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.     

Prostate cancer clinical trials of the Southwest Oncology Group

The changing clinical dynamics of prostate cancer have resulted in a broadening of the research focus of the Genitourinary (GU) Cancer Committee of the Southwest Oncology Group (SWOG). Beginning with an emphasis on hormone-refractory disease in its early years, SWOG prostate cancer trials now cover the entire spectrum of the disease: localized, locally advanced, metastatic and hormone-refractory disease. As the world's largest GU cancer research group, the GU committee of SWOG has pioneered studies in combined androgen therapy for metastatic disease, quality-of-life (QOL) assessments for patients with localized and advanced disease, adjuvant therapy models, and prostate cancer chemoprevention. The committee has also formed the GU Global Group, whose purpose is to convene the chairs of the GU committees of all the major national and international oncology cooperative groups. Meeting semiannually, this group discusses activities within their respective organizations, plans collaborative strategies and protocols, and establishes global strategy in prostate cancer clinical research. The future directions of national and international prostate cancer trials will build on this broad foundation of well-conceived, logically sequenced studies.     

Chicken anemia virus strains with a mutated enhancer/promoter region share reduced virus spread and cytopathogenicity

Clinical cancer prevention studies that use disease as an endpoint are of necessity, large, lengthy, and extremely costly. Development of the field of cancer chemoprevention is being accelerated by the application of intermediate markers to preclinical and clinical studies. Sensitive and specific analytic methods have been developed for detecting and quantifying levels of covalent adducts of aflatoxins with cellular DNA and blood proteins at ambient levels of exposure. Such biomarkers can be applied to the preselection of exposed individuals for study cohorts, thereby reducing study size requirements. Levels of these aflatoxin-DNA and albumin adducts can be modulated by chemopreventive agents such as oltipraz and chlorophyllin in experimental models. Overall, a good concordance is seen between diminution of biomarkers and reductions in tumor incidence and/or multiplicity in these settings. Thus, these markers can also be used to rapidly assess the efficacy of preventive interventions. However, the successful application of these biomarkers to clinical prevention trials will be dependent upon prior determination of the associative or causal role of the marker to the carcinogenic process, establishment of the relationship between dose and response, and appreciation of the kinetics of adduct formation and removal. The general approach that has been utilized for the development, validation and application of aflatoxin-DNA and protein adduct biomarkers to cancer chemoprevention trials is summarized.     

Ex-vivo gene therapy using cytokine-transduced tumor vaccines: molecular and clinical pharmacology

Whether the current generation of cytokine gene-transduced tumor vaccines will show clinical efficacy is under study. Fortunately, the large safety profile so far observed with gene-transduced tumor vaccines can allow outpatient testing in large populations of patients in the adjuvant therapy situation. This will allow large studies statistically powered to see potentially important adjuvant therapy effects in the range that are observed for tamoxifen in breast cancer. For example, the outpatient, adjuvant therapy safety context has been established in the use of GM-CSF gene-transduced autologous prostate cancer vaccines following radical prostatectomy. Similar adjuvant therapy clinical trial efforts are anticipated with allogeneic breast, colon, pancreatic, and ovarian cancer in addition to prostate, renal cell carcinoma, and melanoma. The reverse translation of early clinical data back to basic laboratory research also suggests the field of cytokine gene-transduced tumor vaccine research will remain vibrant. Efforts are currently being directed on optimizing DC activation with polycistronic constructs of cytokine genes, and overexpressing the most relevant tumor-associated peptides. As in the case of antineoplastic drug development, not all lead compounds will become approved drugs in medical oncology. Rigorous yet innovative clinical trial designs will be key to the accelerated identification of cytokine gene-transduced vaccines that improve survival in cancer patients.     

