mesna and Soft-Tissue-Neoplasms

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

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

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

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

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

Topics: Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Cyclophosphamide; Dactinomycin; Disease-Free Survival; Doxorubicin; Etoposide; Female; Fibrosarcoma; Humans; Ifosfamide; Infant; Infant, Newborn; Male; Mesna; Soft Tissue Neoplasms; Vincristine

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

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

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

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Child; Cisplatin; Cystitis; Hemorrhage; Humans; Ifosfamide; Mesna; Methotrexate; Middle Aged; Soft Tissue Neoplasms

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

We undertook this phase II study to evaluate the efficacy and toxicity of epidoxorubicin and ifosfamide in the treatment of locally advanced and/or metastatic soft-tissue sarcomas. We used escalating doses of epidoxorubicin (from 60 to 75 mg/m2) on day 1 and 1.2 g/m2 ifosfamide on days 1-5. Chemotherapy courses were repeated every 3-4 weeks. A total of 16 patients--13 who had not previously been treated and 3 who had undergone prior therapy with anthracyclines--entered the study. In all, 15 patients were evaluable for response and 16, for toxicity. At least two courses of chemotherapy were given. A complete remission (CR) was seen in 1 patient, a partial remission (PR) in 5, and a minor response (MR) in 1, for an objective response rate (CR + PR) of 40% (6/15); this value reached 50% in non-pretreated patients (6/12). Stable disease (SD) was observed in 40% (6/15) of patients. The relative dose intensity of epidoxorubicin ranged from 10 to 23.3 mg/m2 (median, 16.6 mg/m2). The time to objective response ranged from 4 to 12 weeks (median, 8.5 weeks). The duration of response was 4 months for the single CR, and that for the five PRs was 6+ months (range, 4-18 months). Toxicity was evaluated according to WHO criteria in 16 patients; it was mild and consisted mainly of alopecia, nausea and vomiting, and leucopenia. In only three patients did we observe grade 3 leucopenia. In one case an ifosfamide-associated encephalopathy occurred, but it regressed after 24 h. Neither chronic nor acute cardiac toxicity was reported. In this preliminary analysis, the response rate obtained with the combination of epidoxorubicin and ifosfamide was encouraging and the toxicity was acceptable.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Dose-Response Relationship, Drug; Doxorubicin; Drug Evaluation; Epirubicin; Humans; Ifosfamide; Mesna; Methylprednisolone; Metoclopramide; Middle Aged; Soft Tissue Neoplasms; Time Factors

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

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

Myxoinflammatory fibroblastic sarcoma is a soft-tissue neoplasm most frequently found in the distal extremities of middle-aged adults. Most myxoinflammatory fibroblastic sarcoma are low-grade tumors with propensity for local recurrence after incomplete removal. We report a myxoinflammatory fibroblastic sarcoma which developed in the foot of a 41-year-old male and showed an exceptionally aggressive course with metastatic spread and fatal outcome within 16 months. We managed to establish a spontaneously transformed continuous cell line, called JU-PI, from a metastatic lesion. The JU-PI cells have a sub-tetraploid karyotype including the 1;10 chromosomal translocation and amplification of the proximal end of 3p; these features are considered genetic signatures of myxoinflammatory fibroblastic sarcoma. Both the primary tumor and the JU-PI cells showed nuclear expression of the TFE3 transcription factor but TFE3-activating chromosomal rearrangements were not found. To our knowledge, JU-PI is the first established myxoinflammatory fibroblastic sarcoma cell line. JU-PI cells offer a tool for investigating the molecular oncology of myxoinflammatory fibroblastic sarcoma.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Transformed; Cell Proliferation; Dacarbazine; Doxorubicin; Fibrosarcoma; Humans; Ifosfamide; Karyotype; Male; Mesna; Neoplasm Recurrence, Local; Primary Cell Culture; Soft Tissue Neoplasms; Translocation, Genetic; Vincristine

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

The role of adjuvant chemotherapy (AC) in treatment of synovial sarcoma remains controversial. Aim of our study is to investigate the influence of AC on disease-specific survival and metastasis free survival, the difference in time to metastasis (TTM) was also analyzed.. Seventy-six cases of stage IIB/III synovial sarcoma from January 1993 to December 2008 were retrospectively analyzed. All the 76 patients were treated with surgical resection. AC regimen included first line MAID or AIM, second line Gemcitabine + Docetaxel with sufficient dose intensity. The clinical, pathologic, and treatment variables were analyzed for disease specific survival (DSS), metastasis free survival (MFS) and TTM.. Median follow up period was 68 months. 51 patients received AC (51/76, 67%), 25 received no adjuvant chemotherapy (NAC, 25/76, 33%). The 5-year DSS of the AC patients was 73%(58-87%) compared with 31%(19-52%) for the NAC patients (P = 0.001). AC was also independently associated with improved MFS (P = 0.008) and prolonged TTM (P = 0.001).. Patients with stage IIB/III synovial sarcoma might benefit in DSS, MFS, and a prolonged TTM from AC.

