Mehmet F. Fer

Treatment of advanced non-Hodgkin's lymphoma with recombinant leukocyte A interferon

We report the results of a trial of recombinant leukocyte A interferon in previously treated patients with non-Hodgkins lymphoma who were no longer responsive to chemotherapy. Patients received recombinant leukocyte A interferon (50 X 10(6) U per square meter of body-surface area) by intramuscular injection three times weekly for three months or longer. Forty-five patients were enrolled in the study, and 37 were evaluated for a response. Thirteen of 24 (54 per cent) evaluable patients with low-histologic-grade non-Hodgkins lymphoma had objective responses (nine partial responses and four histologically confirmed complete responses). Two of six (33 per cent) with intermediate-grade lymphoma responded (one partially and one completely), and one of seven (14 per cent) with high-grade lymphoma had a partial response. The median duration of responses was eight months. Four of the five complete responders have continued to receive maintenance interferon and have been in complete remission for 3, 7, 9, and 12 months, respectively; one had a recurrence at a site of previous disease seven months after interferon had been stopped. Side effects were noted in most patients. All 16 responders had been heavily pretreated with combination chemotherapy, including doxorubicin in 8 of the 16. These results suggest that recombinant leukocyte A interferon may be an effective new therapy for some patients with low- and intermediate-grade non-Hodgkins lymphoma.

Phase II trial of recombinant leukocyte A interferon in patients with advanced chronic lymphocytic leukemia

Recombinant leukocyte A interferon is a highly purified single molecular species of alpha-interferon prepared by recombinant DNA methods. In 1982, a phase II trial to evaluate the efficacy of recombinant leukocyte A interferon for patients with previously treated chronic lymphocytic leukemia was begun, and 19 patients were entered in this study. Patients received one of two dose schedules depending on their pretreatment platelet counts. Those with platelet counts greater than 100,000/mm3 received 50 X 10(6) units/m2 intramuscularly three times weekly, with dose reductions to 25 X 10(6) units/m2 and 5 X 10(6) units/m2 for unacceptable toxicity. Those with platelet counts less than 100,000/mm3 received 5 X 10(6) units/m2 intramuscularly three times weekly. Toxicity was dose-dependent and included fever, chills, fatigue, anorexia, myalgias, headache, leukopenia, and thrombocytopenia. Response was evaluable in all but one of the patients entered in this study. Two of the 12 patients treated with 50 X 10(6) units/m2 had a partial response, three had no response, and seven had progressive disease. Of the six patients starting at 5 X 10(6) units/m2 in whom response was evaluable, two had no response and four had progressive disease. Five patients with progressive disease (three at 50 X 10(6) units/m2 and two at 5 X 10(6) units/m2) had an acceleration of disease while receiving recombinant leukocyte A interferon. It is concluded that the dose and schedule of recombinant leukocyte A interferon therapy tested in this study are not effective in previously treated patients with advanced chronic lymphocytic leukemia.

A phase I trial of a rhenium 186-labeled monoclonal antibody administered intraperitoneally in ovarian carcinoma : toxicity and clinical response

OBJECTIVES To determine the maximum tolerated dose, spectrum of toxicity, and response of persistent and recurrent ovarian carcinoma to intraperitoneal injection of a conjugate of rhenium 186 (186Re) and a monoclonal antibody; to measure the radiation distribution to normal structures; and to establish the fate of the infused isotope. METHODS Rhenium 186 was conjugated to murine monoclonal antibody NR-LU-10, which binds to a cell surface antigen present on ovarian carcinoma. In a dose-escalating phase I trial, a single dose of 25 mg/m2 of antibody complexed with 25-150 mCi/m2 of 186Re was administered intraperitoneally to 17 women with ovarian carcinoma that was recurrent or persistent after platinum-based chemotherapy. RESULTS Severe myelosuppression was observed at 150 mCi/m2 of 186Re in two evaluable patients. Other clinically significant toxicities included low-grade fever and transient skin rash. Hepatic enzyme elevation was seen in 12 of 17 patients, but was not clinically significant. No chronic enteric toxicity was observed. Decreased tumor size was demonstrated by repeat operation in four of seven patients with disease measuring less than 1 cm at the time of treatment (four of 17 total). All four responders had serum CA 125 levels of 35 U/mL or less at the time of treatment and had received only one regimen of chemotherapy. CONCLUSION This immunoconjugate can be administered intraperitoneally with acceptable toxicity and produces objective responses after a single dose in patients with minimal objective disease.

Atypical tumor lysis syndrome in a patient with T cell lymphoma treated with recombinant leukocyte interferon.

