Clinical Cancer Research Grants Metabolism
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online
Clinical Cancer Research 14, 2095, April 1, 2008. doi: 10.1158/1078-0432.CCR-07-4024
© 2008 American Association for Cancer Research
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Papadimitrakopoulou, V. A.
Right arrow Articles by Boyle, J. O.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Papadimitrakopoulou, V. A.
Right arrow Articles by Boyle, J. O.
Related Collections
Right arrow Clinical Intervention
Right arrow Clinical Intervention: Early-Phase (I/II) Clinical or Translational Trials

Cancer Therapy: Clinical

Pilot Randomized Phase II Study of Celecoxib in Oral Premalignant Lesions

Vassiliki A. Papadimitrakopoulou1, William N. William, Jr.1, Andrew J. Dannenberg4, Scott M. Lippman1, J. Jack Lee2, Frank G. Ondrey6, Douglas E. Peterson7, Lei Feng2, Anthea Atwell1, Adel K. El-Naggar3, Cherie-Ann Nathan8, Joseph I. Helman9, Baoheng Du4, Bevan Yueh10 and Jay O. Boyle5

Authors' Affiliations: Departments of 1 Thoracic/Head and Neck Medical Oncology, 2 Biostatistics and Applied Mathematics, and 3 Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas; 4 Department of Medicine, Weill Cornell Medical College and New York Presbyterian Hospital; 5 Head and Neck Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York; 6 Department of Otolaryngology, University of Minnesota, Minneapolis, Minnesota; 7 School of Dental Medicine and Neag Comprehensive Cancer Center, University of Connecticut Health Center, Farmington, Connecticut; 8 Department of Otolaryngology-Head and Neck Surgery, Louisiana State University, Shreveport, Louisiana; 9 Department of Maxillofacial Surgery, University of Michigan, Ann Arbor, Michigan; and 10 Department of Otolaryngology-Head and Neck Surgery, University of Washington, Seattle, Washington

Requests for reprints: Vassiliki A. Papadimitrakopoulou, Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 432, Houston, TX 77030. Phone: 713-792-6363; Fax: 713-792-1220; E-mail: vpapadim{at}mdanderson.org.


   Abstract
Top
 Abstract
Materials and Methods
 Results
 Discussion
 References
 
Purpose: Cyclooxygenase-2 (COX-2)–specific inhibition suppresses carcinogenesis in preclinical models and is a promising strategy for preventing oral cancer. In this pilot randomized phase II study, we evaluated the efficacy and safety of the COX-2 inhibitor celecoxib in patients with oral premalignant lesions (OPL).

Experimental Design: Patients were randomly assigned to placebo (n = 18), celecoxib 100 mg twice daily (n = 17), or celecoxib 200 mg twice daily (n = 15) for 12 weeks. Six additional patients received celecoxib (400 mg twice daily) in an unblinded extension of the study. Biopsies were obtained at baseline and week 12. All patients entering the study were required to have at least one histologically confirmed early (atypical hyperplasia, atypical hyperkeratosis, or mild dysplasia) or advanced (moderate to severe dysplasia) OPL.

Results: Forty-nine patients (46 of 50 randomized and 3 of 6 open label) were evaluable for efficacy analyses. There were no statistically significant differences between the response rates of the randomly assigned arms: placebo, 33.3% (6 of 18); celecoxib 100 mg twice daily, 41.2% (7 of 17); and celecoxib 200 mg twice daily, 20.0% (3 of 15). Two patients responded on celecoxib 400 mg twice daily. Celecoxib was generally well tolerated. Patients with higher baseline COX-2 mRNA levels had an increased risk of disease progression within 3 months.

Conclusions: Celecoxib at 100 or 200 mg twice daily was ineffective in controlling OPLs in this randomized controlled trial. This result and cardiovascular toxicity results of other (large scale) randomized controlled trials of selective COX-2 inhibitors have discouraged the continued investigation of these agents in oral cancer chemoprevention. Better methods for identifying high-risk patients and more active interventions are needed for future oral cancer chemoprevention trials.

Oral cancer has an annual worldwide incidence of >300,000 cases, severe morbidity, and a 5-year survival rate of <50%. Oral cancer is frequently preceded by multifocal oral premalignant lesions (OPL) resulting from multistep carcinogenesis. OPLs vary histologically from hyperkeratosis with hyperplasia to severe dysplasia or carcinoma in situ and progress to squamous cell carcinoma in a substantial percentage of cases and there is no proven approach for reducing the oral cancer risk of OPLs (1).

