Download Cervical Cancer

Cervical Cancer
Kelley Ratermann, PharmD
Hematology/Oncology Clinical Pharmacist
2
Objectives
• Identify risk factors of this disease.
• Understand the importance of screening
and prevention.
• Understand the staging process of
cervical cancer.
• Evaluate individual patients and select
the most appropriate treatment
option(s).
3
Case 1
• Miley C. is a 13 YOF that just transitioned from middle
school to junior high. Her pediatrician proposes
Gardasil administration during her annual wellness
check. As her parent, when do you feel it is appropriate
for Miley to receive this vaccine?
A.
B.
C.
D.
When she becomes sexually active
Before the age of 26
She should definitely receive the first dose now
Never, that’s an invitation for promiscuous sexual
activity
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Overview of Female Malignancies
• The Global Burden of Disease 2000 Study
BMC Cancer. 2002 Dec 26;2:37.
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http://www.cdc.gov/uscs
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Cervical Cancer Epidemiology
5 year survival = 68%
12,900
4,100
http://seer.cancer.gov/statfacts/html/cervix.html
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Risk by Age
Median Age at Diagnosis = 49 yrs
http://seer.cancer.gov/statfacts/html/cervix.html
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Cervical CA
Stage and
Survival
Screening and
Early Detection
is KEY!!!!!
http://seer.cancer.gov/statfacts/html/cervix.html
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Epidemiology
• Estimated 12,360 new cases in 2014
▫ 4,020 deaths
• Annual pap smears in the US: 50-60 million
▫ 3.5 million abnormal
▫ 2.5 million undergo colposcopy
• Ranked 13th in cancer deaths of women
▫ 2nd most common malignancy in women 20-39 yo
• Nearly 70% reduction over past 5 decades
CA Cancer J Clin. 2014;64(1):9.
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Decreasing Mortality
Prevention
Early
Detection
Treatment
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Decreasing Cervical Cancer
Mortality
• Minimize HPV exposure risks
• Minimize persistent HPV via vaccine
• Screen +/- remove precancerous cells
• Catch and treat cervical cancer early
12
Risk Factors
• HPV
▫ Number of sexual
partners
▫ Partner’s number of
sexual partners
▫ Early age of first
sexual intercourse
• Cervical Cancer
▫ Genital HPV
infection
▫ High parity
▫ Cigarette smoking
▫ Early oral contraceptive
use
▫ Poor diet - Vitamin A or
C deficiency
▫ Low socioeconomic class
Int J Cancer 2006; 118(12):3030–3044.
Ho GY. N Engl J Med.1998; 338 :423 –428
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Pathology
~15 years
There are four major steps in cervical
cancer development
1. Oncogenic HPV infection
2. Persistence of the HPV infection
3. Progression of a clone of epithelial
cells
4. Development of carcinoma and
invasion through the basement
membrane
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http://gtbinf.wordpress.com/2013/11/09/42
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HPV
• The majority of cervical
cancer contain HPV DNA
▫ 93-100%
• Oncogenic types HPV
types 16 and 18 (> 70%)
• 5-year survival rates
correspond with HPV
subtype
• E6 and E7 oncoproteins
▫ Effect on cell cycle,
association with RB, p53
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Prevention
• Avoiding risk factors
▫ STOP smoking
▫ Decrease number of sexual partners
▫ Delay onset of intercourse
• Vaccination
▫ CDC recommends for girls age 11 or 12
(allows to begin at age 9)
▫ Give for ages 13-26 if previously not
vaccinated/did not complete series
Lancet Oncol. 2005 May;6(5):271-8.
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Vaccine Data
• FUTURE I Trial (no exposure)
▫ 5,500 women ages 16-24 randomized
▫ Vaccine 100% effective in women with no
exposure
• FUTURE II Trial (previously exposed)
▫ 12,100 women ages 15-26 randomized
▫ Vaccine reduced rates of all cervical lesions,
regardless of previous HPV exposure
• Led to approval of Gardasil in June of 2006
Br J Cancer. 2006 Dec 4;95(11):1459-66.
Lancet Oncol. 2005 May;6(5):271-8.
