mesna and Bone-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

Topics: Amputation, Surgical; Bone Neoplasms; Chemotherapy, Adjuvant; Child; Cisplatin; Combined Modality Therapy; Cyclophosphamide; Doxorubicin; Humans; Ifosfamide; Leucovorin; Lung Neoplasms; Mesna; Osteosarcoma; Survival Analysis; Tennessee; Treatment Outcome; Vincristine

Topics: Acidosis, Renal Tubular; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Chemotherapy, Adjuvant; Cisplatin; Combined Modality Therapy; Doxorubicin; Humans; Ifosfamide; Leucovorin; Mesna; Methotrexate; Osteosarcoma; Postoperative Care; Preoperative Care; Radionuclide Imaging; Retrospective Studies; Salvage Therapy; Thallium Radioisotopes; Treatment Outcome

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

Influence of age and sex on chemotherapy-related toxicity was evaluated in children (3-9 years), adolescents (10-17 years), and adults (up to 40 years) with localized Ewing sarcoma (ES) enrolled in the ISG/SSG III protocol. Treatment was based on vincristine, doxorubicin, cyclophosphamide, ifosfamide, dactinomycin, and etoposide. High-dose chemotherapy with busulfan and melphalan was given in poor responder patients. The analysis was based on 2191 courses of standard chemotherapy and 230 patients. A lower risk of G4 leukopenia and thrombocytopenia, hospitalization, febrile neutropenia, and red blood cell (RBC) transfusions was observed in males. Use of granulocyte colony-stimulating factor (G-CSF) was more frequent in adults, while children more often received RBC transfusions. A significant correlation between sex and chemotherapy-related toxicity was observed in the study, whereas no significant differences in terms of bone marrow toxicity can be expected according to patient age. Further studies should analyse the role of pharmacokinetics, pharmacogenomics, and clinical characteristics.

Topics: Adolescent; Adult; Age Factors; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Child; Child, Preschool; Cyclophosphamide; Doxorubicin; Etoposide; Female; Follow-Up Studies; Hematologic Diseases; Humans; Ifosfamide; Male; Melphalan; Mesna; Neoplasm Staging; Prognosis; Prospective Studies; Sarcoma, Ewing; Sex Factors; Survival Rate; Vincristine; Young Adult

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

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

Previous WR-2721 human pharmacokinetic studies were limited to plasma levels in patients receiving platinum-based compounds, and none includes the effects of WR-2721 on endogenous thiols. In the present study (Pediatric Oncology Group study no. 9457), we measured the levels of WR-2721, its active metabolites, as well as cysteine and glutathione in whole blood, plasma, and blood cells in patients receiving high-dose alkylating agents with mesna.. WR-2721 was administered (15 min intravenous infusion of 825 mg/m(2) per dose x2) to five patients with metastatic Ewing's sarcoma receiving ifosfamide and cyclophosphamide with mesna. Intracellular and extracellular blood thiols were labeled with monobromobimane (mBBr) at the time of collection, and the low molecular weight (LMW) thiols were subsequently separated by HPLC and detected by fluorescence.. The active metabolite of the drug, WR-1065, peaked at 100 microM in plasma and blood cells at the end of WR-2721 infusion and decayed with a rapid initial half-life. Detectable levels of WR-1065 and its LMW disulfides were present in plasma and blood cells at approximately 1 h after the WR-2721 infusion. By the end of the first WR-2721 infusion (prior to mesna infusion), the mean cysteine level more than doubled and the mean Cys-SS-LMW (cystine and the mixed LMW disulfides) level decreased by approximately 50% in both plasma and blood cells. In four of five patients, reduced glutathione levels in blood cells increased by the end of the first WR-2721 infusions, the average increment being approximately 36%.. (1) WR-1065 is rapidly formed from WR-2721 and equilibrates between plasma and blood cells; (2) WR-1065 decays in plasma and blood cells with similar rapid initial half-lives of approximately 16 min; (3) WR-2721 treatment increases cysteine in plasma and blood cells, an effect similar to that of mesna; (4) WR-2721 treatment appears to increase glutathione levels in blood cells; (5) Mesna does not have a substantial effect on the fate of WR-2721 in patients.