Biochemical and clinical signs of tumor lysis syndrome developed in a 57-year-old man with recurrent T cell lymphoma during therapy with recombinant leukocyte A interferon. When therapy was interrupted due to thrombocytopenia and later resumed, biochemical changes compatible with tumor lysis recurred. This is the first case of tumor lysis syndrome observed during therapy with a biologic response modifier, a new class of agents entering cancer clinical trials. The atypical features of the clinical presentation and possible implications of these observations are discussed.

Cushing's syndrome with small cell carcinoma of the uterine cervix

A 28 year old white women was found to have a cervical tumor in the 25th week of pregnancy. Pathologic examination revealed a nonkeratinizing small cell carcinoma. After delivery by cesarean section, pelvic lymph node exploration was carried out, and all 15 nodes were free of tumor. Her condition was staged as II-A, and she was treated with local radiation. Metastatic disease became manifest almost a year later and was histologically similar to her primary disease. A Cushingoid appearance was noticed and plasma cortisol levels were elevated. Twenty-four hour urinary 17-hydroxycorticosteroid (17-OHCS) and 17-ketosteroid (17-KS) levels were elevated and failed to suppress with dexamethasone. Plasma adrenocorticotropin (ACTH) level was elevated. Electron microscopic examination of the tumor tissue revealed neurosecretory granules. Immunoperoxidase stains for ACTH were positive. The patients course was one of progressive decline and eventual death. A literature review revealed two other cases in which carcinoma of the uterine cervix was considered to be the source of ectopic ACTH. Some small cell carcinomas of the cervix may arise from cells of the APUD series. Small cell carcinoma of the uterine cervix may behave differently from the more commonly encountered keratinizing and large cell nonkeratinizing carcinomas of the cervix and may not respond as well to standard therapy. Ectopic hormone production, production of abnormal peptides or of vasoactive amines may be more common in small cell carcinoma of the cervix than is currently recognized, and these products may be clinically useful as tumor markers.

Randomized study of high-dose versus low-dose methotrexate in the treatment of extensive small cell lung cancer

Forty patients with extensive small cell lung cancer randomly received either high-dose or low-dose methotrexate with leucovorin rescue in combination with cycles of cyclophosphamide, doxorubicin, and vincristine alternating with cycles of VP-16, vincristine, and hexamethylmelamine. Nineteen patients were treated with the high-dose methotrexate regimen, and 21 received the low-dose methotrexate treatment protocol; both treatment groups were similar in median age, performance status and spread of disease. Response rates (74 percent for high-dose therapy; 67 percent for low-dose therapy), median survival (nine months versus nine months), and overall survival were similar for the two treatment groups. Myelosuppression was equivalent in both treatment groups but moderate to severe mucositis developed more often when patients were treated with the high-dose methotrexate regimen as compared with low-dose methotrexate therapy (p less than 0.001). Central nervous system recurrences developed after three patients received high-dose methotrexate therapy. This study indicates that when used with other antineoplastic agents, high-dose methotrexate therapy does not improve the remission rate or survival nor does it decrease central nervous system metastasis in patients with small cell lung cancer when compared with standard doses of methotrexate; high-dose methotrexate is associated with greater cost and toxicity.

Morphologic Changes in Small Cell Lung Cancer

It is generally accepted that the morphology of malignant cells often denotes their cellular origin, predicts the natural history of the neoplasm, and therefore assists in planning therapy. Given this important role of cellular morphology in clinical oncology, observations of changing histology with time or following treatment have baffled physicians and resulted in some intriguing speculation. Changes in morphology with regard to the predominant cell type or the degree of differentiation have been observed in a variety of neoplasms [1–7]. For example, approximately one third of patients with chronic granulocytic leukemia in blast crisis will express morphologic and enzymic properties of acute lymphoblastic leukemia [1, 2]. Malignant germ cell tumors of the testicle when re-biopsied following chemotherapy will often display benign, mature teratoma histology [3,4]. When the morphologic classification of Rappaport is used, it has been noted that many ‘nodular’ lymphomas eventually evolve into aggressive neoplasms with diffuse histology [5, 6]. Changes in the degree of differentiation have been well documented in medullary thyroid carcinoma and prostate cancer [7]. In both instances the time-dependent changes have implied a progressive loss of differentiating features; in the case of medullary thyroid cancer this has been associated with a decline in the production of calcitonin [7]. These observations all suggest that tumors consist of various cell populations which are subject to change with time and/or cytotoxic therapy. While adaptive processes may be involved, it is likely that pre-existing cellular heterogeneities are important [8]. The elucidation of these determinants can provide considerable insight into mechanisms by which tumors evolve, progress and become resistant to therapy.