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Biomedical subjects

S M Lippman

Publications and source records attributed to S M Lippman.

At least 127 records · Page 7Linked to original sources
PubMed1995

Phase II study of cisplatin, 5-fluorouracil and interferon-alpha in recurrent carcinoma of the cervix.

Standard cytotoxic regimens have failed to prolong survival in patients with recurrent cervical cancer; therefore, new agents or combinations of agents are necessary to improve outcome. Cisplatin and 5-fluorouracil are one of the most active regimens currently available for recurrent cervical cancer. Interferon-alpha and potentiate the in vitro and in vivo activity of both agents. Therefore, we sought to define the feasibility and activity of adding interferon-alpha to the cisplatin-5-fluorouracil regimen. Patients with histologically proven recurrent cervical carcinoma received interferon-alpha (5 x 10(6) units/m2/day for 5 days) combined with cisplatin (75 mg/m2 on day 1) plus 5-fluorouracil (500 mg/m2/day for 5 days) in recurrent cervical cancer. Twenty-six patients were included in this study and received a total of 95 courses of therapy. All 26 had prior radiotherapy and five had prior chemotherapy. This regimen was relatively well tolerated as toxicity was comparable to that of cisplatin plus 5-fluorouracil alone. Major response occurred in 8 patients (31%) and 5 (19%) had complete responses. The median response duration was 6 months (range, 2-34 months) and the median survival duration was 9 months (range, 2-38 months). The addition of interferon-alpha to cisplatin plus 5-fluorouracil is feasible. Further studies will be necessary to determine if the addition of interferon-alpha to this regimen is superior to cisplatin plus 5-fluorouracil alone.

Adult↗
PubMed1995

Screening at a health fair to identify subjects for an oral leukoplakia chemoprevention trial.

Screening examinations were conducted at a Chinese community health fair in Houston, Texas, to identify individuals with oral leukoplakia for a chemoprevention trial of oral-cavity squamous cell carcinoma. All 161 volunteer participants were interviewed regarding age, smoking habits, and betel-nut and alcohol use. The screening included an examination of the oral cavity, oropharynx, and neck. One participant had a 1-mm area of oral leukoplakia on the right lateral surface of the oral tongue. Eighteen participants had other head and neck abnormalities. Only 12 participants (7.5%) were active smokers, and eight (5%) reported a prior history of smoking. One participant reported prior betel-nut use. The mean age was 55 years. The authors conclude that a venue such as this has a low yield for screening and recruitment of high-risk individuals for chemoprevention of oral-cavity squamous cell carcinoma, that generally health-conscious individuals attend health fairs, and that only a small percentage volunteer for oral screening.

Adult↗
PubMed1995

Phase II study of carboplatin and continuous infusion bleomycin followed by cisplatin and 5-fluorouracil in recurrent head and neck cancer.

BACKGROUND: Recurrent squamous cell carcinoma of the head and neck is poorly responsive to most chemotherapy regimens. Carboplatin and bleomycin are effective single agents with non-overlapping toxicity; therefore, we sought to explore the efficacy of this regimen in a phase II study. In the second stage of the study, patients who did not respond to carboplatin and bleomycin were given treatment with cisplatin and 5-fluorouracil (5-FU). PATIENTS AND METHODS: Patients with recurrent squamous cell carcinoma of the head and neck were treated with carboplatin 400 mg/m2 followed by bleomycin 15 units intravenously as a continuous infusion for 4 days. Patients with no tumor response after 3 cycles of carboplatin and bleomycin were crossed-over to receive cisplatin 100 mg/m2 and 5-FU 1000 mg/m2/day continuous infusion for 5 days. RESULTS: Among the 20 carboplatin-bleomycin patients evaluable for toxicity, no cases of grade 4 granulocytopenia were reported and grade 3 or 4 thrombocytopenia developed in only three patients. Three partial responses occurred among the 19 patients (16%) [95% C.I. 0% to 32%] evaluable for response to carboplatin-bleomycin. None of the 11 patients crossed-over to cisplatin and 5-FU had a major response. CONCLUSION: The combination of carboplatin and bleomycin is well tolerated in patients with recurrent head and neck cancer, but the activity does not appear to be superior to the activity of either agent alone. Patients who did not respond to carboplatin and bleomycin were also resistant to the cisplatin and 5-FU regimen.

