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Rationale _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _• Prostaglandins (Pgs) are metabolites ofarachidonic acid mobilized from mem-brane phospholipids. As ligands for G-protein–coupled receptors, the short-livedPgs are mediators of paracrine and au-tocrine signaling loops that regulate di-verse biologic functions. Prostaglandinscan stimulate angiogenesis, inhibit im-mune surveillance, decrease apoptosis, andincrease invasive potential. Cyclooxyge-nase-1 (COX-1) and COX-2 are rate-lim-iting enzymes for the conversion of arachi-donic acid to Pgs and other eicosanoids.Cyclooxygenase-1 is ubiquitously ex-pressed, but COX-2 is an inducible geneoften expressed in areas of inflammation.1

• Protein levels of nitric oxide synthase 2(NOS2), vascular endothelial growth fac-tor (VEGF), and COX-2 levels were com-pared with respect to tumor microvesseldensity (MVD), tumor size, histology,and clinical outcome in samples from 106surgically resected non–small-cell lungcancer (NSCLC) samples.2 Both NOS2and COX-2 showed a positive correlationwith VEGF overexpression (P < 0.001and P < 0.003, respectively) and all 3 fac-tors were found to correlate individuallywith MVD (P < 0.001). Reportedly, in-hibitors of COX-2 can block the expres-sion of VEGF, suggesting that COX-2 ac-tivity, presumably acting through Pg syn-thesis, lies in the pathway to VEGF tran-scriptional activation.3

• Genetic studies illustrate the cause-and-effect connection between tumorigenesisand COX-2 expression. Transgenic miceengineered to overexpress human COX-2in mammary glands developed focal mam-

mary gland hyperplasia, dysplasia, andmetastatic tumors.4 Transgenic mice whooverexpressed COX-2 in skin developedepidermal hyperplasia and dysplasia.5

Knockout of COX-2 markedly reduced thedevelopment of intestinal tumors and skinpapillomas.5,6 Similar results were observedin COX-1 knockouts as well.

• Cyclooxygenase-2 is often overexpressedin cancers where its expression is implicatedin invasion and metastasis. In lung cancer,expression of COX-2 correlates with poorprognosis.7 Epidemiologic studies in famil-ial adenomatous polyposis report a 30%-50% reduction in adenomatous colonpolyps, incident disease, and death fromcolorectal cancer with regular use of aspirinor other nonsteroidal antiinflammatorydrugs (NSAIDs),8 indicating the pharma-cologic use of COX-2 inhibitors as a suit-able preventive therapy. Animal studies alsosupport COX-2 inhibitors as preventivetherapy, demonstrating that treatment withCOX-2 inhibitors reduces the number oftumors that form and can also reduce thegrowth rate of established tumors.9,10

Retrospective Analysis ofNSAID Use and Cancer

Numerous retrospective epidemiologicstudies indicate that long-term use of as-

pirin or other NSAIDs has a protectiveeffect against several different cancers.Using data from the National Health andNutrition Examination Survey I(NHANES I) and the NHANES I Epi-demiologic Follow-up Studies,Schreinemachers and Everson character-ized cancer occurrence with respect to as-pirin use based on questions in the base-line interview asking whether subjectshad used aspirin during the previous 30days.11 Data were available from 12,668persons 25-74 years of age who were fol-lowed for an average of 12.4 years.Among these, 1257 were diagnosed withcancer > 2 years after their NHANES Iexamination. The incidence of severalcancers, including lung cancer, was loweramong persons who reported aspirin use.The findings suggested a possible associa-tion between aspirin use and decreasedcancer incidence.

In a separate analysis involving635,031 adults who provided informa-tion on their aspirin use but did not re-port cancer at the time of the interview,Thun and colleagues found that deathrates associated with cancers of theesophagus, stomach, colon, and rectumdecreased with more frequent aspirinuse, but this was generally not the casefor other cancers.12

Cyclooxygenase-2 Inhibitors as Chemopreventive Agents in Lung Cancer

Prepared by: Nancy Price, PhDReviewed by: Chandra P. Belani, MD, Vinay K. Jain, MD

Electronic forwarding or copying is a violation of US and International Copyright Laws.Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by Cancer Information Group, ISSN #1525-7304, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA 978-750-8400.

Figure 1: Phase II Trial to Assess Celecoxib as a Chemopreventive Agent for Lung Cancer in Patients at High Risk

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Celecoxib twice a day for 6 months

Placebo twice a day for 6 months

Former smokers stratified according to presence of preinvasive lesions and history of stage I NSCLC

Placebo twice a day for 6 months

Celecoxib twice a day for 6 months

(N = 180)

Abbreviation: NSCLC = non–small-cell lung cancer

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Retrospective Analysis of NSAIDUse and Lung Cancer

A retrospective case-control analysis todetermine the effect of NSAID use onthe incidence of lung cancer identified1038 patients with lung cancer from areview of pathology data at several largehospital centers.13 A group of 1002 con-trol patients without cancer were identi-fied from the admission roster of thesame hospitals, and were matched forage, sex, and month of interview.

