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Chemoprevention of Cancer: An Update

Chemoprevention of Cancer: An Update. WREN Convocation of Practices May 9, 2009. Howard Bailey, MD UWCCC Chemoprevention Program. Chemoprevention of Cancer. Definition Sporn (1976), use of drugs, biologics, or nutrients to inhibit carcinogenesis Rationale

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Chemoprevention of Cancer: An Update

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  1. Chemoprevention of Cancer: An Update WREN Convocation of Practices May 9, 2009 Howard Bailey, MD UWCCC Chemoprevention Program

  2. Chemoprevention of Cancer Definition • Sporn (1976), use of drugs, biologics, or nutrients to inhibit carcinogenesis Rationale • A 15% decrease in epithelial cancers would prevent >100,000 deaths/yr and save $25 billion/yr Background • Epidemiology • Geographic/cultural differences • Genetics – 98% malignancies have somatic mutations rather than germ line mutations • association of infections with cancer

  3. Chemoprevention of Cancer The study of carcinogenesis has led to the current dogma that human carcinogenesis is a multi-year process Boutwell RK, 1976; The biochemistry of pre-neoplasia in mouse skin Frykberg and Bland, 1993; breast atypical hyperplasia to DCIS to carcinoma may take 30 years Thus providing an opportunity to intervene prior to accumulated mutations or phenotypic changes

  4. Basic Progression Model T(0) 10-30 years O’Shaughnessy, et al. - Clin Cancer Res 2002;8:314-46

  5. Chemoprevention Clinical Trials Candidate Agent Phase I Trial Phase II Trial(s) Phase III Trials Subjects (N) Duration (months) Primary Endpoints 25-75 1-12 pK, safety 50-300 6-36 dose, SEB mod. 300+ 36-60 cancer inc. Risk Cost

  6. Chemoprevention Drug Development • How development differs from – • Cancer Therapy • Accepted surrogate of tumor/disease regression • Primary goal can be determined relatively quickly • Vascular diseases • More similar than cancer therapy • Accepted surrogates • Hypertension • Hyperlipidemia

  7. Chemoprevention Drug Development • Similar to Vascular Health prevention, an accepted surrogate marker/endpoint would make chemoprevention drug development more efficient. • Intraepithelial Neoplasia? • Colonic adenomas • Cervical Carcinoma in situ • Breast ductal carcinoma in situ

  8. Intraepithelial Neoplasia • Cancer and IEN frequently share phenotypic and genotypic changes • IEN is already considered a disease by many and has led to the approval of multiple interventions (celecoxib, diclofenac, topical 5FU, BCG, tamoxifen) • Variability in diagnosis/interpretation • Slow and relatively low rate of progression to cancer • Current complexity and limited understanding

  9. Chemoprevention • Phenotypic surrogates • Skin – actinic keratoses, dysplastic nevi • Oral – leukoplakia, erythroplakia • Lung – bronchial dysplasia • Esophagus – Barrett’s (dysplasia) • Breast – DCIS, LCIS, atypical hyperplasia • Colon – adenomas • Cervix – cervical intraepithelial neoplasia (CIN) • Endometrium – atypical hyperplasia • Prostate – prostatic intraepithelial neoplasia (PIN) • Bladder – superficial bladder cancer

  10. Chemoprevention Agents – Approved agents • Tamoxifen • Selective estrogen receptor modulator (SERM) for breast cancer prevention • NSABP – P1 study (Fischer et al. JNCI 90:1371, 1998), 7000 women in each arm (175 cancers in placebo, 89 cancers in Tam) • Raloxifene • Selective estrogen receptor modulator (SERM) for breast cancer prevention • NSABP – P2 (STAR) study,(Vogel et al. JAMA 295:2727, 2006), approx 4000 post-menopausal women in each arm with an expected BrCa rate of 4% over 5 years, observed only 0.4% in each arm.

