Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Clinical Conundrums in Cancer Chemoprevention: What Should You Recommend to Your Patients? Susan Hingle, MD, FACP Professor of Medicine Division of General Internal Medicine Interim Chair SIU School of Medicine Session Objectives Identify the cancers in which aspirin therapy may play a role in prevention. Learn if aspirin therapy is indicated for cancer prevention. Learn about data on use of 5-alpha reductase therapy in prostate cancer prevention. Recognize the indications for SERMs and AIs in breast cancer prevention. Aspirin and Cancer Chemoprevention Will an aspirin a day keep the oncologist away? What you should tell your patients about aspirin use for cancer chemoprevention. Case #1 A 52 year-old man with a past medical history of GERD and hypertension on omeprazole and lisinopril presents to the clinic for routine follow up. He read on an internet blog that he should start taking a baby aspirin weekly to reduce his risk of colon cancer. He asks for your input. He had a screening colonoscopy at age 50 during which a small (<0.5 cm) tubular adenoma was removed. Family history is negative for colon cancer. On physical exam BP is 122/72. The remainder of his exam is normal. What is your advice for this patient? Aspirin and Cancer Chemoprevention Potential mechanisms of action: Induction of cell apoptosis Inhibition of cyclooxygenase-mediated PG production PGs are associated with: Tumor angiogenesis Cell proliferation Inhibition of immune surveillance & apoptosis ASA Use and the Incidence of Cancer Colorectal cancer: Numerous studies suggest ASA may reduce risk of CR adenomas and CR cancers (post hoc analyses): C. Dubé et al (2007): 22% risk reduction in CRC incidence Physicians’ Health Study Research Group (1989) & Cook et al (2005): No reduction in CRC incidence at 10 years Rothwell et al (2010): Follow-up of above at 20 years showed decreased incidence of CRC Rothwell et al (2012): Analysis of 4 RCTs for ASA prevention of vascular disease, ASA therapy reduced 20-year colon cancer risk, with reduction of colon cancer risk not occurring until 8-10 year point Special Populations Lynch syndrome: There is only one randomized placebo-controlled trial of aspirin (CAPP2) in which colorectal cancer was a primary endpoint: NO benefit from aspirin (600 mg/day) in 937 patients with Lynch syndrome (hereditary nonpolyposis colon cancer) Short study time (2-4 years) Different cancer mechanism for Lynch syndrome?? Familial adenomatous polyposis (FAP): 83 patients with FAP were randomly assigned to celecoxib (100 or 400 mg twice daily) or placebo After six months, patients receiving the higher dose had a modest (15 percent) but statistically significant reduction in the extent of duodenal polyposis as assessed in blinded reviews of endoscopy videotapes. ASA Use and the Incidence of Cancer Other cancers: Meta-analyses of numerous RCTs Daily aspirin therapy: Was associated with a reduction in all cancers (up to 12% relative risk reduction) Benefit after 4 years, independent of age, gender, tobacco use history Reduction in female reproductive tract cancers, lymphoma, and sarcoma Long-term aspirin use may reduce cancer mortality Several ongoing trials to be completed between now and 2019 may give us more information on this subject And Here Is the Bad News . . . Adverse effects of aspirin: Increased risk of bleeding: GI bleeding Intracranial hemorrhage Other major bleeding Possible 50% increase in the RR of major non-fatal extracranial bleeding Associated risk factors: Age, prior history of PUD Mitigators: PPIs Recommendations for the PCP Benefits of daily aspirin (75-100 mg) for cancer prevention may outweigh the risks in select patients: Requires individualization and clinical judgment Age >50 Patient with estimated high cancer risk (e.g., using colorectal and breast cancer risk calculators) or with specific cancer syndromes [Lynch syndrome, FAP (celecoxib)] No concomitant use of medications that increase bleeding risk IMPORTANT: There are no official guidelines that recommend aspirin therapy for primary cancer prevention at this time Back to Case #1 A 52 year-old man with a past medical history of GERD and hypertension on omeprazole and lisinopril presents to the clinic for routine follow up. He read on an internet blog that he should start taking a baby aspirin weekly to reduce his risk of colon cancer. He asks for your input. He had a screening colonoscopy at age 50 which showed one small (<0.5 cm) tubular adenoma. Family history is negative for colon cancer. On physical exam BP is 122/72. The remainder of his exam is normal. What is your advice for this patient? 