Traumeel S in preventing and treating mucositis in young patients undergoing SCT: a report of the Children's Oncology Group.

Mucositis can be a serious complication of hematopoietic SCT (HSCT). A previous phase II trial in 32 children undergoing HSCT reported a beneficial effect of the homeopathic remedy Traumeel S. The Children's Oncology Group sought to replicate the results in a multi-institutional trial. The study was an international multi-center, double-blind, randomized trial comparing Traumeel with placebo in patients aged 3-25 years undergoing myeloablative HSCT. Traumeel/placebo was started on Day -1 as a five-time daily mouth rinse. Efficacy of the treatment was assessed using the modified Walsh scale for mucositis, scored daily from Day -1 to 20 days after HCST. The main outcome was the sum of Walsh scale scores (area-under-the-curve (AUC)) over this period. Other outcomes included narcotic use, days of total parenteral feeding, days of nasogastric feeding and adverse events. In 181 evaluable patients, there was no statistical difference in mucositis (AUC) in the Traumeel group (76.7) compared with placebo (67.3) (P=0.13). There was a trend towards less narcotic usage in the Traumeel patients. No statistically beneficial effect from Traumeel was demonstrated for mucositis. We could not confirm that Traumeel is an effective treatment for mucositis in children undergoing HSCT.

Treatment of intermediate risk rhabdomyosarcoma and undifferentiated sarcoma with alternating cycles of vincristine/doxorubicin/cyclophosphamide and etoposide/ifosfamide.

Over 50% of patients with newly diagnosed rhabdomyosarcoma (RMS) are in the 'intermediate risk' group with a 3-year progression-free survival of approximately 65%. This group consists of stage 1, group III, non-orbit tumours; stage 2, group II and III; and all stage 3 patients utilising the Intergroup Rhabdomyosarcoma Study (IRS) staging system. The role of doxorubicin in the treatment of RMS has been controversial. Ifosfamide, both alone and in combination with etoposide, has significant activity in patients with RMS. The aim of this pilot study was to examine the efficacy and toxicity of a chemotherapy regimen of alternating cycles of vincristine/doxorubicin/cyclophosphamide and etoposide/ifosfamide for intermediate risk RMS. 30 patients with intermediate risk RMS or undifferentiated sarcoma (US) were treated with alternating cycles of vincristine/doxorubicin/cyclophosphamide (VDC) and etoposide/ifosfamide (EI) at planned intervals of 3 weeks. Local treatment of the tumour in most cases was performed after four cycles of chemotherapy, followed by an additional 10 cycles of chemotherapy. At a median follow-up of 37.5 months, the Kaplan-Meier estimate of 3-year event-free survival was 85% (95% confidence interval 72-99%). The overall survival at 3 years was 91% (95% confidence interval 80-100%). No patient died from toxicity. The most common toxicity was febrile neutropenia in 35% of VDC and 26% of EI cycles. No nephrotoxicity or cardiac toxicity was seen. No patient progressed prior to week 12 local therapy. Alternating cycles of VDC and EI are an effective treatment for patients with intermediate risk RMS and US. Toxicity is tolerable. Delaying local treatment until week 12 does not compromise outcome.

Treatment of childhood lymphangiomas with interferon-alpha.

PURPOSE: Nonsurgical treatment of lymphangiomas has shown limited efficacy and often carries unacceptable toxicities, demonstrating the need for a more effective, less toxic therapy. PATIENTS AND METHODS: We describe two patients with lymphangiomatosis treated for 12 to 40 months with recombinant interferon-alpha. RESULTS: Both patients demonstrated stabilization or marked improvement of disease, based on clinical and radiologic findings, with minimal toxicity. CONCLUSIONS: The favorable responses to interferon-alpha therapy in these two cases suggest that this is an effective and well-tolerated treatment for lymphangiomas in children.

Hemorrhagic cystitis after bone marrow transplantation. Risk factors and complications.

