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Biomedical subjects

G E Goodman

Publications and source records attributed to G E Goodman.

At least 37 records · Page 2Linked to original sources
PubMed1992

The clinical evaluation of cancer chemoprevention agents: defining and contrasting phase I, II, and III objectives.

A number of potential chemoprevention agents are now in clinical trials to evaluate their efficacy. A larger number of compounds await clinical investigation. The design of phase I and phase II trials for cancer chemoprevention agents requires a different approach than for cytotoxic agents. The unique nature of the target populations, the scope of side effect evaluation, and the potential duration of treatment must be considered in the design of these trials. This article will discuss the effect these variables have on the evaluation of a chemoprevention agent and propose models for the phase I and phase II trials of chemoprevention agents.

Anticarcinogenic Agents↗
PubMed1991

Treatment of limited small-cell lung cancer with concurrent etoposide/cisplatin and radiotherapy followed by intensification with high-dose cyclophosphamide: a Southwest Oncology Group study.

Between March 1986 and May 1988, the Southwest Oncology Group enrolled 58 previously untreated patients with limited small-cell lung cancer on a treatment program that administered high-dose cyclophosphamide (150 mg/kg) as late intensification. Treatment consisted of induction chemo-radiotherapy, (weeks 1 to 11), consolidation chemotherapy (weeks 11 to 18), and intensification (week 18). Median age was 61.5 years. Eighty-nine percent of patients had a Southwest Oncology Group (SWOG) performance status of 0-1. Twenty-one patients completed all prescribed treatments. There were seven treatment-related deaths, four as a result of intensification. Fifty-six patients are available for response analysis. Thirty-two patients achieved a complete remission (CR) (57%) and fifteen achieved a partial remission (PR) (26%). Median survival for all patients is 11.1 months. Among the 21 patients who received intensification, nine remain alive in a CR with a median survival of 27 months. This sequence of treatments was not associated with a survival advantage for the group as a whole, possibly because of the toxicity of induction and consolidation treatment and the delayed administration of high-dose cyclophosphamide.

Adult↗
PubMed1990

Treatment of limited small-cell lung cancer with etoposide and cisplatin alternating with vincristine, doxorubicin, and cyclophosphamide versus concurrent etoposide, vincristine, doxorubicin, and cyclophosphamide and chest radiotherapy: a Southwest Oncology Group Study.

The Goldie-Coldman model explaining the kinetics of tumor cell kill and drug resistance has a potential application in designing chemotherapy regimes. In this Southwest Oncology Group (SWOG) trial we tested the alternation of two potentially noncrossresistant drug combinations with a concurrent drug combination in patients with limited small-cell lung cancer. The concurrent drug combination consisted of etoposide (VP-16), 75 mg/m2/intravenously (IV), days 1, 2, and 3; vincristine, 1.0 mg/m2/IV, days 1 and 8; Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), 40 mg/m2/IV, day 1; and cyclophosphamide, 750 mg/m2/IV, day 1 (EVAC). The alternating combination consisted of VP-16, 100 mg/m2/IV, days 1, 2, and 3; and cisplatin (CDDP), 100 mg/m2/IV, day 1, alternating with vincristine, 1.0 mg/m2/IV, days 1 and 8; Adriamycin, 50 mg/m2/IV, day 1; and cyclophosphamide, 750 mg/m2/IV, day 1 (VP-16/CDDP-VAC). Chemotherapy was administered at 3-week intervals for six cycles both before and after chest (5,000 rads/5 weeks) and whole brain radiotherapy (3,000 rads/2 weeks). One hundred ninety-nine patients received EVAC and 201 received the alternating combination. There was no significant difference in the response rate to the initial six cycles of treatment with EVAC (CR, 40%) versus the alternating combination (CR, 38%). There was no significant difference between the best response, EVAC (CR, 48%) and VP-16/CDDP-VAC (CR, 51%). Median survival for all randomized patients on EVAC is 15.1 months versus 16.5 months on the alternating combination (P = .58). Toxicities consisted primarily of bone marrow suppression, anorexia, nausea and vomiting, peripheral neuropathies, and alopecia. As in previous trials, the chest was the most common site of relapse (33%). There were no differences in the incidence and sites of relapse between the two treatment arms. These treatments appear equally effective at inducing remission and prolonging survival in patients with small-cell lung cancer.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1990

Phase I trial of murine monoclonal antibody L6 in breast, colon, ovarian, and lung cancer.

