Feasibility of olanzapine, multi acting receptor targeted antipsychotic agent, for the prevention of emesis caused by continuous cisplatin- or ifosfamide-based chemotherapy.

Background To determine the feasibility and efficacy of olanzapine, which is approved by the Pharmaceuticals and Medical Devices Agency as multi acting receptor targeted antipsychotic agent of the thienobenzodiazepine class, for prevention of chemotherapy-induced nausea and vomiting (CINV) in patients undergoing continuous five-day chemotherapy. Patients and methods This study was a prospective dose escalation study at a single center (UMIN ID: UMIN000015386). Patients received a combination of adriamycin and ifosfamide (AI) or a combination of bleomycin, etoposide, and cisplatin (BEP). On days 1-5, all patients received intravenous granisetron (1 mg) and intravenous dexamethasone sodium phosphate (24 mg). Olanzapine was administrated on day-1 to day5 at bedtime. The dose of olanzapine followed a dose-escalation scheme, with monitoring of safety and tolerability at each dose. A 3 + 3 cohort design was used, with three to six patients per cohort. Results Nine patients were enrolled (three for each cohort). No patients experienced dose-limiting toxicity (DLT). The most frequent adverse events were dry mouth and constipation. In each cohort, the maximum severity of nausea was Grade 2, and no patients experienced a vomiting episode. Conclusion A 2.5 mg/day dosage of olanzapine is sufficient to prevent from CINV in Japanese patients receiving continuous five-day chemotherapy. A dose of 10 mg/day, which is recommended by international CINV guidelines, is also tolerated. If CINV is not controlled by an initial dose of 2.5 mg/day of olanzapine, dosage escalation is encouraged. Future studies should compare olanzapine with aprepitant.

EURAMOS-1, an international randomised study for osteosarcoma: results from pre-randomisation treatment.

BACKGROUND: Four international study groups undertook a large study in resectable osteosarcoma, which included two randomised controlled trials, to determine the effect on survival of changing post-operative chemotherapy based on histological response. PATIENTS AND METHODS: Patients with resectable osteosarcoma aged ≤40 years were treated with the MAP regimen, comprising pre-operatively of two 5-week cycles of cisplatin 120 mg/m(2), doxorubicin 75 mg/m(2), methotrexate 12 g/m(2) × 2 (MAP) and post-operatively two further cycles of MAP and two cycles of just MA. Patients were randomised after surgery. Those with ≥10% viable tumour in the resected specimen received MAP or MAP with ifosfamide and etoposide. Those with <10% viable tumour were allocated to MAP or MAP followed by pegylated interferon. Longitudinal evaluation of quality of life was undertaken. RESULTS: Recruitment was completed to the largest osteosarcoma study to date in 75 months. Commencing March 2005, 2260 patients were registered from 326 centres across 17 countries. About 1334 of 2260 registered patients (59%) were randomised. Pre-operative chemotherapy was completed according to protocol in 94%. Grade 3-4 neutropenia affected 83% of cycles and 59% were complicated by infection. There were three (0.13%) deaths related to pre-operative chemotherapy. At definitive surgery, 50% of patients had at least 90% necrosis in the resected specimen. CONCLUSIONS: New models of collaboration are required to successfully conduct trials to improve outcomes of patients with rare cancers; EURAMOS-1 demonstrates achievability. Considerable regulatory, financial and operational challenges must be overcome to develop similar studies in the future. The trial is registered as NCT00134030 and ISRCTN 67613327.

Association of pegylated liposomal doxorubicin and ifosfamide in early recurrent ovarian cancer patients: a multicenter phase II trial.

