Methotrexate cytotoxicity for L5178Y/Asn- lymphoblasts: relationship of dose and duration of exposure to tumor cell viability.

To determine the relative contribution of dose and duration of exposure to methotrexate (MTX) cytotoxicity, suspension cultures of L5178Y/Asn- murine leukemic cells were exposed to 0.1 to 100 microM MTX for 3 to 42 hr. Viability was determined by cloning in soft agar. While there was a linear relationship between dose and MTX cytotoxicity for exposure duration of 3 and 6 hr (r = -0.66), there was a pronounced flattening of this curve at exposure durations of 18 to 42 hr (r = -0.48). Furthermore, there was an excellent correlation (r = -0.85) between MTX cytotoxicity and durations of exposure for 6 to 42 hr (dose range, 1 to 100 microM). Using the linear least-squares method, a best-fit equation for the kinetics of MTX cytotoxicity was determined to be: log viability = 2.25 = 1.76 (log duration) - 0.31 (log dose). In practice, this equation predicts that a 1-log increase in duration of exposure results in almost a 2-log increase in cytotoxicity, whereas a 1-log increase in dose results in only a 0.3-log increase in cytotoxicity. The clinical utility of these data suggest that protracted infusions of lower doses of MTX would be equally as useful as or more useful than short-term high-dose infusions.

A phase II study of recombinant alpha interferon in patients with recurrent or metastatic breast cancer.

Thirty-three patients with advanced breast cancer were treated with a recombinant alpha interferon (rIFN-alpha 2). All patients were ambulatory (performance status greater than or equal to 50 Karnofsky scale) and almost all had received previous chemotherapy. Large intravenous dosages of 30 to 50 X 10(6) IU/m2 were given for five consecutive days every two to three weeks to 22 patients and smaller subcutaneous dosage of 2 X 10(6) IU/m2 three times a week to 11 patients. No complete or partial responses were seen. Two patients had stable disease and the remainder progressed. Flu-like syndromes were seen in all patients. Nausea, vomiting, and anorexia were frequent. Hypotension and confusion were noted in six and five patients, respectively. Life-threatening leukopenia was noted in two patients receiving intravenous dosage and thrombocytopenia was noted in one; no sepsis or bleeding complications were noted. In this study, a highly purified and biologically active rIFN-alpha 2 was not associated with activity in previously treated women with metastatic breast cancer.

In vivo biological response to recombinant interferon-gamma during a phase I dose-response trial in patients with metastatic melanoma.

Interferon-gamma (IFN gamma), as produced by recombinant DNA technology, has shown a wide range of immunomodulatory activity in vitro and in vivo. Clinical studies have attempted to establish a dose-response relationship to define optimal dosage ranges for induction of effector cell function and host response in patients with cancer. We conducted a randomized trial to test the in vivo biologic activity of five daily dosages ranging from 3 to 3,000 micrograms/m2, administered by daily 2-hour bolus injection or by continuous infusion for 14 days. We demonstrate comparable immunobiologic effects of recombinant IFN gamma (rIFN gamma; Biogen, Inc, Cambridge, MA) administered by these two schedules at the various dosages tested, and have defined a relationship of dose to biologic response over this 3-log10 dose range. Oligo 2'5' adenylate synthetase (2'5'As) induction, natural-killer (NK) cell activity, and T-cell subset distribution (heightened T helper/suppressor ratio) showed the most consistent treatment-associated changes and the greatest immunobiologic effects at dosages of 300 to 1,000 micrograms/m2. Mononuclear cell DR and DQ antigen expression showed no consistent dose-related treatment effect. The relevance of the phenotypic, functional, and enzymologic effects observed in this trial to any clinical antitumor effects of IFN gamma in cancer therapy must now be established.

Operational criteria for adverse drug reactions in evaluating suspected toxicity of a popular scabicide.

