mesna and Carcinoma

Ifosfamide is a cyclophosphamide analogue synthesized in the 1960s with antineoplastic activity demonstrated in early broad-ranging phase I studies conducted in Germany in the 1970s. Because of significant urothelial toxicity, phase II studies in ovarian cancer in this country were delayed until the urinary epithelial protector mesna became available in 1985. Since that time, two well-executed prospective trials have shown that this agent produces measurable responses in about 20% of women with ovarian epithelial cancer recurring after primary chemotherapy and in 12% of those with tumors refractory to first-line therapy with regimens including cisplatin. Toxicity includes moderate to severe hematologic toxicity, renal dysfunction which is usually reversible, and CNS abnormalities including lethargy, somnolence, and disorientation. The risk of toxicity may be increased in patients with compromised hepatic or renal function and in those with hydronephrosis or hypoalbuminemia.

Topics: Carcinoma; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Female; Humans; Ifosfamide; Mesna; Ovarian Neoplasms; Urologic Diseases

High-dose chemotherapy combined with autologous peripheral blood stem cell transplantation has shown promise as treatment for recurrent or persistent epithelial ovarian cancer. We evaluated the stem cell mobilization regimen of high-dose ifosfamide plus etoposide in 32 patients with epithelial ovarian cancer, who had a positive second-look laparatomy or recurrent disease. Ifosfamide was given at 10 g/m2 by continuous i.v. from days 1 to 3. Etoposide was given at 150 mg/m2 every 12 h for six doses on days 1-3. Filgrastim was given at 10 microg/kg/d s.c. from day 5 until the completion of peripheral blood stem cell harvest. Fourteen of 32 patients had measurable or evaluable disease before mobilization therapy and were assessed for response. In nine (64%) of the 14 patients, treatment response was demonstrated, and these patients received a second cycle of mobilization therapy. The target CD34+ cell dose (>8 x 106 cells/kg) was achieved with a median of one apheresis (range 1-5). A median of 25.1 (range 8.0-122.5) x 106 CD34+ cells/kg body weight was collected. Non-hematologic toxicity was limited to grade 2 renal dysfunction in one patient and grade 2 hepatic dysfunction in three patients. In this patient group, high-dose ifosfamide plus etoposide with filgrastim support was well tolerated, lead to successful stem cell harvest and had antitumor activity.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Blood Component Removal; Carcinoma; Combined Modality Therapy; Etoposide; Female; Filgrastim; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Humans; Ifosfamide; Mesna; Middle Aged; Ovarian Neoplasms; Recombinant Proteins; Transplantation, Autologous

A phase II trial was performed to evaluate the efficacy and toxicity of a combination of cisplatin (CDDP) and ifosfamide (IFX) as neoadjuvant chemotherapy in advanced cervical carcinoma (ACC). Between August 1991 and September 1993, 57 untreated patients with stages IIB to IVA were entered into this study. Median age was 44 years (range, 25 to 74 years). The distribution by stages (International Federation of Gynecology and Obstetrics) was as follows: IIB, 31 patients; IIIB, 21 patients; and IVA, 5 patients. Therapy consisted of IFX 2000 mg/m(2) 1-h i.v. infusion days 1 to 3; mesna 400 mg/m(2) i.v. bolus at hours 0 and 4, and 800 mg p.o. at hour 8; and CDDP 100 mg/m(2) on day 3. Cycles were repeated every 28 days for a total of three courses. Both staging and response assessment were performed by a multidisciplinary team. An objective response was observed in 30 of 56 patients (54%; 95% confidence interval, 41 to 67%). Four patients (7%) had a complete response (CR) and 26(46%) had a partial response (PR). Patients with CR or operable PR underwent surgery, otherwise received definitive radiotherapy. Toxicity was mild to moderate. There were no toxicity related deaths. These results indicate that IFX/CDDP is an active combination for ACC with mild toxicity. The results of phase III studies that evaluate the real impact of neoadjuvant chemotherapy are awaited.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Chemotherapy, Adjuvant; Cisplatin; Female; Follow-Up Studies; Humans; Ifosfamide; Mesna; Middle Aged; Neoplasm Staging; Prospective Studies; Radiotherapy, Adjuvant; Remission Induction; Survival Rate; Uterine Cervical Neoplasms

