mesna and Neutropenia

Docetaxel, ifosfamide and cisplatin have proven activity in a broad range of solid tumours and interfere with different phases of the cell cycle. We performed a phase I study with the aim to determine the maximum tolerated dose (MTD) of docetaxel, ifosfamide and cisplatin in patients with solid tumours and to define the safety, dose-limiting toxicity (DLT) and the recommended dose and administration schedule of docetaxel, ifosfamide and cisplatin for further phase II testing. Docetaxel was given by 1-h infusion on day 1, followed by ifosfamide 1000 mg/m(2)/day as a continuous infusion for 5 days. Mesna was added at the same doses to the same infusion bag and was continued for 12 h after the end of ifosfamide. Cisplatin was administered as a 24-h infusion concomitantly with ifosfamide, but in separate infusion bags, either on day 5 (schedule A) or on day 1 (schedule B). Escalation steps were planned only for docetaxel (60, 75, 85 mg/m(2)) and cisplatin (50, 75, 100 mg/m(2)). No intrapatient dose escalation was permitted. Prophylactic ciprofloxacin was used after a protocol amendment was implemented. No prophylactic haematopoietic growth factors were used. Cycles of docetaxel, ifosfamide and cisplatin were given at 3-week intervals. Toxicity was scored according to National Cancer Institute Canada-Common Toxicity Criteria 2. The MTD was defined as the dose at which a DLT was observed in fewer than two of six patients during the first treatment cycle. In total, 85 patients received 309 cycles. Only three escalation steps could be explored and DLTs were observed at each dose level. In total, 32 patients and 49 cycles showed DLTs. Febrile neutropenia occurred in 20 patients (24%). Only two DLTs were nonhaematological (one cerebral infarction and one encephalopathy grade 4). Neutropenia grade 4 lasted for greater than 7 days and/or thrombocytopenia grade 4 was dose limiting in 10 patients. Febrile neutropenia occurred in five of 41 patients (12%) who received prophylactic ciprofloxacin and in 15 of 44 patients (34%) who did not. MTD was reached at level 3 (docetaxel, 75 mg/m(2) and cisplatin, 75 mg/m(2)). With a lower dose of docetaxel (60 mg/m(2)) both schedules A and B were feasible, although, overall, schedule A seemed to be better tolerated. On the basis of this phase I study, the recommended docetaxel, ifosfamide and cisplatin regimen is docetaxel (60 mg/m(2)) on day 1, ifosfamide (1000 mg/m(2)/day) on days 1-5 and cisplatin (75 mg/m(2)) given on day 5. It

Topics: Adult; Aged; Antibiotic Prophylaxis; Antineoplastic Combined Chemotherapy Protocols; Brain Injuries; Canada; Cerebral Infarction; Cisplatin; Docetaxel; Drug Administration Schedule; Female; Humans; Ifosfamide; Male; Maximum Tolerated Dose; Mesna; Middle Aged; Neoplasms; Neutropenia; Taxoids; Thrombocytopenia

We investigated dose-dense docetaxel and cisplatin in patients with measurable non-small cell lung cancer in a randomized phase II study without [A] or with [B] a putative chemoprotective agent, BNP7787.. Chemotherapy-naive patients with stage IIIB (effusion) or IV, performance status 0 to 1, and adequate organ function were eligible. Treatment with docetaxel 75 mg/m followed by cisplatin 75 mg/m over 1 hour day 1 with darbepoetin 200 mug day 1 and pegfilgrastim 6 mg day 2 without/with BNP7787 before cisplatin was repeated every other week for up to 6 cycles. The primary end point was to differentiate between grade >/=2 neurotoxicity rates of 30% on [A] and 10% on [B]. Feasibility was prospectively defined as febrile neutropenia in <10% of patients and /=2 occurred in 32% on [A] and 29% on [B]. The incidence of febrile neutropenia was 4% on [A] and 3% on [B]. Treatment delays occurred in 13% and 20% of patients on [A] and [B], respectively. Completion rates for 3/6 cycles were 84%/51% on [A] and 84%/53% on [B]. Objective response rates were 55% on [A] and 51% on [B]. Median progression-free/overall survival times were 5.5/10.7 on [A] and 6.5/14.1 month on [B].. This dose-dense treatment regimen is active, feasible, and tolerable. Its further investigation in the curative setting in non-small cell lung cancer should be considered. BNP7787 did not result in significant protection from neurotoxicity.