OBJECTIVE: To evaluate the efficacy of pegylated liposomal doxorubicin (PLD) and continuous infusion ifosfamide (IFO) in ovarian cancer patients who relapse within 1 year after first-line paclitaxel-platinum-based chemotherapy. METHODS: Patients were stratified according to treatment-free interval (TFI) (or=6 months). PLD (40 mg/m(2), day 1), IFO (1700 mg/m(2), infusion days 1-3), and mesna were given every 28 days for 6-9 cycles. Primary endpoint was objective response rate (ORR). Secondary endpoints were response duration, progression free survival (PFS), overall survival (OS), and toxicity. RESULTS: There were 98 evaluable patients (58%, TFI<6 months). Median number of cycles was 5 (range: 1-9). The frequency of grade 3/4 anemia, thrombocytopenia, and neutropenia was 7%, 3%, and 48%, respectively; febrile neutropenia was 3%. A low rate of grade 3/4 non-hematologic toxicities was reported, including nausea/vomiting (3/4%), hand-foot syndrome (2%), and mucositis (2%). The ORR was 28% (41% and 19% in patients with TFI >or=6, or <6 months, respectively); rate of disease stabilization was 26%; response duration and median OS were 6 (2.4-26) and 14 (1-46) months, respectively. CONCLUSION: The combination of PLD and continuous IFO is a feasible and efficient treatment in patients with relapsed ovarian cancer, especially with TFI between 6 and 12 months. This regimen may represent an alternative to platinum reintroduction and should be evaluated in a randomized trial.

A phase II study of intensive-dose epirubicin/verapamil as induction therapy followed by intensive-dose ifosfamide for advanced breast cancer.

Preliminary data of an ongoing phase II-study in metastatic breast cancer patients are presented. Patients with metastatic breast cancer entered the study after hormone therapy had failed; prior treatment with cyclophosphamide, methotrexate and 5-fluorouracil (CMF) was also allowed. The patients were treated with three cycles of 40 mg/m2 epirubicin i.v. on days 1-3 and 4 x 120 mg oral verapamil on days 0-3, given every 3-4 weeks. After three chemotherapy courses, ifosfamide was given as a short infusion of 3 g/m2 on days 1-3. Mesna (20% of the total ifosfamide dose) was given 0, 4 and 8 h after ifosfamide administration. Response was evaluated after three cycles of epirubicin/verapamil and after the last (third) cycle of ifosfamide. The side effects of this treatment were tolerable. The epirubicin/verapamil combination was no more toxic than epirubicin alone. Despite the high dose of verapamil, systolic blood pressure remained above 80 mm Hg, and patients never had a period of strict bed rest. Alopecia was almost complete after induction therapy with epirubicin/verapamil, and nausea and vomiting were absent or mild during epirubicin/verapamil chemotherapy and were easily controlled by antiemetics during ifosfamide treatment. Stomatitis and mucositis, the main toxic effects, could be ameliorated by intensive mouth-washing procedures. The haematological toxicity was greater after epirubicin/verapamil treatment than after ifosfamide therapy, but neither bleeding nor infections due to thrombocytopenia or leucopenia were observed.

Bioavailability of ifosfamide in patients with bronchial carcinoma.

The pharmacokinetics of ifosfamide (I) were determined in ten patients with bronchogenic carcinoma. In seven patients, doses of 1 and 2 g (I) were given both as a bolus orally and later intravenously and were well tolerated. A further three patients received 5 g (I) as a single oral dose but in two this produced reversible CNS toxicity and severe vomiting. The area under the curve (AUC, microgram . h . l-1) for the 1-g dose was the same following oral and i.v. treatment and this was also true for the 2-g doses. There was a proportionate increase in the AUC for the 5-g oral dose, indicating 100% bioavailability at all three dose levels. We conclude that doses up to 2 g by mouth represent a well-tolerated alternative route of administration.

Phase II trial of induction chemotherapy followed by surgery for squamous cell carcinoma of the oral tongue in young adults.

