dina dumercy, pharm.d., bcop oncology it pharmacist memorial healthcare system miramar, florida...
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DINA DUMERCY, PHARM.D., BCOPONCOLOGY IT PHARMACIST
MEMORIAL HEALTHCARE SYSTEMMIRAMAR, FLORIDA
Update on Common Malignancies in Women:
Breast and Cervical Cancers
Disclosures
Dina Dumercy, Pharm.D. declares no conflicts of interest or financial interests in any product or service mentioned in this activity, including grants, employment, gifts, stock holdings, and honoraria
Objectives
Upon completion of this program, the participant will be able to:
Describe the prevalence and diagnosis of breast and cervical cancers
Recommend the latest screening recommendations for breast and cervical cancers
Review guidelines for appropriate selection of therapy
Describe strategies that pharmacists can use to enhance patient compliance to therapy
Cancer Statistics
About 1, 529, 560 new cancer cases are expected to be diagnosed
569,490Americans are expected to die of cancer (more than 1,500 people a day)
Cancer is the second most common cause of death in the US, exceeded only by heart disease
In the US cancer accounts for nearly 1 of every 4 deaths
African Americans are more likely to develop and die from cancer than any other racial group
American Cancer Society. Cancer Facts and Figures, 2010. Atlanta: American Cancer Society; 2010.
Estimated New Cases and Death By Sex
Commonly Asked Questions
What is cancer?Is there anything to prevent cancer?What is the best treatment for cancer?Where can I get more information on the
guidelines for treatment?What are the risk factors for developing
cancer?They tell me I have cancer, what should I do?
What is cancer?
A group of diseases characterized by uncontrolled growth of abnormal cells, when this spread or growth is uncontrolled it may lead to death.
A multistep process in which an accumulation of genetic events with a single cell line leads to a progressively dysplastic cellular appearance, deregulated cell growth and finally evident disease.
Carcinogenesis
http://www.dkfz.de/en/tox/images/scheme-cancer-prevention.jpg (Permission requested)
What are the risk factors for Cancer?
Genetics Family History Genetic testing
Lifestyle Tobacco Exercise Diet
Environmental Radiation Asbestos
Personal History Cancer Pre-malignant disease Infections Medications
•207, 090 NEW CASES OF INVASIVE BREAST CANCER (IBC) WERE EXPECTED TO OCCUR IN WOMEN IN THE US DURING 2010•ABOUT 1,970 NEW CASES ARE EXPECTED IN MEN•54,010 NEW CASES OF IN SITU BREAST CANCERS ARE EXPECTED (85% DUCTAL CARCINOMA IN SITU)•LIFETIME RISK OF DEVELOPING BREAST CANCER IS 12.3% (1 IN 8 WOMEN)
Breast Cancer
Risk Factors
Female genderIncreasing ageEarly menarcheLate MenopauseOlder age at first
childbirthHormone
replacement therapyChest wall irradiationBenign proliferative
breast disease
Family history Early onset breast
cancer Family with known
mutation 2 or more 1st degree
relatives or 1 with Dx before 50 yrs of age
Genetic mutations (i.e.. BRCA1 or 2, PTEN, p53)
Ovarian/ Fallopian/ peritoneal cancers
Normal Risk Breast Cancer Screening
NCCN Guidelines Version 1.2011 Breast cancer Screening and Diagnosis
Breast Cancer Increased Risk
NCCN Guidelines Version 1.2011 Breast cancer Screening and Diagnosis
Increased Risk Breast Cancer Screening
NCCN Guidelines Version 1.2011 Breast cancer Screening and Diagnosis
Breast Cancer Risk Assessment
Patient with moderate or high risk factors should be seen for genetics counseling
Risk reduction counseling should occur for all women with high lifetime risk
Surgical risk reduction strategies generally reserved for patients with strongly predisposing gene mutation
Risk Reduction agents Tamoxifen and Raloxifene are options after a discussion on the relative risk reduction, adverse reactions and benefits
Risk Reduction agents
Trials Outcome
NSABP P-1(BCPT)(n=13,388)
Placebo vs. Tamoxifen 20 mg/d x 5 y
•Reduce risk of IBC by 49% (P<0.00001)•Risk of IBC reduced by 56% and 86% in LCIS and atypical hyperplasia, respectively
CORE(n=5,213)
Placebo vs. Raloxifene 60 or 120 mg
•Reduce risk of IBC by 66% @ 4 yrs•Risk of IBC and ER+ IBC reduced by 66% and 76%, respectively @ 8 yrs
NSABP P-2(STAR)(n=19,747)
Tamoxifen 20 mg vs. Raloxifene 60mg daily for 5 years
•@8 years follow-up Raloxifene 76% is as effective as Tamoxifen in reducing IBC risk•Raloxifene is as effective as Tamoxifen in reducing risk in Atypical hyperplasia
Fisher, B. CA Cancer J Clin 1999;49(3):159-77. Vogel, VG. JAMA 2006;295(23):2727-41.