  11. Chemoprevention Agents – Approved agents • Tamoxifen P1 study Fisher JNCI 1998

  12. Chemoprevention Agents – Approved agents • Tamoxifen P1 study

  13. Chemoprevention Agents – Approved Agents • Tamoxifen and Raloxifene are approved for women at “high risk” • High risk is a women with a 1.66% chance of developing invasive breast cancer in the next 5 years • All women > 60 yo • Younger women with some number of the following risk factors: early menarche (<12 yo) , late menopause (>55 yo), nulliparity or >30 yo at first full term pregnancy, first degree family relative with breast cancer, prior breast biopsies especially with atypical ductal hyperplasia, …

  14. Chemoprevention Agents – Approved agents Celocoxib • Specific COX-2 inhibitor approved for adenoma prevention in FAP (Steinbach et al. NEJM 342:1946, 2000) • Prevention of sporadic polyps (Bertagnolli et al. NEJM 355:873, 2006) • Increased cardiac risks (Solomon et al. NEJM 352:1071, 2005)

  15. APC Trial Sporadic CRN (n=2,035) 91 participating sites Celecoxib 200 mg bid or 400 mg bid vs. placebo Rec. adenomas at 3 years Advanced Adenomas Recurrent Adenomas Celecoxib Celecoxib 200 mg bid 200 mg bid Placebo bid Placebo bid Celecoxib Celecoxib 400 mg bid 400 mg bid Celecoxib Celecoxib 200 mg bid 200 mg bid Placebo bid Placebo bid Celecoxib Celecoxib 400 mg bid 400 mg bid Sporadic AdenomasPhase III Trials *p<0.0001 vs. placebo; Bertagnolli – NEJM 2006;355:873-84

  16. Chemoprevention Agents – Approved Agents • Quadravalent HPV vaccine for cervical cancer • VLP vaccine against HPV 6, 11, 16, 18 • Initial Pilot study of monovalent (Koutsky et al. NEJM 347:1645-51, 2002) • Initial phase 2 quadravalent (Villa et al. Lancet 6:271-78, 2005) • approved for females 9-26 yo • FUTURE I an II studies (NEJM 356: 1915, 2007)

  17. Chemoprevention Agents • VLP vaccine, bivalent 16/18 • Harper et al. Lancet 367, 2006 • Further f/u on women who received all 3 doses • Seropositivity/immunogenicity maintained for ≥ 5 yrs • Protection beyond 16/18, also decreased 45/31

  18. Chemoprevention Agents – Approved Agents • Are they being used? • Infrequently at best • Reasons are many starting with limited interest from Primary Providers and Lay Public’s negative views • Assessment of Dane County Providers • M Jensen et al. survey of healthcare providers for adolescents opinions regarding the HPV vaccine. • O Olaigbe et al. survey of healthcare providers for women regarding tamoxifen for breast cancer prevention

  19. Prostate Cancer Prevention Trial (PCPT):Specific Rationale • Link between androgens and CaP • TDHT AR • Epidemiology • Finasteride inhibits 5-alpha-reductase • Safety profile from BPH studies 5-alpha-reductase

  20. 1993-96 2000-03 18,882 Men > 55 yrs, < 3 PSA, normal DRE Endpoint: 7-year period prevalence of prostate cancer

  21. Primary Endpoint:Seven-Year Period Prevalence Thompson, et al NEJM 2003

  22. PCPT Conclusions • Misclassification rates on biopsy were higher in the placebo arm and high grade rate on prostatectomies were not higher on finasteride arm • True risk of 8-10 is unknown • Estimates based on PCPT data including possibility of more high grade disease still show significant overall health benefit (person-years saved) to society with finasteride • Use of 5α reductase inhibitors probably won’t evolve unless another study is positive Unger et al. Cancer 2005

  23. Reduction by Dutasteride of Prostate Cancer Events (REDUCE) • Dutasteride • dual inhibitor of type 1 and 2 5α reductase • BPH studies suggested decreased Pr CA incidence • Serum DHT levels further reduced by dutasteride • GSK sponsored study, 650 centers, 8000 subjects • Men 50-75 yo, PSA 2.5-3.0 to 10 ng/ml, must have a neg. prostate bx within 6 mos (no HGPIN or ASAP), prostate volume ≤80 cc Andriole et al. J Urology 2004

