Addressing high cervical cancer rates in the Rio Grande Valley along the Texas-Mexico border: a community-based initiative focused on education, patient navigation, and medical provider training/telementoring.

AIMS: Cervical cancer incidence and mortality rates are approximately 55% higher in the Rio Grande Valley (RGV) along the Texas-Mexico border compared with the average rates in the US. Our aim was to improve cervical cancer prevention efforts in the RGV through a comprehensive multilevel intervention initiative focused on community education, patient navigation, and training of local providers. METHODS: We initiated a program in the RGV which consisted of (1) community education, (2) patient navigation, and (3) a training/mentoring program for local medical providers including hands-on training courses coupled with telementoring using Project ECHO® (Extension for Community Health Outcomes). We assessed the number of women undergoing cervical cancer screening, diagnosis, and treatment at three participating clinics caring for underserved women in the region. RESULTS: From November 2014 to October 2018, 14,846 women underwent cervical cancer screening. A total of 2030 (13.7%) women underwent colposcopy for abnormal results (179% increase over baseline) and 453 women underwent loop electrosurgical excision procedures (LEEPs) for treatment of cervical dysplasia. Invasive cancer was diagnosed in 39 women who were navigated to a gynecologic oncologist for treatment. Seven local medical providers were trained to perform colposcopy and/or LEEP. Project ECHO telementoring videoconferences were held every 2 weeks for a total 101 sessions with an average of 22 participants per session and a total of 180 patient cases presented and discussed. CONCLUSIONS: Our program led to a large number of women undergoing diagnosis and treatment of cervical dysplasia in the RGV. If sustained, we anticipate these efforts will decrease cervical cancer rates in the region. The program is currently being expanded to additional underserved areas of Texas and globally to low- and middle-income countries.

Colorectal premalignancy is associated with consensus molecular subtypes 1 and 2.

Background: Gene expression-based profiling of colorectal cancer (CRC) can be used to identify four molecularly homogeneous consensus molecular subtype (CMS) groups with unique biologic features. However, its applicability to colorectal premalignant lesions remains unknown. Patients and methods: We assembled the largest transcriptomic premalignancy dataset by integrating different public and proprietary cohorts of adenomatous and serrated polyps from sporadic (N = 311) and hereditary (N = 78) patient populations and carried out a comprehensive analysis of carcinogenesis pathways using the CMS random forest (RF) classifier. Results: Overall, transcriptomic subtyping of sporadic and hereditary polyps revealed CMS2 and CMS1 subgroups as the predominant molecular subtypes in premalignancy. Pathway enrichment analysis showed that adenomatous polyps from sporadic or hereditary cases (including Lynch syndrome) displayed a CMS2-like phenotype with WNT and MYC activation, whereas hyperplastic and serrated polyps with CMS1-like phenotype harbored prominent immune activation. Rare adenomas with CMS4-like phenotype showed significant enrichment for stromal signatures along with transforming growth factor-ß activation. There was a strong association of CMS1-like polyps with serrated pathology, right-sided anatomic location and BRAF mutations. Conclusions: Based on our observations made in premalignancy, we propose a model of pathway activation associated with CMS classification in colorectal carcinogenesis. Specifically, while adenomatous polyps are largely CMS2, most hyperplastic and serrated polyps are CMS1 and may transition into other CMS groups during evolution into carcinomas. Our findings shed light on the transcriptional landscape of premalignant colonic polyps and may help guide the development of future biomarkers or preventive treatments for CRC.

Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials.

