A Comprehensive guideline on the Management Strategies for Cervical Carcinoma

I. Foundational Principles in the Management of Cervical Carcinoma

The management of cervical carcinoma is a complex, multidisciplinary endeavor that hinges on a precise and thorough initial evaluation. The therapeutic strategy for any given patient is dictated by a meticulous process of diagnostic confirmation, accurate staging, and detailed pathologic characterization. Recent updates to international guidelines, particularly the adoption of the 2018 Fédération Internationale de Gynécologie et d'Obstétrique (FIGO) staging system, have fundamentally reshaped this foundational framework, moving the field toward a more integrated approach that leverages clinical, radiologic, and pathologic data to optimize treatment selection and prognostication.1

A. Initial Diagnostic Workup and Pathologic Confirmation

The initial evaluation of a patient with suspected cervical cancer begins with a comprehensive history and physical examination, including a detailed gynecologic exam.1 Baseline laboratory assessments are essential, including a complete blood count (CBC) with platelets, and liver and renal function studies to assess the patient's fitness for potential systemic therapies and to screen for organ dysfunction related to advanced disease.1

Pathologic confirmation of invasive carcinoma via a directed cervical biopsy is the cornerstone of diagnosis.1 In situations where the initial biopsy is insufficient to determine the depth of invasion or to rule out microinvasive disease—a critical distinction for treatment planning, especially when fertility preservation is a consideration—a cone biopsy (conization) is indicated.1 The NCCN guidelines recommend cold knife conization (CKC) as the preferred method, as it provides an intact, non-fragmented specimen without thermal artifact at the margins, which is optimal for pathologic assessment. However, a loop electrosurgical excision procedure (LEEP) is an acceptable alternative, provided that care is taken to obtain a non-fragmented specimen with clear margins.1

The guidelines also underscore the importance of a holistic patient assessment, recommending that clinicians consider Human Immunodeficiency Virus (HIV) testing, particularly in younger patients. This recommendation is coupled with the crucial directive that cancer treatment should not be modified solely on the basis of a patient's HIV status, ensuring equitable and standard-of-care therapy for this population.1

Modern pathologic assessment extends far beyond simple histologic confirmation. A comprehensive pathology report is required to include the histologic type (squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma), histologic grade, three-dimensional tumor size, depth of stromal invasion, and the presence or absence of lymphovascular space invasion (LVSI).1 The 2025 guidelines reflect a significant evolution in the pathologic workup of adenocarcinomas. It is now recommended to determine the human papillomavirus (HPV) status for all cervical adenocarcinomas, as HPV-independent subtypes, such as gastric-type adenocarcinoma, are recognized as having a more aggressive clinical course and poorer prognosis.1 Furthermore, the guidelines have incorporated the Silva classification system for evaluating the pattern of invasion in HPV-associated endocervical adenocarcinomas. This system stratifies tumors into three patterns (A, B, and C) based on the morphology of invasion, which has been shown to have powerful prognostic significance. Notably, Silva pattern A tumors are associated with an exceedingly low risk of lymph node metastasis and recurrence, a finding that may guide future de-escalation of therapy.1 This increasing emphasis on detailed biologic and morphologic subtyping at the time of initial diagnosis signals a clear trend toward a more nuanced, biology-driven approach to risk stratification, even in the earliest stages of disease.

B. The 2018 FIGO Staging System: Clinical, Radiologic, and Pathologic Integration

The 2018 revision of the FIGO staging system represents a paradigm shift in the classification of cervical cancer, formally incorporating findings from advanced imaging and pathology to supplement the traditional clinical examination.1 This evolution acknowledges that a purely clinical staging system has inherent limitations in assessing critical prognostic factors such as nodal involvement and deep tumor extension. The integration of cross-sectional imaging and surgical-pathologic findings provides a more accurate and reproducible assessment of disease extent, which is essential for guiding modern, evidence-based treatment.

