Embracing and implementing the WHO cervical cancer elimination campaign goals: A consensus statement by SGO, ACOG, ASCCP, ASTRO, and ABS on minimum quality care standards for cervical cancer patients in the U.S

1. Rationale for standardization of care for cervical cancer

The World Health Organization (WHO) has published the metrics for elimination of cervical cancer as a public health problem: 90 % of girls fully vaccinated against human papillomavirus (HPV) by the age of 15; 70 % of women screened using high-performance tests by the age of 35 and again by the age of 45 years; and 90 % of women with pre-cancer and 90 % of women with invasive cancer managed [1]. Despite the availability of the prophylactic HPV vaccine and well-established cervical cancer screening and management guidelines, over 10,000 cases of cervical cancer are diagnosed annually in the United States, with a disproportionate number diagnosed in minorities and underserved individuals [2]. Both systemic racism and unconscious bias within the healthcare system contribute to disparate treatment. The objective of this paper is to set minimum standards for cervical cancer treatment in the United States to bridge the gap in cervical cancer outcomes by minimizing bias, overcoming access issues, and improving equity. Terminology used for recommendations was adopted from the ASCCP management recommendations for consistency (Box 1) [3]. Standards were arrived at though a multidisciplinary consensus discussion with representatives from the Society of Gynecologic Oncology (SGO), the American College of Obstetricians and Gynecologists (ACOG), ASCCP, the American Society for Radiation Oncology (ASTRO), and the American Brachytherapy Society (ABS); the final document was subsequently endorsed by these organizations, with support from ACOG.

Box 1. Terminology for recommendations (Adopted from ASCCP methodology).

Recommended	Good data to support use when only 1 option is available
Preferred	Option is the best (or one of the best) when there are multiple options
Acceptable	One of multiple options when there are data either indicating that another approach is superior or when there are no data to favor any single option
Not recommended	Weak evidence against use and marginal risk for adverse consequences
Unacceptable	Good evidence against use

2. Vaccination, screening, and treatment disparities in the U.S

Despite the proven efficacy of HPV vaccination and cervical cancer screening in decreasing cervical cancer incidence and mortality, significant disparities still exist in the United States along racial and socioeconomic lines [4–6]. Black patients and those with public insurance are less likely to complete vaccination series [7]. Furthermore, black and Hispanic patients are less likely to undergo screening with HPV-based testing which is more sensitive than traditional liquid-based cytology [8,9]. It is imperative to acknowledge the need for improved HPV vaccine uptake, timely screening, and access to evidence-based management of abnormal results.

The delivery of evidence-based care, including definitive surgery and/or optimal radiation therapy, are both associated with insurance status [10,11]. High quality treatment can negate racial disparities in outcomes for most cancers in general, and cervical cancer specifically. A study of patients in the United States Military Health System revealed that equitable cancer treatments resulted in similar outcomes between non-white and White patients [12]. In addition, a review by the Health Disparities Taskforce of the Society of Gynecologic Oncology on the incidence, treatment and survival of gynecological cancers found that equal treatment for cervical cancer resulted in equal survival outcomes for Black and White patients [13]. The interplay of race, ethnicity and social determinants of health in primary and secondary preventative strategies and cervical cancer treatment are further explored in a companion paper [72].

3. Cervical cancer care standards

3.1. Diagnosis and workup

3.1.1. Pathology testing

• Definitive tissue diagnosis from biopsy or excisional procedure of a gross lesion or excisional procedure on a microscopic lesion to determine tumor size and depth of invasion is recommended.

• PD-L1 testing on all cervical tumors is recommended. Incorporation of additional biomarkers is recommended as standards-of-care for biomarker testing and biomarker-directed treatment evolve.

Accurate staging of cervical cancer is a necessary component of treatment planning and prognostic counseling. Diagnosis requires tissue for pathologic assessment either from an excisional specimen or a biopsy of a cervical mass. The College of American Pathologists (CAP) has set the standard for a two-business day turnaround time for all biopsy results [14]. For oncologic surgical specimens, CAP advocates for synoptic reporting which is a standardized format for reporting surgical pathology elements [15]. This streamlines data processing and improves completeness of surgical pathology reports [16]. As more trainees seek subspecialty training outside of anatomic pathology, ensuring quality surgical pathology will become increasingly challenging, with demand outpacing staffing. [17].

Systemic therapy for cervical cancer is becoming more individualized, with decision-making regarding the addition of immune checkpoint inhibitors often based on tumor PD-L1 expression. At a minimum, PD-L1 testing is recommended for all cervical cancers. Additional biomarker testing should be incorporated as the standard-of-care evolves and as effective biomarker-directed therapies are developed.

3.1.2. Diagnostic imaging

• For Stage IA tumors, pelvic MRI to determine extent of local disease is acceptable.

• For Stage IB to IVA tumors pelvic MRI and PET/CT are preferred to evaluate extent of local disease and to evaluate for metastatic disease, respectively; CT is acceptable if PET is not available.