Adult↗
PubMed1995

Pilot phase II trial of 13-cis-retinoic acid and interferon-alpha combination therapy for advanced pancreatic adenocarcinoma.

The combination of interferons (IFNs) and retinoids in antineoplastic therapy is based upon preclinical, in vitro, and in vivo observations. Retinoid-IFN combinations have shown significant antitumor activity against advanced cutaneous and cervical squamous cell carcinoma (SCC), and the toxic effects do not appear to overlap. Based on in vitro evidence of synergy and observed clinical activity, we conducted a pilot phase II trial of 13-cis-retinoic acid (1 mg/kg/day) and IFN alpha (6 million units/day) in patients with advanced pancreatic adenocarcinoma. No objective responses occurred among six evaluable patients. The toxicities were mild and reversible, and grade 3 fatigue occurred in only one patient. No objective antitumor activity was noted against pancreatic adenocarcinomas at the dose and schedule utilized. Further exploration of this this purely biological approach is not warranted for pancreatic adenocarcinomas.

Adenocarcinoma↗
PubMed1995

Strategies for chemoprevention study of premalignancy and second primary tumors in the head and neck.

Recent strides in epidemiology (mutagen sensitivity assays) and basic molecular study of head and neck carcinogenesis are advancing chemoprevention in the head and neck. The clinical preventive activity of retinoids, the most studied and most active chemopreventive agents in this region, has been established in six randomized head and neck trials. Ongoing translational study of the p53 gene, nuclear retinoid receptors, and other cellular and molecular biomarkers will be necessary to achieve continuing progress in head and neck cancer chemoprevention.

Anticarcinogenic Agents↗
PubMed1995

Phase I evaluation of all-trans retinoic acid with and without ketoconazole in adults with solid tumors.

PURPOSE: All-trans retinoic acid (RA) induces accelerated plasma all-trans RA clearance, presumably via cytochrome P450 enzymes. This accelerated metabolism has been shown to be inhibited in the short term by the cytochrome P450 inhibitor ketoconazole. This study was conducted to evaluate the efficacy of ketoconazole in maintaining plasma all-trans RA levels over time. PATIENTS AND METHODS: Using a randomized crossover study design, we randomly assigned six patients to receive all-trans RA (45 mg/m2 orally twice per day for 14 days of a 21-day cycle) for cycle 1 and the same dose of all-trans RA plus ketoconazole (400 mg orally for one dose, then 200 mg orally three times per day for 14 days) for cycle 2, and seven patients to receive the same treatment in the reverse order. Plasma all-trans RA levels were measured during the initial 8-hour period after all-trans RA ingestion on days 1 and 15 of cycles 1 and 2. RESULTS: There was a marked decrease in plasma all-trans RA levels after 14 days of treatment, as measured by the area under the concentration-time curve (AUC), regardless of whether ketoconazole was given (from a baseline value of 857 to 44 ng/mL/h; P = .025) or not (from 1,355 to 308 ng/mL/h; P = .123). This lack of effect on plasma all-trans RA levels was not due to inadequate plasma ketoconazole levels. Ketoconazole administration was associated with more toxicity. No objective tumor responses were observed. CONCLUSION: Ketoconazole does not appear to maintain adequate plasma all-trans RA levels over time.

Adult↗
PubMed1995

Chemoprevention of lung cancer.

Treatment of lung cancer remains frustrating. Most patients with lung cancer are not candidates for curative therapy, and new therapies have not made a substantial impact on survival. Consequently, some clinical investigators have focused their efforts on developing prevention strategies. Chemoprevention, the administration of agents to block or reverse carcinogenesis, is being investigated in ongoing trials. Studies of chemoprevention in lung cancer have included trials to reverse premalignant lesions such as sputum atypia or squamous metaplasia of the bronchial epithelium. Clinical trials of lung cancer prevention have often studied groups of participants with tobacco or asbestos exposure. Other clinical trials are being conducted among patients who have been treated for an early-stage lung cancer. As the result of diffuse epithelial injury, these patients are at very high risk for developing second primary tumors, predominantly in the lungs and upper aerodigestive tract. It is our hope that these studies may establish a new strategy for preventing lung cancer.

Anticarcinogenic Agents↗
PubMed1995

Co-carcinogenesis and field cancerization: oral lesions offer first signs.

