Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C1261473 (sarcoma)
 25,952 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Docetaxel is a new antimicrotubule agent that has been shown to be active against a variety of solid tumors. Ifosfamide is an alkylating drug that has demonstrated activity against non-small cell lung cancer, testicular cancer, breast cancer, and soft tissue sarcoma. This phase I study of the combination of these drugs was performed to assess the feasibility of using the two agents together, to determine the maximum tolerated dose and the side effects, and to propose a safe schedule for further phase II studies. Thirty-four patients with histologically confirmed solid tumors who had not been treated previously with taxanes or ifosfamide and who had received no more than one line of chemotherapy for advanced disease were entered into the study. Treatment consisted of docetaxel given as a 1-hour infusion followed by ifosfamide as a 24-hour infusion (schedule A), or ifosfamide followed by docetaxel (schedule B) every 3 weeks. Docetaxel doses ranged from 60 to 85 mg/m2 and ifosfamide doses from 2.5 to 5.0 g/m2. Grades 3 and 4 granulocytopenia were observed in 89% of courses and appeared to be of short duration and related to the ifosfamide dose. Febrile neutropenia and sepsis occurred in 17% and 2% of courses, respectively. Severe anemia and thrombocytopenia were uncommon. Nonhematologic toxicities were mild to moderate, and included alopecia, nausea, vomiting, mucositis, diarrhea, sensory neuropathy, skin and nail toxicity, hypersensitivity reactions, and edema. Schedule B appeared to induce more gastrointestinal toxicity than schedule A. One complete response in soft tissue sarcoma and two partial responses, one in cancer of unknown primary and the other in non-small cell lung cancer, were documented. The dose-limiting toxicity for schedule A was neutropenic fever at a dose of 85 mg/m2 docetaxel and 5 g/m2 ifosfamide. The dose-limiting toxicity for schedule B was neutropenic fever at a dose of 75 mg/m2 docetaxel and 4 g/m2 ifosfamide. A dose of 75 mg/m2 docetaxel combined with 5 g/m2 ifosfamide according to schedule A can be recommended for further studies.
 ...
PMID:Docetaxel and ifosfamide in patients with advanced solid tumors: results of a phase I study. 953 8

Ifosfamide is an active drug in the therapy of paediatric tumours such as rhabdomyosarcoma, Ewings' sarcoma, Wilms' tumour, neuroblastoma, germ cell tumours and lymphomas. Myelosuppression is the major toxicity along with haemorrhagic cystitis. The latter is largely prevented by the use of concomitant mesna.
 ...
PMID:The role of ifosfamide in paediatric cancer. 967 60

Ifosfamide is a leading drug in soft tissue sarcoma therapy. Recently high dose therapy (>9 g/m2) has been introduced in different schemes to obtain a higher response rate. All these higher doses can be administered following two different schedules: continuous infusion 24 hours a day for 4-5 days or bolus administration for 5 consecutive days. In this study we compare the differences in the pharmacokinetic profile between the two schedules. In both schemes we saw a very important autoinduction phenomenon, with a corresponding half-life decrease and total body clearance increase during the days of therapy. The clearances were not directly correlated with the administered dose. We can conclude that ifosfamide continuous infusion therapy is equivalent to fractionated administration, at least from a pharmacokinetic point of view. Short-term infusion is subjectively better tolerated and is therefore preferred.
 ...
PMID:Pharmacokinetics of ifosfamide administered according to three different schedules in metastatic soft tissue and bone sarcomas. 982 57

