Waun Ki Hong

Adenovirus-Mediated p53 Gene Transfer in Sequence With Cisplatin to Tumors of Patients With Non–Small-Cell Lung Cancer

PURPOSE To determine the safety and tolerability of adenovirus-mediated p53 (Adp53) gene transfer in sequence with cisplatin when given by intratumor injection in patients with non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Patients with advanced NSCLC and abnormal p53 function were enrolled onto cohorts receiving escalating dose levels of Adp53 (1 x 10(6) to 1 x 10(11) plaque-forming units [PFU]). Patients were administered intravenous cisplatin 80 mg/m(2) on day 1 and study vector on day 4 for a total of up to six courses (28 days per course). Apoptosis was determined by the terminal deoxynucleotidyl- transferase-dUTP nick-end labeling assay. Evidence of vector-specific sequences were determined using reverse-transcriptase polymerase chain reaction. Vector dissemination and biodistribution was monitored using a series of assays (cytopathic effects assay, Ad5 hexon enzyme-linked immunosorbent assay, vector-specific polymerase chain reaction assay, and antibody response assay). RESULTS Twenty-four patients (median age, 64 years) received a total of 83 intratumor injections with Adp53. The maximum dose administered was 1 x 10(11) PFU per dose. Transient fever related to Adp53 injection developed in eight of 24 patients. Seventeen patients achieved a best clinical response of stable disease, two patients achieved a partial response, four patients had progressive disease, and one patient was not assessable. A mean apoptotic index between baseline and follow-up measurements increased from 0.010 to 0.044 (P =.011). Intratumor transgene mRNA was identified in 43% of assessable patients. CONCLUSION Intratumoral injection with Adp53 in combination with cisplatin is well tolerated, and there is evidence of clinical activity.

Phase I Trial of Oral Green Tea Extract in Adult Patients With Solid Tumors

PURPOSE This trial was designed to determine the maximum-tolerated dose, toxicity, and pharmacology of oral green tea extract (GTE) once daily or three times daily. PATIENTS AND METHODS Cohorts of three or more adult cancer patients were administered oral GTE with water after meals one or three times daily for 4 weeks, to a maximum of 6 months, depending on disease response and patient tolerance. Pharmacokinetic analyses were encouraged but optional. RESULTS Dose levels of 0.5 to 5.05 g/m(2) qd and 1.0 to 2.2 g/m(2) tid were explored. A total of 49 patients were studied. PATIENT CHARACTERISTICS median age, 57 years (range, 27 to 77 years); 23 patients were women (47%); 98% had a Zubrod PS of 1%; 98% had PS of 1; and 21 had non-small-cell lung, 19 had head & neck cancer, three had mesothelioma, and six had other. Mild to moderate toxicities were seen at most dose levels and promptly reversed on discontinuation of GTE. Dose-limiting toxicities were caffeine related and included neurologic and gastrointestinal effects. The maximum-tolerated dose was 4.2 g/m(2) once daily or 1.0 g/m(2) three times daily. No major responses occurred; 10 patients with stable disease completed 6 months of GTE. Pharmacokinetic analyses found accumulation of caffeine levels that were dose dependent, whereas epigallocatechin gallate levels did not accumulate nor appear dose related. CONCLUSION A dose of 1.0 g/m(2) tid (equivalent to 7 to 8 Japanese cups [120 mL] of green tea three times daily) is recommended for future studies. The side effects of this preparation of GTE were caffeine related. Oral GTE at the doses studied can be taken safely for at least 6 months.

Patterns of relapse in locally advanced head and neck cancer patients who achieved complete remission after combined modality therapy

Relapse patterns in patients with locally advanced head and neck cancer who achieved complete remission were evaluated. After combined modality therapy with induction chemotherapy followed by surgery and/or radiotherapy, 71 of 103 patients were clinically free of disease. The 5‐year recurrence rate was estimated at 51%, with a 39% local and 26% distant failure rate by 5 years. The factors significantly affecting the relapse patterns were: (1) the site of the primary tumor (those with oral cavity lesions were more likely to fail locally, whereas hypopharynx patients had a higher risk of distant metastases); (2) the type of definitive local treatment (those patients who received surgery and radiotherapy were at lower risk of pure local failure); (3) TN Stage (patients with T4N3 or T3N3 tumor were at higher risk of both local and distant failure); and (4) time to response and presence of oropharyngeal lesions (patients who had a longer period from diagnosis to final complete response [CR] and patients with oropharyngeal primaries were at higher risk for simultaneous local and distant failure). Type of chemotherapy, patient age, tumor differentiation, and response to induction chemotherapy did not significantly influence the patterns of relapse. A combined modality approach with induction chemotherapy, surgery, and/or radiotherapy does not seem to reduce the incidence of distant metastases significantly.

Squamous cell carcinoma of the upper aerodigestive tract. A case comparison analysis

Although the etiologic importance of tobacco in risk of upper aerodigestive malignancies is unquestioned, quantification of subsite‐specific risks is less well delineated. Risk estimates from this case‐control study are derived from self‐administered comprehensive risk factor questionnaires distributed to newly registered patients at The University of Texas M.D. Anderson Hospital and Tumor Institute, Houston. Cases included 185 white patients with histologically confirmed squamous cell carcinoma of the upper aerodigestive tract. An equal number of age‐frequency and sex‐frequency matched patients was randomly selected from the same patient population excluding only patients with diagnoses of squamous cell carcinoma of any site. A statistically significant dose‐response relationship for three categories of cigarette pack‐years was evident for both males (odds ratios [OR] = 1.8, 4.0, and 7.5) and females (OR = 1.5, 9.0, and 12.0). Highest risks were documented for laryngeal cancer (OR = 15.1) and lingual cancer (OR = 14.5). There was interaction between alcohol use and smoking among men, but no independent effect of alcohol consumption among either gender. After 15 years of smoking abstinence, males no longer exhibited increased risk (OR = 1.0) whereas the risk for females after 15 years of cessation was 1.5. There were also significantly increased risks among men associated with snuff dipping, cigar, and pipe use (OR = 3.4, 2.8, and 1.8, respectively). The differences in the magnitude of the risk estimates and dose‐response curves by subsite and by sex suggest a variable susceptibility to carcinogenic action.

