Approach

Pre-invasive disease (cervical intra-epithelial neoplasia [CIN]) may spontaneously regress, but if untreated it may develop into invasive cervical cancer. The management of pre-invasive disease is based on screening test results, age, and CIN grade.[90]

  • For patients at low risk of progression (e.g., CIN 1 or age under 25 years), surveillance (with human papillomavirus [HPV] testing, cervical cytology, and/or colposcopy) is usually the preferred option.

  • For patients at higher risk of progression (e.g., age over 25 years and CIN 2 or CIN 3), treatment may involve colposcopy with biopsy, and/or excision or ablation (e.g., a loop electrosurgical excision procedure, laser cone biopsy, large loop excision of the transformation zone, or cold knife cone biopsy) to remove the transformation zone and produce a specimen for histological analysis.

​Local excisional and ablative treatments for pre-invasive and early invasive disease are associated with an increased risk of preterm birth.[112] Excision is associated with a higher frequency and severity of adverse sequelae than ablation, which increase with greater cone depth and dimensions.

The treatment of invasive cervical cancer is based on disease stage, desire to maintain fertility, performance status (i.e., suitability for surgery), and presence of lymphovascular space invasion (LVSI). Generally, adenocarcinomas are treated in the same way as squamous cell carcinomas.

International Federation of Gynecology and Obstetrics (FIGO) updated 2018 staging is used in this topic.[103][104]​ In patients with early stage disease (stages IA1 to IB2) who wish to maintain fertility, adjustments to treatment may be appropriate in specific circumstances.[113] The reproductive wishes of patients of reproductive age should be discussed, and the infertility risks and fertility-preserving options explained before starting treatment.[114]

Treatment options for invasive cervical cancer include cone biopsy, hysterectomy, trachelectomy, radiotherapy, and chemoradiotherapy. Sentinel lymph node (SLN) mapping or lymphadenectomy may be carried out during surgery to further evaluate lymph node involvement and guide adjuvant treatment.[93]

Treatment plans are based on clinical practice guidelines, local expertise, available resources, and individualised discussion between the patient and physician.

Cone biopsy

Cone biopsy is carried out for evaluation of early stage disease. It may be a fertility-sparing or conservative treatment option for highly selected patients with stage IA1, IA2, or IB1 disease, followed by careful surveillance.[93] Cold knife conisation is the preferred cone biopsy procedure. Loop electrosurgical excision procedure may be acceptable if adequate margins, proper orientation, and a non-fragmented specimen can be obtained.[93] Endocervical sampling should also be performed (except in pregnancy). Cone biopsy may be repeated if margins are positive, to re-evaluate depth of invasion, and to rule out more advanced disease.

Hysterectomy

Hysterectomy is the preferred treatment for early stage disease when fertility preservation is not desired; resection may limit the need for adjuvant treatment.[115][116]​​​​​ The type of hysterectomy performed varies depending on disease stage, treatment intent (e.g., curative), and patient preference. The Querleu and Morrow classification system describes degree of resection and nerve preservation.[117][118]​​ Simple (extrafascial) hysterectomy (Querleu-Morrow type A) and modified radical hysterectomy (type B) are curative options for microinvasive disease and small lesions (stage IA1-IB1 disease); for larger lesions (stage IB1-IIA1), nerve-sparing radical hysterectomy (type C1) is typically recommended.[93][119][120][121]

Open surgery is preferred for radical hysterectomy; minimally invasive radical hysterectomy (i.e., laparoscopic or robot-assisted) is associated with lower disease-free and overall survival compared with open abdominal surgery.[122][123][124]​​ Clinicians should assess the risks and potential benefits of each surgical approach for the individual patient, and counsel accordingly.​[60][93]​​​​​​ Studies are ongoing to identify which patients might safely benefit from minimally invasive surgery.[125][126]

Age does not appear to be a significant contraindication to radical hysterectomy. Class III obesity (i.e., body mass index ≥40) is a relative contraindication to surgery, and operative risk may need to be weighed against the risks of alternative treatment options.[127][128]

Trachelectomy

Trachelectomy is a fertility-sparing option for carefully selected patients with early stage disease. Simple trachelectomy may be considered for microinvasive disease (stage IA1); radical trachelectomy for stages IA1, IA2, IB1, and for select IB2 cases.[93] Minimally invasive procedures may be considered for cervical cancer patients with preoperative tumour size of ≤2 cm, but there is a lack of data on oncological outcomes.[93][129] 