BACKGROUND: The vascular and gastrointestinal effects of non-steroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 inhibitors (coxibs) and traditional non-steroidal anti-inflammatory drugs (tNSAIDs), are not well characterised, particularly in patients at increased risk of vascular disease. We aimed to provide such information through meta-analyses of randomised trials. METHODS: We undertook meta-analyses of 280 trials of NSAIDs versus placebo (124,513 participants, 68,342 person-years) and 474 trials of one NSAID versus another NSAID (229,296 participants, 165,456 person-years). The main outcomes were major vascular events (non-fatal myocardial infarction, non-fatal stroke, or vascular death); major coronary events (non-fatal myocardial infarction or coronary death); stroke; mortality; heart failure; and upper gastrointestinal complications (perforation, obstruction, or bleed). FINDINGS: Major vascular events were increased by about a third by a coxib (rate ratio [RR] 1·37, 95% CI 1·14-1·66; p=0·0009) or diclofenac (1·41, 1·12-1·78; p=0·0036), chiefly due to an increase in major coronary events (coxibs 1·76, 1·31-2·37; p=0·0001; diclofenac 1·70, 1·19-2·41; p=0·0032). Ibuprofen also significantly increased major coronary events (2·22, 1·10-4·48; p=0·0253), but not major vascular events (1·44, 0·89-2·33). Compared with placebo, of 1000 patients allocated to a coxib or diclofenac for a year, three more had major vascular events, one of which was fatal. Naproxen did not significantly increase major vascular events (0·93, 0·69-1·27). Vascular death was increased significantly by coxibs (1·58, 99% CI 1·00-2·49; p=0·0103) and diclofenac (1·65, 0·95-2·85, p=0·0187), non-significantly by ibuprofen (1·90, 0·56-6·41; p=0·17), but not by naproxen (1·08, 0·48-2·47, p=0·80). The proportional effects on major vascular events were independent of baseline characteristics, including vascular risk. Heart failure risk was roughly doubled by all NSAIDs. All NSAID regimens increased upper gastrointestinal complications (coxibs 1·81, 1·17-2·81, p=0·0070; diclofenac 1·89, 1·16-3·09, p=0·0106; ibuprofen 3·97, 2·22-7·10, p<0·0001; and naproxen 4·22, 2·71-6·56, p<0·0001). INTERPRETATION: The vascular risks of high-dose diclofenac, and possibly ibuprofen, are comparable to coxibs, whereas high-dose naproxen is associated with less vascular risk than other NSAIDs. Although NSAIDs increase vascular and gastrointestinal risks, the size of these risks can be predicted, which could help guide clinical decision making. FUNDING: UK Medical Research Council and British Heart Foundation.

Ursodeoxycholate/Sulindac combination treatment effectively prevents intestinal adenomas in a mouse model of polyposis.

BACKGROUND & AIMS: Preclinical studies in animal models, human epidemiological data, and clinical trials in patients with adenomatous polyposis have consistently indicated that sulindac and other nonsteroidal antiinflammatory drugs or cyclooxygenase inhibitors have the greatest potential efficacy among current candidates for colon tumor chemopreventive agents. However, at highly effective doses they all have some risk of toxicity, and their therapeutic profile might be improved by use at lower, more tolerable doses, in combination with a second agent acting via other mechanisms. METHODS: Sulindac was tested in combination with ursodeoxycholic acid (ursodiol), a naturally occurring 7-B-epimer of the bile component chenodeoxycholic acid, for prevention of adenomas in the Min mouse model of adenomatous polyposis. RESULTS: Ursodeoxycholic acid caused a dose-dependent decrease in the number of intestinal tumors. Unlike sulindac and other nonsteroidal anti-inflammatory drugs, which are quite beneficial in the distal intestine but are somewhat less effective in the proximal small intestine (especially the clinically important periampullary duodenum), ursodeoxycholate had equal efficacy throughout the entire intestine, both proximal and distal. Combined treatment with low-dose sulindac was less toxic, with normal weight gain and fewer gastrointestinal ulcerations than high-dose sulindac. Combined treatment with sulindac and ursodeoxycholate was more effective than either agent alone for the prevention of tumors throughout the entire intestine. CONCLUSIONS: These experiments provide the first evidence that ursodeoxycholic acid is effective for preventing adenomas in an animal model. Cyclooxygenase inhibition, when combined with this naturally occurring bile component, may become a promising approach for colon cancer prevention.

Chemoprevention for Barrett's esophagus trial. Design and outcome measures.

