weaken the warfarin response. Therefore, this interaction may be quite powerful and may increase the risk of warfarin toxicity.
CONCLUSION: A patient who was administered both warfarin and IE chemotherapy experienced a rapid increase in INR, suggesting that INR should be closely monitored in patients receiving warfarin with IE chemotherapy.

Weigel BJ, Lyden E, Anderson JR, et al.
Intensive Multiagent Therapy, Including Dose-Compressed Cycles of Ifosfamide/Etoposide and Vincristine/Doxorubicin/Cyclophosphamide, Irinotecan, and Radiation, in Patients With High-Risk Rhabdomyosarcoma: A Report From the Children's Oncology Group.
J Clin Oncol. 2016; 34(2):117-22 [PubMed] Article available free on PMC after 01/05/2017 Related Publications
PURPOSE: Patients with metastatic rhabdomyosarcoma (RMS), except those younger than 10 years with embryonal RMS, have an estimated long-term event-free survival (EFS) of less than 20%. The main goal of this study was to improve outcome of patients with metastatic RMS by dose intensification with interval compression, use of the most active agents determined in phase II window studies, and use of irinotecan as a radiation sensitizer.
PATIENTS AND METHODS: Patients with metastatic RMS received 54 weeks of therapy: blocks of therapy with vincristine/irinotecan (weeks 1 to 6, 20 to 25, and 47 to 52), interval compression with vincristine/doxorubicin/cyclophosphamide alternating with etoposide/ifosfamide (weeks 7 to 19 and 26 to 34), and vincristine/dactinomycin/cyclophosphamide (weeks 38 to 46). Radiation therapy occurred at weeks 20 to 25 (primary) but was also permitted at weeks 1 to 6 (for intracranial or paraspinal extension) and weeks 47 to 52 (for extensive metastatic sites).
RESULTS: One hundred nine eligible patients were enrolled, with a median follow-up of surviving patients of 3.8 years (3-year EFS for all patients, 38% [95% CI, 29% to 48%]; survival, 56% [95% CI, 46% to 66%]). Patients with one or no Oberlin risk factor (age > 10 years or < 1 year, unfavorable primary site of disease, ≥ three metastatic sites, and bone or bone marrow involvement) had a 3-year EFS of 69% (95% CI, 52% to 82%); high-risk patients with two or more risk factors had a 3-year EFS of 20% (95% CI, 11% to 30%). Toxicity was similar to that on prior RMS studies.
CONCLUSION: Patients with metastatic RMS with one or no Oberlin risk factor had an improved 3-year EFS of 69% on ARST0431 compared with an historical cohort from pooled European and US studies; those with two or more risk factors have a dismal prognosis, and new approaches are needed for this very-high-risk group.

Chen B, Yang JZ, Wang LF, et al.
Ifosfamide-loaded poly (lactic-co-glycolic acid) PLGA-dextran polymeric nanoparticles to improve the antitumor efficacy in Osteosarcoma.
BMC Cancer. 2015; 15:752 [PubMed] Article available free on PMC after 01/05/2017 Related Publications
BACKGROUND: Osteosarcoma is a typical bone cancer that primarily affects adolescents. The therapeutic activity of drugs is limited by their severe drug-related toxicities, therefore, a therapeutic approach which is less toxic and highly effective in tumor is of utmost importance.
METHOD: In this study, ifosfamide-loaded poly (lactic-co-glycolic acid) (PLGA)-dextran polymeric nanoparticles (PD/IFS) was developed and studied its anticancer efficacy against multiple osteosarcoma cancer cells. The drug-loaded nanoparticle was characterized for physical and biological characterizations.
RESULTS: The formulated PD/IFS showed a high drug loading capacity and displayed a pH-sensitive release pattern, with a sustained release profile of the IFS. PD/IFS nanoparticles exhibited remarkable in vitro anticancer activity comparable to that of free IFS solution in a concentration dependent manner in MG63 and Saos-2 cancer cells. PLGA-dextran by itself did not affect cell viability of cancer cells indicating its excellent biocompatibility. The formulation exhibited significantly higher PARP and caspase-3/7 expression in both the cancer cells.
CONCLUSION: Our study successfully demonstrated that nanoparticulate encapsulation of antitumor agent will increase the therapeutic efficacy and exhibit a greater induction of apoptosis and cell death.