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Gardasil
• Quadrivalent HPV vaccine
▫ Types 6, 11, 16, 18
• Indicated in females 9 – 26 yo
▫ AND males
• Administration
▫ 3 IM injections at 0, 2, and6 months
▫ Cost: ~$145/dose (CDC)
• Continue to follow screening guidelines
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Cervarix
• Bivalent HPV vaccine (types 16, 18)
• Indicated in females age 10 - 25
• Administration
▫ 3 IM injections at 0, 1, and 6 months
▫ Cost ~$130/dose (Am. Cancer Society)
• Continue to follow screening guidelines
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Vaccination Unknowns
• Duration of efficacy (7 and 9 yrs)
▫ What if you don’t get all three shots?
• Optimal age for vaccination
• Cost effectiveness of widespread
vaccination
▫ Treatment abnormal pap smears
rather than upfront vaccine
www.npr.org/2011/09/19/140543977/hpv-vaccine-the-sciencebehind-the-controversy
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Screening
• Annually for life if risk factors present
• Annually for life if personal hx cervical
cancer or HIV+
• May stop if:
▫ TAH/BSO including removal of cervix
(unless for tx of cervical cancer)
▫ Women >70 yo with intact cervix
 > 3 consecutive, normal cervical cytology
tests within previous 10yrs
http://www.cancer.org/cancer/news/new-screening-guidelines-for-cervical-cancer
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Pap(anicolaou) Smear
• Only ~6% abnormal
• Shown to decrease
morbidity/mortality
• Sensitivity from single
test (55-80%)
▫ High false negative rate
• Repeated tests improve
sensitivity
• Part of OC prescribing,
but direct link is missing
Ann Intern Med 132 (10): 810-9, 2000.
Acta Cytol 35 (1): 8-14, 1991 Jan-Feb.
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Back to Miley C…
• You read in US Weekly that Miley recently
went on a bender and had sexual intercourse
with several individuals. She asks, “for a
friend,” about cervical cancer risk after an
abnormal pap smear.
• What questions do you need to ask to help
her understand her risk?
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Grading of Cervical Cancer
http://www.jci.org/articles/view/28607/figure/2
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Histology and HPV
Squamous (69%)
• HPV 16 – 59%
• HPV 18 – 13%
• HPV 58 – 5%
• HPV 33 – 5%
• HPV 45 – 4%
Adenocarcinoma
(25%)
• HPV 16 – 36%
• HPV 18 – 37%
• HPV 45 – 5%
• HPV 31 – 2%
• HPB 33 – 2%
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Abnormal Findings
0.15% cancer
1.14% cancer
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Miley C’s report says ASC-US
• What is this and what does it mean?
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Bethesda System of Reporting
• ASC–US—atypical squamous cells of
undetermined significance
• ASC-H - atypical squamous cells; cannot exclude a
high-grade squamous intraepithelial lesion
• LSIL—low-grade squamous intraepithelial lesion
• HSIL—high-grade squamous intraepithelial lesion
• AGC—atypical glandular cells
• AIS—endocervical adenocarcinoma in situ
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Treatment Based on Pap
Smear Results
Pap Test
Result
Tests and/or treatments may include
ASC-US
HPV testing - Repeat Pap test - Colposcopy and biopsy
ASC-H
Colposcopy and biopsy
AGC
Colposcopy and biopsy and/or endocervical curettage
AIS
Colposcopy and biopsy and/or endocervical curettage
LSIL
Colposcopy and biopsy
HSIL
Colposcopy and biopsy and/or endocervical curettage
Further treatment with LEEP, cryotherapy, laser
therapy, conization, or hysterectomy
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Colposcopy and Endocervical
Curettage
• Primary method of evaluating women with
abnormal Pap tests
▫ Exam allowing the cervix to be viewed through a
microscope
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Miley’s new symptoms
• About 10 years later – Miley comes in and
is asking about some new mild symptoms:
abnormal vaginal discharge, spotting after
intercourse, and mild pelvic pain.
• Are these consistent w/ cervical cancer?
