Cervical Cancer: Pharmacologic Management

Cervical cancer is the fourth most common cancer in women worldwide, with 604,000 new cases reported in 2020.¹ In 2023, an estimated 13,960 new cases of cervical cancer will be diagnosed, and 4310 deaths will be attributed to the malignancy in the United States.² Most cervical cancers originate from the squamocolumnar junction, called the transformation zone, located between the squamous cells of the outer aspect (ectocervix) and columnar, glandular cells of the inner canal (endocervix) of the cervix.³

Approximately 75% to 90% of cervical cancers are squamous cell carcinomas arising from the cells of the ectocervix, and approximately 10% to 25% are adenocarcinomas that arise from the glandular cells of the endocervix.⁴ Small cell neuroendocrine carcinomas of the cervix, which arise from the embryonic neuroectoderm, account for the remainder (1% to 1.5%).⁵ 

Precancerous lesions, including cervical intraepithelial neoplasia and adenocarcinoma in situ, can develop into invasive cancer.³ Prognosis of early-stage cervical cancer is good, with a 5-year survival rate of 91% for patients with localized cervical cancer.² However, the 5-year survival rate for patients with distant cervical cancer is 15%.² The cure rate for early-stage cervical cancer ranges from 60% to 80%.⁶ Human papillomavirus (HPV) infection is the most significant risk factor for cervical cancer, with more than 95% of cases attributed to the viral infection.⁷ 

Risk factors for cervical cancer include⁸:

• HPV infection, especially subtypes 16 and 18
• Early initial sexual activity
• Multiple sexual partners
• Smoking
• Immunosuppression, such as that due to HIV infection and immunosuppressants  
• Long-term use of oral contraceptives
• High parity
• Exposure to diethylstilbestrol in utero

Cervical cancers are largely preventable with screening using the Papanicolaou test, which has allowed early detection and treatment of precancerous lesions. Additionally, HPV vaccination is highly effective in preventing cervical cancer.⁹ Although the incidence of cervical cancer is decreasing in the United States and other developed countries, it is increasing in developing countries that have limited screening and vaccination programs.^6,10 In 2020, approximately 90% of new cases and deaths attributed to cervical cancer occurred in developing countries, where most are diagnosed at advanced stages.^7,11 

Cervical Cancer Treatment Overview

Recommendations from the National Comprehensive Center Network (NCCN) for cervical cancer staging are based on the 2018 Fédération Internationale de Gynécologie et d’Obstétrique (FIGO) staging system.^3,6 Staging is performed to assess the extent of disease/metastasis/spread and will inform treatment decisions. NCCN recommendations for treatment of cervical cancer include⁶:

• Surgery 
• Radiation therapy
• Chemoradiation therapy
• Systemic therapy

Surgery and radiation therapy are the primary treatment options for early-stage cervical cancer. Chemoradiation therapy and adjuvant systemic therapy are recommended for recurrent and metastatic cervical cancer.   

Surgery

Surgical treatment of cervical cancer involves the following, depending on the stage and metastasis status of disease⁶:

• Trachelectomy 
• Hysterectomy 
• Exenteration 

Decisions on surgical options are made with consideration for fertility preservation. NCCN recommends cone biopsy for carcinoma in situ and stage IA cervical cancer as the fertility-sparing treatment option. Hysterectomy is recommended when fertility preservation is not relevant. NCCN recommendation on hysterectomy is simple hysterectomy for early-stage cervical cancer and radical hysterectomy for later-stage disease.⁶ 

For some patients with stages IA2 to IB1, and some with IB2 cervical cancer with tumors measuring less than 2 cm in diameter, the recommended fertility-sparing option is radical trachelectomy, in which the cervix and the surrounding tissues are removed, leaving the uterus intact. The approach recommended by NCCN for radical hysterectomy is the open abdominal approach. Laparoscopic pelvic lymphadenectomy is recommended with trachelectomy and para-aortic lymph node dissection for patients with stage IB1 or greater disease.⁶  