Uy GL, Hsu YM, Schmidt AP, et al.
Targeting bone marrow lymphoid niches in acute lymphoblastic leukemia.
Leuk Res. 2015; 39(12):1437-42 [PubMed] Article available free on PMC after 01/05/2017 Related Publications
In acute lymphoblastic leukemia (ALL) the bone marrow microenvironment provides growth and survival signals that may confer resistance to chemotherapy. Granulocyte colony-stimulating factor (G-CSF) potently inhibits lymphopoiesis by targeting stromal cells that comprise the lymphoid niche in the bone marrow. To determine whether lymphoid niche disruption by G-CSF sensitizes ALL cells to chemotherapy, we conducted a pilot study of G-CSF in combination with chemotherapy in patients with relapsed or refractory ALL. Thirteen patients were treated on study; three patients achieved a complete remission (CR/CRi) for an overall response rate of 23%. In the healthy volunteers, G-CSF treatment disrupted the lymphoid niche, as evidenced by reduced expression of CXCL12, interleukin-7, and osteocalcin. However, in most patients with relapsed/refractory ALL expression of these genes was markedly suppressed at baseline. Thus, although G-CSF treatment was associated with ALL cell mobilization into the blood, and increased apoptosis of bone marrow resident ALL cells, alterations in the bone marrow microenvironment were modest and highly variable. These data suggest that disruption of lymphoid niches by G-CSF to sensitize ALL cells to chemotherapy may be best accomplished in the consolidation where the bone marrow microenvironment is more likely to be normal.

Mulder RL, Paulides M, Langer T, et al.
Cyclophosphamide versus ifosfamide for paediatric and young adult bone and soft tissue sarcoma patients.
Cochrane Database Syst Rev. 2015; (9):CD006300 [PubMed] Related Publications
BACKGROUND: Alkylating agents, such as cyclophosphamide and ifosfamide, play a major role in the improved survival of children and young adults with bone and soft tissue sarcoma. However, there is still controversy as to their comparative anti-tumour efficacy and possible adverse effects. This is the second update of the first systematic review evaluating the state of evidence on the effectiveness of cyclophosphamide as compared to ifosfamide for paediatric and young adult patients with sarcoma.
OBJECTIVES: The primary obective was to compare the effectiveness, that is response rate, event-free survival and overall survival, of cyclophosphamide with that of ifosfamide for paediatric and young adult patients with sarcoma. Secondary objectives were to determine effects of these agents on toxicities (including late effects) and quality of life.
SEARCH METHODS: We searched CENTRAL (The Cochrane Library 2015, issue 2), MEDLINE/PubMed (from 1966 to March 2015) and EMBASE/Ovid (from 1980 to March 2015) with prespecified terms. In addition, we searched reference lists of relevant articles, conference proceedings and ongoing trial databases (www.controlled-trials.com; searched June 2015).
SELECTION CRITERIA: Randomised controlled trials (RCTs) or controlled clinical trials (CCTs) comparing cyclophosphamide and ifosfamide for the treatment of different types of sarcoma in paediatric and young adult patients (aged less than 30 years at diagnosis). Chemotherapy other than either cyclophosphamide or ifosfamide should have been the same in both treatment groups.
DATA COLLECTION AND ANALYSIS: Two authors independently performed the study selection.
MAIN RESULTS: No studies meeting the inclusion criteria of the review were identified.
AUTHORS' CONCLUSIONS: No RCTs or CCTs comparing the effectiveness of cyclophosphamide and ifosfamide in the treatment of bone and soft tissue sarcoma in children and young adults were identified. Therefore no definitive conclusions can be made about the effects of cyclophosphamide and ifosfamide in these patients. Based on the currently available evidence, we are not able to give recommendations for clinical practice. More high-quality research is needed.

Nataraj V, Batra A, Rastogi S, et al.
Developing a prognostic model for patients with localized osteosarcoma treated with uniform chemotherapy protocol without high dose methotrexate: A single-center experience of 237 patients.
J Surg Oncol. 2015; 112(6):662-8 [PubMed] Related Publications
BACKGROUND: Studies of baseline prognostic factors in patients with localized osteosarcoma treated without high dose methotrexate are limited.
METHODS: This is single-institutional review of localized osteosarcoma patients treated without high dose methotrexate between June 2003-December 2012. A multivariate analysis of impact of baseline and treatment characteristics on outcome was performed and a prognostic model was developed based solely on baseline factors for predicting event-free survival (EFS) and overall survival (OS).
RESULTS: Of 237 patients with median age of 17 years (range 2-66 yrs), neoadjuvant chemotherapy (NACT) was administered in 220 (92.82%) patients. Post NACT, 200/237 (84.38%) patients underwent surgery. At 30 months median follow-up, 5-year EFS and OS were 36.60 ± 0.03%, and 50.33 ± 0.04%, respectively. In multivariate analysis, baseline factors including duration of symptom >4 months (P < 0.001) and good performance status (PS) (P < 0.001) predicted better EFS whereas good PS (P = 0.01) and normal serum alkaline phosphatase (SAP) (P = 0.03) predicted better OS. The 5-year EFS without any risk factor (symptom duration <4 months, PS>1) was 58.7 ± 0.1%, with either one factor 31.5 ± 0.1% and with both factors 21.9 ± 0.1%. The 5-year OS without any risk factor (PS>1, elevated SAP) was 66.9 ± 0.1%, with either one factor 57.9 ± 0.1% and with both factors 25.6 ± 0.1%.
CONCLUSIONS: This prognostic model assists in categorizing risk-groups within localized osteosarcoma.