Barrett's esophagus is a premalignant condition in which normal squamous epithelium of the esophagus is replaced by metaplastic columnar epithelium. It is a known risk factor for the development of esophageal adenocarcinoma. With the incidence of esophageal adenocarcinoma rising, it is reasonable to study Barrett's esophagus as a potential target for therapy that may prevent, delay and/or reverse ongoing tumorigenic processes. Epidemiologic and animal studies support the use of nonsteroidal anti-inflammatory drugs (NSAIDs) in the chemoprevention of several cancers, including esophageal cancer. Cyclo-oxygenase-2 (COX-2) inhibitors are a new class of NSAIDs that inhibit prostaglandin synthesis by selectively blocking the COX-2 enzyme. The COX-2 enzyme has been reported to be over-expressed in premalignant and malignant states, including in Barrett's esophagus and esophageal adenocarcinoma. The Chemoprevention for Barrett's Esophagus Trial (CBET) is a phase IIb, multicenter, randomized, double-masked, placebo-controlled study of the selective COX-2 inhibitor, celecoxib, in patients with Barrett's dysplasia. The sample size is 200 patients with high or low grade Barrett's dysplasia. Celecoxib is administered orally, 200 mg twice per day; the dosing schedule for placebo is the same. Randomization is stratified by dysplasia grade and by clinic. Endoscopy with biopsies is performed at specified time intervals according to the highest grade of dysplasia determined at randomization. The primary outcome measure is the change from baseline to 1 year in the proportion of biopsies exhibiting dysplasia. Secondary outcomes include change from baseline in the maximal grade, extent and surface area of dysplasia. Tertiary outcomes will include measurements of various relevant biomarkers.

A randomised, double blind, placebo controlled study of celecoxib, a selective cyclooxygenase 2 inhibitor, on duodenal polyposis in familial adenomatous polyposis.

BACKGROUND: Non-selective cyclooxygenase (COX) inhibitors (non-steroidal anti-inflammatory drugs) inhibit large bowel carcinogenesis in patients with familial adenomatous polyposis (FAP). Their role in the duodenum of these patients is less certain. The disease modifying activity of specific COX-2 inhibitors has not been explored in humans. PATIENTS AND METHODS: This was a randomised, double blind, placebo controlled study of celecoxib (100 mg twice daily (n=34) or 400 mg twice daily (n=32)) versus placebo (n=17), given orally twice daily for six months to patients with FAP. Efficacy was assessed qualitatively by blinded review of shuffled endoscopy videotapes comparing the extent of duodenal polyposis at entry and at six months and quantitatively by measurement of the percentage change in duodenal area covered by discrete and plaque-like adenomas from photographs of high and low density polyposis. RESULTS: Shuffled and blinded video review showed a statistically significant effect of 400 mg twice daily celecoxib compared with placebo treatment (p=0.033) with all five independent observers scoring a beneficial effect. Overall, patients taking celecoxib 400 mg twice daily showed a 14.5% reduction in involved areas compared with a 1.4% for placebo (p=0.436). However, patients with clinically significant disease at baseline (greater than 5% covered by polyps) showed a 31% reduction in involved areas with celecoxib 400 mg twice daily compared with 8% on placebo (p=0.049). CONCLUSIONS: A panel of five endoscopists found a significant reduction in duodenal polyposis after six months of treatment with celecoxib 400 mg twice daily. COX-2 inhibition may help this otherwise untreatable condition.

Oltipraz concentrations in plasma, buccal mucosa cells, and lipids: pharmacological studies.

Oltipraz is considered one of the most potent cancer chemoprevention agents, as shown in preclinical studies. Its pharmacological effects in humans have been associated with unusual toxicity affecting the fingers and toes. This study was designed to test intermittent dosing schedules using two dosage levels: 500 mg as a single weekly dose and 200 mg as a biweekly dose, each for 30 days. Fifteen men and women were studied in each dosing group. All were heavy smokers considered to be at high risk for developing lung cancer. Plasma, buccal mucosa cell, and lipoprotein concentrations were measured at different intervals corresponding to the time period when most of the adverse effects occur. No serious toxicities were observed using these doses and schedules. The plasma and buccal mucosa cell concentrations of Oltipraz showed substantial interindividual variations at each sampling. Some subjects had no detectable plasma or buccal mucosal cell Oltipraz concentrations. The distribution of Oltipraz incorporation into the lipid fractions and albumin was changed by the administration of different schedules of Oltipraz. The results of this study suggest that the intermittent dosing is well tolerated and does not result in steady state in plasma or buccal mucosa cells. The variation and lack of detectable Oltipraz concentration in plasma, buccal mucosa cells, and lipids may affect both the toxicity and the pharmacological effects when these doses and schedules are used.

