Characterization of bone metastases in patients with renal cell cancer.

OBJECTIVE: To characterize the clinical features of bone metastases in patients with renal cell carcinoma (RCC) treated with interleukin-2 therapy. Bone lesions contribute to significant morbidity and mortality, and although present in up to half of patients with RCC, their behaviour and response to therapy have not been well characterized. PATIENTS AND METHODS: We evaluated skeletal metastases in 19 patients with bone lesions who received either moderate- or high-dose interleukin-2 therapy. Data on bone disease, including location and number of bone lesions, need for bone-specific therapies and use of pain medications, were noted. The response of bone lesions to interleukin-2 was compared with the response of other systemic metastatic sites. RESULTS: Skeletal metastases resulted in significant morbidity by causing pain (75%) and other complications requiring surgical and/or radiotherapeutic intervention (94%) before beginning interleukin-2 therapy. In most patients the response of bone lesions to interleukin-2 was similar to that in their other systemic sites. Treatment with interleukin-2 had no significant effect on the requirement for pain medication for bone pain. However, it may have prevented skeletal complications requiring surgery or radiotherapy. None of the patients had hypercalcaemia; there was no significant association between bone metastases and elevated alkaline phosphatase levels. CONCLUSIONS: Skeletal metastases are a significant contributor to morbidity among patients with RCC. Bone lesions respond similarly to interleukin-2 therapy as other systemic sites. Bisphosphonates appear promising for these predominantly osteolytic lesions.

Phase I study of recombinant human CD40 ligand in cancer patients.

PURPOSE: To determine the toxicity, maximum-tolerated dose (MTD), and pharmacokinetics of recombinant human CD40 ligand (rhuCD40L) (Avrend; Immunex Corp, Seattle, WA), suggested in preclinical studies to mediate cytotoxicity against CD40-expressing tumors and immune stimulation. PATIENTS AND METHODS: Patients with advanced solid tumors or intermediate- or high-grade non-Hodgkin's lymphoma (NHL) received rhuCD40L subcutaneously daily for 5 days in a phase I dose-escalation study. Subsequent courses were given until disease progression. RESULTS: Thirty-two patients received rhuCD40L at three dose levels. A total of 65 courses were administered. The MTD was 0.1 mg/kg/d based on dose-related but transient elevations of serum liver transaminases. Grade 3 or 4 transaminase elevations occurred in 14%, 28%, and 57% of patients treated at 0.05, 0.10, and 0.15 mg/kg/d, respectively. Other toxicities were mild to moderate. At the MTD, the half-life of rhuCD40L was calculated at 24.8 +/- 22.8 hours. Two patients (6%) had a partial response on study (one patient with laryngeal carcinoma and one with NHL). For the patient with laryngeal cancer, a partial response was sustained for 12 months before the patient was taken off therapy and observed on no additional therapy. Three months later, the patient was found to have a complete response and remains biopsy-proven free of disease at 24 months. Twelve patients (38%) had stable disease after one course, which was sustained in four patients through four courses. CONCLUSION: The MTD of rhuCD40L when administered subcutaneously daily for 5 days was defined by transient serum elevations in hepatic transaminases. Encouraging antitumor activity, including a long-term complete remission, was observed. Phase II studies are warranted.

Torsades de pointes in 3 patients with leukemia treated with arsenic trioxide.

Arsenic trioxide is used in clinical trials in the treatment of relapsed and resistant cases of acute promyelocytic leukemia. Adverse effects from arsenic in these studies have been multisystemic. Arsenic is known to cause corrected QT-interval prolongation and T-wave changes, but the potential for serious ventricular arrhythmias is less well understood. Torsades de pointes, a form of ventricular tachycardia, has been reported with arsenic poisoning but not at therapeutic doses used in protocols for hematologic malignancies. We describe 3 patients in whom this arrhythmia developed while they were treated with arsenic trioxide. Early recognition of the arrhythmia or correction of contributory factors is important because arsenic induced ventricular arrhythmias are known to be resistant to most chemical methods and electrical cardioversion.

Phase I clinical and pharmacokinetic study of menogaril (7-con-O-methylnogarol) in previously treated patients with acute leukemia.

Fifteen patients with relapsed or refractory acute leukemia were treated in this phase I study of menogaril (7-con-O-methylnogarol), a nogalamycin anthracycline derivative. Doses ranged from 50 mg/m2/day to 130 mg/m2/day, administered daily for 5 days. Pharmacokinetic studies were performed at each dose level and confirmed the findings of pharmacokinetic data derived from previous studies in patients with solid tumors. All patients experienced grade 4 hematologic toxicity and the dose limiting toxicity was mucositis. Two patients, one with acute myeloid leukemia and one with acute lymphoid leukemia, achieved complete responses. The AML complete response lasted 10 months and the ALL patient died in CR at 2+ months. Both patients were treated at a dose of 100 mg/m2/day for five days. At this dose, a second induction or consolidation course could be given without severe mucositis, and this is the dose recommended for further phase II studies in leukemia using this schedule.

Long-term follow-up of treatment and potential cure of adult acute lymphocytic leukemia with MOAD: a non-anthracycline containing regimen.

A total of 55 previously untreated adults with acute lymphocytic leukemia (ALL), median age 38 years (range 15-73 years), were treated with MOAD (methotrexate, vincristine, L-asparaginase, and dexamethasone). This regimen includes five phases--induction, consolidation, cytoreduction, maintenance, and central nervous system (CNS) prophylaxis with parenteral high-dose methotrexate. Of the 55 evaluable patients, 42 achieved complete remission 76%), with a median CR duration of 12+ months (range 0.5-195+ months). The median survival in remission is 22+ months (range 1-198+ months), with 33% of remitters continuing in long-term remissions (> 5 years). Two out of four patients who developed CNS leukemia did so without marrow relapse, were successfully treated for that complication, and continue in total complete remission at 8+ and 16+ years. Another patient with extramedullary relapse (breast) was treated with radiation to that site and remains in total CR at 16+ years. Expected toxicities included myelosuppression during the induction phase of treatment, with 65% of patients requiring intravenous antibiotics. Mucositis was the next most frequent toxicity and required dose-reduction in seven patients. Minimal toxicity was seen during the post-remission phases of treatment. L-Asparaginase toxicity was more prominent during intravenous administration (24 patients) than when the intramuscular route of administration (30 patients) was used. The remission rate and long-term survivorship achieved with this regimen, without the use of an anthracycline, is comparable to that of other regimens for adult ALL. MOAD was well-tolerated by young and old adults with ALL. Aseptic necrosis of bone, successfully treated in each instance, occurred in four long-term disease-free survivors. The effect of this complication and its treatment on quality of life has been negligible.