Skip to main content
  • AACR Publications
    • Cancer Discovery
    • Cancer Epidemiology, Biomarkers & Prevention
    • Cancer Immunology Research
    • Cancer Prevention Research
    • Cancer Research
    • Clinical Cancer Research
    • Molecular Cancer Research
    • Molecular Cancer Therapeutics

  • Register
  • Log in
Advertisement

Main menu

  • Home
  • About
    • The Journal
    • AACR Journals
    • Subscriptions
    • Permissions and Reprints
    • Reviewing
  • Articles
    • OnlineFirst
    • Current Issue
    • Past Issues
    • Meeting Abstracts
  • For Authors
    • Information for Authors
    • Author Services
    • Best of: Author Profiles
    • Submit
  • Alerts
    • Table of Contents
    • OnlineFirst
    • Editors' Picks
    • Citation
    • Author/Keyword
  • News
    • Cancer Discovery News
  • AACR Publications
    • Cancer Discovery
    • Cancer Epidemiology, Biomarkers & Prevention
    • Cancer Immunology Research
    • Cancer Prevention Research
    • Cancer Research
    • Clinical Cancer Research
    • Molecular Cancer Research
    • Molecular Cancer Therapeutics

User menu

  • Register
  • Log in

Search

  • Advanced search
Cancer Prevention Research
Cancer Prevention Research

Advanced Search

  • Home
  • About
    • The Journal
    • AACR Journals
    • Subscriptions
    • Permissions and Reprints
    • Reviewing
  • Articles
    • OnlineFirst
    • Current Issue
    • Past Issues
    • Meeting Abstracts
  • For Authors
    • Information for Authors
    • Author Services
    • Best of: Author Profiles
    • Submit
  • Alerts
    • Table of Contents
    • OnlineFirst
    • Editors' Picks
    • Citation
    • Author/Keyword
  • News
    • Cancer Discovery News
Research Article

Difluoromethylornithine Plus Sulindac for the Prevention of Sporadic Colorectal Adenomas: A Randomized Placebo-Controlled, Double-Blind Trial

Frank L. Meyskens Jr., Christine E. McLaren, Daniel Pelot, Sharon Fujikawa-Brooks, Philip M. Carpenter, Ernest Hawk, Gary Kelloff, Michael J. Lawson, Jayashri Kidao, John McCracken, C. Gregory Albers, Dennis J. Ahnen, D. Kim Turgeon, Steven Goldschmid, Peter Lance, Curt H. Hagedorn, Daniel L. Gillen and Eugene W. Gerner
Frank L. Meyskens
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Christine E. McLaren
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Daniel Pelot
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Sharon Fujikawa-Brooks
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Philip M. Carpenter
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Ernest Hawk
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Gary Kelloff
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Michael J. Lawson
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jayashri Kidao
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
John McCracken
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
C. Gregory Albers
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Dennis J. Ahnen
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
D. Kim Turgeon
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Steven Goldschmid
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Peter Lance
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Curt H. Hagedorn
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Daniel L. Gillen
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Eugene W. Gerner
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
DOI: 10.1158/1940-6207.CAPR-08-0042 Published June 2008
  • Article
  • Figures & Data
  • Info & Metrics
  • PDF
Loading

Abstract

Preclinical studies of chemoprevention drugs given in combination at low doses show remarkable efficacy in preventing adenomas with little additional toxicities, suggesting a strategy to improve risk to benefit ratios for preventing recurrent adenomas. Three hundred seventy-five patients with history of resected (≥3 mm) adenomas were randomly assigned to receive oral difluoromethylornithine (DFMO) 500 mg and sulindac 150 mg once daily or matched placebos for 36 months, stratified by use of low-dose aspirin (81 mg) at baseline and clinical site. Follow-up colonoscopy was done 3 years after randomization or off-study. Colorectal adenoma recurrence was compared among the groups with log-binomial regression. Comparing the outcome in patients receiving placebos to those receiving active intervention, (a) the recurrence of one or more adenomas was 41.1% and 12.3% (risk ratio, 0.30; 95% confidence interval, 0.18-0.49; P < 0.001); (b) 8.5% had one or more advanced adenomas, compared with 0.7% of patients (risk ratio, 0.085; 95% confidence interval, 0.011-0.65; P < 0.001); and (c) 17 (13.2%) patients had multiple adenomas (>1) at the final colonoscopy, compared with 1 (0.7%; risk ratio, 0.055; 0.0074-0.41; P < 0.001). Serious adverse events (grade ≥3) occurred in 8.2% of patients in the placebo group, compared with 11% in the active intervention group (P = 0.35). There was no significant difference in the proportion of patients reporting hearing changes from baseline. Recurrent adenomatous polyps can be markedly reduced by a combination of low oral doses of DFMO and sulindac and with few side effects.