Chronic inflammation is associated with enhanced prostaglandin synthesis and an increased risk of epithelial malignancy (2); prostaglandins are important in the postinitiation phases of tumorigenesis through modulation of immune surveillance (3), stimulation of cell proliferation, and angiogenesis (4). Increased levels of prostaglandins have been detected in head and neck and other epithelial cancers (5). Cyclooxygenase (COX)-1 and COX-2 are encoded by separate genes and catalyze prostaglandin synthesis (6, 7). However, only COX-2, which is encoded by an immediate-early response gene, is induced by inflammatory stimuli, growth factors, tumor promoters, oncogenes, and carcinogens (8–11). Overexpression of COX-2 inhibits apoptosis (12) and thus encourages the accumulation of genetic damage in epithelial cells. COX-2 is overexpressed in tumors (13), and COX-2–inhibiting agents (selective or not) have been shown to protect against colon, mammary, and oral cancer in experimental animals (14–18) and possibly colorectal cancer in humans (19–23). COX-2 is overexpressed in OPLs and head and neck squamous cell carcinoma (24); in a rat model of tongue carcinogenesis, nimesulide (a selective COX-2 inhibitor) decreased the incidence of 4-nitroquinoline-1-oxide–induced cancer (25). These data led us to hypothesize that inhibiting COX-2–mediated up-regulation of prostaglandin synthesis in premalignant tissue would be an effective chemopreventive strategy in OPL patients. We examined this hypothesis in the presently reported pilot randomized phase II study of celecoxib in OPL patients.


   Materials and Methods
Top
 Abstract
 Materials and Methods
Results
 Discussion
 References
 
This was a pilot, randomized, multicenter, phase II study, with a placebo-controlled arm and double-blinded randomization assignment. The study protocol was approved by the institutional review board of each center and was conducted in accordance with the provisions of the Declaration of Helsinki and Good Clinical Practice guidelines.

Patient eligibility. Major inclusion criteria were as follows: a histologically confirmed early (atypical hyperplasia, atypical hyperkeratosis, or mild dysplasia) or advanced (moderate-to-severe dysplasia) OPL; age ≥18 y; Zubrod performance status of 0 to 1; hemoglobin level above the lower limit of normal, WBC count >3,000/mm3, platelet count >125,000/mm3, total bilirubin, aspartate aminotransferase, and alanine aminotransferase levels ≤1.5x upper limit of normal, and serum creatinine ≤1.5x upper limit of normal; no anticipated need for treatment with oral or i.v. corticosteroids for more than 2 consecutive weeks over any 6-mo period during the study; and willingness to limit aspirin use to ≤100 mg/d and to abstain from chronic use of all other nonsteroidal anti-inflammatory drugs and COX-2 inhibitors for the duration of the study.

Major exclusion criteria were as follows: diagnosis of or treatment for esophageal, gastric, pyloric channel, or duodenal ulceration within 30 d before randomization; history of head and neck cancer in the past 18 mo or of another cancer in the past 3 y (patients with a history of nonmelanoma skin cancer, cervical carcinoma in situ, or chronic lymphocytic leukemia stage 0 were not excluded); chronic or acute renal or hepatic disorder or significant bleeding disorder; history of or active inflammatory bowel syndrome or pancreatic disease; and current use of fluconazole or lithium.

Treatment plan. After signing the informed consent statement, patients underwent a baseline evaluation, including medical history and physical examination (with complete alcohol and tobacco history), clinical laboratory tests, color photography of all lesions, bidimensional measurements of all OPLs, biopsy of the lesions, record of concomitant medications and adverse signs and symptoms, and counseling on smoking cessation. All lesion biopsy slides were centrally reviewed at M.D. Anderson Cancer Center for diagnosis and stratification purposes. In cases of multiple lesions where more than one lesion was biopsied, the biopsy with the highest histologic grade was used for stratification. COX-2 mRNA levels were measured in the baseline biopsy specimens as previously described (24, 26). Briefly, total RNA was isolated from OPLs using RNeasy Mini kits from Qiagen and was reverse transcribed using the GeneAmp RNA PCR kit according to the manufacturer's protocol. Quantitative PCR for COX-2 was carried out as follows: Each PCR was carried out in 25 µL of a reaction mix, containing 10 mmol/L Tris-HCl (pH 8.3), 50 mmol/L KCl, 2 mmol/L MgCl2, 0.2 mmol/L deoxynucleotide triphosphate, 2.5 units AmpliTaq DNA polymerase, and 400 nmol/L primers (sense primer, 5'-GGTCTGGTGCCTGGTCTGATGATG-3'; antisense primer, 5'-GTCCTTTCAAGGAGAATGGTGC-3'). Aliquots (5 µL) of the reverse-transcribed cDNA samples and various known amounts of COX-2 mimic (between 0.001 and 0.05 pg), adjusted to the abundance of the target cDNA, were added to the reaction mix and coamplified for 35 cycles: denaturation at 94°C for 20 s, annealing at 65°C for 20 s, extension at 72°C for 90 s, and final extension at 72°C for 10 min. PCR products (10 µL), 724-bp fragments from endogenous target cDNA, and 569-bp fragments from mimic COX-2 were then separated by electrophoresis on 1% agarose gels and visualized by ethidium bromide staining. A computer densitometer (Eagle Eye II, Stratagene) was used to determine the density of the bands. A comparison of the band densities yielded the quantity of COX-2 mRNA in the reaction.

