CERVICAL

CANCER
APT. HESTY UTAMI, M.CLIN.,PHD
OVERVIEW

Etiology
Epidemiology
Pathophysiology
Risk Factors
Diagnosis
Staging
Treatment
Vaccination
ETIOLOGY
• Cervical cancer results from genital infection with
HPV, which is a known human carcinogen
• Although HPV infections can be transmitted via
nonsexual routes, the majority result from sexual
contact.
• HIV infection is associated with a 5-fold increase
in the risk of cervical cancer, presumably because
of an impaired immune response to HPV
infection.
• Exposure to diethylstilbestrol in utero has been
associated with an increased risk of cervical
intraepithelial neoplasm (CIN) grade 2 or higher
• HPV comprises a heterogeneous group of viruses that contain closed circular
double-stranded DNA.
• The viral genome encodes 6 early open reading frame proteins (ie, E1, E2, E3,
E4, E6, and E7), which function as regulatory proteins, and 2 late open reading
frame proteins (ie, L1 and L2), which make up the viral capsid.
• To date, more than 115 different genotypes of HPV have been identified and
cloned.
• A large multinational cervical cancer study found that more than 90% of all
cervical cancers worldwide are caused by 8 HPV types: 16, 18, 31, 33, 35, 45,
52, and 58.
• Three types—16, 18, and 45—cause 94% of cervical adenocarcinomas. HVP
type 16 may pose a risk of cancer that is an order of magnitude higher than that
posed by other high-risk HPV types.
• The HPVs that infect the human cervix fall into 2 broad risk categories. The low-
risk types (eg, HPV 6 and 11) are associated with condylomata and a very small
number of low-grade squamous epithelial lesions (SILs) but are never found in
invasive cancer. The high-risk types (eg, HPV 16) vary in prevalence according
to the cervical disease state.
EPIDEMIOLOGY
• Cervical cancer is the third most common malignancy in women worldwide.
• The frequency varies considerably between developed and developing countries, however:
Cervical cancer is the second most common cancer in developing countries, but only the
tenth most common in developed countries.
• Similarly, cervical cancer is the second most common cause of cancer-related deaths in
women in developing countries but is not even among the top 10 causes in developed
countries
• In the United States, cervical cancer is relatively uncommon. The incidence of invasive
cervical cancer has declined steadily in the US over the past few decades; for example, since
2004, rates have decreased by 2.1% per year in women younger than 50 years and by 3.1%
per year in women 50 years of age and older. This trend has been attributed to mass
screening with Pap tests and HPV vaccination.
• Cervical cancer rates continue to rise in many developing countries.
CERVICAL CA RISK FACTORS
• Early age of intercourse
• Number of sexual partners
• Smoking
• Lower socioeconomic status
• High-risk male partner
• Other sexually transmitted disease
CERVICAL CA SYMPTOMS:
• Abnormal vaginal bleeding
• Vaginal discomfort
• Malodorous discharge
• Dysuria
PATHOPHYSIOLOGY
• Human papillomavirus (HPV) infection must be present for cervical cancer to occur. HPV
infection occurs in a high percentage of sexually active women.
• However, approximately 90% of HPV infections clear on their own within months to a few
years and with no sequelae, although cytology reports in the 2 years following infection may
show a low-grade squamous intraepithelial lesion.
• On average, only 5% of HPV infections will result in the development of CIN grade 2 or 3
lesions (the recognized cervical cancer precursor) within 3 years of infection. Only 20% of
CIN 3 lesions progress to invasive cervical cancer within 5 years, and only 40% of CIN 3
lesions progress to invasive cervical cancer within 30 years.
• Because only a small proportion of HPV infections progress to cancer, other factors must be
involved in the process of carcinogenesis. The following factors have been postulated to
influence the development of CIN 3 lesions:
➢ The type and duration of viral infection, with high-risk HPV type (e.g. HPV 16,18,45) and
persistent infection predicting a higher risk for progression; low-risk HPV types (e.g HPV 6,
11) do not cause cervical cancer
➢ Host conditions that compromise immunity (eg, poor nutritional status, immunocompromise,
and HIV infection)
➢ Environmental factors (eg, smoking and vitamin deficiencies)
➢ Lack of access to routine cytology screening
• In addition, various gynecologic factors significantly increase the risk of HPV infection. These
include early age of first intercourse and higher number of sexual partners.
 GENETIC SUSCEPTIBILITY
• Genetic susceptibility to cervical cancers caused by HPV infection has been identified via
studies of twins and other first-degree relatives, as well as genome-wide association studies.
• Women who have an affected first-degree biologic relative have a 2-fold relative risk of
developing a cervical tumor compared with women who have a nonbiologic first-degree
relative with a cervical tumor.
• Genetic susceptibility accounts for fewer than 1% of cervical cancers.
• Genetic changes in several classes of genes have been linked to cervical cancer. Tumor
necrosis factor (TNF) is involved in initiating the cell commitment to apoptosis, and the
genes TNFa-8, TNFa-572, TNFa-857, TNFa-863, and TNF G-308A have been associated
with a higher incidence of cervical cancer.
• Polymorphisms in another gene involved in apoptosis and gene repair, Tp53, have been
associated with an increased rate of HPV infection progressing to cervical cancer.
 HPV DIAGNOSIS – PAP SMEAR
Normal, ASCUS – Atypical Squamous Cells of Unclear Significance
 HPV PAP SMEARS
Pap smear:
Normal
ASCUS – atypical cells of unclear significance:
repeat Pap vs test for HPV DNA
LGSIL – low grade squamous intra-epithelial lesion:
colposcopy with biopsy
HGSIL – high grade squamous intra-epithelial lesion:
colposcopy with biopsy and treat