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

Long-term culture-initiating cells (LTC-IC) are arguably the most primitive human hematopoietic cells detectable by in vitro functional assays. We have investigated the mobilization of these cells into the blood of patients with ovarian carcinoma randomized to receive granulocyte colony-stimulating factor (G-CSF; 5 micrograms/kg) plus different doses of stem cell factor (SCF; c-kit ligand) after chemotherapy or G-CSF alone after chemotherapy. We have shown a significant SCF dose response for the mobilization of LTC-IC, with a 5.8-fold increase in LTC-IC mobilization in those patients receiving chemotherapy, G-CSF, and 20 micrograms/kg of SCF, the highest dose used, compared with the patients receiving chemotherapy and G-CSF alone. We have shown a threefold increase in CD34+ cells and up to a 64-fold increase in CD34+/33- cells was seen in patients treated with chemotherapy, G-CSF, and 20 micrograms/kg of SCF compared with those patients treated with chemotherapy and G-CSF alone. However, significant numbers of CD34+/38- cells were only found in the patients receiving 20 micrograms/kg of SCF as part of their mobilization regimen. Patients receiving chemotherapy plus G-CSF and SCF have enhanced mobilization of primitive cells and of the more committed progenitor cells compared with those patients receiving chemotherapy followed by G-CSF alone.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Blood Component Removal; Carcinoma; Cell Count; Clone Cells; Cohort Studies; Cyclophosphamide; Female; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cells; Humans; Infusions, Intravenous; Mesna; Middle Aged; Ovarian Neoplasms; Recombinant Proteins; Stem Cell Factor; Time Factors

A phase II trial of ifosfamide (IFX) and mesna was conducted by the GOG in patients with recurrent or advanced nonsquamous carcinoma of the cervix. A starting dose of 1.5 g/m2 IFX iv daily for 5 days and 300 mg/m2 mesna iv every 4 hr with three doses daily after IFX were given. In patients who had received prior radiotherapy or chemotherapy, the starting dose of IFX was reduced to 1.2 g/m2. Forty-six patients were entered, and 41 are evaluable for toxicity. Forty patients are evaluable for response. Age range was 30-72 yr. GOG performance status was 0-1 for all but 2 patients. Fifteen patients (37.5%) developed GOG grade 3 or 4 granulocytopenia, and 1 developed grade 4 thrombocytopenia. One patient developed transient renal insufficiency. There was one complete response and five partial responses (12.5%) for a response rate of 15.0%. Median response duration was 4.2 months (range, 1.7-22.6 months). Three responses were seen in areas with pelvic disease only. Three responses were observed in extrapelvic sites. IFX possesses activity which compares favorably with that of other agents in this disease.

Topics: Adenocarcinoma; Adult; Aged; Carcinoma; Female; Humans; Ifosfamide; Mesna; Middle Aged; Uterine Cervical Neoplasms