Several key changes define the 2018 system. For Stage I disease, the sub-stratification has been revised to better reflect the prognostic importance of tumor volume. Stage IB is now divided into three subgroups based on the greatest tumor dimension: Stage IB1 (invasive carcinoma >5 mm depth of invasion and ≤2 cm), Stage IB2 (>2 cm and ≤4 cm), and Stage IB3 (>4 cm).1

The most profound change is the introduction of Stage IIIC, which formally incorporates lymph node status into the stage grouping, regardless of the primary tumor's size or local extension. This change elevates nodal status from a prognostic "risk factor" to a primary determinant of stage. Stage IIIC1 is assigned for metastases confined to the pelvic lymph nodes, while Stage IIIC2 is assigned for metastases to the para-aortic lymph nodes. The guidelines mandate that the method of nodal assessment be specified with a suffix: 'r' for radiologic findings (e.g., on CT or PET/CT) and 'p' for pathologic confirmation from surgical dissection.1 This change has critical implications for treatment selection. For example, a patient with a 1 cm tumor (previously Stage IB1) but with a pathologically confirmed positive pelvic lymph node is now classified as Stage IIIC1p. This patient would not be a candidate for primary surgery but would instead be managed with definitive chemoradiotherapy, the standard for node-positive disease. This reclassification ensures that treatment aligns with the patient's true disease burden and prognosis.

It is important to note that while LVSI is a powerful predictor of recurrence and is used to guide decisions regarding adjuvant therapy, its presence does not, by itself, alter the FIGO stage.1

Table 1: 2018 FIGO Staging for Carcinoma of the Uterine Cervix

C. Principles of Imaging: Modality Selection and Role in Staging and Surveillance

Imaging is an indispensable component of the modern workup for cervical cancer, providing critical information for staging, treatment planning, and post-treatment surveillance.1 The choice of imaging modality is tailored to the clinical stage and the specific information required.

For the assessment of local disease extent, pelvic Magnetic Resonance Imaging (MRI) with and without contrast is the preferred modality.1 MRI offers superior soft-tissue resolution compared to other modalities, allowing for precise delineation of tumor size, depth of stromal invasion, parametrial extension, and vaginal involvement. This level of detail is crucial for surgical planning, particularly when considering fertility-sparing procedures like radical trachelectomy or less radical surgery for low-risk disease, where confirming the absence of deep stromal invasion or extensive local spread is paramount.1

For the evaluation of regional lymph node involvement and distant metastatic disease, Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography (FDG-PET/CT) is the preferred imaging modality for patients with FIGO Stage IB1 or higher disease.1 PET/CT has demonstrated higher sensitivity and specificity for detecting nodal metastases compared to CT or MRI alone, and it provides a whole-body survey to identify occult distant disease that would preclude curative-intent local therapy.1 The findings on PET/CT directly influence staging under the 2018 FIGO system (e.g., identifying hypermetabolic pelvic nodes would lead to a Stage IIIC1r designation) and are essential for radiation therapy planning, particularly for defining the extent of nodal volumes that require treatment.

Imaging also plays a defined role in post-treatment surveillance. For patients with early-stage disease managed surgically, routine imaging is generally not recommended in the absence of symptoms. However, for those with higher-risk features requiring adjuvant therapy or for those with locally advanced disease (Stage II-IV) treated with definitive chemoradiation, a follow-up FDG-PET/CT is recommended 3 to 6 months after completion of therapy to assess treatment response and establish a new baseline.1 This post-treatment scan can detect residual or early recurrent disease, potentially allowing for timely salvage therapy.

II. Management of Early-Stage Cervical Cancer (FIGO Stage IA – IIA1)

The management of early-stage cervical cancer is characterized by a highly individualized approach, where treatment decisions are carefully balanced between the goals of oncologic cure and the preservation of quality of life, including fertility. The therapeutic landscape for this population has undergone significant evolution, marked by an evidence-driven trend toward de-escalation of surgical morbidity for patients with low-risk disease, while maintaining aggressive, multimodality therapy for those with higher-risk features. This bifurcation in strategy underscores the critical importance of precise risk stratification based on a combination of clinical stage, pathologic features, and patient-specific factors.