5-Alpha Reductase Inhibitors and Prostate Cancer Prevention 5-alpha reductase inhibitors make the urine flow and the hair grow, but . . . Should primary care physicians prescribe them for prostate cancer prevention? Case #2 A 55-year-old man with hypertension, dyslipidemia, and glaucoma presents for routine follow up to his PCP. He voices no complaints at the visit and has a negative ROS. Although he has no family history of it, he is concerned about getting prostate cancer, as he had a colleague who was recently diagnosed with it. VS and exam are normal. He hands you an article on prostate cancer that he cut out of a magazine and inquires whether he can take any medications to reduce his risk of prostate cancer. What is your advice for this patient? Prostate Cancer 2nd most common cancer in men Increasing incidence since PSA screening initiated Most cancers are clinically indolent Early treatment not proven to improve survival Why Chemoprevention Long latency period Progression from PIN to invasive cancer takes many years Chemoprevention might delay progression to invasive cancer Androgen dependency Men with congenital 5-alpha reductase deficiency do not develop prostate cancer Blocking androgens shown to affect PIN and prostate cancer Drugs are available that are antiandrogenic 5-Alpha Reductase Inhibitors Agents: finasteride & dutasteride Block conversion of testosterone to DHT Prostate Cancer Prevention Trial: 1994-97 with reanalysis of data through 2011 ~19K men at increased risk of prostate cancer Finasteride 5 mg daily versus placebo Decrease in incidence of prostate cancer in finasteride-treated group Increased risk of high-grade prostate cancer in finasteride-treated group however 10-year survival rate after prostate cancer diagnosis in finasteridetreated group was no different than placebo-treated group 5-Alpha Reductase Inhibitors REDUCE Trial ~8400 men at increased risk of prostate cancer Dutasteride 0.5 mg daily versus placebo Reduced incidence of prostate cancer in dutasteride-treated group Increased incidence of cases with Gleason score of 7 to10 Author’s explanation: due to the drug’s ability to reduce the volume of the prostate, which in turn improves the ability to identify high-grade tumors in biopsy samples. They did not exclude the possibility, though, that the drug could be responsible for some high-grade tumors. REDUCE = Reduction by Dutasteride of Prostate Cancer Events Summary: Prostate Cancer Chemoprevention 5-AR inhibitors appear reduce risk of prostate cancer Increased risk of high-grade cancer in the treated groups No conclusive data that these agents reduce risk of death or increase survival Side effects may not be tolerable for most men (e.g., ED, gynecomastia, decreased libido) No FDA approval to use either drug for prostate cancer prevention AUA: “Asymptomatic men with a prostate-specific antigen (PSA) ≤3.0 ng/mL who are regularly screened with PSA or are anticipating undergoing annual PSA screening for early detection of prostate cancer may benefit from a discussion of both the benefits of 5-ARIs for 7 years for the prevention of prostate cancer and the potential risks (including the possibility of high-grade prostate cancer). Men who are taking 5ARIs for benign conditions such as lower urinary tract [obstructive] symptoms (LUTS) may benefit from a similar discussion, understanding that the improvement of LUTS relief should be weighed with the potential risks of high-grade prostate cancer from 5-ARIs (although the majority of the Panel members judged the latter risk to be unlikely).” Other Agents for Prostate Cancer Chemoprevention Vitamin E and selenium: SELECT trial (selenium & vitamin E) Vitamin E increased incidence of prostate cancer Selenium and selenium + Vitamin E increased incidence of prostate cancer (not statistically significant) Physician’s Health Study II Vitamin E (nor beta-carotene, ascorbic acid, or MVI) did not reduce incidence of prostate cancer NSAIDs: Planned trial with rofecoxib was canceled when rofecoxib was pulled from market SELECT = Selenium and Vitamin E Cancer Prevention Trial Back to Case #2 A 55-year-old man with hypertension, dyslipidemia, and glaucoma presents for routine follow up to his PCP. He voices no complaints at the visit and has a negative ROS. Although he has no family history of it, he is concerned about getting prostate cancer, as he had a colleague who was recently diagnosed with it. VS and exam are normal. He hands you an article on prostate cancer that he cut out of a magazine and inquires whether he can take any medications to reduce his risk of prostate cancer. What is your advice for this patient? SERMs and AIs in Breast Cancer Chemoprevention SERMs and AIs: What are good for fighting cancer are also good at preventing it, right? Case #3 A 52-year old postmenopausal caucasian woman with no significant past medical history comes for her annual exam. She voices