For patients with stage IA1 disease with negative margins after cone biopsy and no lymphovascular space invasion, simple hysterectomy is recommended if fertility preservation is not necessary. Modified radical hysterectomy with sentinel lymph node mapping is recommended for patients with positive margins or if invasion into the lymphovascular space is found.⁶ 

For stages IA2, IB1, IB2, and IIA1 cervical cancer, radical hysterectomy with bilateral pelvic lymph node dissection is recommended. To preserve fertility in patients with stage IB1 disease, radical trachelectomy with pelvic lymph node dissection can be performed.⁶ 

For stages IB3 and IIA2 or above, definitive chemoradiation is recommended over radical surgery. Chemoradiation is the recommended primary treatment for stages IB3 and IVA cervical cancer, and when surgery is not an option.⁶ 

For advanced-stage cervical cancer (stage IIB and above), definitive chemoradiation is the treatment of choice. For recurrent or persistent cervical cancer in the central pelvis following radiation, pelvic exenteration performed at a center of excellence is recommended.⁶   

NCCN does not recommend fertility-sparing surgery for small cell neuroendocrine tumors and gastric-type adenocarcinomas because of their potential to be very aggressive.⁶ 

Radiation Therapy

Recommendations by NCCN for radiation therapy for cervical cancer include definitive radiation therapy for patients with an intact cervix without surgery, adjuvant radiation therapy after hysterectomy for any remaining disease, intraoperative radiation therapy usually for recurrent disease, and brachytherapy for patients with primary cervical cancer who are not candidates for surgery. Concurrent chemotherapy with a platinum-containing regimen is recommended for external-beam radiation therapy (EBRT).⁶

Chemoradiation

Chemoradiation is the category 1 recommendation for advanced cervical cancer. Platinum-containing chemotherapy, when combined with definitive radiation, was associated with a 6% improvement in the 5-year survival rate among patients with cervical cancer and decreased the cervical cancer death rate by 30% to 50%.^3,12 A radiosensitizing regimen with cisplatin, carboplatin, or cisplatin/fluorouracil administered concurrently with pelvic EBRT and brachytherapy is recommended for stage IB3, IIA2, and regional disease. For chemotherapy regimen options to be administered with radiotherapy, cisplatin is the preferred option, with carboplatin as an alternative for cisplatin-intolerant patients; another option is cisplatin/fluorouracil given every 3 to 4 weeks.⁶

Extended-field EBRT with concurrent platinum-containing chemotherapy and brachytherapy is recommended for cervical cancer with para-aortic and pelvic lymph node involvement. For assessment of nodal involvement, NCCN recommends radiologic imaging, including positron emission tomography/computed tomography (PET/CT), for stage IB2 or greater cervical cancer. For locally recurrent cervical cancer, NCCN recommends chemoradiation therapy using cisplatin, carboplatin, or cisplatin/fluorouracil, or alternative agents such as paclitaxel or gemcitabine.⁶

Systemic Therapy

The primary treatment of early-stage cervical cancer is either surgery or radiation therapy. 

Systemic therapy is recommended in cases of metastatic or recurrent cervical cancer for which radiotherapy or exenterative surgery is not feasible. Although chemotherapy may relieve pain, it does not improve survival in this population.⁶

General Recommendations

NCCN recommends assessment of HPV status via in situ hybridization or molecular testing on all cervical adenocarcinomas. Programmed cell death-ligand 1 (PD-L1) and mismatch repair (MMR)/microsatellite instability (MSI) testing is recommended for patients with recurrent, progressive, or metastatic cervical cancer. Counseling on the prenatal and perinatal risks of treatment and consultation with reproductive endocrinologists are recommended for patients with cervical cancer who desire to preserve fertility.⁶ 