Topics: Adolescent; Adult; Amifostine; Antineoplastic Combined Chemotherapy Protocols; Blood Cells; Bone Neoplasms; Child; Cyclophosphamide; Cysteine; Female; Humans; Ifosfamide; Infusions, Intravenous; Kinetics; Male; Mesna; Radiation-Protective Agents; Sarcoma, Ewing; Sulfhydryl Compounds; Time Factors

The necrotic effect of chemotherapy on primary osteosarcoma has been shown to be predictive of the final outcome. Little attention has been paid to the local response of the host (LHR), which reflects the tumour-host relationship.. A four-step grading system was developed based on distinct histological patterns of the LHR around the lesion. These responses were correlated with the chemotherapy-induced necrosis or chemosensitivity and analysed in an attempt to ascertain their influence on the patient prognosis. The ability of conventional radiographs and computed tomography to measure LHR was studied.. The grading system was applied to macroslides of specimens obtained from 72 patients with stage II B primary osteosarcoma in various limbs after wide resection and complete courses of pre- and postoperative chemotherapy who were treated between 1985 and 1991 with a median follow-up of 5 years and 9 months. The histological specimens were blindly reviewed by two pathologists and two experienced musculoskeletal oncologists to assign a grade of response. The results were correlated with tumour necrosis, patient survival and response features on conventional radiographs and CT images.. Significant correlation was found between LHR and tumour necrosis or chemosensitivity (r=0.55) and between LHR and CT response (r=0.56). There was no correlation between LHR and the findings on conventional radiographs. A grade 4 LHR was predictive of long-term survival.. The LHR to preoperative chemotherapy has a prognostic influence on patient survival and can be predicted by CT.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Child; Child, Preschool; Cisplatin; Doxorubicin; Etoposide; Female; Humans; Ifosfamide; Infant; Infant, Newborn; Male; Mesna; Methotrexate; Middle Aged; Necrosis; Neoadjuvant Therapy; Osteosarcoma; Predictive Value of Tests; Prognosis; Tomography, X-Ray Computed

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

Recurrent/metastatic, undifferentiated nasopharyngeal carcinoma (UDNPC) is known to be chemosensitive but has rarely been studied in Phase II methodology. No studies concerning its chemoresponsiveness among southern Africans have been demonstrated to date. From 1990 through 1994, 18 African patients from the Johannesburg metropolitan area with recurrent (following radiotherapy failure) or primarily metastatic (bone) UDNPC were treated with ifosfamide (3 g/m), mesna, and cisplatin (50 mg/m) for 2 days. Three patients (15%) attained complete remission and eight (44%) partial remission, yielding an overall response rate of 59%. Median response duration was 28 weeks. Two patients (11%) had stable disease with symptomatic improvement and five (30%) progressed on therapy. Treatment was generally well tolerated but there was one treatment-related death (neutropenic sepsis). The combination of ifosfamide/cisplatin appears to be promising in UDNPC commonly seen in young patients in southern Africa. However, the duration of response still tends to be brief.

Topics: Adolescent; Adult; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Black People; Bone Neoplasms; Carcinoma; Cisplatin; Disease Progression; Female; Humans; Ifosfamide; Male; Mesna; Nasopharyngeal Neoplasms; Neoplasm Recurrence, Local; Neutropenia; Remission Induction; South Africa; Survival Rate

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

Topics: Amputation, Surgical; Bone Neoplasms; Chemotherapy, Adjuvant; Child; Cisplatin; Combined Modality Therapy; Cyclophosphamide; Doxorubicin; Humans; Ifosfamide; Leucovorin; Lung Neoplasms; Mesna; Osteosarcoma; Survival Analysis; Tennessee; Treatment Outcome; Vincristine

