Biomedical subjects
Publications and source records attributed to S M Lippman.
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High incidence and low survival rates of many epithelial cancers remain beyond the control of established preventive and therapeutic modalities. Chemoprevention is a new approach under study that involves the intervention within the premalignant process with specific chemical agents to reverse carcinogenesis and prevent the development of invasive cancer. The two biologic concepts that underlie this research are multistep carcinogenesis and field carcinogenesis. Major clinical issues include trial design and drug development in head and neck, lung, and breast cancer chemoprevention. Within the area of trial design, intermediate end point biomarkers will become very important for providing biologic insights in the short term and greater trial efficiencies in the long term. Drugs that are under the strongest investigation include retinoids and beta-carotene in the head and neck and lung, calcium in the colon, and tamoxifen in the breast. This new field has the potential to make an important contribution toward increasing our control over many deadly epithelial cancers Cancer 1993; 72:984-90.
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BACKGROUND: High-dose isotretinoin therapy has been determined to be an effective treatment for leukoplakia. However, a high rate of relapses and toxic reactions led us to conduct a trial of a much lower dose of isotretinoin in the hope of maintaining a response and limiting toxicity. METHODS: In the first phase of the study, 70 patients with leukoplakia underwent induction therapy with a high dose of isotretinoin (1.5 mg per kilogram of body weight per day) for three months; in the second phase, patients with responses or stable lesions were randomly assigned to maintenance therapy with either beta carotene (30 mg per day) or a low dose of isotretinoin (0.5 mg per kilogram per day) for nine months. RESULTS: In the first phase, the rate of response to high-dose induction therapy in the 66 patients who could be evaluated was 55 percent (36 patients). The lesions of seven patients progressed, and therefore they did not participate in the second phase of the trial. Of the 59 patients included in the second phase, 33 were assigned to beta carotene therapy and 26 to low-dose isotretinoin therapy; these two groups did not differ significantly in prognostic factors. Of the 53 patients who could be evaluated, 22 in the low-dose isotretinoin group and 13 in the beta carotene group responded to maintenance therapy or continued to have stable lesions (92 percent vs. 45 percent, P < 0.001). In situ carcinoma developed in one patient in each group, and invasive squamous-cell carcinoma in five patients in the beta carotene group. Toxicity was generally mild, though greater in the group given low-dose isotretinoin therapy. CONCLUSIONS: When preceded by high-dose induction therapy, low-dose isotretinoin therapy was significantly more active against leukoplakia than beta carotene and was easily tolerated.
BACKGROUND: Oral leukoplakia is an important model for developing chemoprevention approaches for lesions in the upper aerodigestive tract. These lesions most often result from exposure to carcinogens such as tobacco and alcohol and may precede development of invasive cancer. The potent antioxidant alpha-tocopherol (vitamin E) has prevented the development of cancers of the oral cavities in animal models. PURPOSE: The objectives of this study were to evaluate the toxicity and efficacy of alpha-tocopherol in patients with oral leukoplakia and to assess the feasibility of performing chemoprevention trials through the network of the Community Clinical Oncology Program (CCOP). METHODS: A single-arm phase II study using the nontoxic agent alpha-tocopherol to treat oral premalignant leukoplakia was performed at seven institutions affiliated with the CCOP through The University of Texas M. D. Anderson Cancer Center. Patients with symptomatic leukoplakia or dysplasia were treated orally with alpha-tocopherol (400 IU) twice daily for 24 weeks. Follow-up was performed at 6, 12, and 24 weeks after the start of treatment to assess toxicity and response, and serum alpha-tocopherol levels were determined at baseline and at 6 and 24 weeks. RESULTS: Of the 43 patients who have completed 24 weeks of treatment, 20 (46%) had clinical responses and nine (21%) had histologic responses. Mean serum alpha-tocopherol levels were 16.1 micrograms/mL at baseline and increased to 34.29 micrograms/mL after 24 weeks of treatment. Patient-recorded drug calendars, as well as serum drug levels, indicated excellent patient compliance; an average of 95% of the prescribed pills were taken. Treatment was extremely well tolerated; no grade 3 or 4 toxic effects were reported. CONCLUSIONS: Administration of alpha-tocopherol resulted in both clinical and histologic responses in premalignant leukoplakia lesions. The study also demonstrated that chemoprevention trials can be performed through the CCOP. The major problems were that a high percentage of patients were not assessable for response, some patients withdrew because expenses were not reimbursable, and there was limited participation within the CCOP network. These problems may reflect difficulties inherent in the implementation of multi-institutional chemoprevention trials. IMPLICATIONS: The efficacy of alpha-tocopherol alone and in combination with other chemopreventive agents for carcinogenesis in the upper aerodigestive tract should be explored in future trials.
