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Malignant pediatric tumors of the central nervous system (CNS) have a poor prognosis, with local failure rates as high as 50%. In an attempt to improve local tumor control, we used stereotactic interstitial therapy with 125I implants in patients with recurrent/secondary or newly diagnosed CNS malignancies. Catheters were placed using computed tomography (CT) guidance; computerized dosimetry was completed with the aid of orthogonal films. Implants delivered 1,000 cGy/day to the tumor periphery (0.5 cm beyond the boundary of enhancement on CT scans), to a total dose of 60 Gy. Hyperfractionated external beam irradiation (HEBI), started 2-4 weeks after removal of implants, delivered total doses of 66-70.4 Gy in 110-cGy fractions twice daily to a 3-cm margin around the implant volume. Eight of the 11 patients with newly diagnosed tumors also received 48.4 Gy HEBI to the craniospinal axis. Tumor regression was noted at 2 months after implantation in the 4 patients treated for recurrent/secondary tumors; local progression was subsequently documented in 2 cases at 6 and 20 months after implantation, while a third patient died 6 months after implantation with no evidence of local recurrence. The remaining recurrent/secondary tumor patient has no evidence of active recurrence 15 months after implantation. Local control was maintained in 9 of the 11 patients treated for primary tumors for a median of 27 months (range 15 to 48+ months). The two local failures occurred at 5 and 7 months after implantation. Six patients are alive without evidence of progressive disease (median = 23 months after implantation). There were no severe acute toxicities, but 7 patients later developed histologically confirmed tumor necrosis. Quality of life assessment (QLA) following initial primary therapy with implantation was evaluated utilizing an established criteria and found to be excellent with only one child showing marked QLA score decrease which was related to neurosurgical intervention for radiation-induced necrosis and dysfunctional family social situation. This small series suggests that stereotactic 125I implantation followed by HEBI merits further evaluation in selected children with supratentorial malignant lesions.

A phase I clinical trial was initiated to treat patients with stage IV B-derived chronic lymphocytic leukemia (CLL) with the IgG2a murine monoclonal antibody T101. This antibody binds to a 65,000-mol wt (T65) antigen found on normal T lymphocytes, malignant T lymphocytes, and B- derived CLL cells. All of the patients had a histologically confirmed diagnosis of advanced B-derived CLL and were refractory to standard therapy, and more than 50% of their leukemia cells reacted with the T101 antibody in vitro. The patients received T101 antibody two times per week, over two to 50 hours by intravenous administration in 100 mL of normal saline containing 5% human albumin. Twelve patients were treated with a fixed dosage of 1, 10, 50, or 100 mg, and one patient was treated with 140 mg of antibody. It was demonstrated that patients given two-hour infusions of 50 mg developed pulmonary toxicity, with shortness of breath and chest tightness. This toxicity was eliminated when infusions of 50 or 100 mg of T101 were prolonged to 50 hours. All dose levels caused a rapid but transient decrease in circulating leukemia cell counts. In vivo binding to circulating and bone marrow leukemia cells was demonstrated at all dose levels with increased binding at higher dosages. Antimurine antibody responses were not demonstrated in any patients at any time during treatment. Circulating free murine antibody was demonstrated in the serum of only the two patients treated with 100 mg of antibody as a 50-hour infusion and the patient treated with 140 mg of antibody over 30 hours. Antigenic modulation was demonstrated in patients treated at all dose levels but was particularly apparent in patients treated with prolonged infusions of 50 and 100 mg of antibody. We were also able to demonstrate antigenic modulation in lymph node cells, which strongly suggests in vivo labeling of these cells. Overall, T101 antibody alone appears to have a very limited therapeutic value for patients with CLL. The observations of in vivo labeling of tumor cells, antigenic modulation, antibody pharmacokinetics, toxicity, and antimurine antibody formation may be used in the future for more effective therapy when drugs or toxins are conjugated to the antibody.