Eligible patients were stratified by center and by early versus advanced OPL and were randomized in a 1:1:1 ratio to one of the following treatment groups in a double-blinded manner: celecoxib (oral) 100 mg twice daily, celecoxib (oral) 200 mg twice daily, or placebo (oral) twice daily. The choice of dose levels was based on preliminary evidence from the familial adenomatous polyposis study that celecoxib 100 mg twice daily might have chemopreventive activity (20). Moreover, celecoxib at 200 mg twice daily was the maximum recommended dose for the treatment of arthritis. Because a portion of the projected trial participants had histology-defined early premalignant lesions (and thus low risk for cancer development), a dose-finding study that exposed fewer low-risk patients to high doses of celecoxib was considered initially appropriate. After a protocol amendment in March 2003, only patients with early OPLs continued to be randomized as just described, whereas all patients with advanced OPLs received open-label oral celecoxib at 400 mg twice daily, based again on data of the familial adenomatous polyposis study showing significant efficacy of celecoxib only at 400 mg twice daily (20). Because this decision was made while the study was already accruing, the 400 mg twice daily open-label arm was included in an exploratory intent as an attempt to preserve the feasibility of the study while offering a possibly superior intervention for patients at higher cancer risk (i.e., advanced OPL). The planned treatment period was 12 wk for all groups. No dose reductions were permitted. In cases of interrupted study treatment, rechallenge was instituted only after case-by-case evaluations concluding that the initial toxicity was resolved to the satisfaction of the institutional principal investigator, lead (national) principal investigator, and the sponsor's medical monitor.

Patients were followed for adverse signs and symptoms with telephone calls and regular clinic visits throughout the duration of the study. Adverse events were classified according to the National Cancer Institute Common Toxicity Criteria version 2.0. Of note, since the closure of this clinical trial, multiple lines of evidence have indicated that use of COX-2 inhibitors is associated with an increased risk of adverse cardiovascular outcomes. Consequently, the label of celecoxib has been recently revised by the Food and Drug Administration to include a boxed warning about these effects. However, given that these data were unavailable at study initiation, neither the inclusion criteria nor the analysis of the trial was designed to address these effects.

Compliance was measured by telephone queries and remaining capsule counts at weeks 8 and 12. At weeks 12 and 24 (or earlier, if the patient had to be prematurely taken off study), a physical examination was done, including bidimensional measurements and color photography of all lesions. Index lesions (or lesion area) were rebiopsied at week 12 and the slides were also centrally reviewed at M.D. Anderson Cancer Center.

Subjects were discontinued from the study if they completed follow-up (week 26); failed to comply with the scheduled observations and procedures; withdrew consent; and developed invasive or progressive disease (PD), an adverse event grade 3 or 4, intercurrent illness, or a serious adverse event thought to be related to the study drug.

Study end points and statistical analysis. The primary end point of the study was clinical response rate at 12 wk. Response was assessed according to previously described criteria (27), based on bidimensional measurements of lesions, as follows: Disappearance of all evidence of lesions was considered a complete response (CR); 50% or greater decrease in the sum of products of diameters of all measured lesions was considered a partial response (PR); and increase by 25% or greater in size of lesions or appearance of new lesions or progression to invasive cancer was considered PD. On the other hand, any response that did not meet the criteria for CR, PR, or PD was considered stable disease.

The sample size for each arm was calculated assuming an average response rate for the placebo group of 10% and ≤5% for patients with early and advanced premalignant lesions, respectively, and a dropout rate of 20%. It was hypothesized that 60% (early OPLs) and 50% (advanced OPLs) of celecoxib-treated subjects would achieve a final PR or CR. These assumptions were based on the trial of isotretinoin by Hong et al. (28) that reported 67% clinical response rate in the isotretinoin arm and 10% in the placebo arm. Fourteen subjects in each arm for each strata would provide 85% power to detect this difference with a two-sided type I error of 0.05. A separate analysis was planned for the nonrandomized celecoxib 400 mg twice daily arm.

The efficacy end points in patients randomized to the placebo, celecoxib 100 mg twice daily, and celecoxib 200 mg twice daily arms were analyzed according to the intent-to-treat principle. Patients were considered inevaluable if no baseline or week 12 examination was done. Patients with documented disease progression before week 12 were evaluable.

The percentage of patients with a final CR or PR in the placebo arm and the two treatment arms combined (celecoxib at 100 and 200 mg twice daily) was compared using the Cochran-Mantel-Haenszel test, stratified by center. The same test was done to compare placebo with each celecoxib dose (100 or 200 mg twice daily). Type I error of {alpha} = 0.05 (two-sided test) was used. No multiplicity adjustments were made. For the patients assigned to the celecoxib 400 mg twice daily arm, only descriptive statistics were done to report the efficacy end points because this was a single-arm cohort.