Retrospective studies suggest that radical trachelectomy may be associated with an increased but acceptable risk of recurrence compared with radical hysterectomy.[130] Risk of recurrence may be increased in patients with tumour size >2 cm after any type of fertility-sparing procedures.[131] Patients with tumour size >2 cm who undergo radical abdominal trachelectomy may require adjuvant therapy, which will affect their fertility.[93][113][132][133][134][135]​ ​

Radical trachelectomy using a vaginal approach is typically recommended for tumours <2 cm. An abdominal approach allows greater resection of parametrial tissue than the vaginal approach and is favoured for larger tumours.

Risk of loss of pregnancy and preterm labour is increased in patients following radical trachelectomy due to cervical weakness. Systematic reviews suggest that oncological outcomes are similar for different fertility-sparing techniques, but that vaginal radical trachelectomy may achieve improved reproductive outcomes.[136][137][138] Further research is needed to determine fertility and pregnancy outcomes for different procedures.

Radiotherapy and chemoradiotherapy

Radiotherapy, with or without chemotherapy, is used in the definitive and postoperative management of cervical cancer. Radiotherapy alone is an effective option for patients with early stage disease or for those who are not candidates for surgery.[93][139][140]

Radiotherapy

Radiotherapy may be given using external beam radiotherapy (EBRT) and/or brachytherapy. EBRT delivers radiation directly to the tumour site. Intensity-modulated radiotherapy (IMRT) should be considered to reduce acute and chronic toxicity in definitive treatment of the pelvis (with or without para-aortic treatment).[139]

Brachytherapy is an integral component of definitive radiotherapy for patients with primary cervical cancer, performed using an intracavitary and/or an interstitial approach. Brachytherapy is usually given following EBRT, as a radiation boost to the primary tumour. Brachytherapy has been shown to decrease recurrence rates and improve survival in combination with EBRT compared with EBRT alone.[141][142][143][144] In highly selected, very early stage disease, brachytherapy alone (without EBRT) may be an option. Image-guided brachytherapy is recommended; magnetic resonance imaging (MRI)-guided adaptive brachytherapy is the gold standard brachytherapy technique.[139][145][146][147]

Extended-field pelvic and para-aortic EBRT are recommended for locally advanced disease with positive para-aortic and pelvic lymph nodes (stage IIIC, identified by imaging or surgical staging) without distant metastases.[93]

Chemoradiotherapy

Systematic reviews and meta-analyses confirm that chemoradiation is superior to radiotherapy alone in improving progression-free and overall survival, and reducing local and distant recurrence in locally advanced disease.[148][149] Cisplatin was the most commonly used chemotherapeutic agent.[148][149] Acute gastrointestinal toxicity was significantly more common in the chemoradiation groups; cisplatin-based chemoradiation was not associated with increased late toxicity in one randomised trial.[148][149][150]

Cisplatin plus EBRT and brachytherapy is the preferred regimen for patients with locally advanced disease. It may be an option for some patients with stage IB1, IB2, or IIA1 disease (e.g., if surgery is not suitable), with careful consideration of the risks and benefits. Carboplatin may be considered for patients who cannot tolerate cisplatin.[93] Other chemotherapy regimens may be effective, including two-drug regimens (e.g., cisplatin plus fluorouracil, cisplatin plus gemcitabine).[150][151][152] However, chemotherapy regimens that incorporate multiple-drug regimens are not recommended because of increased toxicity.[152][153][154]

Lymphadenectomy and SLN mapping

Pelvic lymphadenectomy or SLN mapping should be performed for most patients having surgical treatment for stage I and II disease to assess for lymph node metastases.[93] These procedures are not generally required for patients with stage IA1 disease without LVSI, because the risk of nodal metastases is very small (less than 1%). For patients with large tumours, para-aortic node dissection may be performed if nodal involvement is suspected or confirmed.[93][155]

SLN mapping may safely reduce the need for extensive pelvic lymph node dissection in many patients with early stage disease.[156][157]​​​​ SLN mapping is associated with fewer complications than lymphadenectomy; however, long-term survival data comparing these techniques is lacking.[158][159]​​ Detection rate for SLN is highest if the tumour is <2 cm, although SLN mapping has been used in tumours up to 4 cm in size.[60][93]

Ultrastaging should be carried out for increased detection of micrometastasis.[93] Sentinel nodes should be detected on both sides, and all suspicious lymph nodes should be removed.[156][157]​ If SLN mapping fails, side-specific nodal dissection should be carried out.[93]

Stage IA1 disease without LVSI

Primary treatment options for patients with stage IA1 disease without LVSI who want to maintain fertility include:[93]

  • Cone biopsy (with negative margins) followed by surveillance.

