mesna and Sarcoma

This paper aims to summarise and critically review the existing published literature with regard to clinical considerations as well as stability testing studies of Ifosfamide and Mesna. It also aims to highlight the factors that should be considered when designing and conducting stability testing experiments.. Ifosfamide and Mesna are currently given to patients for 14 days continuous home-based infusion for the treatment of soft tissue sarcoma. No previous work has evaluated their stability for more than 7 days under real-life conditions so the current regimen involves patients visiting hospital twice during the 14-day treatment. This may create extra disruption to patients' life style as well as increasing the workload for cancer services.. There is a need to conduct stability testing experiments for Ifosfamide and Mesna taking into consideration all of the highlighted factors to mimic standard clinical practice.

Topics: Antineoplastic Agents; Drug Stability; Humans; Ifosfamide; Mesna; Sarcoma

Soft tissue sarcomas comprise a heterogeneous group of malignancies of mesenchymal origin. Although sarcomas can arise virtually anywhere, the most common primary site is the extremity. The development of metastatic disease poses a major clinical problem because it is seldom amenable to a curative treatment. However, with careful and expert multidisciplinary team selection of patients with metastatic sarcoma-balancing probability of benefit with certain toxicity-a combined multimodality approach may provide hope to a select few for prolonged survival and even cure.

Topics: Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Dacarbazine; Doxorubicin; Humans; Ifosfamide; Lung Neoplasms; Mesna; Sarcoma; Treatment Outcome

In high-grade musculoskeletal sarcomas, adjuvant chemotherapy is often performed to prevent distant metastases. The efficacy of chemotherapy varies according to the histological type of sarcoma. Prognoses are poor in patients with osteosarcoma, Ewing's sarcoma, or rhabdomyosarcoma, when surgery alone is performed. However, because these sarcomas are chemosensitive, their prognoses are improved with adjuvant chemotherapy. On the other hand, the efficacy of chemotherapy is not statistically demonstrated in non-round cell sarcomas, e. g., malignant fibrous histiocytoma. Nowadays, several kinds of antitumor agents are usually used for adjuvant chemotherapy, and many authors have reported various kinds of regimens and their clinical results. Commonly used drugs include adriamycin, ifosfamide, cisplatin, methotrexate, cyclophosphamide, dacarbazine, vincristine, and actinomycin-D. Recently, high-dose chemotherapy combined with autologous peripheral blood or bone marrow stem cell transplantation has been begun in patients who do not respond to standard chemotherapy, and a better prognosis is expected.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Combined Modality Therapy; Cyclophosphamide; Dacarbazine; Dactinomycin; Doxorubicin; Drug Administration Schedule; Humans; Ifosfamide; Melphalan; Mesna; Methotrexate; Osteosarcoma; Rhabdomyosarcoma; Sarcoma; Sarcoma, Ewing; Soft Tissue Neoplasms; Vincristine

We present a case of an intimal epitheliod aortic sarcoma. Diagnosis was established after an aortic endarterectomy. The tumor was subsequently resected and an aortic graft was inserted. The patient underwent adjuvant chemotherapy. The patient is alive and free of metastatic disease at 48 months. Aortic tumors are rare, with an extremely poor prognosis and 1-year survival of 0-13%. The diagnosis is usually established postmortem, with metastatic disease being a common finding. The diagnosis should be suspected in patients with symptoms of nonatherosclerotic-related aortic occlusive disease or distal embolic events. Resection followed by adjuvant therapy and close follow-up can offer a prolonged survival for the patient with an extremely lethal aortic sarcoma.

Topics: Antineoplastic Combined Chemotherapy Protocols; Aorta, Abdominal; Aortic Diseases; Chemotherapy, Adjuvant; Combined Modality Therapy; Diagnosis, Differential; Endarterectomy; Humans; Male; Mesna; Middle Aged; Recurrence; Sarcoma; Survival Analysis; Time; Tomography, X-Ray Computed

The sarcomatoid variant of renal-cell carcinoma (SRCC), a clinically aggressive subtype of renal parenchymal tumors, is typically resistant to systemic treatments and carries a poor prognosis. The authors report a case of a 57-year-old male with advanced SRCC who had a durable complete response after MAID (mesna, adriamycin, ifosfamide and dacarbazine) chemotherapy, and remains free of disease four years after completing treatment. To the authors' knowledge, this is the first report of a remission from MAID chemotherapy in SRCC. A review of published literature revealed occasional responses after systemic chemotherapy. Notably, all responses were seen with doxorubicin containing regimens, suggesting that doxorubicin is a critical component in chemotherapy regimens for SRCC.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Dacarbazine; Doxorubicin; Humans; Ifosfamide; Kidney Neoplasms; Male; Mesna; Middle Aged; Sarcoma; Tomography, X-Ray Computed

Ifosfamide is one of the three most active agents in the treatment of soft tissue sarcomas. Ifosfamide-induced urothelial toxicity has been adequately controlled with the use of hydration and the uroprotective agent mesna. This is a review of pilot and phase I and II studies of ifosfamide as a single agent and randomized trials of combination chemotherapy regimens incorporating ifosfamide in the treatment of soft tissue sarcomas. Issues of schedule and dose of ifosfamide will be addressed as well.

Topics: Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Drug Administration Schedule; Fluid Therapy; Humans; Ifosfamide; Mesna; Pilot Projects; Randomized Controlled Trials as Topic; Sarcoma; Urinary Tract

This article gives highlights of ongoing pediatric solid tumor and leukemia trials in the United States that use ifosfamide in combination with mesna. These trials are being carried out both by large cooperative groups and single institutions. Some role for ifosfamide with mesna in the front-line treatment of sarcomas is assured. Neurotoxicity, nephrotoxicity, and other unusual toxicities are discussed.

Topics: Antineoplastic Agents; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Child; Clinical Trials as Topic; Humans; Ifosfamide; Leukemia; Mesna; Multicenter Studies as Topic; Neoplasms; Sarcoma; United States

Important advances have been obtained in the care of soft tissue sarcoma in adults, mainly in the field of locoregional treatment. Surgery or combination of surgery and radiotherapy allow adequate tumor control with preservation of function for the majority of patients. However, the management of locally advanced primaries remains problematic. Moreover, although patients survival mainly depends on the metastatic risk of the disease, controversies remain in definition of pronostic factors as well as in the evaluation of the role of chemotherapy in curative therapeutical strategies. The case reported here allows a discussion of the different modalities of treatment for adults with soft tissue sarcomas and stresses the necessity of a multimodal approach in these patients.

Topics: Antineoplastic Combined Chemotherapy Protocols; Back; Chemotherapy, Adjuvant; Combined Modality Therapy; Dacarbazine; Doxorubicin; Humans; Ifosfamide; Magnetic Resonance Imaging; Male; Mesna; Middle Aged; Neoplasm Invasiveness; Prognosis; Radiotherapy Dosage; Sarcoma; Soft Tissue Neoplasms; Thoracic Neoplasms

Cytotoxic chemotherapy remains the principal modality of treating advanced or unresectable sarcomas of soft tissue. Certain drugs, such as doxorubicin and ifosfamide, are able to induce clinically useful antitumor effects as single agents, and combination chemotherapy regimens have been tested based upon these results. This article summarizes the results of single agent and combination chemotherapy trials for soft tissue sarcomas.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Clinical Trials as Topic; Combined Modality Therapy; Cyclophosphamide; Dacarbazine; Doxorubicin; Humans; Ifosfamide; Mesna; Randomized Controlled Trials as Topic; Salvage Therapy; Sarcoma; Soft Tissue Neoplasms; Treatment Outcome; Vincristine

We have used ifosfamide to treat patients with sarcomas in four completed single-agent protocols and one pilot study since 1985. All the studies have used either N-acetyl-L-cysteine (NAC) or mesna as a uroprotective agent, except in one arm of one study where hydration alone was employed. Mesna has proven superior to NAC in providing protection against ifosfamide-induced hematuria. Mesna given as a loading dose followed by continuous 24-h infusion has been effective and most practical in this regard. Ifosfamide has demonstrated clinically useful antitumor activity in our hands against most sarcoma subtypes. Our studies suggest a dose-response relationship for ifosfamide. At a total dose of 6 g/m2 per course, the overall response rate was 10%; at 10 g/m2 per course, it rose to 21%. Future clinical trials will determine ifosfamide's role in combination chemotherapy and more clearly define the best schedule or schedules for the uroprotective administration of mesna.

Topics: Acetylcysteine; Bone Neoplasms; Fluid Therapy; Humans; Ifosfamide; Mesna; Randomized Controlled Trials as Topic; Sarcoma; Soft Tissue Neoplasms; Treatment Outcome; Urinary Bladder Diseases

Patients with large, high-grade extremity soft tissue sarcoma (STS) are at high risk for both local and distant recurrence. RTOG 95-14, using a regimen of neoadjuvant interdigitated chemoradiotherapy with mesna, doxorubicin, ifosfamide, and dacarbazine followed by surgery and 3 cycles of adjuvant mesna, doxorubicin, ifosfamide, and dacarbazine, demonstrated high rates of disease control at the cost of significant toxicity (83% grade 4, 5% grade 5). As such, this regimen has not been widely adopted. Herein, we report our institutional outcomes utilizing a modified interdigitated chemoradiotherapy regimen, without dacarbazine, and current radiotherapy planning and delivery techniques for high-risk STS.. Adults with large (≥5 cm; median, 12.9 cm), grade 3 extremity STS who were prospectively treated as part of our institutional standard of care from 2008 to 2016 are included. Neoadjuvant chemoradiotherapy consisted of 3 cycles of mesna, doxorubicin, and ifosfamide (MAI) and 44 Gy (22 Gy in 11 fractions between cycles of MAI) after which patients underwent surgical resection and received 3 additional cycles of MAI.. Twenty-six patients received the MAI treatment protocol. At a median follow-up of 47.3 months, 23 (88.5%) patients are still alive. Three year locoregional recurrence-free survival, disease-free survival, and overall survival are 95.0%, 64.0%, and 95.0%, respectively. There have been no therapy-related deaths or secondary malignancies. The nonhematologic grade 4 toxicity rate was 7.7%.. Neoadjuvant interdigitated MAI radiotherapy followed by resection and 3 cycles of adjuvant MAI has resulted in acceptable and manageable toxicity and highly favorable survival in patients at greatest risk for treatment failure.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Arm; Chemoradiotherapy; Doxorubicin; Female; Humans; Ifosfamide; Leg; Male; Mesna; Middle Aged; Neoadjuvant Therapy; Organ Sparing Treatments; Retrospective Studies; Sarcoma; Treatment Outcome

Patients with large, high-grade extremity and truncal soft tissue sarcomas (STS) are at considerable risk for recurrence. A regimen of pre-operative chemotherapy consisting of mesna, adriamycin, ifosfamide and dacarbazine (MAID), interdigitated with radiotherapy (RT), followed by resection and post-operative chemotherapy with or without RT, has demonstrated high rates of local and distant control. The goal of this study is to assess outcomes in a recent cohort of patients treated on this regimen.. We retrospectively reviewed records of 66 consecutive patients with STS of the extremity or trunk who were treated with the aforementioned regimen from May 2000 to April 2011. Clinicopathologic characteristics and patient outcomes were analysed.. Sixty-six patients were analysed and were equally divided between grade 2 and 3 tumours. Margins were negative in 57 (89%) patients and positive in seven (11%) patients. At a median follow-up of 46 months, there were six (9%) locoregional and 20 (30%) distant recurrences. The locoregional and distant 5-year recurrence-free survival (RFS) rates were 91% and 64%, respectively. The 5-year overall (OS) and disease-specific survival rates were 86% and 89%, respectively. There were no treatment-related deaths or secondary myelodysplasias. Thirty-four (52%) patients had grade 3 or 4 acute haematologic chemotherapy-related toxicity. There were no statistically significant predictors of OS or RFS.. For a contemporary cohort of patients with high-risk extremity and truncal STS, a regimen of neoadjuvant chemoradiotherapy and surgery continues to result in high rates of survival with tolerable short- and long-term toxicity.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemoradiotherapy; Chemotherapy, Adjuvant; Dacarbazine; Doxorubicin; Extremities; Female; Follow-Up Studies; Humans; Ifosfamide; Male; Mesna; Middle Aged; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Neoplasm Staging; Prognosis; Radiotherapy, Adjuvant; Retrospective Studies; Sarcoma; Survival Rate; Time Factors; Young Adult

Metastatic soft tissue sarcoma (STS) prognosis remains poor and few cytotoxic agents offer proven efficacy. This randomized open phase III study examines whether high-dose (HD) chemotherapy with peripheral blood stem cells (PBSCs) could improve overall survival (OS) of chemosensitive patients.. Advanced STS patients aged 18-65 years received four courses of standard mesna, adryamycin, ifosfamide and dacarbazine (MAID) treatment. Chemotherapy-responding patients and patients with at least stable disease amenable to complete surgical resection were randomized to receive standard dose (SD) with two successive MAID cycles or HD treatments of one MAID then MICE intensification: mesna (3.6 g/m(2), day 1-5), ifosfamide (2.5 g/m(2), day 1-4), carboplatin [area under the curve (AUC) 5/day 2-4] and etoposide (300 mg/m(2), day 1-4) with PBSC reinjection at day 7.. From 2000 to 2008, 207 patients received four cycles of MAID and 87 assessable patients were randomly assigned to receive the following: 46 SD, 41 HD, with 45 and 38 maintained for analyses after secondary centralized histological review. Futility analyses led to study closure in November 2008. Three-year OS was 49.4% for the SD group versus 32.7% for HD arm, hazard ratio= 1.26, 95% confidence interval 0.70-2.29; progression-free survival was 32.4% and 14.0%, respectively. HD treatment led to higher grades 3-4 toxicity.. This study failed to show an OS advantage for advanced STS patients treated with dose-intensified chemotherapy with PBSC.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Combined Modality Therapy; Consolidation Chemotherapy; Dacarbazine; Disease-Free Survival; Doxorubicin; Etoposide; Female; Humans; Ifosfamide; Kaplan-Meier Estimate; Male; Mesna; Middle Aged; Peripheral Blood Stem Cell Transplantation; Sarcoma; Young Adult

Patients with large, high-grade, extremity soft tissue sarcomas (STS) are at significant risk for distant recurrence and death. A regimen of preoperative chemotherapy consisting of mesna, Adriamycin (doxorubicin), ifosfamide, and dacarbazine (MAID), interdigitated with radiotherapy (RT) and followed by resection and postoperative chemotherapy with or without RT, has demonstrated high rates of local and distant control. We report the long-term follow-up data on 48 patients treated with this regimen compared to an historical matched-control patient population.. Adult patients with high-grade extremity STS ≥ 8 cm were treated with 3 cycles of preoperative chemotherapy combined with 44 Gy of RT followed by surgery. Three cycles of postoperative MAID were planned. For patients with positive surgical margins, 16 Gy of RT was delivered postoperatively.. Patients received the MAID/RT regimen from 1989 through 1999. After a median follow-up of 9.3 years in surviving patients in the MAID group and 13.2 years in surviving patients in the control group, the 7-year disease-specific and overall survival rates were 81% and 50% (P = .004) and 79% and 45% (P = .003) for the MAID and control patients, respectively. Five of 11 patients in the MAID group and 7 of 25 control patients died of sarcoma ≥5 years after treatment. One patient in the MAID group developed a fatal myelodysplasia at 53 months.. For patients with high-risk, extremity STS, the significant survival benefits conferred by an intense regimen of neoadjuvant chemoradiotherapy and surgery are sustained even with long-term follow-up.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemoradiotherapy; Chemotherapy, Adjuvant; Dacarbazine; Disease-Free Survival; Doxorubicin; Extremities; Female; Follow-Up Studies; Humans; Ifosfamide; Male; Mesna; Middle Aged; Neoadjuvant Therapy; Radiotherapy, Adjuvant; Sarcoma; Survival Rate; Treatment Outcome

Ifosfamide is a cornerstone of chemotherapy in bone and soft-tissue sarcoma. Results of pharmacokinetic studies indicate that the optimal schedule of ifosfamide should be repeated doses over several days. With the development of 5-day infusion devices, we developed and evaluated a 5-day infusion regimen of ifosfamide in sarcoma patients in the outpatient setting.. Sarcoma patients requiring chemotherapy after at least one doxorubicin-based line were enrolled in this study. Ifosfamide+mesna was administered as 1:1 concentration for a total of 6 g/m2 of each over 5 days (i.e. 1.2 g/m2 per day as continuous infusion) every 3 weeks. Patients were treated until progression or limiting toxicity, and salvage surgery was attempted when possible. An economic study was run comparing ifosfamide plus mesna as a 5-day infusion regimen and conventional Ifosfamide regimen.. Thirteen sarcoma patients were evaluable. The median number of cycles per patient was 6 (range, 1-8), for a total of 69 cycles. No acute encephalopathy or aggravation of renal function was noted. Acute grade 3 and 4 haematological toxicities were observed in 11.6 and 1.4% of patients, respectively without febrile neutropenia. Median time to progression survival and overall survival were 8.7 and 21.5 months, respectively. Total cost per cycle for a 2-m2 patient body surface area was ambulatory infusion=1,891 euros and conventional ifosfamide=6,256 euros.. The combination of ifosfamide and mesna as a continuous infusion over 5 days is feasible and well tolerated in the outpatient setting using infusion device. Its very favourable cost-effectiveness invites to further develop this approach.