Antioxidant minerals and vitamins. Role in cancer prevention

Cancer is a disease of the genome and free-radicals can damage genomic DNA, hence the interest in the potential protective antioxidant effect of vitamin and minerals. Indeed, the findings of most retrospective studies suggest that diets rich in fruits and vegetables have a protective effect against cancer. Prospective randomized trials have however given controversial results. Beta-carotene, the precursor of vitamin A has been shown to induce regression of precancerous lesions and 13-cis retinoic acid has a preventive effect on the development of a second cancer in patients with epidermoid cancer of the buccal cavity, the pharynx or the larynx although no effect has been observed on the primary cancer. Current research also suggests vitamin C has a potential anticancer effect, particularly for cancer of the stomach, the rectum and the cervix. For vitamin E, epidemiological data give less conclusive results. Several prospective studies suggest the absence of any correlation between vitamin E intake and general risk of cancer. A Chinese trial has shown a decreased incidence of oesophageal and gastric carcinoma while a Finnish trial revealed increased incidence of cancer among smokers treated by beta-carotene and vitamin E. Selenium and zinc intake, based on geographical correlations, has also been suggested to affect cancer incidence, but the results of prospective studies are conflicting. For example in 10 such trials analyzing blood selenium levels and risk of cancer, 4 have demonstrated a significant correlation. Further research is needed but is hindered by the absence of an adequate animal model and the difficulty in conducting large clinical trials. Nevertheless, positive data collected to date must be validated to determine the real effect of dietary preventive measures in the fight against cancer.     

Handicap-related problems in mothers of children with physical impairments

Cancer chemoprevention is defined as the prevention of cancer by the administration of diet supplements or drugs. A drug discovery effort should therefore focus on finding agents that will avert the process of intraepithelial neoplasia which precedes invasive cancer. Over 30 agents developed by the chemoprevention program at the National Cancer Institute are being tested against intraepithelial neoplasia of many organ sites in more than 80 clinical trials. Two basic mechanisms underlie the onset and development of intraepithelial neoplasia. First is the development of the two precursor lesions of chronic diffuse epithelial hyperplasia and genomic instability, the latter being produced by "mutator" mutations in genes responsible for genomic stability, by gene copy amplification or loss from DNA breakage-fusion-anaphase-bridge cycles, by unequal sister chromatid exchange, and by accumulation of double minutes. Second is the development of multicentric intraepithelial neoplastic lesions which independently progress through each of the following processes at a continuously accelerating rate: clonal evolution, hyperproliferation, production of genomic structural variants, and apoptosis. Recommended chemoprevention strategies based on these mechanisms are (i) the development of better technology for early diagnosis, (ii) the development of multiple agents that block intralesional proliferation at steps along the signal pathway of mitotic signal transduction and along the signal pathway of synthesis of daughter cell components, (iii) the development of nontoxic anti-inflammatory agents, anitoxidants, antimutagens, and proapoptotics, (iv) the avoidance of "clonal escape" through use of drug combinations, and (v) the use of computer-assisted quantitative image analysis to assay modulation of surrogate end points in chemoprevention clinical trials.     

Participants' perceptions of a phase I colon cancer chemoprevention trial

To assess participants' perceptions of a phase I colon cancer chemoprevention trial using a calcium intervention, questionnaires were mailed to trial participants at the conclusion of the study. Responses to questionnaire items reported here include (1) perceived benefits and barriers of participation, (2) interest in participating in future trials, (3) willingness to pay trial expenses out of pocket, and (4) posttrial continuation of the calcium regimen. The study found that the most highly rated trial benefit was the perception of potential colon cancer prevention; the trial barrier reported to be the most troublesome was inappropriate or mistaken billing for study visits. Three fourths of the subjects expressed an interest in future trials of the same duration. For trials of longer duration, this percentage decreased to 66%. Approximately half did not object to participation in future trials involving placebos, and just over one third indicated that they would either definitely (8%) or probably (27%) have joined the calcium trial even if they had to pay some study expenses out of pocket. Over 90% indicated they would continue taking the calcium pills if calcium is shown to be effective. The level of perceived benefits was positively associated with reported interest in participating in future trials of the same and longer durations, and the level of reported difficulty with trial pills and procedures was inversely related to interest in future placebo-controlled trials. The results of this study, in conjunction with results of prospective studies of trial participation, may be applied in future chemoprevention trials to facilitate recruitment, reduce attrition, and promote positive trial experiences for participants by emphasizing frequently reported benefits and minimizing frequently reported barriers.     