Pharmacologic Management

The preferred first-line treatment for advanced cervical cancer consists of combination chemotherapy regimens in combination with immunotherapy agents. For patients with metastatic or recurrent cervical cancer, the preferred primary treatment is a combination regimen of platinum-doublet chemotherapy in combination with pembrolizumab and/or bevacizumab.⁶ Pembrolizumab and bevacizumab are immunotherapy agents recently approved by the US Food and Drug Administration (FDA) in combination with other chemotherapy agents for the treatment of advanced cervical cancer. The addition of bevacizumab to combination chemotherapy demonstrated significant improvement in median overall survival among patients with advanced cervical cancer.¹³ 

Immunotherapy

Pharmacologic management of cervical cancer has been transformed with the recent approval of immunotherapy agents that inhibit a number of different pathways involved in cancer cell growth. Pembrolizumab is an immune checkpoint inhibitor that blocks binding of PD-L1, which is expressed in approximately 41% to 57% of cervical tumor cells, to its receptors.^13-15 Pembrolizumab, which targets cancer cells that express programmed cell death-1 (PD-1) for cell death, was approved by the FDA in 2021 for the treatment of PD-1-positive persistent, recurrent, or metastatic cervical cancer.¹⁶ Bevacizumab targets the growth of cancer cells by binding circulating vascular endothelial growth factor-A (VEGF-A), leading to inhibition of angiogenesis.^13,17 Bevacizumab was approved by the FDA in 2014 for the treatment of persistent, recurrent, or metastatic cervical cancer, in combination with cisplatin-containing doublet chemotherapy regimens.¹⁸ Pembrolizumab and bevacizumab have been incorporated into platinum-containing combination chemotherapy regimens to serve as the preferred first-line therapy for recurrent or metastatic cervical cancer.⁶ 

Chemotherapy: Combination Regimens

Cisplatin as a single agent had been the main chemotherapy option until studies showed that regimens combining cisplatin with other chemotherapy agents — paclitaxel or topotecan — significantly improve response and survival.^19,20 Combination regimens containing cisplatin, such as cisplatin/paclitaxel//bevacizumab (preferred, category 1 option) or cisplatin/topotecan (category 2A), are now the standard of care in chemotherapy treatment of cervical cancer.⁶

Based on the results of a recent randomized, phase 3 trial (GOG 240; ClinicalTrials.gov Identifier: NCT00803062) demonstrating improved survival with the addition of bevacizumab to combination chemotherapy regimens,¹⁸ both bevacizumab-containing regimens (cisplatin/paclitaxel/bevacizumab or topotecan/paclitaxel/bevacizumab) are recommended as preferred category 1 options for the first-line treatment of persistent, recurrent, or metastatic cervical cancer.⁶ 

Based on the results of a recent randomized, phase 3 trial (JCOG0505; ClinicalTrials.gov Identifier: NCT00295789) showing noninferiority of carboplatin/paclitaxel to cisplatin/paclitaxel in metastatic or recurrent cervical cancer¹⁹, NCCN recommends carboplatin/paclitaxel as a preferred category option for patients who have undergone cisplatin therapy.⁶ Carboplatin-based therapies carry lower risk for toxicity.²¹

Cisplatin/paclitaxel or carboplatin/paclitaxel regimens are associated with less toxicity than cisplatin/topotecan.²² Topotecan/paclitaxel may be considered as a category 2A alternative to cisplatin/paclitaxel in patients for whom cisplatin is contraindicated.⁶

Combination platinum-containing regimens are recommended over single agents for metastatic cervical cancer if cisplatin was used previously as part of chemoradiation therapy. NCCN recommends carboplatin/paclitaxel/bevacizumab as a category 2A additional preferred regimen for recurrent or metastatic cervical cancer.⁶ 

Chemotherapy: Single Agents

As a single agent, cisplatin is the gold standard, first-line therapy for recurrent or metastatic cervical cancer. Carboplatin and paclitaxel as a single agent can also be an alternative to cisplatin.^23,24 Cisplatin, carboplatin, or paclitaxel as a single agent are options for palliative therapy for recurrent cervical cancer when surgery and radiotherapy are not feasible.⁶   