Highly sensitive imaging is often necessary to determine the full extent of disease and guide treatment planning. Baseline imaging consisting of MRI and PET/CT are preferred, although CT is acceptable if PET/CT is not available [18]. Table 1 depicts the updated 2018 FIGO staging for cervical cancer which incorporates clinical, radiologic, and pathologic findings. Imaging should be reported in a standardized fashion in compliance with American College of Radiology standards to facilitate interpretation and implementation of treatment recommendations based on imaging findings [19]. Unfortunately, access to quality imaging studies with timely reporting may become a limited resource with 53 % of the radiology workforce in the US being 55 years of age or older [20]. Radiology technicians are similarly facing a shortage, further compounding this issue and contributing to scheduling delays. While artificial intelligence has been suggested to bridge the growing demand for radiology services, minimum standards must be met to ensure appropriate radiographic staging [21,22].

Table 1.

Updated FIGO 2018 cervical cancer staging.

FIGO Stage	Description
I	Carcinoma is confined to the cervix
IA	Invasive carcinoma that can only be diagnosed with microscopy, with maximum depth of invasion <5 mm
IA1	Stromal invasion <3 mm in depth
IA2	Stromal invasion ≥3 mm and <5 mm in depth
IB	Invasive carcinoma confined to the uterine cervix, with measured deepest invasion ≥5 mm
IB1	Tumor measures <2 cm in greatest dimension
IB2	Tumor measures ≥2 cm and <4 cm in greatest dimension
IB3	Tumor measures ≥4 cm in greatest dimension
II	Carcinoma invades beyond the uterus, but has not extended into the lower third of the vagina or pelvic wall
IIA	Limited to the upper two-thirds of the vagina without parametrial involvement
IIA1	Tumor measures <4 cm in the greatest dimension
IIA2	Tumor measures ≥4 cm in greatest dimension
IIB	Parametrial involvement but no invasion in pelvic wall
III	Carcinoma involves the lower third of the vagina, and/or extends to the pelvic wall, and/or causes hydronephrosis or nonfunctioning kidney, and/or involves pelvic or para-aortic lymph nodes
IIIA	Involves the lower third of the vagina, with no extension to the pelvic wall
IIIB	Extension to the pelvic wall and/or hydronephrosis or nonfunctioning kidney from tumor
IIIC*	Involvement of pelvic and/or para-aortic lymph nodes
IIIC1	Pelvic lymph node metastasis only
IIIC2	Para-aortic lymph node metastasis
IV	Carcinoma has extended beyond the true pelvis or has involved the mucosa (biopsy-proven) of the bladder or rectum
IVA	Spread to the adjacent pelvic organs
IVB	Spread to distant organs

^*Stage IIIC should be annoted with p (pathologic) or r (radiologic) to indicate the method used to allocate this stage.

3.2. Treatment planning

3.2.1. Multidisciplinary care coordination

• Referral to a gynecologic oncologist for treatment planning and coordination is recommended.

In general, patients with gynecologic malignancies experience better outcomes when treated by a gynecologic oncologist. While more research is needed to examine outcomes for cervical cancer specifically, this has been documented for patients with ovarian cancer and endometrial cancer [23]. Following pathologic diagnosis and radiographic evaluation of disease, a multidisciplinary approach is often needed to deliver optimal care, and gynecologic oncologists are often best situated to coordinate care among the necessary specialties, including radiation oncology and medical oncology. A study in Japan examined survival rates of patients with cervical cancer and found an association with the number of board-certified gynecologic oncologists per hospital [24].

Unfortunately, access to gynecologic oncologist can be difficult. As of 2019, among 3142 counties in the United States, 91.2 % had no gynecologic oncologist in their local county, and 61.8 % had no gynecologic oncologist in local or adjacent counties [25]. In addition, the demand for gynecologic oncologists continues to grow without a sufficient workforce to meet these needs. While better strategies are needed to increase patient access to a gynecologic oncologist, collaborative disease assessments and management can be implemented [25]. For instance, baseline assessments can be performed by the referring gynecologist or primary care provider, including sampling for pathologic diagnosis and baseline imaging to expedite management. Moreover, gynecologists can facilitate discussions about supportive care issues including fertility preservation, sexual health, treatment impact on the pelvic floor and management of treatment-induced menopause.

3.3. Timing to treatment initiation

• Treatment initiation within 4 weeks of diagnosis is preferred.

• For patients undergoing a diagnostic excisional procedure, delay of hysterectomy of up to 6 weeks is acceptable to decrease the risk of infectious complications.

Efficient time to treatment initiation (TTI) plays a significant role in improving patient outcomes and decreasing potential patient distress. Research has demonstrated that delays in initiation of care in all patients with cancer increases the risk of overall mortality from 1 to 3 % per week in patients with potentially curative early-stage cancers [26]. Delays in treatment initiation of more than 4 weeks have been shown to increase the risk of mortality [27–29]. These studies also show that the impact is primarily due to delays in surgically resectable disease, as patients who receive chemotherapy are less likely to experience a delay in TTI. In cervical cancer specifically, there are known disparities including delayed TTI in Black and Hispanic patients [30]. Contributing factors include socioeconomic factors, delays in authorization for diagnostic modalities, having to see multiple providers from various teams, and rural living [31]. In the absence of specific data for metastatic or recurrent cervical cancer and based on other data from other cancer types, the goal should be to initiate therapy within 4 weeks of diagnosis. However, for patients undergoing a surgical excision for diagnostic purposes, scheduling a definitive hysterectomy no earlier than six weeks is generally recommended to decrease infectious complications [32].