More than 50,000 people in the United States will die in 2007 from colorectal cancer. In the United States, cancer is the leading cause of death in people under age 74 years (1), and colorectal cancer is the second most common cause of cancer deaths after lung cancer (2). Colorectal cancer may be prevented by removal of precursor adenomas found during screening sigmoidoscopy or colonoscopy (3), although rates are variable and range from 30% to 90% depending highly on reimbursement policies (4, 5).

Diet and inflammation have been associated with risk of colorectal cancer (6), and a series of clinical trials have been conducted to test the efficacy of individual dietary supplements or anti-inflammatory agents to prevent the incidence or recurrence of colon polyps (7–14). Unfortunately, these trials have not translated into significant changes in medical practice for prevention or management of colon cancer for a variety of reasons, including lack of efficacy, unacceptable toxicities, and the availability of competing strategies for risk reduction (15).

Studies in rodent models have shown that combination chemoprevention strategies are often more effective than those using individual agents (16, 17). Difluoromethylornithine (DFMO) has been identified as a potent inhibitor of intestinal and colon carcinogenesis in animal models, especially in combination with nonsteroidal anti-inflammatory drugs (18–20). DFMO and the nonsteroidal anti-inflammatory drug sulindac also interact additively to prevent the growth and viability of human colon cancer cells (21). The results of a phase III clinical chemoprevention trial evaluating the combination of DFMO and sulindac for the prevention of colon polyp recurrence are reported here.

Materials and Methods

Study design

This study was a randomized, double-blind placebo-controlled trial to test whether the combination of a low dose of DFMO plus a low dose of sulindac reduces the recurrence of colorectal adenomas detected by standard colonoscopy. The trial involved seven clinical sites in the United States. The human subjects committee at each site approved the study protocol and written informed consent was provided by all patients before enrollment. Quality control to promote uniform practice and protocol compliance included meetings before enrollment and site inspections during and after the trial. An independent Data and Safety Monitoring Board reviewed safety and efficacy data twice yearly.

Recruitment and study population

Eligibility required patients of ages 40 to 80 years with a history of ≥1 resected adenoma of at least 3 mm within 5 y before study entry. A screening colonoscopy within 6 mo of study entry was done and all polyps removed and pathologically examined. A 1-mo placebo run-in period was used to assess compliance. Before randomization to the agents, pre-randomization screening was done and included baseline history, physical examination, pure-tone audiometry, and laboratory evaluations for baseline hematologic, renal, and hepatic status. Three years after randomization, colonoscopies were done. Gastroenterologists associated with the trial performed all study colonoscopies.

Subjects were ineligible if they had a history of familial adenomatous polyposis, hereditary nonpolyposis colorectal cancer, inflammatory bowel disease, or invasive cancer within 5 y before enrollment. Also ineligible were subjects with renal, hepatic, or bleeding disorders; subjects hypersensitive to selective inhibitors of cyclooxygenase-2, nonsteroidal anti-inflammatory drugs, salicylates, or sulfonamides; and subjects who had undergone large-bowel resection of >10 cm (excluding appendectomy). Participants with >20 dB uncorrectable hearing loss above age-adjusted norms (assessed by pure-tone audiometry) at any frequency in the normal hearing range were ineligible. To be randomized, participants had to show 80% adherence to the 1-mo run-in medication.

Safety evaluations during the study included physical examinations and laboratory evaluations at return visits after the run-in and 3, 6, 9, 12, and every 6 mo through the end of the study. Pure-tone audiograms were done at 18 and 36 mo or off-study, and repeated 6 mo later. Compliance with the protocol, including in-person and telephone visits, study medication, and blood draws, was monitored throughout the duration of the study.