Lee HS, Lee YG, Koo DH, et al.
Efficacy and safety of ifosfamide in combination with carboplatin and etoposide in small cell lung cancer.
Cancer Chemother Pharmacol. 2015; 76(5):933-7 [PubMed] Related Publications
PURPOSE: Ifosfamide, a potent alkylating agent, is rarely incorporated into small cell lung cancer (SCLC) treatment. The aim of this study was to assess the efficacy and safety of ifosfamide in combination with carboplatin and etoposide (ICE) in previously untreated patients with SCLC.
METHODS: From January 2002 to January 2014, we consecutively enrolled 69 patients with SCLC who were treated with ICE as initial chemotherapy at Kangbuk Samsung Hospital. The modified ICE regimen consists of ifosfamide 1200 mg/m(2)/day on days 1, 2, and 3 with mesna, etoposide 80 mg/m(2)/day on days 1, 2, and 3, and carboplatin AUC 6 on day 1. Treatment was repeated every 3 weeks and continued for up to nine cycles. Response assessments were performed every three cycles with computed tomography.
RESULTS: Among 69 patients with SCLC, the median age was 69 years (range 51-88 years). Sixteen (23 %) patients had limited disease (LD), and 53 (77 %) had extensive disease (ED). The overall response rate was 73 %. Stable disease rate was 20 %. The median overall survival was 11.3 months [95 % confidence interval (CI) 8.9-14.1] in the overall population, 20.6 months (95 % CI 14.2-21.2) for LD and 9.1 months (95 % CI 7.8-11.6) for ED. The median number of administered cycles was 6 (range 1-9). Grade ≥3 hematological toxicities included neutropenia (34 %), anemia (59 %), and thrombocytopenia (31 %). Grade ≥3 non-hematological toxicities included peripheral neuropathy in 2 %.
CONCLUSION: In chemonaïve patients with SCLC, modified ICE is well tolerated and shows favorable efficacy.

Zhou P, Liu P, Zhou SY, et al.
Ifosfamide, Cisplatin or Carboplatin, and Etoposide (ICE)-based Chemotherapy for Mobilization of Autologous Peripheral Blood Stem Cells in Patients with Lymphomas.
Chin Med J (Engl). 2015; 128(18):2498-504 [PubMed] Article available free on PMC after 01/05/2017 Related Publications
BACKGROUND: High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is a promising approach for lymphomas. This study aimed to evaluate the effect of ifosfamide, cisplatin or carboplatin, and etoposide (ICE)-based regimen as a mobilization regimen on relapsed, refractory, or high-risk aggressive lymphoma.
METHODS: From June 2001 to May 2013, patients with lymphomas who mobilized by ICE-based regimen for ASCT were analyzed in this retrospective study. The results of the autologous peripheral blood stem cells collection, toxicity, engraftment after ICE-based mobilization regimen were analyzed in this study. Furthermore, risk factors for overall survival (OS) and progression free survival (PFS) were evaluated by univariate analysis.
RESULTS: The stem cells were mobilized using ICE-based regimen plus rituximab or ICE-based regimen alone in 12 patients and 54 patients, respectively. The results of stem cell mobilization were excellent. Ninety-seven percentages of the patients had the stem cell collection of at least 2.0 × 10 6 CD34 + cells/kg and 68% had at least 5 × 10 6 CD34 + cells/kg. Fifty-eight percentage of the patients experienced Grade 4 neutropenia, 20% developed febrile neutropenia, and only 12% had Grade 4 thrombocytopenia. At a median follow-up of 63.8 months, the 5-year PFS and OS were 64.4% and 75.3%, respectively.
CONCLUSION: ICE is a powerful regimen for stem cell mobilization in patients with lymphomas.