Topics: Adenocarcinoma; Adenocarcinoma, Bronchiolo-Alveolar; Adult; Aged; Anemia; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Cisplatin; Darbepoetin alfa; Docetaxel; Dose-Response Relationship, Drug; Drug Therapy, Combination; Erythropoietin; Feasibility Studies; Female; Filgrastim; Granulocyte Colony-Stimulating Factor; Hematinics; Humans; Lung Neoplasms; Male; Maximum Tolerated Dose; Mesna; Middle Aged; Neoplasm Staging; Neutropenia; Polyethylene Glycols; Prognosis; Recombinant Proteins; Survival Rate; Taxoids

Our aim was to determine the efficacy of ifosfamide, mesna, and interferon alpha combination therapy in malignant mesothelioma (MM) patients. Fourty-two patients (39 evaluable) with histologically proven MM were enrolled into this study from January 1999 to October 2002. The drug schedule consisted of a combination of ifosfamide, 3000 mg/m2 1-3 d intravenous infusion (iv), the uroprotective agent mesna, 3000 mg/m2 1-3 d iv every 3 wk, and interferon alpha2a, 4.5 MU subcutaneously (sc) 3 d/wk for 6 mo as first-line chemotherapy. Overall, 140 cycles were administered to the 39 patients (median, 3.5 cycles; range, 1 to 6 cycles). Among the 39 patients, 8 partial remissions (PR) (21%) were observed. Thirteen patients (33%) had stable disease for at least 8 wk and 18 (46%) had progressive disease. Overall survival (OAS) and progression free survival (PFS) for all patients were 10.0 +/- 2.9 mo (95%CI 4.3-15.7) and 5.0 +/- 1.9 mo (95%CI 1.38-8.62), respectively. One and two year survival rates were calculated as 39% and 5%, respectively. All of the PR patients had the epithelial type of MM. Their survival time was 21.0 +/- 5.7 mo (95% CI 9.9-32.1) and significantly longer than that of nonresponders (p=0.0061). The toxicity of the drug combination was mild and well tolerated. There were no treatment-related deaths. Grade 3-4 neutropenia and febrile neutropenia were seen in 10 patients (26%) and 3 patients (8%), respectively. Chemotherapy was stopped in three patients because of renal function deficiency. One of these patients who had peritoneal MM required hemodialysis. In conclusion, this combination therapy showed encouraging antitumor activity with modest toxicity.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Disease Progression; Female; Humans; Ifosfamide; Infusions, Intravenous; Interferon alpha-2; Interferon-alpha; Male; Mesna; Mesothelioma; Middle Aged; Neutropenia; Recombinant Proteins; Survival Analysis; Treatment Outcome

The aim of this study was to determine the activity and toxicity of a vinorelbine and ifosfamide combination in platinum-resistant advanced ovarian cancer.. Patients were treated with ifosfamide (2 g/m(2)/day) infused over 1 h x 3 days (with mesna uroprotection) and vinorelbine (30 mg/m(2)) on days 1 and 8. Treatment was repeated on a 21-day schedule. In order to avoid unacceptable toxicity in this subset of patients where the chemotherapy is mainly palliative, the Bryant and Day two-stage phase II trial design incorporating toxicity considerations was chosen. A cutoff point for the response rate (10%) and for severe toxicity (25%) was established for the first 14 patients.. Between February 1997 and December 1998, 11 paclitaxel and platinum-resistant patients and 1 potentially platinum-sensitive patient were treated. Five patients (41%) experienced grade 3-4 central nervous toxicity requiring hospital admission. In accordance with the Bryant and Day design, the study was stopped early because greater than 25% of the first 14 patients developed grade 3-4 neurotoxicity. A retrospective review of clinical characteristics of these patients showed at least one well-known risk factor associated with ifosfamide central toxicity. Hematological toxicity was common, mainly grade 4 neutropenia, which was observed in all but 1 patient, usually of short duration, and there were 4 episodes of neutropenic fever. Ten patients were evaluated for response. Two complete responses and 1 partial response according to CA-125 criteria were observed.. This combination may be active in platinum-resistant ovarian cancer but the high toxicity encountered, principally neurotoxicity in those with large central pelvic masses, means that further studies with this schedule may not be warranted.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Central Nervous System Diseases; Drug Administration Schedule; Drug Resistance, Neoplasm; Female; Humans; Ifosfamide; Mesna; Middle Aged; Neutropenia; Organoplatinum Compounds; Ovarian Neoplasms; Paclitaxel; Vinblastine; Vinorelbine