Over 50% of patients with newly diagnosed rhabdomyosarcoma (RMS) are in the 'intermediate risk' group with a 3-year progression-free survival of approximately 65%. This group consists of stage 1, group III, non-orbit tumours; stage 2, group II and III; and all stage 3 patients utilising the Intergroup Rhabdomyosarcoma Study (IRS) staging system. The role of doxorubicin in the treatment of RMS has been controversial. Ifosfamide, both alone and in combination with etoposide, has significant activity in patients with RMS. The aim of this pilot study was to examine the efficacy and toxicity of a chemotherapy regimen of alternating cycles of vincristine/doxorubicin/cyclophosphamide and etoposide/ifosfamide for intermediate risk RMS. 30 patients with intermediate risk RMS or undifferentiated sarcoma (US) were treated with alternating cycles of vincristine/doxorubicin/cyclophosphamide (VDC) and etoposide/ifosfamide (EI) at planned intervals of 3 weeks. Local treatment of the tumour in most cases was performed after four cycles of chemotherapy, followed by an additional 10 cycles of chemotherapy. At a median follow-up of 37.5 months, the Kaplan-Meier estimate of 3-year event-free survival was 85% (95% confidence interval 72-99%). The overall survival at 3 years was 91% (95% confidence interval 80-100%). No patient died from toxicity. The most common toxicity was febrile neutropenia in 35% of VDC and 26% of EI cycles. No nephrotoxicity or cardiac toxicity was seen. No patient progressed prior to week 12 local therapy. Alternating cycles of VDC and EI are an effective treatment for patients with intermediate risk RMS and US. Toxicity is tolerable. Delaying local treatment until week 12 does not compromise outcome.
 ...
PMID:Treatment of intermediate risk rhabdomyosarcoma and undifferentiated sarcoma with alternating cycles of vincristine/doxorubicin/cyclophosphamide and etoposide/ifosfamide. 984 84

Ifosfamide is an alkylating antineoplastic agent with documented activity against a variety of solid tumor types, most notably lung cancer, testicular cancer, and sarcoma. Ifosfamide has been included in various drug combination protocols, usually on an empirical basis. To gather more insight into the mechanisms that underlie these drug interactions and to develop guidelines for further improvement of clinical combination protocols, we performed a broad preclinical evaluation program of ifosfamide-based combination regimens using isobologram analysis of drug interactions. In established cisplatin-sensitive and cisplatin-refractory ovarian carcinoma cell lines, a schedule-dependent drug interaction between paclitaxel and activated hydroperoxy-ifosfamide (4-OOH-IF) could be demonstrated. When both drugs were given for 2 hours, simultaneous exposure or the sequence of paclitaxel followed by 4-OOH-IF were additive or synergistic. In contrast, application of 4-OOH-IF before paclitaxel resulted in pronounced antagonism. Based on the sequence-dependent synergistic interactions a phase I trial was initiated with paclitaxel given on day 1 and ifosfamide given on days 2 to 5 in patients with cisplatin-refractory ovarian cancer. Four dose levels were evaluated in 18 patients. The maximum tolerated dose was paclitaxel 175 mg/m2 on day 1 and ifosfamide 2,000 mg/m2 on days 2 to 5, with central nervous system toxicity and nephrotoxicity being dose-limiting. The recommended dose for further evaluation of this combination was paclitaxel 175 mg/m2 on day 1 and ifosfamide 1,500 mg/m2 on days 2 to 5. Although all patients were heavily pretreated with multiple agents, nine of 18 patients achieved an objective response. Ifosfamide also has been shown to reduce cellular glutathione content; thus, a series of experiments evaluated the ability of activated cyclophosphamide or ifosfamide to deplete cellular glutathione in vitro. It was demonstrated that glutathione depletion is dose- and time-dependent, with 4-OOH-IF leading to a more pronounced suppression of cellular glutathione compared with 4-OOH-Cy. The decrease in cellular glutathione content was maximal at 2 hours after drug treatment; however, cellular glutathione levels returned to normal within 24 hours. When 4-OOH-IF was combined in vitro with cisplatin, schedule-dependent interactions again became obvious. The highest antitumor activity was seen when both drugs were given concurrently; sequential application with 4-OOH-IF given before cisplatin resulted in antagonism. Since adequate glutathione levels are necessary for multidrug resistance protein (MRP) function, glutathione depletion might lead to reversal of MRP-mediated drug resistance. Preliminary data showed that 4-OOH-IF significantly decreases glutathione concentrations in MRP-expressing human HT1080/DR4 sarcoma cells, leading to maximum steady-state reduction after a 90-min exposure to 4-OOH-IF. Taken together the data reported here demonstrate that in vitro ifosfamide may potentiate the antitumor activity of a variety of cytotoxic agents and therefore merits further clinical evaluation in drug combinations (eg, taxanes, anthracyclines).
 ...
PMID:Ifosfamide-based drug combinations: preclinical evaluation of drug interactions and translation into the clinic. 1069 38