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

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

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

Neuroblastoma is the most common extracranial solid malignancy in children but rarely described in adults, being 10% of all cases diagnosed after the first decade of life. We report a 23 year-old black woman with a mass at paravertebral region of T3-T5, multiple lesions in vertebral bodies and expanding skull-brain lesion at the right parietal region. Immunohistochemical analysis (negative for CD99, CD20, CD3 and desmin; and positive chromogranin, synaptophysin and NB84) confi rmed the diagnosis of neuroblastoma. The patient was submitted to 12 cycles of chemotherapy receiving VAC (vincristine/doxorubicin/cyclophosphamide) interspersed with ICE (ifosfamide/mesna/etoposide) and doxorubicin was replaced by actinomycin in the 7th cycle. She had good tolerance to this therapy, and has been clinically stable.

Topics: Antineoplastic Combined Chemotherapy Protocols; Biopsy; Bone Neoplasms; Brain Neoplasms; Carboplatin; Cyclophosphamide; Doxorubicin; Etoposide; Female; Humans; Ifosfamide; Mesna; Neuroblastoma; Spinal Cord Compression; Spinal Cord Neoplasms; Thoracic Vertebrae; Vincristine; Young Adult

The outcome of Ewing's sarcoma depends on the anatomical site of the tumor. Studies conducted in high-risk patients are limited. We evaluated the outcome of high-risk Ewing's sarcoma patients that received long-term treatment protocol. Twenty-five patients (22 males, 3 females) with poor prognostic features were treated according to long-term Ewing's sarcoma protocol. Central-axis localization, inadequacy or unavailability of surgical resection, older than 15 years of age, are accepted as high-risk factors. The median age of patients was 23 years (range, 18-55). The tumor localization was pelvis (9), femur (1), tibia (1), fibula (1), maxilla (1), clavicle (1), vertebrae (5), metatarse (1), and ribs (5). Neoadjuvant chemotherapy was applied between weeks 0 and 6, local therapy on week 9, and adjuvant maintenance chemotherapy between weeks 11 and 41. All patients received neoadjuvant and adjuvant maintenance chemotherapy. Local therapy consisted of radiotherapy (32%), surgery alone (12%), or surgery and radiotherapy (56%). The median total treatment period was 10 months. The median follow-up was 25 months (range, 7-89). Three-year cumulative OS and DFS rates were 43% (95% CI, 28.5-57.85) and 40% (95% CI 23.63-52.19), respectively. The most common grade III/IV toxicities observed during the treatment protocol were neutropenia (16%) and gastrointestinal toxicities (16%). Our study indicated that long-term multiagent combination chemotherapy may result in better outcome in adult high-risk patients undergoing adequate surgical resection of the tumor and local radiotherapy. Further randomized studies are needed to assess the efficacy of this treatment protocol in patients with adequate surgical margins.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Combined Modality Therapy; Disease-Free Survival; Doxorubicin; Drug Administration Schedule; Etoposide; Female; Humans; Ifosfamide; Kaplan-Meier Estimate; Male; Mesna; Middle Aged; Neoplasm Recurrence, Local; Proportional Hazards Models; Remission Induction; Sarcoma, Ewing; Treatment Outcome; Young Adult

The role of tandem high-dose chemotherapy (HDC) with autologous peripheral hematopoietic progenitor cell rescue (APHPCR) in patients with Ewing Family Tumors (EFT) is controversial. We initiated treatment for eight consecutive patients with high-risk EFT with HDC and APHPCR from 1992 to 2003. There were no treatment related deaths. Four patients remain in complete remission, including three who did not undergo local therapy to bone at either the primary or metastatic sites. Our experience has shown that treatment of EFT patients with tandem HDC with APHPCR may benefit a subgroup of high-risk patients in whom optimal local therapy is not possible.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Child; Combined Modality Therapy; Cyclophosphamide; Doxorubicin; Drug Administration Schedule; Etoposide; Feasibility Studies; Female; Humans; Ifosfamide; Lung Neoplasms; Male; Mesna; Neoadjuvant Therapy; Neuroectodermal Tumors, Primitive; Pelvic Bones; Peripheral Blood Stem Cell Transplantation; Remission Induction; Risk; Sarcoma, Ewing; Scapula; Transplantation Conditioning; Transplantation, Autologous; Treatment Outcome; Vincristine