3.4. Treatment by stage

3.4.1. Localized disease

• For stage IA1 cervical cancer without lymphovascular space invasion (LVSI) a simple (extrafascial) hysterectomy is recommended.

• For stage IA1 cervical cancer with LVSI or stage IA2 cervical cancer lymph node evaluation is recommended, and either a radical hysterectomy or simple hysterectomy is acceptable if low-risk disease criteria are met (see Table 2); radical hysterectomy is recommended for disease not meeting low-risk criteria.

• Fertility-sparing surgery is acceptable for Stage IA1 to IB1 disease provided all of the disease (including pre-invasive disease) can be removed without removing the uterus. For Stage IA1 cervical cancer without LVSI cervical conization is preferred. For Stage IA1 cervical cancer with LVSI and low-risk stage IA2 to IB1 disease lymph node sampling is recommended and either radical trachelectomy or cervical conization with negative margins is acceptable (see Table 2, ConCERV eligibility, FIGO 2009 staging); for tumors not meeting the low-risk criteria, radical trachelectomy is recommended.

• For stage IB2 and IIA cervical cancer, radical hysterectomy with lymph node sampling is recommended.

• Open surgery is preferred over a minimally invasive surgical approach pending additional clinical trial results. Minimally invasive surgery is acceptable as part of shared decision-making and after carefully weighing risks and benefits of the surgical approaches.

• For lymph node sampling, either full pelvic lymphadenectomy or sentinel lymph node biopsies is acceptable.

• For localized tumors with intermediate risk factors on hysterectomy pathology either adjuvant radiation therapy or observation is acceptable. For localized tumors with high-risk features adjuvant chemoradiation therapy is recommended.

• For Stage IA1 cervical cancer with LVSI to Stage IB2, primary chemoradiation therapy rather than surgical management is acceptable.

Table 2.

Inclusion and Exclusion criteria for ConCerv and SHAPE trials for non-radical surgery for stage I cervical cancer.

ConCERV Trial Inclusion and Exclusion Criteria1
Inclusion Criteria	Exclusion Criteria
- FIGO 2009 stage IA2 or IB1 (tumor size no greater than 2 cm)	- Other histologic subtypes
- Squamous cell carcinoma (any grade), Grade 1 or 2 adenocarcinoma	- Grade 3 adenocarcinoma
- Tumor size ≤ 2 cm based on imaging or physical examination	- Lesions measuring more than 2 cm
- Absence of lymphovascular space invasion	- Any evidence of metastatic disease on preoperative imaging
- Absence of metastatic disease on CT, MRI or PET/CT imaging	- Margins <1.0 mm for both the endo-and ectocervical in terms of invasive cancer, adenocarcinoma in situ of cervical intraepithelial neoplasia 2 or 3
-Depth of invasion ≤ 10 mm
-Negative conization margins and endocervical curettage for both malignancy and high-grade dysplasia
SHAPE Trial Inclusion and Exclusion Criteria2
Inclusion Criteria	Exclusion Criteria
-FIGO 2009 stage IA2 or IB1 (tumor size no greater than 2 cm)	-Other histologic subtypes
-Squamous cell carcinoma, adenocarcinoma, adenosquamous carcinoma	-Lesions measuring more than 2 cm
-Cervical stromal invasion <10 mm (depth of invasion) on the tissue sample (LEEP or conization) or MRI showing invasion of less than 50 % of cervical stromal tissue (MRI required for lesions > Stage IA2)	-Any evidence of metastatic disease on preoperative imaging
-Any histologic grade
-No evidence of lymph node metastasis on imaging
-MRI mandatory except for stage IA2 with LEEP or cone

¹Schmeler et al. [33].

²Plante et al. [35].

Management of early-stage cervical cancer depends on tumor factors after cervical excision, desire for future fertility, and medical fitness for surgery. For patients diagnosed with stage IA1 disease without lymphovascular space invasion (LVSI), a simple (extrafascial) hysterectomy is sufficient. For Stage IA1 disease with LVSI and Stage IA2 disease, the National Comprehensive Cancer Network guidelines version 4.2024 recommend radical hysterectomy with lymph node evaluation. It is important to note, however, that less radical surgeries have been studied in comparison to radical hysterectomy and found to be noninferior in select low risk disease [33–35]. Most recently, the SHAPE trial showed that for patients with low risk cervical cancer defined as FIGO 2009 stage IA2-IB1 squamous cell or adenocarcinomas of any grade and tumors <2 cm, depth of invasion of <10 mm on conization specimen or <50 % of the cervical stromal tissue on MRI and no evidence of lymph node metastases on preoperative imaging, that a simple hysterectomy with lymph node assessment was non-inferior to radical hysterectomy with a similar incidence of pelvic recurrence at 3-years [35]. Specifically, the incidence of pelvic recurrence at three years was 2.17 % for those treated with a radical hysterectomy as compared to 2.52 % for the simple hysterectomy group. The ConCERV trial, which included a similar patient population but excluded disease with LVSI and grade 3 adenocarcinoma showed a 3.8 % recurrence rate at a median follow-up of 36.3 months among patients who underwent cone biopsy followed by simple hysterectomy and lymph node assessment [33]. Table 2 depicts inclusion and exclusion criteria for the ConCerv and SHAPE trials for non-radical surgical management. Implementation of less radical surgery may reduce surgical morbidity but is imperative that thorough preoperative evaluation is performed prior to performing less radical surgery.

