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S M Lippman

Publications and source records attributed to S M Lippman.

At least 181 records · Page 10Linked to original sources
PubMed1992

Determination of biomarkers for intermediate end points in chemoprevention trials.

Renewed interest is being directed toward chemoprevention as a means of reducing cancer mortality. To overcome the inherent problems associated with using cancer development as a study end point, there has recently been a great surge of interest in defining the biomarkers associated with specific stages of the carcinogenic process as intermediate end points. We have detailed the evidence supporting the concept of field cancerization, a concept of general importance that is probably applicable to carcinogenesis and chemoprevention at many organ sites in humans, and presented results of tests of the potentially useful biomarkers proliferating cell nuclear antigen and blood group antigen. Because microassay techniques are more readily applicable to small biopsy samples, further expansion of these studies and exploration of panels of additional biomarkers are expected to generate exciting results in the field of chemoprevention.

ABO Blood-Group System↗
PubMed1992

Chemoprevention strategies for lung and upper aerodigestive tract cancer.

The field cancerization hypothesis suggests that carcinogen exposure affects the entire epithelial lining of the lungs and upper aerodigestive tract. The concept that common exposures place the entire epithelium at risk for the development of invasive cancer is supported both by the occurrence of premalignant lesions such as leukoplakia and squamous metaplasia, and by the development of multiple primary tumors within the field. Chemoprevention trials in lung and upper aerodigestive tract cancer have included studies to reverse premalignant lesions and to prevent second primary tumors. Promising results have been reported in both settings using the retinoid 13-cis-retinoid acid. Several clinical trials are in progress which attempt both to reduce cancer incidence and to determine the mechanisms and biological markers of successful chemoprevention.

Anticarcinogenic Agents↗
PubMed1992

13-cis-retinoic acid and interferon alpha-2a: effective combination therapy for advanced squamous cell carcinoma of the skin.

BACKGROUND: Retinoids (vitamin A derivatives) and interferon-alpha (IFN-alpha) are potent regulators of malignant cell differentiation and proliferation, and both have immunomodulatory and antiangiogenesis activity. A large body of preclinical and clinical data supports the use of combination therapy with 13-cis-retinoic acid (13-cRA) and IFN-alpha in patients with squamous cell carcinoma of the skin. This carcinoma is an extremely common and frequently severely disfiguring cancer, for which about 10% of patients remain uncured following standard local therapy. PURPOSE: Our purpose was to test whether a 20% or greater complete response rate could be achieved using a combination of these two agents in patients with advanced squamous cell carcinoma of the skin in whom local therapy had failed or was unfeasible or who had regional and/or distant metastases. METHODS: Thirty-two patients with heavily pretreated, advanced inoperable cutaneous squamous cell carcinoma of the skin were given a combination of oral 13-cRA (1 mg/kg per day) and subcutaneous recombinant human IFN alpha-2a (3 million units per day) for at least 2 months, unless disease progressed earlier, in a phase II trial. RESULTS: Nineteen (68%) of the 28 assessable patients responded, seven (25%) of whom had complete responses. Response rates were 93% (13 of 14) in patients with advanced local disease (six complete responses), 67% (four of six) in patients with regional disease (no complete responses), and 25% (two of eight) in patients with distant metastases (one complete response). The relationship between decreased response rate and increased extent of disease was highly statistically significant (P less than .005, chi-square test). The median response duration was greater than 5 months. No life-threatening toxic effects occurred in assessable patients treated with this combination, although dose reductions were required in 18 patients. The major limiting side effect in this elderly patient population (median age, 67 years) was cumulative fatigue. CONCLUSION: These results indicate that combined systemic therapy with 13-cRA and IFN alpha-2a is highly effective in patients with advanced squamous cell carcinoma of the skin.

Aged↗
PubMed1992

13-cis-retinoic acid plus interferon alpha-2a: highly active systemic therapy for squamous cell carcinoma of the cervix.