Topics: Adult; Aged; Anemia; Antineoplastic Combined Chemotherapy Protocols; Diarrhea; Drug Administration Schedule; Female; Humans; Ifosfamide; Infusion Pumps; Male; Mesna; Middle Aged; Nausea; Outpatients; Pilot Projects; Sarcoma; Survival Analysis; Time Factors; Treatment Outcome; Vomiting

Patients with locally advanced or metastatic/recurrent soft tissue and Ewing's sarcoma (EWS) have few treatment options. The purpose of our phase II study was to assess the feasibility, safety and efficacy of tandem high-dose chemotherapy (HDCT) followed by autologous stem cell transplantation (ASCT) in such patients.. Thirteen patients were enrolled onto this study. The first cycle of HDCT consisted of doxorubicin (150 mg/m(2)) and ifosfamide (14 g/m(2)) mixed with mesna (14 g/m(2)), while the second cycle consisted of melphalan (150 mg/m(2)) and cisplatin (200 mg/m(2)).. Eleven out of 13 patients were able to complete both cycles of HDCT. No treatment-related mortality occurred and grade 3 or 4 toxicity was clinically tolerable. The 5-year progression-free survival (PFS) and overall survival (OS) for all patients was 23% (confidence interval, CI: 0-46%) and 31% (CI: 14-70%), respectively. Out of the four patients still alive, two had EWS and measurable disease at the time of ASCT and achieved a complete remission, remaining progression free 126 and 155 months after ASCT.. Our study demonstrates the feasibility and safety of tandem HDCT in patients with high-risk or metastatic/recurrent sarcoma, with some patients achieving long-term PFS and OS.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Cisplatin; Combined Modality Therapy; Disease Progression; Doxorubicin; Feasibility Studies; Female; Hematopoietic Stem Cell Transplantation; Humans; Ifosfamide; Immunoenzyme Techniques; Male; Melphalan; Mesna; Neoplasm Recurrence, Local; Neoplasm Staging; Neuroectodermal Tumors, Primitive, Peripheral; Osteosarcoma; Prognosis; Prospective Studies; Protective Agents; Remission Induction; Rhabdomyosarcoma; Safety; Sarcoma; Sarcoma, Ewing; Survival Rate; Transplantation, Autologous; Treatment Outcome; Young Adult

This report compares a traditional full-dose ifosfamide administration modality (24-hr hyperhydration and mesna infusion) with a simplified 9-hr hyperhydration and mesna infusion for use in outpatients. Acute ifosfamide toxicity was the same, suggesting that ifosfamide could be safely administered to outpatients, reducing the currently-recommended prolonged hyperhydration and mesna uroprotection, thus resulting in shorter hospital stays and consequently lower costs.

Topics: Adolescent; Ambulatory Care; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Dactinomycin; Dose-Response Relationship, Drug; Humans; Ifosfamide; Infant; Mesna; Retrospective Studies; Sarcoma; Soft Tissue Neoplasms; Vincristine

On the basis of a positive reported single-institution pilot study, the Radiation Therapy Oncology Group initiated phase II trial 9514 to evaluate its neoadjuvant regimen in a multi-institutional Intergroup setting.. Eligibility included a high-grade soft tissue sarcoma > or = 8 cm in diameter of the extremities and body wall. Patients received three cycles of neoadjuvant chemotherapy (CT; modified mesna, doxorubicin, ifosfamide, and dacarbazine [MAID]), interdigitated preoperative radiation therapy (RT; 44 Gy administered in split courses), and three cycles of postoperative CT (modified MAID).. Sixty-six patients were enrolled, of whom 64 were analyzed. Seventy-nine percent of patients completed their preoperative CT and 59% completed all planned CT. Three patients (5%) experienced fatal grade 5 toxicities (myelodysplasias, two patients; infection, one patient). Another 53 patients (83%) experienced grade 4 toxicities; 78% experienced grade 4 hematologic toxicity and 19% experienced grade 4 nonhematologic toxicity. Sixty-one patients underwent surgery. Fifty-eight of these were R0 resections, of which five were amputations. There were three R1 resections. The estimated 3-year rate for local-regional failure is 17.6% if amputation is considered a failure and 10.1% if not. Estimated 3-year rates for disease-free, distant-disease-free, and overall survival are 56.6%, 64.5%, and 75.1%, respectively.. This combined-modality treatment can be delivered successfully in a multi-institutional setting. Efficacy results are consistent with previous single-institution results.

Topics: Adult; Aged; Amputation, Surgical; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Dacarbazine; Disease-Free Survival; Doxorubicin; Extremities; Female; Humans; Ifosfamide; Male; Mesna; Middle Aged; Neoadjuvant Therapy; Radiotherapy, Adjuvant; Risk Assessment; Sarcoma; Survival Analysis; Treatment Failure; Treatment Outcome

To determine clinical activity and toxic effects of ifosfamide when used to treat cats with vaccine-associated sarcoma (VAS).. 27 cats with a nonresectable, recurrent, or metastatic VAS.. Each cat received ifosfamide (900 mg/m(2) of body surface area) as an IV infusion during a 30-minute period. Diuresis by infusion of saline (0.9% NaCl) solution and administration of mesna were used to prevent urothelial toxicosis. Treatments were administered every 3 weeks, and tumor response was assessed after the second treatment. All ifosfamide-associated toxic effects were graded in accordance with predetermined criteria.. 61 treatments were administered to 27 cats (median, 2 treatments/cat; range, 1 to 4 treatments/cat). After ifosfamide treatment, 1 cat had a complete response and 10 had partial responses for an overall response rate of 11 of 27 (41%; 95% confidence interval [CI], 25% to 59%). Responses lasted from 21 to 133 days (median, 70 days; 95% CI, 60 to 113 days). The acute dose-limiting toxicosis was neutropenia, which was detected 5 to 28 days (median, 7 days) after treatment. Median nadir neutrophil count was 1,600 cells/muL (range, 200 to 5,382 cells/microL). Nine (33%) cats had adverse gastrointestinal effects (primarily salivation during the ifosfamide infusion and inappetence after treatment). Two cats were euthanatized because of severe nephrotoxicosis, and 1 cat developed pulmonary edema during diuresis.. Ifosfamide has antitumor activity against VAS in cats and is tolerated well by most cats. Ifosfamide should be evaluated as an adjuvant treatment for cats with VAS.

Topics: Animals; Antineoplastic Agents, Alkylating; Cat Diseases; Cats; Drug Administration Schedule; Female; Ifosfamide; Male; Mesna; Sarcoma; Sodium Chloride; Vaccines

To describe the response rate and survival of children and adolescents with unresected or metastatic nonrhabdomyosarcomatous soft tissue sarcomas (NRSTS) treated with vincristine, ifosfamide, and doxorubicin.. Between September 1996 and June 2000, 39 eligible patients received vincristine (1.5 mg/m(2) weekly for 13 doses), ifosfamide (3 g/m(2) daily for 3 days every 3 weeks for seven cycles), doxorubicin (30 mg/m(2) daily for 2 days for six cycles), and mesna (750 mg/m(2) for four doses after ifosfamide). Granulocyte colony-stimulating factor was administered daily (5 mug/kg) after each cycle of chemotherapy. Radiotherapy was administered from weeks 7 through 12.. The median patient age at diagnosis was 11.7 years; the most common primary tumor site was lower extremity (36%); and synovial sarcoma was the predominant histology. More than three fourths of all tumors were 5 cm or greater at their largest diameters. The overall objective combined partial and complete response rate was 41% (95% CI, 25.7% to 56.7%). The estimated 3-year overall survival and progression-free survival rates (+/- standard deviation) for eligible patients were 59% +/- 8.2% and 43.6% +/- 7%, respectively. Patients with clinical group III disease had significantly better 3-year and progression-free survival rates compared with patients who presented with metastatic disease.. The vincristine, ifosfamide, and doxorubicin regimen was moderately active against pediatric NRSTS. Patients with synovial sarcoma had higher response rates than other patients, and patients with unresected disease had improved outcomes. Patients with metastatic disease continue to fare poorly, and newer approaches are indicated for these patients.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Child; Combined Modality Therapy; Doxorubicin; Female; Granulocyte Colony-Stimulating Factor; Humans; Ifosfamide; Male; Mesna; Neoadjuvant Therapy; Protective Agents; Sarcoma; Soft Tissue Neoplasms; Survival Analysis; Treatment Outcome; Vincristine

The purpose of this study was to retrospectively analyze the relationship between neo-adjuvant chemotherapy (NAC) and outcome in patients with high-grade extremity sarcomas.. Inclusion criteria were high-grade, deep, >5 cm extremity soft tissue sarcomas. Patients diagnosed between 1990 and 2001 were treated with surgery only (n=282) or NAC containing doxorubicin/ifosfamide/mesna (AIM) (n=74). The stratified Cox proportional hazards model was used to test the effect of NAC on disease-specific survival and recurrence while adjusting for known prognostic factors.. NAC was associated with improved disease-specific survival for this cohort of patients (P=0.02). This overall improvement appears to be driven by the benefit of NAC on disease-specific survival for patient with tumors >10 cm. The 3-year disease-specific survival for tumors >10 cm was 0.62 (95% CI: 0.53-0.71) for patients not receiving NAC and 0.83 (95% CI: 0.72-0.95) for patients receiving NAC.. NAC with AIM was associated with a significant improvement in disease-specific survival in patients with high-grade extremity soft tissue sarcomas >10 cm. These data emphasize the need for further prospective clinical studies of neo-adjuvant or adjuvant chemotherapy for patients with large high-grade extremity sarcomas.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Cohort Studies; Extremities; Humans; Ifosfamide; Mesna; Middle Aged; Proportional Hazards Models; Prospective Studies; Retrospective Studies; Sarcoma; Soft Tissue Neoplasms; Survival Analysis; Time Factors; Treatment Outcome

Ifosfamide and doxorubicin are the most effective agents in the treatment of sarcomas, although their contributions to survival are usually limited. High-dose ifosfamide can be used as a salvage treatment in patients with recurrent or advanced sarcoma. We evaluated efficacy and toxicity of high-dose ifosfamide in the patients with recurrent or advanced sarcoma in this study.. 39 patients with recurrent or advanced sarcoma were enrolled onto the study between 1996 and 2002. All patients had histological proven high grade sarcoma with measurable or evaluable disease. Ifosfamide was administered at the dose of 2 g/m(2) as continuous intravenous infusion for 24 h on day 1-9, in conjunction with the continuous infusion of mesna. Granulocyte-macrophage colony-stimulating factor or granulocyte colony-stimulating factor was given every cycle. The efficacy and toxicity of high dose ifosfamide (HDI) were evaluated clinically before subsequent cycle. The objective response was evaluated every two cycles. Histopathologic response was also evaluated in patients who underwent surgical resection.. Male/female ratio was 24/15, with a median age of 20 (11-48) years. 9 patients had locally inoperable advanced disease and 30 patients had metastatic disease. 10 patients were chemo-naive. The total number of HDI-chemotherapy cycles was 103 (median 2 cycles (range, 1 to 7)). 2 patients refused the further treatment after the first cycle and 1 patient died due to neutropenic sepsis in the first cycle of treatment. 36 patients were available for the evaluation of treatment efficacy. Overall response rates were 53.8% and 90% in pre-treated patients and in chemo-naive patients, respectively. Median follow-up time was 43 months. 13 patients underwent total surgical tumor resection. Pathologic complete response was observed in 5 of 13 these patients who underwent surgery. Median progression-free survival (PFS) was 7 months (95%CI: 3.8-10.2). The median progression-free survival (PFS) were 3 and 12 months in patients who did not have tumor resection, and in those having complete tumor resection (p = 0.002). Median overall survival (OS) was 10 months (95%CI: 0.0-20) in all patients. Median OS times were 8 months in patients without tumor resection and 26.5 months in patients with those underwent surgical treatment (p = 0.0369). 2 patients who underwent surgery are still alive and disease-free. Major toxicity was myelosuppression.. HDI seems to be feasible and effective in selected patients with advanced or recurrent sarcomas. Survival advantage of HDI is better when the total tumor resection can be done.

Topics: Adolescent; Adult; Antineoplastic Agents, Alkylating; Bone Neoplasms; Child; Disease-Free Survival; Dose-Response Relationship, Drug; Female; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Ifosfamide; Infusions, Intravenous; Male; Mesna; Middle Aged; Sarcoma; Treatment Outcome

Treatment of extremity soft-tissue sarcomas yields excellent local control, but distant failure is common with large, high-grade tumors. A regimen of preoperative chemotherapy consisting of mesna, adriamycin, ifosfamide, and dacarbazine (MAID) interdigitated with radiotherapy followed by resection and postoperative chemotherapy with or without radiotherapy was designed to improve treatment outcome. We report the mature outcome data on 48 treated patients and compare them with the data of an historical matched control patient population.. Adult patients with high-grade extremity soft-tissue sarcomas >or=8 cm were treated with three cycles of preoperative chemotherapy combined with 44 Gy of radiotherapy followed by surgery. Three cycles of postoperative MAID were planned. For patients with positive surgical margins, 16 Gy was delivered postoperatively.. All 48 patients (M0) received the MAID protocol treatment, and their outcome was superior to that of the historical control patients. The 5-year actuarial local control, freedom from distant metastasis, disease-free survival, and overall survival rate was 92% and 86% (p = 0.1155), 75% and 44% (p = 0.0016), 70% and 42% (p = 0.0002), and 87% and 58% (p = 0.0003) for the MAID and control patient groups, respectively. Acute hematologic toxicity in the MAID group included febrile neutropenia in 12 patients (25%). Wound healing complications occurred in 14 (29%) of 48 MAID patients. One MAID patient developed late fatal myelodysplasia.. After aggressive chemoradiation and surgery, these patients showed a significant reduction in distant metastases, with a highly significant gain in disease-free and overall survival compared with a historical control group. On the basis of this experience, the Radiation Therapy Oncology Group conducted a multi-institutional trial.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Dacarbazine; Disease-Free Survival; Doxorubicin; Extremities; Female; Humans; Ifosfamide; Male; Mesna; Middle Aged; Neoadjuvant Therapy; Radiotherapy; Sarcoma; Soft Tissue Neoplasms; Treatment Outcome

We conducted our study to determine the pharmacokinetics (PK) and clinical efficacy of oral mesna in patients receiving ifosfamide for soft tissue sarcoma.. Seventeen patients were enrolled in a randomized prospective Phase I/II study. Seventeen patients were exposed to study medication. Ifosfamide was given at a dose of 2 g/m2/day for 5 days on a 21-day cycle. Before the first cycle, all patients were randomized onto a crossover design and received either the approved i.v. or i.v./oral mesna regimen, with crossover for the second cycle of chemotherapy. The i.v. mesna regimen consisted of dosings (20% ifosfamide dose) at 0, 4, and 8 h. The i.v./oral arm consisted of an i.v. mesna dosing (20% ifosfamide dose) at 0 h, followed by oral tablet dosing (40% ifosfamide dose) at 2 and 6 h. In-patient clinical monitoring and phlebotomy and urine sampling for mesna, dimesna, and ifosfamide PK were performed on all chemotherapy days.. Thirteen patients were evaluable for PK and 17 for efficacy and toxicity. No significant differences were detected in the plasma PK of the concomitantly infused ifosfamide. Rates of hemorrhagic cystitis were similar across mesna schedules. Four of 10 evaluable patients demonstrated objective response.. On the basis of our study, an i.v./oral mesna regimen is at least as uroprotective as the approved i.v. regimen. The i.v./oral regimen will improve patient tolerance and convenience, allow for a reduction in elective hospitalizations for ifosfamide chemotherapy, reduce the potential morbidity associated with inpatient administration of chemotherapy, and likely result in decreased costs of care.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Agents, Alkylating; Cross-Over Studies; Female; Humans; Ifosfamide; Infusions, Intravenous; Male; Mesna; Middle Aged; Prospective Studies; Protective Agents; Sarcoma; Soft Tissue Neoplasms; Treatment Outcome

Chemotherapy combined with other therapeutic modalities is the main option for advanced and metastatic soft tissue sarcoma(STS). So far there is no standard regimen for STS yet. Adrimycin, ifosfamide, and dacarbazine are the most effective agents at present. The purpose of this clinical trial was to evaluate the efficacy and toxicity of MAID regimen (mesna/ifosfamide + Adriamycin + dacarbazine) in the treatment of advanced soft tissue sarcoma.. Twenty-two patients with advanced STS were treated by MAID(Adriamycin 60 mg/m2, ifosfamide 6,000 mg/m2, and dacarbazine 1,000 mg/m2). These drugs were administered as continuous intravenous infusion for 72 hours while mesna was infused continuously for 96 hours.. Partial response rate was 36.4% without complete remission. The duration of response ranged from 2-10 months with median of 4.6 months. Main toxicities were myelosuppression, gastrointestinal toxicity and alopecia. Percentage of leucopenia, nausea/vomiting, and alopecia in WHO grade III and IV were 63.6%, 27.3%, and 50%, respectively.. The response rate of MAID for advanced STS was not satisfactory with evident myelosuppression. Further study on new anti-cancer agents and regimen are needed.