  24. The Selenium and Vitamin E Cancer Prevention Trial (SELECT) • NCI sponsored prostate chemoprevention trial opened 2001 • 32,000 men, ≥ 50-55 yo, PSA ≤4.0 ng/ml, DRE-negative • Selenomethionine 200 µg, α tocopherol 400 IU • Followup every 6 mos • Primary endpoints – Prostate Ca incidence • Factorial design with 5 comparisons • Each agent vs placebo, the combination vs placebo, combination vs each agent Lippman et al. JNCI 2005

  25. SELECT • Preliminary Results • Neither Selenium or Vitamin E alone or together prevented prostate cancer • Uncertain findings –an increase in prostate cancers in men taking Vit E alone; and small increase in the number of cases of adult onset diabetes in men taking selenium

  26. Chemoprevention Agents/Issues with Micronutrients • CARET, ATBC, and NPC Results • Concerning negative results • Micronutrients assumed not to be harmful • Replacement doses vs supraphysiologic (pro-oxidant effects?) • Regular dietary consumption vs supplementation • Smokers and gender differences in metabolism

  27. Nutrients and Cancer • Dietary Nutrients • Polyphenols (primarily green tea) • Strong epidemiologic data • Important constituents are catechins (specifically epigallocatechin gallate/EGCG) • Cup of green tea contains 3-400 mg of polyphenols (10-30 mg EGCG) • Encouraging clinical research at 400-800 mg of EGCG/day • Isoflavones/Soy • Phytoestrogen • Genistein – UW bladder prevention study

  28. Chemoprevention Agents - Genistein Genistein inhibits growth of carcinoma cells of multiple tumor types in vitro. It is a potent inhibitor of tyrosine kinase, a key enzyme in signal transduction. Glycoside conjugates account for more than 2/3 of the total isoflavone content of soybeans.

  29. Nutrients and Cancer • Dietary Nutrients (cont.) • Carotenoids •  carotene • Lycopene • Polyphenolic constituent of tomatoes and some fruits • How tomatoes are cooked/processed influences amount of lycopene • Epidemiologic studies • Positive in vitro/in vivo effects • Ongoing chemoprevention studies • Lutein • Organosulfurs/seleniums • Anethole dithiolethione (ADT) • Flavanoids • Quercetin

  30. Nutrients and Cancer • Dietary Nutrients (cont.) • Curcumin • Perillyl alcohol • Resveratrol • Isothiocyanates/indoles • Indole-3-carbinol/Diindolymethane (DIM) • UW prostate study • Phenylethyl isothiocyanate (PEITC)

  31. Meta-analysis of Antioxidants for GI Cancer Prevention Bjelakovic et al. Lancet 364:1219, 2004

  32. Chemoprevention Development: Directions? • Better risk stratification • Genomics, unbiased pursuit e.g. quantitative trait loci • Proteomics, a less invasive way to assess intervention • Non-invasive imaging of preneoplasia/intraepithelial neoplasia • Cross-disciplinary studies of health maintenance, e.g. WHI • WREN • Wisconsin Network for Health Research (WiNHR)

  33. Cancer Chemoprevention • Possible study idea • Green tea polyphenols in patients with or at risk of metabolic syndrome • Compelling data for beneficial effects of green tea polyphenols in Cancer, CardioVascular and Neurodegenerative disease and Insulin resistance.

  34. Chemoprevention of Cancer • Clinical trials pose both new and old issues for cancer-related drug development • We should look to other disciplines for advice, e.g. renal or vascular preventive health • We need to “understand our audience better” Thank you.

  35. Chemoprevention Agents • Selenium Clinical studies • NPC Trial • 1300 subj (Eastern U.S.) with skin CA hx randomized to 200 g/d of selenized brewer’s yeast or placebo (Duffield-Lillico et al. JNCI, 2003) • Effects on skin cancer contradictory • Significant decrease in prostate CA (Clark et al. Br J Urol 89:730, 1998), but other cancer incidence was examined also.