Cervical biopsy:
CIN I – mild dysplasia – usually spontaneously regresses
CIN II – moderate dysplasia - treat
CIN III – severe dysplasia – treat
Carcinoma – in-situ – treat
Invasive cervical cancer – treat
COLPOSCOPY
 CERVICAL CANCER
SCREENING METHODS

HPV DNA Testing for questionable cases:

• Normal PAP smear - usual follow up

• ASCUS - may be cost-effective

• LGSIL - most regress

• HGSIL - refer for colposcopy and biopsy

 CERVICAL CANCER
SCREENING METHODS
HYBRID CAPTURE II (HCII) or PCR

Collect a cervical swab for DNA testing from all women

and store them

HCII – positive for high-risk HPV – then refer to colposcopy

negative for high-risk HPV – then routine yearly screening

 HYBRID
CAPTURE II
DIAGNOSIS: PHYSICAL EXAMINATION
• In patients with early-stage cervical cancer, physical examination findings can be relatively
normal. As the disease progresses, the cervix may become abnormal in appearance, with
gross erosion, ulcer, or mass. These abnormalities can extend to the vagina. Rectal
examination may reveal an external mass or gross blood from tumor erosion.
• Pelvic examination findings often reveal pelvic or parametrial metastasis. If the disease
involves the liver, hepatomegaly may develop. Pulmonary metastasis usually is difficult to
detect on physical examination unless pleural effusion or bronchial obstruction becomes
apparent. Leg edema suggests lymphatic or vascular obstruction caused by tumor.
 DIAGNOSIS
• Complete evaluation starts with Papanicolaou (Pap) testing. Positive results should prompt
colposcopy and biopsies with further workup of cervical intraepithelial neoplasia (CIN),
including excisional procedures.
• If pathologic evaluation suggests invasive cancer with positive margins, the patient should be
referred to a gynecologic oncologist. Patients with suspicious or grossly abnormal cervical
lesions on physical examination should undergo biopsy regardless of the cytologic findings.
• Once the diagnosis is established, a complete blood count (CBC) and serum chemistries for
renal and hepatic function should be ordered to look for abnormalities from possible
metastatic disease, and imaging studies should be performed for staging purposes.
• Cystoscopy and proctoscopy should be performed in patients with a bulky primary tumor to
help rule out local invasion of the bladder and the colon.
• More complex radiologic imaging studies are often done to guide the choice of therapeutic
options. These may include computed tomography (CT), magnetic resonance imaging (MRI),
and positron-emission tomography (PET)
STAGING
There are 2 major staging systems that are frequently used in cervical cancer :
• The FIGO system, developed in collaboration with the World Health Organization (WHO)
• The TNM system, developed by the International Union Against Cancer (UICC) and the
American Joint Committee on Cancer (AJCC)
PROGNOSIS
• The prognosis in patients with cervical cancer depends on the disease stage. In general, the
5-year survival rates are as follows:
❖ Stage I - Greater than 90%
❖ Stage II - 60-80%
❖ Stage III - Approximately 50%
❖ Stage IV - Less than 30%
TREATMENT
The treatment of cervical cancer varies with
the stage of the disease.