Topics: Adult; Aged; Alopecia; Antineoplastic Combined Chemotherapy Protocols; Dacarbazine; Doxorubicin; Female; Humans; Ifosfamide; Infusions, Intravenous; Leukopenia; Male; Mesna; Middle Aged; Nausea; Sarcoma; Soft Tissue Neoplasms; Treatment Outcome; Vomiting

Most institutional teams utilize multimodality therapy in their efforts to cure patients with primary high-grade extremity soft tissue sarcomas, although the value of adjuvant systemic chemotherapy is still disputed by some oncologists. This single-institution Phase II study describes an effort to control metastasis by the use of two cycles of chemotherapy as the initial preoperative treatment.. Between March 1994 and October 1997, 20 women and 19 men with primary extremity or limb girdle high-grade soft tissue sarcomas were registered to a study of preoperative ifosfamide, mitomycin, doxorubicin, cisplatin (IMAP) plus granulocyte macrophage-colony-stimulating factor (GM-CSF) followed by preoperative irradiation and subsequent limb-sparing surgery. The two sequential monthly cycles of IMAP involved intravenous ifosfamide, 2500 mg/m(2), and mesna, 2500 mg/m(2), on Day 0, followed by identical doses of these agents plus intravenous mitomycin, 4 mg/m(2), doxorubicin, 40 mg/m(2), and cisplatin, 60 mg/m(2), on Day 1. Sargramostim (GM-CSF) 250 microg/m(2) was given subcutaneously every 12 hours for 4 days beginning 6 days before the chemotherapy, and then for 14 more days beginning the day after chemotherapy was completed. At the beginning of the third month, external beam irradiation was administered daily, 5 days each week for 5 consecutive weeks to total preoperative doses of 4500 centigrays (cGy). This was accompanied by reduced doses of MAP chemotherapy (mitomycin, 6 mg/m(2), doxorubicin, 30 mg/m(2), and cisplatin, 45 mg/m(2)) intravenously on Days 0, 21, and 42 of the radiation therapy segment. Approximately 1 month after preoperative irradiation ended, each patient had complete surgical excision with curative intent, using limb-sparing techniques when possible. Radiation to total doses of 5500-6500 cGy was accomplished by delivery of an additional 1000-2000 cGy to the tumor bed via intraoperative electron beam, brachytherapy, or external beam irradiation at the completion of surgery.. All except 5 patients had tumors at least 5 cm in diameter. Chemotherapy toxicity grade three or higher consisted primarily of vomiting (23%), leukopenia (54%), and thrombocytopenia (77%). Six patients have died of metastatic sarcoma, and one other died in a motorcycle accident. Kaplan-Meier curves indicate estimated 5-year survival of approximately 80% and freedom from metastasis at 2 years of approximately 85%.. IMAP plus GM-CSF is satisfactory as initial treatment for primary extremity soft tissue sarcomas in two monthly cycles preceding irradiation. The prescribed irradiation was generally tolerable and effective in permitting limb-sparing surgery. Although the outcome of patients treated on this regimen has been favorable, the metastasis problem has not been eliminated.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Combined Modality Therapy; Doxorubicin; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Ifosfamide; Infusions, Intravenous; Injections, Subcutaneous; Leukopenia; Male; Mesna; Middle Aged; Mitomycin; Neoadjuvant Therapy; Sarcoma; Soft Tissue Neoplasms; Thrombocytopenia; Treatment Outcome; Vomiting

Adjuvant chemotherapy for soft tissue sarcoma is controversial because previous trials reported conflicting results. The present study was designed with restricted selection criteria and high dose-intensities of the two most active chemotherapeutic agents.. Patients between 18 and 65 years of age with grade 3 to 4 spindle-cell sarcomas (primary diameter > or = 5 cm or any size recurrent tumor) in extremities or girdles were eligible. Stratification was by primary versus recurrent tumors and by tumor diameter greater than or equal to 10 cm versus less than 10 cm. One hundred four patients were randomized, 51 to the control group and 53 to the treatment group (five cycles of 4'-epidoxorubicin 60 mg/m(2) days 1 and 2 and ifosfamide 1.8 g/m(2) days 1 through 5, with hydration, mesna, and granulocyte colony-stimulating factor).. After a median follow-up of 59 months, 60 patients had relapsed and 48 died (28 and 20 in the treatment arm and 32 and 28 in the control arm, respectively). The median disease-free survival (DFS) was 48 months in the treatment group and 16 months in the control group (P =.04); and the median overall survival (OS) was 75 months for treated and 46 months for untreated patients (P =.03). For OS, the absolute benefit deriving from chemotherapy was 13% at 2 years and increased to 19% at 4 years (P =.04).. Intensified adjuvant chemotherapy had a positive impact on the DFS and OS of patients with high-risk extremity soft tissue sarcomas at a median follow-up of 59 months. Therefore, our data favor an intensified treatment in similar cases. Although cure is still difficult to achieve, a significant delay in death is worthwhile, also considering the short duration of treatment and the absence of toxic deaths.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Disease-Free Survival; Dose-Response Relationship, Drug; Epirubicin; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Ifosfamide; Male; Mesna; Middle Aged; Sarcoma; Soft Tissue Neoplasms; Treatment Outcome

To improve the prognosis for pediatric patients with metastatic sarcomas, including the Ewing sarcoma family of tumors (ESFT), rhabdomyosarcoma (RMS), and undifferentiated sarcoma (UDS), we tested the feasibility of a brief, intensive regimen of chemotherapy that maximizes dose intensity.. Twenty-four children and adolescents with metastatic sarcomas received VACIME chemotherapy, consisting of eight courses of vincristine 2 mg/m(2) on day 0; doxorubicin 20 mg/m(2)/day on days 0-3; cyclophosphamide 360 mg/m(2)/day on days 0-4; ifosfamide 1,800 mg/m(2)/day on days 0-4; mesna 2,400 mg/m(2)/day; and etoposide 100 mg/m(2)/day on days 0-4. Doxorubicin was omitted in courses 7 and 8. Granulocyte colony-stimulating factor (G-CSF) was used routinely following each course of therapy. Courses of therapy were repeated every 21 days or as soon as hematopoietic recovery and resolution of nonhematopoietic toxicities permitted. Surgical resection followed course 6, and radiotherapy followed the completion of all therapy.. Thirteen patients achieved a complete response (CR) with chemotherapy alone, and seven more achieved a CR following surgical resection after course 6 (overall CR rate 83%). There was one toxic death. Thirteen patients developed progressive disease, with 2- and 4-year event-free survivals (95% confidence interval) of 50% (30-70%) and 45% (25-65%), respectively. Myelosuppression was severe and cumulative, leading to dose reductions and chemotherapy interval delays. Mucositis was the most common nonhematopoietic toxicity.. VACIME chemotherapy was a feasible dose-intensive regimen for pediatric patients with metastatic sarcomas. Cumulative hematopoietic toxicity and severe mucositis limited the delivery of chemotherapy as prescribed. The CR and 2-year event-free survival rates were superior to those of most previously reported regimens.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Bacteremia; Child; Child, Preschool; Cyclophosphamide; Dose-Response Relationship, Drug; Doxorubicin; Etoposide; Female; Humans; Ifosfamide; Infant; Male; Mesna; Mouth Mucosa; Neoplasm Metastasis; Neutropenia; Prospective Studies; Remission Induction; Sarcoma; Stomatitis; Time Factors; Treatment Outcome; Vincristine

This study was conducted to determine the maximum tolerated dose of an intensified MAID (mesna, adriamycin, ifosfamide, dacarbazine) regimen with the support of lenograstim in patients with advanced soft tissue sarcomas. Following 1 cycle of MAID at the standard dose, four patients were to be treated at each of five dosage levels: +25%, +45%, +65%, +85%, +100%. Sixteen patients were treated. Because there were no significant differences in hematologic toxicity between patients receiving lenograstim 5 or 10 microg/kg/day (levels 1-5 and 1-10), the data were pooled for comparison with level 2. The median duration of absolute neutrophil count < 0.5 x 10(9)/l was 3 days at level 1 and 7 days at level 2 (p < 0.01). The median platelet nadir was 25 x 10(9)/l at level 1 and 10 x 10(9)/l at level 2 (p < 0.01). The median duration of toxicity-related hospitalization was 3.5 days and 11 days at levels 1 and 2, respectively, (p < 0.001). Mucositis > or = grade III occurred after 3/29 cycles at level 1 and 10/15 cycles at level 2 (p < 0.001). After 4 cycles at level 1, 8/8 patients still had performance status scores < or = 2, and only 4/8 had performance status scores < or = 2 after the second cycle at level 2. Lenograstim enabled an increase of 25% of the MAID regimen. At higher dose levels, severe mucositis and deterioration in performance status were dose limiting.

Topics: Adjuvants, Immunologic; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Dacarbazine; Doxorubicin; Drug Administration Schedule; Female; Granulocyte Colony-Stimulating Factor; Humans; Ifosfamide; Lenograstim; Male; Mesna; Middle Aged; Recombinant Proteins; Sarcoma; Survival Analysis

The aim of this study was to assess the pharmacology, toxicity and activity of high-dose ifosfamide mesna +/- GM-CSF administered by a five-day continuous infusion at a total ifosfamide dose of 12-18 g/m2 in adult patients with advanced sarcomas.. Between January 1991 and October 1992 32 patients with advanced or metastatic sarcoma were entered the study. Twenty-seven patients were pretreated including twenty-three with prior ifosfamide at less than 8 g/m2 total dose/cycle. In 25 patients (27 cycles) extensive pharmacokinetic analyses were performed.. The area under the plasma concentration-time curve (AUC) for ifosfamide increased linearly with dose while the AUC's of the metabolites measured in plasma by thin-layer chromatography did not increase with dose, particularly that of the active metabolite isophosphoramide mustard. Furthermore the AUC of the inactive carboxymetabolite did not increase with dose. Interpatient variability of pharmacokinetic parameters was high. Dose-limiting toxicity was myelosuppression at 18 g/m2 total dose with grade 4 neutropenia in five of six patients and grade 4 thrombocytopenia in four of six patients. Therefore the maximum tolerated dose was considered to be 18 g/m2 total dose. There was one CR and eleven PR in twenty-nine evaluable patients (overall response rate 41%).. Both the activation and inactivation pathways of ifosfamide are non-linear and saturable at high-doses although the pharmacokinetics of the parent drug itself are dose linear. Ifosfamide doses greater than 14-16 g/m2 per cycle appear to result in a relative decrease of the active metabolite isophosphoramide mustard. These data suggest a dose-dependent saturation or even inhibition of ifosfamide metabolism by increasing high dose ifosfamide and suggest the need for further metabolic studies.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Area Under Curve; Dose-Response Relationship, Drug; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Ifosfamide; Male; Mesna; Middle Aged; Prodrugs; Protective Agents; Remission Induction; Sarcoma; Time Factors

A new polychemotherapy schedule involving high dose intensity and shortened intervals has been developed for patients with advanced sarcomas. Mesna at 2500 mg/m2 for 3 days, epidoxorubicin at 60 mg/m2 on day 1, ifosfamide at 2500 mg/m2 for 3 days, and dacarbazine at 450 mg/m2 for 2 days were given every 2 weeks to a consecutive series of 20 patients. All patients received granulocyte colony-stimulating factor (G-CSF; Filgrastim) subcutaneously at 300 microg from day 5 to day 12 of each cycle. The treatment was feasible and toxicity was acceptable, with grade IV myelotoxicity being observed only in one case. In all, 6 of 14 evaluable patients had an objective response; the median survival was 12 months. Toxicity was milder than that observed for the classic combination MAID, and the planned dose intensity was maintained in the majority of cases.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Dacarbazine; Doxorubicin; Drug Administration Schedule; Female; Filgrastim; Granulocyte Colony-Stimulating Factor; Hematologic Tests; Humans; Ifosfamide; Infusions, Intravenous; Male; Mesna; Middle Aged; Neutropenia; Pilot Projects; Recombinant Proteins; Sarcoma

Adriamycin (ADM) and ifosfamide (IFO) are the two most active agents in the treatment of soft tissue sarcomas (STS) with a clear dose-response relationship. We evaluated the feasibility and toxicity of a high-dose IFO-plus-ADM combination.. Fourteen patients with advanced disease and nine patients in adjuvant setting received IFO 12.5 g/m2 in 120-hour continuous infusion with Mesna uroprotection and ADM 20 mg/m2 on days 1-3 and G-CSF every three weeks.. Twenty-three patients received 89 chemotherapy cycles (70 cycles at full dose). Seventeen patients received the planned treatment, and nine patients required dose reductions. We observed grade 3-4 neutropenia in 52 cycles (59%)/20 patients; grade 3-4 thrombocytopenia in 16 cycles (18%)/nine patients; grade 3-4 anaemia in 24 cycles (27%)/11 patients. Eight patients experienced febrile neutropenia and six patients required blood transfusions.. While feasible, this regimen showed heavy toxicity. Nevertheless, 74% of the patients were able to complete the planned treatment. Adjustment of the schedule of IFO continuous infusion to improve this combination is currently under investigation.

Topics: Adolescent; Adult; Aged; Anemia; Antineoplastic Combined Chemotherapy Protocols; Doxorubicin; Feasibility Studies; Female; Granulocyte Colony-Stimulating Factor; Humans; Ifosfamide; Infusions, Intravenous; Male; Mesna; Middle Aged; Neutropenia; Sarcoma; Soft Tissue Neoplasms; Thrombocytopenia

To evaluate the efficacy and feasibility of high-dose ifosfamide (HDI) at a total dose of 14 g/m2 per cycle with mesna in combination with granulocyte colony-stimulating factor (G-CSF) in adult patients with sarcomas.. Between July 1991 and February 1994, 74 patients with sarcomas (37 bone and 37 soft tissue) were treated on two simultaneous phase II studies that evaluated HDI given as a continuous infusion over 74 hours. G-CSF was started on day 5 at 5 microg/kg/d until recovery of granulocyte count. Additionally, between March 1993 and March 1994, 15 similar patients with previously treated bone or soft tissue sarcomas were treated on a pilot study in which the same total dose of ifosfamide was administered by a bolus schedule, along with mesna and G-CSF. Patients were treated until maximal response, and where possible, surgical resection of gross disease was performed.. Seventy-two patients from the phase II study using continuous infusion are assessable for response. Four complete responses (CRs) and 17 partial responses (PRs) were noted, for an overall response rate of 29% (95% confidence interval [CI], 19% to 39%). The response rate was 40% (95% CI, 24% to 56%) for bone sarcomas and 19% (95% CI, 6% to 32%) for soft tissue sarcomas. Fourteen patients from the pilot study that used a bolus schedule are assessable for response. One CR and seven PRs were noted, for an overall response rate of 57% (95% CI, 31% to 83%) and a response rate of 45% for soft tissue sarcomas. Two patients developed grade 3 to 4 renal toxicity, three developed grade 3 CNS toxicity, one had possible grade 3 cardiac toxicity, and two developed severe painful peripheral neuropathy. There were no treatment-related deaths.. HDI at 14 g/m2 with mesna and G-CSF is an active salvage regimen for patients with bone and soft tissue sarcomas. There is a definite positive dose-response curve, and bolus administration appears to be more active than continuous infusion.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents, Alkylating; Bone Neoplasms; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; Granulocyte Colony-Stimulating Factor; Humans; Ifosfamide; Male; Mesna; Middle Aged; Pilot Projects; Sarcoma; Soft Tissue Neoplasms; Treatment Outcome

A phase I study was designed for the amalgamation of two previously studied antisarcoma regimens (ifosfamide+doxorubicin and mitomycin+doxorubicin+cisplatin) supported by molgramostim. Thus, we hoped to develop a better regimen for the treatment of advanced sarcomas.. Fifteen adult advanced sarcoma patients and six other patients were registered and sequentially assigned to receive three progressively more myelosuppressive levels of chemotherapy: level I-ifosfamide 2500 mg/m2 + doxorubicin 40 mg/m2 + cisplatin 60 mg/m2 all given on day 0, followed by molgramostim 5 micrograms/kg every 12 hours for 14 days; level II-exactly the same chemotherapy from level I given on day 1 preceded on day 0 by ifosfamide 2500 mg/m2 and an additional four days of molgramostim given on days-6 through-3; level III-same as level II except for the addition of mitomycin 4 mg/m2 immediately prior to cisplatin on day 1. MENSA 500 mg/m2 was given five times on each day that involved ifosfamide treatment. For all levels, treatment was repeated at four-week intervals.. Preliminary results and toxicity were reported three years ago (J Natl Cancer Inst 86: 312-4, 1994). Mature results confirm these unexpectedly favorable results with five advanced sarcoma patients still surviving after more than three years (four more than four years).. Molgramostim given subcutaneously in a relatively intensive schedule might enhance the antitumor effects initiated by cytotoxic drugs in patients with advanced sarcomas. This idea should be tested formally in phase III studies.