Murine monoclonal antibody (MAb) L6 binds to an antigen expressed on the surface of breast, colon, ovary, and nonsmall-cell lung cancer. This antibody effects antibody-dependent cellular cytotoxicity (ADCC) with human mononuclear cells and complement-dependent cytotoxicity (CDC) with human complement. Because of these activities, we conducted a phase I trial of MAb L6 in patients with advanced cancer. Nineteen patients whose tumors highly expressed antigen were selected for this trial. Eighteen were evaluable. MAb L6 was administered at dose levels ranging from 5 mg/m2/d to 400 mg/m2/d for 7 days and was well tolerated. The only side effects detected were fever and headaches at the highest dose levels. The serum half-life of L6 was directly related to dose and ranged from a mean of 7.7 hours at 5 mg/m2/d to 29.1 hours at 400 mg/m2/d. Peak serum concentrations ranged from 0.22 micrograms/mL to 362 micrograms/mL. Biopsies at the end of treatment showed L6 to localize well to tumor cells with apparent in vivo saturation occurring at dose levels above 100 mg/m2/d. Thirteen patients formed human antimouse antibodies (HAMA), some as early as day 13. One patient with recurrent breast cancer on the chest wall achieved a complete remission. The response was first noted at 5 weeks and a pathologic complete remission occurred at 14 weeks. Because of its favorable binding properties and the encouraging clinical effect observed, future evaluation of this MAb appears warranted.

Adult↗
PubMed1989

Small cell lung cancer.

Lung cancer is the most common cause of cancer death in the United States, with approximately 135,000 men and women dying each year. While much has been learned about the etiologic risk factors, less progress has been made in therapy. Five-year survival rates remain at less than 10%. However, there has been some progress in the therapy of one histological subtype of lung cancer, small cell lung cancer. Totaling around 20% of lung cancer cases, small cell lung cancer is distinct from the other histologic subtypes in its biologic behavior and responsiveness to therapy. In the 1960s, the median survival for patients with small cell lung cancer was approximately 3 months. With combination chemotherapy and radiotherapy median survivals now range from 1 to 2 years, and there is evidence for a curative potential since approximately 10% of patients who initially present with limited disease survive greater than 2 years. The unique clinical aspects of this histological subtype potentially relate to its underlying cell of origin. This behavior is reflected in the numerous paraneoplastic syndromes that frequently accompany small cell lung cancer. Its propensity for early dissemination have made staging the extent of disease an important part of the clinical evaluation. Since small cell lung cancer is sensitive to both chemotherapy and radiation therapy, there have been multiple clinical trials evaluating drug/radiotherapy combinations. This article will briefly describe the unique aspects of small cell lung cancer as opposed to other histological subtypes of lung cancer and give an overview of the current clinical approach and treatment of this disease.

Antineoplastic Agents↗
PubMed1988

Association of food frequency questionnaire estimates of vitamin A intake with serum vitamin A levels.

To assess the validity of nutrient intake estimates from a food frequency questionnaire, the authors compared estimates of intake of preformed retinol (dietary plus supplements), beta-carotene, other active carotenoids, and total vitamin A computed from questionnaire responses with serum retinoid and carotenoid concentrations. Data were obtained from 302 male and female current or former smokers, participants in a lung cancer chemoprevention trial at the Fred Hutchinson Cancer Research Center in Seattle, Washington, during 1985-1986. Both serum beta-carotene and serum alpha-carotene were associated, although weakly, with food frequency estimates of total vitamin A intake, dietary vitamin A, beta-carotene, other carotenoids, and total carotenoids (0.18 less than or equal to r less than or equal to 0.26). Serum retinol was associated with supplementary vitamin A intake (r = 0.16). Nondietary factors were also associated with serum nutrient concentrations--in particular, cigarette smoking, alcohol intake, and body mass index. Cigarette smoking emerged as an important modifying factor of the relation between serum beta-carotene and dietary beta-carotene (r = 0.14 for current smokers, r = 0.30 for former smokers).