Data from all subjects who received at least one dose of study medication were included for safety evaluation.

As an exploratory analysis, baseline COX-2 mRNA levels in early versus advanced OPL and in patients with PD at 3 mo versus no change (NC) + PR + CR were compared using the Wilcoxon rank sum test to investigate whether increased COX-2 mRNA levels would be associated with a more aggressive histologic phenotype and worse prognosis of OPLs in a prospectively followed cohort of patients.


   Results
Top
 Abstract
 Materials and Methods
 Results
Discussion
 References
 
Patient characteristics. A total of 56 patients (45 with early OPLs and 11 with advanced OPLs) were enrolled in the trial at M.D. Anderson and seven collaborating U.S. centers between November 2000 and January 2004 and received at least one dose of the study medication. The last patient visit was registered in April 2004. The accrual goal was reached for patients with early OPLs, but accrual in the advanced OPL arms was slow. Shortly after opening the 400 mg twice daily arm for patients with advanced OPLs, the first reports potentially linking use of selective COX-2 inhibitors with serious adverse cardiovascular events emerged, leading to early closure of this arm. The baseline characteristics of the patients are shown in Table 1 . Of note, 10 of 32 (31%) patients in the combined 100 and 200 mg twice daily arms versus none of 18 in the placebo arm had prior remote history of squamous cell cancer of the oropharynx (9) or larynx (1). The numbers of current smokers were balanced between the randomized arms: two (11%) in the placebo group and three (9%) in the combined 100 and 200 mg twice daily groups; only one patient (on the 200 mg twice daily arm) quit smoking during the intervention.


View this table:
[in this window]
[in a new window]

  		Table 1. Baseline characteristics of patients

 
Treatment characteristics. Forty-five of 56 total patients completed all 12 planned weeks of treatment. Among the 11 patients who discontinued the treatment prematurely, the reasons for termination were as follows: lost to follow-up (4 patients), disease progression (3 patients), withdrawal of consent (2 patients), and occurrence of adverse events (2 patients).

The percentage of patients with compliance ≥80% in each group was as follows: placebo (83%), celecoxib 100 mg twice daily (82%), and celecoxib 200 mg twice daily (87%). No patients required temporary treatment discontinuation due to adverse events.

Toxicity. Overall, treatment was safe and well tolerated. Table 2 summarizes the most common adverse events in each arm observed in two or more patients, irrespective of their association to the study medication. No grade 4 toxicities were observed, and only four patients presented grade 3 adverse events: One patient had hyperglycemia (placebo arm); one patient had hypertension (placebo arm); one patient had syncope (celecoxib 100 mg twice daily arm); and one patient had dizziness, paresthesia, and an ischemic cerebrovascular accident (celecoxib 200 mg twice daily arm). Two patients permanently discontinued treatment due to an adverse event (grade 2 vision abnormality and hypertension in a patient receiving 400 mg twice daily of celecoxib and a grade 3 ischemic cerebrovascular accident in a patient receiving 200 mg twice daily of celecoxib).


View this table:
[in this window]
[in a new window]

  		Table 2. Most common adverse events (all grades; >2 cases in all arms combined) in descending order of frequency

 
Magnetic resonance angiography indicated that the patient with a grade 3 cerebrovascular accident had hypoplastic or occluded right P1 segment of the circle of Willis with flow to the right posterior cerebral artery through the dominant right posterior communicating artery. The patient had a prior history of palpitations and supraventricular tachyarrhythmia and was maintained on digoxin. The patient was removed from study. Although this event was not initially attributed to study treatment, subsequent data from other studies indicating adverse cardiovascular effects of celecoxib raised the possibility that it was drug related.

Efficacy. Efficacy end points in the 50 randomized patients are reported in Table 3 . Four patients were considered inevaluable due to lack of baseline or week 12 examination (one, one, and two patients in the placebo, celecoxib 100 mg twice daily, and celecoxib 200 mg twice daily arms, respectively). Three of six patients were inevaluable for the same reasons on the celecoxib 400 mg twice daily open-label arm.


View this table:
[in this window]
[in a new window]

  		Table 3. Clinical response at week 12 in randomized patients according to treatment arm by intent to treat

 
For all subjects (early and advanced OPLs combined), the clinical response rates (CR + PR) at week 12 were 33.3% for the placebo arm and 31.3% for the celecoxib 100 and 200 mg twice daily combined (P = 1.0, Fisher's exact test; Table 3). Two of the three evaluable patients in the open-label celecoxib 400 mg twice daily arm had a clinical PR. Two patients on placebo and three patients on celecoxib 200 mg twice daily had clinical PD manifested as increase in size in three cases and appearance of a new lesion in two cases. No cancer development was observed at 12 weeks. Similar to the findings of clinical response, there were no statistically significant differences in histologic improvement rates (e.g., reversal of dysplasia or improvement in degree of dysplasia) between the combined celecoxib treatment arms (28%) and placebo arm (20%; P = 0.71, Fisher's exact test). The mean total OPL size (mm3) ± SD for all four arms at baseline was 553 ± 542, 867 ± 761, 772 ± 744, and 335 ± 261, respectively. After 12 weeks of treatment, the mean size recorded was 603 ± 881, 518 ± 513, 530 ± 500, and 247 ± 260, respectively.