Study treatment

DFMO was given orally at a dose of 500 mg and sulindac at a dose of 150 mg/d. The randomization used a blocked design and was stratified by clinical site and on the basis of the use (defined as ≤81 mg daily or ≤325 mg twice weekly) or nonuse of low-dose aspirin at study entry.

Assessment of end points, adverse events, and follow-up

The reports for all polyps removed during colonoscopies were submitted for central pathology review and the diagnosis of adenomas was confirmed using standard diagnostic criteria. Secondary efficacy end points included the number and size of colorectal adenomas and the total adenoma burden over the 3-y period. An additional a priori secondary end point was the detection of an advanced adenoma with any of the following characteristics: size of at least 1.0 cm by endoscopic measurements, villous or tubulovillous histologic features, high-grade dysplasia, and intramucosal or invasive carcinoma. Safety analyses were based on investigator-reported adverse events, serious adverse events, laboratory measurements, and physical examinations. Adverse events were coded according to the Coding Symbols for Thesaurus of Adverse Reaction Terms (COSTART) Body System.

Statistical analysis

Based on the two-sample test of binomial proportions, the trial was designed with a statistical power of 90% to detect a 50% decrease in the rate of recurrent adenomas experienced by the DFMO plus sulindac group, assuming a 35% cumulative incidence rate of adenomas in the placebo group, and 0.025 one-sided level of significance. Based on these assumptions, 292 subjects were required for end point evaluation. To account for a dropout rate of as much as 25%, a total of 375 subjects were randomized. The trial included a prespecified stopping rule allowing for early stopping in favor of efficacy or futility. Interim analyses were planned when ∼60% and 80% of the maximal planned information for the trial were available. The stopping rule was chosen to maintain an overall one-sided type I error rate of 2.5%, using a one-sided O'Brien-Fleming (22) efficacy bound with a futility bound parameterized via the unified family of group sequential designs with P = 0.9 (23). Adjustments to the stopping rule to account for shifts in the actual timing of analyses while maintaining the desired type I error rate were done using the constrained boundaries method (24). Based on results observed at the second interim analysis, the Data Safety and Monitoring Board of the study recommended early termination in favor of efficacy. Here we present the results of data on the final intention-to-treat cohort of 267 evaluable patients. For the primary efficacy analysis, bias-adjusted estimates of the difference in recurrence rates and corresponding repeated confidence intervals were computed to account for the stopping rule (25).

In patients treated with DFMO plus sulindac compared with those treated with placebo, the relative risks of recurrent adenomas and of the development of at least one advanced adenoma were assessed by log-binomial regression. Treatment groups were compared with regard to the estimated censoring distribution due to early treatment termination using the Kaplan-Meier method. Investigator-reported adverse events were analyzed in total and according to prespecified categories to describe gastrointestinal, hematologic, and cardiovascular disorders; ototoxocity; and hospitalizations. The analyses included all events occurring after the first dose of study medication. The relative risk of hearing loss of at least 15 dB was assessed by log-binomial regression.

Results

Baseline characteristics

Baseline variables were similar across the two treatment groups (Table 1). Patient characteristics included age, gender, race/ethnicity, body mass index, colorectal cancer risk factors, prior use of low-dose aspirin, history of diabetes, hypertension, cardiovascular events, current smoking status, and colorectal cancer risk factors (i.e., number and characteristics of prestudy polyps).

View this table:
  • View inline
  • View popup
Table 1

Baseline characteristics of the patients were evenly distributed between arms

Subject disposition

The study schema, presented in Fig. 1, indicates the number of patients randomized to treatment groups, the number of patients with data included in the final analyses, and the number of patients who had colonoscopies at time points other than between the 33- and 39-month window and timing of follow-up colonoscopies. Adherence to the treatment regimen was adequate. Seventy percent of patients in both groups adhered to the active intervention from 50% to 90% of the time. Twenty-five percent of patients adhered to the active intervention at least 90% of the time compared with 24% of patients receiving placebos.

Fig. 1
  • Download figure
  • Open in new tab
  • Download powerpoint
Fig. 1

Study schema.