Secondary chemoprevention of upper aerodigestive tract tumors.

Patients with successfully treated upper aerodigestive tract (UADT) tumors commonly develop second primary tumors (SPTs). These tumors occur more often than chance would predict, arise in both the upper or lower aerodigestive tracts, are frequently preceded by leukoplakia, and are a major cause of treatment-related failure. Measures to control SPTs include primary prevention with tobacco and alcohol abstinence, surveillance endoscopy, and secondary chemoprevention. Chemoprevention is the administration of natural or synthetic substances to suppress or reverse the malignant process. Secondary chemoprevention of the UADT is the suppression or reversal of leukoplakia and/or SPTs. Classic antioxidant micronutrients such as retinoids, carotenoids, and certain other agents have been effective in nonrandomized and randomized clinical trials, but treatment is uncertain and recurrences common. These facts, coupled with recent harmful effects of beta-carotene in two clinical trials, stress the need for additional basic science, translational, and clinical research. Chemoprevention is a promising new technology, but is not currently standard therapy for the secondary prevention of UADT tumors.

Surrogate end-point biomarkers in chemopreventive drug development.

Relevant and feasible surrogate end-points are needed for the evaluation of intervention strategies against cancer and other chronic, life-threatening diseases. Carcinogenesis can be viewed as a process of progressive disorganization. This process is characterized by the accumulation of genotypic lesions and corresponding tissue and cellular abnormalities, including loss of proliferation and apoptosis controls. Potential surrogate end-points for cancer incidence include both phenotypic and genotypic biomarkers of this progression. In the US National Cancer Institute chemoprevention programme, histological modulation of a precancer (intraepithelial neoplasia) has so far been the primary phenotypic surrogate end-point in chemoprevention trials. Additionally, high priority has been given to biomarkers measuring specific and general genotypic changes correlated with the carcinogenesis progression model for the targeted cancer (e.g., progressive genomic instability as measured by loss of heterozygosity or amplification at specific microsatellite loci). Other potential surrogate end-points include proliferation and differentiation indices, specific gene and general chromosome damage, cell growth regulatory molecules, and biochemical activities (e.g., enzyme inhibition). Serum biomarkers thought to be associated with cancer progression (e.g., prostate-specific antigen) are particularly appealing surrogate end-points because of accessibility. Potentially chemopreventive effects of the test agent may also be measured (e.g., tissue and serum estrogen levels in studies of steroid aromatase inhibitors). To establish chemopreventive efficacy, prevention of virtually all biomarker lesions, or of those lesions with particular propensity for progression, may be required. Ideally, the phenotype and genotype of any new or remaining precancers in the target tissue of chemopreventive agent-treated subjects would show less, and certainly no greater, potential for progression than those of placebo-treated subjects.

The future of colon cancer prevention.

Chemoprevention science is in flux owing to rapid advances in postgenomic technology. We have witnessed enormous advances in the areas of early detection and molecular profiling of colorectal carcinogenesis; however, unique interpretive and technologic challenges persist. Neoplastic hallmarks must be iteratively tested and validated as markers of risk, targets for intervention, and/or markers of response in order to expedite the development of preventive interventions. In this review, we highlight several of the technologies that are revolutionizing our understanding of carcinogenesis and our approach to colorectal cancer prevention.

Biomarkers as surrogates for cancer development.

Biomarkers are routinely applied in the management of chronic diseases to reduce morbidity and mortality through early diagnosis, as well as to assess the necessity for, and responsiveness to, applied interventions. Biomarkers yield mechanistic insights into layers of biologic organization from molecule to organelle, to cell, and finally to cellular organization and tissue. A step-wise approach to the development of tissue-based biomarkers is presented. These biomarkers may serve as molecular targets for scientific inquiry and intervention, as well as approvable endpoints for clinical trials.