If cone biopsy reveals positive margins, options include:[93]

  • Repeat cone biopsy (to re-evaluate depth of invasion and rule out more advanced disease), or

  • Trachelectomy.

Primary treatment options for patients with stage IA1 disease without LVSI not desiring fertility include:[93]

  • Cone biopsy (with negative margins) followed by simple (type A) hysterectomy (if surgical candidate), or followed by surveillance (non-surgical candidate).

If cone biopsy reveals positive margins, options include:[93]

  • Repeat cone biopsy (to re-evaluate depth of invasion and rule out more advanced disease), or

  • Simple (type A) hysterectomy (if margins are positive for dysplasia), or

  • Modified radical (type B) hysterectomy plus SLN mapping or pelvic lymphadenectomy (if margins are positive for carcinoma), or

  • Brachytherapy with or without pelvic EBRT (if non-surgical candidate).

Stage IA1 disease with LVSI

Primary treatment options for patients with stage IA1 disease with LVSI who want to maintain fertility include:[93]

  • Radical trachelectomy plus SLN mapping or pelvic lymphadenectomy, or

  • Cone biopsy (with negative margins) plus SLN mapping or pelvic lymphadenectomy.

If cone biopsy reveals positive margins, options include:[93]

  • Repeat cone biopsy (to re-evaluate depth of invasion and rule out more advanced disease) or radical trachelectomy plus SLN mapping or pelvic lymphadenectomy.

Primary treatment options for patients with stage IA1 disease with LVSI not desiring fertility include:[93]

  • Modified radical (type B) hysterectomy plus SLN mapping or pelvic lymphadenectomy (if surgical candidate), or

  • Pelvic EBRT plus brachytherapy (if non-surgical candidate).

Stage IA2 disease: non-conservative surgery candidate

Primary treatment options for patients with stage IA2 disease who want to maintain fertility include:[93]

  • Radical trachelectomy plus SLN mapping or pelvic lymphadenectomy (with positive or negative margins), or

  • Repeat cone biopsy (with positive margins; to re-evaluate depth of invasion and rule out more advanced disease), or

  • Cone biopsy (with negative margins) plus SLN mapping or pelvic lymphadenectomy.

Primary treatment options for patients with stage IA2 disease not desiring fertility include:[93]

  • Modified radical (type B) hysterectomy plus SLN mapping or pelvic lymphadenectomy (if surgical candidate), or

  • Pelvic EBRT plus brachytherapy (if non-surgical candidate).

Stage IA2 and IB1 disease: conservative surgical treatment

Patients with stage IA2 or IB1 disease may be considered for conservative surgical treatment if they meet all of the following criteria: no LVSI; negative cone margins; squamous cell (any grade) or usual type adenocarcinoma (grade 1 or 2 only); tumour size ≤2 cm; depth of invasion ≤10 mm; and negative imaging for locoregional (for fertility-sparing treatment) or metastatic disease.[93][119][121]​​

Conservative surgical treatment for patients who want to maintain fertility is:

  • Cone biopsy (with negative margins) plus SLN mapping or pelvic lymphadenectomy.

Conservative surgical treatment for patients not desiring fertility is:

  • Simple (type A) hysterectomy plus SLN mapping or pelvic lymphadenectomy.

Stage IB1, IB2, and IIA1 disease

Primary treatment option for patients with stage IB1 disease (not meeting conservative surgery criteria) and select patients with IB2 disease who want to maintain fertility is:[93]

  • Radical trachelectomy plus SLN mapping or pelvic lymphadenectomy, with or without para-aortic lymphadenectomy.