Human-murine hybridomas, generated by fusion of human CLL cells with non-Ig-secreting murine myeloma NS-1, and secreting the IgM kappa expressed on the CLL cell surface, were grown in the peritoneal cavity of doubly pristane-primed nude mice to produce large quantities of highly concentrated human IgM kappa for the development of anti-idiotype monoclonal antibodies. Although the hybridomas secreted only 0.8 to 1.5 micrograms/ml/10(6) cells in tissue culture, they produced 8 to 12 ml of ascites from two mice containing 1.7 mg/ml of human IgM. Partial purification was then easily accomplished by euglobulin precipitation. Two weekly injections of 100 micrograms of this material into BALB/c mice resulted in the development of both anti-idiotypic and anti-human IgM antibodies. This system overcomes the major hurdle of generating sufficient quantities of the human idiotypic Ig to immunize and screen for specific murine antiidiotypes, and provides the material to produce these therapeutically promising reagents rapidly for clinical trials. This is, to our knowledge, the first report of a human Ig produced in mouse ascites.

Central nervous system (CNS) "prophylaxis" is critical in the treatment of acute lymphocytic leukemia (ALL). The standard method employed combines cranial radiation (CRT) and intrathecal methotrexate (IT MTX). Recently, a 52% incidence of abnormal computed tomography (CT) brain scans was found in asymptomatic children with ALL whose CNS prophylaxis consisted of CRT and either IT MTX or intrathecal cytosine arabinoside (IT Ara-C). In the present study, CT brain scans were studied in 43 asymptomatic children with ALL in continuous complete remission. The CNS prophylaxis consisted of IT MTX alone in 10 patients and IT MTX combined with intermediate-dose intravenous MTX in 33 patients. No patient had received CRT. The patients' ages at the time of diagnosis ranged from 22 months to 17 years, 7 months. The time interval from completion of CNS prophylaxis to CT scanning ranged from ten to 59 months. Only one CT scan was clearly abnormal; it showed mildly dilated ventricles and visualization of the cortical sulci. The CT scans of 7 additional patients were classified as abnormal because of borderline dilatation of the lateral ventricles (3 patients) and/or visualization of the cortical sulci (7 patients). No patient demonstrated areas of decreased cerebral attenuation coefficient or intracerebral calcification--findings previously ascribed to the use of methotrexate. Clinical leukoencephalopathy has not been observed in any of our patients. This would suggest that MTX alone in the absence of CNS leukemia or CRT is highly unlikely to produce structural CNS abnormalities detectable by CT.

Eight patients with advanced metastatic osteogenic sarcoma were treated with cis-dichlorodiammineplatinum(II) (DDP). Prior to DDP, seven patients had amputations and all had received adjuvant adriamycin (ADR) therapy. In addition, prior to DDP, six patients had received high-dose methotrexate. There was one complete response (pulmonary metastases) and four partial responses (three metastases in the lungs and one in the bone). One additional patient, with local recurrence of osteogenic sarcoma of the mandible following initial resection and adjuvant ADR, was retreated with surgery and DDP and is disease-free for greater than 3 years. The cumulative dose ranged from 300 to 660 mg/m2. Toxicity included irreversible kidney damage in two patients, transient severe hematologic suppression in two patients, and nausea and vomiting in all patients. DDP is a new effective agent in the treatment of osteogenic sarcoma.

The leukemias of childhood have provided an excellent model with which to test novel therapeutic strategies for human neoplasias [1]. In 1984, we devised an intensive multi-drug regimen for treatment of newly diagnosed patients with acute lymphocytic leukemia (ALL). This therapy is being evaluated in Study XI of the Total Therapy series at St. Jude Children’s Research Hospital, and features drug combinations and scheduling that differ radically from those tested in previous studies. Our rationale follows predictions of the somatic mutation theory of Goldie and Coldman [2] that early and repeated use of nonspecific but intensive combination chemotherapy should decrease the likelihood of drug resistance and, therefore, improve the end results of treatment. However, we encountered unexpectedly severe toxicity from early intensification of therapy that led to amendment of the protocol [3]. In this article, we review the toxic effects of the original treatment regimen and its subsequent modifications, emphasizing the potential hazards of intensive combination chemotherapy for ALL.