After the first interim analysis (60% of patients completed the 3-y colonoscopy follow up), the Data and Safety Monitoring Board endorsed an accelerated analysis, following which the trial was stopped with appropriate follow-up of the remaining patients as the prescribed efficacy end points had been met and because long-term follow-up of the remaining patients on trial was unlikely to change the conclusions about efficacy.

Based on power calculations, 292 subjects would provide maximal information for end point evaluation; the rate of colonoscopy was 91% (267 of 292) in this cohort and the final analysis was based on data from these 267 evaluable patients, comprising 71% of the randomized cohort. The primary analysis for efficacy measured adenomas at any time after randomization (Table 2). In the placebo group, 53 patients had at least one adenoma, compared with 17 patients in the treatment group. The estimated cumulative recurrence was 41.1% in the placebo group and 12.3% in the treatment group, corresponding to a risk ratio of 0.30 [95% confidence interval (95% CI), 0.18-0.49; P < 0.001] or a reduction of 70%. Accounting for the interim analyses, the bias-adjusted point estimate of the difference in polyp recurrence between the treatment and placebo groups was −0.2793 with a corrected 95% CI of −0.3933 to −0.1718. Aspirin (≤81 mg) use did not seem to affect the number of total adenomas in either group. A sensitivity analysis in which adenomas were imputed at the observed placebo rate of recurrence for all patients without an end-of-study colonoscopy (Table 2) gave a risk ratio of 0.49 (95% CI, 0.36-0.69).

View this table:
  • View inline
  • View popup
Table 2

Risk of adenomas; evidence of substantial effect in active arm

In the placebo group, 11 patients had advanced adenomas, whereas in the DFMO plus sulindac group only one advanced adenoma was detected. This corresponds to a risk ratio of 0.085 (0.011-0.65; P < 0.001) or a reduction of 92%. In the placebo group, 17 patients had more than one adenoma, compared with one patient randomized to active intervention, indicating a reduction of 95% (risk ratio, 0.055; 95% CI, 0.0074-0.41; P < 0.001). Similar results were obtained in a smaller group of patients who had colonoscopies between 36 and 39 months on treatment (Table 2).

Safety

Adverse events were carefully monitored throughout the study (Tables 3 and 4). At least one serious adverse event requiring an overnight hospitalization was reported in 31 of 184 (16.9%) patients in the placebo group and in 42 of 191 (22.0%) patients in the DFMO plus sulindac group (risk ratio, 1.31; 95% CI, 0.86-1.98; P = 0.21). There was also no significant difference between the two arms in those patients experiencing a serious adverse event of grade ≥3 (Table 3). No drug-associated changes in serum levels of creatinine, alanine aminotransferase, or hemoglobin were measured. Reported renal, hypertensive, gastrointestinal, and cardiovascular disorders were analyzed separately, and no differences were detected between the two groups. Serious cardiovascular side effects (Table 4) occurred in 16 (8.4%) patients in the treatment arm and in 9 (4.9%) patients in the placebo arm (risk ratio, 1.71; 95% CI, 0.78-3.78; P = 0.17).

View this table:
  • View inline
  • View popup
Table 3

Incidence of adverse events after randomization categorized by COSTART

View this table:
  • View inline
  • View popup
Table 4

Detailed assessment of adverse events

There was no significant difference between groups in the proportions of patients with self-reported hearing loss (Table 3; risk ratio, 1.22; 95% CI, 0.90-1.64; P = 0.19), and in the normal speech range (500-3,000 Hz) no significant difference was noted between arms in the 259 tested participants (P = 0.17). For these models, after adjustment for age and gender, differences between groups remained nonsignificant (P = 0.19 and P = 0.15, respectively).