BACKGROUND: We conducted a phase II clinical trial of induction chemotherapy followed by surgery ± radiotherapy for squamous cell carcinoma of the oral tongue (SCCOT) in young adults. METHODS: From September 2001 to October 2004, 23 patients aged 18 to 49 years with clinical T2-3 N0-2 M0 SCCOT and no prior radiotherapy, chemotherapy, or neck dissection underwent induction chemotherapy (paclitaxel, ifosfamide, and carboplatin) followed by glossectomy and neck dissection ± radiotherapy and chemotherapy. RESULTS: On final surgical pathology, 9 patients (39%) had a complete/major (2 complete) histologic response at the primary tumor site; 8 patients (35%) had no response or progression. Similarly, 9 patients (39%) had a complete response in the neck or remained node negative; 6 patients (26%) had an increase in nodal category. No treatment-associated deaths occurred, and toxicity was modest. At a median follow-up from the end of treatment of 52 months (minimum, 23 months), 10 patients (43%) developed recurrence, and all 10 died of cancer. Crude recurrence/cancer death rates were associated with ≤ a partial response at the tongue (p = .029), poor histologic differentiation (p = .012), and multiple adverse features on final surgical pathology (p = .040). CONCLUSION: Response rates and overall survival with this induction chemotherapy regimen were limited, but complete/major response at the tongue was associated with excellent prognosis. Additionally, improved patient selection and predictive tumor biomarkers will be needed for induction chemotherapy to be routinely incorporated into the treatment of oral tongue cancer in young adults.

Investigation into modification of mass transfer kinetics by acrolein in a renal biochip.

In this study we present a method for investigating the effect of acrolein, a nephrotoxic and urotoxic metabolite of the anticancerous prodrugs ifosfamide and cyclophosphamide, in a blood-renal barrier biochip. The real time monitoring of mass transfers of caffeine, vitamin B12 and albumin in the biochip was performed thanks to an in vitro dialysis method. The diffusion coefficients of the solutes and their dialysance from the apical to the basolateral compartments were found to be molecular weight and cell-membrane dependent, thus demonstrating the cell-barrier functionality. The toxicity induced by the acrolein led to modifications to mass transfer properties which appeared to be acrolein dose, time and solute molecular weight dependent. Solute mass transfer across the cell layer increased with acrolein concentrations. The sensitivity of this analysis method contributes to identify the mass transfer properties and to monitor the modification to the renal parameter when submitted to toxic cell compounds. The results provide the foundation for exploring kidney behavior in response to drugs thanks to a blood-tissue barrier model using a technique based on in vitro dialysis and real time analysis.

Sequential salvage chemotherapy for recurrent intracranial hemangiopericytoma.

OBJECTIVE: Hemangiopericytoma (HPC) is an uncommon primary brain tumor with an almost invariable tendency to recur and metastasize. We undertook a retrospectively collected case series of recurrent intracranial HPCs treated with salvage chemotherapy with the primary objective of evaluating progression-free survival. METHODS: Fifteen patients, ages 26 to 62 years, with recurrent HPC and who were previously treated with surgery and involved-field radiotherapy were studied. Eight (53%) of these patients had undergone re-resection before study entry. Ten patients (67%) were treated with stereotactic radiotherapy. Chemotherapy was administered to 5 patients at first relapse, 8 at second relapse, and 2 at third relapse (none of these patients were candidates for reoperation or stereotactic radiotherapy). Eight patients developed disseminated disease, all with multifocal intracranial disease (5 with cerebrospinal fluid dissemination, 4 with extraneural metastases). All patients were initially treated with cyclophosphamide, doxorubicin, and vincristine (CAV). After disease progression despite the administration of CAV in clinically appropriate patients, alpha-interferon (alpha-IFN) (9 patients) was administered. Five patients were treated with ifosfamide, cisplatin, and etoposide after they failed to respond to alpha-IFN. Neurological and neuroradiographic evaluations were performed every 8 weeks. RESULTS: All patients were evaluable. A median of 4 cycles of CAV; 8 cycles of alpha-IFN; and 2 cycles of ifosfamide, cisplatin, and etoposide were administered. Chemotherapy-related toxicity included alopecia (100%), anemia (40%), thrombocytopenia (27%), and neutropenia (40%). Best response included 6 patients (40%) with a neuroradiographic partial response (2 with CAV, 4 with alpha-IFN), 14 (93%) had stable disease (9 with CAV, 5 with alpha-IFN), and 9 (60%) had progressive disease (4 with CAV, 5 with ifosfamide, cisplatin, and etoposide). The median overall survival was 14 months (range, 2-24 mo). CONCLUSION: Salvage chemotherapy demonstrated modest efficacy with acceptable toxicity in this cohort of adult patients with recurrent surgery- and radiotherapy-refractory intracranial HPC.