For second-line therapy in the treatment of PD-L1-positive or MSI-H/dMMR cervical tumors, NCCN recommends pembrolizumab as a category 2A option. Other agents recommended for second-line therapy of advanced cervical cancer include bevacizumab and chemotherapy agents, albumin-bound paclitaxel, docetaxel, fluorouracil, gemcitabine, ifosfamide, irinotecan, mitomycin, pemetrexed, topotecan, and vinorelbine.⁶ 

Table 1. First-Line Therapy for Recurrent or Metastatic Cervical Cancer* 

Systemic Therapy Agent	Tumor Type	NCCN Category of Preference	Therapy Setting	NCCN Category of Evidence and Consensus
Pembrolizumab + cisplatin/paclitaxel ± bevacizumab	PD-1-positive tumors	Preferred	First-line	Category 1
Pembrolizumab + carboplatin/ paclitaxel ± bevacizumab	PD-1-positive tumors	Preferred	First-line	Category 1
Cisplatin/paclitaxel/bevacizumab		Preferred	First-line	Category 1
Carboplatin/paclitaxel/bevacizumab		Preferred	First-line
Cisplatin/paclitaxel		Other	First-line	Category 1
Carboplatin/paclitaxel		Other	First-line	Category 1 for patients who have received prior cisplatin therapy
Topotecan/paclitaxel/bevacizumab		Other	First-line	Category 1
Topotecan/paclitaxel		Other	First-line
Cisplatin/topotecan		Other	First-line
Cisplatin		Other	First-line
Carboplatin		Other	First-line

*Squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma.

From NCCN cervical cancer treatment guidelines.⁶

Table 2. Second-Line or Subsequent Therapy for Recurrent or Metastatic Cervical Cancer*

Systemic Therapy Agent	Tumor Type	NCCN Category of Preference	Therapy Setting	NCCN Category of Evidence and Consensus
Pembrolizumab	TMB-H, PD-L1-positive, or MSI-H/dMMR tumors	Preferred	Second-line or subsequent therapy
Tisotumab vedotin-tftv		Preferred	Second-line or subsequent therapy
Bevacizumab		Other	Second-line or subsequent therapy
Paclitaxel		Other	Second-line or subsequent therapy
Albumin-bound paclitaxel		Other	Second-line or subsequent therapy
Docetaxel		Other	Second-line or subsequent therapy
Fluorouracil		Other	Second-line or subsequent therapy
Gemcitabine		Other	Second-line or subsequent therapy
Pemetrexed		Other	Second-line or subsequent therapy
Topotecan		Other	Second-line or subsequent therapy
Vinorelbine		Other	Second-line or subsequent therapy
Irinotecan		Other	Second-line or subsequent therapy	Category 2B
Nivolumab	PD-L1-positive tumors	Useful in certain circumstances	Second-line or subsequent therapy
Selpercatinib	RET gene fusion-positive tumors	Useful in certain circumstances	Second-line or subsequent therapy
Larotrectinib or entrectinib	NTRK gene fusion-positive tumors	Useful in certain circumstances	Second-line or subsequent therapy	Category 2B

*Squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma.

dMMR = mismatch repair deficient; MSI-H = microsatellite instability-high; NTRK = neurotrophic tyrosine receptor kinase; PD-L1 = programmed cell death-ligand 1; TMB-H = tumor mutational burden-high. 

From NCCN cervical cancer treatment guidelines.⁶

Cervical Cancer Chemotherapy Agents

Cisplatin 

Cisplatin is a cytotoxic chemotherapy agent that induces cell death by binding to genomic DNA and interfering with DNA transcription and replication.^25,26 Cisplatin is used widely and constitutes the main chemotherapy agent in the treatment of cervical cancer.^27,28 Cisplatin has been associated with response rates ranging from 17% to 38% and a median overall survival of 6.1 to 7.1 months in patients with cervical cancer with distant recurrence or loco-regional recurrence not eradicated by surgery or radiation therapy.²⁹ Cisplatin as a single agent is the preferred chemotherapy treatment in chemoradiation therapy of squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma cervical cancers.⁶ As a first-line therapy agent, cisplatin is given in combination with other agents, including paclitaxel, bevacizumab, pembrolizumab, and topotecan.⁶ 

Dosing and Administration

As a single agent, the recommended dosage of cisplatin is 50 mg/m² intravenously (IV) every 3 weeks. 