Breast Cancer Work-up
History and PhysicalDiagnostic bilateral mammogram +/-
ultrasoundPathology review (ER/ PR/ HER2 status/
Histology, etc)MRI (if necessary)Additional studies based on symptoms and
stage Bone scans CT/ PET/ Chest Imaging/ MRI
Breast Cancer Staging
Breast Cancer Histopathologic Types
Treatment Approach
SurgeryRadiationChemotherapyBiological therapyEndocrine therapyTreatment of Breast cancer is determined by
prognostic and predictive factors and patient preference Histology, TNM status, PS, pathology, age, co-
morbidities, menopausal status
Adjuvant Treatment
ER/ PR (+) HER2 (-) Adjuvant Endocrine +/- Adjuvant Chemotherapy
1, 2
ER/ PR(+) HER2 (+) Adjuvant Endocrine +/- Adjuvant Chemotherapy + Trastuzumab
1
ER/ PR (-)/ HER2 (+) Adjuvant chemotherapy + Trastuzumab
ER/PR (-)/ HER2 (-) Adjuvant chemotherapy 3
1 Endocrine Tx and Chemo given sequentially with Chemo given first2 21 Gene RT-PCR Assay to determine recurrence risk score to assist in treatment decision, must be done within3 Triple negative breast cancer
Adjuvant Endocrine Therapy
Adjuvant chemotherapy
AC-> Paclitaxel weekly or Docetaxel Q3W +/- TDose dense AC -> Paclitaxel Q2WTACFEC/ CEF-> Docetaxel Q3W or Paclitaxel
weekly+/- TTCECCMFFAC/ CAFTCH (Docetaxel/ Carboplatin/ Trastuzumab)
CEF vs. EC/T vs. AC/T
N= 2104Endpoints: RFS, OS, toxicity as assessed by
the NCI Common Toxicity Criteria and QOLInterim analysis for recurrence-free survival
(RFS) at median follow-up of 30.4 mos
Burnell, M. et. al. J Clin Oncol. 2010 January 1; 28(1): 77–82.
Results- Toxicity
Weekly vs Q3W Taxanes
N= 4950AC->Paclitaxel Q3w vs. weekly vs. Docetaxel
Q3w vs. WeeklyEndpoints
DFS OS
Exploratory Analysis Impact of treatment by HER2 status
Soprano, JA et. al. N Engl J Med 2008; 358:1663-1671.