Eighty-one patients with a variety of refractory disseminated malignant neoplasms have been treated in the first multiple fixed-dose phase I trial of recombinant leukocyte A interferon (IFL-rA). Each patient received IFL-rA by intramuscular injection, three times weekly for 28 days. Dosages were escalated in different patients from 1 to 136 x 10(6) units per injection. The toxic reactions seen with IFL-rA resembled those of nonrecombinant leukocyte interferon and included fever, chills, fatigue, anorexia, myalgia, headache, occasional nausea and vomiting, and dose-dependent reversible leukopenia and hepatic transaminase elevations. The pharmacokinetics of IFL-rA were also comparable with nonrecombinant leukocyte interferon. Objective evidence of antitumor activity was seen in non-Hodgkin's lymphoma, chronic lymphocytic leukemia, Hodgkin's disease, breast cancer, and melanoma, indicating that IFL-rA, the first genetically engineered biological response modifier available for testing in cancer patients, is biologically active in vivo.

Two patients with advanced lymphoma involving the lungs that was resistant to chemotherapy had an initial excellent response to interferon therapy. After two months of stable disease, alpha interferon A therapy was discontinued, with relapse of a few months later. Both patients had extensive pulmonary involvement with relapse of the lymphoma, and both showed a dramatic response to retreatment with alpha interferon A. Unusual interferon-related pulmonary complications were observed in one patient, and their management is detailed.

Thirty-three patients were treated in an escalating single-dose trial of partially purified nonrecombinant interferon-gamma (IFN-gamma). The first seven patients received intramuscular injections of IFN-gamma in doses up to 20 X 10(6) units/m2. When it became clear that these patients had no detectable antiviral activity in their serum, subsequent patients were treated by the intravenous route of administration, generally with 2-h infusions. A total of 26 patients received the agent intravenously in single escalating doses ranging from 0.2 to 60 X 10(6) units/m2, on a twice-weekly schedule for 4-6 weeks. The most common toxicities encountered included fever, chills, fatigue, anorexia, and occasional nausea and vomiting. No myelosuppression or hepatic toxicity was observed. A maximum tolerated dose for single-dose intravenous administration was defined as 50 X 10(6) units/m2 on the basis of unacceptable fatigue and prolonged systolic hypotension. Antiviral activity was detected in the serum following doses greater than 2 X 10(6) units/m2 when the IFN-gamma was administered intravenously. No evidence of antitumor activity was seen in this Phase I trial, although the treatment regimen employed did not lead to high or prolonged levels of serum IFN activity in the majority of patients. An accurate assessment of the antitumor activity of this particular IFN-gamma preparation will require Phase II trials employing multiple-treatment regimens.

Human-murine hybridomas, generated by fusion of human CLL cells with non-Ig-secreting murine myeloma NS-1, and secreting the IgM kappa expressed on the CLL cell surface, were grown in the peritoneal cavity of doubly pristane-primed nude mice to produce large quantities of highly concentrated human IgM kappa for the development of anti-idiotype monoclonal antibodies. Although the hybridomas secreted only 0.8 to 1.5 micrograms/ml/10(6) cells in tissue culture, they produced 8 to 12 ml of ascites from two mice containing 1.7 mg/ml of human IgM. Partial purification was then easily accomplished by euglobulin precipitation. Two weekly injections of 100 micrograms of this material into BALB/c mice resulted in the development of both anti-idiotypic and anti-human IgM antibodies. This system overcomes the major hurdle of generating sufficient quantities of the human idiotypic Ig to immunize and screen for specific murine antiidiotypes, and provides the material to produce these therapeutically promising reagents rapidly for clinical trials. This is, to our knowledge, the first report of a human Ig produced in mouse ascites.

Thirty-two patients with small cell carcinoma of the lung were given chest radiotherapy to progressive intrathoracic tumor after failing chemotherapy. Two-thirds of these patients received split-course treatment at a dose of 4000 rad in 10 fractions. Sixteen of 25 evaluable patients (64%) had an objective response, but only five responders did not progress within the port during life. Median time to local progression was 16 weeks. Two patients, one of whom was given concurrent chemotherapy, survived greater than 18 months, and one is free of disease at 31+ months. Short-term palliation of chest disease and occasional long-term survival are possible with this regimen, although most patients will die with systemic disease within several months. Small cell carcinoma of the lung is less responsive to irradiation as second-line therapy than as initial therapy, but doses of greater than or equal to 4000 rad can offer symptomatic relief in many cases and, rarely, survival beyond 18 months.