Association of the epstein-barr virus with lymphoepithelioma of the thymus

A 30‐year‐old woman with the histologic diagnosis of lymphoepithelioma of the thymus is reported on. Investigation of Epstein‐Barr serology showed evidence of infection, and Southern blot analysis showed the presence of the viral genome in the tumor specimen. The patient achieved complete remission after treatment with combination chemotherapy, autologous bone marrow transplant, and radiotherapy. These findings suggest that lymphoepithelioma of the thymus may have a viral pathogenesis similar to that of nasopharyngeal carcinoma.

The Biology and prevention of aerodigestive tract cancers

New approaches to basic research, and the success of various chemotherapies for cancer of the aerodigestive tract, are among the topics of the 20 papers, from a February 1991 conference in Houston. Risk factors such as alcohol, smokeless tobacco, and asbestos, are considered, as are possible methods

Chemoprevention in head and neck cancer: Basic science and clinical application

The concept of field cancerization and the multistep carcinogenesis theory are the premises on which the development of chemoprevention efforts has been based. The first concept underlies the fact that patients who have been cured of a cancer in the aerodigestive tract are still at risk of developing additional primary tumors in the same field, and the multistep carcinogenesis theory implies that the conceivable arrest of one of the steps by chemoprevention might be enough to impede the development of cancer. There is ongoing research for development of new candidate-chemopreventive substances in most areas of oncology. Most of the clinical experience in chemoprevention of head and neck cancer is based on the use of retinoids. Retinoids in high doses have demonstrated activity in treating oral premalignant lesions (OPLs) but with frequent side effects and early relapse after cessation of therapy. Subsequent trials showed better tolerability of retinoids in lower doses. Ongoing trials are currently evaluating whether chemoprevention over 3 years might have longer-lasting effect both on OPLs and in the prevention of second primary tumors.

The use of retinoids in head and neck cancer

Squamous cell carcinoma (SCC) of the head and neck, which occurs in this country most commonly between the ages of 40 and 70 years, accounts for 5% of all tumors and affects approximately 26,000 persons each year [1]. More than 90% of patients with head and neck cancer will have a history of tobacco consumption [2–4]. The estimated age-standardized mortality rate for laryngeal cancer is 0.96 deaths per 100,000 person years, less than one-twentieth of the heavy smoker [3]. Evidence from multiple independent investigations indicates that tobacco usage is linearly related to the development of head and neck cancer [4–7]. Areas within the upper aerodigestive tract at risk for the development of SCC relate to the manner in which tobacco is consumed [7]. Moore and Catlin have postulated that the relationship of tobacco usage to the site of head and neck cancer depends on prolonged contact of concentrated carcinogens suspended in saliva and subsequent ‘pooling’ in mucous reservoirs [8]. Such a hypothesis accounts for the observation that in this country 75% of cancers in the oral cavity originate in a horseshoe-shaped area consisting of only 20% of the surface area of the entire oral mucosa. This region extends from the anterior floor of the mouth backward along both lingual-alveolar sulci to include the lateral margin of the mobile tongue and the anterior tonsillar pillar-retromolar trigone complex.

Biomarkers as Intermediate Endpoints in Chemoprevention Trials: Biological Basis of Lung Cancer Prevention

Lung cancer remains a common cause of mortality throughout the world; in the U.S. alone, 177000 new cases were predicted for 1996 and an estimated 158000 Americans died of lung cancer [1]. The impact of improvements in multimodality therapy on lung cancer mortality remains modest [2]. Although substantial reduction in adult smoking has been achieved in the U.S. (50% of adults are former smokers) [3], many new lung cancers are being diagnosed among former smokers [4, 5]. Data analysis from both M.D. Anderson Cancer Center and Harvard-affiliated hospitals showed that more than 50% of lung cancer cases occur in former smokers. From the current smoking trends, it appears that former smokers will account for a growing percentage of all lung cancer patients. We must therefore examine which former smokers are at high risk for lung cancer.

Erratum: Epidermal growth factor receptor and KRas mutations and resistance of lung cancer to insulin-like growth factor 1 receptor tyrosine kinase inhibitors (Cancer DOI: 10.1002/cncr.26656)

This work was supported by a grant from the National Research Foundation of Korea (NRF) (No. 2011-0017639), the Global Core Research Center (GCRC) grant (No. 2011-0035681), the Converging Research Center Program (No. 2011-K000975) funded by Ministry of Education, Science and Technology (MEST), Republic of Korea (H-Y. Lee), a National Institutes of Health grant R01 CA100816 (H-Y. Lee), and in part by the Department of Defense, through grants W81XWH-04-1-0142 VITAL and W8XWH-06-1-0303 BATTLE (to WKH). We thank OSI Pharmaceuticals for providing PQIP, OSI906, and erlotinib.