Patients must receive pretreatment hydration before undergoing treatment with cisplatin. Antiemetics can be administered, as appropriate.²⁵  

Adverse Reactions

Serious adverse reactions associated with cisplatin include²⁵:

• Hypersensitivity reactions, including anaphylaxis and death
• Nephrotoxicity
• Peripheral neuropathy
• Nausea and vomiting 
• Bone marrow suppression
• Ototoxicity
• Ocular toxicity
• Secondary leukemia
• Embryo-fetal toxicity
• Injection site reactions

Drug Interactions

Due to the increased risk of kidney toxicity and ototoxicity, caution is advised when using nephrotoxic and ototoxic drugs concurrently with cisplatin treatment.²⁵ 

Special Populations

The pregnancy status of female patients should be verified prior to initiating treatment with cisplatin, and pregnant patients should be advised of the risk of harm from cisplatin to the fetus. Breastfeeding should be discontinued. Contraception should be used to avoid pregnancy for 14 months in female patients and for 11 months in male patients with female partners with reproductive potential.²⁵ 

Ototoxicity induced by cisplatin may be more severe in pediatric patients, particularly those younger than 5 years. Hearing loss and impairment in pediatric patients can potentially affect cognitive and social development. Monitoring of audiometric and vestibular function is therefore advised.²⁵ 

Patients aged 65 years and older undergoing treatment with cisplatin experience more severe neutropenia, thrombocytopenia, leukopenia, peripheral neuropathy, nephrotoxicity, myelosuppression, and infection than younger patients. Renal function should be closely monitored in patients aged 65 and older, and the cisplatin dose may be decreased, if necessary.²⁵ 

Serum creatinine, blood urea nitrogen, creatinine clearance, and serum electrolytes should be closely monitored before starting cisplatin treatment in patients with renal impairment.  The cisplatin dose may need to be reduced or alternative treatment may be necessary for patients with baseline renal impairment or patients who develop significant creatinine clearance reduction during treatment.²⁵ 

Carboplatin

Carboplatin is a cytotoxic chemotherapy agent that induces interstrand DNA crosslinks to prevent DNA replication, leading to cell death. Carboplatin is used off-label in patients with cervical cancer as an alternative to cisplatin due to its lower toxicity profile.³⁰ Results from the phase 3 JCOG0505 trial demonstrated carboplatin/paclitaxel to be noninferior to cisplatin/paclitaxel in the treatment of advanced cervical cancer.¹⁹ Carboplatin is a preferred option in chemoradiation for cervical cancer as an alternative to cisplatin.⁶

Dosing and Administration

In a combination regimen with paclitaxel, carboplatin is given at an area under the curve (AUC) of 5 mg/mL/min IV as a 1-hour infusion on day 1 of a 3-week cycle immediately after paclitaxel administration. The cycle is continued until disease progression or unacceptable toxicity.¹⁹

Adverse Reactions

Serious adverse reactions associated with carboplatin include⁶:

• Bone marrow suppression
• Hematologic toxicity
• Emesis 
• Neurotoxicity 
• Hypersensitivity, including anaphylaxis

Other side effects associated with carboplatin include⁶:

• Nausea and vomiting
• Injection site reactions
• Hepatic toxicity
• Electrolyte changes

Drug Interactions

Concurrent administration of the following medications with carboplatin should be avoided⁶:

• Ototoxic drugs (eg, aminoglycosides)
• Nephrotoxic drugs

Special Populations

Pregnant patients should be advised of the risk to the fetus, and pregnancy should be avoided by patients undergoing treatment with carboplatin. Breastfeeding should be discontinued during treatment with carboplatin.⁶ 

