13-cis-retinoic acid plus interferon-alpha 2a in locally advanced squamous cell carcinoma of the cervix.
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Adult↗
Biomedical subjects
W K Hong
Publications and source records attributed to W K Hong.
Head and neck cancer.
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Carcinoma, Squamous Cell↗
Overview of combined modality therapies for head and neck cancer.
The survival rate is 40% for patients with advanced squamous cell carcinoma of the head and neck whose tumors are completely resected and 20% for those with unresectable tumors treated with radiotherapy alone. During the past 10 years, combined modality approaches have been developed in an effort to enhance locoregional disease control, reduce distant metastases, and preserve anatomic function. They include the following: (a) neoadjuvant chemotherapy followed by standard therapy with surgery and/or radiation, (b) adjuvant chemotherapy after surgery or radiotherapy with or without neoadjuvant chemotherapy, and (c) neoadjuvant chemotherapy concurrent with radiotherapy. Even early studies of cisplatin plus fluorouracil (5-FU) reported 50%-90% overall response rates, and this is the main drug combination used in clinical trials. In the Veterans Affairs Cooperative Study Program, 5-FU and cisplatin followed by radiotherapy achieved a 49% complete response rate and preservation of the larynx in 64% of the patients. These results supported the findings of other nonrandomized trials that sequential induction chemotherapy and radiotherapy results in laryngeal preservation without compromising overall survival. The Head and Neck Cancer Intergroup Trial compared adjuvant postoperative cisplatin plus 5-FU prior to radiotherapy with postoperative radiotherapy. Survival at 4 years was 44% with radiotherapy alone and 48% with chemotherapy and radiotherapy. Biochemical modulation of 5-FU with leucovorin and biologic response modifiers such as interferon has achieved complete response rates as high as 66%, but severe mucositis continues to be the dose-limiting toxic effect. Standard radiotherapy for advanced nasopharyngeal carcinoma--a unique type of head and neck cancer--resulted in 5-year survival of 10%-40%, but neoadjuvant chemotherapy plus radiotherapy has achieved overall complete response rates greater than 80% with median survival of 5 or more years. We conclude that curability of nasopharyngeal carcinoma with a combined modality approach appears to be an achievable goal, but adequate evaluation in large-scale randomized trials is hampered by low accrual to clinical trials. In summary, neoadjuvant therapy for squamous cell head and neck carcinoma results in complete response rates of 22%-66%, but addition of adjuvant therapy may be necessary for a survival advantage over standard therapy. Although concurrent chemoradiotherapy has produced increased survival, additional trials are needed to determine optimal dosages.
Combined Modality Therapy↗
Comparison of low-dose isotretinoin with beta carotene to prevent oral carcinogenesis.
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.
Adult↗
Regression of oral leukoplakia with alpha-tocopherol: a community clinical oncology program chemoprevention study.
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.
Alcohol Drinking↗
Early genetic changes during upper aerodigestive tract tumorigenesis.
Upper aerodigestive tract tumorigenesis has been hypothesized to represent a field cancerization process with multistep events based on its association with known carcinogens, its frequent associated premalignant lesions, and its multifocal clinical manifestation. To further explore this working hypothesis, we have examined normal tissue and premalignant lesions in the field of tumors for evidence of genetic change. Paraffin sections of head and neck tumors harboring neighboring premalignant lesions were explored for the presence of chromosome polysomies using in situ hybridization and chromosome-specific centromeric probes. Cells exhibiting random polysomy were observed in the premalignant regions near the tumors. The frequency of polysomy in the tumor field increased as the tissue progressed from normal morphology (33%), to hyperplasia (67%), to dysplasia (95%), and to squamous cell carcinoma (96%). These results support the notions of field cancerization and multistep tumorigenesis in the aerodigestive tract. To determine whether the degree of accumulated genetic alterations might serve as a biomarker for risk of developing malignancy, a set of biopsies of oral premalignant lesions (leukoplakia, erythroplakia) were retrospectively chosen for polysomy analysis from two groups of individuals: one group who subsequently developed oral cancer and one group who did not develop oral cancer. Three of the five individuals who showed significant chromosome polysomies in their biopsies subsequently developed oral cancer, whereas only one of eight individuals with little evidence of polysomy subsequently progressed to oral cancer. These results suggest that evidence of generalized genetic change or instability might be useful as a genetic biomarker for risk assessment.
Digestive System Neoplasms↗
Micronuclei: a potential intermediate marker for chemoprevention of aerodigestive tract cancer.
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.
Anticarcinogenic Agents↗
Retinoids in chemoprevention of head and neck carcinogenesis.
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.
Anticarcinogenic Agents↗
Phase II trial of 13-cis-retinoic acid plus interferon-alpha in recurrent 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.
Adult↗
Retinoic acid and interferon combination studies in human 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.
Adult↗
Activation of ribosomal protein S2 gene expression in a hamster model of chemically induced oral carcinogenesis.