There is a critical need to find new antineoplastic drugs that are active in platinum-refractory ovarian cancer. We conducted a phase II trial of single-agent ifosfamide with mesna uroprotection in patients with ovarian cancer previously treated with an organoplatinum compound to assess its activity in this clinical setting.. Ifosfamide (1.0 or 1.2 g/m2/d for 5 days, delivered on a monthly schedule) was administered to the 57 patients entered onto this trial. Dose reductions were permitted for unacceptable toxicities.. Toxicity included severe bone marrow suppression (WBC count less than 1,000/microL and/or platelet count less than 50,000/microL), renal dysfunction (serum creatinine level greater than 2.0 mg/dL), and reversible CNS dysfunction (disorientation, hallucinations, somnolence, and agitation), which occurred in 20%, 14%, and 12% of patients, respectively. Of 41 patients with strictly defined platinum-refractory ovarian cancer, five (12%) demonstrated a partial (four) or complete (one) response to this treatment program.. Single-agent ifosfamide has modest but unequivocal activity in platinum-resistant ovarian cancer. Further studies of this drug used as a front-line agent along with an organoplatinum compound or as part of a dose-intensification program with bone marrow, peripheral stem cell, or colony-stimulating factor support are indicated. In addition, single-agent ifosfamide is a reasonable standard second-line treatment strategy in appropriately selected patients with platinum-refractory ovarian cancer.

Topics: Acute Kidney Injury; Adult; Aged; Carcinoma; Drug Evaluation; Drug Resistance; Female; Humans; Ifosfamide; Mesna; Middle Aged; Ovarian Neoplasms; Platinum

Thirty-six patients with recurrent carcinoma of the head and neck and no prior exposure to chemotherapy were treated with Ifosfamide. This drug was administered, concomitantly with Mesna, as a 24-hr infusion at a dose of 5-6.25 g/m2 every 3 weeks. Objective activity in 32 evaluable patients was 28% (9/32, 95% C.I. 17%-39%); 40% of patients had leukocyte values less than 2000 mm3 and 6% platelets less than 50,000 mm3. Nonhematologic toxicity consisted mainly of nausea/vomiting (66% greater than or equal to grade 2) and alopecia (80% greater than or equal to grade 2). The activity encountered warrants further studies with this drug in head and neck cancer.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Drug Evaluation; Head and Neck Neoplasms; Humans; Ifosfamide; Leukocyte Count; Male; Mesna; Middle Aged; Neoplasm Recurrence, Local; Platelet Count; Survival Rate

Ifosfamide (isophosphamide) and mesna (2-mercaptoethane sodium sulfonate) were administered intravenously at monthly intervals to 46 patients with advanced epithelial ovarian carcinoma refractory to or recurrent after cisplatin-containing combination chemotherapy. Initially, ifosfamide was given as 1.5 g/m2/d x 5 days and mesna as 300 mg/m2 every 4 hours for three doses following ifosfamide, but the initial dose of ifosfamide was reduced to 1.2 g/m2 because of toxicity. Four of the patients initially entered were found to be ineligible: two who had had more than one prior chemotherapy regimen and two who did not have ovarian primaries. One patient received an inadequate trial and four patients had discontinuation of therapy because of toxicity, leaving 41 evaluable for response. Three patients (7.0%) had complete responses and five (13.0%) had partial responses for an overall response rate of 20.0%. Response duration ranged from 2.1 to 20.3 + months with a median of 6.9 + months. Two patients died of renal failure, one of whom had no known renal disease and received 1.5 g/m2/d x 5 days ifosfamide. The second patient received the 1.2 g/m2 dose and was found to have chronic pyelonephritis and pyonephrosis at autopsy. Gynecologic Oncology Group (GOG) grade 3 or 4 granulocytopenia was seen in eight (19.5%), grade 3 or 4 thrombocytopenia in four (9.8%), and grade 3 or 4 neurotoxicity in six (14.6%) of the 41 patients evaluable for toxicity. Ifosfamide/mesna is active in epithelial ovarian cancer. GOG trials in untreated patients are being initiated and toxicity is being evaluated.