Because they may be used as a quantifiable estimate of the extent of recent DNA injury, micronuclei, extrachromosomal fragments of DNA, are among the most studied potential intermediate markers of cancer chemoprevention. Serial measurements of micronuclei frequency may be easily performed on scrapings from the oral cavity or on bronchial brushings. Assessment of micronuclei frequency and its response to chemopreventive agents has been incorporated into studies of upper aerodigestive tract and lung cancer chemoprevention. These studies have helped define the characteristics of micronuclei and have suggested a role for this test in future chemoprevention studies. Micronuclei frequency has been shown to be increased in the oral and bronchial mucosa of individuals with known carcinogen exposure and is higher at the site of the greatest carcinogen exposure, such as the site where tobacco quids are held, than in grossly normal-appearing mucosa. Treatment with chemopreventive agents leads to a reduction in micronuclei frequency. In oral leukoplakia studies, this effect followed treatment with beta-carotene, retinol, alpha-tocopherol, and 13-cis-retinoic acid. The multistep process of epithelial carcinogenesis results from DNA damage and specific genetic events. That micronuclei reflect ongoing DNA injury suggests the hypothesis that long term suppression of cellular genotoxicity, as reflected by a reduction in micronuclei frequency, ultimately leads to a reduction in cancer incidence.
There is currently considerable excitement about the prospects of developing effective chemoprevention strategies for head and neck cancer. The field cancerization model provides the basic assumptions which guide current head and neck chemoprevention trials. The retinoid 13-cis-retinoic acid, as well as other agents, is currently being studied in clinical trials and will hopefully establish the role of chemoprevention in head and neck cancer.
13-cis-retinoic acid (isotretinoin) and interferon-alpha have limited activity as single agents in advanced cancer. Preclinical data indicate that these agents have different mechanisms of action and, in combination have greater activity (that is, the ability to modulate growth and differentiation) in a number of malignant cell types than either agent alone. In clinical trials, the new biological regimen of 13-cis-retinoic acid and interferon-alpha was shown to have major activity in advanced squamous cell carcinoma of the skin and cervix. We conducted a phase II trial of this regimen in recurrent squamous cell carcinoma of the head and neck. Of the 21 evaluable patients, none had a complete response, and only one had a partial response (5%). Two patients had minor responses, four had stable disease, and 14 experienced disease progression. Five patients developed grade 3 toxic effects, including skin toxicity, fatigue, headache, and anorexia/weight loss. The median survival duration was 25.5 weeks (range, 4-95). The combination of 13-cis-retinoic acid and interferon-alpha at this dose and schedule is ineffective for the treatment of recurrent squamous cell carcinoma of the head and neck.
Sulofenur is a member of a new class of antineoplastic agents with a novel chemical structure and unique pharmacological and biological properties. Preclinical studies have demonstrated a wide spectrum of anti-tumor activity against murine solid tumors and human tumor xenografts. In phase I trials, only mild toxicities were observed. Twenty-six patients (pts), two of whom were inevaluable, with advanced non small cell lung cancer without prior chemotherapy were entered on this phase II trial. Pts received 800 mg/m2 sulofenur po Monday-Friday x 21 days, q 28 days. Seventeen male and 9 female pts with median performance status 1 received a median of 2 courses. Twenty pts had stage IV disease and 19 pts had adenocarcinoma, 6 squamous cell and 1 undifferentiated carcinoma. The main toxicity was grade 1 to 3 anemia in 16 (62%) pts, with hemolysis noted in 9 pts. Although methemoglobinemia was observed in 19 pts, it was severe in only 3 pts. Transient elevation of alkaline phosphatase was seen in 11 pts and one pt had a minor abnormality in glucose metabolism. Other common chemotherapy related side effects such as granulocytopenia or alopecia were not encountered with this agent. Of 24 evaluable pts, two pts had stable disease or minor response and 22 pts had progressive disease. In conclusion although sulofenur had only minor side effects, in the dosage and schedule used, it did not produce any significant response in advanced non-small cell lung cancer.
Retinoic acid and interferon-alpha have limited single-agent activity in advanced cancer. Cell culture data indicate that in combination these agents have enhanced activity (modulating growth and differentiation) in a number of malignant cell types. Recent clinical work in advanced squamous cell carcinoma reports major activity with this regimen. This paper reviews the preclinical and clinical data testing retinoic acid in combination with interferons and presents recent work integrating these agents with radiotherapy in locally advanced cervical cancer.
The combination of interferon (IFN)-alpha 2a and 13-cis-retinoic acid (13-cRA) has demonstrated significant antitumor activity in patients with advanced squamous cell cancer of the skin and cervix. We performed a prospective phase II trial of this combination in patients with locally advanced or metastatic squamous cell lung cancer. Twenty-one patients were enrolled on the study. All patients were evaluable for toxicity and 17 were evaluable for response, four with locally advanced and 13 with metastatic disease. One partial response was obtained in a patient with locally advanced disease. Toxicity consisted mainly of constitutional side effects (fatigue, anorexia), which resulted in eight patients coming off-study. The combination of IFN-alpha 2a and 13-cRA is unlikely to exhibit significant clinical activity in patients with metastatic squamous cell lung cancer, but activity in patients with locally advanced disease has not been excluded.