Potential use of lipoxygenase inhibitors for cancer chemoprevention.

Increasing evidence suggests that lipoxygenase (LO)-catalysed metabolites have a profound influence on the development and progression of human cancers. Compared with normal tissues, significantly elevated levels of LO products have been found in breast tumours, colon cancers, lung, skin and prostate cancers, as well as in cells from patients with both acute and chronic leukaemias. LO-mediated products elicit diverse biological activities needed for neoplastic cell growth, influencing growth factor and transcription factor activation, oncogene induction, stimulation of tumour cell adhesion and regulation of apoptotic cell death. Agents that block LO catalytic activity may be effective in preventing cancer by interfering with signalling events needed for tumour growth. In the past ten years, pharmaceuticals agents that specifically inhibit the 5-LO metabolic pathway have been developed to treat inflammatory diseases such as asthma, arthritis and psoriasis. Some of these compounds possess anti-oxidant properties and may be effective in preventing cancer by blocking free radical-induced genetic damage or by preventing the metabolic activation of carcinogens. Other compounds may work by negatively modulating DNA synthesis. Pharmacological profiles of potential chemopreventive agents are compiled from enzyme assays, in vitro testing (e.g., cell proliferation inhibition in human cancer cells) and in vivo animal carcinogenesis models (e.g., N-methyl-N-nitrosourea-induced rat mammary cancer, benzo(a)pyrene-induced lung tumours in strain A/J mice and hormone-induced prostate tumours in rats). In this way, compounds are identified for chemoprevention trials in human subjects. Based on currently available data, it is expected that the prevention of lung and prostate cancer will be initially studied in human trials of LO inhibitors.

Primary cancer prevention trials.

Great progress has been made in cancer chemoprevention during the past 2 decades. Nevertheless, the field could benefit from the experiences of investigators studying the prevention of cardiovascular disease. During the past 50 years, prevention of cardiovascular disease has gone from a dream to a reality, with major clinical impact. The trend during the last 30 years has been impressive and sustained. From 1987 to 1994, there was a sustained major decrease in age-adjusted mortality from coronary heart disease in both men (from 3.1 to 2.2 per thousand persons) and women (from 1.1 to 0.9 per thousand persons). This trend is believed to have resulted from improvements in the treatment of myocardial infarction and, more substantively, from improvements in secondary prevention. This explanation is consistent with earlier computer simulations of trends in cardiovascular mortality during the 1980s, which estimated that 25% of the declines were attributable to primary prevention and 70% were caused by reductions in risk factors or treatment. The greatest effect of primary prevention had previously been noted in the late 1960s and 1970s. Most of these important findings occurred before cholesterol-lowering drugs became widely available, so further improvements are expected. Researchers in cancer prevention should follow in the footsteps of their cardiovascular colleagues. The tools are now available to make prevention of cancer a clinical reality. As the science of prevention improves, it must be remembered that effective and efficient preventive services do not help if they are not used. It is difficult to motivate practitioners and patients to implement preventive services. Also, preventive services are often considered a luxury. Persons without health insurance and those covered by Medicaid are much more likely to be diagnosed with late-stage cancer; therefore, they are key cohorts to target for effective preventive approaches. Finally, the most effective cancer prevention program will probably use both rational drug therapy targeting specific risk factors and public health efforts to promote healthy lifestyle choices in the population at large.

The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis.