  36. NPC Trial: Incidence and Relative Risk of non-melanoma skin cancer Baseline Se levelRRP value <105 ng/ml 0.87 .42 105-122 1.49 .03 >122 1.59 .01 Duffield-Lillico, JNCI, 2003

  37. Chemoprevention / Development • Clinical Testing • Phase I testing • normal volunteers vs increased risk population • dose de-escalation or escalation • randomization to one of multiple dose levels (for de-escalation studies) or placebo • Examples • Phase I de-escalation study of DFMO, Love et al. JNCI 85:732, 1993 • Phase I escalation study of UAB30, J. Kolesar et al. • Phase Ib study of diindolymethane in subjects undergoing prostatectomy, J Gee et al.

  38. Chemoprevention / Development • Clinical Testing • Phase 2 testing • 2a – shorter duration (days to weeks) biomarker studies • 2b – randomized, double-blinded, placebo-controlled longer duration (>3 mos) biomarker studies • Provide rationale for the design of a phase 3 study • Examples • Phase 2a study of genistein in subjects with superficial bladder cancer, E Messing, & J. Gee • Phase 2b study of DFMO in Organ Transplant Recipients at risk of skin cancer,

  39. Chemoprevention/Development • Clinical Testing (cont.) • Phase 3 – randomized, double-blinded, placebo controlled studies • Demonstrate a significant decrease in cancer incidence or mortality or an accepted surrogate • Validate surrogate markers • Hopefully lead to improved population health • Examples • Phase 3 Study of DFMO in subjects with a history of skin cancer • Phase 3 Study of Tamoxifen in women at risk of breast cancer

  40. PreSAP Trial (n=1,561) 107 participating sites Celecoxib 400 mg qd vs. placebo Rec. adenomas at 3 years RR=0.64 (0.56-0.75); any RR=0.49 (0.33-0.73); adv. APPROVe Trial (n=2,587) 108 participating sites Rofecoxib 25 mg qd vs. placebo Rec. adenomas at 3 years RR=0.76 (0.69-0.83); any RR=0.70 (0.57-0.73); adv. Phase III Trials N Engl J Med 2006;355:885-95 and Gastroenterol 2006; epub

  41. Rofecoxib APPROVe Trial N=2,586 subjects Follow-up = 3,327 pt-years CV Adverse events (%): Placebo (2%); RR=1.0 25 mg QD (3.6%); RR=1.9 Celecoxib APC Trial N=2,035 subjects Follow-up = 2.8-3.1 years CV deaths (%): Placebo (1%); RR=1.0 200 mg BID (2.3%) ; RR=2.3 400 mg BID (3.4%) ; RR=3.4 www.washingtonpost.com; 4/7/05 www.theoaklandpress.com; 12/18/04 Cardiovascular Toxicity N Engl J Med. 2005;352:1071-80 and 1092-102

  42. Celecoxib and Colon Cancer Prevention • Psaty and Potter (NEJM 355:950, 2006) • Reviewed APC and PreSAP trials and concluded the following • Celecoxib decreases adenoma formation • Celecoxib increases the risk of cardiovascular adverse events • The potential increase in CV event/mortality outweighs the projected decrease in colon cancer incidence • Could Celecoxib be an option in people with low cardiac risk?

  43. N = 4368 N = 4692 Gleason Score: Percent of Men Evaluated 1.25 RR Not graded: Finasteride N = 46, Placebo N = 79

  44. PCPT: Increased rate of High Grade Cancers, Detection-bias? • The increase in HG was based on biopsies • RP is the gold-standard for determining GS • HG was not significantly increased at RP • Detection bias • Increased PSA sensitivity • Increased biopsy sensitivity Lucia, et al JNCI September 2007

  45. SIMULATED BIOPSY: Sampling Bias Median Prostate Volume: 38.8 cc vs 24.4 cc (p = 0.001) Placebo Finasteride

  46. Lucia, et al, JNCI, 2007; 1375-83

  47. Detection-bias: The Evidence Bx findings in GS 8-10 tumors Finasteride (n=98) mean sd med Placebo (n=61) mean sd med % cores pos Greatest lin extent (mm) Aggregate lin ext (mm) Bilateral disease26.5% 44.3% (p=0.02) Perineural invasion9.2% 16.4% Lucia, et al JNCI September 2007

  48. Does Finasteride Make the Grade?

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