This article describes two cases of multifocal synchronous cell squamous cell carcinoma in high-risk patients. The initial presentation in both instances was an erythroplakic oral lesion. The importance of the team approach between the dentist and the oncologist for quality patient care is underscored.

Aged↗
PubMed1995

Phase I study of paclitaxel, cisplatin, and ifosfamide in patients with recurrent or metastatic squamous cell cancer of the head and neck.

The prognosis for patients with recurrent or metastatic squamous cell cancer of the head and neck is poor. Chemotherapy has not significantly improved survival. New agents and regimens are being developed in hopes of improving the outcome for these patients. A phase I/II trial using a combination of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), cisplatin, and ifosfamide is being performed. The phase I portion is completed and reported here. Granulocytopenia was the dose-limiting toxicity. Overall, the regimen was well tolerated. Major responses were observed in four of 10 evaluable patients in the phase I study. The phase II trial is ongoing.

Adenocarcinoma↗
PubMed1995

Current status of retinoid chemoprevention of lung cancer.

Clinical trials have suggested that retinoid chemoprevention prevents the development of second primary tumors following head and neck or non-small-cell lung cancer. The findings of these initial studies are now being evaluated in large multi-institution chemoprevention trials. If successful, these ongoing trials will establish the clinical role of retinoids in lung cancer prevention. The findings of these trials may also lead to strategies for primary lung cancer prevention. Until the results of these studies become available, however, lung cancer chemoprevention remains an experimental approach. The recent unexpected findings of increased lung cancer incidence in a beta-carotene study in Finnish smokers stresses the importance of establishing the efficacy of chemoprevention agents in carefully conducted clinical trials.

Carcinoma, Non-Small-Cell Lung↗
PubMed1995

Cancer chemoprevention.

A new direction for cancer prevention and control is chemoprevention, defined as the use of specific natural and synthetic chemical agents to reverse or suppress carcinogenesis and prevent the development of invasive cancer. The chemopreventive approach depends on the ability of certain chemical agents to block mutagenesis and control cellular differentiation and proliferation in epithelial tissues. Support for the chemopreventive approach is based on the biologic concepts of field cancerization and multistep carcinogenesis, as well as the clinical efficacy already shown by agents such as retinoids and tamoxifen in reversing premalignancy and preventing second primary tumors. Although chemoprevention is not yet established as a standard therapy, the results of reported trials are very promising and have raised tremendous interest in this strategy for cancer prevention. The development of more effective, less toxic chemopreventive agents remains a high priority in furthering the use of this clinically valuable approach to the prevention and control of cancer.

Antineoplastic Agents↗
PubMed1995

Increased expression of cytokeratins CK8 and CK19 is associated with head and neck carcinogenesis.

Malignant transformation is often associated with alterations in the expression of normal differentiation markers, which may serve as intermediate end points in carcinogenesis and cancer prevention. To identify early changes in differentiation markers during head and neck cancer development, we examined the expression of cytokeratins (CK1, CK8, CK13, and CK19) and involucrin by immuohistochemical methods in surgical specimens from 29 head and neck squamous cell carcinoma patients that included, in addition to carcinoma, adjacent dysplastic lesions (17 cases), hyperplastic lesions (21 cases), and adjacent histologically normal tissues (15 cases) and in specimens from 31 subjects with premalignant oral lesions (e.g, oral leukoplakia) without cancer, CK13 and involucrin were detected in all specimens from the cancer patients, and no differences in their expression were found among the different histopathological group. CK8 was detected in only 2.7% (1 of 36) of adjacent normal and hyperplastic tissues but in 58.8% (10 of 17) and 75.9% (22 of 29) of dysplastic and carcinoma tissues. The corresponding figures for CK19 expression in adjacent normal, hyperplastic, dysplastic, and carcinoma tissues were 13.3, 70, 71.4, and 82.1%, respectively. The expression of CK1 was not related to the progression from normal to malignant. In the leukoplakia lesions, CK8 CK13, CK19 and involucrin were detected in 13.8, 100, 74.2 and 100% of the specimens, respectively. These results demonstrate that CK19 expression increases in hyperplastic lesions and continues to be expressed in dyplastic and malignant lesions, whereas CK8 expression in low in adjacent normal and hyperplastic tissues and increases only in dysplastic and malignant lesions. Thus, CK19 and CK8 could be markers of sequential premalignant changes in head and neck carcinogenesis.