Palassini E, Ferrari S, Verderio P, et al.
Feasibility of Preoperative Chemotherapy With or Without Radiation Therapy in Localized Soft Tissue Sarcomas of Limbs and Superficial Trunk in the Italian Sarcoma Group/Grupo Español de Investigación en Sarcomas Randomized Clinical Trial: Three Versus Five Cycles of Full-Dose Epirubicin Plus Ifosfamide.
J Clin Oncol. 2015; 33(31):3628-34 [PubMed] Related Publications
PURPOSE: We report on feasibility of preoperative chemotherapy with or without radiation therapy (RT) in the context of a phase III randomized clinical trial involving localized, high-risk, soft tissue sarcomas.
PATIENTS AND METHODS: Of 321 eligible patients, 161 were randomly assigned to three preoperative cycles of epirubicin 120 mg/m(2) plus ifosfamide 9 g/m(2), and 160 were randomly assigned to three preoperative plus two postoperative cycles. Among them, 303 patients were included in this analysis; 169 were male and 134 were female, with a median age of 48 years (range, 15 to 79 years). One hundred fifty-two patients received concurrent RT preoperatively at a total dose of 44 to 50 Gy. Preoperative chemotherapy-related hematologic toxicity and early postoperative complications were reported. The influence of RT, age, and sex on hematologic grade 3 or 4 toxicities and wound complications was analyzed. Chemotherapeutic dose intensity (DI) was analyzed.
RESULTS: Among the patients, 61.4%, 22.4%, and 23.8% experienced, grade 4 leucopenia, grade 3 or 4 anemia, and grade 3 or 4 thrombocytopenia, respectively. Respective rates were 66.4%, 24.3%, and 31.6% when RT was added preoperatively, and 56.3%, 20.5%, and 15.9% when preoperative chemotherapy was administered alone. Patient age affected grade 3 or 4 thrombocytopenia. Grade 4 leucopenia and grade 3 or 4 anemia presented 2.5 times more frequently in female patients than in male patients. Wound complications were observed in 13.5% of patients: 17% with preoperative RT and 10% without. Chemotherapeutic DI was greater than 90%, even in patients receiving preoperative RT and in patients age 65 years or older.
CONCLUSION: This preoperative chemotherapy is feasible and can also be proposed for selected elderly patients. Grade 3 or 4 hematologic toxicity was common, but DI was excellent. Concurrent preoperative RT is safe, although an increased rate of grade 4 thrombocytopenia and limited increase in wound complications may be observed.

van den Berg H, Paulussen M, Le Teuff G, et al.
Impact of gender on efficacy and acute toxicity of alkylating agent -based chemotherapy in Ewing sarcoma: secondary analysis of the Euro-Ewing99-R1 trial.
Eur J Cancer. 2015; 51(16):2453-64 [PubMed] Related Publications
BACKGROUND: Based on the randomised Euro-EWING99-R1 trial, vincristine, adriamycin, cyclophosphamide (VAC) may be able to replace vincristine, adriamycin, ifosfamide (VAI) in the treatment of standard-risk Ewing sarcoma. However some heterogeneity of treatment effect by gender was observed. The current exploratory study aimed at investigating the influence of gender on treatment efficacy and acute toxicity.
PATIENTS AND METHODS: Impact of gender on event-free survival (EFS), acute toxicity by course, switches between treatment arms and cumulative dose of alkylating agents was evaluated in multivariable models adjusted for age including terms to test for heterogeneity of treatment effect by gender. The analysis of the EFS was performed on the intention-to-treat population.
RESULTS: EFS did not significantly differ between the 509 males and 347 females (p=0.33), but an interaction in terms of efficacy was suspected between treatment and gender (p=0.058): VAC was associated with poorer EFS than VAI in males, hazard ratio (HR) (VAC/VAI)=1.37 [95% confidence interval (CI), 0.98-1.90], contrasting with HR=0.81 [95%CI, 0.53-1.24] in females. Severe toxicity was more frequent in females, whatever the toxicity type. Thirty patients switched from VAI to VAC (9/251 males, 4%, and 21/174 females, 12%) mostly due to renal toxicity, and three from VAC to VAI (2/258 males, 0.8%, and 1/173 females, 0.6%). A reduction of alkylating agent cumulative dose >20% was more frequent in females (15% versus 9%, p=0.005), with no major difference between VAC and VAI (10% versus 13%, p=0.15).
CONCLUSION: Differences of acute toxicity rate and cumulative doses of alkylating agents could not explain the marginal interaction observed in the Euro-EWING99-R1 trial data. Effects of gender-dependent polymorphism/activity of metabolic enzymes (e.g. known for CYP2B6) of ifosfamide versus cyclophosphamide should be explored. External data are required to further evaluate whether there is heterogeneity of alkylating agent effect by gender.
TRIAL NUMBERS: NCT00987636 and EudraCT 2008-003658-13.