Topics: Adult; Analysis of Variance; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Dacarbazine; Deoxycytidine; Disease-Free Survival; Docetaxel; Doxorubicin; Drug Administration Schedule; Extremities; Female; Gemcitabine; Humans; Ifosfamide; Kaplan-Meier Estimate; Male; Mesna; Middle Aged; Neoplasm Grading; Neoplasm Recurrence, Local; Neoplasm Staging; Radiotherapy, Adjuvant; Remission Induction; Sarcoma, Synovial; Soft Tissue Neoplasms; Taxoids

To analyze the clinical features, treatment and prognosis of Stage IV alveolar soft part sarcoma.. To analyze the clinical and pathological features, therapeutic methods and follow-up results in 21 patients with stage IV alveolar soft part sarcoma. There were 11 males and 10 females, in the age of 26-57 years (average 37.0 years old). All the 21 patients had metastasis: nine cases had multiple pulmonary metastasis, three cases had multiple pulmonary and brain metastasis, two cases had multiple brain metastasis, two cases had multiple pulmonary and bone metastasis, two cases had single pulmonary metastasis, one case had single bone metastasis, one case had single brain metastasis and one case had single soft tissue metastasis. Eight patients were treated by surgical operation, including five cases of complete resection for the primary and (or) metastatic tumor and 3 cases of palliative operation for the primary tumor. All patients received chemotherapy, including seven cases of CAVD regimen and 14 cases of MAID regimen treatment. One patient with single bone metastasis and five patients with multiple brain metastasis received post-operative whole brain radiation therapy.. All the eight patients with surgical operation had healing by first intention, and pathological examination showed that seven patients achieved R0 surgical margin and one case with R2 status. One patient with single brain metastasis had recurrence after operation. The toxic and adverse reactions of all patients treated with chemotherapy were tolerable. Among them, 17 cases had stable disease and 4 cases had disease progression after chemotherapy. The disease control rate (DCR) was 81.0%. The DCR of patients with CAVD regimen chemotherapy was 85.7% and that of patients treated with MAID regimen was 78.6% (P = 0.862). All patients were followed up for 8 - 86 months (average 32.4 months). The median survival time of all patients was 32.6 months. The 2-year survival rate was 55.1% and the 5-year survival rate was 21.8%. The median survival time in the patients with complete resection was 60.0 months, and that in patients with palliative operation was 27.0, showing a significant difference between them (P = 0.048). The median progression-free survival in patients with complete excision was 57.2 months and that in patients with palliative operation or without operation was 19.6 months, with a significant difference (P = 0.029). The median survival time in patients who received CAVD regimen chemotherapy was 30.0 months, and that in patients with MAID regimen was 51.0 months, with a non-significant difference (P = 0.511). The median progression-free time in patients with CAVD regimen chemotherapy was 13.0 months, and that in patients with MAID regimen was 38.0 months, also with a non-significant difference (P = 0.066).. Alveolar soft part sarcomas are rarely seen and highly malignant tumors, and the prognosis of stage IV ASPS is poor. Complete resection of all tumors is the key of successful treatment of Stage IV ASPS, and the site and number of tumor metastasis are important factors affecting prognosis. The curative effects of radiotherapy and chemotherapy for ASPS need to be further investigated.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Brain Neoplasms; Dacarbazine; Disease-Free Survival; Doxorubicin; Female; Follow-Up Studies; Humans; Ifosfamide; Lower Extremity; Lung Neoplasms; Male; Mesna; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Particle Accelerators; Remission Induction; Salvage Therapy; Sarcoma, Alveolar Soft Part; Soft Tissue Neoplasms; Survival Rate

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

Alveolar soft part sarcoma is a rare malignant tumor with unusual clinical behavior. Treatment of alveolar soft part sarcoma has been difficult to evaluate because of the small numbers of cases seen, but it seemed that although treatment of the primary tumor in alveolar soft part sarcoma often is successful, treatment of metastatic tumors is unsuccessful. A review of outcome after treatment of primary and metastatic disease in the 15 patients in our database with alveolar soft part sarcoma was done in order to evaluate this issue. Nine of 15 patients presented with metastatic disease and one further patient developed metastases. Treatment of primary tumors involved surgical excision in all but one patient and radiation in all patients. Adjuvant chemotherapy was administered to one patient with localized disease and to six patients with metastatic disease. There were no local recurrences. Treatment of metastatic tumors involved chemotherapy in seven patients, metastectomy in three patients, and radiation in two patients. All instances of the metastatic disease either recurred or progressed. Overall survival was 75% at 5 years and 40% at 10 years with a mean survival of 6.5 years, despite the high number of patients with metastatic disease. Current treatment results in good local control of primary tumors, but poor control of metastatic tumors. New approaches to treatment of metastatic alveolar soft part sarcoma must be investigated and applied.. Therapeutic study, Level IV-1 (case series). See the Guidelines for Authors for a complete description of levels of evidence.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Cyclophosphamide; Dacarbazine; Doxorubicin; Female; Humans; Ifosfamide; Male; Mesna; Neoplasm Metastasis; Neoplasm Staging; Sarcoma, Alveolar Soft Part; Soft Tissue Neoplasms; Survival Rate