Aged↗
PubMed1987

Effect of verapamil on in vitro cytotoxicity of adriamycin and vinblastine in human tumor cells.

Verapamil has been shown to reverse acquired drug resistance to Adriamycin (ADR) and vinblastine in the P388 leukemia and Ehrlich ascites carcinoma model systems. Because of its potential clinical application, we evaluated the ability of verapamil to modulate the effect of ADR and vinblastine on the in vitro cloning of fresh human tumor cells. Fifty-three tumors were cloned in a soft agar system. Continuous exposure to verapamil at concentrations of 1.0, 5.0, and 10.0 micrograms/ml, did not significantly modulate the overall inhibitory activity of ADR and vinblastine (P greater than 0.05). There was no evidence of an effect when results were analyzed by tumor type or previous treatment except in the subgroup of 13 tumors obtained from patients who previously had a clinical response to ADR but were relapsing at the time the tumor specimen was obtained. In this population, at three concentrations of ADR, there was a significant modulation of drug effect (P = 0.10, 0.03, 0.03, respectively). In each subgroup, some tumors showed marked modulation of drug effect by verapamil. These results suggest that the mechanisms of acquired in vivo resistance to ADR may be similar to those occurring in cell lines. However, the effect on human tumors was minor as compared to the results with cell lines. The in vivo significance of this finding remains to be determined.

Breast Neoplasms↗
PubMed1987

Micronutrient assay for cancer prevention clinical trials: serum retinol, retinyl palmitate, alpha-carotene, and beta-carotene with the use of high-performance liquid chromatography.

Assay of serum levels of retinol, retinyl palmitate, alpha-carotene, and beta-carotene to assess nutritional status, to trials of retinol and/or beta-carotene to assess nutritional status, to monitor compliance with medication schedules, and to conduct toxicity surveillance. The optimal assay method for clinical trial use represents a balance between analytical power and speed/simplicity. Three such methods were evaluated by means of shared samples between two laboratories. Each method required less than 15 minutes per assay and detected all of the analytes of interest. Careful evaluation of calibration materials and procedures permitted different laboratories using different methods to produce results with an interlaboratory variability smaller than the within-laboratory variability for each separate method. Typical precisions for the analytes in serum samples are: retinol, 0.06 relative standard deviation (RSD; standard deviation divided by mean value); retinyl palmitate, 0.08 RSD; alpha-carotene, 0.15 RSD; and beta-carotene, 0.11 RSD. Application of these methods to several hundred samples indicated that retinyl palmitate and beta-carotene levels were indicative of administered retinol and beta-carotene, whereas retinol itself was not. Population variability in pretreatment serum levels of these micronutrients expressed as RSD (retinol, 0.24; alpha-carotene, 1.11; and beta-carotene, 0.98) far exceeded the analytical imprecision in these determinations, confirming that the present assays could meet the needs of current clinical intervention trials.

Carotenoids↗
PubMed1986

Phase II trial of retinol in patients with advanced cancer.

We have completed a phase II trial of oral retinol (200,000 units/m2) in 65 patients with advanced cancer. All patients were followed at 4-week intervals for tumor response and clinical or chemical evidence of toxicity. Seventeen patients had non-small cell lung cancer, 15 had melanoma, 12 had adenocarcinoma of the colon, and 17 had miscellaneous tumors. There were one partial response, five mixed responses, two patients with stable disease, and 47 patients with progressive disease. Thirty-seven of 60 patients reported no side effects; 13 developed mild cutaneous symptoms; and 12 developed reversible central nervous system symptomatology. Oral retinol appears to have limited activity in patients with advanced cancer.

Adenocarcinoma↗
PubMed1985

13-Cis-retinoic acid: pharmacology, toxicology, and clinical applications for the prevention and treatment of human cancer.

