Sections

Medication

Medication Summary

Chemotherapy should be administered in conjunction with radiation therapy to most patients with stage IB (high-risk) to stage IVA cervical cancer. Cisplatin is the agent used most commonly, although 5-fluorouracil also is used frequently. For patients with metastatic disease, cisplatin remains the most active agent. Topotecan, ifosfamide, and paclitaxel also have significant activity in this setting. The combination of topotecan and cisplatin improves overall survival. However, acute toxicities are also increased.

Class Summary

Alkylating chemotherapy agents inhibit cell growth and proliferation. They inhibit DNA synthesis through the formation of DNA cross-links.

Cisplatin (Platinol)

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Intrastrand cross-linking of DNA and inhibition of DNA precursors are among the proposed mechanisms of action for cisplatin. This agent is used in combination with radiation therapy.

Ifosfamide (Ifex)

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Ifosfamide forms DNA interstrand and intrastrand bonds that interfere with protein synthesis. Although the US Food and Drug Administration (FDA) has approved this agent only for the treatment of testicular cancer, it has several off-label indications, including treatment of cervical cancer.

Class Summary

Antimetabolite antineoplastic agents inhibit cell growth and proliferation. They interfere with DNA synthesis by blocking the methylation of deoxyuridylic acid.

Fluorouracil (Adrucil)

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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.

Class Summary

Antimicrotubular antineoplastic agents prevent cell growth and proliferation. They work by enhancing tubulin dimers, stabilizing existing microtubules, and inhibiting their disassembly.

Paclitaxel (Taxol)

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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.

Class Summary

Topoisomerase-inhibiting antineoplastic agents prevent cell growth and proliferation. They work by binding to topoisomerase and causing single-strand DNA breaks.

Topotecan (Hycamtin)

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Topotecan inhibits topoisomerase I, inhibiting DNA replication. It acts in the S phase of the cell cycle. Patients who have received prior chemotherapy should be given a lower dose initially.

Class Summary

Vascular endothelial growth factor (VEGF) is crucial to angiogenesis. VEGF inhibitors directly bind to the VEGF protein to disrupt angiogenesis.

Bevacizumab (Avastin)

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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.

Class Summary

Monoclonal antibodies that bind the programmed cell death-1 protein (PD-1) ligands, PD-L1 and PD-L2, to the PD-1 receptor found on T cells, inhibits T cell proliferation and cytokine production.

Pembrolizumab (Keytruda)

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Indicated for treatment of recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS 1 or greater) as determined by an FDA-approved test. Pembrolizumab is also indicated for unresectable or metastatic tumor mutational burden-high (TMB-H) [≥10 mut/Mb] solid tumors in patients that have progressed following prior treatment and who have no alternative treatment options.

Class Summary

The 9-valent HPV vaccine is indicated for prevention of HPV-associated neoplasias and precancerous genital lesions. The 2-valent and 4-valent vaccines were discontinued from the US market in 2016.

Children and adolescents aged 15 years and younger need two, not three, doses of the HPV vaccine; this ACIP recommendation stems from the 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.

Human papillomavirus vaccine, nonavalent (Gardasil 9)

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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).

Human papillomavirus vaccine, bivalent (Cervarix)

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October 21, 2016: HPV bivalent vaccine discontinued in the United States.

The bivalent recombinant HPV vaccine is prepared from the L1 protein of HPV types 16 and 18. It is indicated for girls and women (ages 9-25 years) to prevent the following diseases caused by oncogenic HPV types 16 and 18:

- Cervical cancer

- CIN grade 2 or higher

- Cervical adenocarcinoma in situ

- CIN grade 1

Questions

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Media Gallery

Cervical carcinoma with adnexa.
Squamous cell cervical carcinoma.
Cervical intraepithelial neoplasia grade I.
Cervical intraepithelial neoplasia grade III.
CT scan of cervical cell carcinoma demonstrates markedly enlarged lymph node at left pelvic sidewall. This is consistent with pelvic lymph node metastasis, which is indicative of stage IIIB disease. Cystic consistency is not unusual for metastatic cervical carcinoma. Primary tumor is well depicted as hypoattenuating circumscribed mass. Cyst is present in anteriorly located left ovary.

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Table 1. Human Papillomavirus Types Associated With Cervical Cancer

HPV Alpha Group	Types	Evidence for Cervical Cancer Causation
1	16	Most carcinogenic HPV type, known to cause cancer at several sites
1	18,31,33,35,39,45,51,52,56,58, 59	Sufficient evidence
2A	68	Limited evidence in humans and strong mechanistic evidence
2B	26,53,66,67,70,73,82	Limited evidence in humans
2B	30,34,69,85,97	Classified by phylogenetic analogy to HPV types with sufficient or limited evidence in humans
3	6,11	Inadequate epidemiological evidence and absence of carcinogenic potential in mechanistic studies
HPV = human papillomavirus.