BACKGROUND: Patients with familial adenomatous polyposis have a nearly 100 percent risk of colorectal cancer. In this disease, the chemopreventive effects of nonsteroidal antiinflammatory drugs may be related to their inhibition of cyclooxygenase-2. METHODS: We studied the effect of celecoxib, a selective cyclooxygenase-2 inhibitor, on colorectal polyps in patients with familial adenomatous polyposis. In a double-blind, placebo-controlled study, we randomly assigned 77 patients to treatment with celecoxib (100 or 400 mg twice daily) or placebo for six months. Patients underwent endoscopy at the beginning and end of the study. We determined the number and size of polyps from photographs and videotapes; the response to treatment was expressed as the mean percent change from base line. RESULTS: At base line, the mean (+/-SD) number of polyps in focal areas where polyps were counted was 15.5+/-13.4 in the 15 patients assigned to placebo, 11.5+/-8.5 in the 32 patients assigned to 100 mg of celecoxib twice a day, and 12.3+/-8.2 in the 30 patients assigned to 400 mg of celecoxib twice a day (P=0.66 for the comparison among groups). After six months, the patients receiving 400 mg of celecoxib twice a day had a 28.0 percent reduction in the mean number of colorectal polyps (P=0.003 for the comparison with placebo) and a 30.7 percent reduction in the polyp burden (the sum of polyp diameters) (P=0.001), as compared with reductions of 4.5 and 4.9 percent, respectively, in the placebo group. The improvement in the extent of colorectal polyposis in the group receiving 400 mg twice a day was confirmed by a panel of endoscopists who reviewed the videotapes. The reductions in the group receiving 100 mg of celecoxib twice a day were 11.9 percent (P=0.33 for the comparison with placebo) and 14.6 percent (P=0.09), respectively. The incidence of adverse events was similar among the groups. CONCLUSIONS: In patients with familial adenomatous polyposis, six months of twice-daily treatment with 400 mg of celecoxib, a cyclooxygenase-2 inhibitor, leads to a significant reduction in the number of colorectal polyps.

Male pattern baldness and clinical prostate cancer in the epidemiologic follow-up of the first National Health and Nutrition Examination Survey.

Male pattern baldness (MPB) and prostate cancer are common in American males; however, MPB is clinically observable decades earlier. Aging, androgens, and heritability are risk factors for both conditions. We prospectively studied the association between MPB and clinical prostate cancer in a cohort representative of the United States male population. A total of 4,421 men 25-75 years old without a history of prostate cancer were examined for baldness in the Epidemiologic Follow-up Study of the first National Health and Nutrition Examination Survey. Participants were followed from baseline (1971-1974) through 1992. Incident cases of prostate cancer were identified by interviews, medical records, and death certificates. Age-standardized incidence rates and proportional hazards models were used to examine the association between MPB and clinical prostate cancer. Prostate cancer was diagnosed in 214 subjects over 17-21 years of follow-up. The age-standardized incidence of prostate cancer was greater among men with baldness at baseline (17.5 versus 12.5 per 10,000 person-years). The adjusted relative risk for prostate cancer among men with baldness was 1.50 (95% confidence interval, 1.12-2.00) and was similar regardless of the severity of baldness at baseline and was independent of other risk factors, including race and age. MPB seems to be a risk factor for clinical prostate cancer.

Adenocarcinoma of the esophagus: risk factors and prevention.

Esophageal cancer, with an estimated number of 12,300 new cases in the year 2000, is relatively uncommon in the United States but produces a high number of annual deaths, estimated at 12,100. Moreover, the incidence of the adenocarcinoma histologic type of esophageal cancer has been rising over the past two decades. Identification of risk factors could lead to primary prevention, as well as earlier diagnosis, treatment, and increased survival. Multiple risk factors are associated with the development of esophageal adenocarcinoma. These include Barrett's esophagus, acid peptic disorders, motor disorders of the esophagus, other malignancies, medications, environmental exposures, diet, and nutrition. However, no one particular risk factor is responsible for the rising incidence of esophageal cancer. Several preventive strategies are under investigation using such agents as nonsteroidal anti-inflammatory drugs (NSAIDs), selenium, alpha-difluoromethylornithine (DFMO), and retinoids. As we gain more insight into the biology of this disease, other risk factors will hopefully be identified that will enable us to develop effective prevention strategies and, thus, reverse the current rising incidence of esophageal carcinoma.

Chemopreventive efficacy of combined piroxicam and difluoromethylornithine treatment of Apc mutant Min mouse adenomas, and selective toxicity against Apc mutant embryos.