Retinoids, particularly 13-cis-retinoic acid, have shown great promise against a number of benign, but serious dermatological conditions. In animal models, 13-cis-retinoic acid functions is a potent antipromoter whether a cancer has been initiated by chemical, physical, or viral agents. Additionally, substantial antiproliferative activity of this compound has been demonstrated in vitro in many culture systems. Clinical activity noted against several types of skin malignancies has led to several investigations to determine the anticancer activity of 13-cis-retinoic acid. Response of a variety of preneoplastic and neoplastic lesions of epithelial histology has been demonstrated. The toxicity of 13-cis-retinoic acid largely reflects its tissue distribution with skin and subcutaneous side-effects limiting dose escalation. The pharmacology and pharmacokinetics of 13-cis-retinoic acid has been explored in a number of patients and a long terminal half-life demonstrated. This review will discuss 13-cis-retinoic acid as a good model for a biological response modifier.

Animals↗
PubMed1985

Pilot trial of murine monoclonal antibodies in patients with advanced melanoma.

We have performed a pilot trial with two murine monoclonal antibodies (MAbs) directed against two surface membrane antigens, p97 (MAb 96.5) and a proteoglycan antigen (MAb 48.7) primarily expressed in human melanoma. Five patients with disseminated melanoma were studied, all of whom had multiple cutaneous metastases. Four patients received 212 mg each of antibodies 96.5 and 48.7, and one patient received 424 mg of antibody 96.5 alone. MAbs were administered in escalating doses over ten days in four patients and over six days in one patient. There was no clear treatment-related toxicity. Immunohistologic studies on biopsies taken two to 240 hours after treatment showed extensive binding of murine immunoglobulin to melanoma cells, but not to normal cells in the same section. The intensity of antibody binding was uniform across the diameter of the tumor nodules. In two patients, no murine immunoglobulin was detected in biopsies taken ten days after the last treatment. The mean initial elimination half-life (T1/2) of infused MAbs was 40.5 hours in two patients who received a combination of both antibodies and 53.0 hours in a third patient who received only antibody 96.5; none of these patients had previously been exposed to mouse immunoglobulin. The elimination T1/2 was 21 hours in a fourth patient, who three months previously had tumor imaging with 2-mg radiolabeled antigen-binding fragments (Fab) prepared from antibody 48.7. Serum from this patient appeared to contain anti-idiotypic antibodies which specifically bound Fabs of antibody 48.7. Three other patients also developed human anti-mouse antibodies. There were no objective tumor regressions, and no histologic changes were noted on biopsy.

Adult↗
PubMed1985

Rationale and design of cancer chemoprevention studies in Seattle.

Three cancer prevention trials are currently in their early phases at The Fred Hutchinson Cancer Research Center, the University of Washington School of Public Health and Community Medicine, and the Swedish Hospital. All 3 studies are randomized and placebo controlled. One large-scale study involves the daily administration of retinoids to persons with asbestos-related lung disease in an attempt toward reduction of their high risk for bronchogenic carcinomas and mesotheliomas. A second study involves administration of the same agents to long-term heavy smokers; a substantial feasibility and toxicity pilot study will precede a full-scale prevention trial. In the third trial, folic acid administration is evaluated in relation to the progression and regression of cervical dysplasia among women with abnormal Pap smears. We report here the rationale and the design for these 3 studies.

Asbestosis↗
PubMed1984

Plasma kinetics of oral retinol in cancer patients.

Concurrent with a phase I trial of retinol in patients with advanced cancer, we studied the plasma kinetics of both retinol and its major metabolites, retinyl palmitate and retinyl stearate. Retinol was administered to 12 patients in daily oral doses of 60,000, 100,000, 150,000, or 200,000 units/m2. Patients remained on treatment until the development of dose-limiting toxic effects or disease progression. Retinoid plasma kinetics were studied on the first day of treatment, at Weeks 2 and 4, and every 2-3 months thereafter as long as the patient remained on therapy. A high-performance liquid chromatography assay was used to quantitate the plasma concentration of both retinol and its fatty acid esters. There was no significant change in the plasma retinol concentration up to 24 hours after a single oral dose of retinol (P greater than 0.05). However, the plasma concentration of retinyl palmitate and retinyl stearate markedly increased with a mean time to peak plasma concentration of 4.3 +/- 0.7 hours. Retinyl palmitate rapidly disappeared from the plasma with an initial phase half-life of 2.2 +/- 0.9 hours. The terminal phase half-life appeared prolonged and could not be accurately determined. Retinyl stearate was detected in the plasma of all patients with plasma concentrations paralleling and ranging from 20% to 40% those of retinyl palmitate. With prolonged retinol administration, peak plasma retinyl palmitate concentrations increased with both increasing retinol dose (P less than 0.001) and increasing duration of treatment (P = 0.001). In three patients with low pretreatment plasma retinol concentrations, daily retinol administration was associated with a rise in plasma retinol concentration. Because only one patient developed serious toxic effects and all patients had markedly increased plasma concentrations of retinyl esters, no conclusion could be made about the relationship between plasma retinyl ester concentration and retinol toxicity.