An increased incidence of peripheral neurotoxicity and low platelet levels was reported in patients 65 years of age and older undergoing treatment with carboplatin. Therefore, the dosage of carboplatin may need to be reduced in these patients due to decreased renal function in general.⁶ 

Paclitaxel 

Paclitaxel is an antimicrotubule agent that inhibits cancer cell growth by blocking cell division.³¹ In cervical cancer, paclitaxel is used off-label in combination with pembrolizumab with or without bevacizumab for PD-L1-positive tumors or as a single agent in first-line therapy for recurrent and metastatic disease.³¹ 

Dosing and Administration

The recommended dosage of paclitaxel is 135 mg/m² to 175 mg/m² IV infusion over 3 to 24 hours, depending on other agents in combination, on day 1 of a 3-week cycle. In combination with cisplatin, the recommended dosage of paclitaxel is 135 mg/m² over 24 hours on day 1, followed by cisplatin 50 mg/m² IV infusion over 60 minutes.¹⁹ In combination with carboplatin, the recommended dosage of paclitaxel is 175 mg/m² over 3 hours on day 1, immediately followed by carboplatin infusion at an AUC of 5 mg/mL/min over 1 hour on the same day.¹⁹  

Contraindications

Paclitaxel should be avoided in patients with the following conditions³¹:

• Baseline neutrophil count <1500 cells/mm³ in patients with solid tumors
• Baseline neutrophil count <1000 cells/mm³ in patients with AIDS-related Kaposi sarcoma
• Severe hypersensitivity to paclitaxel

Adverse Reactions

Serious adverse reactions associated with paclitaxel include⁶:

• Severe bone marrow suppression 
• Severe hypersensitivity, including anaphylaxis
• Embryo-fetal toxicity

Other side effects associated with paclitaxel include³¹:

• Alopecia
• Nausea and vomiting
• Diarrhea
• Peripheral neuropathy
• Injection site reaction

Drug Interactions

Paclitaxel is metabolized by cytochrome P450 isoenzymes CYP2C8 and CYP3A4. Concurrent administration of paclitaxel with the following medications should therefore be avoided³¹:

• Inhibitors and inducers of CYP3A4 (eg, midazolam, buspirone, felodipine, lovastatin, eletriptan, sildenafil, simvastatin, triazolam, atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, carbamazepine)
• Inhibitors and inducers of CYP2C8 (eg, repaglinide, rosiglitazone, gemfibrozil, rifampin)  

Special Populations

Pregnant patients should be advised of the risk of fetal harm with paclitaxel treatment. Pregnancy should be avoided during paclitaxel treatment. Breastfeeding should be discontinued during treatment with paclitaxel.³¹

The incidence of severe bone marrow depression, severe neuropathy, and cardiovascular events was found to be higher in patients aged 65 years and older undergoing treatment with paclitaxel compared with younger patients.³¹

Topotecan

Topotecan is a topoisomerase-I inhibitor that induces double-stranded DNA breaks in cancer cells.³² Based on the results of a phase 3 study (GOG179) showing improved overall response and survival, topotecan was approved by the FDA in 2006 for the treatment of stage IVB, recurrent, or persistent cervical cancer in patients for whom surgery and/or radiotherapy are not feasible.^20,33 The combination of topotecan and cisplatin led to an improvement in overall survival over cisplatin monotherapy.^20,34 

Dosing and Administration

The recommended dosage of topotecan is 0.75 mg/m² IV infusion over 30 minutes daily on days 1, 2, and 3 of a 21-day cycle. When topotecan is administered as combination therapy with cisplatin, the dosage of cisplatin is 50 mg/m² IV infusion on day 1 of a 21-day cycle.³²

Contraindications

Patients with a history of severe hypersensitivity reactions to topotecan should not receive topotecan treatment.³² 

Adverse Reactions

Serious adverse reactions associated with topotecan include³²:

• Bone marrow suppression
• Neutropenia colitis, including fatal cases
• Interstitial lung disease
• Embryo-fetal toxicity

Other common side effects associated with topotecan include³²:

• Anemia
• Neutropenia
• Thrombocytopenia
• Pain
• Nausea and vomiting

Special Populations

Pregnant patients should be advised of the risk of harm to the fetus. Breastfeeding should be discontinued during topotecan treatment.³² 

Cervical Cancer Targeted Therapy

With the recent FDA approval of multiple targeted therapies inhibiting the immune checkpoint, angiogenesis, and cell division, targeted therapy has taken center stage in the treatment of advanced cervical cancer.  