Primary treatment options for patients with stage IB1 (not meeting conservative surgery criteria) or IB2 disease not desiring fertility, and all patients with stage IIA1 disease include:[93]

  • Radical (type C1) hysterectomy plus SLN mapping or pelvic lymphadenectomy, with or without para-aortic lymphadenectomy (if surgical candidate), or

  • Pelvic EBRT plus brachytherapy with or without concurrent platinum-containing chemotherapy (if non-surgical candidate).

Stage IB3 and IIA2 disease

Chemoradiation is preferred in patients with bulky tumours measuring ≥4 cm (stage IB3 and IIA2) given the high likelihood that postoperative chemoradiation will be required for adverse pathological findings if hysterectomy is carried out initially.[148][160][161][162]

Primary treatment options for patients with stage IB3 or IIA2 disease include:[93]

  • Pelvic EBRT plus concurrent platinum-containing chemotherapy plus brachytherapy (preferred treatment), or

  • Radical (type C1) hysterectomy plus pelvic lymphadenectomy with or without para-aortic lymphadenectomy.

Adjuvant (completion) hysterectomy may be considered if there is a poor response (with evidence of residual disease) after chemoradiation (including brachytherapy), or if brachytherapy is not feasible.[93][163]​​

Stage IIB to IVA disease

Primary treatment for patients with stage IIB to IVA disease is:[93]

  • Pelvic EBRT plus concurrent platinum-containing chemotherapy plus brachytherapy (if no lymph node involvement).

Imaging studies are recommended for evaluation of nodal or extrapelvic involvement and to guide treatment. Para-aortic lymph node EBRT or extended-field EBRT may be indicated depending on pelvic and para-aortic lymph node status on imaging or surgical staging.[93]

Stage IVB (metastatic disease)

Molecular biomarker analysis, including programmed death ligand 1 (PD-L1), human epidermal growth factor receptor 2 (HER2), and microsatellite instability/mismatch repair (MSI/MMR) status, is recommended for patients with metastatic disease to help guide targeted therapy options and/or eligibility for clinical trials.

Molecular profiling may be considered using an FDA-approved assay or validated test including at least HER2, MMR/MSI, tumour mutational burden (TMB), and NTRK and RET gene fusions.[93] If analysis of tissue is not possible, comprehensive genomic profiling (using a validated plasma circulating tumour DNA assay) may be an option.[93] 

First-line therapies for metastatic disease

Combination chemotherapy plus bevacizumab (a vascular endothelial growth factor-directed monoclonal antibody) is a preferred first-line treatment option for metastatic disease.[93] Cisplatin plus paclitaxel is the preferred chemotherapy regimen. Carboplatin plus paclitaxel is a less toxic option, recommended for patients who have received previous cisplatin therapy. Cisplatin plus topotecan is an option if taxanes are not suitable.[93][164][165][166]​ The addition of bevacizumab has been shown to increase survival rate.[167][168]​​

The checkpoint inhibitor pembrolizumab (an anti-programmed death 1 monoclonal antibody) may be combined with chemotherapy (with or without bevacizumab) in patients with PD-L1-positive metastatic disease.[93] The addition of pembrolizumab to chemotherapy (with or without bevacizumab) improves progression-free and overall survival in PD-L1-positive patients, without reducing patient-reported quality of life.[169][170][171][172]​​​

Further first-line options include:[93]

  • Combination chemotherapy regimens without bevacizumab (e.g., cisplatin plus paclitaxel, carboplatin plus paclitaxel, topotecan plus paclitaxel, cisplatin plus topotecan); or

  • Single-agent chemotherapy (e.g., cisplatin or carboplatin).

Distant metastases amenable to local treatment

In patients with isolated distant metastases that are amenable to local treatment, the following therapy options can be considered:[93]

  • Surgical resection with or without EBRT

  • Local ablative therapies with or without EBRT

  • EBRT with or without chemotherapy

Consideration may be given to adjuvant chemotherapy for these patients.

Subsequent therapies for metastatic disease

If first-line combination chemotherapy-based regimens or local treatments fail or are not tolerated, individualised discussion between the oncology specialist, the patient, and the family regarding personal goals of treatment, perceived quality of life, and baseline performance status guides the decision on further therapy.