Surgery for cervical cancer in the United States should be performed by a gynecologic oncologist who is uniquely trained to perform the complex surgeries and detailed counseling necessary for the treatment of cervical cancer. Importantly, route of surgery may impact outcomes. Results from the LACC trial showed surgery performed via a minimally invasive approach was associated with a higher 3-year risk of recurrence or disease (HR 3.74, 95 % CI 1.63–8.58), and once again made the open approach to surgery for cervical cancer the preferred approach [36,37]. Reasons for this difference are unclear, and proposed mechanisms include lack of adequate preoperative imaging assessment, use of a transcervical uterine manipulator, and lack of tumor containment. Ongoing clinical trials which control for these factors, such as the ROCC trial (NCT 04831580), will further define the acceptable minimally invasive surgical approach. Until level 1 evidence showing non-inferiority of minimally invasive surgery for treatment of stage I cervical cancer is available, the open surgical approach is preferred, with minimally invasive surgery reserved for clinical trial participants, or off-trial as part of shared decision-making and after careful consideration of surgical and disease risks and benefits.

Fertility-sparing therapy can be performed for stage IA1 to IB1 disease provided all of the disease can be removed without removing the uterus. For patients with stage IA1 disease without LVSI, a cervical conization with negative margins is sufficient. If a patient has stage IA1 disease with LVSI, evaluation of the lymph nodes must be performed in addition to a conization with negative margins; alternatively, these patients may be treated with radical trachelectomy and lymph node evaluation. For patients with Stage IA2 to IB1 disease with ≤10 mm depth of invasion, no LVSI and squamous cell or grade 1–2 adenocarcinoma histology who desire to retain their fertility (ConCerv eligibility, FIGO 2009 staging, Table 2), pelvic lymph node sampling with either a cervical conization with negative margins or a radical trachelectomy is an option. For Stage IA2 to IB1 disease not meeting those criteria, a radical trachelectomy with lymph node sampling is recommended. Fertility-sparing therapy for tumors >2 cm is not generally recommended, and radical trachelectomy should only be performed in very select patients. Fertility sparing options are not recommended for aggressive histology such as small cell neuroendocrine or gastric type adenocarcinoma.

While historically a full pelvic lymphadenectomy has been utilized for nodal evaluation, sentinel lymph node mapping and biopsies is acceptable by those adept at the procedure [18]. The prospective SENTIREC trial evaluated sentinel lymph node biopsies in patients with Stage IA2 disease with LVSI, and IB1 to IIA1 disease (FIGO 2009 staging). Patients with stage IA2 to IB1 disease and tumor size ≤20 mm underwent sentinel lymph node biopsies only; tumors >20 mm, Stage IB2 and IIA underwent sentinel lymph node biopsy followed by full pelvic lymphadenectomy. Results from this study showed sensitivity of sentinel lymph node biopsies of 96.3 % (95 % CI 81.0–99.9 %) and negative predictive value of 98.7 % (95 % CI 93.0–100 %) [38].

For Stage IA1 or IA2 disease with LVSI and stage IB1 to IB2 disease primary chemoradiation therapy is also an option with similar oncologic outcomes. However, surgery is generally preferred if it is feasible due to higher risk for long-term morbidity associated with chemoradiation therapy.

Following surgery, adjuvant pelvic radiation therapy should be considered for tumors with intermediate risk factors (Table 3). A randomized controlled trial showed a decreased risk of recurrence at 2 years (88 % vs. 79 %), but a follow-up study showed no difference in overall survival [39,40]; Grade 3–4 urologic and gastrointestinal adverse events were more common in patients receiving adjuvant radiation therapy [39], although these adverse events may be mitigated with newer radiation techniques. The role of adding chemotherapy to radiation therapy for adjuvant treatment of intermediate risk tumors explored in the phase III GOG-263 clinical trial (NCT01101451) indicated that the addition of chemotherapy did not improve outcomes and increased toxicity for patients.

Table 3.

Post-radical hysterectomy intermediate and high-risk criteria.

Intermediate risk criteria1 (a combination of LVSI, stromal invasion, tumor defined in a single row)
LVSI	Stromal invasion	Tumor Size (on palpation)
Positive	Deep 1/3	Any
Positive	Middle 1/3	≥2 cm
Positive	Superficial 1/3	≥5 cm
Negative	Deep or middle 1/3	≥4 cm
High risk criteria2 (any one criterion)
Positive surgical margin
Parametrial invasion
Positive lymph nodes (micro- or macrometastases)

LVSI, lymphovascular space invasion.

¹“Sedlis criteria:” Sedlis et al. [39].

²“Peters criteria:” Peters et al. [41].

Adjuvant chemoradiation therapy is recommended following hysterectomy for tumors with high-risk pathologic features including positive margins, parametrial invasion, or lymph node metastasis. This is based on randomized controlled trial results showing double the risk of progression (HR 2.01, p = 0.003) and death (HR 1.96, p = 0.007) for radiation therapy alone compared to radiation therapy combined with cisplatin chemotherapy [41]. The phase III GOG-0724/RTOG-0724 clinical trial (NCT01414608) showed no benefit to adding carboplatin and paclitaxel chemotherapy after concurrent adjuvant chemoradiation therapy for high-risk disease, with 4-year disease free survival estimates of 76 % (90 % CI 69–83 %) in the standard chemoradiation arm, and 77 % (90 % CI 70–84 %) for the chemoradiation followed by chemotherapy arm [42].