A. Treatment of Microinvasive Disease (Stage IA1): Balancing Oncologic Safety and Fertility Preservation

Stage IA1 carcinoma, defined as stromal invasion ≤3 mm, represents the earliest and lowest-risk form of invasive cervical cancer. Treatment is stratified based on the presence of lymphovascular space invasion (LVSI), a key predictor of nodal metastasis, and the patient's desire for fertility preservation.1

For patients with Stage IA1 disease without LVSI, the risk of lymph node metastasis is less than 1%.1 For those who wish to preserve fertility, a cone biopsy with negative margins (preferably

≥1 mm) is considered definitive and curative treatment, followed by surveillance.1 If fertility is not a concern, a Type A (extrafascial or simple) hysterectomy is the standard of care, providing excellent oncologic outcomes with minimal surgical morbidity.1

The presence of LVSI in Stage IA1 disease elevates the risk of nodal involvement and necessitates a more comprehensive surgical approach. For patients desiring fertility preservation, the options are more extensive than for their LVSI-negative counterparts. Acceptable approaches include a cone biopsy with negative margins combined with a nodal assessment (either sentinel lymph node mapping or a full pelvic lymphadenectomy), or a radical trachelectomy with nodal assessment.1 For those not seeking to preserve fertility, the standard surgical procedure is a Type B (modified radical) hysterectomy, which involves a wider resection of the paracervical tissues than a simple hysterectomy, combined with SLN mapping or pelvic lymphadenectomy.1 For patients who are medically inoperable, definitive radiation therapy with pelvic external beam radiation therapy (EBRT) and a brachytherapy boost is an effective alternative.1

B. Stage IA2-IB1: The SHAPE Trial and the Paradigm of De-escalated Surgery for Low-Risk Disease

A pivotal development in the management of early-stage cervical cancer, reflected in the 2025 NCCN guidelines, is the integration of the findings from the SHAPE trial.1 This landmark study has established a new standard of care for a well-defined population of patients with low-risk disease, enabling a significant de-escalation of surgical treatment and its associated long-term morbidity.

The SHAPE trial was a randomized, non-inferiority study that compared simple hysterectomy to radical hysterectomy in patients with low-risk, early-stage cervical cancer. The specific eligibility criteria, now referred to in the NCCN guidelines as "conservative surgery criteria," include FIGO Stage IA2 or IB1 disease, tumor size ≤2 cm, depth of stromal invasion <10 mm on cone biopsy, absence of LVSI, and favorable histology (squamous cell carcinoma or grade 1-2 adenocarcinoma).1 The trial demonstrated that for this select group, simple (Type A) hysterectomy was non-inferior to radical hysterectomy with respect to the 3-year pelvic recurrence rate. Crucially, patients who underwent simple hysterectomy experienced significantly lower rates of surgical morbidity, including urinary incontinence and sexual dysfunction.1

Based on this high-level evidence, the NCCN guidelines have established a distinct treatment pathway for patients who meet all conservative surgery criteria. For those not desiring fertility preservation, the recommended procedure is now a Type A hysterectomy with nodal assessment (SLN mapping or pelvic lymphadenectomy), rather than the previously standard radical hysterectomy.1 This change represents a major advancement in patient-centered care, preventing overtreatment and preserving quality of life without compromising oncologic safety.