Results
Results
More neuropathy in the paclitaxel weekly arm
Increased Neutropenia and infection in Docetaxel Q3w arm
Recurrent or metastatic disease
Recurrent or Metastatic Disease
Preferred Single Agents Doxorubicin Epirubicin Paclitaxel Docetaxel Capecitabine Gemcitabine Vinorelbine Eribulin Paclitaxel
+Bevacizumab
Preferred Combinations AC CAF/FAC FEC AT Docetaxel/ Capecitabine Gemcitabine/ Paclitaxel Trastuzumab + Other 1st
line agents Trastuzumab or
Lapatininb+Capecitabine Trastuzumab + Lapatinib
Combination Anti- HER2 Therapy
(N = 296)Lapatinib + Trastuzumab vs. Lapatinib alonePFS ( [HR] = 0.73; 95% CI, 0.57 to 0.93; P = .008)CBR (24.7% v 12.4%; P = .01) CR+PR+SD >24
weeksOS (HR = 0.75; 95% CI, 0.53 to 1.07; P = .106). ORR (10.3% v 6.9; P = .46). Most frequent ADR: diarrhea, rash, nausea, and
fatigue; diarrhea was higher in the combination arm (P = .03).
Symptomatic cardiac events was low (2% vs 0.7%)
The Role of Bevacizumab
PFS
Paclitaxel + Bev vs. Paclitaxel 11.8 vs 5.9 mos (P<0.001)
Docetaxel + Bev vs. Docetaxel 10.1 vs. 8.2 mos(P<0.006)
Ribbon-1 Bev ChemoCapecitabine+ Bev vs CapecitabineTax or Anthracycline arm combo
8.6 vs 5.7 mos (P<0.0002)9.2 vs 8.0 mos (P<0.0001)
•No Increase in OS or QOL when analyzed alone or in meta analysis•Modest increase in PFS with the greatest increase seen in combination with Paclitaxel•FDA Reversed approval in breast cancer
1Miller, K. N Engl J Med. 357:2666-2676 (2007). 2 Miles, D. Cancer Res. 69 (Suppl. 3), 495S (2009). 3 Robert, N. J. Clin. Oncol. 29, 1252–1260 (2011).
Eribulin
Microtubular inhibitor FDA approved in November 2010 for Metastatic breast cancer after 2 lines of therapy
Phase III open-label, randomized, multicenter study(n=762)
2-5 prior CT (≥2 for advanced disease), including an anthracycline and a taxane, unless contraindicated
Pts were randomized 2:1 to E 1.4 mg/m2 2-5 min IV bolus on days 1 and 8 of a 21-day cycle or treatment of physician's choice (TPC)
Endpoint: OS; ORR, PFS, DOR
Eribulin
Results of Phase III OS: 13.1 vs 10.6 mos. (HR 0.81, 95% CI 0.66 to
0.99(P=0.041) No difference in TTP Objective response rate by the RECIST criteria
was 11% (95% CI: 8.6%, 14.3%) Median response duration was 4.2 months (95%
CI: 3.8, 5.0 months) Common ADR: neutropenia, anemia,
asthenia/fatigue, alopecia, peripheral neuropathy (DLT), nausea, and constipation
Denosumab
XGEVA approval to prevent skeletal-related events in cancer patients with solid tumors and bone metastases
Human monoclonal antibody that binds to RANK ligand, a protein found on osteoclasts and involved in bone breakdown
•Randomized, double-blind, phase III clinical trial in women with bone metastases from breast cancer •Denosumab 120 mg SQ monthly vs. Zoledronic acid 4 mg IV monthly
Denosumab Results
•Non-inferiority Trial•Delayed the time to first SRE•Overall survival and progression-free survival were similar between arms
Xgeva™ (denosumab)Prescribing information. 2010.Amgen Inc.