3.4.2. Locally advanced cervical cancer (LACC)

• For stage IB3 to IVA cervical cancers, primary chemoradiation therapy with brachytherapy is recommended. Concurrent external beam radiation therapy with weekly cisplatin chemotherapy is recommended unless there are contraindications to cisplatin.

• For Stage IB3 to IVA cervical cancers, induction carboplatin and paclitaxel chemotherapy followed by chemoradiation therapy is acceptable provided radiation therapy can be initiated within 1 week of completion of induction chemotherapy.

• For Stage III to IVA tumors that are PD-L1+, chemoradiation therapy with cisplatin and pembrolizumab followed by adjuvant pembrolizumab is recommended. For PD-L1− tumors chemoradiation with cisplatin and pembrolizumab is acceptable.

• External beam therapy with brachytherapy is recommended. Stereotactic body radiotherapy is not an acceptable substitution for brachytherapy.

• Completion of primary radiation therapy (external beam and brachytherapy) within 56 days of initiation is recommended.

Primary chemoradiation with brachytherapy is recommended for stages IB3 and IIA2 to IVA cervical cancers. The addition of chemotherapy to radiation therapy for LACC has been recommended by the National Cancer Institute since 1999 after the publication of five clinical trials showing decreased recurrence and improved survival compared to radiation therapy alone. Since that time, pelvic radiation therapy with the addition of weekly cisplatin chemotherapy has been the standard therapy. The phase III GOG-274/RTOG01174 “Outback” trial evaluated the addition of adjuvant carboplatin and paclitaxel chemotherapy following primary chemoradiation therapy for patients with LACC [43]. Unfortunately, this trial failed to show a survival advantage, with 5- year overall survival of 72 % (95 % CI 67–76 %) in the chemoradiation and adjuvant chemotherapy arm compared to 71 % (95 % CI 66–75) in the standard chemoradiation arm (HR 0.90, 95 % CI 0.70–1.17, p = 0.81), and chemoradiation therapy remained the standard of care.

More recently, two phase III trials building on the cisplatin chemoradiation therapy backbone showed improvements in survival. The phase III GCIG INTERLACE study evaluated induction chemotherapy comprising 6 weekly doses of carboplatin and paclitaxel followed by standard chemoradiation therapy for FIGO 2018 stages IB3, IIA, IIB, IIIB, IIIC1 or IVA disease [44]. At a median follow-up of 67 months progression-free survival (HR 0.65, 95 % CI 0.46–0.91, p = 0.013) and overall survival (HR 0.60, 95 % CI 0.40–0.91, p = 0.015) were significantly improved in the induction chemotherapy arm, with 5-year progression free and overall survival rates of 72 % and 80 %, respectively, in the induction chemotherapy arm. The one-week interval between completion of induction chemotherapy and initiation of chemoradiation therapy has been emphasized due to concern for tumor repopulation, defined as rapid proliferation of surviving cancer cells following induction chemotherapy. Some of the controversy regarding adoption of the INTERLACE regimen include the exclusion of some high-risk groups, including stage IIIA disease and para-aortic lymph node metastases. Additionally, the impact of tumor profiles, including PD-L1 status, is not known.

The phase III GOG-3047/KEYNOTE-A18 trial evaluated the addition of 5 cycles of pembrolizumab to cisplatin chemoradiation therapy followed by 15 cycles of pembrolizumab maintenance for FIGO 2018 stage IIIC1 to IVA disease [45]. Initial results from this trial with a median study follow-up period of 17.9 months, showed improved progression free survival in the pembrolizumab arm (HR 0.70, 95 % CI 0.55–0.89, on-sided p = 0.0020) with 24-month progression free survival of 68 % (95 % CI 62–73 %) compared to 57 % (95 % CI 51–63 %) in the standard chemoradiation therapy arm. Evaluation by tumor PD-L1 status showed a HR for disease progression or death of 0.72 (95 % CI 0.56–0.92) for PD-L1+ tumors (combined positive score, CPS ≥1 %) and 0.61 (95 % CI 0.18–2.07) in the PD-L1− tumors. Subgroup analysis by stage showed a HR for progression or death of 0.91 (95 % CI 0.63–1.31) for FIGO 2014 Stage IB2 (tumors >2 cm and ≤4 cm) and Stage IIB with positive nodes (FIGO 2018 stage IIIC1 and IIIC2), and HR of 0.58 (95 % CI 0.42–0.80) for FIGO stage III (distal vaginal extension or extension to the pelvic sidewall) and stage IVA disease irrespective of lymph node status. While the trial was not powered for these subgroup analyses, these findings resulted in FDA approval for the addition of pembrolizumab to primary chemoradiation therapy only for FIGO 2014 stage III to IVA disease (extension of disease to the distal vagina or pelvic sidewall, or involvement of the bladder or rectal mucosa; lymph node metastases not included in the staging), irrespective of tumor PD-L1 status. An updated analysis, with a median follow-up of 29.9 months, demonstrated significantly improved overall survival in the pembrolizumab arm with a HR of 0.67 (95 % CI 0.50–0.90), further supporting the role of immuno-chemoradiotherapy [40]. In the absence of prospective data directly comparing the use of primary chemoradiation with pembrolizumab (KEYNOTE-A18) to induction chemotherapy followed by chemoradiation (INTERLACE), patients with FIGO 2018 stage IIIB and IIIC1 disease can be offered either modality of treatment.