Genetic knockout or pharmacological inhibition of cyclooxygenase-2 decreases the number and size of adenomas in mouse models of familial adenomatous polyposis. Epidemiological and clinical studies in humans indicate that the entire class of nonsteroidal anti-inflammatory drugs (NSAIDs) that inhibit both COX-1 and COX-2 enzymes are promising colon cancer chemopreventive agents. We used the Apc mutant Min mouse model to test combinations of agents that might maximize preventive benefit with minimal toxicity because they act via different mechanisms. Min mice (n = 144) were exposed to low doses of the nonselective COX inhibitor piroxicam and the ornithine decarboxylase (ODC) inhibitor difluoromethylornithine (DFMO), beginning at the time they were weaned and continuing throughout the duration of the experiment. Piroxicam at 12, 25, and 50 ppm in the diet caused dose-dependent decreases in the number of tumors in the middle and distal portions of the small intestine. This decrease in tumor multiplicity was associated with a striking decrease in the size of those tumors that did grow out. In contrast, none of the doses of piroxicam alone decreased tumor multiplicity in the proximal portion of the intestine (duodenum). Exposure to DFMO (0.5 or 1.0% in water) caused a dose-dependent decrease in tumor multiplicity in the middle and distal portions of the small intestine. However, this decreased multiplicity was not associated with a striking decrease in the size of the tumors. Combined treatment of mice with piroxicam plus DFMO was much more effective than either agent alone and resulted in a significant number of mice totally free of any intestinal adenomas (P < 0.001), in contrast to the 100% incidence and high multiplicity in control Min mice. In addition to this profound effectiveness in reducing tumor number, the few residual tumors in mice treated with the combined drugs were markedly smaller in size than tumors that arose from control Min mice. These experiments suggest that selective COX-2 inhibition combined with ODC inhibition is a very promising approach for colon cancer prevention. These COX-2 and ODC inhibitor drugs were not overtly toxic at the doses used when administered to mice after weaning. However, when treatment was begun in utero, the Mendelian expected progeny ratio of 1:1 that we routinely obtained in untreated control litters was no longer observed. Apc(min)/+ progeny of pregnant dams treated with piroxicam and/or DFMO were reduced in number and their ratio to Apc+/+ progeny was decreased to approximately 0.28:1. Thus, these agents are effective against adenomas that have homozygous mutation of the APC gene and also select against fetuses bearing a heterozygous mutation in the APC gene.

Perspectives on surrogate end points in the development of drugs that reduce the risk of cancer.

This paper proposes a scientific basis and possible strategy for applying surrogate end points in chemopreventive drug development. The potential surrogate end points for cancer incidence described are both phenotypic (at the tissue, cellular, and molecular levels) and genotypic biomarkers. To establish chemopreventive efficacy in randomized, placebo-controlled clinical trials, it is expected that in most cases it will be critical to ensure that virtually all of the biomarker lesions are prevented or that the lesions prevented are those with the potential to progress. This would require that both the phenotype and genotype of the target tissue in agent-treated subjects, especially in any new or remaining precancers, are equivalent to or show less progression than those of placebo-treated subjects. In the National Cancer Institute chemoprevention program, histological modulation of a precancer (intraepithelial neoplasia) has thus far been the primary phenotypic surrogate end point in chemoprevention trials. Additionally, we give high priority to biomarkers measuring specific and general genotypic changes correlating to the carcinogenesis progression model for the targeted cancer (e.g., progressive genomic instability as measured by loss of heterozygosity or amplification at a specific microsatellite loci). Other potential surrogate end points that may occur earlier in carcinogenesis are being analyzed in these precancers and in nearby normal appearing tissues. These biomarkers include proliferation and differentiation indices, specific gene and general chromosome damage, cell growth regulatory molecules, and biochemical activities (e.g., enzyme inhibition). Serum biomarkers also may be monitored (e.g., prostate-specific antigen) because of their accessibility. Potentially chemopreventive drug effects of the test agent also may be measured (e.g., tissue and serum estrogen levels in studies of steroid aromatase inhibitors). These initial studies are expected to expand the list of validated surrogate end points for future use. Continued discussion and research among the National Cancer Institute, the Food and Drug Administration, industry, and academia are needed to ensure that surrogate end point-based chemoprevention indications are feasible.