For early invasive cancer, surgery is the

treatment of choice.

In more advanced cases, radiation combined

with chemotherapy is the current standard of
care.

In patients with disseminated disease,

chemotherapy or radiation provides symptom
palliation
TREATMENT RECOMMENDATION:
STAGE IA1
• Primary treatment of stage IA1 cervical
cancer depends on the results of cone biopsy
and whether the patient wishes to preserve
her fertility.
• For patients who desire fertility preservation
and have negative margins on cone biopsy (3
mm) and no evidence of lymphovascular
invasion, observation may be an option.
• Surgical options for all other individuals may
include trachelectomy, pelvic lymph node
dissection, sentinel lymph node
mapping, and simple hysterectomy.
TREATMENT
RECOMMENDATION:
STAGE IA2

• For patients who wish to preserve their fertility,

radical trachelectomy and pelvic lymph node
dissection is recommended
• For medically operable patients who do not desire
fertility preservation, radical hysterectomy and
bilateral pelvic lymph node dissection with or
without para-aortic lymph node sampling is
recommended; radiation therapy may also be an
option in select cases.
• Pelvic beam radiation with brachytherapy is a
treatment option for patients who are medically
inoperable or who refuse surgery.
TREATMENT RECOMMENDATION: STAGE IB AND IIA

• Patients with stage IB or IIA disease can be treated with surgery, radiation therapy, or
concurrent chemoradiation, depending on the stage and bulk of their disease
• Primary surgery consists of radical hysterectomy plus bilateral pelvic lymph node dissection
with or without para-aortic lymph node sampling (for tumors < 2 cm)
• If lymph nodes are positive, then a hysterectomy is not recommended; instead, the patient
should receive chemoradiation.
• Patients with stage IB or IIA may also be given pelvic radiotherapy and brachytherapy with
(or without) concurrent cisplatin-based chemotherapy . The addition of concurrent
cisplatin-containing chemotherapy has been shown to improve survival
• Cisplatin 40 mg/m 2 IV once weekly plus radiation therapy, 1.8-2 Gy daily per fraction, for
six cycles or
• Cisplatin 50-75 mg/m 2 IV on day 1 plus 5-flurouracil (5-FU) 1000 mg/m 2 continuous IV
infusion over 24 h on days 1-4 (total dose 4000 mg/m 2 each cycle) every 3 wk plus radiation
therapy, 1.8-2.0 Gy daily, for a total of three to four cycles
TREATMENT RECOMMENDATIONS FOR ADVANCED STAGE:
IIB, IIIA, IIIB & IVA

• Traditionally, advanced disease includes stages IIB-IVA; however, many oncologists now also
include patients with IB2 and IIA in the advanced disease category
• Radiologic imaging studies (including PET/CT) are recommended for stage IB2 or greater
disease, especially for evaluation of nodal or extrapelvic tumors
• Treatment recommendations for advanced disease include concomitant chemoradiation
and brachytherapy
• Cisplatin 40 mg/m2 IV once weekly (not to exceed 70 mg/wk) plus radiation therapy 1.8-2
Gy per fraction (minimum 4 cycles; maximum 6 cycles) for a total of 45 Gy or
• Cisplatin 50-75 mg/m2 IV on day 1 plus 5-fluorouracil (5-FU) 1000 mg/m2 continuous IV
infusion over 24 h on days 1-4 (total dose 4000 mg/m2 each cycle) every 3 wk for a total of
three or four cycles; plus radiation therapy, 1.8-2 Gy per day for a total for 45 Gy or
• Cisplatin 40 mg/m2 IV once weekly and gemcitabine 125 mg/m2 weekly for 6 weeks with
concurrent radiation therapy for total of 50.4 Gy in 28 fractions, followed by brachytherapy
30 to 35 Gy in 96 hours, and then two adjuvant 21-day cycles of cisplatin, 50 mg/m2 on day
1, plus gemcitabine, 1000 mg/ m2 on days 1 and 8
TREATMENT RECOMMENDATIONS FOR METASTATIC DISEASE:
STAGE IVB