COX-2 mRNA levels. Forty-two patients had the mRNA levels of COX-2 evaluated in the baseline biopsy specimen. There was no statistically significant difference between the COX-2 mRNA levels in patients with early versus advanced OPLs (mean, 51.7 ± 76.2 fg/µg versus 57.3 ± 103.6 fg/µg; P = 0.55, Wilcoxon).

Patients with a PD at 3 months had statistically significantly higher baseline levels of COX-2 mRNA levels when compared with patients without disease progression (NC + PR + CR; Fig. 1 ). This difference remained statistically significant within the placebo group (P = 0.050 for PD versus NC + PR + CR, Wilcoxon) and the combined celecoxib groups (P = 0.046 for PD versus NC + PR + CR, Wilcoxon).


Figure 1
View larger version (4K):
[in this window]
[in a new window]
[Download PPT slide]
  		Fig. 1. Blip plots of baseline COX-2 mRNA levels according to clinical response. The overall COX-2 mRNA levels (mean ± SD) associated with the two response categories (NC + PR + CR and PD) were 37.1 ± 61.9 fg/µg (NC + PR + CR) versus 201.3 ± 96.8 fg/µg (PD; P = 0.0031, Wilcoxon rank sum test).

 

   Discussion
Top
 Abstract
 Materials and Methods
 Results
 Discussion
References
 
Previous randomized chemoprevention trials in patients with OPLs have shown (a) that a high dose of the retinoid isotretinoin suppressed OPLs but with intolerable side effects and high relapse rates after stopping treatment (28) and (b) that low-dose isotretinoin did not reduce head and neck cancer risk (29). No effective chemopreventive treatment for reducing the oral cancer risk of OPL patients has yet been found (30). Our present study showed that, although generally well tolerated, celecoxib at a dose of 100 or 200 mg twice daily did not effectively control early to advanced OPLs. We have observed a higher-than-anticipated spontaneous response rate in the placebo group [33% versus 10% in the historical controls from the study of Hong et al. (28)] possibly due to a lower frequency of advanced OPLs in the present study (11%) when compared with the previous trial (30%). Spontaneous regression of leukoplakia is a known phenomenon with variable incidence as high as 37% (31). Lack of celecoxib efficacy in our study could also be ascribed to other confounding factors that we could not control. Indeed, the higher number of participants with prior remote history of oral cancer on the active treatment arms (32%) may have confounded the results because these patients are believed to harbor more aggressive OPLs, with increased number of genetic abnormalities (32, 33), and are theoretically less responsive to chemopreventive agents. Taken together, the smaller-than-anticipated accrual of this trial, the unexpected high spontaneous response rate in the placebo group (both of which ultimately affect the power of the study), and, most importantly, the imbalances in the baseline patient characteristics about previous cancer history do not allow for definitive conclusions to be made from this single study alone. Nonetheless, the results presented herein add to the pool of data suggesting a limited role for COX inhibitors in cancer prevention, either due to toxicity (as discussed below) or lack of efficacy. Topical ketorolac, a dual inhibitor of COX-1 and COX-2, also seemed to be inactive (possibly because of inadequate tissue levels of drug due to a lack of lesion penetration or to a short duration of drug exposure; refs. 34, 35).

Others have shown that COX-2 mRNA is higher in oral cancer and OPLs compared with normal mucosa (24, 36). We did not find a correlation between elevated COX-2 mRNA levels and the degree of histologic abnormality in OPLs at baseline. This result is consistent with findings of Banerjee et al. (37) also showing that increased levels of COX-2 protein in OPLs (versus in normal epithelium) did not correlate with the degree of OPL dysplasia (mild to severe). The present study prospectively showed for the first time, however, that patients with higher baseline levels of COX-2 mRNA had a statistically significantly increased risk of disease progression within 3 months, suggesting that COX-2 may be involved in the malignant transformation of OPLs. The lack of correlation of COX-2 levels with degree of dysplasia suggests that this molecular marker might be an independent predictor of aggressive behavior. However, due to the exploratory nature of these findings, the results need to be confirmed in larger studies.