Twenty-one percent of the control pa-tients regularly used NSAIDs (defined as≥ 3 tablets per week for ≥ 1 year). Seven-teen percent of patients with lung cancerwere reported to use NSAIDs regularly aswell. After adjustment for other demo-graphic variables, the risk of lung canceramong smokers who regularly usedNSAIDs was 32% lower than that in thecomparable group who did not regularlyuse NSAIDs. Comparing the few indi-viduals with lung cancer who neversmoked (84 of 1038 patients) with pa-tients in the control group, no protectiveeffect was found with regular use ofNSAIDs in nonsmokers. The study sug-gested that smokers who regularly useNSAIDs might benefit from a possibleprotective effect against lung cancer.

In a separate retrospective study,NSAID use among 489 patients withlung cancer and 978 control patients wascompared.14 Only heavy smokers wereincluded for the analysis and were com-pared with a matched nonsmoker con-trol group. Daily NSAID use for ≥ 2years before the interview was associated

with a 68% reduction in the relative riskof lung cancer (P < 0.01). The study alsofound a highly significant inverse trendof increasing NSAID use with reducedlung cancer risk (P < 0.01).

Prospective Studies of PreventiveUse of NSAIDs and OtherEicosanoid Modulators

Cumulatively, the retrospective lungcancer data present the intriguing possi-bility that NSAIDs may provide a protec-tive benefit for patients at high risk forlung cancer. The National Cancer Insti-tute is sponsoring a randomized, double-blind, placebo-controlled prospectivephase II study to determine the effective-ness of celecoxib in preventing the devel-opment or recurrence of lung cancer informer heavy smokers who are at risk ofdeveloping cancer. Patients were requiredto (1) be ≥ 45 years of age and have a ≥ 30pack-year smoking history or (2) have hadsurgery to remove lung cancer and be ≥18 years old with a ≥ 10 pack-year smok-ing history. Patients must have quit smok-ing ≥ 1 year before entering the study andmust have had no previous chemotherapyor radiation therapy. Patients were strati-fied according to presence of preinvasivelesions and history of stage I NSCLC.

As illustrated in Figure 1, 180 patients(90 per treatment arm) will be randomlyassigned to receive placebo twice dailyfor 6 months followed by celecoxib twicedaily for 6 months or the reverse se-quence. In the absence of disease pro-gression or unacceptable toxicity, treat-ment will continue indefinitely in both

arms. Patients will be evaluated yearly for4 years and be given a quality-of-life as-sessment every 6 months during treat-ment and then annually for 4 years.

The objectives of the study are to deter-mine the feasibility of celecoxib as achemopreventive therapy against lungcancer in former heavy smokers at risk fordeveloping primary or second primarylung cancer. Additionally, the study willassess the safety of long-term use of cele-coxib in this patient population as well asthe role of COX-2–specific inhibitors onimmunologic effects in these patients.

A second major pathway in the metab-olism of arachidonic acid is the formationof leukotrienes and lipoxins.15 Generally,eicosanoids play an important role in in-flammation and are associated with leuko-cyte trafficking. Zileuton inhibits the en-zyme 5-lipoxygenase, which catalyzes theconversion of arachidonic acid to hy-droperoxide 5(S)-hydroperoxy-6-trans-8,11,14-cis-eicosatetranoic acid. 5-Lipoxygenase activity is found mainly inmyeloid cells, including monocytes, Blymphocytes, granulocytes, and mast cells.

5-Leukotriene pathway inhibitors in-cluding zileuton were evaluated as chemo-preventive agents in female strain A miceinjected with vinyl carbamate (2 × 16mg/kg) to induce lung tumors.16 Twoweeks later, the mice received leukotrieneinhibitors in their diet as single agents orin various combinations. Zileuton aloneor in combination with a second agent re-duced the size and number of lung tu-mors. The promising results in this animalmodel suggested that zileuton might alsohave antitumor activity in humans.

A randomized, double-blind, placebo-controlled phase II study will assess thesafety and efficacy of zileuton in patients athigh risk for bronchial dysplasia (Figure 2).The objectives of the study include safety,the ability of zileuton to stabilize or re-verse dysplasia, and the 6-month stabilityof the chemopreventive effect in patientswho are randomized to receive zileutoninitially versus placebo.