To assess the role of preoperative radiotherapy in patients with nonmetastatic high-grade osteosarcoma of the extremities for limb-sparing surgery and to compare the response of neoadjuvant therapies, local control, and survival with the literature results.. Forty-six patients with osteosarcoma of the limbs who were treated within a limb salvage protocol including preoperative radiotherapy and chemotherapy between 1987 and 2002, were retrospectively analyzed. Median age was 17 years (range, 14-66 years). Treatment was started with neoadjuvant chemotherapy. Cisplatin, epidoxorubicin, ifosfamide, and methotrexate were used in different combinations. Preoperative radiotherapy was applied, usually between the second and third cycle of chemotherapy. Radiotherapy was given (35 Gy in 10 fractions) to 44 patients. Two patients were treated with 46 Gy at 2 Gy/day. Definitive surgery was administered after the third course of chemotherapy. Chemotherapy was complete 6 courses postsurgery.. Median follow-up time was 44 months (range, 2-154 months). Forty-four patients had limb-sparing surgery, whereas 2 had amputation. Tumor necrosis rate was >/=90% in 87% of the patients (Huvos Grade 3-4). Two patients had local failures, and 26 patients (56.5%) had distant metastases. The 5-year local control and overall survival rates were 97.5% and 48.4%, respectively. On univariate analysis, age

Topics: Adolescent; Adult; Aged; Amputation, Surgical; Analysis of Variance; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Chemotherapy, Adjuvant; Cisplatin; Epirubicin; Extremities; Humans; Ifosfamide; Limb Salvage; Male; Mesna; Methotrexate; Middle Aged; Osteosarcoma; Prognosis; Radiotherapy Dosage; Retrospective Studies; Survival Rate

The purpose of this report is to summarize information on drugs recently approved by the U.S. Food and Drug Administration. Three drugs have recently been approved: Gleevec (imatinib mesylate) at a starting dose of 400 or 600 mg daily for the treatment of malignant unresectable and/or metastatic gastrointestinal stromal tumors; Mesnex (mesna) tablets as a prophylactic agent to reduce the incidence of ifosfamide-induced hemorrhagic cystitis, and Zometa (zoledronic acid) for the treatment of patients with multiple myeloma and for patients with documented bone metastases from solid tumors, in conjunction with standard antineoplastic therapy. Prostate cancer should have progressed after treatment with at least one hormonal therapy. The recommended dose and schedule is 4 mg infused over 15 minutes every 3-4 weeks. These three drugs represent three different types of drug approval: Gleevec is an accelerated approval and supplemental new drug application (NDA); Mesnex tablets represent an oral formulation of a drug approved 14 years ago as an intravenous formulation, and Zometa represents a standard NDA for a noncytotoxic, supportive-care drug. Information provided includes rationale for drug development, study design, efficacy and safety results, and pertinent literature references.

Topics: Antineoplastic Agents; Antineoplastic Agents, Alkylating; Benzamides; Bone Neoplasms; Cystitis; Diphosphonates; Drug Approval; Gastrointestinal Neoplasms; Hematuria; Hemorrhage; Humans; Ifosfamide; Imatinib Mesylate; Imidazoles; Mesna; Multiple Myeloma; Orphan Drug Production; Piperazines; Protective Agents; Pyrimidines; Randomized Controlled Trials as Topic; United States; United States Food and Drug Administration; Zoledronic Acid

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Female; Humans; Ifosfamide; Mesna; Methylene Blue; Neurotoxicity Syndromes; Oncology Nursing; Osteosarcoma