7,12-Dimethylbenz[a]anthracene (DMBA)-induced carcinogenesis of the hamster buccal pouch has been an excellent model for the study of squamous cell carcinogenesis in human head and neck cancer. Using a differential hybridization of cDNA cloning technique, we isolated a cDNA clone that is expressed in N-ras-transformed PA-1 cells but poorly expressed in non-tumorigenic PA-1 cells; the cDNA codes for the human ribosomal S2 gene product. To define the involvement of S2 gene expression during carcinogenesis in this animal model, we used in situ hybridization technique with non-radioactive digoxigenin-11-dUTP-labeled cDNA. S2 gene was expressed at low levels in basal and suprabasal cell layers of the epidermis in the control, but showed marked elevation throughout the epidermis other than the keratin layer in samples treated for 4 or 8 weeks; S2 was highly expressed in all malignant squamous cell carcinoma cells resulting from DMBA treatment for 16 weeks. As tumors progress from normal epithelium to squamous cell carcinomas, mRNA of the S2 gene was not only elevated sequentially, but also demonstrated the marked heterogeneity among transformed populations, particularly in dysplastic lesions and squamous cell carcinomas. The S2 gene was expressed in a stage-specific manner in the hamster tumor model; S2 could be useful as a neoplastic marker for the detection of certain epithelial origin of tumors and premalignant lesions as well.
9,10-Dimethyl-1,2-benzanthracene↗
Phase II study of 13-cis-retinoic acid and interferon-alpha 2a in patients with advanced squamous cell lung 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.
Adult↗
Effectiveness of combined induction chemotherapy and radiotherapy in advanced nasopharyngeal carcinoma.
PURPOSE: This prospective trial was conducted with the goal of achieving an improvement in both overall and progression-free survival in previously untreated patients with stage IV nasopharyngeal carcinoma who received an induction chemotherapy regimen of fluorouracil (5-FU) and cisplatin followed by radiotherapy. PATIENTS AND METHODS: From January 1985 to January 1990, 47 patients with T1-4N2-3M0 squamous cell carcinoma of the nasopharynx were treated at The University of Texas M.D. Anderson Cancer Center with two to three cycles of 5-FU (1,000 mg/m2 continuous infusion per day x 5 days) plus cisplatin (100 mg/m2 continuous infusion on day 1 only) followed by radiotherapy using the conventional time/dose schedule. RESULTS: The response rate to chemotherapy was 93.2% (20.5% complete response [CR]; 72.7% partial response [PR]), and the overall CR rate after radiotherapy was 86%. With a median follow-up period of 53 months, the 2-, 4-, and 6-year survival rates were 80%, 71.6%, and 67.4%; the overall treatment failure rate was 27%. Treatment was well tolerated and without significant acute or chronic toxic effects. CONCLUSION: The results of this prospective study demonstrate that 5-FU plus cisplatin followed by radiotherapy can induce a durable remission in a high proportion of patients with poor-prognosis stage IV nasopharyngeal carcinoma.
Adolescent↗
Warfarin and small-cell lung cancer.
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Antineoplastic Combined Chemotherapy Protocols↗
Phase I evaluation of all-trans-retinoic acid in adults with solid tumors.
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.
Adult↗
Not yet standard: retinoids versus second primary tumors.
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Anticarcinogenic Agents↗
Chemoprevention strategies in lung carcinogenesis.
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.
Carotenoids↗
Squamous metaplasia of the bronchial mucosa and its relationship to smoking.
We performed flexible fiberoptic bronchoscopy (FFB) on 106 heavy cigarette smokers. Six bronchial biopsy specimens, obtained from the carina and five major bronchi, were screened for squamous metaplasia. Individual biopsy specimens were sectioned into 4-microns sections, and a metaplasia index (MI), or percentage of sections containing squamous metaplasia, was determined. Metaplasia was noted at one or more biopsy sites in 66 of 99 subjects (seven were excluded from the analysis). Twenty-five percent of the subjects showed metaplasia at three or more biopsy sites, and one subject had metaplasia on all six biopsy specimens. The presence of squamous metaplasia varied from 40.4 percent in the right lower lobe to 15.3 percent in the left upper lobe. The subjects were grouped into simple categories based on the number of packs smoked per day and the pack-year history of smoking. Subjects who smoked more than two packs per day (n = 11) had the highest MI (37.4 +/- 4.9 percent, mean +/- SEM). Fifty-seven subjects smoked more than one pack per day but fewer than or equal to two packs per day, and they had a mean MI of 22.3 +/- 2.9 percent. Subjects who smoked one pack per day or less (n = 31) had a mean MI of only 12.9 +/- 2.8 percent. The MI of those who smoked more than two packs per day was significantly greater than the MI of those who smoked one pack per day or less (p < or = 0.003). While the MI varied from 12.9 +/- 3.5 percent in subjects who had smoked less than 20 pack-years to a maximum of 29.1 +/- 4.5 percent in those who had smoked greater than 60 pack-years, no statistically significant difference was detected between these two groups. Thus, we conclude that heavy tobacco use is associated with important alterations of bronchial mucosa. Furthermore, the intensity of tobacco use (packs per day) rather than the number of pack-years appears to be the more important factor in promoting squamous metaplasia of the bronchial mucosa.
Adult↗