Topics: Adult; Antineoplastic Agents; Cisplatin; Doxorubicin; Drug Synergism; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Ifosfamide; Mesna; Mitomycins; Recombinant Proteins; Sarcoma; Survival Analysis

Ifosfamide has important activity in pretreated soft tissue sarcomas (STS), and recent data support a clinically significant dose-response relationship for this agent. Administration by continuous infusion and hematopoietic support have rendered dose intensification regimens possible by reducing both hematologic and non-hematologic toxicities. The optimal dose and schedule of ifosfamide when given at high doses remain to be defined. In a previous phase I study, we demonstrated the feasibility of a continuous infusion (c.i.) high-dose ifosfamide (HDI) regimen in the ambulatory setting for patients with advanced solid tumors. The objective of the present phase II study was to assess the antitumor activity and toxicity of such a schedule in patients with advanced pretreated STS.. Thirty-eight patients with advanced and/or metastatic STS, all pretreated with an anthracycline with or without standard-dose ifosfamide, were treated. Ifosfamide was given by c.i. at a dose of 3.5 g/m2/day over four consecutive days, with equidose mesna uroprotection over five days. G-CSF was added at a dose of 200 micrograms/m2/day subcutaneously from day 6 to day 12. Cycles were repeated every three weeks in the outpatient setting.. A total of 159 cycles of therapy were given (median 4 per patient, range 3-6). Treatment compliance was generally satisfactory. The major toxicity was hematologic, with six febrile neutropenic episodes requiring hospitalisation and parenteral antibiotics. Acute renal failure occurred in one patient after three cycles of therapy; central nervous system toxicity was mild. An overall response rate of 39% was observed (95% confidence interval, 26% to 55%), with one complete and 14 partial remissions. All but one of the responder patients had previously received standard-dose ifosfamide. The median response duration was nine months (range 5-21+ months), and the overall median survival ranged from 6-30+ months (median 13 months).. High-dose ifosfamide is an active regimen in anthracycline-pretreated STS. Future clinical trials should be aimed at evaluating the impact of different administration schedules on clinical response and outcome. The potential role of HDI as front-line chemotherapy as well as in the adjuvant treatment of STS needs to be investigated in randomized trials.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Drug Administration Schedule; Female; Granulocyte Colony-Stimulating Factor; Humans; Ifosfamide; Infusions, Intravenous; Male; Mesna; Middle Aged; Sarcoma; Soft Tissue Neoplasms; Treatment Outcome

Since dose intensity of doxorubicin is correlated with the clinical response of patients with soft tissue sarcomas and since doxorubicin dose intensity may be compromised in combination chemotherapy, we evaluated the use of recombinant granulocytemacrophage colony-stimulating factor (rGM-CSF) to ameliorate myelosuppression and allow doxorubicin dose escalation in a phase I trial utilizing the MAID combination [Mesna 2.5 g/m2/day x 4 days, Adriamycin (doxorubicin) 15 mg/m2/day x 4 days, ifosfamide 2.0 g/m2/day x 3 days, dacarbazine 250 mg/m2/day x 4 days; to be repeated every 21 days]. Thirteen patients were treated. The doxorubicin dose for the first 6 patients was at the standard dose of 15 mg/m2/day x 4 days (level 1), while the doxorubicin dose for the next 7 patients was escalated by 25% to 18.75 mg/m2/day x 4 days (level 2). rGM-CSF was given at 5 micrograms/kg/day, days 5-14. All patients experienced moderate to severe myelosuppression, with all patients at dose level 2 requiring doxorubicin dose reduction to dose level 1 or lower by their third course of treatment. rGM-CSF failed to allow sustained escalation of the doxorubicin dose in the MAID regimen.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Dacarbazine; Doxorubicin; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Ifosfamide; Leukopenia; Mesna; Recombinant Proteins; Sarcoma; Treatment Failure

The study was designed to assess the toxicity and activity of high-dose ifosfamide (HDI) administered by continuous infusion at a dose of 4 g/m2/d over 3 days every 4 weeks in adult patients with advanced soft tissue sarcomas (ASTS) pretreated with doxorubicin and/or a standard-dose ifosfamide (SDI)-containing regimen.. Between January 1991 and November 1993, 40 patients with progressive ASTS were entered onto the study. Twenty-eight patients had been pretreated with a multidrug regimen that contained SDI and were classified as follows: SDI-refractory (n = 21), SDI-resistant (n = 2), and indeterminate SDI-sensitive (n = 5). Patients were treated until progression or major toxicity.. One hundred forty-seven cycles of HDI were administered. Neutropenia was dose-limiting, with 100% of patients experiencing grade 3 to 4 toxicity and 12 admissions for febrile neutropenia (30% of patients). Neurotoxicity (17% of patients) was significantly associated with acute renal failure (n = 4) (P < .001), grade 4 thrombocytopenia (P < .01) and febrile neutropenia (P = .048). Chronic renal toxicity (n = 4) was significantly associated with retroperitoneal masses and/or prior nephrectomy (P = .008). Partial responses (PRs) were observed in 12 of 36 assessable patients (33%) and eight patients (22%) experienced disease stabilization. All but one response occurred in patients pretreated with SDI, with five PRs among SDI-refractory patients. Leiomyosarcomas appear resistant to HDI. The median response duration was 8 months (range, 6 to 13+) and the median overall survival time was 12 months.. The activity of HDI in these pretreated ASTS patients and the apparent circumvention of SDI resistance suggest a real dose-response relationship for ifosfamide and deserve further evaluation. Although toxic, this treatment appears feasible and manageable using routine clinical support. Since prophylaxis of ifosfamide-induced renal damage remains unknown, frequent monitoring of renal and tubular functions during therapy is highly recommended.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Brain Diseases; Dacarbazine; Doxorubicin; Drug Administration Schedule; Drug Resistance; Female; Granulocyte Colony-Stimulating Factor; Humans; Ifosfamide; Kidney; Male; Mesna; Middle Aged; Neoplasm Recurrence, Local; Neutropenia; Sarcoma

This two-arm, double-blind, randomized trial was conducted to determine the effects of lenograstim, a glycosylated recombinant human granulocyte colony-stimulating factor (rHu-G-CSF), on the hematologic tolerance of patients with sarcoma treated with mesna, doxorubicin, ifosfamide, and doxorubicin (MAID) chemotherapy.. Forty-eight patients with metastatic or locally advanced soft tissue sarcoma were, following the first cycle of a combination with doxorubicin 60 mg/m2, ifosfamide 7.5 g/m2, and dacarbazine 900 mg/m2, ifosfamide 7.5 g/m2, and dacarbazine 900 mg/m2 given on days 1 to 3, randomized to receive either lenograstim 5 micrograms/kg/d by once-daily injection from day 4 to day 13, or its vehicle. For subsequent cycles, 28 patients continued on the same chemotherapy and lenograstim was systematically given as prophylactic treatment in an open manner.. Following the first cycle of MAID, the duration of neutropenia was reduced in patients who received lenograstim as compared with those who received placebo, with a median duration of neutropenia ( < 0.5 x 10(9)/L neutrophils) of 0 days (range, 0 to 3) and 5 days (range, 0 to 10), respectively (P < .001). All patients who received lenograstim had recovered at least 1 x 10(9)/L neutrophils (polymorphonuclear lymphocytes [PMN]) on day 14, compared with only one of 26 in the placebo group (P < .001). The median time to recover this neutrophil level was 12 days (range, 10 to 13) and 17 days (range, 14 to 21), respectively (P < .001). Neutropenic fever occurred in five (23%) and 15 (58%) patients respectively (P = .02). Twenty-eight patients received at least two cycles (median, four) of MAID at the same dose. Toxicity remained constant across all treatment cycles. A progressive increase in thrombocytopenia was noted, with median platelet nadirs of 102 x 10(9)/L at cycle 2 and 19.5 x 10(9)/L at cycle 6, but did not result in significant treatment modifications. Consequently, median relative dose-intensities remained greater than 0.95 for up to six consecutive MAID cycles.. Lenograstim significantly improved hematologic tolerance in patients treated with the MAID chemotherapy regimen and, therefore, allowed optimal adhesion to the theoretic doses planned for up to six cycles. Whether such an optimization in relative dose-intensity will result in an improvement of treatment efficacy remains to be determined.

Topics: Adult; Aged; Alopecia; Antineoplastic Combined Chemotherapy Protocols; Dacarbazine; Double-Blind Method; Doxorubicin; Female; Follow-Up Studies; Granulocyte Colony-Stimulating Factor; Hematuria; Hemoglobins; Humans; Ifosfamide; Injections, Subcutaneous; Length of Stay; Lenograstim; Leukocyte Count; Male; Mesna; Middle Aged; Nausea; Neutropenia; Platelet Count; Recombinant Proteins; Regression Analysis; Sarcoma; Soft Tissue Neoplasms; Stomatitis

Chemotherapy given by continuous infusion may have different toxicity profiles and different degrees of therapeutic efficacy than when given by bolus administration. The potential therapeutic benefits of continuous infusion chemotherapy and the advantages of outpatient treatment led us to study a continuous infusion of ifosfamide with mesna and oral etoposide.. The authors performed a Phase I-II trial in which 9 g/m2 ifosfamide was administered for 6 days and 10.5 g/m2 mesna was administered for 7 days, both by continuous infusion, in combination with 50 mg/m2/d oral etoposide for 8 days in 21 patients with sarcomas or other solid tumors. Courses were repeated every 28 days.. A total of 65 treatment cycles were given. Only six patients required hospitalization for treatment, all because of an initial poor performance status, and most carried out normal activities on an ambulatory basis. Treatment was stopped during the first course in five patients because of central nervous system toxicity, each with a poor pretreatment performance status; neurologic recovery was complete in each patient. The dose of etoposide was decreased by 20% in 11 patients and unchanged in 7 following the first treatment. Hematologic toxicity was predominantly manifested by leukopenia. An absolute neutrophil count less than 500 neutrophils/microliters occurred in 22 of 50 cycles; thrombocytopenia (platelets less than 100,000/microliters) was seen in two patients, requiring platelet transfusion in one. Neutropenic fevers occurred in 13 of 65 cycles; in 4 of these, cultures demonstrated a bacterial infection. Nausea and vomiting were mild. Objective responses occurred in 6 of 16 patients with soft tissue sarcomas (6 partial responses [PR]) (95% confidence interval, 15-65%), and 3 of 5 bone sarcomas, all of whom had been previously treated with doxorubicin and dacarbazine.. The authors concluded that ifosfamide and mesna given by ambulatory continuous intravenous infusion with wearable pump systems in combination with oral etoposide was well tolerated and showed substantial anti-tumor activity. This combination represents a rational therapeutic approach to patients with advanced soft tissue sarcomas and may have application to other malignancies.

Topics: Administration, Oral; Adult; Aged; Ambulatory Care; Antineoplastic Combined Chemotherapy Protocols; Etoposide; Feasibility Studies; Female; Humans; Ifosfamide; Infusion Pumps; Infusions, Intravenous; Male; Mesna; Middle Aged; Remission Induction; Sarcoma; Soft Tissue Neoplasms

Doxorubicin alone or with dacarbazine (DTIC; AD) is considered the best available therapy for metastatic adult sarcomas. Ifosfamide is active in sarcomas that have failed to respond to a doxorubicin-based regimen. This study was designed to determine if ifosfamide added to doxorubicin and DTIC (ADI) significantly effects toxicity, response rate, and survival. Patients with measurable metastatic or unresectable sarcoma were randomized to receive AD or ADI. Patients with chondrosarcomas, fibrosarcomas, and other sarcomas of bone were eligible, although those with osteosarcoma, rhabdomyosarcoma, Ewing's sarcoma, Kaposi's sarcoma, and mesothelioma were excluded, as were patients with prior chemotherapy for sarcoma or prior doxorubicin.. Between 1987 and 1989, 340 eligible patients were randomized. Significantly more myelosuppression, a higher response rate (17% v 32%; P < .002) and longer time to progression (4 v 6 months; P < .02) were observed for patients who received ifosfamide. An overall survival advantage for the two-drug regimen (12 v 13 months; P = .04) was not significant by multivariate analysis.. In all three randomized trials of doxorubicin with and without ifosfamide (Eastern Cooperative Oncology Group [ECOG], European Organization for Research and Treatment of Cancer [EORTC], and this study), the response rate was higher for the ifosfamide-containing arm, significantly so in this and the ECOG studies. An improved response rate may be particularly important for the preoperative management of high-grade, borderline resectable lesions or pulmonary metastases, particularly in younger patients. In older patients, or for low-to intermediate-grade lesions, doxorubicin and DTIC followed by ifosfamide on progression is preferred.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Dacarbazine; Doxorubicin; Female; Humans; Ifosfamide; Male; Mesna; Middle Aged; Sarcoma; Soft Tissue Neoplasms; Survival Analysis; Treatment Outcome; Urinary Bladder Diseases

A total of 37 adult patients with locally advanced or metastatic soft-tissue sarcoma (STS) entered a pilot study of combination chemotherapy based on the CYVADIC (cyclophosphamide, vincristine, doxorubicin, and dacarbazine) regimen, in which cyclophosphamide was replaced by ifosfamide and mesna (1 g/m2 ifosfamide given daily on days 1-5 as 2-h infusions, 1.5 mg/m2 vincristine given on day 1 as a bolus injection, 50 mg/m2 doxorubicin given on day 1 as a 5-min infusion, and 250 mg/m2 dacarbazine given daily on days 1-5 as 30-min infusions). The overall response rate in 24 patients who were evaluable for response was 46% [95% confidence interval (CI), 25%-67%] and that in subjects who had not undergone prior chemotherapy was 50% (CI, 27%-73%). In all, 4 patients achieved a complete response (17%; CI, 5%-37%) and 2 remain in remission; 3 additional subjects were surgically rendered disease-free after they had shown a partial response. Overall, 31 patients were evaluable for toxicity. Toxicity was mainly hematological; in 3 patients the nadir WBC was less than 0.5 x 10(9)/l, and in 2 cases the nadir platelet count was less than 50 x 10(9)/l. During neutropenia, infections requiring intravenous antibiotics occurred in 8 patients (26%) and in 14 of 190 cycles (7.5%); 1 of these was fatal. We conclude that this new regimen offers promise for the treatment of advanced STS, producing acceptable toxicity.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Dacarbazine; Doxorubicin; Drug Administration Schedule; Drug Evaluation; Female; Humans; Ifosfamide; Male; Mesna; Middle Aged; Sarcoma; Soft Tissue Neoplasms; Vincristine

The dose-limiting toxicity in two separate phase I trials of the high-dose single agents ifosfamide and carboplatin was renal insufficiency at 18 g/m2 and hepatic and ototoxicity at 2,400 mg/m2, respectively. In this phase I study, 16 adults were treated with ifosfamide at 75% of the single-agent maximum-tolerated dose (MTD) (12 g/m2) and escalating doses of carboplatin (400 to 1,600 mg/m2) to determine the nonhematologic dose-limiting toxicity and the maximum-tolerated dose of the combination. Both drugs as well as mesna for uroprotection were given by continuous infusion over 4 days with an additional day of mesna (total dose per course, 15 g/m2). Autologous bone marrow support was stipulated for subsequent dose levels once granulocytes remained less than 500/microL for more than 14 days in two of three to five patients entered at a given dose level. Autologous bone marrow support was used at doses above the 400 mg/m2 carboplatin dose level. At the maximum-tolerated dose level of 1,600 mg/m2 of carboplatin, renal toxicity precluded further dose escalation. Of the five patients entered at this dose level, reversible creatinine elevation greater than 2 mg/dL (median peak, 2.6 mg/dL) was observed in three patients, and irreversible renal failure occurred in an additional patient (peak creatinine, 6.9 mg/dL. Transient gross hematuria appeared more common with the combination than with ifosfamide alone. Two patients developed severe somnolence and confusion associated with a rising creatinine. There were two complete (CRs) and four partial responses (PRs) in 14 heavily pretreated assessable patients (including four partial or complete responses in eight assessable patients with advanced refractory sarcoma, and one CR in two patients with germ cell carcinoma). Carboplatin and ifosfamide appear to have overlapping renal toxicity. Nevertheless, carboplatin and ifosfamide can be combined at 80% and 75% of the single-agent maximum-tolerated doses, respectively, with acceptable nonhematologic toxicity. Ifosfamide and carboplatin are an attractive core combination for further studies in the treatment of sarcoma, germ cell, ovarian, and lung carcinomas.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Carboplatin; Combined Modality Therapy; Creatinine; Drug Administration Schedule; Drug Evaluation; Female; Hematologic Diseases; Humans; Ifosfamide; Kidney Diseases; Male; Mesna; Middle Aged; Neoplasms; Neoplasms, Germ Cell and Embryonal; Nervous System Diseases; Sarcoma; Survival Rate

In a phase II trial of ifosfamide 2 g/m2 days 1 to 4 with mesna uroprotection in 124 patients who had previously failed treatment for sarcomas, 3% achieved a complete response (CR), and 18% had a CR or partial response (PR). In the subset of patients with soft-tissue sarcomas, the response rate for the 64 patients who received bolus administration was 26% compared with 9% for the 60 patients who received a continuous infusion (Cl) schedule (P = .03). When mesna was unavailable, the incidence of hematuria was significant in patients, with three of four patients affected. Microscopic hematuria was uncommon in patients receiving mesna. Hematuria in the group as a whole was not associated with prior treatment with cyclophosphamide, pelvic radiotherapy, age, or a bolus versus Cl schedule. Thus, this and other studies confirm that ifosfamide is active in failed sarcomas. In sequential phase I/II trials, 111 patients who were previously untreated for metastatic or inoperable sarcomas received doxorubicin, ifosfamide, dacarbazine at doses of 60, 7,500, and 900 mg/m2, respectively, by Cl over 72 hours; myelosuppression was dose-limiting. Eleven patients (10%) achieved CRs, with an overall response rate of 47%. Most responses (approximately 70%) were observed within two cycles, and median times to progression were 10 and 9 months for CR and PR, respectively. Following CR, two patients remained disease-free at 32 and 16 months. Of 15 additional patients rendered disease-free with surgery following at least a minor response to chemotherapy, two remained disease-free at 30 and 18 months with no further therapy. Central nervous system (CNS) metastases developed in 11 patients, all of whom had high-grade sarcomas; seven of these patients were still responding systemically (three CRs). This regimen is undergoing evaluation in a randomized trial versus doxorubicin and dacarbazine alone in untreated advanced sarcoma and is being compared with observation in the adjuvant treatment of high-grade sarcomas.(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Central Nervous System Diseases; Child; Child, Preschool; Combined Modality Therapy; Dacarbazine; Doxorubicin; Drug Administration Schedule; Female; Heart Diseases; Humans; Ifosfamide; Lung Diseases; Male; Mesna; Middle Aged; Randomized Controlled Trials as Topic; Sarcoma; Survival Analysis; Urologic Diseases

In two sequential trials, 154 patients were treated with dosages of ifosfamide, ranging between 8 and 18 g/m2 divided over 4 days, with mesna uroprotection. The first was a phase II efficacy trial in 125 advanced sarcoma patients (Antman et al: J Clin Oncol 7:126-131, 1989), while the second was a dose escalation trial involving 29 patients (Elias et al: J Clin Oncol 8:170-178, 1990). In the first trial, patients received 8 to 10 g/m2 ifosfamide either by bolus or continuous infusion. The response rate for the 64 patients receiving bolus administration was 23% compared with 12% for the 60 patients receiving a continuous infusion schedule (P = .09). Of the 154 patients, 144 had sarcoma and had failed at least one previous regimen. Of these 144, 4% responded completely and 23% had a complete or partial response. The maximum tolerated dose of ifosfamide was 16 g/m2 in the second trial. Dose-limiting renal toxicity was observed at 18 g/m2 ifosfamide (Elias et al: J Clin Oncol 8:170-178, 1990). The duration of myelosuppression and the frequency and severity of mucositis and renal tubular acidosis were dose-dependent. A median of 11 days (range, 8 to 18) of granulocytopenia (less than 500/microL) were observed. Thus, autologous bone marrow reinfusion was not required. Severe central nervous system toxicity (transient confusion, hallucinations, and somnolence) was observed sporadically at both low- and high-dose levels. The first four patients on the standard-dose study did not receive mesna because it was unavailable; three developed gross hematuria. In patients who received mesna, hematuria was uncommon. Hematuria in the group as a whole was significantly associated with a lack of uroprotection, but was not associated with prior cyclophosphamide, pelvic radiotherapy, age, or bolus versus a continuous infusion schedule. Patients receiving ifosfamide with mesna uroprotection can tolerate considerable dose escalation over the usual prescribed doses before nonhematologic toxicity becomes dose-limiting. Ifosfamide, with its broad activity in solid tumors, may prove to be an important addition to high-dose combination-chemotherapy regimens (Elias et al: J Clin Oncol 8:170-178, 1990).