Considered a potential surrogate for the oral cancer end point in definitive trials (38), OPLs are a long-standing model for oral cancer chemoprevention study. OPLs have a well-described natural history and are highly accessible for clinical, pathologic, and biological evaluation. OPLs and oral cancer share the etiology of exposure mainly to tobacco carcinogens and frequently to alcohol as well. Therefore, the present and other early-stage trials have used the end point of OPL response to gauge the potential efficacy and thus candidacy of various natural and synthetic chemopreventive agents for definitive testing (39). The true value of OPL response in predicting oral cancer development has not been substantiated, however, because there has yet to be a definitive prevention randomized controlled trial that could assess this relationship. Molecular findings in oral or laryngeal premalignant lesions of a discordance between clinical or histologic responses (to chemoprevention) and persisting underlying genetic abnormalities suggest that clinical/histologic response may not reduce cancer risk (40). Although the present study was stratified by the presence and/or degree of dysplasia, a major limitation of OPL clinical research heretofore has been the inability to identify individuals at even higher risks than that associated with dysplasia. Major foci of current OPL research include identifying patients at a higher, molecularly marked cancer risk and identifying novel risk and other biomarkers that can improve the prospects of clinical trials in this setting. One ongoing trial, Erlotinib Prevention of Oral Cancer, is investigating both molecular epidemiologic high-risk and novel biomarkers while clinically evaluating the ability of erlotinib to reduce oral cancer risk in OPL patients with a high risk marked by loss of heterozygosity profiles, including the 3p and 9p loci (32, 33, 41–43).

The only serious cardiovascular event during our trial was a case of cerebrovascular ischemia (on celecoxib at 200 mg twice daily) that was not originally coded as a drug-related event because the patient had a prior history of palpitations and was using the anti-arrhythmia medication digoxin. Data emerging from other trials during the course of our trial, however, indicated that the use of selective COX-2 inhibitors is associated with serious cardiovascular toxicity (44), possibly due to an exaggerated thrombotic response to the suppression of COX-2–mediated prostacyclin production in the endothelium and unaffected generation of COX-1–derived thromboxane A2 by platelets (45). Therefore, it is possible that this case was due to celecoxib 200 mg twice daily, although the 12 weeks of treatment in our trial is far short of the selective COX-2 inhibitor treatment durations associated with cardiovascular toxicity reported in the literature (44).

In conclusion, the randomized doses of celecoxib (100 and 200 mg twice daily) were not active in this pilot randomized phase II study, and results of 400 mg twice daily involved too few patients to be interpretable. The finding that the expression of COX-2 correlated with OPL progression is provocative and deserves further evaluation. Unfortunately, the tissue was not available to evaluate levels of prostaglandin E2 before and after treatment with celecoxib. Hence, it remains possible that celecoxib 200 mg twice daily was insufficient to completely suppress COX-2 activity. Our results do not exclude the possibility that celecoxib at 400 mg twice daily might be more active than at 200 mg twice daily as previously shown in a colorectal polyp prevention trial (21).


   Acknowledgments
 
We thank Dr. W.K. Hong for invaluable advice and support during the conduct of this study.


   Footnotes
 
Grant support: Pfizer, Inc.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 8/27/07; revised 12/13/07; accepted 12/30/07.