• Patients with metastatic disease are primarily treated with cisplatin-based

chemotherapy
• Individualized radiation therapy can be considered for control of pelvic
disease and other symptoms
• Combination of platinum-based regimens are preferred over single agents in
the setting of metastatic disease
FIRST-LINE THERAPY FOR STAGE IV RECURRENT OR METASTATIC DISEASE :
• Bevacizumab 15 mg/kg IV over 30-90 min on day 1 plus cisplatin 50 mg/m2 IV over
60 min on days 1 or 2 plus paclitaxel 175 or 135 mg/m2 IV over 3 h or 24 h on day 1
every 3 wk OR
• Bevacizumab 15 mg/kg IV over 30-90 min plus paclitaxel 175 mg/m2 IV over 3 h on
day 1 plus topotecan 0.75 mg/m2 IV over 30 min on days 1-3 every 3 wk OR
• Paclitaxel 135 mg/m2 IV over 24 h on day 1 (dosing at 175 mg/m2 IV over 3 h on
same day as cisplatin is also acceptable) followed by cisplatin 50 mg/m2 IV on day 2
every 3 wk OR
• Paclitaxel 175 mg/m2 IV over 3 h followed by carboplatin on day 1 every 3 wk for
patients who received prior cisplatin therapy
• Other combinations—including cisplatin/topotecan, carboplatin/paclitaxel, and
topotecan/paclitaxel—can also be considered for appropriate individuals
• Cisplatin is generally the most active agent and may be used as first-line single
agent chemotherapy for recurrent or metastatic cervical cancer.
SECOND-LINE THERAPY FOR STAGE IV RECURRENT OR METASTATIC
DISEASE:
• Docetaxel
• Ifosfamide
• 5-FU
• Mitomycin
• Irinotecan
• Pemetrexed
• Gemcitabine
• Albumin-bound paclitaxel
• Vinorelbine
• Pembrolizumab
• Topotecan
 CISPLATIN
• Cisplation is one of alkylating chemotherapy agents
• Alkylating chemotherapy agents inhibit cell growth and proliferation. They inhibit DNA
synthesis through the formation of DNA cross-links.
• Cisplatin is used in combination with radiation therapy
Monitor

• Complete blood count (CBC); audiometric testing before each dose

Dosing Considerations
• Pretreatment hydration: 1-2 L fluid infused for 8-12 hr before dose
• 75-100 mg/m² IV q4Weeks when used with cyclophosphamide or 100 mg/m² IV
q4Weeks as single agent
• May use concomitant amifostine to decrease nephrotoxicity
• Do not repeat course until SCr <1.5 mg/dL [<133 micromoles/L] or BUN <25 mg/dL
[<8.93 mmol/L] or WBC >4000/mm³ AND platelets >100,000/mm³
Renal Impairment
• CrCl 10-50 mL/min: Decrease dose by 25%
• CrCl <10 mL/min: Administer 50% of dose
Pharmacokinetics

• Half-life elimination: up to 47 days

• Protein bound: >90%
• Excretion: Urine (90%); feces (10%)
• Clearance: 15 L/hr/m²
• Vd: 11 L/m²
Common adverse effects
• Nausea (76-100%)
• Vomiting (76-100%)
• Nephrotoxicity (28-36%)
• Ototoxicity, especially in children (31%)
• Myelosuppression (25-30%)
• Anaphylaxis (1-20%)
• Alopecia
 IFOSFAMIDE (ALKYLATING ANTINEOPLASTIC AGENT)
Mechanism of Action

• Synthetic analog of cyclophosphamide; cross-links DNA strands; inhibits DNA synthesis and protein synthesis
Administration

• Use concomitant mesna (20% of the ifosfamide dose 15 min before, 4hr after, and 8 hr after ifosfamide) to
prevent hemorrhagic cystitis
• Maintain oral or IV hydration >2 L fluid/day before & for 72 hr after therapy is recommended
• Slow IV infusion over 30 min, or continuous infusion over 5 d
Monitor: CBCs
Renal Impairment