Time to completion of chemoradiation therapy is an important factor. An interval from initiation to completion of radiation therapy (external beam and brachytherapy) of >56 days has been associated with inferior tumor control in the pelvis [46]. Additionally, external beam radiation therapy followed by brachytherapy is imperative for high-quality curative-intent treatment for LACC. A phase II trial showed worse cervical tumor control with higher toxicity when stereotactic body radiotherapy was substituted for brachytherapy [47], and retrospective studies show improved local control and overall survival with the administration of brachytherapy over an external beam boost [48,49]. Unfortunately, a recent review of the literature has shown a 50 % decrease in the use of brachytherapy over the past 20–30 years, with disparities in administration of brachytherapy among older individuals, Black and Hispanic patients, and among patients who are underinsured and who have low income [50]. Minimum standards for radiation therapy and treatment disparities are further explored in companion papers.

3.5. Metastatic, persistent, and recurrent cervical cancer

3.5.1. First-line systemic therapy

• For metastatic (Stage IVB) and recurrent cervical cancer multiagent therapy with platinum, paclitaxel and bevacizumab is recommended. Omitting bevacizumab in cases where risk of fistula is high or for patients/disease meeting low-risk “Moore criteria” (Table 4) is acceptable.

• For PD-L1+ tumors (CPS ≥ 1) addition of pembrolizumab to platinum, paclitaxel ± bevacizumab therapy is recommended.

Table 4.

Moore Criteria predicting outcomes with platinum-based therapy in recurrent cervical cancer.¹

Risk factors	Risk Factors per Multivariable Analysis*	Risk level
African ancestry	Yes	Low risk (0–1 factors)
Performance status	>0	Moderate risk (2–3 factors)
Pelvic disease (measurable)	Yes	High risk (4–5 factors)
Prior platinum radiation sensitizer	Yes
Progression-free interval	≤12 months

^*1 point for each risk factor. Sum determines risk level.

¹Tewari et al. [52].

Modern clinical trials for the treatment of recurrent and metastatic cervical cancer have been transformative. While platinum-based doublet therapy with paclitaxel has been the backbone for first-line therapy in metastatic or recurrent disease, GOG 240 demonstrated that the addition of bevacizumab to chemotherapy improved overall survival by 3.7 months (17.0 vs 13.3 months) among the entire study population [51]. Of note, bevacizumab is associated with an increased risk of fistula in patients who have received prior radiotherapy. Furthermore, the “Moore criteria” should be considered when contemplating the addition of bevacizumab [52] (Table 4). The Moore criteria assign 0–1 point for each of 5 factors: race; performance status; measurable pelvic disease; prior platinum as a radiosensitizer; platinum free interval. Patients with moderate-high risk disease (score 3–5 out of 5) were found to benefit the most from the addition of bevacizumab with an increase in median OS of 5.8 months (moderate risk HR for death 0.673, 95 % CI 0.5–0.91, p = 0.0094; high risk HR 0.536, 95 % CI 0.32–0.905, p = 0.0196, vs. low-risk HR 0.96, 95 % CI 0.51–1.83, p = 0.9087). While perhaps not commonly utilized, chemotherapy without bevacizumab can be considered for disease meeting low-risk Moore criteria [52]. Although cisplatin is the preferred platinum agent in cervical cancer, carboplatin may be substituted for those previously treated with cisplatin [53].

The GOG 240 triplet regimen is still considered the standard-of-care, although one now generally limited to treatment of PD-L1 negative tumors [51]. KEYNOTE-826 randomized over 600 patients with advanced, recurrent or metastatic disease to pembrolizumab or placebo in addition to platinum and paclitaxel chemotherapy, with or without bevacizumab (provider-choice) [54]. The addition of pembrolizumab was associated with a HR for disease progression of 0.57 (95 % CI 0.45–0.73) with a median progression free survival of 15.2 months (95 % CI 10.5–23.3 months) in the pembrolizumab arm compared to 10.2 months (o5% CI 8.3–12.2 months) in the control arm. The addition of pembrolizumab was also associated with improved overall survival, with HR for death of 0.61 (95 % CI 0.47–0.80) and median overall survival of 37.6 months in the pembrolizumab arm (95 % CI 27.0 months to not reached) versus 22.5 months (95 % CI 16.6–25.0 months) in the control arm. KEYNOTE-826 clearly demonstrated that the addition of pembrolizumab to therapy for individuals with PD-L1+ tumors (defined as CPS ≥ 1 %) have marked improvement overall survival with a median of 43.9 months (95 % CI 28.6 months to not reached). In 2021 the addition of pembrolizumab to chemotherapy with or without bevacizumab was FDA-approved for treatment of persistent, recurrent or metastatic cervical cancer that expresses PD-L1. While addition of bevacizumab was per provider-choice, results of KEYNOTE-826 do suggest benefit to quadruplet therapy even in patients with PD-L1+ tumors receiving pembrolizumab, median overall survival decreased to 17.5 months (95 % CI 14.9–22.3 months) in the pembrolizumab arm without bevacizumab. The phase III BEATcc trial compared platinum, paclitaxel and bevacizumab with or without atezolizumab [55]. In this trial the addition of atezolizumab was associated with improvement in both progression free survival (HR 0.62, 95 % CI 0.49–0.78, p < 0.0001) and overall survival (HR 0.68, 95 % CI 0.52–0.88, p = 0.0046) with overall median overall survival of 32.1 months in the atezolizumab arm compared to 22.8 months in the control arm. While atezolizumab is not currently FDA-approved for treatment of cervical cancer, the results of BEATcc support the principle of the addition of immune checkpoint inhibitor.