Of 262 participants who had air conduction audiograms at baseline and repeated audiograms from 18 to 36 months after beginning treatment, there were 25 of 136 (18.4%) in the DFMO plus sulindac group and 12 of 123 (9.8%) in the placebo group (P = 0.05) who experienced at least a 15-dB hearing reduction from baseline in ≥2 consecutive frequencies across the entire range tested (230-8,000 Hz; Table 4). Based on end-of-study audiograms, 30 patients had unilateral or bilateral hearing reductions of ≥15 dB from baseline in ≥2 consecutive frequencies across the entire range of frequencies tested. Of these, 12 had bilateral audiometric hearing reductions, 10 of 21 (48%) in the treatment arm and 2 of 9 (22%) in the placebo arm (P = 0.18). Follow-up audiograms obtained in these 12 patients showed that improvement occurred in 1 of 2 (50%) patients in the placebo arm and in 3 of 10 (30%) in the treatment group.

Discussion

The results from this randomized trial (Table 2) indicate that a low dose of the polyamine synthesis inhibitor DFMO plus the nonspecific nonsteroidal anti-inflammatory drug sulindac at a dose one half the usual therapeutic dose markedly reduced the recurrence of all adenomas (70% decrease), advanced adenomas (92% decrease), and recurrence of more than one adenoma (95% decrease) in a population of individuals at moderately high risk for sporadic adenomas (41% of patients receiving placebos developed recurrent adenomas). Although this study was not structured to determine whether colorectal cancer occurrence itself was affected, two participants in the placebo group, but none in the active treatment group, were diagnosed with colon cancer by the end of the study.

A major feature of this trial was the selection of a low dose of DFMO based on two sequential biomarker studies, the first 1 month in length and the second 12 months in length, in which a dose deescalation strategy was used (26–28). These studies allowed selection of the lowest dose of DFMO that produced a decrease in polyamine levels in the target of interest, colorectal mucosa. In the 12-month study, no evidence of a difference in toxicities between placebo and the low dose selected for the current trial was evident. Nevertheless, patients were carefully monitored for possible toxicities in the current trial.

At the time the current study was designed in 1997, there was no known concern about the cardiovascular toxicity of nonsteroidal anti-inflammatory drugs, including celecoxib and sulindac, with almost the entire focus on the decreased occurrence of gastrointestinal toxicity with cyclooxygenase-2 inhibitors (29, 30). At the time the current study was started (1999), selection of sulindac was based on its long-term prior broad use with an excellent clinical profile including gastrointestinal toxicity in the low range for nonsteroidal anti-inflammatory drugs and evidence of activity in familial adenomatous polyposis (31). Although the clinical cardiovascular (and cerebrovascular) toxicity had not yet surfaced at that time, we were concerned with using a specific or selective cyclooxygenase-2 inhibitor based on mechanistic considerations (32). No statistically significant increase of gastrointestinal, hematologic, or cardiovascular or cerebrovascular toxicity was found in our trial; however, the study was not designed to have adequate power to identify differences in toxicity rates between treatment groups.

Self-reported hearing changes were also not significantly different between the two groups. Although no evidence of a decrement in the normal speech range was documented, serial audiograms suggested a possible effect across a broader range of frequencies tested that was reversible in some cases. The complex details of the audiologic studies and analyses will be reported elsewhere.

The results in this randomized trial confirm the value of deescalation studies before launching a full phase III trial in identifying a dose and regimen for the therapeutic prevention of adenomas that is both efficacious and with minimal toxicity. Larger and longer-term trials will be needed to determine the absolute risk of cardiovascular and cerebrovascular events and the clinical implications of audiologic changes from this regimen. Longer-term studies will also be needed to determine whether this combination regimen can reduce colorectal cancer incidence or improve/complement colorectal surveillance strategies in very high-risk individuals, in patients with low stage prior colorectal cancers, or in the post-adjuvant setting.

Disclosure of Potential Conflicts of Interest

MJ Lawson: Bristol-Myers Squibb Commercial Research Grant, Elan Pharmaceuticals Consultant. The other authors disclosed no potential conflicts of interest.

Acknowledgments

We thank the writing committee: Frank L. Meyskens, Jr., Christine E. McLaren, Eugene W. Gerner, and Ernest Hawk; the members of the Data Safety and Monitoring Board: John Baron (Chair; Dartmouth College), Scott Emerson (University of Washington), Frank Sinicrope (Mayo Clinic, Rochester, MN), Tom O'Brien (Lankenau Institute), Mikel Aickin (University of Arizona), and Gerald R. Popelka (Stanford University); and the staff involved in this long-term study: Sharon Maxwell, Wesley Lagerberg, Rhonda Gage, Tashia Orr, Ellen Richmond, Angela Garcia, Rachel Gonzalez, Wen-Pin Chen, Kuo-Tung Li, Lu Wu, and Ann Booth.