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

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

A prospective trial to evaluate the efficacy and toxicity of ifosfamide (IFX) and vinorelbine (VNB) in patients with prior anthracycline therapy for metastatic breast cancer (MBC) was conducted. At the same time, the scheduling of VNB in order to minimize toxicity of the combination was also evaluated.. Twenty-three patients with MBC who had already received initial chemotherapy with doxorubicin-containing regimens either as adjuvant or as first-line treatment in MBC were entered into the study. IFX 3 g/m(2) and mesna 3 g/m(2) were given in divided doses over 2 days. In 4 patients, VNB was given 25 g/m(2) on days 1 and 3 in 3-h infusion. In 8 patients, VNB was given on days 1 and 8 and in 5 patients VNB was given on days 1 and 15. Thirteen patients had received doxorubicin in adjuvant setting, while 10 patients received doxorubicin as first-line treatment in metastatic disease. Dominant disease sites were soft tissues in 7 patients, visceral in 12 patients, and bone in 4 patients. The median age was 47 years.. Overall objective response was seen in 12/23 patients (52.2%). Four patients achieved complete remission (CR), 8 patients achieved partial remission (PR). The median duration of response was 9 months in responding patients, and the median overall survival duration was 15 months. The major dose-limiting toxicities were neutropenia grade III and IV in 8/17 patients and asthenia grade III and IV in 4 patients.. IFX and VNB is an active combination. Neutropenia and asthenia were most significant when VNB was given on days 1 and 3. In the best-tolerated regimen, VNB was given on days 1 and 8.

Topics: Adult; Aged; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Asthenia; Breast Neoplasms; Doxorubicin; Drug Administration Schedule; Drug Resistance, Neoplasm; Female; Humans; Ifosfamide; Infusions, Intravenous; Mesna; Middle Aged; Neoplasm Metastasis; Neutropenia; Prospective Studies; Treatment Outcome; Vinblastine; Vinorelbine

Ifosfamide and paclitaxel are antineoplastic agents with broad activity and with different mechanisms of action. A Phase I trial was conducted to determine the maximum tolerated dose and associated toxicities of these agents when used in combination.. Patients with refractory, incurable solid tumors were entered on a 5-step Phase I trial of ifosfamide, given in doses of 2-3 g/m2 intravenous (i.v.) bolus for 3 days with mesna support, and paclitaxel, given in doses of 135-190 g/m2 i.v. by continuous infusion over 24 hours. Paclitaxel was given after the first dose of ifosfamide on Day 1.. Twenty-three patients were treated, and the maximum tolerated dose was the highest planned dose level of the trial: ifosfamide, 3 g/m2/day i.v. for 3 days, and paclitaxel, 190 mg/m2 i.v. over 24 hours. Hematologic toxicity was not dose-limiting, and although neutropenia occurred, it was brief (median, 2-4 days) and resulted in hospitalization for neutropenia and fever in only 7 of 111 courses of therapy. For patients treated at the highest dose level, only 1 of 50 courses of therapy resulted in hospitalization for neutropenia and fever. Nonhematologic toxicity also was not severe and no significant neuropathy occurred. Although patients entered into the study were heavily pretreated, responses were observed, particularly in patients with breast or ovarian carcinoma.. Ifosfamide and paclitaxel can be administered safely in the doses used in this study and there are indications of significant antitumor effect. Further studies are necessary to explore the antineoplastic activity of this regimen, particularly for patients with breast and ovarian carcinoma.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Colonic Neoplasms; Female; Granulocyte Colony-Stimulating Factor; Humans; Ifosfamide; Lung Neoplasms; Male; Mesna; Middle Aged; Neoplasms; Neutropenia; Ovarian Neoplasms; Paclitaxel