Preclinical drug development paradigms for chemopreventives

Preclinical screening studies and animal efficacy testing models currently are used by the National Cancer Institute's chemoprevention drug discovery program to assess and identify chemical agents and natural products that may have the potential to prevent human cancer. Identification of potential cancer preventing agents begins by subjecting each compound to a sequential series of short-term, in vitro prescreens of mechanistic, biochemical assays to provide quantitative data to help establish an early indication of chemopreventive efficacy and to assist in prioritizing agents for further evaluation in longer-term, in vitro transformation bioassays and whole animal models. Promising chemical agents or combinations of agents that work through different inhibitory mechanisms subsequently are tested in well-established, chemically induced, animal tumor models, which include models of the lung, bladder, mammaries, prostate, and skin. These preclinical bioassays afford a strategic framework for evaluating agents according to defined criteria, and not only provide evidence of agent efficacy, but also serve to generate valuable dose-response, toxicity, and pharmacokinetic data required prior to phase I clinical safety testing. Based on preclinical efficacy and toxicity screening studies, only the most successful agents considered to have potential as human chemopreventives progress into clinical chemoprevention trials.     

Glycation accelerates the oxidation of low density lipoprotein by copper ions

The American Cancer Society recommends periodic mammography, clinical breast examination and breast self-examination beginning at age 40 years for asymptomatic women at average risk of breast cancer. Although there is substantial evidence from meta-analyses and non-randomized studies to support these recommendations, individual randomized clinical trials of breast cancer screening have not demonstrated mortality reduction in women aged 40-49 years. The opportunity to study this issue further in the United States has been diminished by the high prevalence of screening already being conducted in that population of younger women. The International Union Against Cancer, the American Cancer Society and the National Cancer Institute of the United States have convened a series of workshops and planning meetings to consider the available data and outline plans for future research. Plans are being developed to conduct a randomized trial of mammography in women younger than 50 years in multiple European sites. Successful completion of this trial may provide critical data on efficacy of breast cancer screening in younger women.     

Colorectal cancer--chemoprevention

Colorectal cancer is the second leading cause of death from cancer in The United States. During the last fifteen years, emphasis has been placed on identification of high risk patients and families and outline of appropriate surveillance regimens for normal and high risk patients for colorectal cancer. Parallel to this effort, abundant clinical data has been accumulated that chemoprevention of colorectal cancer with nonsteroidals and aspirin may be possible. Interruption of prostaglandin metabolism appears to be one of the mechanisms of action but not the only therapeutic arm. Currently, sulindac, aspirin, calcium and selenium supplementation are attractive recommendations to at risk patients awaiting results of clinical trials. Other agents in development add excitement to the concept of colorectal cancer chemoprevention.     

Impact of rapid advancement of international standardization on technical requirements for new drug registration

Internationalization of new drug research and development is rapidly progressing. When mutual international acceptance of clinical trial data is realized, scientifically superior data will eradicate and replace all not so scientific data. This means that healthy competition would benefit the data of clinical trials. The same is true of anti-tumor drugs. Some Japan originated antitumor drugs were developed in foreign countries prior to domestic clinical development. In future, geographic centralization of clinical trials in areas which can conduct scientifically more consistent trials is expected. There are only a limited number of institutes which can conduct high-quality clinical trials of antitumor drugs, so they want Japan, a potential country, to come to other areas to produce high-quality clinical trial data. The resolution of a number of daily stumbling blocks such as informing the patient that he or she is suffering from cancer is a prerequisite for conducting high-quality clinical trials. But every effort must be made so that it will not be said: "Data produced overseas are better. There is no need for Japan to use its knowledge and effort in the field of clinical development."     