Habbel P, Kurreck A, Schulz CO, et al.
Cisplatin Plus Ifosfamide with/without Etoposide as Salvage Treatment in Heavily-pre-treated Patients with Metastatic Breast Cancer.
Anticancer Res. 2015; 35(9):5091-5 [PubMed] Related Publications
BACKGROUND: The efficacy of platinum- and ifosfamide-based chemotherapy regimens as salvage treatment in metastatic breast cancer (MBC) has not yet been sufficiently evaluated.
PATIENTS AND METHODS: Patients with MBC treated with cisplatin plus ifosfamide with (PEI) and without (PI) etoposide in our clinic between 04/2005 and 04/2014 were retrospectively analyzed.
RESULTS: A total of 20 patients (median four prior chemotherapies) treated with PEI/PI were identified, out of whom 18 were evaluable for objective response. Treatment with PEI/PI resulted in one complete remission, nine partial remissions and two cases of stable disease. The median (range) progression-free survival was 4 (0-18) months and median overall survival from therapy initiation was 8.5 (0-50) months. PEI/PI therapy caused grade 3/4 toxicities (mainly hematological) in 80% of patients.
CONCLUSION: PEI/PI is an adequate salvage treatment for patients with MBC but cannot be generally recommended due to toxicity. However, comparison with platinum monotherapy trials suggests that PEI/PI might be a more effective treatment for patients with triple-negative breast cancer.

Dandamudi RK, Aslam S, Walji N, et al.
Chemotherapy for Uterine Carcinosarcoma with Carboplatin, Ifosfamide and Mesna.
Anticancer Res. 2015; 35(9):4841-7 [PubMed] Related Publications
BACKGROUND/AIM: Uterine carcinosarcomas (UCSs) are highly aggressive, rare, biphasic tumors composed of epithelial and mesenchymal elements. Surgery remains the mainstay of treatment in early-stage disease. Adjuvant pelvic radiotherapy improves locoregional control without proven overall survival (OS) benefit. Although adjuvant ifosfamide-based combination chemotherapy with cisplatin or paclitaxel has shown superiority to radiotherapy or single-agent chemotherapy in randomized controlled trials, there is no consensus on a standard regimen due to toxicities. The aim of this retrospective study was to assess the efficacy and toxicity of a novel combination chemotherapy using carboplatin, ifosfamide and mesna (CIM) and compare with other regimens for patients with UCSs in both the adjuvant and palliative setting.
PATIENTS AND METHODS: Between 1997 and 2010, 60 patients with UCS, 70% of whom with international federation of gynecology and obstetrics (FIGO) stage III/IV disease, were treated with adjuvant or palliative chemotherapy. Two groups were identified: Group1 (n=22) included patients receiving CIM chemotherapy; and group 2 (n=38) receiving other regimens (carboplatin/paclitaxel/cisplatin/doxorubicin/epirubicin).
RESULTS: After a median follow-up of 60 months, disease in seven patients in group 1 (CIM) and 20 patients in group 2 had progressed/relapsed. Out of these, six patients in group 1 and 13 patients in group 2 had died. The progression-free survival (PFS) and OS for patients treated with adjuvant or palliative CIM was 35 months [95% confidence interval (CI) =0.26-0.43] and 47 months (95% CI=0.38-0.56; log-rank, p=0.001) respectively, whereas for group 2 patients treated with other regimens, PFS was 27.48 months (95% CI=0.20-0.33) and OS was 30 months (95% CI=0.21-0.38; log-rank, p=0.001). While none of the patients in group 1 experienced neurotoxicity or other grade 3 or 4 toxicities, 3/38 patients in group 2 experienced grade 3 neutropenia, 4/38 had peripheral sensory neuropathy, 6/38 patients had treatment deferred due to toxicities or allergic reaction to paclitaxel.
CONCLUSION: In the phase III randomized controlled trial combination of ifosfamide and taxanes has shown PFS and OS benefit when compared to single-agent ifosfamide at the expense of significant toxicities. Results from our study show that the combination of CIM is an effective and safe alternative regimen for patients with advanced UCSs. In addition to improved OS and PFS, the main advantage of this regimen over taxane-based regimens includes minimal neuropathy, less use of steroids, and low risk of allergic reaction. CIM should be considered in future prospective studies looking at the treatment of UCS.