   References
Top
 Abstract
 Materials and Methods
 Results
 Discussion
 References
 

  1. Mao L, Hong WK, Papadimitrakopoulou VA. Focus on head and neck cancer. Cancer Cell 2004;5:311–6.[CrossRef][Medline]
  2. Weitzman SA, Gordon LI. Inflammation and cancer: role of phagocyte-generated oxidants in carcinogenesis. Blood 1990;76:655663.[Abstract/Free Full Text]
  3. Marnett LJ. Aspirin and the potential role of prostaglandins in colon cancer. Cancer Res 1992;52:5575–89.[Free Full Text]
  4. Tsujii M, Kawano S, Tsuji S, Sawaoka H, Hori M, DuBois RN. Cyclooxygenase regulates angiogenesis induced by colon cancer cells. Cell 1998;93:705–16.[CrossRef][Medline]
  5. Jung TT, Berlinger NT, Juhn SK. Prostaglandins in squamous cell carcinoma of the head and neck: a preliminary study. Laryngoscope 1985;95:307–12.[Medline]
  6. Eling TE, Thompson DC, Foureman GL, Curtis JF, Hughes MF. Prostaglandin H synthase and xenobiotic oxidation. Annu Rev Pharmacol Toxicol 1990;30:1–45.[Medline]
  7. Eling TE, Curtis JF. Xenobiotic metabolism by prostaglandin H synthase. Pharmacol Ther 1992;53:261–73.[CrossRef][Medline]
  8. Kujubu DA, Fletcher BS, Varnum BC, Lim RW, Herschman HR. TIS10, a phorbol ester tumor promoter-inducible mRNA from Swiss 3T3 cells, encodes a novel prostaglandin synthase/cyclooxygenase homologue. J Biol Chem 1991;266:12866–72.[Abstract/Free Full Text]
  9. O'Banion MK, Sadowski HB, Winn V, Young DA. A serum- and glucocorticoid-regulated 4-kilobase mRNA encodes a cyclooxygenase-related protein. J Biol Chem 1991;266:23261–7.[Abstract/Free Full Text]
  10. DuBois RN, Awad J, Morrow J, Roberts LJ II, Bishop PR. Regulation of eicosanoid production and mitogenesis in rat intestinal epithelial cells by transforming growth factor-{alpha} and phorbol ester. J Clin Invest 1994;93:493–8.[Medline]
  11. Kelley DJ, Mestre JR, Subbaramaiah K, et al. Benzo[a]pyrene up-regulates cyclooxygenase-2 gene expression in oral epithelial cells. Carcinogenesis 1997;18:795–9.[Abstract/Free Full Text]
  12. Tsujii M, DuBois RN. Alterations in cellular adhesion and apoptosis in epithelial cells overexpressing prostaglandin endoperoxide synthase 2. Cell 1995;83:493–501.[CrossRef][Medline]
  13. Sano H, Kawahito Y, Wilder RL, et al. Expression of cyclooxygenase-1 and -2 in human colorectal cancer. Cancer Res 1995;55:3785–9.[Abstract/Free Full Text]
  14. Rao CV, Rivenson A, Simi B, et al. Chemoprevention of colon carcinogenesis by sulindac, a nonsteroidal anti-inflammatory agent. Cancer Res 1995;55:1464–72.[Abstract/Free Full Text]
  15. McCormick DL, Moon RC. Inhibition of mammary carcinogenesis by flurbiprofen, a non-steroidal antiinflammatory agent. Br J Cancer 1983;48:859–61.[Medline]
  16. Kawamori T, Rao CV, Seibert K, Reddy BS. Chemopreventive activity of celecoxib, a specific cyclooxygenase-2 inhibitor, against colon carcinogenesis. Cancer Res 1998;58:409–12.[Abstract/Free Full Text]
  17. Oshima M, Dinchuk JE, Kargman SL, et al. Suppression of intestinal polyposis in Apc {Delta}716 knockout mice by inhibition of cyclooxygenase 2 (COX-2). Cell 1996;87:803–9.[CrossRef][Medline]
  18. Tanaka T, Nishikawa A, Mori Y, Morishita Y, Mori H. Inhibitory effects of non-steroidal anti-inflammatory drugs, piroxicam and indomethacin on 4-nitroquinoline 1-oxide-induced tongue carcinogenesis in male ACI/N rats. Cancer Lett 1989;48:177–82.[CrossRef][Medline]
  19. Giardiello FM, Hamilton SR, Krush AJ, et al. Treatment of colonic and rectal adenomas with sulindac in familial adenomatous polyposis. N Engl J Med 1993;328:1313–6.[Abstract/Free Full Text]
  20. Steinbach G, Lynch PM, Phillips RK, et al. The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. N Engl J Med 2000;342:1946–52.[Abstract/Free Full Text]
  21. Bertagnolli MM, Eagle CJ, Zauber AG, et al. Celecoxib for the prevention of sporadic colorectal adenomas. N Engl J Med 2006;355:873–84.[Abstract/Free Full Text]
  22. Arber N, Eagle CJ, Spicak J, et al. Celecoxib for the prevention of colorectal adenomatous polyps. N Engl J Med 2006;355:885–95.[Abstract/Free Full Text]
  23. Baron JA, Sandler RS, Bresalier RS, et al. A randomized trial of rofecoxib for the chemoprevention of colorectal adenomas. Gastroenterology 2006;131:1674–82.[CrossRef][Medline]
  24. Chan G, Boyle JO, Yang EK, et al. Cyclooxygenase-2 expression is up-regulated in squamous cell carcinoma of the head and neck. Cancer Res 1999;59:991–4.[Abstract/Free Full Text]
  25. Shiotani H, Denda A, Yamamoto K, et al. Increased expression of cyclooxygenase-2 protein in 4-nitroquinoline-1-oxide-induced rat tongue carcinomas and chemopreventive efficacy of a specific inhibitor, nimesulide. Cancer Res 2001;61:1451–6.[Abstract/Free Full Text]
  26. Heath EI, Canto MI, Piantadosi S, et al. Secondary chemoprevention of Barrett's esophagus with celecoxib: results of a randomized trial. J Natl Cancer Inst 2007;99:545–57.[Abstract/Free Full Text]