Gene therapy for colon cancer

The enormous number of newly diagnosed cases of colorectal cancer that occur each year and the lack of agents that are highly effective for all patients underscore the need for novel approaches to combating the disease. Gene therapy as a developing treatment modality is already well established, with a number of trials ongoing and a vast range of other approaches being assessed in animal and cell culture experiments. In this brief review, we have discussed five gene therapy trials in colon carcinoma that are ongoing or in the approval process in the United States. The gene therapy approaches being employed can be divided into three major categories: (1) enzyme/prodrug systems (HSVtk/ganciclovir; CD/5-fluorocytosine); (2) tumor suppressor gene replacement therapy with wild-type p53; and (3) immune-gene therapy which is based on cytokine or tumor antigen expression to induce tumor immunity (e.g., CEA). Replication-deficient recombinant adenoviral vectors are predominantly used for colon cancer gene therapy, because they can be produced at high titer and they readily infect a number of different cell types. One trial uses polynucleotide therapy for antitumor immunization with intramuscular injection. All of these studies are phase I trials, principally designed to evaluate safety, but they will also provide data on gene delivery. Some trials may provide some insight into potential therapeutic effects. We have alluded to some of the concerns on toxicity related to the use of adenovirus, risks and side effects from transgenes, lack of tumor-specificity of transgene expression, and potential problems with efficient gene delivery to solid tumors. The clinical trials, however, will provide insight that will inform design of future studies with respect to dose, form, and frequency of administration, as well as to the value of biologic and clinical endpoints. The molecular analysis of the fundamental basis of colon cancer has moved at a remarkable pace and that progress seems set to continue. Thus, the basic foundations for gene therapy are undoubtedly in place: a clinical need; growing understanding of basic tumor biology; and ever-improving delivery systems. The field is at a very early stage in its evolution, and one concern is that the considerable hurdles that must be overcome are seen as examples of the failure of cancer gene therapy; however, we believe these challenges will be overcome. The authors also believe that colon cancer gene therapy is likely to take new directions, such as use as adjuvant to radical surgery, rather than attempts to treat end-stage disease when the liver is replaced by metastases. Other new directions might include prophylactic gene-based immunization against a panel of well-characterized tumor antigens, at least for persons shown to be at high risk of colon cancer because of genetic or other predisposition. A marriage between gene therapy approaches and conventional anticancer treatments such as radiotherapy and chemotherapy also seems likely. There is already evidence of this move with demonstration of synergism between p53 replacement and radiotherapy and chemotherapy. It is also likely that therapies will be developed that combine elements from the cancer gene therapies discussed previously, namely, suicide gene transfer, immune modulation, and modulation of defective cancer genes. Perhaps one of the main concerns is not that researchers in cancer gene therapy want to walk before they can run, but that the public and government agencies believe they can. The next 10 years will be an interesting time in the development of novel treatments against colon cancer.     

Evaluation of the National Cancer Institute's clinical trials booklet

Evaluating the impact of written materials is a means to enhance the effectiveness of patient education, yet few controlled studies of publications have been completed. In 1984, as a result of a needs assessment, the National Cancer Institute (NCI) developed and pretested the booklet "What Are Clinical Trials All About?" The booklet was designed to help cancer patients make informed decisions about participation in clinical trials, which are critical for improving cancer treatment. The booklet, which is currently available, has been used internationally as a model for communicating information on clinical trials. Since 1985, the booklet has been used by the Cancer Information Service (CIS) as an educational tool for answering questions from cancer patients about treatment and clinical trials. The CIS, which has traditionally assisted NCI in the development and testing of educational materials, was involved in the pretesting and particularly the posttesting of this booklet. The CIS regional offices at Fox Chase Cancer Center and Sylvester Comprehensive Cancer Center together with National Institutes of Health Clinical Center and North Memorial Medical Center conducted a posttest evaluation of the booklet's effectiveness for cancer patients. Two hospitals tested the booklet on patients who were eligible for a specific clinical trial, and two hospitals tested the booklet on patients who were theoretically eligible for a clinical trial (with a cancer site and stage for which a trial existed). Patients were randomly assigned: 203 experimental subjects received the booklet, and 194 control subjects were not given the booklet until after a 2-week posttest examining attitudes, knowledge, and beliefs about clinical trials.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Cell fate and morphogenetic movement in the late mouse primitive streak