Table 2. Cervical Cancer Staging: Primary Tumor (T)

TNM Stage	FIGO Stage
TX	-	Primary tumor cannot be assessed
T0	-	No evidence of primary tumor
Tis	0	Carcinoma in situ
T1	I	Cervical carcinoma confined to uterus (extension to corpus should be disregarded)
T1a	IA	Invasive carcinoma diagnosed only by microscopy. All macroscopically visible lesions—even with superficial invasion—are T1b/1B. Stromal invasion with a maximal depth of 5.0 mm measured from the base of the epithelium and a horizontal spread of 7.0 mm or less. Vascular space involvement, venous or lymphatic, does not affect classification.
T1a1	IA1	Measured stromal invasion 3 mm or less in depth and 7 mm or less in lateral spread
T1a2	IA2	Measured stromal invasion more than 3 mm but not more than 5 mm with a horizontal spread 7 mm or less
T1b	IB	Clinically visible lesion confined to the cervix or microscopic lesion greater than IA2
T1b1	IB1	Clinically visible lesion 4 cm or less in greatest dimension
	IB2	Clinically visible lesion more than 4 cm
T2	II	Cervical carcinoma extends beyond the cervix but not to the pelvic sidewall or to the lower third of vagina
T2a	IIA	Tumor without parametrial invasion
T2b	IIB	Tumor with parametrial invasion
T3	III	Tumor extends to the pelvic wall and/or involves the lower third of the vagina and/or causes hydronephrosis or nonfunctioning kidney
T3a	IIIA	Tumor involves lower third of vagina; no extension to pelvic sidewall
T3b	IIIB	Tumor extends to pelvic sidewall and/or causes hydronephrosis or nonfunctioning kidney
-	IV	Cervical carcinoma has extended beyond the true pelvis or has involved (biopsy proven) the bladder mucosa or rectal mucosa. Bullous edema does not qualify as a criteria for stage IV disease.
T4	IVA	Spread to mucosa of adjacent organs (bladder, rectum, or both)
M1	IVB	Distant metastasis

Table 3. UICC/AJCC Staging for Cervical Cancer

Stage	Tumor	Node	Metastasis
0	Tis	N0	M0
IA1	T1a1	N0	M0
IA2	T1a2	N0	M0
IB1	T1b1	N0	M0
IIA	T2a	N0	M0
IIB	T2b	N0	M0
IIIA	T3a	N0	M0
IIIB	T1	N1	M0
-	T2	N1	M0
-	T3a	N1	M0
-	T3b	Any N	M0
IVA	T4	Any N	M0
IVB	Any T	Any N	M1

Table. 1

Patient Status	Recommended Screening Method	Comments
< 21 years old	No screening	Sexual history is not a consideration
21-29 years old	Cytology alone every 3 years
30-65 years old	Preferred: HPV and cytology co-testing every 5 years Acceptable: Cytology alone every 3 years
>65 years old	Screening can be discontinued after either three consecutive negative cytology tests or two negative cytology and HPV tests within 10 years, provided the most recent test was within 5 years	Women with a history of cervical intraepithelial neoplasia (CIN) 2, CIN 3, or adenocarcinoma in situ should continue routine age-based screening for at least 20 years
After total hysterectomy	No screening necessary	Applies to women without a cervix and without a history of CIN 2, CIN 3, adenocarcinoma in situ, or cancer in the past 20 years
After HPV vaccination	Follow the same age-specific recommendations as unvaccinated women

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Author

Cecelia H Boardman, MD Virginia Gynecologic Oncology

Cecelia H Boardman, MD is a member of the following medical societies: Society of Gynecologic Oncology, American College of Obstetricians and Gynecologists, American College of Surgeons, Minnesota Medical Association

Disclosure: Received salary from Merck for speaking and teaching; Received salary from Glaxo for speaking and teaching; Partner received salary from Depuy for speaking and teaching.

Coauthor(s)

Kirk J Matthews, Jr, MD Resident Physician, Department of Obstetrics and Gynecology, Virginia Commonwealth University Medical Center

Disclosure: Nothing to disclose.

Specialty Editor Board

Jori S Carter, MD, MS Assistant Professor, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Virginia Commonwealth University School of Medicine

Jori S Carter, MD, MS is a member of the following medical societies: Alpha Omega Alpha, American College of Obstetricians and Gynecologists, Society of Gynecologic Oncology, Association of Women Surgeons, International Society for Magnetic Resonance in Medicine, American Society of Clinical Oncology

Disclosure: Nothing to disclose.

Chief Editor

Leslie M Randall, MD, MAS, FACS Professor and Director, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Diane Harris Wright Professor of Gynecologic Oncology Research, Massey Cancer Center, Virginia Commonwealth University School of Medicine

Leslie M Randall, MD, MAS, FACS is a member of the following medical societies: Academy for Innovation in Medical Education, American College of Surgeons, American Medical Association, American Society of Clinical Oncology, International Gynecologic Cancer Society, Society of Gynecologic Oncology

Disclosure: Nothing to disclose.

Acknowledgements

A David Barnes, MD, PhD, MPH, FACOG Consulting Staff, Department of Obstetrics and Gynecology, Mammoth Hospital (Mammoth Lakes, California), Pioneer Valley Hospital (Salt Lake City, Utah), Warren General Hospital (Warren, Pennsylvania), and Mountain West Hospital (Tooele, Utah)

A David Barnes, MD, PhD, MPH, FACOG is a member of the following medical societies: American College of Forensic Examiners, American College of Obstetricians and Gynecologists, American Medical Association, Association of Military Surgeons of the US, and Utah Medical Association