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Brain Diseases; Child; Child, Preschool; Cystitis; Drug Administration Schedule; Drug Evaluation; Hematologic Diseases; Humans; Ifosfamide; Kidney Diseases; Mesna; Middle Aged; Pulmonary Fibrosis; Sarcoma

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Child; Dactinomycin; Doxorubicin; Etoposide; Female; Humans; Ifosfamide; Male; Mesna; Sarcoma; Soft Tissue Neoplasms

European and American investigators have reported response rates of 38% to 83% for ifosfamide alone in pretreated sarcomas. In a phase II trial of ifosfamide 2.0g/m2 days 1 to 4 with mesna uroprotection in 124 patients with previously failed sarcomas, four (3%) responded completely (95% exact confidence interval, 1% to 8%) and 26 (21%) had a complete or partial response (95% exact confidence interval, 14% to 29%). The median time to progression was 5 and 9 months for partial and complete responders, respectively. In the subset of soft tissue sarcomas, the response rate for the patients receiving bolus administration was 26%, compared with 9% for the patients receiving a continuous infusion schedule (P = .03). The response rates among patients with soft tissue and bony sarcomas with a performance score of 0-2 and 0-1 prior to chemotherapy administration were 20% and 40%, respectively. Somnolence or confusion developed in 19%. Neurotoxicity was significantly associated with poor performance status (P less than .01), elevated creatinine (P less than .01), and low bicarbonate levels (P = .05). A serum bicarbonate less than 20 developed in 31% of the patients and was significantly associated with older age (P = .01), elevated creatinine (P = .02), and female sex (P = .06). Hematuria was significantly associated with no uroprotection (the first four patients did not receive mesna because it was unavailable), but was not associated with prior cyclophosphamide, pelvic radiotherapy, age, or bolus v continuation infusion schedule. Thus, ifosfamide is active in failed sarcomas and warrants further study in previously untreated patients with sarcoma.

Topics: Adolescent; Adult; Aged; Child; Child, Preschool; Clinical Trials as Topic; Female; Hematuria; Humans; Ifosfamide; Male; Mercaptoethanol; Mesna; Middle Aged; Sarcoma; Soft Tissue Neoplasms

In this phase II trial, 105 eligible patients with no prior chemotherapy and advanced sarcoma received doxorubicin, ifosfamide, and dacarbazine (DTIC) with mesna uroprotection (MAID). Starting doses of these drugs were 60, 7,500, and 900 mg/m2 divided over 72 hours by continuous infusion, respectively. Mesna was given for 84 to 96 hours at 2,500 mg/m2/d. Myelosuppression was dose limiting, causing the only toxic death (sepsis). Nonhematologic toxicity consisted predominantly of anorexia and vomiting. Severe mucositis, macroscopic hematuria, renal tubular acidosis, renal failure, and CNS toxicity occurred in less than 5% of cycles. No cardiotoxicity was detected. The overall response rate (10% complete response [CR]) was 47% (95% confidence intervals, 5% to 18% and 37% to 57%, respectively). Most responses (approximately 70%) were observed within two cycles. Median times to progression were 10 and 9 months, respectively. Histologic high tumor grade, lesions less than 5 cm, and less than 1 year from diagnosis to study entry correlated with the probability of response. The median survival was 16 months. Time from diagnosis to study entry, performance status, and extent of disease, but not histologic grade, correlated with survival. Following CR, two patients remain disease-free at 32 and 16 months. Of the 15 additional patients rendered disease-free with surgery, two remain disease-free at 30 and 18 months with no further therapy. While most relapses occurred in sites of prior involvement, death from CNS metastases occurred in 11 of the 80 patients with high-grade sarcomas, of whom seven were still responding systematically (three complete responders). Because of its substantial response in this phase II trial, the MAID regimen is being compared with doxorubicin and DTIC alone in advanced sarcomas and to observation in the adjuvant treatment of high-grade sarcomas in randomized trials.

Topics: Actuarial Analysis; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Brain Neoplasms; Clinical Trials as Topic; Dacarbazine; Doxorubicin; Drug Administration Schedule; Drug Evaluation; Female; Humans; Ifosfamide; Male; Mesna; Middle Aged; Remission Induction; Sarcoma; Soft Tissue Neoplasms; Spinal Cord Neoplasms

The regimen of doxorubicin (DOX), ifosfamide (IFF), and dacarbazine (DTIC) (AID) for previously untreated inoperable or metastatic sarcoma has acceptable toxicity with significant activity. Twenty patients received 79 courses of DOX (60-75 mg/m2) with or without DTIC (900 mg/m2) by continuous infusion over 72 hours with escalating doses of IFF and mesna uroprotection. Nineteen patients were evaluable for toxicity. Myelosuppression was dose-limiting. The maximum tolerated dose was DOX at 60 mg/m2, DTIC at 900 mg/m2, and IFF at 7500 mg/m2 per course. Of the 79 courses analyzed, 33 (42%) resulted in wbc counts less than 1000/microliter; 14 (18%) were complicated by fever and neutropenia, and three by sepsis. There were no toxic deaths. Relative platelet sparing was observed and nadirs were brief. In contrast to bolus-dose DTIC divided over 5 days, DTIC by continuous infusion did not add significantly to gastrointestinal toxicity. Nausea and vomiting was well controlled by antiemetics. Mucositis occurred sporadically. Unlike our phase II study of IFF alone, no CNS or renal toxicity was observed. No cardiac toxicity was encountered, although only four patients have received greater than 450 mg/m2 of cumulative DOX. One episode of DOX extravasation occurred despite a long iv line that extended to the axilla. No serious tissue damage was observed, perhaps due to the dilute solutions of DOX used. Partial responses were seen in eight of 18 evaluable patients (44%) and in six of 11 patients at or near the phase II level. Two additional patients with minimal response have continued tumor regression. The median number of courses before partial response was four (range, one to five). The median duration of response has not been reached (3+ to 10+ months). An inoperable primary has been rendered surgically resectable in one patient. Activity in previously untreated sarcomas should be further evaluated in a randomized phase III study against a standard DOX-containing combination.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Dacarbazine; Doxorubicin; Drug Evaluation; Female; Humans; Ifosfamide; Male; Mesna; Middle Aged; Sarcoma

One hundred and seventy-one patients with advanced soft tissue sarcoma entered a randomized crossover phase II study comparing cyclophosphamide (CYCLO) with a new analogue, ifosfamide (IFOS), both administered as 24 h i.v. infusions every 3 weeks. The doses used were CYCLO 1.5 g/m2 and IFOS 5 g/m2, with provision for dose escalation. All patients received mesna 400 mg/m2 as an i.v. bolus 4 hourly X 9 doses, commencing at the start of the oxazophosphorine infusion. Patients who had received previous chemotherapy were eligible provided this did not include a classical alkylating agent. There were 22 patients who were ineligible, and response could not be evaluated in 12 additional patients. IFOS produced two complete and ten partial remissions, for an overall response rate of 18%. CYCLO was significantly (P = 0.04) less active, producing one complete and five partial remissions, an overall response rate of 9%. Stabilization of disease was similar in both arms (27% and 24% respectively), but fewer patients showed progression on IFOS. The response rate was higher (20% vs 5%) for patients who had not received previous chemotherapy, and also for female compared with male patients (21% vs 5%). When only patients who had not received previous chemotherapy were considered, the respective response rates for IFOS and CYCLO were 24% and 15%. There were no responses in previously treated patients receiving CYCLO. There were four partial responses in 33 patients crossing from CYCLO to IFOS, but no responses in 18 patients receiving CYCLO after IFOS. Leucopenia was significantly more pronounced (P = 0.0004) with CYCLO, both after the first course and throughout treatment, although the incidence of severe infections, 6%, was the same in both arms. Nausea and vomiting were more severe with IFOS (P = 0.022), but other toxicities were mild. Grade 1 or 2 bladder (haematuria) or renal (rise in serum creatinine) toxicity was slightly more frequent with IFOS (7 vs 3 patients) and was a reason for stopping treatment for one patient in each arm. Three episodes of mild to moderate drowsiness after IFOS were reported, but no severe encephalopathy. A higher response rate with less myelosuppression suggests that IFOS may have advantages over CYCLO in combination with such active agents as adriamycin.

Topics: Adolescent; Adult; Aged; Cyclophosphamide; Drug Evaluation; Female; Humans; Ifosfamide; Infections; Leukopenia; Male; Mesna; Middle Aged; Random Allocation; Sarcoma; Soft Tissue Neoplasms

We compared the outcomes in soft tissue sarcoma (STS) treated with olaratumab and doxorubicin (OD) versus doxorubicin, ifosfamide, and mesna (AIM) to assess whether OD could supersede AIM in STS therapy.. A single-institution, retrospective study of STS treated for advanced disease with OD or AIM in 2013 to 2017 was conducted. Demographic and clinical parameters were compared by Fisher's exact test. Kaplan-Meier and Cox analyses examined progression-free survival (PFS) and overall survival (OS). Adverse events were compared.. Thirty patients (13 OD, 17 AIM) were included. OD was administered more commonly after first-line therapy (54% OD vs. 6% AIM, P=0.0005). The 2 groups did not differ in other parameters. Median OS [OD: 14.2 mo, 95% confidence interval (CI): 7.1-not reached; AIM 19.9 mo, 95% CI 9.5-35.5; hazard ratio: 0.99, 95% CI: 0.38-2.59, P=0.99] and PFS (OD: 2.6 mo, 95% CI: 1.3-7; AIM 6.4 mo, 95% CI: 1.5-14.5; hazard ratio: 0.57, 95% CI: 0.26-1.24, P=0.16) were not statistically different, although median values favored AIM. Grade 3 to 4 neutropenia, but not febrile neutropenia, was more frequent with OD.. OD and AIM did not differ with respect to either OS or PFS. Although this study's size initially appeared the most likely explanation, lack of significant activity of olaratumab was subsequently reported in the phase III trial of OD. Our results suggest that future conditional oncology drug approvals should be accompanied by mandated registries to monitor outcomes of patients treated after conditional approval, but before full approval.

Topics: Adult; Aged; Antibiotics, Antineoplastic; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Doxorubicin; Female; Humans; Ifosfamide; Male; Mesna; Middle Aged; Neoplasm Staging; Protective Agents; Retrospective Studies; Sarcoma; Soft Tissue Neoplasms; Treatment Outcome; Young Adult

Pulmonary pleomorphic carcinoma (PC) is a rare type of lung tumor with a dismal prognosis. There is no consensus on a chemotherapy regimen for PC, and conventional platinum-based chemotherapy has been associated with disappointing response rates and PFS. In searches for a new regimen, the sarcomatoid (spindle or giant cell) component has been assumed to be susceptible to chemotherapy used for soft tissue sarcoma.. The medical records of 17 patients who received mesna, doxorubicin, ifosfamide, and dacarbazine (MAID) for advanced PC between January 2010 and February 2017 were retrospectively analyzed for clinicopathological features and outcomes.. The median age was 59 years. Sixteen patients were male, and only one patient had never smoked. Six patients achieved partial response to MAID, leading to an objective response rate of 35%. The median PFS was 2.8 months, and the median OS was 8.7 months. Hematologic toxicity-related adverse events were the most frequent, which comprised grade 3-4 anemia in 35% of patients, neutropenia in 47%, thrombocytopenia in 24%, and febrile neutropenia in 29%. No febrile neutropenia was reported in patients who received 5-day granulocyte-colony stimulating factor (G-CSF) prophylaxis. Most adverse events resolved without complications, except for one death due to sepsis. MAID is an effective, and possibly important, regimen for PC. MAID could be more safely used in clinical practice with appropriate dose modifications and G-CSF primary prophylaxis according to patients' status.

Topics: Adult; Aged; Dacarbazine; Doxorubicin; Female; Humans; Ifosfamide; Lung Neoplasms; Male; Mesna; Middle Aged; Neoplasms, Complex and Mixed; Retrospective Studies; Sarcoma; Survival Analysis

Conservative surgery for soft-tissue sarcoma (STS) within multimodality treatment attempts to reconcile two contradictory requirements: assuring a good oncological outcome through a wide resection and preserving the function. The aim of our study is to verify whether our conservative approach to STS met these objectives.. A retrospective database analysis was performed in adults with primary limb or trunk wall STS operated in a single center from 1989 to 2012. Predictive factors for postoperative complications and functional impairment were tested in a multivariate analysis.. 728 patients were operated (resection R0: 68%). Neoadjuvant chemotherapy (NAC) was given to 28%, postoperative radiotherapy to 70% of patients. Median follow-up was 103 months. At five years, overall survival was 80% and local recurrences 11%. Major postoperative complications occurred in 8% and functional impairment in 13% of the patients. Independent predictive factors for postoperative complications were American Society of Anesthesiologist classes 2 and 3 (OR: 2.3, CI: 1.2-4.5 and 4.0 CI: 1.7-9.3), tumor size >80 mm (OR: 2.5, CI: 1.3-4.9), tumor site (trunk wall/lower limb, OR: 4.1, CI: 1.3-13.6) and multifocal/multicompartmental spread (OR: 2, CI: 1.1-3.6). Independent predictive factors for function impairment were postoperative complications (OR: 5.3, CI: 2.8-10.1), NAC (OR: 3.6, CI: 2.2-5.8), and bone or neurovascular involvement (OR 3.3, CI 2.0-5.3), whereas Early Rehabilitation after Surgery (ERAS) improved outcome (OR: 0.5, CI: 0.3-0.9).. Postoperative complications induced functional impairment. They may be reduced by acting on comorbidity factors and careful tumor evaluation prior to surgery. Furthermore, ERAS measures improved function.

Topics: Abdominal Wall; Activities of Daily Living; Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Dacarbazine; Doxorubicin; Extremities; Female; Follow-Up Studies; Humans; Ifosfamide; Male; Mesna; Middle Aged; Multivariate Analysis; Neoadjuvant Therapy; Postoperative Complications; Radiotherapy, Adjuvant; Retrospective Studies; Risk Factors; Sarcoma; Soft Tissue Neoplasms; Survival Rate; Thoracic Wall; Torso; Tumor Burden; Young Adult

To assess the long term clinical outcome of preoperative radiotherapy with or without chemotherapy followed by limb sparing surgery in patients with non-metastatic soft tissue sarcomas (STS) of the extremities.. Sixty patients with locally advanced STS were retrospectively analyzed. The median tumor diameter was 12 cm. All patients were treated with preoperative radiotherapy delivered with two different fractionation schedules (35Gy/10fr or 46-50Gy/23-25fr). Neoadjuvant chemotherapy was added to 44 patients with large and/or high grade tumors. Surgery was performed 2-6 weeks after radiotherapy. Chemotherapy was completed up to 6 courses after surgery in patients who had good responses.. Median follow-up time was 67 months (8-268 months). All of the patients had limb sparing surgery. The 5-year local control (LC), disease free (DFS) and overall survival (OSS) rates for all of the patients were 81%, 48.1% and 68.3% respectively. 5-year LC, DFS and cause specific survival (CSS) were 81.7%, 47%, 69.8%, and 80%, 60%, 60% in the chemoradiotherapy and radiotherapy groups, respectively. On univariate analysis, patients who were treated with hypofractionation experienced significantly superior LC, DFS and CSS rates with similar rates of late toxicity when compared with patients who were treated with conventional fractionation and statistical significance was retained on multivariate analysis.. Treatment results are consistent with the literature. As neoadjuvant chemoradiotherapy provides effective LC and CSS with acceptable morbidity, it should be preferred for patients with large and borderline resectable STS.