This paradigm shift also extends to fertility-sparing approaches for this low-risk population. The guidelines now recommend that a cone biopsy with negative margins, combined with a negative nodal assessment (via SLN mapping or pelvic lymphadenectomy), is a sufficient and preferred fertility-sparing option. This allows eligible patients to avoid the greater morbidity and potential obstetric complications associated with a radical trachelectomy.1

C. Fertility-Sparing Management for Higher-Risk Early Stage Disease (Stage IA2-IB2)

For patients with early-stage disease who desire fertility preservation but do not meet the stringent low-risk criteria for conservative surgery, radical trachelectomy remains the standard of care.1 This procedure is an option for patients with Stage IA2 or IB1 disease with LVSI, or for select patients with Stage IB2 disease (tumors

>2 cm and ≤4 cm). It involves the removal of the cervix, the upper 1-2 cm of the vagina, and the parametrial tissues, while preserving the uterine corpus.1 A pelvic lymphadenectomy, with or without SLN mapping, is a mandatory component of the procedure. For larger tumors (Stage IB2), an abdominal approach to the trachelectomy is generally favored over a vaginal approach, as it allows for a more extensive parametrial resection.1

It is critical to note that radical trachelectomy is not recommended for patients with aggressive or rare histologies, such as small cell neuroendocrine carcinoma or gastric-type adenocarcinoma, due to their higher risk of early and widespread metastasis.1 Careful patient selection and comprehensive counseling regarding both the oncologic risks and the potential for adverse pregnancy outcomes (e.g., second-trimester loss, preterm labor) are essential before proceeding with this complex fertility-sparing surgery.1

D. Definitive Surgical Management (Non-Fertility Sparing): Stratification of Hysterectomy and Nodal Assessment

For patients with early-stage disease who are not candidates for or do not desire fertility preservation, and who do not meet the criteria for conservative surgery, radical hysterectomy remains the cornerstone of surgical treatment. The extent of the hysterectomy is tailored to the stage and risk factors. For patients with Stage IB1 (not meeting conservative criteria), IB2, or IIA1 disease, the recommended procedure is a Type C1 radical hysterectomy.1 This procedure, as defined by the Querleu-Morrow classification, involves a wide resection of the parametria out to the internal iliac vessels, providing robust local control for tumors that have the potential for lateral spread.1

A critical and unequivocal recommendation within the guidelines is that the standard of care for radical hysterectomy is an open abdominal approach (laparotomy).1 This is a Category 1 recommendation based on the results of the prospective, randomized LACC trial, which demonstrated significantly worse disease-free and overall survival outcomes for patients who underwent minimally invasive surgery (laparoscopic or robotic) compared to those who had an open procedure.1 This finding has led to a major reversal in surgical practice, and patients must be counseled about the oncologic risks associated with MIS for this procedure.

Nodal assessment is a mandatory component of definitive surgery. Sentinel lymph node mapping has evolved into the preferred method of nodal staging for tumors up to 4 cm in size.1 The technique offers a dual advantage: it can reduce the morbidity associated with a full bilateral pelvic lymphadenectomy (most notably, the risk of chronic lymphedema) while simultaneously improving the accuracy of staging. The improved accuracy stems from the practice of ultrastaging the harvested sentinel nodes, a process of detailed pathologic sectioning and immunohistochemical analysis that can detect low-volume disease (micrometastases or isolated tumor cells) that might be missed on routine examination.1 The detection of such low-volume disease has profound clinical implications, as it can upstage a patient and identify them as being at high risk for recurrence, thereby mandating adjuvant therapy. To ensure oncologic safety, the guidelines specify a strict SLN algorithm that must be followed: all mapped nodes must be excised, any grossly suspicious node must be removed regardless of mapping, and if mapping fails on one side of the pelvis, a complete side-specific lymphadenectomy must be performed.1

Table 2: Surgical Approaches for Early-Stage Cervical Cancer

E. Adjuvant Therapy for Early-Stage Disease: Risk Stratification Post-Surgery

Following primary surgical management, the final pathologic evaluation of the hysterectomy specimen and lymph nodes is used to stratify patients into risk categories that determine the need for and type of adjuvant therapy.1 This postoperative risk assessment is crucial for identifying patients who remain at a high risk of recurrence despite complete surgical resection.