In the present paper, we review the evidence for chemotherapy in patients with bone and soft part sarcoma and discuss the contributions and improvements made by chemotherapy to the treatment of patients with bone and soft part sarcoma. In the osteosarcoma and Ewing's sarcoma family, neoadjuvant and adjuvant chemotherapy have improved the 5-year disease-free survival to 60%, and limb-salvage operations have improved this to 70-80% in cases of non-metastatic malignant bone tumor. Several trials were conducted in order to overcome rate relapses and metastatic bone sarcoma. With osteosarcoma, thoracotomy improved the survival of lung metastatic patients, but CDDP-ADM branch switched according to the neoadjuvant chemotherapy and failed to elevate the continuous disease-free survival of patients. Dose intensive use of cytotoxic drugs with G-CSF or autologous bone marrow transplantation and multidrug programs were conducted in preliminary studies and achieved favorable results in a high risk factors group for tumors of the Ewing's sarcoma family. Surgical techniques have brought improvements in the treatment of soft tissue sarcoma, but there has been no impact by chemotherapy. Ifosfamide and adriamycin combination is being evaluated in the treatment of local advanced and metastatic soft part sarcoma by local control rate or survival from relapse.
 ...
PMID:[Evidence-based chemotherapy for patients with bone and soft part sarcoma]. 1070 Aug 89

Localized fibrous tumor is an unfrequent mesenchymal neoplasm. The malignant variant of the pleura is exceptional and differential diagnosis with the more frequent benign type or with other neoplasms such as soft tissue sarcoma and mesothelioma is rarely possible in a preoperative setting. The best treatment of this disease is radical surgical resection. No definitive data exist about the role of chemotherapy. We report a case of a giant right intrathoracic mass whose preoperative diagnosis, from an open biopsy, was consistent with sarcoma and, in a second review, with fibrous tumor of the pleura without any indication about malignancy. A right pleuropneumonectomy and pericardial resection was performed through a right hemiclam-shell approach. Histology demonstrated an aggressive behaviour: high mitosis rate, Ki 67 of 34% and diffuse necrosis were present. In consideration of the apparent local radicality we did not perform any adjuvant treatment. Six months after the operation a wide local recurrence was evident and a systemic treatment with Ifosfamide and Adriamicina is still in progress. So far a good response has been documented. Preoperative diagnosis of malignancy has an important role as a therapeutic strategy in management of fibrous tumours of the pleura. When there is suspicion of a malignant form neoadjuvant chemotherapy can represent a further tool to control poorly differentiated and large tumors, and a wide surgical resection of the lesion must be performed.
 ...
PMID:Huge malignant localized fibrous tumor of the pleura. 1114 49