3.5.2. Second-line therapy and beyond

• Clinical trial participation is recommended when available.

• Next generation sequencing is recommended for all metastatic, persistent, or recurrent cervical cancers to guide therapy.

• Pembrolizumab or other immune checkpoint inhibitor is acceptable for treatment of PD-L1+, TMB-H and/or MSI-H/dMMR tumors, either as a single agent or in combination with a platinum doublet ± bevacizumab for patients who have not previously or recently received immune checkpoint inhibition.

• Tisotumab vedotin-tftv is acceptable for treatment of cervical cancer in the second-line and beyond.

• Targeted therapies are acceptable for treatment of tumors expressing the integral biomarker.

Historically, overall response rates to second-line cytotoxic therapy have been poor [56]. When available, clinical trial participation should be encouraged. Several agents have now been developed with improvement in patient outcomes. Some of these include immunotherapy, tisotumab vedotin-tftv, or targeted therapies.

Single agent Pembrolizumab as a second-line regimen is an option for those with TMB—H, MSI-H/dMMR or PD-L1 positive tumors. The phase II KEYNOTE-158 study showed an overall response rate among patients with PD-L1+ tumors of 14.3 % (95 % CI 7.4–24.1 %) who had received one or more prior lines of therapy, with 65 % having received two or more prior lines of therapy [57]. Although not FDA approved but potentially commercially available, cemiplimab (PD-1 inhibitor) is another immunotherapy option for patients with recurrent cervical cancer. A phase III trial showed second-line cemiplimab was associated with superior median overall survival of 12.0 months compared to 8.5 months with single-agent chemotherapy (HR 0.69, 95 % CI 0.56–0.84, p < 0.001). Single-agent checkpoint inhibition may become more of a historical therapy option though as patients increasingly receive immunotherapy in the frontline/first-line setting and often in combination with a platinum doublet. While the role of treatment with checkpoint inhibition after prior treatment with a checkpoint inhibitor is unclear at this time, it can be reasonably offered until further prospective data is available [58].

Tisotumab vedotin-tftv, an FDA approved antibody drug conjugate, is another treatment option and eligibility is not based on biomarker expression. A phase III trial of tisotumab vedotin-tftv compared to investigator’s choice single agent chemotherapy showed significantly prolonged overall survival of 11.5 months (95 % CI 9.8–14.9 months) in the tisotumab vedotin-tftv group compared to the chemotherapy group (9.5 months, 95 % CI 7.9–10.7 months; HR 0.70, 95 % CI 0.54–0.89, p = 0.004). Adverse events of special interest include ocular toxicity, occurring in 52.8 % of patients (4.0 % grade 3 or greater). Importantly risk mitigation with steroid, vasoconstrictor and lubricating eye drops and baseline and follow-up ophthalmologic examinations are recommended. Other adverse events of special interest include peripheral neuropathy and bleeding events, and these risks need to be considered based on pre-existing neuropathy or bleeding risk due to tumor or other factors.

Outside of clinical trial participation, considerations for treatment of disease with no standard-of-care options include targeting a mutation identified on tumor testing. Next generation sequencing is recommended for all recurrent and metastatic cervical cancers to guide therapy. The phase II DESTINY-PanTumor02 trial evaluated the efficacy and safety of HER2-expressing (IHC 3+/2+) solid tumors [59]. Among 35 participants with cervical cancer, overall response rate was 70 % (95 % CI 34.8–93.3 %) among HER2 3+ tumors, and 24.0 (95 %CI 9.4–45.1 %) among HER2 2+ tumors. Additionally, in this heavily pretreated population the overall survival at 18 months was 90 % (95 % CI 47.3–98.5 %) among participants with HER2 3+ tumors and 31.3 % (95 % CI 13.4–51.0 %) among those with HER2 2+ tumors. Targeted therapy options continue to expand, and extrapolating from other solid tumors, options may include selpercatinib for tumors with a RET mutation or gene fusion; and larotrectinib or entrectinib for tumors with NTRK gene fusion [60–62]. Phase 1 clinical trials are also often tumor agnostic and should be explored.

While advances in therapy are incrementally improving survival for patients with cervical cancer, there are financial barriers to accessing these costly therapies, especially in a disease that disproportionately affects underserved and socioeconomically disadvantaged populations. The federal 340B Drug Pricing Program allows institutions serving financially vulnerable populations to purchase drugs, including cancer therapies, at a reduced cost. However, whether this program results in improved access to effective therapies is variable depending on how an institution utilizes the cost savings [63]. We must continue to advocate against excessive hospital price mark-ups which decrease patient access to effective therapies.