Fresneau B, Orbach D, Faure-Conter C, et al.
Sex-Cord Stromal Tumors in Children and Teenagers: Results of the TGM-95 Study.
Pediatr Blood Cancer. 2015; 62(12):2114-9 [PubMed] Related Publications
BACKGROUND: We present the results of the TGM-95 study for gonadal sex-cord stromal tumors (SCT).
METHODS: Between 1995 and 2005, children (<18 years) with gonadal SCT were prospectively registered. Primary gonadal resection was recommended whenever feasible. Patients with disseminated disease or an incomplete resection received neoadjuvant or adjuvant VIP chemotherapy (etoposide, ifosfamide, cisplatinum).
RESULTS: Thirty-eight children with ovarian SCT were registered. Median age was 10.7y. Endocrine symptoms were present in 21 cases. The histological diagnoses were as follows: juvenile (23) and adult (3) granulosa cell tumors, Sertoli-Leydig cell tumors (11), and mixed germ cell SCT (1). An initial oophorectomy ± salpingectomy led to complete resection in 23 patients who did not receive adjuvant treatment; two of them relapsed: one achieved second complete remission whereas the other one died of disease. Fifteen patients had tumor rupture and/or malignant ascites: 11 received chemotherapy and did not relapse, four did not receive chemotherapy and relapsed with a fatal outcome in two cases. With a median follow-up of 5.9y, the 5-y EFS and OS rates were respectively 85% and 94%. Eleven patients had localized testicular tumors (median age 0.83y): juvenile granulosa cell tumors (4), Sertoli or Leydig cell tumors (5) and not otherwise specified SCT (2). Treatment was surgery alone with an inguinal orchiectomy. None have relapsed (median follow-up: 5.4y).
CONCLUSIONS: Childhood SCT carry favorable prognosis. In ovarian SCT, surgery should be complete and non-mutilating. Adjuvant chemotherapy efficiently prevents recurrences in cases of tumor rupture. In childhood testicular SCT, the prognosis is excellent with an inguinal orchiectomy, prompting the debate on testis-sparing surgery.

Winter S, Fasola S, Brisse H, et al.
Relapse after localized rhabdomyosarcoma: Evaluation of the efficacy of second-line chemotherapy.
Pediatr Blood Cancer. 2015; 62(11):1935-41 [PubMed] Related Publications
PURPOSE: About one-third of patients with rhabdomyosarcoma relapse despite appropriate treatment and experience a poor outcome. Little meaningful improvement in the outcome of this disease has been observed over the last 30 years. There is no clear international recommendation concerning the use of salvage chemotherapy at relapse. A retrospective multicenter analysis was therefore conducted to analyze the efficacy of various second-line chemotherapy regimens in this setting.
METHODS: Forty-nine patients under the age of 18, with initially localized rhabdomyosarcoma, who relapsed after first complete remission, treated in three SFCE centers (Société Française des Cancers de l'Enfant) between 1995 and 2013, were analyzed.
RESULTS: First relapse occurred after a median interval of 22 months and remained localized in 71.4% of cases. All patients received second-line chemotherapy with an overall response to this salvage therapy of 39.1%. Best specific response rates were 73.3 and 42.9% for carboplatin/epirubicin/vincristine-ifosfamide/vincristine/etoposide (CEV/IVE) (15 patients) and vincristine/irinotecan ± temozolomide (VI[T]) (seven patients), respectively. Overall, 40 patients (81.6%) were then eligible for delayed local treatment (surgery and/or radiotherapy) and 30 of them (61.2%) achieved second complete remission. After a median follow-up of 5.4 years since the diagnosis of first relapse, 5-year overall survival is 49.4% (95% CI: 34.2-64.6).
CONCLUSION: Salvage chemotherapy plays a central role in the management of patients with relapsed rhabdomyosarcoma. CEV/IVE and VI(T) regimens can be recommended as neoadjuvant chemotherapy before local treatment for patients with relapsed rhabdomyosarcoma.