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

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

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

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

To evaluate the effect of two filgrastim dosages after autologous bone marrow transplantation (ABMT) in patients with Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL).. Eighty-six patients were enrolled onto a multicenter, randomized, open-label study. The study compared the efficacy and safety of two different doses of filgrastim, 5-microgram/kg/d subcutaneous (SC) bolus injection and 10-microgram/kg/d SC continuous infusion, starting on day 1 following ABMT.. Both patient groups were well matched in terms of demography and disease. The results showed no statistical difference in the median time to reach an absolute neutrophil count (ANC) of 0.5 x 10(9)/L (11 days; P = .685) and no difference in the median duration of neutropenia (10 v 11 days, respectively; P = .567) between either dose of filgrastim. The incidence and duration of fever and neutropenic fever were the same in both groups. The number and mean duration of clinically and documented infections, duration of intravenous (IV) antibiotics, time to discharge from hospital, and tumor response also were similar in both groups.. This study demonstrates that a dose of filgrastim 5 micrograms/kg/d administered as a daily SC bolus injection has a similar efficacy and safety profile compared with the 10-microgram/kg/d dose administered as a SC continuous infusion. The lower dose of filgrastim has potential cost-saving implications in terms of both the dose of drug administered and the ease of administration. Based on these findings, the recommended dose of filgrastim after ABMT should be 5 micrograms/kg/d.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Carmustine; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Etoposide; Female; Filgrastim; Granulocyte Colony-Stimulating Factor; Hodgkin Disease; Humans; Lymphoma, Non-Hodgkin; Male; Melphalan; Mesna; Middle Aged; Neutropenia; Patient Selection; Recombinant Proteins; Thiotepa

Two studies were performed to determine the maximum tolerated dose (MTD) of paclitaxel and vinorelbine, respectively, in combination with a fixed dose of ifosfamide in previously untreated patients with stage IIIB or IV non-small cell lung cancer. Response rate and survival were also assessed. Both regimens were given with mesna and granulocyte colony-stimulating factor support. The maximum tolerated dose of paclitaxel in combination with 1.6 g/m2/d X 3 ifosfamide was 300 mg/m2, and the recommended dose for phase II study is 250 mg/m2. Among 31 patients treated with ifosfamide/paclitaxel, there were seven partial responses; additionally, 10 patients had either minor regression or stable disease. The maximum tolerated dose of vinorelbine in combination with 1.6 g/m2/d X 3 ifosfamide was 35 mg/m2/d X 3, and the recommended dose for phase II study is 30 mg/m2/d X 3. Among 42 patients treated with ifosfamide/vinorelbine, responses have been encouraging, and final analysis is pending. The dose-limiting toxicity for both regimens was neutropenia. These findings indicate that ifosfamide-containing combination chemotherapy regimens have activity in advanced non-small cell lung cancer and are well tolerated when administered with granulocyte colony-stimulating factor.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Drug Tolerance; Expectorants; Female; Granulocyte Colony-Stimulating Factor; Humans; Ifosfamide; Lung Neoplasms; Male; Mesna; Middle Aged; Neoplasm Staging; Neutropenia; Paclitaxel; Remission Induction; Survival Rate; Vinblastine; Vinorelbine