BACKGROUND: Chemotherapeutic study of cervical squamous cell carcinoma has shown some positive results. Complete plus partial (overall) response rates of 15%-35% (complete response rate, less than 5%) were achieved with the use of a small number of cytotoxic single agents in patients with advanced disease. In addition, overall response rates of 60%-70% (complete response rates, 10%-20%) were achieved with cisplatin-based, multiagent regimens in patients with primary, locally advanced disease. However, the lack of clear evidence that existing chemotherapy can achieve a survival benefit, coupled with the worldwide annual deaths of hundreds of thousands of women from cervical cancer, indicates the urgent need for effective systemic therapy for this disease. PURPOSE: In view of the preclinical and clinical evidence that supports testing of the novel combination of 13-cis-retinoic acid (13-cRA) plus interferon-alpha (IFN-alpha) in cervical squamous cell carcinoma, we conducted a phase II study of this regimen in locally advanced disease. METHODS: Twenty-six patients with untreated, locally advanced squamous cell carcinoma of the cervix were treated daily for at least 2 months with oral 13-cRA (1 mg/kg) and subcutaneous recombinant human IFN alpha-2a (6 million units). In 21 patients (81%), the disease was stage II or higher. RESULTS: Thirteen patients (50%) experienced major responses (tumor regression greater than or equal to 50%) in association with resolution of symptoms; one achieved complete response, and 12 experienced partial response. Seven with partial response are improving further, four are being maintained in partial response, and one responder has relapsed during therapy. The response rate is 58% (11 of 19) in patients with stage IIB or higher disease and 66% (10 of 15) in patients with bulky disease (at least one dimension greater than or equal to 10 cm). Of the 13 non-responders, nine have stable disease and four have had disease progression during therapy. Toxicity was minimal. CONCLUSION: These preliminary results indicate that systemic 13-cRA plus IFN alpha-2a is a highly active, well-tolerated therapy for locally advanced cervical cancer.

Adult↗
PubMed1992

Intermediate biomarkers in upper aerodigestive tract and lung chemoprevention trials.

Chemoprevention trials in lung and upper aerodigestive tract (UADT) cancer are guided by the field cancerization hypothesis. Inhaled carcinogens place the entire epithelial lining at risk for the development of cancer. The hypothesis is supported by the occurrence of premalignant lesions, such as leukoplakia or squamous metaplasia, and multiple primary tumors within the field. The concept of carcinogenesis as a multistep process suggests the possibility of blocking or reversing the progression to invasive cancer with systemic treatment. A series of ongoing clinical trials will determine the efficacy of retinoid chemoprevention and will attempt to develop intermediate biomarkers. Biomarkers which reliably reflect progression towards cancer could be used to dramatically improve the efficiency of chemoprevention trials and also would aid in screening potential chemoprevention agents. Genomic biomarkers include non-specific estimates of ongoing DNA injury, such as micronuclei, as well as development of aneuploidy and alterations in oncogenes. A class of biomarkers of increasing importance assess proliferation and growth regulation, and include proliferating cell nuclear antigen (PCNA), TGF-beta, EGFR and retinoid receptors. Other markers, such as the blood group antigens, reflect differentiation and may be associated with the development of premalignant lesions. Preliminary data from several of these markers has suggested an association with carcinogenic exposures and premalignant lesions, but none of these markers either alone or in panels have yet been validated as a reliable surrogate for the development of invasive cancer.

Anticarcinogenic Agents↗
PubMed1992

A phase II study of interleukin-2 and interferon-alpha in head and neck cancer.

The capacity to modulate host response against metastatic head and neck cancer may eventually lead to improved survival. This phase II study in patients with advanced head and neck cancer evaluated the efficacy of combination systemic recombinant interleukin-2 (IL-2) and interferon-alpha (INF-a) and evaluated laboratory correlates between tumor response and a) tumor differentiation and b) NK cell activation. Five of fourteen patients responded; two had partial responses and three had transient responses (one complete and two partial, each lasting less than four weeks). Patients that responded had relatively lesser tumor burden and poorly-differentiated metastases. No response was observed in those few individuals in whom natural immune function was only minimally enhanced by therapy. Major toxicity, including but not limited to fever, fatigue and pulmonary compromise, allowed only 3 of 14 patients to complete three cycles of therapy. This preliminary phase II study shows that combination IL-2/INF-a therapy has clinical anti-tumor activity and that the level of NK cell activation and the degree of tumor differentiation may correlate with response.