Goldman S, Bouffet E, Fisher PG, et al.
Phase II Trial Assessing the Ability of Neoadjuvant Chemotherapy With or Without Second-Look Surgery to Eliminate Measurable Disease for Nongerminomatous Germ Cell Tumors: A Children's Oncology Group Study.
J Clin Oncol. 2015; 33(22):2464-71 [PubMed] Article available free on PMC after 01/05/2017 Related Publications
PURPOSE: This phase II trial evaluated the effect of neoadjuvant chemotherapy with or without second-look surgery before craniospinal irradiation on response rates and survival outcomes in children with newly diagnosed non-germinomatous germ cell tumors.
PATIENTS AND METHODS: Induction chemotherapy consisted of six cycles of carboplatin/etoposide alternating with ifosfamide/etoposide. Patients demonstrating less than complete response after induction chemotherapy were encouraged to undergo second-look surgery. Patients who did not achieve complete response or partial response after chemotherapy with or without second-look surgery proceeded to high-dose chemotherapy with thiotepa and etoposide and autologous peripheral blood stem-cell rescue before craniospinal irradiation.
RESULTS: The study included 102 patients treated between January 2004 and July 2008. Median age was 12 years, and 76% were male; 53.9% had pineal region masses, and 23.5% had suprasellar lesions. Sixty-nine percent of patients achieved complete response or partial response with neoadjuvant chemotherapy. At 5 years, event-free survival was 84% ± 4% (SE) and overall survival was 93% ± 3%. During the median follow-up of 5.1 years, 16 patients recurred or progressed, with seven deaths after relapse. No deaths were attributed to therapy-related toxicity. Relapse occurred at the site of primary disease in 10 patients, at a distant site in three patients, or both in one patient. In two patients, progression was detected by marker increase alone. Increased serum α-fetoprotein was a negative prognostic variable. Histologic subtype and increase of beta-human chorionic gonadotropin were not significantly correlated with worse outcomes.
CONCLUSION: Neoadjuvant chemotherapy with or without second-look surgery achieved high response rates contributing to excellent survival outcomes in children with newly diagnosed non-germinomatous germ cell tumors. This regimen should be included as a backbone for further studies.

Feldman DR, Glezerman I, Patil S, et al.
Phase I/II Trial of Paclitaxel With Ifosfamide Followed by High-Dose Paclitaxel, Ifosfamide, and Carboplatin (TI-TIC) With Autologous Stem Cell Reinfusion for Salvage Treatment of Germ Cell Tumors.
Clin Genitourin Cancer. 2015; 13(5):453-60 [PubMed] Article available free on PMC after 01/05/2017 Related Publications
BACKGROUND: Salvage high-dose (HD) chemotherapy with autologous stem cell transplant (ASCT), consisting of 2 to 3 sequential cycles of HD carboplatin and etoposide (CE) can achieve durable remissions in approximately half of patients with relapsed germ cell tumors. To improve on these results and based on success with paclitaxel, ifosfamide, and cisplatin (TIP) as salvage conventional-dose chemotherapy, we conducted a phase I/II trial of HD paclitaxel with ifosfamide (TI), substituting carboplatin for cisplatin to allow dose escalation.
PATIENTS AND METHODS: Treatment consisted of 1 to 2 cycles of TI and granulocyte colony-stimulating factor for stem cell mobilization followed by 3 cycles of HD TI with carboplatin (TIC) with ASCT every 21 to 28 days. Twenty-six patients were enrolled. For phase I, a standard 3+3 dose-escalation design was used.
RESULTS: With no dose-limiting toxicities observed, the maximum tolerated dose (MTD) was not reached and the highest prespecified dose level (paclitaxel 250 mg/m(2), ifosfamide 9990 mg/m(2), carboplatin area under the curve 24) was considered the MTD. In phase II, a Simon 2-stage design was used to estimate the complete response (CR) rate at the MTD. With 7 of 11 phase II patients who achieved a CR, efficacy was demonstrated. However, 3 patients developed delayed chronic kidney disease, resulting in premature trial closure.
CONCLUSION: TI-TIC was active in relapsed germ cell tumors but treatment-emergent chronic renal impairment, possibly from overlapping ifosfamide and carboplatin, preclude its further use. TI-CE, consisting of 2 cycles of TI with 3 cycles of HD CE remains the standard of care HD chemotherapy regimen at Memorial Sloan Kettering Cancer Center.

Davis EJ, Chugh R, Zhao L, et al.
A randomised, open-label, phase II study of neo/adjuvant doxorubicin and ifosfamide versus gemcitabine and docetaxel in patients with localised, high-risk, soft tissue sarcoma.
Eur J Cancer. 2015; 51(13):1794-802 [PubMed] Related Publications
BACKGROUND: Doxorubicin and ifosfamide (AI) is standard therapy for high-risk soft tissue sarcoma (STS) but often causes severe toxicities resulting in hospitalisation. Gemcitabine and docetaxel (GD) has efficacy in metastatic STS and may be better tolerated. We conducted a study to compare toxicities and efficacies of these regimens.
METHODS: This open-label, phase II, single institution trial randomised 80 patients with localised, resectable, high grade STS ⩾ 5 cm to either neo/adjuvant AI or GD. AI was doxorubicin (75 mg/m(2)) and ifosfamide (2.5 g/m(2)/d) on days 1-3 with mesna 500 mg/m(2)/dose. GD was gemcitabine 900 mg/m(2) on days 1, 8 and docetaxel 100mg/m(2) day 8. Both arms included filgrastim. The primary end-point was hospitalisation rate. Secondary end-points included disease-free survival (DFS) and overall survival (OS).
RESULTS: Between November 2004 and August 2012, 80 evaluable patients were randomised, 37 to AI and 43 to GT. In the AI arm, 13/37 (35%) patients were hospitalised versus 11/43 (26%) in the GD arm (p=0.25). Hospitalisation rates were not significantly different after adjusting for age, gender, location, chemotherapy and number of cycles (p=0.17). The 2-year and median DFS in the AI arm were 57% and 37 months, respectively, and 74% and not yet reached, respectively, in the GD arm. The most common serious adverse events with AI were haematologic. Metabolic derangements and constitutional symptoms were most common with GD.
CONCLUSIONS: Hospitalisation rate was less with GD but not statistically significant. There was a trend towards longer DFS with GD, and the regimen was tolerable, suggesting GD merits further study.