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

We report a 69-year-old man who suffered an extraosseous tumor of immunoglobulin D myeloma (lambda type) in the shoulder girdle, mimicking a primary soft tissue sarcoma. The tumor was isointense with adjacent muscle on T1-weighted MR images, and hyperintense on T2-weighted images. No continuity with the neighboring bone was noted. After administration of gadolinium, the central part of the tumor showed marked contrast enhancement. Although the tumor showed a complete response to the initial chemotherapy, the patient died of the disease 31 months after its initial manifestation. Several bone marrow aspirations and biopsies of the ilium and sternum had shown no increase in plasma cells (range 0.6-1.2%) until the disease became advanced 19 months after its initial manifestation.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Dacarbazine; Doxorubicin; Humans; Ifosfamide; Immunoglobulin D; Immunoglobulin lambda-Chains; Magnetic Resonance Imaging; Male; Mesna; Multiple Myeloma; Shoulder; Soft Tissue Neoplasms

Peripheral blood stem cell support allows dose intensification of multiple cycle chemotherapy for metastatic tumors, including pediatric sarcomas. The VACIME protocol (vincristine, adriamycin, cyclophosphamide, ifosfamide, mesna and etoposide) utilizes peripheral blood stem cells (PBSC) collected following the treatment cycle as support for subsequent dose- and time-intensive chemotherapy. A critical assumption is that PBSC collected in this manner will be purged of residual tumor cells in vivo. We tested this assumption using sensitive reverse-transcriptase polymerase chain reaction (RT-PCR) to assess the presence of the characteristic translocations of the Ewing's sarcoma family of tumors (ESFT) and alveolar rhabdomyosarcoma (ARMS), t(11;22), and t(2;13), respectively. We used RT-PCR to evaluate 122 samples of peripheral blood (PB), bone marrow (BM) and PBSC collected from 12 pediatric patients with metastatic ESFT and ARMS. The samples included pre-therapy BM and PB, as well as BM, PB, and PBSC collections at various times in the VACIME treatment course. Molecular evidence of tumor contamination was detected in 1/40 PBSC collections from 12 patients. In all patients, we documented clearance of disease by RT-PCR in peripheral blood and bone marrow by week 9 of the VACIME protocol. In vivo purging in combination with the intensive VACIME regime appears to be effective in removing tumor cells from PBSC, bone marrow, and peripheral blood as detected by RT-PCR.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Bone Marrow Purging; Bone Neoplasms; Child; Chromosomes, Human, Pair 11; Chromosomes, Human, Pair 13; Chromosomes, Human, Pair 2; Chromosomes, Human, Pair 22; Combined Modality Therapy; Cyclophosphamide; DNA-Binding Proteins; Doxorubicin; Etoposide; Female; Forkhead Box Protein O1; Forkhead Transcription Factors; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Humans; Ifosfamide; Male; Mesna; Neoplasm Proteins; Neoplastic Cells, Circulating; Oncogene Proteins, Fusion; Paired Box Transcription Factors; PAX3 Transcription Factor; Proto-Oncogene Protein c-fli-1; Reverse Transcriptase Polymerase Chain Reaction; Rhabdomyosarcoma, Alveolar; RNA-Binding Protein EWS; Sarcoma, Ewing; Sensitivity and Specificity; Soft Tissue Neoplasms; Transcription Factors; Translocation, Genetic; Vincristine

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

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Combined Modality Therapy; Doxorubicin; Etoposide; Female; Follow-Up Studies; Humans; Hyperthermia, Induced; Ifosfamide; Male; Mesna; Middle Aged; Neoplasm Recurrence, Local; Soft Tissue Neoplasms; Survival Rate

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

A case report of a woman with perineal leiomyosarcoma who was cured by combination chemotherapy is presented, and the literature on chemotherapy of soft tissue is reviewed.

Topics: Antineoplastic Combined Chemotherapy Protocols; Doxorubicin; Drug Administration Schedule; Female; Humans; Ifosfamide; Leiomyosarcoma; Mesna; Middle Aged; Perineum; Soft Tissue Neoplasms; Vincristine

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

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

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

Ifosfamide and mesna were administered to 77 patients with advanced malignancies. Seven (9%) experienced a severe but reversible encephalopathy. In 56% of patients in whom EEG data was available, characteristic changes were seen with or without mild clinical toxicity. Discriminant analysis identified low serum albumin concentration, high serum creatinine concentration and the presence of pelvic disease as variables which predispose patients to the development of severe encephalopathy. A nomogram has been constructed which can be used to determine the probability that an individual patient may be given ifosfamide and mesna safely. This has important implications for the clinical use of a highly active chemotherapy regimen.

Topics: Antineoplastic Combined Chemotherapy Protocols; Brain Diseases; Electroencephalography; Female; Humans; Ifosfamide; Lung Neoplasms; Male; Mercaptoethanol; Mesna; Soft Tissue Neoplasms; Uterine Cervical Neoplasms; Uterine Neoplasms

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: Female; Humans; Ifosfamide; Infusions, Intravenous; Male; Mercaptoethanol; Mesna; Middle Aged; Osteosarcoma; Soft Tissue Neoplasms

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