Metastatic breast cancer remains incurable by conventional means and is the second leading cause of all cancer deaths in women in the United States. Laboratory and clinical studies have shown chemotherapy dose intensity may be important in breast cancer therapy, and therefore clinical trials have been investigating high-dose chemotherapy (HDC) with autologous stem cell rescue (ASCR) for the past decade. Initial Phase I trials in heavily pretreated patients demonstrated good response rates but short survival times. The next generation of trials used HDC as initial treatment for metastatic breast cancer and showed improved results. Most recently, patients receive HDC after "induction" chemotherapy to minimize tumor burden prior to HDC. Results from these most recent trials are encouraging, with complete remissions (CR) achievable in at least half of patients and long-term survivors noted. An ongoing randomized trial of HDC versus conventional chemotherapy should answer whether HDC is superior to conventional chemotherapy for metastatic breast cancer. Based on encouraging data from a preliminary trial, two ongoing randomized trials are comparing HDC versus conventional chemotherapy in high-risk primary breast cancer. Technological improvements, better supportive care and experience have all contributed to decrease the morbidity and mortality of this procedure. Additionally, hospitalizations have become shorter and costs may be decreasing. This review will discuss the issues pertinent to this modality in the past and present, including chemotherapy regimens, stem cell technology and related issues, outcomes, ongoing trials and future directions for consideration.     

Is the randomized controlled trial overvalued as a basis for clinical decision-making? A review with comments

The randomized controlled trial (RCT) may have considerable limitations in clinical research. Lacking the possibility of blinding impairs the internal validity of the trials. The external validity is often impaired, as results of RCTs obtained in an ideal situation, may be difficult to generalize to a clinical routine situation. Pragmatic randomized trials move from ideal situations towards routine situations, and by modifying the design it is possible to reduce selection bias due to patient and physician preferences. Quasi-experimental studies have varying degrees of problems with internal validity but are necessary contributions to our knowledge of the effect of treatment in clinical routine situations. Limitations of the usefulness of RCTs as well as pragmatic and quasi-experimental studies in clinical research make it necessary to recognise that different methods complement one another. Research in development of RCTs and new methods in clinical research should be encouraged.     

Gene therapy for lung cancer

Gene therapy has received considerable attention and some speculation as to its value. Although few patients have been treated, the preliminary results of the phase I lung cancer gene therapy clinical trials are very promising. Clinically relevant basic research in the molecular pathogenesis and immunology of lung cancer is progressing. As improved vector technologies are developed, new opportunities will be available to initiate lung cancer gene therapy trials that are based on a more detailed understanding of lung cancer biology. In conclusion, although important biologic and technical questions remain unanswered, recent research suggests that gene therapy will have a profound impact on lung cancer treatment.     

Menopause and hormone replacement therapy

Menopause is a normal part of life of most women and can be made easier with appropriate information about the events that occur. For those women who desire help for bothersome menopausal symptoms, effective therapy can be offered. The use of HRT for prevention is more complex. Several large randomized clinical trials, including the Women's Health Initiative (WHI) and the Heart and Estrogen Replacement Therapy Study (HERS) in the United States, are currently underway. These trials, which have as end points clinical events such as myocardial infarction, sudden death, fractures, and cancer, will provide answers to many of the questions raised in this discussion. Until the results of these trials are available, clinicians must be prudent in their recommendations and should keep their patients apprised of the relevant uncertainties of preventive HRT.     

Localization by immunoelectron microscopy of Schistosoma mansoni antigens in the glomerulus of the hamster (Mesocricetus auratus) kidney

Gene therapy has the potential to provide cancer treatments based on novel mechanisms of action with potentially low toxicities. This therapy may provide more effective control of loco-regional recurrence in diseases such as non-small cell lung cancer (NSCLC), as well as systemic control of micrometastases. Despite current limitations, retroviral and adenoviral vectors can in certain circumstances provide an effective means of delivering therapeutic genes to tumour cells. Although multiple genes are involved in the process of carcinogenesis, mutations of the p53 gene are the most frequent abnormality identified in human tumours. Pre-clinical studies both in vitro and in vivo have shown that restoration of p53 function can induce apoptosis in cancer cells. Phase I clinical trials now show that p53 gene replacement therapy is feasible and safe using both retroviral and adenoviral vectors, and that it induces tumour regression in patients with advanced NSCLC and recurrent head and neck cancer. Other pre-clinical studies indicate that gene therapy may have useful synergy with cytotoxic and radiation therapy. This paper describes the different gene therapy strategies under investigation and the pre-clinical data that provides a rationale for the gene replacement approach, reviews clinical trial data and presents novel ideas for improving current vectors and gene delivery to tumours.