Denosumab ADR
Severe Hypocalcemia Corrected serum calcium <7 mg/dL or < 1.75 mmol/L) -3.1% Patients with a creatinine clearance less than 30
mL/min or receiving dialysis are at greater risk of severe hypocalcemia
Severe Hypophosphatemia Serum phosphorus <2 mg/dL or < 0.6 mmol/L -15.7%
ONJ Perform an oral examination and appropriate
preventive dentistry prior to the initiation
Common ADR fatigue/asthenia, and nausea
NCCN Guidelines Version 2.2011 Invasive Breast Cancer
Denosumab Summary
Denosumab, Zoledronic acid or amidronate (all with Calcium and vitamin D) should be given in addition to Chemo or endocrine therapy if bone mets is present, expected survival is > 3 months, and renal function is adequate
3RD MOST COMMON CANCER WORLD WIDE78% OF CASES IN DEVELOPING COUNTRIES
2ND MOST FREQUENT CAUSE OF CANCER DEATH IN FEMALES
Cervical Cancer
Cervical Cancer Risk Factors
Persistent HPV most important contributing factor
SmokingParityContraceptive useEarly onset of coitusMultiple sexual partnerHistory of sexual transmitted diseaseChronic Immunosuppression
HPV and Cervical Cancer
Most common sexually transmitted virus in the US
At least 50% of sexually active people will have HPV at some point in their lives
HPV Cause epithelial proliferations at cutaneous and mucosal surfaces
20 million Americans 15- 40 years of age (15% of population)are currently infected
There are more than 100 types of the virus and about 40 types of HPV are associated with genital HPV
www.cdc.gov/HPV/cancer.html
Human Papillomavirus Types and Disease Association
nonmucosal/cutaneous(~60 types)
skin warts
(hands and feet)
mucosal/genital(~40
types)
high-risk types16, 18, 31, 45(and others)
low-risk types6, 11
(and others)
•low grade cervical abnormalities•cancer precursors•anogenital cancers
•low grade cervical abnormalities•genital warts•laryngeal papillomas
http://www.cdc.gov/vaccines/pubs/pinkbook/downloads/Slides/HPV11.ppt
HPV types and disease association
HPV-16 and HPV-18 are the most prevalent of the oncogenic types Associated with cervical, vulvar and vaginal cancers
HPV- 6 and HPV-11 "low-risk" types can cause genital warts and usually benign (abnormal but non-cancerous) changes in the cervix
The high efficacy of the vaccines may dramatically decrease cervical cancer, preventing up to 70% of newly diagnosed cases
Natural History of HPV Infection
Screening Recommendations
NCCN adopted the American College of Obstetricians and Gynecologists screening recommendations
Screening should begin at 21 years of age regardless of sexual intercourse status Every 2 years between 21 and 29 years of age
Adolescents who are immunocompromised (HIV, steroid use, post transplant, etc.) should also have cervical cytology screened
Both liquid based and conventional methods of cervical cytology are acceptable
Screening Recommendations
Combination of cytology and HPV DNA testing is appropriate for women greater than 30 years old Women who are low risk with both negative result should
be screened every 3 years HPV DNA testing is not indicated in women < 21 years old
Women 30 year and older who had 3 consecutive negative cervical cytology screening test, not immunocompromised, no history of cervical intra-epithelial neoplasia (CIN), not HIV infected, and were not exposed to DES in utero may extend the interval between cervical cytology to every 3 years
CDC Vaccines and Immunization
Contact Information
Telephone 800.CDC.INFO
Email nipinfo@cdc.gov
Website www.cdc.gov/vaccines
Screening Recommendation
Women who have been immunized against HPV-16 and HPV-18 should be screened by the same schedule as non-immunized
Annual gynecologic examination may still be appropriate even if cervical cytology is not tested at each visit
Women treated in the past or CIN, or cancer including status post hysterectomy should have annual screening for at least 20 years after surveillance
Screening Recommendation
Screening can be discontinued; In women who have had a total
hysterectomy for benign indication and have no history of high grade CIN