• Dose adjustments not described in package insert; some clinicians have used the following guidelines
• CrCl >60 mL/min: 100% of regular dose
• CrCl 30-60 mL/min: 75% of regular dose
• CrCl 10-30 mL/min: 50% of regular dose
• CrCl <10 mL/min: Not recommended
Adverse Effects (frequency >10%)
• Alopecia (83%)
• Nausea (58%)
• Vomiting (58%)
• Leukopenia (50%)
• Hematuria (46%)
• Metabolic acidosis (31%)
• Thrombocytopenia (20%)
• CNS toxicity (12%)
• Neurotoxicity (10-20%)
Adverse effects (frequency 1-10%)

• Infection (8%)
• Nephrotoxicity (6%)
 FLUOROURACIL
• Antimetabolite antineoplastic agents inhibit cell growth and proliferation. They interfere with DNA
synthesis by blocking the methylation of deoxyuridylic acid.
• Fluorouracil is a pyrimidine antimetabolite. Several mechanisms of action have been proposed,
including inhibition of thymidylate synthase and inhibition of RNA synthesis. This agent is also a
potent radiosensitizer.
Pharmacology
• Half-Life: 16 min
• Onset: 2-7 d, but may take up to 12 wk
• Duration: 24 hr
• Metabolites: urea, fluorouracil, dihydrofluorouracil, expired CO2 metabolite
• Excretion: urine
Pharmacogenomics

• Dihydropyrimidine dehydrogenase (DPD), an enzyme encoded by the DPYD gene, is the rate-
limiting step in pyrimidine catabolism and deactivates >80% of 5FU standard doses and the 5FU
prodrug capecitabine
• Contraindicated in patients with DPD deficiency; causes severe toxicity with conventional doses
(ie, grade III/IV toxicity and potentially fatal neutropenia, mucositis, and diarrhea)
• IV Administration
• Direct IV push injection (50 mg/mL solution needs
no further dilution) or by IV infusion
• Toxicity may be reduced by giving the drug as a
constant infusion
• Bolus doses may be administered by slow IVP or
IVPB
• Warm to body temperature before using IV Piggyback
• Continuous IV infusion may be administered in D5W
or NS
• Solution should be protected from direct sunlight
• 5-FU may also be administered intra-arterially or
intra-hepatically

IV Push
Common Adverse Effects
• Loss of appetite
• Headache
• Nausea
• Vomiting
• Diarrhea
• Mucositis
• Myelosuppression
• Alopecia
• Photosensitivity
• Hand-foot syndrome
• Maculopapular eruption (pruritic)
 PACLITAXEL (TAXOL)

• It is one of antimicrotubular antineoplastic agents

• The mechanisms of action of paclitaxel are tubulin polymerization and microtubule
stabilization. This agent also participates in the breakage of chromosomes and modulation of
immune response.
Pharmacokinetics

• Protein bound: 89-98%

• Vd: 227-688 L/m²
• Metabolism: Metabolized by CYP2C8, CYP3A4
• Metabolites: 6-alpha-hydroxypaclitaxel (major)
• Half-life elimination: 27hr
• Excretion: Feces & urine
IV Administration

• Irritant
• Recommended administration is over 1-24 hr
• Administer taxane derivatives before platinum derivatives (cisplatin, carboplatin) in sequential
infusions to limit myelosuppression and to enhance efficacy
• Administer corticosteroids, H1-antagonists, H2 antagonists (antihistamines), prior to paclitaxel
administration to minimize potential for anaphylaxis
• Non-PVC tubing should be used to minimize leaching
• Adverse Effects (>10%)
• Neutropenia (78-100%)
• Alopecia (55-96%)
• Anemia (47-96%)
• Arthralgia/myalgia (93%)
• Diarrhea (90%)
• Leukopenia (90%)
• Nausea/vomiting (9-88%)
• Opportunistic infections (76%)
• Peripheral neuropathy (42-79%)
• Thrombocytopenia (4-68%)
• Mucositis (5-45%)
• Hypersensitivity (2-45%)
• Renal impairment (34%)
• Hypotension (17%)
Adverse effect (1-10%)