Topics: Adolescent; Adult; Aged; Antibiotics, Antineoplastic; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Chemoradiotherapy; Chemotherapy, Adjuvant; Disease-Free Survival; Doxorubicin; Extremities; Female; Granulocyte Colony-Stimulating Factor; Humans; Ifosfamide; Male; Mesna; Middle Aged; Preoperative Care; Protective Agents; Radiotherapy, Adjuvant; Retrospective Studies; Sarcoma; Treatment Outcome; Turkey; Young Adult

Metformin, a biguanide drug used in the treatment of type II diabetes, was evaluated alone and in combination with amifostine, captopril, MESNA or N-acetyl-cysteine (NAC) for its ability to protect when administered 24 h after irradiation. Mouse embryo fibroblasts (MEF), human microvascular endothelial cells (HMEC) and SA-NH mouse sarcoma cells were exposed to 4 Gy in vitro. C3H mice were exposed to 7 Gy and evaluated utilizing an endogenous spleen colony assay system. Amifostine and WR1065, administered 30 min prior to irradiation, were used as positive controls. Treatment of MEF, HMEC and SA-NH cells with metformin elevated survival levels by 1.4-, 1.5- and 1.3-fold compared to 1.9-, 1.8- and 1.6-fold for these same cells treated with WR1065, respectively. Metformin (250 mg/kg) was effective in protecting splenic cells from a 7 Gy dose in vivo (protection factor = 1.8). Amifostine (400 mg/kg), administered 30 min prior to irradiation resulted in a 2.6-fold survival elevation, while metformin administered 24 h after irradiation in combination with NAC (400 mg/kg), MESNA (300 mg/kg) or captopril (200 mg/kg) enhanced survival by 2.6-, 2.8- and 2.4-fold, respectively. Each of these agents has been approved by the FDA for human use and each has a well characterized human safety profile. Metformin alone or in combination with selected sulfhydryl agents possesses radioprotective properties when administered 24 h after radiation exposure comparable to that observed for amifostine administered 30 min prior to irradiation making it a potentially useful agent for radiation countermeasures use.

Topics: Acetylcysteine; Acute Radiation Syndrome; Amifostine; Animals; Captopril; Cell Line, Transformed; Cell Line, Tumor; Cells, Cultured; Colony-Forming Units Assay; Drug Evaluation, Preclinical; Drug Synergism; Endothelial Cells; Fibroblasts; Free Radical Scavengers; Humans; Mesna; Metformin; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Radiation Injuries, Experimental; Radiation-Protective Agents; Sarcoma; Sulfhydryl Compounds

Good local control of high-grade non-small round cell soft tissue sarcomas (NSRCSTSs) has been achieved with significant advances in surgical techniques and radiotherapy. However, the role of chemotherapy remains controversial. Our aim was to investigate the efficacy, feasibility and adverse effects of neoadjuvant and adjuvant chemotherapy with modified mesna, adriamycin, ifosfamide and dacarbazine (MAID) regimen for NSRCSTSs.. We conducted a retrospective review of 40 consecutive patients (29 men, 11 women; median age 47 years) with high-grade NSRCSTSs treated in two referral centers between 2004 and 2009 (median follow-up 38.5 months). Patients with distant or nodal metastases at diagnosis were excluded. The regimen consisted of ifosfamide 2,500 mg/m(2)/6 h (days 1-3), mesna 2,500 mg/m(2)/6 h (days 1-3), tetrahydropyranyl adriamycin 20 mg/m(2)/0.5 h (days 1-3), and dacarbazine 300 mg/m(2)/1 h (days 1-3).. Among the 26 evaluable patients, there were 8 with a partial response, 15 with stable disease, and 3 with progressive disease. Two- and 5-year overall survival rates were 92 and 86%, respectively, and corresponding disease-free survival rates were 80 and 77%. All relapses were metastases without local recurrence. Grade 3-4 neutropenia, anemia and thrombocytopenia were observed in 38, 18, and 21 patients, respectively. No serious infectious complications occurred due to the administration of granulocyte colony-stimulating factor and prophylactic antibiotics. No other life-threatening serious adverse events were observed.. The modified MAID regimen achieved a better outcome with less serious adverse events than previously reported and is a potential option in the management of NSRCSTSs. Further evaluation with long-term follow-up is required.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Dacarbazine; Disease-Free Survival; Doxorubicin; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Ifosfamide; Male; Mesna; Middle Aged; Neoadjuvant Therapy; Neoplasm Staging; Retrospective Studies; Sarcoma; Treatment Outcome

Topics: Antineoplastic Combined Chemotherapy Protocols; Child; Humans; Ifosfamide; Mesna; Sarcoma

A 51-year-old man complained of left facial swelling and recurrent nasal bleeding. A giant solid tumor in the left maxillary sinus was detected on head CT and MRI, and this tumor was destroying the maxilla and extending into the orbit, pterygoid muscle and posterior paranasal sinuses. The resected specimen consisted of spindle cells containing necrotic material. Histological examination revealed immature tumor cells, and immunohistological study of the tumor showed staining was only positive for vimentin. We accordingly diagnosed undifferentiated sarcoma in the maxillary sinus. Combination chemotherapy with vincristine, doxorubicin, cyclophosphamide/ifosfamide with mesna and etoposide was administered; however, the tumor was unresponsive and the patient died after around 3 months.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Doxorubicin; Etoposide; Fatal Outcome; Humans; Ifosfamide; Male; Maxillary Sinus Neoplasms; Mesna; Middle Aged; Protective Agents; Sarcoma; Vincristine

Topics: Antibiotics, Antineoplastic; Antineoplastic Agents, Alkylating; Doxorubicin; Female; Humans; Ifosfamide; Immunohistochemistry; Mediastinal Neoplasms; Mesna; Middle Aged; Protective Agents; Radiography, Thoracic; Sarcoma; Tomography, X-Ray Computed; Trachea; Vimentin

The response of adult soft tissue sarcoma (STS) to chemotherapy is uncertain. This study was to evaluate the role of chemotherapy in treating adult soft tissue sarcoma.. Clinical data of 109 adult soft tissue sarcoma patients, treated with chemotherapy at Cancer Center of Sun Yat-sen University from Jan. 2000 to Dec. 2005, were analyzed.. Of the 109 patients, 66 received palliative chemotherapy, 40 received adjuvant chemotherapy, and 3 received neoadjuvant chemotherapy. The overall response rate for first line chemotherapy was 22.7%. The median survival was 16.9 months. The 1-and 2-year survival rates were 63.6% and 33.3%. The patients with lung metastasis had a significantly longer median survival than those with liver metastasis did (25.1 months vs. 11.8 months, P<0.05). MAID and CYVADIC were the most commonly used first-line chemotherapy regimens; the response rates were 28.0% and 22.2%, respectively. When anthracycline and/or standard dose ifosfamide failed, the patients could still benefit from high dose ifosfamide (14.0 g/m(2)). The median survival was significantly shorter in the patients who got metastasis within 6 months after diagnosis than in those that got metastasis more than 6 months after diagnosis (11.8 months vs. 42.9 months, P=0.04). Of the 40 patients who received adjuvant chemotherapy, 16 developed progression during follow-up: 10 had relapse and 6 had distant metastasis.. MAID and CYVADIC are two effective chemotherapy regimens for adult soft tissue sarcoma. We recommend to take a high dose ifosfamide when anthracycline and/or standard dose ifosfamide failed. The patients with liver metastasis are more resistant to chemotherapy than those with lung metastasis. Developing metastasis within 6 months after diagnosis is a poor prognostic factor.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Cyclophosphamide; Dacarbazine; Doxorubicin; Extremities; Female; Follow-Up Studies; Humans; Ifosfamide; Liver Neoplasms; Lung Neoplasms; Male; Mesna; Middle Aged; Neoadjuvant Therapy; Neoplasm Staging; Palliative Care; Pelvic Neoplasms; Remission Induction; Retrospective Studies; Sarcoma; Soft Tissue Neoplasms; Survival Rate; Vincristine; Young Adult

Topics: Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Dacarbazine; Doxorubicin; Humans; Ifosfamide; Mesna; Meta-Analysis as Topic; Neoadjuvant Therapy; Radiotherapy, Adjuvant; Randomized Controlled Trials as Topic; Sarcoma; Survival Analysis; Treatment Failure; Treatment Outcome

To report the experience of a single institution in the south of Israel with doxorubicin and ifosfamide-mesna in patients with advanced/recurrent uterine sarcomas.. The hospital records of five patients with advanced/recurrent uterine sarcomas who had combination chemotherapy with doxorubicin and ifosfamide-mesna were retrospectively reviewed. Doxorubicin 30 mg/m2 was given on days 1 and 2 and ifosfamide 2000 mg/m2 (+ mesna, W/W 60%) was given on days 1, 2 and 3 of every 21 days. Dose intensity, relative dose intensity and average relative dose intensity (ARDI) of chemotherapy were calculated. Response was determined using clinical evaluation and radiological reports. Toxicity was graded using the National Cancer Institute (NCI) criteria.. The median ARDI of the combination of doxorubicin and ifosfamide received by the patients was 0.68 (range, 0.53-0.74). One (20%) patient had disease complete response lasting three months and four (80%) patients had progressive disease. Toxicity was mainly hematological with grade 3 or 4 leukopenia--four (80%) patients, neutropenia--four (80%), thrombocytopenia--one (20%) and anemia--one (20%). Non-hematological toxicity was negligible. At follow-up, four (80%) patients had died of disease and one (20%) was alive with disease.. Although the combination of doxorubicin and ifosfamide has certain activity in advanced/recurrent uterine sarcomas, the toxicity is of much concern and the results of treatment in terms of response duration and survival are poor.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Doxorubicin; Female; Humans; Ifosfamide; Mesna; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Protective Agents; Retrospective Studies; Sarcoma; Treatment Outcome; Uterine Neoplasms

This case report includes the results of long-term follow-up after extended total sacrectomy in a 13-year-old boy with a sarcoma originating in the sacrum with an extraskeletal extension and infiltration into the left ilium.. To report and discuss a case of sacral tumor treated by extended sacrectomy.. Sacral tumors are often at an advanced stage with a large volume at diagnosis. Although total or extended sacrectomy is the only radical means to treat the massive sacral tumor, unavoidable complications in total sacrectomy are serious in the treatment selection.. Initial histologic findings indicated a synovial sarcoma. Additional genetic analysis redesignated the tumor as an unclassified sarcoma. Preoperative neoadjuvant chemotherapy and radiotherapy were completed. The response to the preoperative treatment appeared as a reduction in tumor size (approximately 50%) on radiographs. After extended sacrectomy, the L5 vertebral body was fixed between the ilia, and the pelvic ring was compressed by the Zielke system. The ISOLA instrumentation system connected the lumbar spine and both ilia. All sacral nerve roots and the L5 root on the left side were cut.. At the 5-year follow-up examination, the patient was disease-free, could walk with crutches, and could climb stairs using the handrail and one crutch.. The patient's excellent response to preoperative antitumor treatment was considered crucial to the long-term outcome. But the decision between a radical resection with reconstruction and a less extensive procedure with combined therapy remains controversial.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Cisplatin; Combined Modality Therapy; Dacarbazine; Diagnostic Errors; Doxorubicin; Fibula; Follow-Up Studies; Humans; Ifosfamide; Ilium; Internal Fixators; Intervertebral Disc Displacement; Laminectomy; Lumbar Vertebrae; Male; Mesna; Neoadjuvant Therapy; Neoplasm Invasiveness; Radiotherapy, Adjuvant; Recovery of Function; Rhizotomy; Sacrum; Sarcoma; Spinal Neoplasms; Spinal Nerve Roots

Alveolar soft-part sarcoma (ASPS) is a very rare malignant tumor, usually of the extremities, and is seen most often in adolescents and young adults. Surgical excision of the primary and pulmonary metastases has resulted in prolonged survival in some patients, but adjuvant radiation and/or chemotherapy are generally thought to be ineffective. The authors describe a 13-year-old patient with ASPS of an extremity who presented with multiple bilateral pulmonary metastases at diagnosis. Following intensive multiagent chemotherapy, pulmonary metastases showed in vivo evidence of tumor death. The patient has remained disease-free for 10 years following treatment.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Doxorubicin; Female; Humans; Leg; Mesna; Neoplasm Metastasis; Sarcoma; Treatment Outcome; Vincristine

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Dacarbazine; Doxorubicin; Extremities; Humans; Ifosfamide; Mesna; Risk Factors; Sarcoma; Soft Tissue Neoplasms

To increase the dose intensity (DI) of chemotherapy for pediatric patients with metastatic sarcomas, including the Ewing sarcoma family of tumors (ESFT) and rhabdomyosarcoma (RMS), the authors tested the feasibility of an intensive regimen supported by granulocyte-colony stimulating factor (G-CSF) and peripheral blood stem cells (PBSC).. Twenty-three children and adolescents with metastatic sarcomas received vincristine, doxorubicin, cyclophosphamide, ifosfamide, sodium mercaptoethanesulfonate (mensa), and etoposide (VACIME) chemotherapy, consisting of 8 courses of vincristine 2 mg/m(2) on Day 0, doxorubicin 37.5 mg/m(2) per day on Days 0-1, cyclophosphamide 360 mg/m(2) per day on Days 0-4, ifosfamide 1800 mg/m(2) per day on Days 0-4, mesna 2400 mg/m(2) per day, and etoposide 100 mg/m(2) per day on Days 0-4. Doxorubicin was omitted in Courses 7 and 8. G-CSF was given after each course of therapy. Courses of therapy were repeated every 21 days or as soon as hematopoietic recovery permitted. PBSC were collected twice: first, after Course 2 (infused after Courses 3 and 4) and, second, after Course 4 (infused after Courses 5 and 6). Surgical resection followed Course 6, and radiotherapy followed Course 8.. PBSC collections were adequate in 91% of all harvests. The mean DI was 82% (standard deviation, 14%) of the intended DI, which was greater than historic data without PBSC support. Seventeen patients (74%) achieved a complete response (CR), 12 patients with chemotherapy alone and 5 more patients after undergoing surgical resection. Fifteen patients developed progressive disease, with a 2-year event free survival (EFS) rate of 39% (95% confidence interval, 19-59%). Hematopoietic toxicity was severe and cumulative, although it was less than that seen previously without PBSC support.. PBSC-supported multicycle chemotherapy is a feasible method to increase chemotherapy DI for pediatric patients with metastatic sarcomas. Although the CR rate compared favorably with previously reported response rates, the 2-year EFS rate was similar to that achieved with other intensive regimens.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Combined Modality Therapy; Cyclophosphamide; Doxorubicin; Etoposide; Feasibility Studies; Female; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Transplantation; Humans; Ifosfamide; Infant; Male; Mesna; Neoplasm Metastasis; Remission Induction; Sarcoma; Sarcoma, Ewing; Soft Tissue Neoplasms; Treatment Outcome; Vincristine

Our objective was to assess the efficacy of a standard dose ifosfamide and doxorubicin containing regimen in the treatment of advanced soft tissue sarcomas. Forty consecutive patients with a median age of 35.5 years were treated. Ifosfamide was administered at a dose of 2.5 g/m(2)/day as 72-hour continuous infusion with mesna at the same dosage and schedule. Doxorubicin was given at the dose of 60 mg/m(2)/day as 2-hour infusion on day 1. Six patients had a complete response (15%), and 9 (22.5%) had a partial response, fourteen patients (35%) stable disease, and 11 (27.5%) did not respond to chemotherapy. The median duration of response was 13 and 5 months for the complete and partial responders, respectively. The median survival was 37 months. Febrile neutropenia was encountered in 9 cases (22.5%). The present ifosfamide and doxorubicin combination is a moderately effective and well-tolerable regimen in the treatment of advanced soft tissue sarcomas.