Patients are considered to have intermediate-risk disease if the final pathology reveals a combination of adverse features in the absence of positive nodes, margins, or parametria. These features are defined by the "Sedlis criteria" and include deep stromal invasion (greater than one-third), large tumor size (≥4 cm), and the presence of LVSI.1 For patients meeting these criteria, adjuvant pelvic EBRT is a Category 1 recommendation. This is based on the GOG 92 trial, which demonstrated that postoperative radiation significantly reduced the risk of pelvic recurrence in this population.1 The addition of concurrent platinum-based chemotherapy to adjuvant radiation in the intermediate-risk setting is a Category 2B recommendation, and its role is currently under investigation in clinical trials.1

Patients are classified as having high-risk disease if the final pathology demonstrates positive pelvic lymph nodes, positive surgical margins (at the vaginal or parametrial margin), or microscopic parametrial involvement.1 For this group, the risk of both local and distant recurrence is substantial. The standard of care is adjuvant pelvic EBRT administered concurrently with platinum-based chemotherapy (typically weekly cisplatin).1 This is a Category 1 recommendation based on the results of several randomized trials, including GOG 109, which showed a significant survival benefit for combined modality therapy over radiation alone in this setting.1 For patients with a positive vaginal margin, a vaginal brachytherapy boost may be considered in addition to chemoradiation to deliver a higher dose to the area at greatest risk of recurrence.1

If para-aortic lymph nodes are found to be positive on surgical staging, the patient is upstaged to IIIC2p. The recommended treatment is extended-field EBRT, which encompasses both the pelvic and para-aortic nodal basins, with concurrent platinum-based chemotherapy.1

III. Management of Locally Advanced Cervical Cancer (FIGO Stage IB3 – IVA)

The treatment of locally advanced cervical cancer, encompassing bulky early-stage tumors (FIGO Stage IB3, IIA2) and disease that has extended beyond the cervix (Stage IIB through IVA), represents a distinct clinical challenge. While these stages are not typically metastatic at presentation, the significant tumor volume and high propensity for regional nodal spread preclude primary surgery as a curative option for the majority of patients. The therapeutic cornerstone for this population is definitive, high-dose radiation therapy combined with concurrent chemotherapy. The modern era of treatment for locally advanced disease is characterized not only by technical refinements in radiation delivery that have improved local control and reduced toxicity, but also by the recent, successful integration of novel systemic agents aimed at addressing the primary mode of treatment failure: distant metastatic relapse.

A. The Standard of Care: Definitive Concurrent Chemoradiotherapy (CCRT)

For patients with FIGO Stage IB3 through IVA cervical cancer, definitive concurrent chemoradiotherapy (CCRT) is the established Category 1 standard of care.1 This standard is built on the foundation of multiple randomized clinical trials from the late 1990s that collectively demonstrated a 30% to 50% reduction in the risk of death when concurrent cisplatin-based chemotherapy was added to radiation therapy compared to radiation alone.1

The standard CCRT regimen consists of two main components delivered sequentially. The first is external beam radiation therapy (EBRT) to the pelvis, typically delivering a dose of 45 Gy in 1.8 Gy daily fractions over 5 weeks. During this phase, concurrent chemotherapy is administered, with weekly cisplatin at a dose of 40 mg/m² being the most widely used and preferred radiosensitizing agent.1 For patients who are intolerant to cisplatin due to factors such as pre-existing renal dysfunction or significant hearing loss, weekly carboplatin is an acceptable substitute.1 Following the completion of EBRT, the second critical component is a brachytherapy boost, which delivers a highly-conformal, high dose of radiation directly to the cervix and residual tumor.1 For optimal oncologic outcomes, the entire course of treatment, from the first day of EBRT to the completion of brachytherapy, should be completed within 8 weeks, as treatment prolongation has been associated with poorer local control and survival.1

B. Technical Principles of Modern Radiation Therapy: EBRT, IMRT, and Image-Guided Brachytherapy

The efficacy and safety of definitive radiation therapy for cervical cancer have been significantly enhanced by technological advancements in treatment planning and delivery. The NCCN guidelines emphasize the use of modern techniques to maximize the therapeutic ratio—that is, to deliver a curative dose to the tumor while minimizing radiation exposure to surrounding normal tissues.