• Bradycardia (3%)
 TOPOTECAN
• Topoisomerase Inhibitors
• Topotecan inhibits topoisomerase I, inhibiting DNA replication. It acts in the S phase of the cell
cycle.
• Indicated for combination therapy with cisplatin for stage IV-B, recurrent or persistent cervical
carcinoma which cannot be treated with surgery and/or radiation therapy
• Dosing 0.75 mg/m² IV infused over 30 min on Days 1,2, & 3 (with cisplatin 50 mg/m² on Day
1); repeat at 21-day cycles
Dosing Considerations

• Verify dose using body surface area prior to dispensing

• Recommended dosage should generally not exceed 4 mg IV
• Prior to administration of the first treatment course, baseline counts for neutrophils should be
>1,500/mm³ and platelets >100,000/mm³
• Monitor: CBC
 DOSING CONSIDERATION IN RENAL IMPAIRMENT

• IV infusion (monotherapy)
o Mild (CrCl 40-60 mL/min): No dosage adjustment necessary

o Moderate (CrCl 20-39 mL/min): Decrease dose to 0.75 mg/m² qDay

o Severe (CrCl <20 mL/min): Safety and efficacy has not been established
• Capsules
o CrCl 30-49 mL/min: Decrease dose to 1.5 mg/m² PO day

o CrCl <30 mL/min: 0.6 mg/m² PO Day

o Dose may be increased after first course by 0.4 mg/m²/day if no severe hematologic or
gastrointestinal toxicities occur
 DOSING CONSIDERATION
IN HEMATOLOGIC TOXICITIES

• Do not administer subsequent courses of until neutrophils recover to >1,000 cells/mm³, platelets recover to >100,000 cells/mm³,
hemoglobin levels recover to ≥9.0 g/dL (with transfusion if necessary)

• IV infusion (monotherapy)
o Neutrophil count <500 cells/mm³: Reduce dose to 1.25 mg/m² alternatively, granulocyte-colony stimulating
factor (G-CSF) starting no sooner than 24 hours after topotecan administration has been completed

o Platelet count < 25.000 cells/mm³ during previous cycle: Reduce dose to 1.25 mg/m²
• Combination therapy with cisplatin
o Severe neutropenia (neutrophil counts <1,000 cells/mm³ with temperature of ≥38.0°C (100.4°F)): Reduce
dose to 0.60 mg/m² (and further to 0.45 mg/m² if necessary); alternatively, G-CSF starting no sooner than
24 hours after topotecan administration has been completed

o Platelet count <25.000 cells/mm³: Reduce dose to 0.60 mg/m² (and further to 0.45 mg/m² if necessary)
IN DIARRHEA (CAPSULE ONLY)

• Do not administer to patients with Grade 3 or 4 diarrhea

• After recovery to ≤Grade 1, reduce the dose by 0.4 mg/m²/day PO for subsequent courses
Adverse Effect (IV infusion, Combination therapy with cisplatin)
o Pain, grade 3 or 4 (59%)

o Neutropenia, grade 4 (48%)

o Vomiting, grade 3 or 4 (40%)

o Anemia, grade 3 (34%)

o Thrombocytopenia, grade 3 (26%)

o Neutropenia, grade 3 (26%)

 ADVERSE EFFECTS (CAPSULE)

• All grades
o Anemia (98%)

o Sepsis (43%)

o Nausea (33%)
o Thrombocytopenia (29%)

o Neutropenia (24%)
• Grade 3 or 4
o Neutropenia (24-32%)

o Thrombocytopenia (6-29%)

o Anemia (7-18%)
 BEVACIZUMAB

• VEGF inhibitor
• Vascular endothelial growth factor (VEGF) is crucial to angiogenesis. VEGF inhibitors directly
bind to the VEGF protein to disrupt angiogenesis.
• Bevacizumab is a recombinant humanized monoclonal antibody to VEGF. It blocks the
angiogenic molecule VEGF, thereby inhibiting tumor angiogenesis and starving the tumor of
blood and nutrients. It is indicated as part of a combination chemotherapy regimen for
persistent, recurrent, or metastatic carcinoma of the cervix.
• Indicated in combination with paclitaxel plus cisplatin or paclitaxel plus topotecan, for
persistent, recurrent, or metastatic cervical cancer with dosing 15 mg/kg IV q3Weeks
 DOSING MODIFICATION: DISCONTINUE TREATMENT