The projected accrual is 134 patients(67 patients per arm) stratified accordingto clinical site, smoking status, and cancerhistory. Eligible patients have histological-

Figure 2: Treatment Schema for a Phase II Trial Testing the Effectiveness of Zileuton to Prevent Lung Cancer in Patients with Bronchial Dysplasia

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Zileuton q.i.d. for6 months

Placeboq.i.d. for6 months

Patients who exhibit sufficient compliance with placebo q.i.d. for 2 weeks are randomized to treatment arms

Placeboq.i.d. for

6 months*

Zileutonq.i.d. for

6 months*

Patients stratified by clinical site, smoking status, and previous cancer (none vs. lung or head/neck)

*Patients proceed if there is no sign of disease progression or unacceptable toxicity.

(N = 134)

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ly confirmed mild to severe bronchial dys-plasia and are current or former smokers(< 10 years since complete smoking cessa-tion) who have smoked ≥ 30 pack-years.Patients may have been curatively treatedfor stage I NSCLC or curatively treatedfor stage I/II squamous cell carcinoma ofthe head and neck.

Iloprost is a synthetic analogue ofprostacyclin (ie, PgI2) that is chemicallystable and has a longer half-life than thenaturally occurring substance. Preclinicalstudies suggest that modulation of Pgmetabolism by iloprost might halt or re-verse pulmonary carcinogenesis.17 TheSPORE (Specialized Programs of Re-search Excellence) Lung Cancer Bio-markers and Chemoprevention Consor-tium is exploring this hypothesis by ex-amining the bronchial epithelium beforeand after the administration of iloprostor placebo (50-150 μg twice daily [b.i.d.]for 6 months) in subjects at high risk forlung cancer (≥ 20 pack-years and sputumatypia). The planned sample size for thismulticenter trial is 152 patients, with 76patients—38 smokers and 38 formersmokers—per arm.

Measurement of response will includehistology before and after treatment ac-cording to the World Health Organiza-tion classification for bronchial epitheli-um, Ki-67 labeling index (a secondaryendpoint), and a panel of biomarkers(including immunohistochemistry andquantitative polymerase chain reactionfor prostacyclin synthase, COX-2, perox-isome proliferators–activated receptor–δand –γ, along with MCM2, ER-β, p53,tyrosine kinase receptor proteins [EGFR,HER2/neu, ErbB3, ErbB4, and Akt],and microvessel density). The serumsamples from the study participants willbe analyzed for proteomics.

NSAIDs May Enhancethe Effects of CytotoxicChemotherapy in Lung Cancer

Preclinical studies indicated thatNSAIDs may act synergistically with cy-totoxic agents.18 The addition of celecox-ib to a preoperative chemotherapy regi-men of paclitaxel/carboplatin in a phase

II trial with 29 patients with stage IB-IIIA NSCLC appeared to enhance theresponse compared with historical con-trols.19 In addition, levels of PgE2 in theprimary tumors and in the adjacent nor-mal lung tissue were compared in 17study patients and 13 control subjectswho received preoperative paclitaxel/car-boplatin without celecoxib. The additionof celecoxib to the paclitaxel/carboplatinregimen appeared to abrogate themarked increase in levels of PgE2 detect-ed in primary tumors after treatmentwith paclitaxel/carboplatin alone.

At the 39th Annual Meeting of theAmerican Society of Clinical Oncologyin 2003, the preliminary results of 2phase II trials treating NSCLC withdocetaxel in combination with celecoxibreported encouraging time to progres-sion and overall survival data20 and re-ported an effect of celecoxib on the re-duction of serum angiogenic factors.21

Another ongoing phase II trial spon-sored by Cancer and Leukemia Group B(CALGB 30203; Figure 3) will treat pa-tients with stage IIIB/IV NSCLC withgemcitabine 1000 mg/m2 intravenouslyover 30 minutes on days 1 and 8 andcarboplatin to an AUC of 5.5 over 30minutes on day 1, with cycles repeatedevery 3 weeks, along with treatment witheicosanoid pathway modulators. Duringchemotherapy, patients will be random-ized to 1 of 3 arms, in which they will re-ceive celecoxib (400 mg b.i.d.), zileuton

600 mg p.o. q.i.d., or both. The primaryendpoint is achievement of a 1-year sur-vival rate ≥ 35%.

Clinical RelevancePreclinical and animal studies suggest

a role for COX-2 enzyme activity in tu-morigenesis and metastasis. Along withretrospective analyses that indicate a pro-tective effect of NSAIDs on smokers,prospective trials are ongoing in whichselective COX-2 inhibitors are expectedto impact the incidence of lung cancer.Other prevention trials are investigatingthe inhibition of a parallel eicosanoidpathway, the leukotriene pathway. Exam-ination of the steps downstream ofarachidonic acid oxidation in theeicosanoid pathway may more clearlyidentify which branches of the pathwaysare essential for tumor progression. Cy-clooxygenase-2 inhibitors could have alarge impact on the incidence of lungcancer if they can successfully prevent orretard the progression of lung cancer inthe high-risk smoking population.