Adult↗
PubMed1992

A quantitatively scored cancer-risk assessment tool: its development and use.

Achievement of NIH and ACS goals for reduction in cancer mortality will require increased efforts directed at risk reduction and early detection in the general population. Primary care providers will play a major role. This paper describes the development and use of a quantitative cancer-risk appraisal tool designed to promote cancer prevention and screening and provide a framework for advancing education on these critical issues at all levels of medical training, to assist physicians in risk identification and patient counseling. The risk assessment questionnaire is close-ended and easily completed by the patient within 10 to 15 minutes. The IBM-compatible format permits easy quantitation by laser scanning and computer analysis. This program quantitates risks arising from interacting independent factors and estimates the effects of primary prevention interventions. Program output includes age- and sex-specific ACS screening guidelines and discussion of intensified screening measures in high-risk subjects.

Breast Neoplasms↗
PubMed1992

The incidence of second primary tumors in long-term survivors of small-cell lung cancer.

PURPOSE AND METHODS: A review of 446 patients who were enrolled consecutively in small-cell lung cancer (SCLC) protocols was performed to identify in long-term survivors the frequency of new primary tumors and their clinical impact. RESULTS: Forty-seven patients (10.5%) were identified to be free of disease at 2 years. Second primary tumors (SPTs) were diagnosed in 14 patients. The overall risk for developing an SPT was 10.3% per person-year. Actuarial risk at 8 years was 50.3% for an SPT. CONCLUSIONS: In this review, SCLC showed one of the highest incidences of SPTs reported in aerodigestive tract malignancies. A long-term survivor was more likely to have an SPT than a relapse of SCLC. Consequently, the odds of death from an SPT compared with that from a relapse increased sharply from 1:13 within 4 years from diagnosis to 8:1 afterwards. Long-term survivors of SCLC would be excellent candidates for chemoprevention trials.

Adult↗
PubMed1992

Current status of chemoprevention of head and neck cancer.

Chemoprevention involves efforts to block or reverse carcinogenesis before the development of invasive cancer. Natural agents, such as retinol and beta carotene, as well as synthetic retinoids have been studied as potential chemopreventive agents. In the head and neck, chemoprevention studies have included efforts both to reverse premalignant lesions such as oral leukoplakia and to prevent the development of second primary tumors. In one recent trial, high-dose 13-cis-retinoic acid treatment resulted in a dramatic reduction in the incidence of second primary tumors. However, significant toxicities were associated with the high dosage. This trial, as well as previous studies of oral leukoplakia, have led to the development of a chemoprevention trial using a low dose of 13-cis-retinoic acid to prevent second primary tumors following head and neck cancer. The rationale and design of this study are discussed in detail.

Head and Neck Neoplasms↗
PubMed1992

13-cis-retinoic acid and cancer chemoprevention.

Chemoprevention is the newest strategy for controlling and managing cancer. At present, the multistep character of epithelial carcinogenesis makes this disease process the most amendable to chemopreventive interventions, which occur in the postinitiation, preinvasive phases. Chemoprevention study has focused on oral carcinogenesis because of its excellent preclinical models, well-defined premalignant phase (leukoplakia), ease of monitoring, and link through field carcinogenesis to other epithelial carcinogeneses of the upper and lower aerodigestive tract. Retinoids, the derivatives of vitamin A, are the most-studied chemopreventive agents, and 13-cis-retinoic acid is the best-studied chemopreventive retinoid. Laboratory study of the newly discovered nuclear receptors of retinoic acid is closing in on the precise mechanism of retinoid action. Only 13-cis-retinoic acid, at high doses, has established chemopreventive activity, which is in suppressing oral premalignancy and preventing second primary head-and-neck tumors. Preclinical and clinical work in the other aerodigestive sites of the lung and esophagus are at an early phase of study with no conclusive results currently available. High-dose 13-cis-retinoic acid also has achieved significant activity in preventing invasive carcinomas of the skin. High-dose 13-cis-retinoic acid, however, is not ideal for widespread chemoprevention approaches because of its toxicity. The toxicity-to-risk balance is delicate and complicated.(ABSTRACT TRUNCATED AT 250 WORDS)

Esophageal Neoplasms↗
PubMed1991

Edatrexate improves the antitumor effects of cyclophosphamide and cisplatin against non-small cell lung cancer.