Pembrolizumab

Pembrolizumab is an antibody against PD-1, which targets cancer cells for cell death by releasing the inhibition of immune surveillance found in many cancer cells.³⁵ Based on the results of a phase 2 trial (KEYNOTE-158; ClinicalTrials.gov Identifier: NCT02628067) showing efficacy and lasting response, pembrolizumab was approved by the FDA for the treatment of recurrent or metastatic cervical cancer with tumors that express PD-L1 and with disease progression on or after chemotherapy.^35,36 PD-1 expression should be confirmed by an FDA-approved test prior to the initiation of pembrolizumab treatment.⁶ 

Dosing and Administration

The recommended dosage of pembrolizumab is 200 mg IV infusion over 30 minutes every 3 weeks.³⁷ 

Adverse Reactions

Serious adverse reactions associated with pembrolizumab include³⁷:

• Immune-related pneumonitis 
• Immune-related colitis 
• Immune-related hepatitis
• Immune-mediated endocrinopathies
  • Hypophysitis
  • Thyroid disorders
  • Type 1 diabetes mellitus
• Immune-mediated nephritis
• Immune-mediated skin adverse reactions
• Infusion-related reactions
• Embryo-fetal toxicity

Other common side effects associated with pembrolizumab include³⁷:

• Fatigue 
• Nausea and vomiting
• Alopecia
• Anemia
• Rash
• Diarrhea

Special Populations

The pregnancy status of female patients should be confirmed before starting treatment with pembrolizumab. Pregnant patients should be advised of the risk of harm to the fetus, and pregnancy should be avoided during and for at least 4 months after treatment. Breastfeeding should be discontinued during and after pembrolizumab treatment.³⁷ 

Some side effects — which include fatigue, vomiting, abdominal pain, increased transaminases, and hyponatremia — were seen at a higher rate in pediatric patients undergoing treatment with pembrolizumab.³⁷ 

Bevacizumab

Bevacizumab is a human monoclonal antibody that targets cancer cells for cell death through its inhibition of angiogenesis.¹³ It binds circulating VEGF and decreases the availability of circulating VEGF that can activate angiogenesis. Bevacizumab is the first monoclonal antibody to show survival benefit in patients with advanced cervical cancer.¹³ Based on the results of a phase 3 trial demonstrating that adding bevacizumab to combination chemotherapy regimens (cisplatin/paclitaxel or topotecan/paclitaxel) significantly improved overall survival, it was approved by the FDA in 2014 for the treatment of advanced cervical cancer.¹³ Bevacizumab is indicated for the treatment of persistent, recurrent, or metastatic cervical cancer.³⁸

Dosing and Administration

The recommended dosage of bevacizumab is 15 mg/kg IV injection every 3 weeks with paclitaxel and cisplatin or paclitaxel and topotecan.³⁸

Adverse Reactions

Serious adverse reactions associated with bevacizumab include³⁸:

• Gastrointestinal perforations and fistula
• Surgery and wound healing complications
• Hemorrhage
• Cardiovascular toxicity (eg, arterial and venous thromboembolic events)
• Hypertension
• Posterior reversible encephalopathy syndrome (PRES)
• Kidney injury and proteinuria
• Infusion-related reactions
• Embryo-fetal toxicity
• Ovarian failure
• Congestive heart failure

Other side effects associated with bevacizumab include³⁸: 

• Epistaxis
• Headache
• Rhinitis
• Taste alteration
• Back pain
• Exfoliative dermatitis