The aim of this phase II study was to evaluate the efficacy and toxicity of two regimens of ifosfamide in metastatic soft tissue sarcoma patients given as first- and second-line chemotherapy. Two different schedules of ifosfamide were investigated in a randomised manner: Ifosfamide was given either at a dose of 5 g/m(2) over 24 h (5 g/m(2)/1 day), every 3 weeks or at a dose of 3 g/m(2) per day, administered over 4 h on three consecutive days (3 g/m(2)/3 days), every 3 weeks. Both schedules were given as first-line or second-line chemotherapy. A total of 182 patients was entered, 103 in first- and 79 in second-line, of whom 8 patients were ineligible, 5 in the first- and 3 in the second-line study. Most patients had a leiomyosarcoma, 46 of the 98 in the first-line and 34 of the 76 in the second-line. The two study arms were well balanced in both the first- and second-lines with respect to sex, age and performance status. In first-line treatment, 5 g/m(2)/1 day yielded five partial responses (PR) (Response Rate (RR) 10%), versus 12 PR (RR 25%) for the 3 g/m(2)/3 days. As second-line treatment, the 24-h infusion yielded: one CR and one PR (RR 6%) and the 3-day schedule one CR and two PR (RR 8%). Survival did not differ between the two regimens. The major World Health Organization (WHO) grade 3 and 4 toxicities encountered were: leucopenia in 19% of all courses in the first-line and 32% in the second-line with the 5 g/m(2)/1 day, while for the 3 g/m(2)/3 days schedule the rates were 57 and 63% respectively. Grade 3 or 4 infections were seen in 4% of patients treated with 5 g/m(2)/1 day first-line and 10% of patients given 3 g/m(2)/3 days, both as first- and second-lines. No such infections were seen in patients receiving 5 g/m(2)/1 day as second line treatment. In advanced soft-tissue sarcomas in the first-line, ifosfamide 3 g/m(2), given over 4 h on three consecutive days, is an active regimen with acceptable toxicity while the 5 g/m(2) over 24 hours schedule resulted in a disappointing response rate.
 ...
PMID:Results of randomised studies of the EORTC Soft Tissue and Bone Sarcoma Group (STBSG) with two different ifosfamide regimens in first- and second-line chemotherapy in advanced soft tissue sarcoma patients. 1246 Jul 84

Anthracyclines and alkylating agents (ifosfamide, Mitoxana) are the mainstays of chemotherapy for soft tissue sarcoma and as there is a close correlation between dose-intensity and response, methods should be developed to ameliorate the clinical tolerability of these agents. Improvements in the efficacy of medical treatments for soft tissue sarcomas may derive from old strategies by aiming to counteract the side effects of standard chemotherapy regimes and from new, less toxic, anticancer drugs. This paper reviews the currently available options for reducing the cardiotoxicity of anthracyclines, the role of growth factors and autologous stem cell transplantation in dose-intensification of chemotherapy and also examines the clinical impact of the more promising new agents.
 ...
PMID:Improved tolerability of chemotherapy in soft tissue sarcomas: old and new strategies. 1272 76

The management of soft tissue sarcomas has been highlighted in the last few years by the responsiveness of gastrointestinal stromal tumors to imatinib (Gleevec, Novartis). In this article, the use of chemotherapeutic agents in the management of this and some of the 50 or more subtypes of sarcomas are discussed, and a brief review of the use of chemotherapy in the adjuvant or neoadjuvant setting for people with large extremity sarcomas is provided. Doxorubicin and ifosfamide (Mitoxana, Bristol-Myers Squibb) remain the best individual drugs for sarcomas overall, although dacarbazine and gemcitabine (Gemzar, Eli Lilly) with or without a taxane has activity in at least a subset of sarcomas. The data regarding adjuvant chemotherapy for extremity soft tissue sarcomas is still quite mixed, with little if any overall survival advantage found to support its incorporation into disease management. The finding of tyrosine kinase inhibitors such as imatinib with demonstrated activity in gastrointestinal stromal tumors and dermatofibrosarcoma protuberans, as well as the finding of new agents such as ecteinascidin-743 (Yondelis, PharmaMar) with at least some activity against soft tissue sarcomas, reinforces the idea that we should target individual subtypes of sarcoma, just as treatment varies by subtype for the hematological malignancies.
 ...
PMID:Role of chemotherapy in patients with soft tissue sarcomas. 1505 53


<< Previous 1 2 3 4 5 6 Next >>