• Gastrointestinal perforation

• Tracheoesophageal fistula

• Fistula formation involving any internal organ

• Necrotizing fasciitis

• Grade 3 or 4 hemorrhage

• Severe arterial thromboembolic events

• Grade 4 venous thromboembolic events, including pulmonary embolism

• Hypertensive crisis or hypertensive encephalopathy

• Posterior reversible encephalopathy syndrome (PRES)

• Nephrotic syndrome

• Congestive heart failure

• Severe infusion reactions

 DOSING MODIFICATION
Withhold treatment
• Any wound healing complications; resume after resolution of wound healing complications
has not been established

• Recent history of hemoptysis ≥1/2 tsp (2.5 mL)

• Severe hypertension not controlled with medical management; resume once controlled

• Proteinuria ≥2 grams/24 hr in absence of nephrotic syndrome; withhold until proteinuria <2

grams/24 hr

• Withhold for at least 28 days before elective surgery or until at least 28 days following major
surgery
Absorption

• Steady-state concentration is 84 days

• Accumulation ratio: 2.8 (following 10 mg/kg dose)
Distribution

• Vd: 2.9 L (mean); 3.2 L (males); 2.7 L (females)

Elimination

• Clearance: 0.23 L/day (mean); 0.26 L/day (males); 0.21 L/day (women)
• Half-life: 20 days

IV Administration

• IV infusion only; do not administer as IV push or bolus

• First infusion: Infuse over 90 min
• Second infusion: Infuse over 60 min if first infusion is tolerated
• Subsequent infusions: Infuse over 30 min if second infusion over 60 min is tolerated
 COMMON ADVERSE EFFECTS
• Fatigue (72-80%)

• Nausea (53-58%)

• Arthralgia (33-41%)

• Diarrhea (38-40%)

• Headache (26-34%)

• Hypertension (24-32%)

• Epistaxis (30-31%)

• Dyspnea (26-28%)

• Stomatitis (19-25%)

• Pain in extremity (19-25%)

• Muscular weakness (13-15%)

• Dysarthria (10-12%)
 PEMBROLIZUMAB
(KEYTRUDA)
• PD-1/PD-L1 Inhibitors
• Tumor cells may circumvent T-cell–mediated
cytotoxicity by expressing PD-L1 on the tumor itself
or on tumor-infiltrating immune cells, resulting in the
inhibition of immune-mediated killing of tumor cells

• Binding of PD-1 to its ligand PD-L1 can trigger an

inhibitory signal, leading to reduced T-cell
proliferation, and anti-tumor immunity.
• Blocking the binding of PD-1 to PD-L1, has been
shown to reinvigorate T-cell activity and the anti-
tumor immune response, which supports the
rationale for PD-1/PD-L1 inhibitors as promising
therapeutics
• Pembrolizumab is indicated for recurrent or
metastatic cervical cancer with disease
progression on or after chemotherapy whose
tumors express PD-L1
• Dose: 200 mg IV q3Weeks OR 400 mg q6Weeks
until disease progression, unacceptable toxicity,
or up to 24 months without disease progression
 DOSING MODIFICATION
• Renal impairment (eGFR ≥15 mL/min/1.73 m²): No dosage adjustment required
Hepatic impairment
• Mild: No dosage adjustment required

• Moderate or severe: Pharmacokinetics of pembrolizumab is unknown

Withhold dose (resume when recover to Grade <1)
• Grade 3 or 4 endocrinopathies (eg, hypophysitis, hypo- or hyperthyroidism)

• Grade 4 hematological toxicity

• Grade 3 severe skin reactions or suspected Stevens-Johnson syndrome (SJS) or toxic

epidermal necrolysis (TEN)