Topics: Adolescent; Adult; Antibiotics, Antineoplastic; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Doxorubicin; Female; Fever; Follow-Up Studies; Humans; Ifosfamide; Infusions, Intravenous; Logistic Models; Male; Mesna; Middle Aged; Neutropenia; Protective Agents; Remission Induction; Sarcoma; Survival Rate

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.. 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/m(2)/day x 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.. 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 x2, nausea and vomiting x1). All significant toxicity was eliminated with dose reduction.. 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.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Chemotherapy, Adjuvant; Female; Humans; Ifosfamide; Infusions, Intravenous; Leiomyosarcoma; Mesna; Middle Aged; Mixed Tumor, Mullerian; Neoplasm Staging; Protective Agents; Rhabdomyosarcoma; Sarcoma; Survival Analysis; Uterine Neoplasms

To assess the role of consolidative radiation therapy (CRT) in conjunction with myeloablative therapy with or without total body irradiation (TBI) in children and young adults with metastatic or recurrent sarcoma.. Twenty-one pediatric sarcoma patients with metastatic (10) or recurrent (11) disease were entered on a prospective feasibility study of intensive myeloablative therapy with or without TBI. Median patient age was 17.8 years (range, 9.4-24.7 years). Primary histologies included Ewing's (12), PNET (3), and other soft tissue sarcomas (6). Twenty patients received induction chemotherapy. Myeloablative therapy consisted of TBI in 11 patients with either high dose melphalan/etoposide (9) or high dose cytoxan/thiotepa (2). TBI consisted of 12 Gy in 2 Gy fractions delivered twice daily over 3 days. Ten patients received high dose chemotherapy alone, either with thiotepa/carboplatinum/etoposide (8) or cytoxan/carboplatinum (2). Myeloablative therapy was followed by autologous stem cell rescue (ASCR) 24 to 48 hours after completing chemotherapy. Fourteen patients (67%) received CRT either prior to (5) or following (9) myeloablative therapy. Median CRT dose was 37.2 Gy (range, 20-60). Fifty-one disease sites were present prior to myeloablative therapy. Twelve (24%) were bulky (> 8 cm) and 18 (35%) underwent surgical debulking. The median follow-up of surviving patients was 15 months (range, 8-20) with 25% of patients having been followed for more than 20 months.. The 3-year actuarial disease-free (DFS) and overall survival (OS) rates for the entire group were 36% and 27%, respectively. Following myeloablative treatment, responses were: 11 complete, 6 partial, 1 stable, and 3 progressive disease. Sixteen patients (71%) have relapsed. The most common site of relapse was the lung (13). Of the 51 disease sites present prior to myeloablative therapy, 36 sites (71%) were amenable to CRT. Nonamenable sites were: multiple lung metastases (13) and bone marrow (2). Twenty-six amenable sites (51%) received CRT either prior to (14) or following (12) ASCR. Amenable sites treated with CRT had a better 3-year actuarial local control (80 vs 37%) (p = 0.0065) than amenable sites not treated with CRT. Factors associated with improved disease-free survival (DFS) in univariate analysis were induction chemotherapy response (p = 0.002) and extent of surgical resection (p = 0.045). There was a trend toward improved DFS on univariate analysis with the use of TBI as part of myeloablative therapy (p = 0.07). The one factor associated with improved OS on univariate analysis was induction chemotherapy response (p = 0.007). Multivariate analysis revealed that induction chemotherapy response is the only factor that remains significant for DFS (p = 0.032) as well as for OS (p = 0.017). Patients with complete response to induction therapy had 40% probability of survival versus all other patients who had 10% survival (p = 0.05).. Consolidative radiotherapy is feasible in primary metastatic or recurrent pediatric sarcoma patients treated with myeloablative therapy with or without TBI. CRT to sites amenable to irradiation provided an improved 3-year actuarial local control than that seen in sites amenable to CRT that did not undergo radiotherapy. There was a trend for improved DFS with the use of TBI. Improved DFS and OS can be predicted by response to induction therapy. This intensive regimen may improve the cure rate of advanced pediatric sarcomas in select patients.

Topics: Adolescent; Adult; Analysis of Variance; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Neoplasms; Bone Neoplasms; Child; Cyclophosphamide; Dactinomycin; Feasibility Studies; Female; Hematopoietic Stem Cell Transplantation; Humans; Ifosfamide; Lung Neoplasms; Male; Mesna; Neoplasm Recurrence, Local; Prognosis; Prospective Studies; Radiotherapy Dosage; Retrospective Studies; Salvage Therapy; Sarcoma; Treatment Failure; Vincristine; Whole-Body Irradiation

A small but not insignificant number of patients experience a prolonged survival after treatment of metastatic soft tissue sarcoma. This must be weighed against the majority of the patients who benefit little from the therapy, but nevertheless experience its side-effects. It would therefore be of utmost importance to be able to screen for those patients who respond to the treatment. Since proliferating cells are more sensitive to chemotherapy than non-proliferative cells, we measured the proliferation rate of the primary tumour of 55 soft tissue sarcoma patients with locally advanced or metastatic disease by determining the flow cytometric S phase fraction and immunohistochemical Ki-67 and cyclin A scores. S phase fraction or Ki-67 score did not predict chemotherapy response or progression-free survival. A high cyclin A score, however, correlated with a better chemotherapy response (P = 0.02) and longer progression-free survival time (P = 0.04). Our results suggest that a high cyclin A score predicts chemotherapy sensitivity.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Cell Division; Cyclin A; Dacarbazine; Disease Progression; Doxorubicin; Female; Humans; Ifosfamide; Male; Mesna; Middle Aged; Prognosis; Prospective Studies; Sarcoma; Soft Tissue Neoplasms; Survival Analysis; Vincristine

From January 1990 to December 1995 we treated 35 patients (pts) with bone and soft tissue sarcoma with ifosfamide (IFM). Sixteen patients had measurable metastatic pulmonary lesion and 9 had primary lesion. Histology of the tumor included osteosarcoma in 13 pts, Ewing sarcoma in 5 pts, malignant fibrous histiocytoma of bone in 2 pts, synovial sarcoma in 7pts, primitive neuroectodermal tumor in 2 pts, and other in 7 pts. The IFM at the dose of 12-18g/m2 (mean 15. 4g/m2) for 5 to 8 days continuous infusion was administered to patients in each treatment course. The uroprotector, mesna, was also given concomitantly in 60-100% dose of IFM. Eighteen pts received one course of IFM treatment. Other pts received 2 to 8 courses of IFM treatment at three to four week intervals. The overall response rate was 40% (PR in 14 pts, NC in 18 pts, and PD in 3 pts). The response rate of 13 pts with osteosarcoma was 54% (PR in 7 pts) and 30% in 15 pts with soft tissue sarcoma (PR in 5 pts).

Topics: Adolescent; Adult; Antineoplastic Agents, Alkylating; Bone Neoplasms; Child; Drug Administration Schedule; Female; Histiocytoma, Benign Fibrous; Humans; Ifosfamide; Lung Neoplasms; Male; Mesna; Middle Aged; Osteosarcoma; Sarcoma; Sarcoma, Ewing; Soft Tissue Neoplasms

The objective of this study was to determine the tolerance and toxicities of high-dose cyclophosphamide (CPA) at 7 g/m2 given in four fractions over 8 h in children with advanced solid tumors.. Twenty children aged 1 1/2-19 years (median, 12 years) received 24 courses of high-dose CPA at 7 g/m2 for the treatment of advanced malignant solid tumor. CPA was given in four 1-h infusions of 1.75 g/m2 each, with 1 h of rest between each dose. MESNA was used as a uroprotective agent and was continued for 24 h after the final dose of CPA. With only one exception, all patients were discharged at the end of MESNA infusion and received granulocyte colony-stimulating factor, prophylactic ciprofloxacin, and co-trimoxazole.. Severe but transient myelosuppression was observed. The median time to neutrophil and platelet recovery was 17 and 19 days, respectively. Fever developed after 13 of the 24 courses, and hospitalization was required. Extramedullary toxicities were mild. No patient showed cardiomyopathy or hemorrhagic cystitis. Forty-six percent of the courses were managed entirely on an outpatient basis. Objective tumor response was seen in five patients.. CPA at 7 g/m2 is well tolerated by children with advanced malignancies and should be considered in earlier phases of antineoplastic therapy.

Topics: Adolescent; Antineoplastic Agents, Alkylating; Child; Child, Preschool; Cyclophosphamide; Drug Administration Schedule; Feasibility Studies; Female; Granulocyte Colony-Stimulating Factor; Humans; Infant; Male; Mesna; Neoplasms; Neuroblastoma; Osteosarcoma; Sarcoma; Sarcoma, Ewing; Treatment Outcome

Twenty patients with advanced sarcomas entered a pilot study with ifosfamide (IF) and mercaptoethane sulfonate sodium (Mesna) as a second-line treatment for six planned cycles. All patients had received prior doxorubicin- and cyclophosphamide-based chemotherapies. IF was administered at a dose of 3 g/m2 given as continuous intravenous infusion for 24 hr on day 1-5 with Mesna. In the absence of disease progression, chemotherapy was planned to be repeated every 4 weeks for six consecutive cycles. Following chemotherapy, only 2 patients (11%) achieved partial response with response durations of 6 and 9 months. There was no complete response. When considered for only high-grade tumors, the response rate reached up to 22%. Toxicity was reported for 48 cycles and the dose-limiting toxicities were myelosuppression (22%) and encephalopathy (17%). Chemotherapy protocol was changed after two or three courses in 16 patients with stable or progressive disease. IF/Mesna chemotherapy at this dose and schedule was not found to be very promising in refractory sarcomas as a second-line chemotherapy.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Blood Cell Count; Doxorubicin; Female; Humans; Ifosfamide; Male; Mesna; Middle Aged; Pilot Projects; Sarcoma

Four patients with metastatic ovarian mixed Müllerian sarcoma (2 homologous, 2 heterologous) were treated with mesna, doxorubicin, ifosfamide, and dacarbazine (MAID) chemotherapy. Two of four patients had optimal debulking. Three of four patients responded to chemotherapy, with two complete responses of 34- and 46-month duration. The MAID regimen appears to be active in patients with ovarian sarcoma.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; CA-125 Antigen; Combined Modality Therapy; Dacarbazine; Doxorubicin; Female; Humans; Ifosfamide; Mesna; Middle Aged; Mixed Tumor, Mullerian; Ovarian Neoplasms; Sarcoma; Treatment Outcome

The objective of this prospective study was to evaluate the mortality and morbidity of sarcoma pulmonary metastasis resection with continuous chemotherapy. Ifosfamide was administered at the daily dose of 1200 mg/m2/24 h. Twenty-six resections of pulmonary sarcoma were performed from December 1990 to April 1992. The primary lesion was already resected in all patients. Peri-operatory chemotherapy was started 30 minutes before surgery and continued for 6 days. Chemotherapy was associated with an uroprotector, antiemetic drugs and adequate hydration. Patients had a mean age of 30.6 years. The delay between initial and thoracic surgery was 81 months. The following was performed: tumorectomy (32), wedge (18), lobectomy (7), diaphragm resection (1), left pneumectomy (1). All patients had the 6-days chemotherapy course. None of the patients died. Respiratory failure following superinfection, but not necessitating assisted ventilation, was observed in one case. The following adverse events were noted: nausea (34.6%), uncomplicated cystitis (15.4%), leucopenia (7.6%), fever (3.8%). Mean duration of hospitalization was 11.8 days. Chemotherapy adverse effects did not result in significant morbidity. Bronchial fistula was not observed. Following the results of this pilot study, we feel that perioperatory chemotherapy can be added to sarcoma pulmonary metastasis resection surgery without increasing patient morbidity and mortality.

Topics: Adult; Combined Modality Therapy; Female; Humans; Ifosfamide; Infusions, Intravenous; Intraoperative Period; Lung Neoplasms; Male; Mesna; Ondansetron; Prospective Studies; Sarcoma; Survival Analysis

The sulfhydryl status of cells, particularly the intracellular concentration of glutathione, is a critical determinant of the response of tumor and normal cells to cytostatic drugs. Recent data indicate that the administration of mercaptoethane sulfonate (mesna), which is often combined with ifosfamide, markedly decreases the circulating concentration of total cysteine and could thereby influence the response of the organism to the cytotoxic effects of chemotherapy. The aim of the present study was to assess the effects of the combination of ifosfamide/mesna on sulfhydryl and disulfide homeostasis in tumor patients. Ifosfamide was infused into 14 patients with advanced sarcoma for 5 days at a dose of 2.4-3.2 g/m2 per day together with mesna. The plasma concentrations of total mesna, cysteine, glutathione, and homocysteine were measured before and on days 1 and 6 of the first course of ifosfamide/mesna therapy and prior to the next course of chemotherapy, and the urinary excretion of cysteine and mesna was monitored daily using a high-performance liquid chromatography (HPLC) method. Ifosfamide/mesna resulted in a marked depletion of circulating total cysteine, i.e., cysteine, cystine, and cysteine mixed disulfides [from 245 +/- 36 to 50 +/- 14 nmol/ml (mean +/- 95% CI) on day 6], total glutathione (from 6.9 +/- 1.1 to 2.5 +/- 1.1 nmol/ml), and total homocysteine (from 12.3 +/- 2.1 to 1.4 +/- 1.1 nmol/ml). The values returned to baseline levels prior to the next course of chemotherapy. The urinary excretion of cysteine increased significantly from 0.28 to 1.82 mmol/day on the 1st day, whereupon it returned toward baseline. An average of 62% +/- 6% of the delivered dose of mesna was recovered in urine. The combination of ifosfamide/mesna results in depletion of circulating total cysteine, glutathione, and homocysteine. This marked derangement of sulfhydryl and disulfide homeostasis could modulate the efficacy and toxicity of ifosfamide/mesna therapy.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chromatography, High Pressure Liquid; Cysteine; Female; Glutathione; Homeostasis; Homocysteine; Humans; Ifosfamide; Infusions, Intravenous; Male; Mesna; Middle Aged; Sarcoma

Two trials using ifosfamide-based combination chemotherapy for advanced soft-tissue sarcoma have been completed. In the first study, 50 evaluable patients received ifosfamide (5 g/m2) with mesna (5 g/m2) and doxorubicin (40 or 60 mg/m2) intravenously (i.v.) every 3 weeks. In all, 11 patients (22%) achieved an objective response [3 complete responses (CRs) and 8 partial responses (PRs)]. Toxicities included leukopenia, febrile neutropenia, nausea and vomiting, and alopecia. The overall median survival was 12 months. In the second study, 51 evaluable patients received ifosfamide (3 g/m2) with mesna (3 g/m2), both being given i.v. on day 1, together with etoposide (100 mg/m2) infused i.v. daily for 3 days. Six patients (12%) achieved objective responses (1 CR, 5 PRs). Toxicities included leukopenia, nausea and vomiting, and alopecia. The overall median survival was 7.4 months. Neither of these combination regimens appears to be more effective in advanced soft-tissue sarcoma than single-agent therapy with either ifosfamide or doxorubicin. If the results of chemotherapy in the management of these tumors are to be improved a new approach to therapy is clearly required.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Doxorubicin; Etoposide; Female; Humans; Ifosfamide; Male; Mesna; Middle Aged; Sarcoma; Soft Tissue Neoplasms; Treatment Outcome; Urologic Diseases

The response of ifosfamide-based chemotherapeutic regimens was retrospectively analyzed in adult patients with advanced soft-tissue sarcoma who were treated at the West German Tumor Center, Essen, between 1978 and 1990. Single-agent ifosfamide was given either in split doses of 60-80 mg/kg by 4-h infusion over 5 days or as a continuous 24-h infusion of 5 g/m2. Ifosfamide was given either in split doses of 40-50 mg/kg over 5 days or as a continuous infusion of 5 g/m2 in combination with doxorubicin (40-60 mg/m2, day 1), cisplatin (20 mg/m2, days 1-5), or etoposide (100 mg/m2, days 1, 3, and 5). Mesna was given to all patients as prophylaxis against urotoxicity. Of 54 evaluable patients receiving single-agent ifosfamide, 5 achieved a complete response (CR) and 10 showed a partial response (PR), for an overall response rate of 28%. Objective responses were more frequent in previously untreated patients (47%) than in pretreated patients (15%; P < 0.01). The addition of doxorubicin (n = 41) or cisplatin (n = 29) to ifosfamide did not significantly increase the response rate (29% and 41%, respectively) or median duration of remission as compared with ifosfamide alone. In addition, no significant difference was observed between the two ifosfamide regimens used: the 24-h continuous-infusion schedule (5 g/m2 per course, 27% response rate) and the 5-day fractionated regimen (10-15 g/m2 per course, 19% response rate). We conclude that the response and the median duration of remission produced by single-agent ifosfamide compare favorably with the results achieved using single-agent doxorubicin and the usually more toxic combination regimens.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Doxorubicin; Drug Administration Schedule; Etoposide; Female; Humans; Ifosfamide; Infusions, Intravenous; Male; Mesna; Middle Aged; Retrospective Studies; Sarcoma; Soft Tissue Neoplasms; Treatment Outcome; Urologic Diseases

The mesna, doxorubicin, ifosfamide, dacarbazine regimen produced a 47% response rate (including 10% complete responses) in 105 eligible adults with advanced sarcoma. The major dose-limiting toxicity was granulocytopenia. There was one toxic death from sepsis. Central nervous system and renal toxicity occurred infrequently, perhaps as a result of the continuous-infusion schedule. This regimen is being evaluated further in advanced disease, the adjuvant setting, and in combination with bone marrow colony-stimulating factors.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Combined Modality Therapy; Dacarbazine; Doxorubicin; Drug Evaluation; Female; Humans; Ifosfamide; Lung Neoplasms; Male; Mesna; Middle Aged; Remission Induction; Sarcoma; Survival Rate

Ifosfamide and cyclophosphamide have many toxicities in common. Interstitial pneumonitis has not been reported previously as a side effect of ifosfamide therapy. The authors report the case of a 58-year-old woman who was treated with ifosfamide for soft tissue sarcoma. After the fifth cycle of chemotherapy she developed clinical evidence of interstitial pneumonitis, a diagnosis that was later confirmed at autopsy. The authors suggest that ifosfamide therapy was directly related to this patient's fatal case of interstitial pneumonitis.

Topics: Antineoplastic Combined Chemotherapy Protocols; Dacarbazine; Doxorubicin; Female; Humans; Ifosfamide; Lung Neoplasms; Mesna; Middle Aged; Pulmonary Fibrosis; Sarcoma

Starting in July 1985, the Gynecologic Oncology Group conducted a series of phase II trials with ifosfamide/mesna in advanced or recurrent gynecologic malignancies. Previously untreated patients received 1.5 g/m2 i.v. ifosfamide daily for 5 days. Mesna was given i.v. q4h x 3 following ifosfamide; each dose was 20% of the daily ifosfamide dose. All patients with ovarian and 87% of those with cervical cancer had previously undergone platinum-based therapy. Because of the toxicity encountered in previously treated patients with ovarian carcinoma, the dose of ifosfamide was reduced to 1.2 g/m2 daily in all patients who had received prior chemo- or radiotherapy. In epithelial ovarian carcinoma, responses were observed in 8 (20.0%) of 41 evaluable patients, with 3 (7.0%) complete responses. Response duration was 2.1-20.3+ months, with a median of 6.9+ months. In squamous-cell carcinoma of the cervix, 3 (11.1%) of 27 evaluable patients showed partial responses of 1.8, 2.2, and 3.1 months' duration. Of 26 untreated patients with mixed mesodermal tumors of the uterus, 5 (19.2%) achieved complete and 3 (11.5%) showed partial responses, for an overall response rate of 30.7%. Response duration was 1.4(+)-8.6 months, with a median of 3.8 months. Toxicity included two deaths due to renal insufficiency and a third related to neurologic impairment. Hematologic toxicity was manageable. Ifosfamide/mesna has activity in a wide range of gynecologic malignancies.