The purpose of this phase I study is to determine the maximally tolerated doses of paclitaxel and carboplatin (dosed by area under the concentration-time curve) when given at specified times in combination with 6 g/m2 ifosfamide (3 g/m2 at 8 AM on days 1 and 2) with mesna and 5 microg/kg/d filgrastim (from day 4 until the absolute neutrophil count is > 10,000/microL) every 21 days for six cycles. Twelve patients have been treated thus far, 10 of whom are currently eligible for toxicity and response analyses: three each at dose levels 1 and 2, and four at dose level 3. Hematologic toxicity has been the only grade 4 toxicity noted. Only one episode of neutropenic fever occurred in the 43 cycles delivered to date, and only one patient experienced an ifosfamide-related change in mental status. Two patients have developed reversible renal tubular acidosis. No other significant neurologic or renal toxicities have been noted. Patient disease distribution is three non-small cell lung cancer, two breast cancer, two adenocarcinomas of unknown primary site, one prostate cancer, one angioimmunoblastic lymphadenopathy, and one mesothelioma. The median age is 48 years (age range, 34 to 75 years), and median prior chemotherapy treatments was zero. One patient on dose level 1 required a dose delay on cycle 6 because of inadequate hematologic recoveries and one patient required a 50% reduction of the ifosfamide dose during cycle 4 due to mental status change. No patients receiving dose level 2 required dose reductions or delays. One patient at dose level 2 was removed from study due to deterioration of performance status and subsequently died. At dose level 3 dose delays have been required in six of 15 cycles, but no dose reductions have been necessary. Four patients have achieved a complete response (40%) and six a partial response (60%), for a total response rate of 100%. At the completed dose levels, this regimen appears to be tolerable and active with minimal nonhematologic toxicities.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Drug Administration Schedule; Drug Tolerance; Female; Filgrastim; Granulocyte Colony-Stimulating Factor; Humans; Ifosfamide; Leukocyte Count; Male; Mesna; Middle Aged; Neoplasms; Neutropenia; Neutrophils; Paclitaxel; Recombinant Proteins; Remission Induction

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

Twenty patients with locally advanced or metastatic breast cancer were treated with four cycles of ifosfamide/mesna 5 g m-2 and epirubicin 60 mg m-2 every 14 days with granulocyte colony-stimulating factor (G-CSF, Filgrastim). Complete remission occurred in six out of the 20 patients (30%, 95% confidence interval 12-54%) and there were 12 partial responders (60%, 95% confidence interval 37-81%), thus giving an overall response rate of 90% (95% confidence interval 63-97%). Two patients had progressive disease. The median duration of response for those patients with metastatic disease was 7.3 (1.3-20.1+) months. The median survival time for these patients was 15 (5.3-27.9+) months. Of the four patients treated with locally advanced disease three achieved a complete clinical response and one a partial response. Three out of four of these patients subsequently underwent a mastectomy, and in one of these no viable tumour was seen. Our conclusion is that this regimen is excellent palliation for metastatic disease and possibly useful neoadjuvant treatment.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Drug Administration Schedule; Epirubicin; Female; Granulocyte Colony-Stimulating Factor; Humans; Ifosfamide; Mesna; Middle Aged; Neoplasm Metastasis; Neutropenia

There is evidence that continuous infusion allows the delivery of higher doses of a drug while reducing the incidence of neurologic and renal toxicity. To verify prior to phase II testing the feasibility of ambulatory treatment with high-dose ifosfamide/mesna by continuous infusion in adult solid tumours, the maximum tolerated dose (MTD) and the non-haematological dose-limiting toxicities for the achievement of 2 courses of therapy were determined.. Thirty-two patients with advanced solid tumours were given continuous-infusion ifosfamide, from 9 to 16 g/m2, over 4 consecutive days, with equidose mesna uroprotection and granulocyte colony-stimulating-factor support; courses were repeated every 3 weeks. Total dose/course was escalated by 1 g/m2, in cohorts of 3 to 5 patients until the MTD was determined.. At 16 g/m2, the dose-limiting toxicity was renal, with 2 of the 5 patients treated developing renal failure. Haematological toxicity was dose-related and significant at higher dosages, but generally surmountable. Ifosfamide at 15 g/m2/course with mesna uroprotection was identified as the MTD.. The present study shows that high-dose continuous-infusion ifosfamide, administered by portable infusion pumps, is feasible in an ambulatory regimen, with acceptable non-haematological toxicity and good patient compliance.