Administration, Oral↗
PubMed1983

Posttreatment laparotomy for Hodgkin's disease.

We examined and surgically restaged (using posttreatment laparotomy) 26 patients with stage III and IV Hodgkin's disease treated with combination chemotherapy and in apparent remission to determine the status of their clinical remission. Eleven patients had normal clinical restaging and surgical restaging. Fifteen patients had abnormal clinical restaging, mainly consisting of abnormal lymphangiograms or abdominal CT scans. Ten lymphangiograms were abnormal and could not exclude persistent lymphoma. Two of the 15 patients proved to have Hodgkin's disease involving the para-aortic nodes and the spleen. With a median follow-up of 24 months, two patients had relapses in supradiaphragmatic sites and no patient with a negative laparotomy had a recurrence abdominal sites. Restaging laparotomy in selected patients with Hodgkin's disease with abnormal lymphangiograms or CT scans may identify additional patients with residual lymphoma who require further therapy and, more importantly, may identify those patients who have no residual disease and, therefore, may be spared additional therapy. Mortality and morbidity were nil.

Adolescent↗
PubMed1983

Phase I trial of retinol in cancer patients.

Vitamin A (all-trans-retinol) and its analogues are undergoing evaluation as antineoplastic and chemoprevention agents. Because its toxicity and activity are poorly defined, we have completed a phase I trial of retinol. Retinol was administered to 13 cancer patients in daily doses ranging from 100,000 units/m2 to 350,000 units/m2. Neuropsychiatric changes were the earliest dose-limiting symptomatic toxicities, noted in 3 of 5 patients receiving more than 240,000 U/m2 for 3-4 months. Two patients receiving more than 270,000 U/m2 developed hepatomegaly after 3 and 4 months. Liver biopsies were consistent with vitamin A toxicity. Three patients receiving 200,000 U/m2 developed an increase in serum triglycerides concentration. Mild skin and mucous membrane dryness occurred in most patients receiving more than 150,000 U/m2. A mixed response was seen in one patient with melanoma. Because of neuropsychiatric and hepatic toxicity a retinol dose of 200,000 U/m2/day is recommended for future phase II trials.

Adult↗
PubMed1983

Treatment of small cell lung cancer with VP-16, vincristine, doxorubicin (Adriamycin), cyclophosphamide (EVAC), and high-dose chest radiotherapy.

Seventy-one previously untreated patients with small cell lung cancer (SCLC) received a combination of VP-16, vincristine, doxorubicin (Adriamycin), and cyclophosphamide (EVAC) repeated every three weeks. Limited-disease (LD) patients and extensive-disease (ED) patients achieving a complete response (CR) or partial response (PR) after four to six cycles of EVAC received 4,000 rads over four weeks whole-brain radiotherapy (RT) and 5,000 rads over five weeks RT to the original pulmonary primary and mediastinum. ED patients with persisting disease outside the chest after six cycles of EVAC continued chemotherapy and did not receive RT. After RT was completed, EVAC was continued for a total treatment duration of 24 months. Of 65 patients evaluable for response 76% (25 of 33) of LD patients and 34% (11 of 32) of ED patients achieved a CR prior to RT; two additional ED patients achieved a CR after RT. Median survival for all 71 patients was 48 weeks (range, one to 207 weeks); median survival for 33 LD patients was 92 weeks and for 38 ED patients it was 36 weeks. Nine of 25 LD patients and 10 of 13 ED patients have relapsed from CR. The EVAC-RT protocol is promising in view of the high CR rate and long remission duration achieved, especially among patients with LD.

Antineoplastic Combined Chemotherapy Protocols↗