Special Populations

Pregnant patients should be advised of the risk of harm to the fetus with bevacizumab treatment. Pregnancy should be avoided during treatment and for 6 months after bevacizumab treatment. Breastfeeding should be discontinued during and for 6 months following the last dose.³⁸ 

The safe and effective use of bevacizumab has not been established in pediatric patients. Patients aged 65 years and older were found to have an increased incidence of arterial thromboembolic events (ATE) with bevacizumab in combination with chemotherapy.³⁸ 

Tisotumab vedotin-tftv

Tisotumab vedotin-tftv is a tissue factor (TF)-directed antibody-drug conjugate comprising a human anti-TF IgG1-κ antibody connected to the microtubule-disrupting agent monomethyl auristatin E (MMAE) via a protease-cleavable valine-citrulline linker.³⁹ Based on the results of a phase 2 trial (innovaTV 204; ClinicalTrials.gov Identifier: NCT03438396) showing durable response, tisotumab vedotin-tftv was granted accelerated approval by the FDA in 2021 for the treatment of recurrent or metastatic cervical cancer.⁴⁰ It is indicated for the treatment of recurrent or metastatic cervical cancer with disease progression on or after chemotherapy.⁴¹ 

Dosing and Administration

The recommended dosage of tisotumab is 2 mg/kg (up to a maximum of 200 mg) IV infusion over 30 minutes every 3 weeks until disease progression or unacceptable toxicity.⁴¹

Adverse Reactions

Serious adverse reactions associated with tisotumab include⁴¹:

• Ocular toxicity, including vision loss and corneal ulceration
• Peripheral neuropathy
• Hemorrhage
• Pneumonitis
• Embryo-fetal toxicity

Other side effects associated with tisotumab include⁴¹:

• Nausea
• Peripheral neuropathy
• Alopecia
• Diarrhea
• Rash
• Nosebleed
• Decreased leukocytes
• Increased creatinine
• Decreased hemoglobin
• Decreased lymphocyte level

To reduce the risk of ocular adverse reactions, patients are advised to undergo a baseline ophthalmic examination and use topical corticosteroid eye drops, topical ocular vasoconstrictor drops, and topical lubricating eye drops.⁴¹

Drug Interactions

Due to the risk of increased exposure to unconjugated MMAE, close monitoring is advised if tisotumab is used together with strong inhibitors of CYP3A4.⁴¹

Special Populations

The pregnancy status of female patients should be confirmed before starting treatment with tisotumab. Pregnant patients should be advised of the risk of fetal harm. Contraception should be used to avoid pregnancy during and for 2 months after the last dose of tisotumab. Breastfeeding should be discontinued during and for 3 weeks after treatment.⁴¹ 

The incidence of adverse reactions was found to be higher in patients aged 65 years and older. Use of tisotumab should be avoided in patients with moderate to severe liver impairment.⁴¹ 

Cervical Cancer Treatment Guidelines

The following guidelines have been provided to assist clinicians with decision-making when managing patients with cervical cancer.

NCCN Clinical Practice Guidelines in Oncology – Cervical Cancer. Version 1.2023, available here.

Cervical Cancer Treatment (PDQ^®) – Health Professional Version from the National Cancer Institute, available here.

Updated Cervical Cancer Screening Guidelines from the American College of Obstetricians and Gynecologists, available here.

Sexually Transmitted Infections Treatment Guidelines, 2021. HPV-Associated Cancers and Precancers, from the US Centers for Disease Control and Prevention, available here. 

Radiation Therapy for Cervical Cancer: An ASTRO Clinical Practice Guideline, from the American Society for Radiation Oncology, available here.

References

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Author Bio

Bora Lee, PhD, earned a BS in biology from Boston College and a PhD in Molecular and Cellular Biology from the University of Massachusetts Amherst. She has more than 10 years of translational research experience in reproductive medicine and women’s health, with a focus on fertility and placental health. She is passionate about improving people’s lives by helping them to make informed health decisions.