Second-line or subsequent options may include single-agent chemotherapy, immunotherapy, targeted therapies (including bevacizumab), enrolment in a clinical trial, or supportive care. Preferred second-line treatments include pembrolizumab (for tumours positive for PD-L1 or MSI/MMR deficiency, or with high MTB) or tisotumab vedotin.[93][173][174]

The most active single-agent chemotherapy is cisplatin (response rate is approximately 20% to 30%).[93] If cisplatin has been used previously, or is contraindicated or not tolerated, alternative single agents include: carboplatin or paclitaxel. 

Targeted therapies may include trastuzumab deruxtecan (a HER2-directed antibody-conjugate) for HER2-positive tumours.[93]

Supportive care

Offered alongside treatment for metastatic disease or as an alternative to further chemotherapy in some patients.[93] Best supportive care addresses physical, psychological, social, and spiritual issues. Common medical challenges include pain, nausea and vomiting, lymphoedema, obstruction (genitourinary and gastrointestinal), and fistulae.

Adjuvant treatment

Following surgery, it is essential to evaluate surgical pathology to guide decisions on adjuvant therapy.

Postoperative chemoradiation is required if surgical pathology reveals positive nodes, involvement of the parametrium, or positive margins in patients with stage IA2, IB, or IIA disease.[93][160][175] Cisplatin plus EBRT with or without brachytherapy is the standard regimen for postoperative chemoradiation.[160]

Adjuvant treatment should also be considered in patients with negative nodes, no parametrial involvement, and negative margins, if they have two or more of the following intermediate-risk factors (i.e., the Sedlis criteria): LVSI, deep stromal invasion, and/or large tumour size.[176] Postoperative EBRT with or without concurrent platinum-containing chemotherapy may be considered.[176][177] Optimal adjuvant treatment for intermediate-risk disease has not been determined.[139][178]

No further treatment is required for patients with negative nodes, no parametrial involvement, negative margins, and with one or no intermediate-risk factors. Patients should be monitored for recurrence.[93]

Local or regional recurrent disease

In patients with local or regional recurrence who have not had previous radiotherapy, surgical resection (if possible) followed by tumour-directed EBRT with chemotherapy and/or brachytherapy may be considered.[93]

In patients with central pelvic recurrence after radiotherapy, the following options may be considered:

  • Pelvic exenteration with or without intraoperative radiotherapy, or

  • In carefully selected patients (with small central lesions <2 cm): radical hysterectomy, or brachytherapy, or EBRT with or without chemotherapy.

For patients with non-central recurrence, options may include:

  • EBRT with or without chemotherapy, or

  • Surgical resection with or without intraoperative radiotherapy, or

  • Chemotherapy, or

  • Supportive care.

The long-term survival for patients who undergo successful exenterative surgery (pathological negative margins and no unresectable or extrapelvic disease) is approximately 50%, but treatment-related severe morbidity is high.[179] Rehabilitation programmes should be provided following exenterative surgery.

Drug therapy (e.g., chemotherapy, immunotherapy, bevacizumab), a clinical trial, and supportive care are options for further recurrence (metastases).[93]

Pregnant patients

A positive screening test or acute presentation of cervical cancer during pregnancy is unusual. Most patients have stage I disease, but those with invasive disease may have to make difficult decisions, such as whether to delay treatment or terminate the pregnancy.

Surgery is typically avoided, and radiotherapy absolutely contraindicated as it would result in pregnancy termination and fetal death. Treatment options depend on the stage of cancer at diagnosis and the trimester of pregnancy.

When diagnosed in the first trimester, pregnancy termination is often discussed to allow for standard treatment that entails surgery or definitive chemoradiation.[180]

A cone biopsy (without endocervical sampling) may be used to treat stage IA1 tumours without LVSI.[93] For stage IA1 tumours with LVSI, IA2 and IB1, staging lymphadenectomy may be performed up to 22 weeks.[181] Radical trachelectomy with successful pregnancy preservation has been reported in a few patients with early stage disease.[93] Termination of pregnancy is usually recommended if there are nodal metastases (including micrometastases).

In patients with node positive or locally advanced disease who wish to preserve their pregnancy, chemotherapy during the second or third trimester appears to be safe, but there are little data on the risk of late complications.[182] Alternatively, chemotherapy may be delayed until after delivery and the patient followed up regularly.[181]

Patients diagnosed with cervical cancer in the third trimester who proceed with pregnancy should have multidisciplinary care and delivery by caesarean section after 35 weeks.

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