Footnotes

  • Grant support: National Cancer Institute contract no. NO1-CN75019 (F.L. Meyskens, Jr. and C.E. McLaren) and grants CA59024 (F.L. Meyskens, Jr.); CA88078 (F.L. Meyskens, Jr. and C.E. McLaren); CA47396, CA72008, and CA95060 (E.W. Gerner); and CA63640 (C.H. Hagedorn).

  • Received February 29, 2008.
  • Accepted March 3, 2008.
  • ©2008 American Association for Cancer Research.

References

  1. ↵
    1. Minino AM,
    2. Heron MP,
    3. Murphy SL,
    4. Kochanek KD
    . Centers for Disease Control and Prevention National Center for Health Statistics National Vital Statistics S. Deaths: final data for 2004. Natl Vital Stat Rep 2007;55:1–119.
    OpenUrlPubMed
  2. ↵
    1. Jemal A,
    2. Siegel R,
    3. Ward E,
    4. Murray T,
    5. Xu J,
    6. Thun MJ
    . Cancer statistics, 2007. CA Cancer J Clin 2007;57:43–66.
    OpenUrlCrossRefPubMed
  3. ↵
    1. Winawer SJ,
    2. Zauber AG,
    3. Ho MN,
    4. et al.
    The National Polyp Study Workgroup. Prevention of colorectal cancer by colonoscopic polypectomy. N Engl J Med 1993;329:1977–81.
    OpenUrlCrossRefPubMed
  4. ↵
    1. Seeff LC,
    2. Manninen DL,
    3. Dong FB,
    4. et al
    . Is there endoscopic capacity to provide colorectal cancer screening to the unscreened population in the United States? Gastroenterology 2004;127:1661–9[see comment].
    OpenUrlCrossRefPubMed
  5. ↵
    1. Gross CP,
    2. Andersen MS,
    3. Krumholz HM,
    4. McAvay GJ,
    5. Proctor D,
    6. Tinetti ME
    . Relation between Medicare screening reimbursement and stage at diagnosis for older patients with colon cancer. JAMA 2006;296:2815–22.
    OpenUrlCrossRefPubMed
  6. ↵
    1. Greenwald P
    . Lifestyle and medical approaches to cancer prevention. Recent Results Cancer Res 2005;166:1–15.
    OpenUrlPubMed
  7. ↵
    1. Alberts DS,
    2. Martinez ME,
    3. Roe DJ,
    4. et al.
    Phoenix Colon Cancer Prevention Physicians' Network. Lack of effect of a high-fiber cereal supplement on the recurrence of colorectal adenomas. N Engl J Med 2000;342:1156–62.
    OpenUrlCrossRefPubMed
    1. Arber N,
    2. Eagle CJ,
    3. Spicak J,
    4. et al
    . Celecoxib for the prevention of colorectal adenomatous polyps. N Engl J Med 2006;355:885–95.
    OpenUrlCrossRefPubMed
    1. Baron JA,
    2. Beach M,
    3. Mandel JS,
    4. et al
    . Calcium supplements for the prevention of colorectal adenomas. N Engl J Med 1999;340:101–7.
    OpenUrlCrossRefPubMed
    1. Baron JA,
    2. Cole BF,
    3. Sandler RS,
    4. et al
    . A randomized trial of aspirin to prevent colorectal adenomas. N Engl J Med 2003;348:891–9.
    OpenUrlCrossRefPubMed
    1. Baron JA,
    2. Sandler RS,
    3. Bresalier RS,
    4. et al
    . A randomized trial of rofecoxib for the chemoprevention of colorectal adenomas. Gastroenterology 2006;131:1674–82.
    OpenUrlCrossRefPubMed
    1. Bertagnolli MM,
    2. Eagle CJ,
    3. Zauber AG,
    4. et al
    . Celecoxib for the prevention of sporadic colorectal adenomas. N Engl J Med 2006;355:873–84.
    OpenUrlCrossRefPubMed
    1. Sandler RS,
    2. Halabi S,
    3. Baron JA,
    4. et al
    . A randomized trial of aspirin to prevent colorectal adenomas in patients with previous colorectal cancer. N Engl J Med 2003;348:883–90.
    OpenUrlCrossRefPubMed
  8. ↵
    1. Solomon SD,
    2. McMurray JJ,
    3. Pfeffer MA,
    4. et al
    . Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med 2005;352:1070–80.
    OpenUrl
  9. ↵
    1. Lippman SM
    . The dilemma and promise of cancer chemoprevention. Nat Clin Pract Oncol 2006;3:523.
    OpenUrlCrossRefPubMed
  10. ↵
    1. Sporn MB