A recently developed algorithm for the diagnosis of adverse drug reaction (ADR) was used to investigate the quality of evidence in reported cases of ADRs to 1% gamma benzene hexachloride (GBH), a popular scabicide and pediculicide currently under suspicion as a cause of central nervous system (CNS) toxicity, especially in children. Of the 53 reported cases of alleged toxicity, 37 were associated with lindane insecticide (greater than 1% GBH), which is not a pharmaceutical preparation. Of these 37 cases, 34 scored as definite or probable reactions on the algorithm. Of the 26 reports associated with the drug, 1% GBH, none scored as definite and only 6 as probable ADRs. Of these 6 probable cases, 5 represented inappropriate application or unintended ingestion. The use of rigorous operational criteria, such as those developed in this algorithm, permits a scientifically disciplined assessment of whether or not a drug has been fairly indicted, and also provides valuable clinical information about other aspects of suspected drug toxicity.

OKT3E, an anti-CD3 antibody that does not elicit side effects or antiidiotype responses in chimpanzees.

Chimpanzees were injected with OKT3 and two other anti-CD3 antibodies, OKT3D and OKT3E. Both of the new antibodies were of the mouse IgG2b isotype. Administration of the antibodies was identical to the clinical regimen used for OKT3 in humans: 5 mg i.v., daily for 10 consecutive days. All animals were monitored for fever during administration of the antibodies, and blood samples were taken throughout the treatment period for monitoring the effects of the antibodies on peripheral lymphocyte subsets and the appearance of circulating cytokines. OKT3 produced similar clinical effects to those observed in humans; fever (2/3), as well as elevations in cytokines were observed. As in humans, peripheral T cells were cleared with the first dose and remained absent or modulated of their T cell receptor molecules throughout treatment. OKT3D, IgG2b also produced fevers (2/3) and elevations of cytokines. Although it also cleared circulating T cells with the first dose and T cell counts remained low throughout treatment, remaining circulating T cells were coated with administered antibody and were able to reexpress the CD3 antigen. OKT3E, IgG2b produced no temperature elevations and no elevations in cytokines. Although it cleared the circulation of T cells with the first does, cells reappeared during treatment, modulated of their CD3 antigens or coated with the administered antibody. All three antibodies raised antimouse antibodies, and OKT3 and OKT3D also produced blocking antiidiotype antibodies. OKT3E treatment did not result in anti-OKT3E blocking antibodies.

The radiologic diagnosis of pancreatic cancer. The effect of new imaging techniques.

The objective of this study was to evaluate how the introduction of radiologic studies affected the diagnostic workup for pancreatic cancer, from 1955 through 1979. For 961 patients diagnosed as having pancreatic cancer at three teaching hospitals, we reviewed medical records, autopsy reports, and death certificates for results from all radiologic studies, surgical and pathologic procedures, and for the final diagnosis. The number of radiologic studies per patient increased as new studies were introduced; 1.6 for 1955-1959, 3.5 for 1975-1979 (P less than 0.0001). Depending on the cutoff level chosen, the sensitivity of the overall radiologic diagnosis increased over time, 0.17-0.43 for 1955-1959, to 0.54-0.78 for 1975-1979; CT, US, and ERCP accounted for much of the increase. As newer radiologic studies are introduced, continued use of previously accepted studies should be carefully evaluated.

Reversible arrhythmias observed in patients treated with recombinant alpha 2 interferon.

We have treated 25 patients, 7 with breast cancer and 18 with non-Hodgkin's lymphoma, with recombinant alpha 2 interferon. In 5 patients we observed cardiac arrhythmias that were unexpected and required treatment. No deaths have occurred that we can attribute to interferon, though 1 patient had to be resuscitated. Age, prior cardiac disease, prior treatment with doxorubicin, and interferon dose appear to be predisposing factors for this toxicity.

A phase I trial of recombinant leukocyte alpha 2 interferon in patients with advanced malignancy.