Topics: Carcinoma; Drug Evaluation; Female; Humans; Ifosfamide; Leukocyte Count; Mercaptoethanol; Mesna; Multicenter Studies as Topic; Ovarian Neoplasms; Platelet Count

A Phase II study of VP-16 (etoposide), ifosfamide/mesna, and cisplatin (VIP) in advanced and recurrent carcinoma of the cervix was initiated March 1989. VP-16, 75 mg/m2, ifosfamide, 1.0 g/m2, and cisplatin, 25 mg/m2, were administered intravenously daily for 3 consecutive days, every 28 days to a maximum of six cycles. Fourteen patients were entered on protocol. Eight patients had objective responses, all complete. Response duration ranged from 7+ to 24+ months. The chemotherapy was well-tolerated. Hematologic toxicity was the major toxicity and was manageable. VIP appears to be active in advanced carcinoma of the cervix.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Cisplatin; Etoposide; Female; Hematologic Diseases; Humans; Ifosfamide; Mesna; Middle Aged; Neoplasm Recurrence, Local; Uterine Cervical Neoplasms

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

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

A 62-year-old woman developed subacute renal failure after the repeated administration of ifosfamide (IFX), despite its combination with continuous sodium 2-mercaptoethane sulfonate (mesna) infusion. Biopsy findings, the possible underlying mechanism, and the existing literature are discussed.

Topics: Acute Kidney Injury; Antineoplastic Combined Chemotherapy Protocols; Biopsy; Carcinoma; Dose-Response Relationship, Drug; Female; Humans; Ifosfamide; Kidney; Mercaptoethanol; Mesna; Middle Aged; Ovarian Neoplasms

The Gastrointestinal Tumor Study Group (GITSG) investigated the efficacy of ifosfamide with mesna uroprotection in 30 patients with advanced inoperable pancreatic carcinoma that was confirmed histologically. All patients were required to have at least one bidimensional measurable lesion that could be followed by palpation or radiologic examination. Genitourinary toxicity presenting as hematuria occurred in five patients, but was not severe enough to curtail treatment in any of these patients. The major toxicity was neurologic, with 12 patients (41%) reporting at least one episode; four of which were graded as severe and two as fatal. Three partial tumor responses to treatment were reported (10%) and the median survival time was just 11 weeks. In our experience, ifosfamide with mesna uroprotection does not appear to be active in pancreatic carcinoma.

Topics: Adult; Aged; Carcinoma; Drug Evaluation; Female; Hematuria; Humans; Ifosfamide; Male; Mesna; Nervous System Diseases; Pancreatic Neoplasms

The Gynecologic Oncology Group initiated a series of phase II trials of ifosfamide/mesna in women with advanced or recurrent gynecologic malignancies in July 1985. Previously untreated patients received ifosfamide, 1.5 g/m2/d, intravenously (IV) for five days. Mesna was given IV in three doses every four hours after ifosfamide; each dose was 20% of the daily ifosfamide dose (ie, 300 mg/m2). All patients with ovarian and 87% of those with cervical cancer had undergone platinum-based therapy previously. Because of the toxicity encountered in previously treated ovarian cancer patients, the dose of ifosfamide was reduced to 1.2 g/m2/d in patients who had received prior chemotherapy or radiotherapy. In epithelial ovarian carcinoma, responses were observed in eight (21.6%) of 37 evaluable patients with three (8.1%) complete responses. Response duration was 2.1 to 20.3+ months with a median of 6.9+ months. In squamous carcinoma of the cervix, three (11.1%) of 27 evaluable patients had partial responses of 1.8, 2.2, and 3.1 months' duration. Of 29 untreated patients with mixed mesodermal tumors of the uterus, five (17.9%) had complete and four (14.3%) had partial responses for an overall response rate of 32.2%. Response duration was 1.4+ to 8.6 months with a median of 3.8 months. Toxicity included two deaths from renal insufficiency and a third related to neurologic impairment. Hematologic toxicity was manageable. Ifosfamide/mesna has activity in a wide range of gynecologic malignancies.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma; Carcinoma, Squamous Cell; Cisplatin; Drug Evaluation; Female; Humans; Ifosfamide; Mercaptoethanol; Mesna; Middle Aged; Neoplasms, Germ Cell and Embryonal; Organoplatinum Compounds; Ovarian Neoplasms; Uterine Cervical Neoplasms; Uterine Neoplasms