Influence of low-energy laser in the prevention of oral mucositis in children with cancer receiving chemotherapy.

BACKGROUND: This study assessed the use of low-energy laser in the prevention or reduction of the severity of oral mucositis. PROCEDURE: A randomized clinical trial was carried out. Patients from 3 to 18 years of age treated with chemotherapy or hematopoietic stem-cell transplantation between May, 2003 and February, 2005 were eligible. The intervention group received laser application for 5 days following the start of chemotherapy. The grade of oral mucositis was assessed by the WHO per NCI-CTC common toxicity criteria and the assessments were made on days 1, 8 and 15 by a trained examiner blind to the intervention. RESULTS: Sixty patients were evaluable for analysis; thirty-nine (65%) were males, 35 (58%) patients had a diagnosis of leukemia or lymphoma, and 25 (42%) had solid tumors. The mean age was 8.7 +/- 4.3 years. Twenty-nine patients were randomized in the laser group and 31 in the control group. On day 1, no patients presented with mucositis. On day 8, of 20 patients (36%) who developed mucositis, 13 of them were from the laser group and 7 from the control group. On day 15, of 24 patients (41%) who developed mucositis, 13 of them were from the laser group and 11 from the control group. There was no significant difference between groups concerning the grades of mucositis on day 8 (P = 0.234) or on day 15 (P = 0.208). CONCLUSIONS: This study showed no evidence of benefit from the prophylactic use of low-energy laser in children and adolescents with cancer treated with chemotherapy when optimal dental and oral care was provided.

Combination therapy with ifosfamide and liposome-encapsulated muramyl tripeptide: tolerability, toxicity, and immune stimulation.

A phase IIb trial using liposome-encapsulated muramyl tripeptide phosphatidylethanolamine (L-MTP-PE) in combination with ifosfamide (IFX) for patients with relapsed osteosarcoma was undertaken to determine (a) the tolerability of the combination therapy, (b) if L-MTP-PE increased the toxicity of IFX, and (c) whether IFX altered or suppressed the in vivo immune response to L-MTP-PE. Patients had histologically proven osteosarcoma and pulmonary metastases that either developed during adjuvant chemotherapy or were present at diagnosis, persisted despite chemotherapy, and recurred following surgical excision. Stratum A patients were rendered clinically free of disease within 4 weeks of study entry prior to receiving combination therapy. IFX was administered at 1.8 g/m2 for 5 days every 21 days for up to eight cycles. L-MTP-PE was administered twice weekly for 12 weeks, then once weekly for 12 weeks. Once cycle of combination therapy was defined as 5 days of IFX and 3 weeks of L-MTP-PE therapy. Stratum B patients had measurable disease at study entry that was judged to be amenable to surgical resection. Stratum B patients received three cycles of combination therapy prior to surgery to judge clinical and histologic response. Postoperatively, patients received an additional five cycles. A total of nine patients were entered into the protocol: six on stratum A and three on stratum B. Serial blood samples were collected and assayed for cytokine levels (tumor necrosis factor-alpha [TNF alpha], interleukin-6 [IL-6], IL-8, neopterin, C-reactive protein). In addition, peripheral blood monocyte tumoricidal activity was evaluated pre- and post-combination therapy. Complete blood counts with differential and platelet counts were followed weekly. No increase in the toxic side effects of IFX was demonstrated when administered with L-MTP-PE nor were delays in IFX administration due to neutropenia experienced. The toxic side effects of L-MTP-PE were also not increased. Elevations of serum C-reactive protein, plasma neopterin, IL-6, IL-8, and TNF alpha following combination therapy were similar to those observed in patients treated with L-MTP-PE alone. Monocyte-mediated tumoricidal activity was elevated 24 and 72 h following L-MTP-PE and IFX therapy, similar to what has been reported following L-MTP-PE alone. Tumor specimens obtained from stratum B patients showed the histologic characteristics consistent with a "chemotherapy effect," i.e., dead, amorphous, acellular osteoid with cell drop-out.(ABSTRACT TRUNCATED AT 400 WORDS)