    . Combination chemoprevention of cancer. Nature 1980;287:107–8.
    OpenUrlCrossRefPubMed
  11. ↵
    1. Torrance CJ,
    2. Jackson PE,
    3. Montgomery E,
    4. et al
    . Combinatorial chemoprevention of intestinal neoplasia. Nat Med 2000;6:1024–8.
    OpenUrlCrossRefPubMed
  12. ↵
    1. Nigro ND,
    2. Bull AW,
    3. Boyd ME
    . Inhibition of intestinal carcinogenesis in rats: effect of difluoromethylornithine with piroxicam or fish oil. J Natl Cancer Inst 1986;77:1309–13.
    OpenUrlPubMed
    1. Meyskens FL Jr..,
    2. Gerner EW
    . Development of difluoromethylornithine (DFMO) as a chemoprevention agent. Clin Cancer Res 1999;5:945–51.
    OpenUrlAbstract/FREE Full Text
  13. ↵
    1. Gerner EW,
    2. Meyskens FL Jr..,
    3. Goldschmid S,
    4. Lance P,
    5. Pelot D
    . Rationale for, and design of, a clinical trial targeting polyamine metabolism for colon cancer chemoprevention. Amino Acids 2007;33:189–95Epub 2007 Mar 30.
    OpenUrlCrossRefPubMed
  14. ↵
    1. Lawson KR,
    2. Ignatenko NA,
    3. Piazza GA,
    4. Cui H,
    5. Gerner EW
    . Influence of K-ras activation on the survival responses of Caco-2 cells to the chemopreventive agents sulindac and difluoromethylornithine. Cancer Epidemiol Biomarkers Prev 2000;9:1155–62.
    OpenUrlAbstract/FREE Full Text
  15. ↵
    1. O'Brien PC,
    2. Fleming TR
    . A multiple testing procedure for clinical trials. Biometrics 1979;35:549–56.
    OpenUrlCrossRefPubMed
  16. ↵
    1. Kittelson JM,
    2. Emerson SS
    . A unifying family of group sequential test designs. Biometrics 1999;55:874–82.
    OpenUrlCrossRefPubMed
  17. ↵
    1. Burington BE,
    2. Emerson SS
    . Flexible implementations of group sequential stopping rules using constrained boundaries. Biometrics 2003;59:770–7.
    OpenUrlCrossRefPubMed
  18. ↵
    1. Jennison C,
    2. Turnbull BW
    . Group sequential methods with applications to clinical trials. New York (NY): Chapman and Hall, CRC Press; 1999.
  19. ↵
    1. Meyskens FL Jr..,
    2. Emerson SS,
    3. Pelot D,
    4. et al
    . Dose de-escalation chemoprevention trial of α-difluoromethylornithine in patients with colon polyps. J Natl Cancer Inst 1994;86:1122–30.
    OpenUrlAbstract/FREE Full Text
    1. Meyskens FL Jr..,
    2. Gerner E,
    3. Emerson S,
    4. et al
    . Effect of α-difluoromethylornithine on rectal mucosal levels for polyamines in a randomized, double-blinded trial for colon cancer prevention. J Natl Cancer Inst 1998;90:1212–8.
    OpenUrlAbstract/FREE Full Text
  20. ↵
    1. Gerner EW,
    2. Meyskens FL Jr..
    . Polyamines and cancer: old molecules, new understanding. Nat Rev Cancer 2004;4:781–92.
    OpenUrlCrossRefPubMed
  21. ↵
    1. McCarthy D
    . Nonsteroidal anti-inflammatory drug-related gastrointestinal toxicity: definitions and epidemiology. Am J Med 1998;105:3–9S.
    OpenUrlCrossRef
  22. ↵
    1. McCarthy DM
    . Comparative toxicity of nonsteroidal anti-inflammatory drugs. Am J Med 1999;107:37–46S; discussion 46–7S[review].
    OpenUrlCrossRef
  23. ↵
    1. Giardiello FM,
    2. Hamilton SR,
    3. Krush AJ,
    4. et al
    . Treatment of colonic and rectal adenomas with sulindac in familial adenomatous polyposis. N Engl J Med 1993;328:1313–6.
    OpenUrlCrossRefPubMed
  24. ↵
    1. Mukherjee D,
    2. Nissen SE,
    3. Topol EJ
    . Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA 2004;286:954–9.
    OpenUrlCrossRef
View Abstract
PreviousNext
Back to top
Cancer Prevention Research: 1 (1)
June 2008
Volume 1, Issue 1
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Index by Author