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

Ewing's sarcoma of the pelvic bones was diagnosed in a 21-year childbearing woman, raising major medical and ethical problems. The diagnostic and therapeutic approaches during the sixth month of gestation were tailored in order to cure the patient and avoid unnecessary toxicity to the fetus. Ancillary tests included ultrasound and MRI studies of the pelvis. Ifosfamide and adriamycin, premedicated by granisetron, were administered during gestation, and were found to be safe. Cesarean section was the preferred way of delivery since the tumor involved the pelvic bones. The outcome was a disease-free patient and a small healthy baby who is now two years of age.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Cesarean Section; Disease-Free Survival; Doxorubicin; Female; Follow-Up Studies; Humans; Ifosfamide; Infant, Newborn; Infusion Pumps, Implantable; Infusions, Intravenous; Magnetic Resonance Imaging; Mesna; Pelvic Bones; Pregnancy; Pregnancy Complications, Neoplastic; Pregnancy Outcome; Pregnancy Trimester, Third; Prenatal Diagnosis; Sarcoma, Ewing; Ultrasonography, Prenatal

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

We report the case of a patient with a rare miliary variant of osteosarcoma associated with symptomatic hypocalcemia and review the literature regarding the pathogenesis of multifocal osteosarcoma, treatment options, and the associated hypocalcemia.

Topics: Adult; Antibiotics, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Cisplatin; Doxorubicin; Expectorants; Fatal Outcome; Female; Follow-Up Studies; Granulocyte Colony-Stimulating Factor; Humans; Hypocalcemia; Ifosfamide; Lung Neoplasms; Mesna; Osteosarcoma

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

Ewing's sarcoma and primitive neuroectodermal tumour (ES/PNET) are rare, limiting opportunities for therapy studies in adults. Chemotherapy regimens adapted from paediatric studies are often used for adults but concerns about poor outcome and treatment toxicity may adversely affect drug dose intensity. We present our experience using a paediatric protocol at full dose.. Records of 34 patients with ES/PNET who received the IVAD chemotherapy regimens were reviewed. Received drug dose intensity, toxicity and survival data were collected.. Received dose intensity in 30 evaluable patients was 0.92 compared to the standard IVAD schedule. Myelosuppression was the major toxicity, 83% of patients experienced grade 4 neutropenia. There was no major renal or cardiac toxicity. In patients without metastases at presentation, five-year overall survival was 63% and progression free survival was 39%. Tumour burden at presentation was statistically significantly associated with survival (P = 0.002). The five-year survival rate of 80% in patients presenting with low volume non metastatic disease was equivalent to published paediatric series.. Although the IVAD chemotherapy regimens are myelotoxic in adults, they can be given safely. We recommend that adults with ES/PNET should be included in current multicentre, multidisciplinary treatment studies directed at children.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Brain Neoplasms; Cyclophosphamide; Disease-Free Survival; Dose-Response Relationship, Drug; Doxorubicin; Drug Administration Schedule; Etoposide; Feasibility Studies; Female; Humans; Ifosfamide; Infusions, Intravenous; Injections, Intravenous; Male; Mesna; Middle Aged; Neuroectodermal Tumors, Primitive; Neutropenia; Sarcoma, Ewing; Vincristine

The purpose of this study was to develop a canine experimental model for neoadjuvant chemotherapy of primary bone tumors with ifosfamide, which is safe and clinically relevant for use in human beings with bone tumors. Our study was divided into two steps, each with four dogs. In the first step ifosfamide was administered for 4 consecutive days in three cycles with 3-week intervals between each cycle. For this first step a daily dosage of 300 mg/m2 of body surface resulted in only moderate leukopenia, whereas a daily dosage of 450 mg/m2 caused severe leukopenia. Therefore, to determine the maximal dose tolerable and to verify the results from step 1, we administered the higher daily dosage of 450 mg/m2 in step 2 for four successive cycles with 3-week intervals. In each step one dog died acutely after the first cycle of chemotherapy. In addition during step 2 one dog died of overwhelming sepsis after the second cycle of ifosfamide. The remaining five dogs survived without other appreciable laboratory abnormalities. Neither hematuria nor proteinuria was observed throughout the course of study, and relevant findings were not observed at autopsy. We determined that 450 mg/m2 was the maximal tolerated dosage of ifosfamide for our regimen, with the dose-limiting factor being myelosuppression, specifically leukopenia. Using this canine model, we can estimate the effect of ifosfamide on bone graft incorporations and the fixation of biologic prostheses that is clinically the most important aspect of limb salvage surgery.