Topics: Antineoplastic Agents; Carcinoma; Drug Evaluation; Female; Humans; Ifosfamide; Mercaptoethanol; Mesna; Middle Aged; Ovarian Neoplasms; Sarcoma; Uterine Cervical Neoplasms

From July 1986 to July 1989, 40 patients (92% pretreated) with deep-seated, advanced soft tissue sarcomas (STS, 25 patients), Ewing's sarcomas (ES, eight patients), osteosarcomas (OS, three patients) and chondrosarcomas (ChS, four patients) were treated at the University of Munich in a protocol involving regional hyperthermia (RHT) combined with ifosfamide plus etoposide. A total of 265 RHT treatments (mean, 6.6 RHT per patient) were applied including 33 pelvic, four extremity, and three abdominal sites. The mean tumor volume was 537 cc (range, 50 to 2,980 cc). For systemic chemotherapy, all patients received ifosfamide (1.5 g/m2, days 1 to 5), etoposide (100 mg/m2, days 1, 3, and 5), and mesna (300 mg/m2 x 4, days 1 to 5) with RHT given only on days 1 and 5 in repeated cycles every 4 weeks. Acute toxicity consisted primarily of pain (57%) combined with local discomfort within the annular phased array applicator (AA) of the BSD hyperthermia system (BSD Medical Corp, Salt Lake City, UT). The average maximum systemic temperature was 37.4 +/- 0.5 degrees C, and there was no indication of enhanced bone marrow toxicity due to the addition of RHT to the systemic chemotherapy. Detailed thermal mapping by invasive thermometry was performed in all patients. In 38 assessable patients, the overall objective response rate was 37%: six complete responses (CRs), four partial responses (PRs), and four favorable histologic responses (FHRs) (95% confidence limits, 22% to 54%). Complete responders are alive and disease-free at 40, 35, 23, 19, 19, and 8 months. Of patients with PR and FHR, two died from metastatic disease after 4 and 17 months and one died from other disease after 27 months. The remaining five patients are stable at 37, 25, 21, 13, and 8 months. Eleven patients showed no change (NC), and 13 patients showed local tumor progression (PD). The mean observation time for all patients was 11.6 months. The time-averaged temperatures (Ts) of all RHT treatments calculated as 20% (T20), 50% (T50), or 90% (T90) of measured tumor sites differed significantly between responders and nonresponders (T20, P = .003; T50, P = .006; and T90, P = .004; respectively). These data support activity for ifosfamide-etoposide combined with RHT in pretreated patients with advanced sarcomas.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Combined Modality Therapy; Drug Evaluation; Etoposide; Female; Humans; Hyperthermia, Induced; Ifosfamide; Male; Mesna; Middle Aged; Regression Analysis; Sarcoma; Soft Tissue Neoplasms

The oxazaphosphorine prodrug Ifosfamide (IFO) in conjunction with the uroprotective agent Mesna is becoming a standard alkylating agent. It has an increased therapeutic index when given as a fractionated dosage over 3-5 days. Maximal fractionation is achieved by continuous infusion over several days and has been shown to be less emetic and neurotoxic than regimens with bolus infusions. We have studied in patients with advanced cancer the feasibility and bioavailability of a subcutaneously administered isotonic and neutral (pH 7) IFO solution given continuously over 10 h for up to 5 days. A portable disposable gas-driven infusor syringe was used. Our results show 90-100% bioavailability of sc administered IFO. The isotonic solution of IFO (pH 7) showed no significant local toxicity during or after sc administration. Haematotoxicity was equal for sc and iv application. No uro- or neurotoxicity has been observed in 24 sc cycles. We conclude that this novel continuous sc IFO infusion over several days is a rational, well-tolerated and economical way of delivering this drug on an outpatient basis.

Topics: Aged; Ambulatory Care; Antineoplastic Combined Chemotherapy Protocols; Biological Availability; Drug Administration Schedule; Feasibility Studies; Female; Humans; Hydrogen-Ion Concentration; Ifosfamide; Infusion Pumps, Implantable; Infusions, Intravenous; Injections, Subcutaneous; Male; Mesna; Middle Aged; Pancreatic Neoplasms; Sarcoma; Soft Tissue Neoplasms

Between 1982 and 1986, 38 patients with soft tissue sarcomas were treated with a combination of ADM/DTIC (group A), another 45 (group B) received ADM/IFO between 1986 and 1990. Clinical characteristics were comparable in both groups. Remission rate was 34% in group A and 43% in group B. Duration of remission was 10 months and median survival 13 months in both groups. Toxicity, especially myelotoxicity, was severe without marked differences between both groups. We conclude that adriamycin/DTIC and adriamycin/ifosfamide are both active regimens in metastatic soft tissue sarcomas, nevertheless, overall prognosis remains poor.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Dacarbazine; Dose-Response Relationship, Drug; Doxorubicin; Female; Follow-Up Studies; Humans; Ifosfamide; Male; Mesna; Middle Aged; Neoplasm Metastasis; Retrospective Studies; Sarcoma; Soft Tissue Neoplasms; Survival Rate

The objective of this phase II trial was to assess the therapeutic activity and toxicity of doxorubicin plus ifosfamide in previously untreated patients with advanced soft tissue sarcoma. Treatment was doxorubicin 50 mg/m2 followed by a 24 h infusion of ifosfamide 5 g/m2 plus mesna 2.5 g/m2 repeated every 3 weeks until disease progression or unacceptable toxicity occurred. Of 203 patients entered, 175 were evaluable for response. The response rate was 35% (95% CI 28-42%), with 9% of the patients achieving a complete remission and 26% a partial remission. The median time to progression was 29 weeks for all evaluable patients, and 67, 40 and 28 weeks for complete and partial responders and patients with stable disease, respectively. The median duration of survival was 58 weeks. Myelosuppression was the dose-limiting toxicity, resulting in leukopenia (WHO grade 3 and 4) in 73% of evaluable treatment courses. Other side-effects were rare and usually well manageable.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Doxorubicin; Drug Evaluation; Female; Humans; Ifosfamide; Leukopenia; Male; Mesna; Middle Aged; Sarcoma; Soft Tissue Neoplasms; Thrombocytopenia

A phase-II study of ifosfamide with mesna, given intravenously daily for five days by bolus injection, has demonstrated the activity of ifosfamide against a spectrum of childhood malignant solid tumors. Ifosfamide presently is being investigated in alternative phase-I schedules, daily times three or every other day times three with the aim of delivering comparable amounts of ifosfamide without increasing toxicity--specifically, neurotoxicity. Additionally, response following ifosfamide treatment is being evaluated for previously untreated children with osteosarcoma and rhabdomyosarcoma after 6 weeks of treatment, and for previously untreated patients with Ewing's sarcoma after 9 weeks of treatment with ifosfamide/VP-16 (etoposide) given in combination.

Topics: Adolescent; Child; Child, Preschool; Drug Evaluation; Humans; Ifosfamide; Infant; Mercaptoethanol; Mesna; Neoplasms; Remission Induction; Sarcoma

Topics: Drug Administration Schedule; Humans; Ifosfamide; Infusions, Intravenous; Injections, Intravenous; Mercaptoethanol; Mesna; Sarcoma; Soft Tissue Neoplasms

Between April 1987 and July 1988, 44 adults with histologically proven, objectively assessable advanced nonosseous sarcomas were treated with 2.5 g of ifosfamide/m2, 100 mg of etoposide/m2, and 2.5 g of mesna/m2 (500 mg/m2 X 5) daily for 3 consecutive days every 4 weeks. This regimen was generally well tolerated as outpatient treatment. Because of the potential CNS effects of ifosfamide, we recommended that elderly patients, persons receiving high doses of opiates, and patients susceptible to the syndrome of vertigo, perspiration, and hypotension (without tachycardia) be hospitalized for treatment. At initial treatment, leukocyte count nadirs were less than 1,000/microL and platelet count nadirs were less than 100,000/microL in 38% and 15%, respectively, of the 39 patients for whom such data were available. Objective tumor regression occurred in approximately 16% (95% confidence interval, 7%-30%) of the 44 patients (six, partial responses; one, complete response). For the 44 patients, median time to disease progression was 2.3 months; median time to death was 9.4 months. While this regimen was effective in three of 20 patients who had been previously treated with a doxorubicin-based regimen, only one of the 12 patients whose tumors had been primarily refractory to the doxorubicin-based regimen experienced objective tumor regression on our ifosfamide-based regimen.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Drug Evaluation; Etoposide; Female; Humans; Ifosfamide; Male; Mesna; Middle Aged; Remission Induction; Sarcoma

In a phase II study, 16 adult patients with locally advanced or metastatic soft tissue sarcomas were treated with i.v. infusions of ifosfamide/mesna 5 g/m2 plus i.v. doxorubicin 40 mg/m2. Courses were given every 3 weeks up to a maximum of six courses in responding patients. Six patients (37.5%) had either complete (1 patient) or partial responses (5 patients). Confidence limits for this response rate were 15.2%-64.5% (95% confidence level). There was one toxic death in association with encephalopathy, renal and bone marrow failure. Unilateral pneumothoraces occurred in 2 patients with large pulmonary metastases. Recurrent severe ifosfamide/mesna encephalopathy occurred in 2 patients at risk for this complication; patients who develop severe ifosfamide/mesna encephalopathy should not be retreated with this drug. Ifosfamide/mesna with doxorubicin is an active combination to treat adult soft tissue sarcoma but, despite the feasibility of the combination, sequential monotherapy with these drugs might provide similar or better clinical benefit.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Brain; Doxorubicin; Drug Evaluation; Female; Humans; Ifosfamide; Male; Mercaptoethanol; Mesna; Middle Aged; Sarcoma; Soft Tissue Neoplasms

Mesna is a sulfhydryl compound that reacts with the metabolites of cyclophosphamide that are excreted in the urine and may produce bladder wall irritation. Mesna is converted in the blood to a biochemically inactive compound that is reduced back to mesna in the kidneys. In this way it has the potential to protect the bladder mucosa without interfering with the antineoplastic effect of cyclophosphamide. Twenty-two patients who had developed hemorrhagic cystitis from cyclophosphamide were treated again with cyclophosphamide and mesna prophylaxis. A total of 68 cycles of cyclophosphamide were given with mesna, with a median of three cycles per patient. A recurrence of cystitis was prevented in all but one patient. Thus, mesna is effective in preventing recurrent cystitis in patients receiving further cyclophosphamide.

Topics: Adolescent; Adult; Child; Cyclophosphamide; Cystitis; Cystoscopy; Female; Hematuria; Humans; Male; Mercaptoethanol; Mesna; Prospective Studies; Rhabdomyosarcoma; Sarcoma

One hundred twenty-four children and young adults with recurrent tumors, predominantly sarcomas, were treated with the combination of ifosfamide, etoposide, and the uroprotector, mesna (2-mercaptoethane sulphonate), in a phase II trial. The treatment regimen consisted of 12 cycles of therapy administered every 3 weeks. After evaluation of the tumor response to chemotherapy alone, radiation or surgery was used to eradicate residual sites of metastatic disease where possible. At the present time, 77 patients are evaluable for response to the chemotherapy; 43 of the patients have experienced a significant reduction in the tumor size in response to the chemotherapy alone (39 partial responses [PR] and four complete responses [CR]). Sixteen of 17 patients with Ewing's sarcoma, nine of 13 with rhabdomyosarcoma, four of eight with peripheral neuroepithelioma, three of eight with osteosarcoma, and 11 of 31 with other tumors have responded with a PR or CR. The toxicity of the regimen was acceptable. Moderate or severe toxicity evaluated on a per cycle basis included: neutropenia, 97%; thrombocytopenia, 32%; nephrotoxicity, less than 1%; mucositis, 1%; neurologic toxicity, 2%; nausea and vomiting, 13%; hemorrhagic cystitis, less than 1%. Fever was present after 33% of cycles and sepsis following 7%. One patient died due to sepsis and pancytopenia. At the present time, only seven of the 43 patients who responded to the chemotherapy regimen have relapsed, with a median follow-up of 10 weeks after the response. This drug combination is highly active in the treatment of recurrent sarcomas and other tumors in children and young adults.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Diseases; Child; Combined Modality Therapy; Cystitis; Drug Evaluation; Etoposide; Humans; Ifosfamide; Mesna; Neoplasm Recurrence, Local; Sarcoma

Early results with ifosfamide plus mesna in soft tissue sarcoma showed an initial response rate of 38% in 42 patients. All these patients treated at The Royal Marsden Hospital plus 30 more (total 67) have now been analysed. Single doses of 5 or 8 g/m2 ifosfamide were given over 24 h by infusion in dextrose saline together with 400 mg/m2 or 600 mg/m2, respectively, of mesnum every 4 h to give a total of 9 doses. A diuresis of 200 ml/hour was maintained during therapy. Treatment was repeated 3-weekly. CR was seen in 6 and PR in 10 patients. More recently doxorubicin was added to ifosfamide therapy in an attempt to improve on these results. At first only 20 mg/m2 doxorubicin was given but this was escalated to 40 mg/m2 and 60 mg/m2. Mesna has been given in higher dosage (5 g/m2 over 24 h), but otherwise the schedule is as above. In all 60 patients have been treated and most are now evaluable for response. Encephalopathy has been seen with both regimens. The incidence and patient characteristics are reported.

Topics: Adolescent; Adult; Aged; Alopecia; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Doxorubicin; Female; Humans; Ifosfamide; Kidney Diseases; Leukopenia; Male; Mesna; Middle Aged; Nausea; Sarcoma; Soft Tissue Neoplasms; Vomiting

Topics: Brain Diseases; Carcinoma, Small Cell; Cyclophosphamide; Female; Humans; Ifosfamide; Lung Neoplasms; Male; Mercaptoethanol; Mesna; Middle Aged; Sarcoma

Ifosfamide given to 42 patients iv at 2-2.5 g/m2/day X 4 resulted in partial responses in ten of 28 (36%) evaluable patients with adult soft tissue sarcomas, including two of two with chondrosarcoma; none of nine with pediatric sarcomas (Ewing's sarcoma, osteogenic sarcoma, or rhabdomyosarcoma) achieved partial response. All of the pediatric patients had failed to respond to complicated three- to six-drug regimens of up to 18 months in duration. The response rates in patients with and without prior cyclophosphamide (32%; seven responses among 22 patients; and 20%, three responses among 15 patients) were not significantly different, supporting in vitro evidence of a lack of cross-resistance between the two related compounds. Myelosuppression was dose-limiting. Hemorrhagic cystitis was not observed in patients treated with 400-500 mg of mesna iv every 4 hours during ifosfamide treatment. Nausea and vomiting were generally mild or moderate. Alopecia was universal but reversible. Of the first 11 patients, five became somnolent or developed visual hallucinations (during six of the 12 total courses administered to the five patients). Only one patient had two episodes of neurotoxicity. After reduction of the use of iv antiemetics and major narcotics, single episodes of neurotoxicity were seen in five of the next 27 patients. An asymptomatic acidosis developed in most patients, requiring bicarbonate replacement in one. Ifosfamide appears to be active in previously treated patients with sarcomas and should be evaluated in patients with less extensive prior treatment.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Cystitis; Drug Evaluation; Female; Humans; Ifosfamide; Male; Mesna; Middle Aged; Sarcoma; Soft Tissue Neoplasms

Topics: Adolescent; Adult; Aged; Cyclophosphamide; Female; Humans; Ifosfamide; Male; Mercaptoethanol; Mesna; Middle Aged; Sarcoma; Soft Tissue Neoplasms

In a phase II study, 42 patients with advanced soft-tissue sarcoma were treated with ifosfamide by 24-h infusion and mesna by 4-h IV bolus, repeated every 3 weeks. Ten patients received ifosfamide 5.0 g/m2, 20 had the dosage increased to 8.0 g/m2, and 12 received 8.0 g/m2 from the outset. Mesna was given in doses of 400 mg/m2 or 600 mg/m2. Of 40 patients evaluable for response, six (15%) achieved complete response and nine (23%) partial response. The overall response rate was 38%. The median duration of response was 11 months. Treatment was associated with falls in peripheral WBC and alopecia in all patients. Most experienced severe nausea and vomiting. In seven nephrotoxicity developed, and two of these died of renal failure. Renal tubular defects and cerebral effects also occurred. Mesna largely prevented haemorrhagic cystitis. Ifosfamide offers a new alternative to previous chemotherapy for advanced soft-tissue sarcoma, but alterations in dose or method will be necessary to reduce toxicity.

Topics: Adolescent; Adult; Aged; Cyclophosphamide; Drug Evaluation; Drug Therapy, Combination; Female; Humans; Ifosfamide; Kidney; Male; Mercaptoethanol; Mesna; Middle Aged; Sarcoma; Soft Tissue Neoplasms