Hemorrhagic cystitis (HC) is a major cause of morbidity after BMT; we have analyzed its incidence, risk factors, and complications in 977 patients undergoing BMT between 1974 and 1988. Despite vigorous hydration and frequent voiding in all patients receiving cyclophosphamide, 135/977 (15% by Kaplan-Meier projection) developed HC (micro- or gross hematuria, dysuria, bladder pain) between -11 and +100 days (median +22) after BMT. Of these, 60 had severe HC, including major urinary obstruction (4/60), renal failure (13/60), or need for surgical or chemical bladder cauterization (16/60). By univariate analysis, allogeneic BMT recipients had more frequent HC than autologous patients (17% vs. 9%, P = 0.002). In addition, allogeneic patients with adenoviruria were at increased risk for the development of HC. Patients with aplastic anemia conditioned with high dose cyclophosphamide and total lymphoid irradiation had the highest rate of HC (22%) versus those with hematologic malignancies (15%, P = 0.03). A Cox proportional hazards regression model was used to further identify those factors independently associated with HC. In all regression models, the factor most highly associated with the development of HC was the finding of adenovirus in the urine preceding the onset of hematuria. HC-related morbidity, and its associated increased hospitalization costs, frequently complicates BMT. Improved prophylactic measures, perhaps including the use of 2-mercaptoethane sulfonate, are needed, at least for allogeneic BMT patients with their attendant risk of adenovirus infection.

Depot characteristics and biodistribution of interleukin-2 liposomes: importance of route of administration.

Due to rapid clearance of interleukin-2 (IL-2), it has had limited effective use as an in vivo immunostimulant. Current experimental and clinical protocols generally must utilize large doses, multiple injections, or continuous infusions of IL-2 in order to achieve significant immunostimulation, often at the expense of systemic toxicity. Therefore, the pharmacodynamics of IL-2 liposomes were investigated. IL-2 liposome incorporation efficiency was 80.4% (SD 5.5); vesicle diameter was 1.65 microns (SD 0.09) as determined by fluorescence-activated cell sorting (FACS). Both formulation (free cytokine vs. IL-2 liposomes) and route of administration were important variables in determination of the biodistribution and pharmacokinetic characteristics of IL-2. When free [125I]IL-2 was given i.v. to mice, only 6.5% was in the blood and 3% in liver and spleen 2 h after injection; on the other hand, at 2 h greater than 70% of i.v. [125I]IL-2 liposomes were detected in the blood, liver, spleen, and lungs. Mean i.v. elimination t1/2 from the blood of rats given 20 x 10(6) U/kg free cytokine or IL-2 liposomes was 41 versus 102 min, respectively, as measured by bioassay and 59 and 119 min as measured by enzyme immunoassay (EIA). After i.v. administration, the estimated Vd of IL-2 liposomes was 13-fold smaller than the free cytokine. Intrathoracic (i.tx.), i.p., and s.c. administration of [125I]IL-2 to mice also demonstrated significant depot effects when IL-2 was incorporated into liposomes. These data suggest IL-2 liposomes may provide in vivo immunostimulation superior to the free cytokine due to biodistribution and depot characteristics.

Anti-tumor vaccine adjuvant effects of IL-2 liposomes in mice immunized against MCA-102 sarcoma.

MCA-102, a murine sarcoma previously reported to be non-immunogenic in C57/BL6 murine tumor models was used in a tumor vaccine preparation which included liposome encapsulated IL-2 as an adjuvant. C57/BL6 mice were immunized in the right hind footpad with irradiated MCA-102 murine sarcoma cells on days 0, 7, and 21 with or without IL-2 liposome adjuvant at 25,000 IL-2 units/injection. Mice were challenged with live tumor in the right flank on day 35. Survival of mice given IL-2 liposomes with irradiated MCA-102 cells was significantly prolonged over mice given tumor antigen with saline, and non-immunized mice. In addition, mice which received the IL-2 liposome adjuvant also had prolonged survival over those mice immunized with the additional control adjuvants of free IL-2 or dimyristoyl phosphatidyl choline (DMPC) lipid in the form of empty liposomes. IL-2 liposome plus tumor antigen also yielded a significant local protective response against live MCA-102 tumor challenge. When live tumor was injected into the site of previous immunizations on day 21 after two immunizations, the IL-2 liposome adjuvant group showed significantly delayed local growth of tumor compared to animals immunized without adjuvant, or with the adjuvants of empty liposomes or free IL-2. Finally, immunized mice were challenged with irradiated tumor cells and saline intradermally in the ears and delayed type hypersensitivity (DTH), an indicator of helper T cell response, was measured.(ABSTRACT TRUNCATED AT 250 WORDS)