Topics: Animals; Antineoplastic Agents, Alkylating; Blood Platelets; Bone Neoplasms; Dogs; Drug Administration Schedule; Erythrocyte Count; Fever; Ifosfamide; Leukopenia; Male; Mesna; Survival Rate

We studied the efficacy of mesna as a protectant for urotoxicity in pediatric patients receiving chemotherapy including oxazaphosphorines. Nineteen patients with malignant diseases (5 neuroblastoma, 3 acute lymphocytic leukemia, 4 acute non-lymphocytic leukemia, 2 non-Hodgkin lymphoma, 3 osteosarcoma and 2 rhabdomyosarcoma) were treated with a total of 106 courses of therapy between June of 1986 and May of 1989. Of these, no gross hematuria were seen. Microhematuria transiently occurred only in 2 courses (5%) of 1 patient (2%). These data indicated that mesna was highly effective for urotoxicity of oxazaphosphorines without any side effects, especially in pediatric patients.

Topics: Bone Neoplasms; Child; Cyclophosphamide; Cystitis; Female; Hematuria; Humans; Ifosfamide; Leukemia; Lymphoma, Non-Hodgkin; Male; Mercaptoethanol; Mesna; Neuroblastoma; Osteosarcoma; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Rhabdomyosarcoma

The German Society of Pediatric Oncology (GPO) has studied the efficacy of high-dose ifosfamide with mesna uroprotection in patients with Ewing's sarcoma. A phase II trial of ifosfamide (IFO) (2 g/m2 per day, days 1-5) in eight patients with recurrent evaluable disease resulted in three partial and two complete responses lasting from 3 to 12 months (median, 6 months). In a second phase II trial in 15 patients, the combination of IFO and cisplatin (20 mg/m2 per day, days 1-5) resulted in 7 partial and 2 complete responses lasting from 3 to 32 months (median, 6 months). Consequently, in 1985 IFO was incorporated into first-line chemotherapy for newly diagnosed patients (replacing cyclophosphamide) and given in combination with vincristine, actinomycin D, and adriamycin (VAIA) in patients considered to be at high risk for relapse. IFO was given at a dose of 3 g/m per day on days 1 and 2 as a 48-h continuous infusion, in combination with actinomycin D (0.5 mg/m2 per day on days 1-3) or Adriamycin (30 mg/m2 per day on days 1 and 2). The study was piloted from March to December 1985 and has been open since January 1986; 37 patients were entered during the pilot phase and 65 have been entered in the ongoing main trial since January 1986. At present, Kaplan-Meier disease-free survival projects that disease-free survival in patients with large primary tumors has improved compared with that reported for the previous CESS 81 trial. The toxicity of the VAIA regimen was comparable with that of the conventional vincristine, actinomycin D, cyclophosphamide, and adriamycin (VACA) regime used in the previous CESS 81 trial.

Topics: Actuarial Analysis; Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Child; Child, Preschool; Cyclophosphamide; Dactinomycin; Doxorubicin; Drug Evaluation; Drug Therapy, Combination; Female; Humans; Ifosfamide; Male; Mercaptoethanol; Mesna; Neoplasm Recurrence, Local; Sarcoma, Ewing; Vincristine

The authors have had the opportunity to see two cases of CNS side effects of Ifosfamide-Mesna association in children. Data in the medical literature about this subject remains poor. Only a few observations are available. In the referred cases, CNS side effects (lethargy, apathy and mutism) appeared a few hours after the second day of treatment and were spontaneously reversible in a few days. After reviewing possible mechanisms of this toxicity the authors pointed out the necessity to keep this type of side effects of Ifosfamide-Mesna association in mind, and to avoid it in susceptible patients.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Central Nervous System Diseases; Child; Female; Humans; Ifosfamide; Mesna; Osteosarcoma