no concerns, and ROS is negative. Family history is positive for breast cancer in her mother (diagnosed at age 60). She had menarche at age 11, has never been pregnant, and has never smoked. She has been getting mammograms regularly since age 40. She had one breast biopsy for a lesion seen on screening mammography at age 42, but the pathology was proliferative benign breast disease without atypia. Her VS and physical exam are normal. She is concerned about getting breast cancer and wants to know if there is any medical therapy that can reduce her risk. What advice do you give this patient? Breast Cancer Most common nonskin cancer in women ~232,000 women diagnosed with invasive breast cancer and ~40,000 died of breast cancer in 2013 Risk factors: Age Age at menarche Race Age at first childbirth Family history (of breast OR ovarian cancer) History of atypical hyperplasia Previous breast biopsy Dense breast tissue Risk assessment models are, in general, better at predicting at-risk study populations rather than at-risk individual women Selective Estrogen Receptor Modulators (SERMs) Studies Agents: tamoxifen & raloxifene Randomized controlled trials have shown they reduce the risk for ER-positive breast cancer Selection criteria: Age > 60 Age > 35 with h/o LCIS, DCIS, or atypical ductal or lobular hyperplasia Women between 35 and 59 with ≥1.66% 5-year risk Reduced incidence by 7-9 events per 1000 postmenopausal women over 5 years Tamoxifen reduced incidence more than raloxifene Tamoxifen also reduced incidence of invasive breast cancer in premenopausal women SERMs At-risk women were more likely to benefit from chemoprevention: Highest benefit in women who had ≥ 3% 5-year risk e.g., NCI Breast Cancer Risk Assessment Tool (based on Gail model) http://www.cancer.gov/bcrisktool/ Not recommended for women with PMH of breast cancer, history of chest radiation, or with possible family history of BRCA1 and BRCA2 mutations Minimal benefit in women who were not at increased risk Adverse Effects of SERMs Deep-venous thromboses Endometrial cancer (tamoxifen) Cataracts (tamoxifen) Hot flashes NOTE: no increased risk of CAD or stroke was seen Tamoxifen versus Raloxifene Tamoxifen slightly more effective Raloxifene has lower risk of DVTs, endometrial cancer, and cataracts Recommendations for SERMs ASCO & USPSTF: Both recommend SERMs for breast cancer prevention in highrisk patients ≥ 35 ASCO: USPSTF: ≥ 1.66% 5-year risk (or with LCIS) ≥ 3% 5-year risk Tamoxifen 20 mg daily for 5 years Pre- and postmenopausal women Raloxifene 60 mg daily for 5+ years* Postmenopausal women only * can be used longer than 5 years in women with osteoporosis, in whom BC risk reduction is a secondary benefit. Contraindications: History of DVT/PE, stroke, transient ischemic attack, or during prolonged immobilization. Combination with hormone therapy Pregnant women, women who may become pregnant, or nursing mothers Aromatase Inhibitors Agents: anastrozole & exemestane Mechanism of action: inhibit aromatase, which is responsible for conversion of androgens to estrogens, and hence, will reduce plasma estrogen levels Are regularly used in breast cancer treatment Aromatase Inhibitors Studies NCIC Clinical Trials Group Mammary Prevention.3 Trial, 2011: ~4,500 women at high risk for breast cancer Received exemestane or placebo 65% relative reduction in invasive breast cancer with exemestane Reduction in DCIS seen, too International Breast Cancer Intervention Study (IBIS-II), 2013: ~4,000 postmenopausal women at high risk for breast cancer Received anastrozole or placebo 50% reduction in number of invasive breast cancer and DCIS with anastrozole compared to placebo Side effects: musculoskeletal pain, hypertension, vaginal dryness, vasomotor symptoms, SUMMARY: ASCO Recommendations for Breast Cancer Prevention Tamoxifen (20 mg per day orally for five years) should be discussed as an option to reduce the risk of invasive, estrogen receptor (ER)-positive breast cancer in premenopausal or postmenopausal women. . . . Raloxifene (60 mg per day orally for five years) should also be discussed as an option to reduce the risk of invasive, ER-positive breast cancer. . . . Its use is limited to postmenopausal women. Exemestane (25 mg per day orally for five years) should be discussed as an alternative to reduce the risk of invasive, ER-positive breast cancer in postmenopausal women. . . . . . While exemestane is approved for the treatment of breast cancer, the FDA has not yet approved its use in breast cancer prevention. This recommendation is based on encouraging data from a single clinical trial that showed up to a 70 percent reduction in overall and ER-positive invasive breast cancer incidence with exemestane compared to placebo over a three year period. All three agents should be discussed (including risks and benefits) with women aged 35 years or older without a personal history of breast cancer who are at increased risk of developing invasive breast cancer (5-year risk ≥ 1.66%), based on risk factors such as the woman’s age, race, and medical and reproductive history. SUMMARY: USPSTF Recommendations for Breast Cancer Prevention “. . . recommends that clinicians engage in shared, informed decision making with women who are at increased risk for breast cancer about medications to reduce the risk. For women, who are at increased risk for breast cancer and at low risk for medication side effects, clinicians should offer to prescribe risk-reducing medications, such a tamoxifen or raloxifene. (B recommendation)” Back to Case #3 A 52-year old postmenopausal caucasian woman with no significant past medical history comes for her annual exam. She voices no concerns, and ROS is negative. Family history is positive for breast cancer in her mother (diagnosed at age 60). She had menarche at age 11, has never been pregnant, and has never smoked. She has been getting mammograms regularly since age 40. She had one breast biopsy for a lesion seen on screening mammography at age 42, but the pathology was proliferative benign breast disease without atypia. Her VS and physical exam are normal. She is concerned about getting breast cancer and wants to know if there is any medical therapy that can reduce her risk. What advice do you give this patient? Breast Cancer Risk Assessment Tool Take-Home Points Aspirin may be beneficial for colorectal adenoma and cancer prevention in certain populations No formal recommendations to use aspirin for cancer prevention yet 5-alpha reductase inhibitors appear to reduce the incidence of prostate cancer at the risk of increasing high grade cancers ASCO/AUA guidelines suggest consideration in select men SERMs are recommended for breast cancer prevention in high-risk women ≥ 35 by ASCO & USPSTF: Tamoxifen: pre and postmenopausal women Raloxifene: postmenopausal women only AIs can be considered for breast cancer prevention in highrisk women ≥ 35: Exemestane: postmenopausal women (not FDA approved) Bibliography Chen WY. Selective estrogen receptor modulators and aromatase inhibitors for breast cancer prevention. In: UpToDate, Basow DS (Ed), UpToDate, Waltham, MA. (Accessed on January 15, 2014.) Cook NR et al. Low dose aspirin in the primary prevention of cancer: the Women’s Health Study: a randomized controlled trial. JAMA 2005;294:47. Cook NR et al. Alternate-day, low-dose aspirin and cancer risk: Long-term observational follow-up of a randomized trial. Ann Intern Med 2013;159:77-85. Crawford ED . Chemoprevention strategies in prostate cancer. In: UpToDate, Basow DS (Ed), UpToDate, Waltham, MA. (Accessed on January 15, 2014.) Dubé C et al. The use of aspirin for primary prevention of colorectal cancer: a systematic review prepared for the US Preventive Services Task Force. Ann Intern Med 2007;146:365. Final report on the aspirin component of the ongoing Physicians’ Health Study. Steering Committee of the Physicians’ Health Study Research Group. N Engl J Med 1989;321:129. Fortmann SP et al. Vitamin and mineral supplements in the primary prevention of car Goss PE. Exemestane for breast-cancer prevention in postmenopausal women. N Engl J Med 2011;364:2381-91. Klein EA et al. Vitamin E and the risk of prostate cancer: the selenium and vitamin E cancer prevention trial (SELECT). JAMA 2011;306:1549. Moyer VA. Medications for risk reduction of primary breast cancer in women: US Preventive Services Task Force recommendation statement. An Intern Med. 2013;159:698-708. Rothwell PM et al. Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomized trials. Lancet 2010;376:1741. Rothwell PM et al. Short-term effects of daily aspirin on cancer incidence, mortality, and non-vascular death: analysis of the time course of risks and benefits in 51 randomized controlled trials. Lancet 2012;379:1602. Spencer FA and Guyatt G. Aspirin in the primary prevention of cardiovascular disease and cancer. In: UpToDate, Basow DS (Ed), UpToDate, Waltham, MA. (Accessed on January 15, 2014.) Sutcliffe P et al. Aspirin for prophylactic use in the primary prevention of cardiovascular disease and cancer: a systematic review and overview of reviews. Health Technol Assess 2013 Sep;17(43):1-253. Thompson IM et al. Long-term survival of participants in the prostate cancer prevention trial. N Engl J Med 2013;369:603. Visvanatha K et al. Use of pharmacologic interventions for breast cancer risk reduction: American Society of Clinical Oncology clinical practice guidelines. J Clin Oncol 2013 Aug 10;31(23):2942-62. Wolin KY and Colditz GA. Cancer prevention. In: UpToDate, Basow DS (Ed), UpToDate, Waltham, MA. (Accessed on January 15, 2014.)