Topics: Adult; Aged; Ambulatory Care; Female; Granulocyte Colony-Stimulating Factor; Humans; Ifosfamide; Immunologic Factors; Infusions, Intravenous; Kidney Diseases; Male; Mesna; Middle Aged; Neoplasms; Neutropenia; Recombinant Proteins; Remission Induction; Treatment Outcome

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

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

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

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

28 patients with recurrent advanced breast cancer were treated with a salvage regimen consisting of vincristine, epirubicin and ifosfamide/mesna (VIE). All patients had poor prognostic characteristics defined as relapse within 12 months of chemotherapy or as relapse within a radiotherapy field. Chemotherapy was infused continuously through a central venous catheter using a portable pump. Ifosfamide (3 g/m2) mixed with mesna (3 g/m2) was infused for 7 days followed by epirubicin (50 mg/m2) mixed with vincristine (1.5 mg/m2) over a further seven days and alternated for a total of 6 weeks. 9 of the 28 patients (32%) responded to VIE (six partial and three complete responses). This included 6 of the 18 patients (33%) who had previously received doxorubicin or mitoxantrone, 6 of the 17 patients (35%) who had an inoperable in-field relapse after radiotherapy for locally advanced cancer, and 5 of the 21 patients (24%) relapsing within 6 months of previous chemotherapy. Median duration of response and overall survival were 3.7 and 6.9 months, respectively. Myelotoxicity was mild. One patient had neutropenic sepsis, 3 patients ahd grade 3 nausea and vomiting and one patient developed paralytic ileus attributed to vincristine. Central venous catheter complications occurred in 12 of 33 catheters requiring removal in 6. Continuous infusional chemotherapy using vincristine, epirubicin and ifosfamide achieves a 32% overall response rate in treatment-resistant advanced breast cancer, and is associated with minimal toxicity and a short treatment period. VIE may be a suitable alternative to conventional chemotherapy.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Epirubicin; Female; Hemoglobins; Humans; Ifosfamide; Infusions, Intravenous; Mesna; Middle Aged; Neutropenia; Salvage Therapy; Time Factors; Vincristine

Ifosfamide has previously been shown to be active as a single agent and in combination with doxorubicin, etoposide, and teniposide in pediatric solid tumors and adult acute leukemia. The authors performed a dose-escalation trial of ifosfamide with a fixed dosage of etoposide, with mesna uroprotection, in children with multiply recurrent acute leukemia.. Chemotherapy was administered daily for 5 days. Etoposide 100 mg/m2 was followed by ifosfamide at an initial dosage of 1.6 g/m2. The ifosfamide was escalated in 20% increments to the maximum tolerated dosage in cohorts of three patients. Mesna 400 mg/m2 was given immediately before the ifosfamide and then at 3 and 6 hours after ifosfamide in the initial patients. Subsequent patients were treated with mesna 400 mg/m2 just before ifosfamide, and then every 2 hours to a total dosage equal to the ifosfamide dosage.. Forty-four heavily pretreated patients were entered on study. Forty were evaluable for toxicity and 36 for response as well. The maximum tolerated dosage of ifosfamide was 4.0 g/m2/d for 5 days (20 g/m2/course). Overall, 10 patients achieved complete remission, and 3 achieved partial remission. Remissions were brief, although four patients went on to bone marrow transplant while in remission. One patient is still alive.. The combination of etoposide and ifosfamide with mesna uroprotection showed promising activity in children with multiply recurrent acute leukemia.

Topics: Acute Disease; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Bone Marrow Transplantation; Child; Drug Tolerance; Etoposide; Humans; Ifosfamide; Leukemia, Myeloid; Mesna; Neoplasm Recurrence, Local; Neutropenia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Remission Induction; Urinary Tract