Seventeen patients with advanced, previously treated malignancies were entered into a phase I trial utilizing recombinant DNA produced alpha 2 leukocyte interferon (rIFN-alpha 2). Sixteen patients were evaluable. Patients were to receive rIFN-alpha 2 by either the I.V. or I.M. route for 35 consecutive days. The dosage was identical by both routes, and patients were escalated from 3 X 10(6) to 10 X 10(6) to 30 X 10(6) to 50 X 10(6) and to 100 X 10(6) I.U. every 7 days. No patient was able to tolerate the consecutive treatment protocol as planned. Dose-limiting toxicity was a flu-like syndrome in 10 patients and was usually associated with a fall in performance status. Confusion resulted in study withdrawal for five patients, four receiving rIFN-alpha 2 by the I.M. route. Hematologic and liver function abnormalities were common, usually transient, and not associated with clinical sequelae. One patient with non-Hodgkin's lymphoma showed substantial improvement; otherwise, all had stable or progressive disease. Pharmacologic studies indicated substantial serum levels at doses greater than or equal to 10 X 10(6) I.U. regardless of route. No consistent changes in NK activity, lymphocyte subpopulations, or immunoglobulin levels were noted, and no patient developed antibodies to rIFN-alpha 2. The dose and schedule used here indicate that high levels of serum rIFN-alpha 2 activity are obtainable by either the I.M. or I.V. route. Intermittent rather than daily dosage is more likely to be better tolerated and should be considered for phase II trials.

The identification of a murder victim using a comparison of the postmortem and antemortem records.

Since the murder victim could not positively be identified by fingerprints, facial appearance, or personal effects, dental techniques of identification were requested by the police and carried out at the city morgue. An exam of the deceased incorporated dental X-rays, models of the maxillary and mandibular teeth, and a written and taped description of the dental structures. Comparing the antemortem with the postmortem dental records, a positive identification was confirmed. When other methods of identification have been exhausted, dental techniques can be employed to identify positively an individual and should be regarded as efficacious as fingerprints.

Use of cost-effectiveness analysis in planning cancer chemoprophylaxis trials.

We present a conceptual framework for the use of cost-effectiveness analysis in planning cancer chemoprophylaxis trials and evaluating such choices as sample size, study design, diagnostic evaluation, and duration of follow-up. The approach is illustrated by cost-effectiveness calculations for a trial of synthetic retinoids as cancer prophylaxis agents. Our work emphasizes the need for studies large enough to have a reasonable power of detecting 10%-20% reductions in mortality. Conversely, we note that rare but serious idiosyncratic side effects such as those seen the the "swine-flu" vaccination program are likely to escape detection even in trials involving tens of thousands of subjects.

Phase I/II study of recombinant interferon gamma in advanced renal cell carcinoma.

A phase I and II evaluation of 42 patients with advanced renal cell carcinoma treated with recombinant interferon gamma was done. Patients were treated with either a daily 2-hour infusion or 24-hour infusion for 7 days every 3 weeks for at least 2 cycles. Patients who demonstrated stable disease or improvement on therapy then were continued on a maintenance program of 5 days of recombinant interferon gamma administered every 3 to 4 weeks. The initial starting dose was 10 mcg. per m.2 per day with escalations to 30, 100, 300, 1,000 and 3,000 mcg. per m.2. Dose-limiting toxicity occurred at 1,000 to 3,000 mcg. per m.2, and included leukopenia, chills, fevers, rigors and hepatotoxicity as manifested by elevation in the transaminase and bilirubin levels. Tumor responses were seen initially at the 300 mcg. per m.2 dose level. Over-all, of 41 patients evaluable for therapeutic effectiveness 1 demonstrated a complete response 6 months in duration and 3 demonstrated partial responses 2, 9 and 13 months in duration. However, 6 patients demonstrated organ site responsiveness, including resolution of pulmonary lesions (2 complete and 1 partial responses), lymphadenopathy (1 complete and 1 partial responses), a pleural-based lesion in 1 patient with a partial response and complete resolution of hepatic metastases in 1 patient. We conclude that recombinant interferon gamma at a dose of 1,000 to 3,000 mcg. per m.2 for 7 days and repeated every 2 to 3 weeks had demonstrable anticancer activity in patients with metastatic renal carcinoma.

High dose cytosine arabinoside (HDARAC) in refractory acute leukemia.