Biomarkers, Tumor↗
PubMed1995

Retinoid chemoprevention of aerodigestive cancer: from basic research to the clinic.

Epithelial cancers in the lung and head and neck are a devastating group of diseases which account for approximately 35% of cancer deaths in the United States. Chemoprevention is a new strategy to block or reverse the carcinogenic process. Biological concepts including field carcinogenesis and multistep carcinogenesis strongly support the rationale for using chemopreventive approaches. Our group has focused on applications of translational retinoid studies to increase our knowledge of the molecular events in biology and chemoprevention. In this review, we will focus on four issues, biology, retinoids, retinoid clinical trials, and translational research, in the chemoprevention of aerodigestive cancers.

Anticarcinogenic Agents↗
PubMed1994

Micronuclei, a biomarker for chemoprevention trials: results of a randomized study in oral pre-malignancy.

Biomarkers are being sought that could serve as surrogate end points for chemoprevention trials. Micronuclei, cytoplasmic fragments of DNA, have been proposed as a biomarker and studied in oral pre-malignancy. This study evaluated micronuclei frequency in a randomized chemoprevention trial of oral pre-malignancy. A recent clinical trial evaluated the responses of pre-malignant oral lesions to 3 months of therapy with isotretinoin followed by 9 months of either low-dose isotretinoin or beta-carotene. For 57 study participants, micronuclei were counted in mucosal scrapings of the lesion and in normal-appearing mucosa at baseline and following 3 months and 12 months of therapy. Micronuclei counts were higher in scrapings from the lesion than in the normal-appearing mucosa. Following 3 months of isotretinoin, the micronuclei counts in scrapings of the lesion were significantly reduced. With treatment, the mean micronuclei count declined at 3 months. In a randomized comparison, both isotretinoin and beta-carotene maintained the suppression of micronuclei. The change in micronuclei count was not associated with the clinical or histological response to treatment. Chemoprevention treatment with isotretinoin led to a reduction in frequency of micronuclei, a marker of recent DNA injury, which was then maintained by both isotretinoin and beta-carotene.

Biomarkers, Tumor↗
PubMed1994

Epidemiology, biology, and chemoprevention of aerodigestive cancer.

Cancers of the aerodigestive tract are a major cause of worldwide morbidity and mortality. Long term survival rates for these epithelial cancers have not improved substantially in the past 20 years despite intensive efforts to improve the prevention and therapy of these diseases. Therefore, new approaches are needed. One new investigative approach is chemoprevention, the chemical prevention of cancer. Chemoprevention studies in the upper aerodigestive tract have focused on the reversal of premalignant lesions and the prevention of second primary tumors. These chemoprevention efforts have resulted from an understanding of the multistep nature of epithelial carcinogenesis and the diffuse epithelial injury that results from carcinogen exposure. Ongoing research efforts are attempting to define these processes. The interaction between carcinogen exposure and host susceptibility in the development of cancers of the aerodigestive tract is being evaluated (e.g., with an assay of chromosomal sensitivity to the clastogen bleomycin). This review discusses several new aspects of the epidemiology, biology, and chemoprevention of aerodigestive tract carcinogenesis.

Biomarkers, Tumor↗
PubMed1994

Retinoid chemoprevention studies in upper aerodigestive tract and lung carcinogenesis.

Chemoprevention is a clinical strategy to block or reverse carcinogenesis before the development of invasive cancer. Studies of chemoprevention in the lungs and upper aerodigestive tract have relied on the field carcinogenesis hypothesis, which predicts that diffuse epithelial injury will result from exposure of that epithelium to carcinogens. This hypothesis is supported by the frequent occurrence of multiple primary tumors within the exposed field. In addition, the understanding of carcinogenesis as a multistep process supports the use of interventions in damaged epithelium before the development of clinically invasive cancer. Current efforts are focused on applying to chemoprevention studies the increasing knowledge of the molecular events in carcinogenesis. In our program, clinical trials in lung and head and neck chemoprevention have focused on individuals with evidence of field carcinogenesis, i.e., a history of previous epithelial cancer or the presence of premalignant lesions. These trials include studies to develop clinically applicable intermediate markers of carcinogenesis and large Phase III trials to evaluate the efficacy of the retinoid isotretinoin in preventing second primary tumors following head and neck or lung cancers.

Anticarcinogenic Agents↗