This Phase I study was designed to determine the maximum tolerated dose of ifosfamide-mesna with a fixed dose of cisplatin without growth factor or hematopoietic precursor support.. Twenty-five patients with previously untreated advanced non-small cell lung cancer were treated at four dose levels. Initially, the cisplatin dose was 100 mg/m2 given on day 1. Seven patients were treated with ifosfamide 2.0 g/m2 days 1 to 3, and six patients received ifosfamide 2.5 g/m2 days 1 to 3. Mesna was given at 20% of the ifosfamide dose at 0, 4, and 6 hours after ifosfamide. Cycles were repeated every 4 weeks.. Dose-limiting toxicities (myelosuppression and renal toxicity) were seen at dose level 2 (ifosfamide 2.5 g/m2). Because 5 of the first 13 patients experienced Grade 3 renal toxicity, the study was amended to give cisplatin in divided doses. An additional six patients each were treated at dose level 3 (ifosfamide 2.0 g/m2 days 1-3) and dose level 4 (ifosfamide 2.5 g/m2 days 1-3) with cisplatin 33 mg/m2 days 1 to 3. Dose-limiting toxicity (myelosuppression) was reached at ifosfamide 2.5 g/m2. No further Grade 3 renal toxicity was seen. Grade 3 or worse toxicities were seen as follows: neutropenia 80%, thrombocytopenia 48%, nausea/vomiting 36%, anemia 32%, renal 20%, central nervous system 16%, and infection 16%. Two toxic deaths occurred, both with infection, renal failure, and neutropenia. Partial responses were seen in 8 of 25 eligible patients (32%).. The maximum tolerated dose in this group of patients was defined as ifosfamide 2.0 g/m2 days 1 to 3 when given with cisplatin 33 mg/m2 days 1 to 3. When combining high-dose cisplatin with ifosfamide, it is advisable to give cisplatin in divided doses.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Cisplatin; Drug Administration Schedule; Female; Fluid Therapy; Humans; Ifosfamide; Lung Neoplasms; Male; Mesna; Middle Aged; Neutropenia; Thrombocytopenia; Vomiting

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

Topics: Adult; Aged; Aged, 80 and over; Anemia; Antineoplastic Combined Chemotherapy Protocols; Brachytherapy; Carcinosarcoma; Chemoradiotherapy; Cisplatin; Disease-Free Survival; Female; Humans; Ifosfamide; Mesna; Middle Aged; Neoplasm Staging; Neutropenia; Protective Agents; Retrospective Studies; Treatment Outcome; Uterine Neoplasms

Patients aged >10 years with rhabdomyosarcoma have an inferior outcome compared with patients ages 1 to 9 years, which may be explained by toxicities (adverse events [AEs]) that result in chemotherapy dose reductions.. AEs observed during 1 of 3 randomized chemotherapy regimens (vincristine, dactinomycin, and cyclophosphamide [VAC]; vincristine, dactinomycin, and ifosfamide [VAI]; or vincristine, ifosfamide, and etoposide [VIE]) in the Fourth Intergroup Rhabdomyosarcoma Study were recorded. The incidence of toxicities by age and treatment regimen was determined. The odds of developing AEs in a particular age group (ages 5-9 years, 10-14 years, and 15-20 years) were compared with the odds in the control group of patients ages 1 to 4 years.. In total, 657 patients were eligible for analysis. The estimated 5-year event-free survival rates were 78%, 83%, 67%, and 58% for the groups ages 1 to 4 years, 5 to 9 years, 10 to 14 years, and 15 to 20 years, respectively. Patients ages 15 to 20 years experienced less neutropenia (odds ratio [OR], 0.43; P < .0001), thrombocytopenia (OR, 0.41; P < .0001), anemia (OR, 0.34; P < .0001), and infection (OR, 0.41; P < .0001) compared with younger patients, although they received similar amounts of chemotherapy. In contrast, peripheral nervous system toxicity was higher in adolescents aged >10 years (OR, 4.18; P < .0001). Females experienced more neutropenia (OR, 1.28; P = .05) and thrombocytopenia (OR, 1.26; P = .06) compared with males.. Adolescents who received treatment for rhabdomyosarcoma experienced significantly less hematologic toxicity and more peripheral nervous system toxicity compared with younger children despite receiving similar amounts of chemotherapy. Although outcomes were inferior in adolescents, it was unclear whether the differences in toxicity observed in the current study had an impact on outcome. The authors concluded that future studies examining the age-related and sex-related differences in pharmacokinetics of chemotherapy are necessary.