The authors treated 32 patients with Stage IIIB or IV non-small cell lung cancer (NSCLC) with an outpatient regimen of edatrexate (10-ethyl-10-deaza-aminopterin) (10-EdAM) on days 1 and 8, cyclophosphamide on day 1, and cisplatin on day 1, repeated every 3 weeks with dose modification. The 22 men and 10 women (median age, 57 years of age) had no prior chemotherapy and a Zubrod performance status less than or equal to 2. A schedule with initial doses of 80 mg/m2, 800 mg/m2, and 80 mg/m2, respectively, yielded a 47% major response rate with two complete responses (95% confidence interval [CI], 25% to 70%), but it also yielded significant stomatitis and myelosuppression. A schedule with reduced starting doses (70 mg/m2, 700 mg/m2, and 70 mg/m2) was better tolerated, but dropped the major response rate to 27% with no complete responses (95% CI, 11% to 52%). Median survival time was 39 weeks for all 30 evaluable patients without a significant difference between the treatment groups (which were comparable in patient characteristics). Major response, however, was associated with longer survival time than minor response or no change (P = 0.024) or progressive disease (P = 0.001) (median survival times, 55, 39, and 27 weeks, respectively). When the doses delivered were compared, patients treated with the reduced dose schedule received less mean 10-EdAM per course (P = 0.01), although the doses of cyclophosphamide and cisplatin were comparable to the original dose schedule for the second course and thereafter. These results suggest that this three-drug regimen may have synergistic antitumor effects, with a steep dose-response relationship, particularly with 10-EdAM. With amelioration of the dose-limiting stomatitis of 10-EdAM, it seems possible to maximize the antitumor effects of this regimen.

Adult↗
PubMed1991

Recent advances in cancer chemoprevention.

The CCPC 90 conference and workshop included presentations by basic scientists describing the key in vitro and in vivo model systems used to study epithelial carcinogenesis and its associated biochemical and molecular alterations. A major conference theme was the identification of markers identifying specific carcinogenic stages. Current work focuses on defining the biology of preneoplasia, the critical specific molecular events in multistep carcinogenesis, and the dynamic interplay between viral, behavioral, dietary, and genetic factors in human carcinogenesis. Studies of molecular epidemiology and genetic susceptibility are identifying new risk groups and contributing to preventive strategies. Another major theme of the conference was the concept of field carcinogenesis and the study of carcinogen-exposed tissue "at risk" for the development of cancer. A specific example discussed by several investigators was the issue of SPT development in head and neck and lung cancers. Novel studies of biologic markers for use in early detection and as intermediate end points were described. The latter application, if validated in human trials, may allow short-term screening of chemopreventive agents and determinations of optimal doses/schedules for phase III chemoprevention trials. These biomarker trials may serve as a bridge between preclinical work and full-scale randomized trials. The status of the major phase III clinical trials was presented. Major problems in chemoprevention trials include (1) selection of agents, doses, and schedules, (2) lack of pharmacologic and pharma quality control, (5) adherence (drop-out and drop-in), and (6) trial-specific feasibility/recruitment, issues.

Animals↗
PubMed1991

Chemoprevention in head and neck cancer.

It is not a coincidence that the aerodigestive tract has proven such a fertile ground for the evaluation of chemoprevention. The incidence of second primaries and the concept of field cancerization made the need for prevention acute and showed the limitations of even the most curative of treatments. New and presumably less toxic agents are being evaluated; chemoprevention is being applied to asymptomatic populations at higher risk for lung, colon, breast, and other neoplasias. Biomarkers may be instrumental in rapid development of these new clinical applications, but much is still to be done. Yet unanswered is whether suppression of premalignant lesions will ultimately decrease cancer incidence. Survival in the second primary prevention trial has not thus far shown a significant improvement and toxicities were significant. Many questions remain in the study of chemoprevention; head and neck cancer provides a conducive model in which these answers might be found.

Biomarkers, Tumor↗