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Clinical Presentation and
Diagnosis
Symptoms
Diagnostics
• Often asymptomatic
(Screening)
• Vaginal discharge
• Postcoital
spotting/bleeding
• Pelvic pain
• Flank pain
• Weight loss
• Incontinence
• Signs/Symptoms
• Tissue required for
diagnosis
▫ Pap smear
▫ Colposcopy
▫ Endocervical
curettage (ECC)
▫ Conization
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Conization
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Prognostic Factors
• Stage (Primary prognostic guide)
▫ Size of primary tumor
▫ Presence of lymph node metastases
• Other High Risk Features
▫ Lymph-vascular invasion
▫ Tumor grade - poorly differentiated is
worse
Cancer 67 (11): 2776-85, 1991.
JAMA 262 (7): 931-4, 1989.
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Simplified Staging
NCCN Guidelines. Cervical Cancer. V1.2014.
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Miley C’s follow-up
• MC is diagnosed w/ stage IB cervical
cancer.
• How does this compare to most women?
• What is her prognosis?
• What treatment should she receive?
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Stage IB
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Treatment Options
• Surgery
▫ Hysterectomy +/- lymph node sampling
(no sampling if depth < 3mm – negative
margins)
• Radiation (non-surgical candidates)
▫ External beam (invasion > 3 mm)
▫ Brachytherapy
• Chemotherapy (with or without XRT)
• Multimodality treatment is common
NCCN Guidelines. Cervical Cancer. V1.2014.
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Early Stage Treatment
Stage
•0
•I
• IIA
Intervention
Local surgical removal
Hysterectomy +/- lymph node sampling or
radiation*
Hysterectomy + lymph node sampling or
radiation +/- chemotherapy*
*MC’s stage = High Risk Patients (tumor > 4
cm or + lymph nodes or + margins) should
receive adjuvant chemotherapy and radiation
NCCN Guidelines. Cervical Cancer. V1.2014.
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Locally Advanced Treatment
Stage
Intervention
IIB
Radiation therapy plus
chemotherapy
Radiation therapy plus
chemotherapy
Radiation therapy plus
chemotherapy
III
IVA
NCCN Guidelines. Cervical Cancer. V1.2014.
42
Treatment of Stage IIB, III,
and IVA
• Radiation is the primary treatment
▫ Whole pelvis radiation therapy
▫ Brachytherapy
• Chemosensitization
▫
▫
▫
▫
▫
▫
▫
▫
Reduces the risk of death by 6% and increases PFS by 8%
Cisplatin monotherapy*
Cisplatin + 5-FU
Paclitaxel
Mitomycin
Hydroxyurea
Bleomycin
Carboplatin
J ClinOncol2008; 26:5802-12
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Cisplatin
• Cisplatin is cornerstone of therapy – several
regimens used
• GOG 1235
▫ Concurrent chemo and XRT >> than sequential
• GOG 1203
▫ Cisplatin 40 mg/m2 IV weekly x 6 with XRT*
• SWOG 87974/GOG 851
▫ Cisplatin 75 mg/m2 IV day 1 with XRT and 5FU 1
gram/m2/day day 1-5
▫ Repeat every 3 weeks
*Recommended
NCCN Guidelines. Cervical Cancer. V1.2014.
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Metastatic Disease (IVB)
Treatment
• Cure is not achievable
• Goal is palliation
• No standard of care
• Local radiation may help with palliation
• CLINICAL TRIALS
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Treatment: Metastatic disease
• Palliative Radiation
• Chemotherapy:
▫ Cisplatin (15%-25% response rate)
▫ Ifosfamide (31% response rate)
▫ Paclitaxel (17% response rate)
▫ Ifosfamide-cisplatin (31% response rate)
▫ Irinotecan (21% response rate in patients
previously treated with chemotherapy)
▫ Paclitaxel/cisplatin (46% response rate)
▫ Cisplatin/gemcitabine (41% response rate)
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Cervical Cancer
Stage 0/I*
Stage IIB-IVA
Stage IVB
Surgery
no adjuvant
Radiation +
chemotherapy
Palliative
therapy
Recurrent Disease
Radiation with chemotherapy and/or surgery
* High risk stage I (i.e., IB) should receive adjuvant therapy
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Conclusions
• Prevention
▫ Behavioral changes
▫ HPV vaccine
• Screening, screening, screening…
• Outcome related to clinical stage
• Multimodality approach
• Chemotherapy
Chemotherapy in advanced disease does
not change overall survival of patients
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Questions?