Phase II trials of the novel biologic combination of 13-cis-retinoic acid plus interferon (IFN)-alpha have achieved major activity in advanced squamous cell carcinomas of the skin and cervix, but not of the lung or head and neck. Very limited study of this combination has occurred in cancers other than those of squamous type. Although uncommon, cases of unresectable or metastatic endometrial adenocarcinoma are virtually incurable, and chemotherapy has had no impact on survival in these cases. This report describes our use of 13-cis-retinoic acid plus IFN-alpha to treat a case of cisplatin- and hormone-resistant, locally advanced and distantly metastatic adenocarcinoma of the endometrium. In this worst-prognosis case, the biologic therapy achieved a major response, which persisted for 4 months. Based on the dramatic activity in this case, we believe that depthful mechanistic and clinical study of this promising new biologic combination should be expanded to include non-squamous tumors of many different sites and histopathologic types.
PURPOSE: Prompted by recent demonstrations that all-trans-retinoic acid (all-trans-RA) had efficacy in acute promyelocytic leukemia, a phase I trial of all-trans-RA was conducted to establish the maximum-tolerated dose (MTD) before phase II testing. PATIENTS AND METHODS: Forty patients with a histologic or cytologic diagnosis of malignancy other than leukemia were treated with single daily oral doses of all-trans-RA ranging from 45 mg/m2 to 200 mg/m2. Doses of all-trans-RA were escalated in the next cohort of patients until the MTD was determined if the preceding dose level was not associated with significant toxicity. RESULTS: Lung cancer was the most common type of tumor included in the study (26 cases) followed by head and neck squamous cell carcinomas (three cases), and squamous cell carcinoma of the skin (two cases); other miscellaneous solid tumors were also represented. Toxicities included cheilitis, skin reactions, headache, and nausea and vomiting, as well as transient elevations of liver enzymes and triglyceride levels. Skin toxicities, consisting of erythema with desquamation and paronychia, were considered to be the dose-limiting toxicity, and were observed in two of six patients who received 175 mg/m2/d, and in two of five patients who received 200 mg/m2/d. Of the 30 patients with assessable lesions, response was evaluated in 26 patients and no major objective tumor response was observed. Two patients were able to receive the drug for longer than 1 year without significant toxicities. There was considerable variation in individual patients' peak plasma all-trans-RA levels, and a decrease in the area under the curve of all-trans-RA plasma concentration was observed in all four patients evaluated. CONCLUSION: For phase II study of adult patients, we recommend 150 mg/m2 of all-trans-RA administered orally once a day. However, for better optimization of drug administration schedules, further studies are needed.
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Chemoprevention entails using specific agents to suppress carcinogenesis and thereby prevent the development of primary or second primary cancers. Because the concept of chemoprevention in patients with or at risk of lung cancer is new, ongoing clinical trials are based on data from epidemiologic and preclinical research, as well as on results of chemoprevention studies in head and neck cancer. The latter studies have provided a model for such studies in lung cancer, considering the two diseases have a similar etiology and biology of field carcinogenesis. Beta-carotene, natural vitamin A, and the retinoids may be effective chemopreventive agents. However, chronic administration of such agents may be required to prevent the development of cancer. Results of chemoprevention trials in head and neck cancer have demonstrated effective inhibition of the development of second primary tumors with the synthetic retinoid 13-cis-retinoic acid; investigators are hopeful this will be repeated in patients with lung cancer. Results of ongoing phase III trials and continued advances in the epidemiologic and biologic study of lung carcinogenesis should contribute to future research in this area.
Once considered a futuristic concept, chemoprevention for pre-malignant oral leukoplakia lesions is now a reality. Oral leukoplakia can proceed to invasive disease and expose the upper aerodigestive tract to carcinoma. Risk factors, diagnosis and research in chemoprevention are discussed.
Bronchial micronuclei, small fragments of extra-nuclear DNA formed during cell division, provide a non-specific but quantifiable marker of DNA damage. Micronuclei have been used to assess carcinogen exposure and as an intermediate endpoint in chemoprevention trials. As part of an ongoing chemoprevention trial, heavy smokers underwent screening bronchoscopy, with biopsies taken at 6 standardized sites. Micronuclei counts were obtained for each site in each of the 40 volunteers found to have squamous metaplasia. Unlike squamous metaplasia, the average micronuclei counts among these heavy smokers were not associated with smoking history. Micronuclei counts were also not associated with the presence or extent of metaplasia. A striking degree of intra-individual variability was observed by comparing the micronuclei counts from different biopsy sites within individuals. The findings suggest that use of micronuclei from single sites may be misleading as a marker of carcinogen exposure or as an estimate of cancer risk. Serial measurements in individuals may provide the most useful information concerning carcinogenic exposure and the impact of chemopreventive agents.