Richard V. Smalley

Interferon alfa combined with cytotoxic chemotherapy for patients with non-Hodgkin's lymphoma.

BACKGROUND Interferon alfa has been found to be effective as an antitumor agent (with a response rate of 30 percent) in patients with low-grade non-Hodgkins lymphoma, but its effectiveness in those with intermediate-grade non-Hodgkins lymphoma has been less adequately tested. In a prospective randomized study we evaluated the effectiveness of adding interferon alfa to cytotoxic chemotherapy in patients with clinically aggressive, low-grade non-Hodgkins lymphoma and certain histologic variants of intermediate-grade non-Hodgkins lymphoma, not including diffuse histiocytic lymphoma. METHODS The patients were randomly assigned to a regimen of cyclophosphamide, vincristine, prednisone, and doxorubicin or to this regimen combined with recombinant interferon alfa. Treatment was administered every four weeks, for 8 to 10 cycles. RESULTS The two regimens produced comparable objective responses, but the regimen including interferon had a greater effect in prolonging the time to treatment failure (P < 0.001) and the duration of complete response (P = 0.03). Interferon alfa also had a greater effect on overall survival (P = 0.014) when the results were adjusted for important covariates. CONCLUSIONS Interferon alfa, when added to a four-drug doxorubicin-based chemotherapy regimen, is an effective antitumor agent in patients with clinically aggressive low-grade or intermediate-grade non-Hodgkins lymphoma.

Allopurinol: Intravenous Use for Prevention and Treatment of Hyperuricemia

PURPOSE To tabulate data obtained over a 21-year period to determine the efficacy and safety of an intravenous (IV) allopurinol preparation. PATIENTS AND METHODS IV allopurinol was provided on a compassionate plea basis to patients of any age in whom xanthine oxidase inhibitor therapy was indicated as an adjunct to chemotherapy and for whom oral intake was restricted. Three hundred twenty-seven investigators at multiple hospitals in the United States treated 1,172 patients with IV allopurinol. The vast majority of these patients had a malignancy and were in danger of developing tumor lysis syndrome (TLS) and subsequent acute uric acid nephropathy (AUAN) and were unable to take oral allopurinol. Data referable to the time period of IV allopurinol administration were collected, collated, and analyzed retrospectively. There was no randomization. RESULTS In patients initiating treatment for an elevated serum uric acid (SUA), the SUA normalized or improved in 87% of adult patients and normalized or improved in 95% of pediatric patients. IV allopurinol, administered prophylactically to patients at high risk of developing hyperuricemia and TLS, prevented an increase in SUA levels in 93% of adults and 92% of children. Toxicities caused by IV allopurinol were minimal and consisted of 10 instances of mild to moderate skin or allergic reactions. CONCLUSION IV allopurinol is as efficacious and safe as oral allopurinol and will be of significant benefit to patients at risk of TLS and AUAN and unable to take oral medication.

Interferon Alfa plus Chemotherapy for Non-Hodgkin's Lymphoma: Five-Year Follow-up

To the Editor: As we previously reported (November 5, 1992, issue),1 interferon alfa, when added to a four-drug, doxorubicin-based chemotherapy regimen, is an effective antitumor agent in patients ...

Interferons: Current status and future directions of this prototypic biological

ConclusionAs phase II trials with alpha interferon are nearing completion it is clear that they have anti-tumor activity in several malignancies. When compared to other drugs currently used for malignant disease, the level of activity suggests their ultimate usefulness in clinical practice. Some patients have manifested complete responses to interferon administration: others have had long-term sustained anti-tumor effect. In addition to their significant clinical activity, interferons are prototypic biologic response modifiers. In this role, the development of the interferons has provided a model for other biologicals which are currently entering phase I clinical trials. As a model for the clinical application of biologics in general and for the clinical use of specific protein molecules, interferons are fulfilling their substantial promise.

Oral piritrexim : a phase II study in patients with advanced soft tissue sarcoma

Piritrexim is a lipid soluble dihydrofolate reductase (DHFR) inhibitor that rapidly and passively diffuses into cells [1,2]. It has been synthesized as an antifolate compound potentially capable of circumventing methotrexate resistance from arising via various mechanisms [3]. A phase II evaluation of this drug was organized at the Memorial Sloan Kettering Cancer Center (MSKCC) to evaluate the anti-tumor activity and toxicity in patients with advanced soft tissue sarcoma. Preliminary results have been previously presented [4]. Adult patients with soft tissue sarcoma with a clearly measurable indicator lesion(s) and a Karnofsky Performance Status of 70% or greater were eligible for entry regardless of prior treatment. Classic oncologic response criteria were used. Patients were scheduled to receive a dose of 160 mg/m 2, administered orally twice daily for five consecutive days every three weeks. Following unexpected severe toxicity in two patients (both with prior pelvic irradiation who initiated treatment at a dose of 120 mg/m2), the protocol was amended to initiate treatment at a dose of 120 mg/m 2 in all patients and 80 mg/m 2 in those patients with prior radiation to the pelvis. The dose was subsequently escalated or deescalated based on toxicity. Twenty-six patients with soft tissue sarcoma were entered on study. Table 1 summarizes the demographic data and the results. One-hundred and thirty-one courses of therapy were administered to the 26 patients for a mean of 5 courses and a median of 3.5 courses per patient. Fourteen of the patients initiated treatment at a dose of 120 mg/m 2 bid, eleven initiated treatment at a dose of 80 mg/m 2 bid and one initiated treatment at a dose of 160 mg/m z. Two patients obtained a partial response. Of twelve evaluable patients with leiomyosarcoma, one patient obtained a partial response (for response rate of leiomyosarcoma upper limit 95% confidence interval = 34%). The other patient who obtained a partial response was the only patient entered with endometrial stromal sarcoma. Grade 2 or greater toxicity was observed in 80% of patients. Severe (grade 3 -4 ) myelopoietic toxicity was associated with 17 courses of treatment in nine patients, severe oral mucositis with nine courses of treatment in seven patients, severe maculo-papular pruritic rash with four courses in four patients and severe emesis with three courses in three patients. Generally, these toxicities occurred concurrently. This complex of toxicities represents the dose limiting toxicity of piritrexim. Piritrexim was evaluated in this phase II study because of its activity in the sarcoma 180 preclinical model, because of the activity of methotrexate in patients with soft tissue sarcoma and because of the anti-tumor efficacy of metoprine in previous studies in patients with sarcoma. Two clinically beneficial objective responses were observed, an overall response rate of 11%. Piritrexim is a potentially active agent in the treatment of soft tissue sarcoma but with an upper limit of a 95~ confidence

A phase II study of crisnatol mesylate in patients with ovarian carcinoma

SummaryFourteen patients with advanced ovarian cancer received a 72 hour infusion of a new DNA intercalator, crisnatol mesylate, administered intravenously. There was no evidence of antitumor efficacy. A syndrome of nausea and vomiting associated with vertigo, dizziness and ataxia was observed in nearly all patients. Two of the patients developed severe CNS toxicity manifested in one by a grand-mal seizure and in the other by peripheral neuropathy. Further explorations into the potential efficacy of crisnatol mesylate administered intraperitoneally are underway.

Interferons: therapy for cancer

Isaacs and Lindemann, in England, first characterized interferon (IFN) in 1957 and coined the word to signify a protein, elaborated by virus-infected cells, that functions to prevent their infection by a second virus [82]. However, difficulties with chemical isolation and characterization led to great skepticism about the molecule’s existence; indeed, ‘the scientific community dubbed the discovery “imaginon”’ [141].