Thirteen leukemic patients with disease refractory to conventional chemotherapy were treated with 1.0 to 7.5 g/m2 of Cytosine Arabinoside (Ara-C) over 29 drug cycles. Drug infusions were spaced at 12-hour intervals; a maximum of four doses was administered over 36 hours. After single dose tolerance had been established, three or four dose cycles were given at 2- to 30-day intervals. There were three partial remissions (PR) and one complete remission (CR) in a treatment group of four patients with AML, five with ALL, two with lymphoma converted to leukemic phase, one CML in blast crisis, and one promyelocytic leukemia. Five of the patients were septic and considered terminally ill at the time of treatment. All other patients had evidence of drug responsiveness. The nadir of the white count occurred from 3 to 12 days after treatment, with subsequent recovery of the peripheral granulocyte count between days 12 and 28. Toxicity included nausea and vomiting (GI symptoms) in twelve patients, central nervous system (CNS) disturbances in eight patients, one episode of inappropriate antidiuretic hormone syndromes (SIADH), one of hyperuricemia, and fever in eleven patients. There was no evidence of hepatic or renal dysfunction. These high doses of Ara-C appear useful for treatment of patients with refractory leukemia. Hospitalization is brief and toxicity acceptable.

Use of the flexible sigmoidoscope in women with previous pelvic irradiation.

Pelvic irradiation has been reported to be a risk factor for colonic malignancy. We performed flexible sigmoidoscopy with serial pinch biopsies in 20 asymptomatic women treated with irradiation for cervical cancer more than 10 years ago in order to determine the feasibility of the technique and to detect late radiation effects. The examination was well tolerated by 14 (70%) of the patients, and the instrument was passed to 40 cm in 14 (74%) of 19 women. Abnormal mucosal or vascular changes were found in 12 (60%) and nonspecific microscopic abnormalities were seen in 18 (90%) of the 20 women.

Comparison of intramuscular and intravenous recombinant alpha-2 interferon in melanoma and other cancers.

In two phase I-II trials, 33 patients were given recombinant interferon alpha-2 daily at dosages of 3, 10, 30, 50, or 100 MU/d for up to 4 weeks by intramuscular or intravenous routes. Dose-limiting toxicities, including neutropenia, elevated hepatocellular enzyme levels, fatigue, and disturbed mentation, correlated with differing serum pharmacokinetics of interferon in the two trials. In the intramuscular study, dose-limiting toxicity occurred at all dosages greater than 10 MU/d, at a median of 6 to 9 days of treatment. In the intravenous dose-study, limiting toxicity was seen only at dosages of 100 MU/d, at a median of day 8. Twenty-three patients had metastatic melanoma and 4 had objective partial or complete responses at dosages of 10 to 50 MU/d in the first month. Two patients with complete responses are free of tumor after 2.5 years of follow-up. A fifth patient had delayed complete regression, requiring 1 year to achieve maximum response, but remains free of disease at 26 months since entry to the trial. Interferon had antitumor activity against melanoma by both routes tested, at dosages of 10 to 50 MU/d.

High-dose methotrexate in small cell lung cancer. Lack of efficacy in preventing CNS relapse.

Few studies have incorporated high-dose methotrexate (MTX) with leucovorin rescue in the treatment of small cell lung cancer (SCLC). Potentially therapeutic levels of MTX can be achieved in the central nervous system (CNS) by systemic administration of high doses of this drug. Utilizing a combination chemotherapy program of Adriamycin, vincristine, cyclophosphamide, and methotrexate, 31 patients were sequentially assigned to receive either low-dose MTX (40 mg/m2), or high-dose MTX (500 mg/m2) with leucovorin rescue. Radiation therapy to the primary site was also administered. At these dosage levels there were no statistically significant differences in response rate or survival between the two groups. High-dose MTX did not prevent the appearance of CNS disease; there being 2/15 and 3/15 CNS relapses in the HD MTX and LD MTX treated groups, respectively. The occurrence of CNS disease did not significantly affect overall survival as compared to patients not similarly affected.