  27. Lippman SM, Batsakis JG, Toth BB, et al. Comparison of low-dose isotretinoin with β carotene to prevent oral carcinogenesis. N Engl J Med 1993;328:15–20.[Abstract/Free Full Text]
  28. Hong WK, Endicott J, Itri LM, et al. 13-cis-Retinoic acid in the treatment of oral leukoplakia. N Engl J Med 1986;315:1501–5.[Abstract]
  29. Khuri FR, Lee JJ, Lippman SM, et al. Randomized phase III trial of low-dose isotretinoin for prevention of second primary tumors in stage I and II head and neck cancer patients. J Natl Cancer Inst 2006;98:441–50.[Abstract/Free Full Text]
  30. Lodi G, Sardella A, Bez C, Demarosi F, Carrassi A. Interventions for treating oral leukoplakia. Cochrane Database Syst Rev 2006:CD001829.
  31. Silverman S, Jr., Gorsky M, Lozada F. Oral leukoplakia and malignant transformation. A follow-up study of 257 patients. Cancer 1984;53:563–8.[CrossRef][Medline]
  32. Mao L, Lee JS, Fan YH, et al. Frequent microsatellite alterations at chromosomes 9p21 and 3p14 in oral premalignant lesions and their value in cancer risk assessment. Nat Med 1996;2:682–5.[CrossRef][Medline]
  33. Rosin MP, Lam WL, Poh C, et al. 3p14 and 9p21 loss is a simple tool for predicting second oral malignancy at previously treated oral cancer sites. Cancer Res 2002;62:6447–50.[Abstract/Free Full Text]
  34. Mulshine JL, Atkinson JC, Greer RO, et al. Randomized, double-blind, placebo-controlled phase IIb trial of the cyclooxygenase inhibitor ketorolac as an oral rinse in oropharyngeal leukoplakia. Clin Cancer Res 2004;10:1565–73.[Abstract/Free Full Text]
  35. Boyle JO. Cyclooxygenase inhibition as a target for prevention of tobacco-related cancers. Clin Cancer Res 2004;10:1557–8.[Free Full Text]
  36. Santhi WS, Sebastian P, Varghese BT, Prakash O, Pillai MR. NF-{kappa}B and COX-2 during oral tumorigenesis and in assessment of minimal residual disease in surgical margins. Exp Mol Pathol 2006;81:123–30.[CrossRef][Medline]
  37. Banerjee AG, Gopalakrishnan VK, Bhattacharya I, Vishwanatha JK. Deregulated cyclooxygenase-2 expression in oral premalignant tissues. Mol Cancer Ther 2002;1:1265–71.[Abstract/Free Full Text]
  38. O'Shaughnessy JA, Kelloff GJ, Gordon GB, et al. Treatment and prevention of intraepithelial neoplasia: an important target for accelerated new agent development. Clin Cancer Res 2002;8:314–46.[Abstract/Free Full Text]
  39. Kelloff GJ, Lippman SM, Dannenberg AJ, et al. Progress in chemoprevention drug development: the promise of molecular biomarkers for prevention of intraepithelial neoplasia and cancer—a plan to move forward. Clin Cancer Res 2006;12:3661–97.[Abstract/Free Full Text]
  40. Mao L, El-Naggar AK, Papadimitrakopoulou V, et al. Phenotype and genotype of advanced premalignant head and neck lesions after chemopreventive therapy. J Natl Cancer Inst 1998;90:1545–51.[Abstract/Free Full Text]
  41. Lippman SM, Lee JJ. Reducing the "risk" of chemoprevention: defining and targeting high risk—2005 AACR Cancer Research and Prevention Foundation Award Lecture. Cancer Res 2006;66:2893–903.[Abstract/Free Full Text]
  42. Lippman SM, Heymach JV. The convergent development of molecular-targeted drugs for cancer treatment and prevention. Clin Cancer Res 2007;13:4035–41.[Abstract/Free Full Text]
  43. Rosin MP, Cheng X, Poh C, et al. Use of allelic loss to predict malignant risk for low-grade oral epithelial dysplasia. Clin Cancer Res 2000;6:357–62.[Abstract/Free Full Text]
  44. Bertagnolli MM. Chemoprevention of colorectal cancer with cyclooxygenase-2 inhibitors: two steps forward, one step back. Lancet Oncol 2007;8:439–43.[CrossRef][Medline]
  45. McAdam BF, Catella-Lawson F, Mardini IA, Kapoor S, Lawson JA, FitzGerald GA. Systemic biosynthesis of prostacyclin by cyclooxygenase (COX)-2: the human pharmacology of a selective inhibitor of COX-2. Proc Natl Acad Sci U S A 1999;96:272–7.[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 Clin. Cancer Res.Home page
F. Ondrey
Peroxisome Proliferator-Activated Receptor {gamma} Pathway Targeting in Carcinogenesis: Implications for Chemoprevention
Clin. Cancer Res., January 1, 2009; 15(1): 2 - 8.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Prevention ResearchHome page
E. Szabo
Assessing Efficacy in Early-Phase Cancer Prevention Trials: The Case of Oral Premalignancy
Cancer Prevention Research, October 1, 2008; 1(5): 312 - 315.
[Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Papadimitrakopoulou, V. A.
Right arrow Articles by Boyle, J. O.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Papadimitrakopoulou, V. A.
Right arrow Articles by Boyle, J. O.
Related Collections
Right arrow Clinical Intervention
Right arrow Clinical Intervention: Early-Phase (I/II) Clinical or Translational Trials

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online