Topics: Adolescent; Age Factors; Anemia; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Cyclophosphamide; Dactinomycin; Doxorubicin; Epirubicin; Female; Humans; Ifosfamide; Incidence; Male; Mesna; Neutropenia; Rhabdomyosarcoma; Sex Characteristics; Survival Rate; Thrombocytopenia; Vincristine; Young Adult

A rare cause of high anion gap acidosis is 5-oxoproline (pyroglutamic acid), an organic acid intermediate of the gamma-glutamyl cycle. Acetaminophen and several other drugs have been implicated in the development of transient 5-oxoprolinemia in adults. We report the case of a patient with lymphoma who was admitted for salvage chemotherapy. The patient subsequently developed fever and neutropenia and was administered 20.8 g of acetaminophen during 10 days. During this time, anion gap increased from 14 to 30 mEq/L (14 to 30 mmol/L) and altered mental status developed. After usual causes of high anion gap acidosis were ruled out, a screen for urine organic acids showed 5-oxoproline levels elevated at 58-fold greater than normal values. Predisposing factors in this case included renal dysfunction and sepsis. Clinicians need to be aware of this unusual cause of anion gap acidosis because it may be more common than expected, early discontinuation of the offending agent is therapeutic, and administration of N -acetylcysteine could be beneficial.

Topics: Acetaminophen; Acid-Base Equilibrium; Acidosis; Adult; Analgesics, Non-Narcotic; Antineoplastic Combined Chemotherapy Protocols; Bicarbonates; Candidiasis; Chlorides; Cytarabine; Etoposide; Fatal Outcome; Fever; Humans; Ifosfamide; Kidney Tubular Necrosis, Acute; Lymphoma, Follicular; Lymphoma, Large B-Cell, Diffuse; Male; Mesna; Neutropenia; Polycystic Kidney, Autosomal Dominant; Pyrrolidonecarboxylic Acid; Salvage Therapy; Systemic Inflammatory Response Syndrome

Topics: Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma, Squamous Cell; Clinical Trials, Phase II as Topic; Data Interpretation, Statistical; Endpoint Determination; Head and Neck Neoplasms; Humans; Ifosfamide; Mesna; Neutropenia; Paclitaxel; Reproducibility of Results; Survival; Taxoids

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Chemotherapy, Adjuvant; Child; Child, Preschool; Cisplatin; Combined Modality Therapy; Cranial Irradiation; Drug Administration Schedule; Etoposide; Germany; Humans; Ifosfamide; Lomustine; Medulloblastoma; Mesna; Nervous System Diseases; Neutropenia; Postoperative Period; Prospective Studies; Radiotherapy, Adjuvant; Randomized Controlled Trials as Topic; Treatment Outcome; Vincristine

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

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

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

Twenty-one consecutive patients with refractory or relapsed non-Hodgkin's lymphomas were treated with a novel combination chemotherapy (MINE-BOP), comprising myelosuppressive (ifosfamide, mitoxantrone, etoposide) and non-myelosuppressive (bleomycin, vincristine and prednisone) drugs. Median age of the patients was 42 years and all had intermediate or high-grade lymphoma. Fifteen patients had refractory disease. All patients had previously been treated with one or two regimens, containing anthracyclines. In all cases the duration between the last chemotherapy and the MINE-BOP regimen was shorter than 12 months. Response rate was 57% with 33% complete remission (CR). Median disease-free and overall survivals were 7 and 10 months respectively. The serum LDH level was the only significant prognostic factor in this study. The toxicity of this regimen was moderate with 24% of febrile neutropenia and 9% of microscopic hematuria. Toxic death due to febrile neutropenia was observed in one patient who had bone marrow involvement. To conclude, the addition of non-myelosuppressive drugs to the chemotherapy regimen and shortening the interval between the application of cytotoxic drugs as used in the present study did not show any improvement of response and survival in this group of patients.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Cisplatin; Cytarabine; Disease-Free Survival; Etoposide; Female; Hematuria; Humans; Ifosfamide; Lymphoma, Non-Hodgkin; Male; Mesna; Middle Aged; Mitoxantrone; Neutropenia; Prednisone; Prospective Studies; Recurrence; Survival Rate; Vincristine