Sign up for alerts

View this article with LENS

Open full page PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for sharing this Cancer Prevention Research article.

NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses.

Enter multiple addresses on separate lines or separate them with commas.
Difluoromethylornithine Plus Sulindac for the Prevention of Sporadic Colorectal Adenomas: A Randomized Placebo-Controlled, Double-Blind Trial
(Your Name) has forwarded a page to you from Cancer Prevention Research
(Your Name) thought you would be interested in this article in Cancer Prevention Research.
Citation Tools
Difluoromethylornithine Plus Sulindac for the Prevention of Sporadic Colorectal Adenomas: A Randomized Placebo-Controlled, Double-Blind Trial
Frank L. Meyskens Jr., Christine E. McLaren, Daniel Pelot, Sharon Fujikawa-Brooks, Philip M. Carpenter, Ernest Hawk, Gary Kelloff, Michael J. Lawson, Jayashri Kidao, John McCracken, C. Gregory Albers, Dennis J. Ahnen, D. Kim Turgeon, Steven Goldschmid, Peter Lance, Curt H. Hagedorn, Daniel L. Gillen and Eugene W. Gerner
Cancer Prev Res June 1 2008 (1) (1) 32-38; DOI: 10.1158/1940-6207.CAPR-08-0042

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Share
Difluoromethylornithine Plus Sulindac for the Prevention of Sporadic Colorectal Adenomas: A Randomized Placebo-Controlled, Double-Blind Trial
Frank L. Meyskens Jr., Christine E. McLaren, Daniel Pelot, Sharon Fujikawa-Brooks, Philip M. Carpenter, Ernest Hawk, Gary Kelloff, Michael J. Lawson, Jayashri Kidao, John McCracken, C. Gregory Albers, Dennis J. Ahnen, D. Kim Turgeon, Steven Goldschmid, Peter Lance, Curt H. Hagedorn, Daniel L. Gillen and Eugene W. Gerner
Cancer Prev Res June 1 2008 (1) (1) 32-38; DOI: 10.1158/1940-6207.CAPR-08-0042
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • Materials and Methods
    • Results
    • Discussion
    • Disclosure of Potential Conflicts of Interest
    • Acknowledgments
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • PDF
Advertisement

Related Articles

Cited By...

More in this TOC Section

  • Role of Sugars, Sugary Foods and Beverages in Cancer Risk
  • Topical TLR4 Inhibition Blocks Skin Photocarcinogenesis
  • Metabolomics Profiles of Hepatocellular Carcinoma
Show more Research Articles
  • Home
  • Alerts
  • Feedback
Facebook   Twitter   LinkedIn   YouTube   RSS

Articles

  • Online First
  • Current Issue
  • Past Issues

Info for

  • Authors
  • Subscribers
  • Advertisers
  • Librarians
  • Reviewers

About Cancer Prevention Research

  • About the Journal
  • Editorial Board
  • Permissions
  • Submit a Manuscript
AACR logo

Copyright © 2018 by the American Association for Cancer Research.

Cancer Prevention Research
eISSN: 1940-6215
ISSN: 1940-6207

Advertisement