Loschi S, Dufour C, Oberlin O, et al.
Tandem high-dose chemotherapy strategy as first-line treatment of primary disseminated multifocal Ewing sarcomas in children, adolescents and young adults.
Bone Marrow Transplant. 2015; 50(8):1083-8 [PubMed] Related Publications
The prognosis of primary disseminated multifocal metastatic Ewing's sarcoma (PDMES) is poor even if a slight improvement has been achieved with high-dose alkylating agent-containing chemotherapy. To enhance treatment efficacy, we assessed the feasibility, safety and efficacy of a tandem high-dose chemotherapy (HDC) regimen. In a single institution, patients with PDMES received six courses of vincristine/ifosfamide/doxorubicin/etoposide induction therapy, followed by high-dose thiotepa, and then melphalan-busulfan, 8 weeks apart. Surgical resection of primary tumour was carried out between the two HDC regimens and 70 days after the last HDC regimen for post-operative radiotherapy or irradiation alone. From October 2002 to 2009, 13 of the 18 consecutive patients with PDMES (72%) received the full treatment programme. The other five patients experienced early progression and died. Among the 13 patients, 11 relapsed after the end of the treatment programme within 6 months (2.2-11.9) from end of therapy. Only two patients are still alive in first complete remission after 9 years. The 3-year event-free survival (EFS) and overall survival (OS) rates were 11 and 22%, respectively. The median EFS and OS duration from the diagnosis were 13.4 and 17.3 months, respectively. Neither major complications nor treatment-related death occurred. The tandem-HDC regimen was feasible, with expected side effects, but it did not improve the outcome of patients with PDMES.

Noy A, Lee JY, Cesarman E, et al.
AMC 048: modified CODOX-M/IVAC-rituximab is safe and effective for HIV-associated Burkitt lymphoma.
Blood. 2015; 126(2):160-6 [PubMed] Article available free on PMC after 01/05/2017 Related Publications
The toxicity of dose-intensive regimens used for Burkitt lymphoma prompted modification of cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate/ifosfamide, etoposide, and high-dose cytarabine (CODOX-M/IVAC) for HIV-positive patients. We added rituximab, reduced and/or rescheduled cyclophosphamide and methotrexate, capped vincristine, and used combination intrathecal chemotherapy. Antibiotic prophylaxis and growth factor support were required; highly active antiretroviral therapy (HAART) was discretionary. Thirteen AIDS Malignancy Consortium centers enrolled 34 patients from 2007 to 2010. Median age was 42 years (range, 19-55 years), 32 of 34 patients were high risk, 74% had stage III to IV BL and CD4 count of 195 cells per μL (range, 0-721 cells per μL), and 5 patients (15%) had CD4 <100 cells per μL. Twenty-six patients were receiving HAART; viral load was <100 copies per mL in 12 patients. Twenty-seven patients had at least one grade 3 to 5 toxicity, including 20 hematologic, 14 infectious, and 6 metabolic. None had grade 3 to 4 mucositis. Five patients did not complete treatments because of adverse events. Eleven patients died, including 1 treatment-related and 8 disease-related deaths. The 1-year progression-free survival was 69% (95% confidence interval [CI], 51%-82%) and overall survival was 72% (95% CI, 53%-84%); 2-year overall survival was 69% (95% CI, 50%-82%). Modifications of the CODOX-M/IVAC regimen resulted in a grade 3 to 4 toxicity rate of 79%, which was lower than that in the parent regimen (100%), without grade 3 to 4 mucositis. Despite a 68% protocol completion rate, the 1-year survival rate compares favorably with 2 studies that excluded HIV-positive patients. This trial was registered at http://clinicaltrials.gov as #NCT00392834.

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