Women between 65 and 70 years of age and older with 3 or more negative cytology test in a row and no abnormal test in the past 10 years
HPV DNA Testing
HPV high risk DNA test- detects whether any of the 14 high risk (oncogenic) types of HPV are present, does not indicate which type is present
HPV 16/18- detects whether HPV 16 or 18 is present, used together with the HPV high-risk DNA test
Hybrid Capture 2 HPV DNA test- asses whether women are positive for any of 13 high-risk, false- positive results due to cross reactivity with non-oncogenic subtypes
HPV Vaccines
Quadrivalent HPV vaccine protect against certain types of HPV (6, 11, 16, 18)
Bivalent vaccine protects against HPV 16 and 18Vaccine most effective if started before
intercourse FDA approved for 9- 26 and 10 – 25 year old
females respectively to prevent cervical cancer and precancerous lesions due to HPV
Not clear how long immunity is present after vaccination, data suggest 5- 10 years
Diagnosis of Cervical cancer
Diagnosis often from cervical cytology, PAP smears and biopsies (Conization used to determine invasiveness)
Colposcopy, and colposcopy directed biopsies is the primary method for evaluating abnormal cervical cytology
CT scans, MRI, PET-CT and surgical staging are used to guide treatment
Cervical Cancer Staging
Cervical Cancer Treatment
Surgery for lower stage disease Observation is appropriate for lower stage (IA2, IB1,
IIA1) and no risk factors and negative nodes Adjuvant XRT indicated if large primary tumor, LVSI, deep
stromal invasion, +LN, +Sx Margins, and + parametrium
Chemo-radiation for higher stages or patients who are not candidates for hysterectomy Cisplatin based chemotherapy Chemo/XRT have shown a 30-50% decrease in risk of
death compared to XRT alone 3 trials have shown improved PFS and OS with
Chemo/XRT
Treatment Continued
Metastatic Disease Surgical resection +/- IORT Radiation +/- Chemo Chemotherapy (Cisplatin Based)
GOG 169
N= 264Cisplatin+ Paclitaxel vs Cisplatin aloneRR= 36% vs 19%PFS= 4.8 mos vs 2.8 os (P= 0.001)
GOG 179
n= 294Randomized Phase III trialCisplatin + Topotecan vs CisplatinRR 27% vs 13% (P=0.004)PFS 4.6 mos vs 2.9 mos (P=0.014)Median survival 9.4 mos vs 6.5 mos (P= 0.017)Increase marrow suppression but no decrease
in QOLFirst study to show survival advantage over
single agent cisplatin
GOG 204
N= 513 Women with advanced (stage IVB), recurrent, or persistent cervical cancer
Cis/ Topotecan, Cis/ Gemcitabine, Cis/Vinorelbine, vs Cis/ Paclitaxel
Survival was the primary end point with a 33% improvement relative to PC considered
importantClosed early due to non-superiority of other
regimens
Monk BJ et al. Phase III Trial of Four Cisplatin-Containing Doublet Combinations in Stage IVB, Recurrent, or Persistent Cervical Carcinoma: A Gynecologic Oncology Group Study. J Clin Oncol 2009; 27:4649-4655.
GOG 204 Results
Monk BJ et al. J Clin Oncol 2009; 27:4649-4655.
GOG 204
Advantage seen in women of Hispanic origin and in recurrent disease PFI of 30+ months
Monk BJ et al. J Clin Oncol 2009; 27:4649-4655.
Cervical Cancer Surveillance
Based on NCCN consensusCervical cytology Q3- 6 mos x 2 years, then
Q6 mos for 3- 5 years, then annuallyCareful surveillance due to increased risk for
secondary cancers at and near radiated sites
Role of a pharmacist
Drug Interaction screening Complementary and Alternative Medications can be
prevalent in cancer patients
Supportive Care Pain Management Anti-coagulation Monitoring Side Effect Management
Compliance and Adherence Monitoring Increased use of oral chemotherapy medications Endocrine therapies
The role of a pharmacist
Patient education on where to get additional information American Cancer Society www.cancer.org National Cancer Institute www.cancer.gov National Comprehensive Cancer Network
www.nccn.com Center for Disease Control and Prevention www.cdc.gov
Patient Assistance Programs NeedyMeds www.needymeds.com RxAssist www.rxassist.org Prior Authorizations or recommending therapeutic
substitutions to maximize benefits
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