• Immune-mediated hepatitis in patients without HCC: AST/ALT>3 and up to 5x upper limit of

normal (ULN) or total bilirubin >1.5 and up to 3x ULN
 COMMON ADVERSE EFFECTS
• Anemia (54%) • ALT increased (21%)
• Lymphocyte count decreased (47%) • Decreased appetite (21%)
• Hypoalbuminemia (44%) • Hypokalemia (20%)
• Fatigue (43%) • Hemorrhage (19%)
• Alkaline phosphatase increased (42%) • Pain (19%)
• Hyponatremia (38%) • Nausea (19%)
• Hyperglycemia (38%) • Vomiting (19%)
• AST increased (34%) • Urinary tract infection (UTI) (18%)
• Increased creatinine (32%) • Rash (17%)
• Musculoskeletal pain (27%) • Infection (16%)
• Hypocalcemia (27%) • Peripheral edema (15%)
• Anemia, Grade 3 or 4 (24%) • Constipation (14%)
• Diarrhea (23%) • Hyponatremia, Grade 3 or 4 (13%)
• Abdominal pain (22%) • Hypothyroidism (11%)
• Pain (22%)
COMPLICATIONS OF THERAPY: RADIATION
• During the acute phase of pelvic radiation therapy, the surrounding normal tissues (eg,
intestines, bladder, and perineal skin) often are affected. Acute adverse gastrointestinal (GI)
effects include diarrhea, abdominal cramping, rectal discomfort, and bleeding. Diarrhea can
usually be controlled by giving either loperamide or atropine sulfate. Small steroid-containing
enemas are prescribed to alleviate symptoms from proctitis.
• Cystourethritis also can occur, leading to dysuria, frequency, and nocturia. Antispasmodics
often are helpful for symptom relief. Urine should be examined for possible infection. If urinary
tract infection (UTI) is diagnosed, therapy should be instituted without delay.
• Proper skin hygiene should be maintained for the perineum. Topical lotion should be used if
erythema or desquamation occurs.
• Late sequelae of radiation therapy usually appear 1-4 years after treatment. The major
sequelae include rectal or vaginal stenosis, small bowel obstruction, malabsorption, radiation
enteritis, and chronic cystitis.
COMPLICATIONS OF
THERAPY: SURGICAL
• The most frequent complication of radical
hysterectomy is urinary dysfunction resulting
from partial denervation of the detrusor
muscle.
• Other complications include foreshortened
vagina, ureterovaginal fistula, hemorrhage,
infection, bowel obstruction, stricture and
fibrosis of the intestine or rectosigmoid
colon, and bladder and rectovaginal fistulas.
• Invasive procedures (eg, nephrostomy or
diverting colostomy) sometimes are
performed in this group of patients to
improve their quality of life.
SCREENING
Screening recommendations for specific patient age groups are as follows :
• < 25 years – No screening recommended
• 21-29 years – Cytology (Pap smear) alone every 3 years
• 30-65 years – Human papillomavirus (HPV) and cytology cotesting every 5 years (preferred)
or cytology alone every 3 years (acceptable)
• >65 years – No screening recommended if adequate prior screening has been negative and
high risk is not present
 VACCINATION

• Recombinant vaccine that targets 9 HPV types (6, 11, 16, 18, 31, 33, 45, 52, and 58).
• It is indicated for females aged 9 through 45 years to prevent cervical, vulvar, vaginal, and
anal cancer. It is also indicated to prevent genital warts and dysplastic lesions (eg, cervical,
vulvar, vaginal, anal).
• It is also indicated for males aged 9 through 45 years for prevention of neoplasias and
dysplasias (eg, anal cancer).
• Children and adolescents aged 15 years and younger need two, not three, doses of the HPV
vaccine; due to vaccine’s enhanced immunogenicity in preteens and adolescents aged 9-14
years.
• The schedule for older adolescents and young adults aged 15 through 45 years is three
inoculations within 6 months.
• Three HPV vaccines—9-valent HPV vaccine (Gardasil® 9, 9vHPV),
quadrivalent HPV vaccine (Gardasil®, 4vHPV), and bivalent HPV
vaccine (Cervarix®, 2vHPV). All three HPV vaccines protect against
HPV types 16 and 18 that cause most HPV cancers.
• Gardasil-9, a nine-valent HPV vaccine (9vHPV) that protects against
HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58
• Gardasil, a quadrivalent (4vHPV) that protects against HPV types
6,11,16,18.
• Cervarix, a bivalent (2vHPV) that protects against HPV types 16 and
18