References _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _1. FitzGerald GA. COX-2 and beyond: Approaches to

prostaglandin inhibition in human disease. Nat RevDrug Discov 2003; 2:879-890.

2. Marrogi AJ, Travis WD, Welsh JA, et al. Nitric oxidesynthase, cyclooxygenase 2, and vascular endothelialgrowth factor in the angiogenesis of non-small celllung carcinoma. Clin Cancer Res 2000; 6:4739-4744.

3. Tsujii M, Kawano S, Tsuji S, et al. Cyclooxygenase reg-ulates angiogenesis induced by colon cancer cells. Cell1998; 93:705-716.

4. Liu CH, Chang SH, Narko K, et al. Overexpression of

Figure 3: CALGB 30203 Treatment Schema

Gemcitabine 1000 mg/m2 I.V. over 30 minutes on days 1 and 8Carboplatin to an AUC of 5.5* I.V. over 30 minutes on day 1

Zileuton 600 mg p.o. q.i.d.

Gemcitabine 1000 mg/m2 I.V. over 30 minutes on days 1 and 8Carboplatin to an AUC of 5.5* I.V. over 30 minutes on day 1

Celecoxib 400 mg p.o. b.i.d.

Gemcitabine 1000 mg/m2 I.V. over 30 minutes on days 1 and 8Carboplatin to an AUC of 5.5* I.V. over 30 minutes on day 1

Zileuton 600 mg p.o. q.i.d.Celecoxib 400 mg p.o. b.i.d.

*Patients with prior chest radiation therapy should receive gefitinib to an AUC of 5.0. Abbreviations: AUC = area under the curve; CALGB = Cancer and Leukemia Group B

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in transgenic mice. J Biol Chem 2001; 276:18563-18569.

5. Tiano HF, Loftin CD, Akunda J, et al. Deficiency ofeither cyclooxygenase (COX)-1 or COX-2 alters epi-dermal differentiation and reduces mouse skin tumori-genesis. Cancer Res 2002; 62:3395-3401.

6. Chulada PC, Thompson MB, Mahler JF, et al. Genet-ic disruption of Ptgs-1, as well as Ptgs-2, reduces intes-tinal tumorigenesis in Min mice. Cancer Res 2000;60:4705-4708.

7. Khuri FR, Wu H, Lee JJ, et al. Cyclooxygenase-2 over-expression is a marker of poor prognosis in stage I non-small cell lung cancer. Clin Cancer Res 2001; 7:861-867.

8. Steinbach G, Lynch PM, Phillips RK, et al. The effectof celecoxib, a cyclooxygenase-2 inhibitor, in familialadenomatous polyposis. N Engl J Med 2000;342:1946-1952.

9. Harris RE, Alshafie GA, Abou-Issa H, et al. Chemo-prevention of breast cancer in rats by celecoxib, a cy-clooxygenase 2 inhibitor. Cancer Res 2000; 60:2101-2103.

10. Jacoby RF, Seibert K, Cole CE, et al. The cyclooxyge-nase-2 inhibitor celecoxib is a potent preventive andtherapeutic agent in the min mouse model of adeno-matous polyposis. Cancer Res 2000; 60:5040-5044.

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15. Diaz BL, Arm JP. Phospholipase A2. ProstaglandinsLeukotrienes Essent Fatty Acids 2003; 69:87-97.

16. Gunning WT, Kramer PM, Steele VE, et al. Chemo-prevention by lipoxygenase and leukotriene pathwayinhibitors of vinyl carbamate-induced lung tumors inmice. Cancer Res 2002; 62:4199-4201.

17. Iloprost [Investigators Brochure]. Berlin: ScheringDeutschland GmbH, 1998.

18. Hida T, Kozaki KI, Ito H, et al. Significant growth in-hibition of human lung cancer cells both in vitro andin vivo by the combined use of a selective cyclooxyge-nase 2 inhibitor, JTE-522, and conventional anti-cancer agents. Clin Cancer Res 2002; 8:2443-2447.

19. Altorki NK, Keresztes RS, Port JL, et al. Celecoxib, aselective cyclo-oxygenase-2 inhibitor, enhances the re-sponse to preoperative paclitaxel and carboplatin inearly-stage non-small-cell lung cancer. J Clin Oncol2003; 21:2645-2650.

20. Nugent FW, Graziano S, Levitan N, et al. Docetaxeland COX-2 inhibition with celecoxib in relapsed/re-fractory non-small cell lung cancer (NSCLC): promis-ing progression-free survival in a phase II study. ProcAm Soc Clin Oncol 2003; 22:671 (Abstract #2697).

21. Johnson DH, Csiki I, Gonzalez A, et al. Cyclooxyge-nase-2 (COX-2) inhibition in non-small cell lung can-cer (NSCLC): preliminary results of a phase II trial.Proc Am Soc Clin Oncol 2003; 22:640 (Abstract#2575).