3.6. The role of clinical trials

• Participation in clinical trials at all stages of treatment is recommended when available.

• Clinical trial design which increases access to clinical trials for underrepresented minorities, individuals of lower socioeconomic status, and rural patients is urgently needed to develop effective therapies for the population disproportionately affected by cervical cancer.

While progress in developing and evaluating active therapeutics has been made, continued focus on not only the drug development but equitable patient clinical trial enrollment and access is paramount [64]. While new treatments have significantly improved cervical cancer outcomes in recent years, additional advances in cervical cancer treatment are needed, and clinical trials should always be considered and discussed with patients when an option is available. Clinical trial design also needs to be optimized to increase access to clinical trials. This includes but is not limited to decentralization of clinical trials, omitting eligibility/exclusion criteria which are not relevant to the treatment under study, participant financial assistance for transportation and other needs, such as child and/or dependent care among others as well as the and availability of consents and trial information in multiple languages [65]. Decentralization could include local lab collection or radiographic assessment at local sites. Labs and tests which are not clinically relevant to the treatment under study should be omitted to decrease costs as well as time and transportation barriers to clinical trial participation.

Clinical trial populations also need to represent the individuals affected by the disease. It is well-documented that clinical trials comprise predominantly White participants, limiting the ability to assess for differences in effects by race or ethnicity. While there are studies demonstrating adequate or overrepresentation of Black participants in cervical cancer trials, Asian and Hispanic patients continue to be underrepresented [64]. Further, even when there is “adequate” representation of minority race or ethnic groups, the number of participants is smaller. We need to continue to work toward equal representation so that trials are sufficiently powered to assess for variations in effect among minority patient groups.

3.7. Palliative and end-of-life care

3.7.1. Palliative care

• Early integration of palliative care is recommended for patients with cervical cancer who often have a high burden of disease-related symptoms.

Compared to patients with other gynecologic cancers, patients with cervical cancer require higher doses of opioids for adequate pain control and are more likely to present to the emergency room for a pain-related visit [66]. Palliative care for cervical cancer may include short courses of radiation therapy to control pelvic hemorrhage and pain management with opiate medications in settings where radiation therapy and systemic tumor-directed therapies are more limited. Recurrence of pelvic tumors and sequelae of pelvic radiation may result in pain, bleeding, fistulae, and require bowel and/or bladder diversion. Greater than 50 % of patients with advanced cervical cancer may experience pain, anorexia, a poor feeling of well-being, fatigue, and insomnia [67]. The 2017 ASCO Clinical Practice Guidelines recommend integration of palliative care into the active management of advanced stage disease, with best practice involving interdisciplinary palliative care teams [68]. Further, a recent pilot study demonstrated that integrating palliative care with curative-intent chemoradiation for locally advanced cervical cancer improved social and emotional quality of life compared to standard treatment[69].In addition to helping manage symptoms, engagement with palliative care teams early during a patient’s disease can also help define patients’ values and goals of care and ensure timely advanced-care planning.

Unfortunately, less than half of patients who died of cervical cancer at two well-resourced tertiary-care centers received palliative care consultation, and those who did, they had their consult late in their disease course [70]. Differences in insurance and local services available may further limit access to optimal palliative care.

3.7.2. End-of-life care

Cervical cancer commonly affects those with lower socioeconomic status and limited coverage for end-of-life care. It is vital to address potential end of life care considerations when a patient has metastatic or recurrent disease [71]. Discussions should define goals of care and services available to the individual, especially if coverage for typical home or inpatient hospice services is limited. Exploring alternative end-of-life care options may be necessary if insurance coverage is limited. Encouraging open discussion about outcomes and death with the patient and family can ease bereavement and help develop congruent goals. A multidisciplinary approach with qualified hospice or palliative services should be used when possible.

4. Conclusions

To meet the WHO cervical cancer elimination goal, 90 % of patients with cervical cancer need to receive effective therapy. Timely initiation and completion of therapy is imperative to optimizing disease outcomes. Appropriate surgery performed by a gynecologic oncologist is imperative for patients with localized disease. Patients with locally advanced disease need to receive optimal chemoradiation therapy, including brachytherapy. Access to effective but expensive systemic therapies is required for patients with advanced or recurrent disease. Despite therapy advances, we have failed as a society to ensure that all patients with cervical cancer have access to quality-of-life improving and, increasingly, lifesaving, therapies. The United States needs to commit to implementation of interventions to eradicate cervical cancer as a public health problem.

5. Recommendations

1. Standardizing the minimum quality of cervical cancer-related services rendered across the US is urgently needed. In addition to standardization, full implementation regardless of patient socioeconomic and other characteristics will bridge the gap in cervical cancer diagnosis and outcomes by minimizing bias, access issues, and improving equity.

2. Involvement of a gynecologic oncologist for treatment planning and surgery when indicated is recommended.

3. Ineffective substitutes for brachytherapy are not acceptable. Novel financial incentives or penalties should be considered to ensure widespread access to optimal radiation therapy and brachytherapy, for all patients with locally advanced cervical cancer to maximize known superior treatment outcomes.

4. Engagement with palliative care teams early during a patient’s disease is recommended to manage disease-related symptoms, help define patients’ values and goals of care and ensure timely advanced-care planning.