Intensity-Modulated Radiation Therapy (IMRT) is the preferred technique for delivering EBRT.1 Compared to older 3D-conformal techniques, IMRT uses advanced computer planning and modulated radiation beams to create highly sculpted dose distributions that conform tightly to the target volumes (cervix, uterus, parametria, and pelvic lymph nodes) while actively sparing adjacent organs at risk, such as the small bowel, bladder, and rectum. This has been shown to significantly reduce rates of acute and chronic gastrointestinal and hematologic toxicity.1 For patients with positive para-aortic lymph nodes (Stage IIIC2), extended-field IMRT is used to treat the entire nodal chain from the pelvis up to the level of the renal vessels.1

Brachytherapy is an indispensable component of curative-intent radiotherapy for intact cervical cancer and should not be omitted.1 It allows for the delivery of a very high, ablative dose of radiation to the central tumor, which is not possible with EBRT alone without causing unacceptable toxicity. The modern standard for brachytherapy is Image-Guided Adaptive Brachytherapy (IGABT), preferably planned using MRI.1 MRI-based planning allows for the precise delineation of the residual gross tumor volume and surrounding normal tissues at the time of each brachytherapy fraction. This enables the radiation oncologist to adapt the dose distribution to the patient's specific anatomy and tumor response, ensuring that a curative dose (a high-risk clinical target volume D90 of

≥85 Gy in 2 Gy equivalent dose) is delivered to the tumor while strictly adhering to dose constraints for the bladder, rectum, and sigmoid colon.1 The implementation of IGABT has been a major driver of the excellent local control rates, often exceeding 90%, seen in contemporary clinical trials.1

C. The KEYNOTE-A18 Trial: Integrating Pembrolizumab into Curative-Intent Therapy

While modern CCRT provides excellent local control, distant metastatic failure remains a significant problem for patients with locally advanced disease. The KEYNOTE-A18 trial represents a landmark effort to address this challenge by integrating systemic immunotherapy into the definitive treatment paradigm. This randomized, double-blind, phase 3 trial evaluated the efficacy of adding the anti-PD-1 antibody pembrolizumab to standard CCRT for patients with high-risk, locally advanced cervical cancer.1

The trial demonstrated that the addition of pembrolizumab, given concurrently with CCRT and continued as maintenance therapy for up to 15 cycles, resulted in a statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared to CCRT with placebo.1 An exploratory subgroup analysis revealed that this benefit was most pronounced in patients with higher-stage disease, specifically FIGO 2014 Stage III-IVA.1

Based on these high-level data and subsequent FDA approval, the 2025 NCCN guidelines have incorporated this regimen as a new standard of care. The addition of pembrolizumab to CCRT is now a Category 1 recommendation for patients with FIGO 2014 Stage III-IVA disease.1 This marks the first time that immunotherapy has been successfully integrated into the curative-intent setting for cervical cancer and represents a major therapeutic advance for this high-risk patient population.

D. The INTERLACE Trial: The Role of Induction Chemotherapy in High-Risk Disease

Another innovative strategy aimed at improving outcomes in locally advanced cervical cancer is the use of induction (or neoadjuvant) chemotherapy prior to standard CCRT. The rationale is that a short course of systemic chemotherapy could eradicate distant micrometastases, reduce tumor volume to improve the efficacy of subsequent radiation, and enhance tumor oxygenation, thereby increasing radiosensitivity. The GCIG INTERLACE trial was a large, international, randomized phase 3 study designed to definitively test this hypothesis.1

The trial randomized patients with locally advanced cervical cancer (FIGO Stage IB2-IVA) to either standard CCRT alone or six weeks of induction chemotherapy with weekly carboplatin and paclitaxel followed by the same standard CCRT. The results, published in 2024, were practice-changing. The addition of induction chemotherapy led to a significant improvement in both 5-year PFS (73% vs. 64%) and 5-year overall survival (87% vs. 80%) compared to CCRT alone.1

In response to these compelling data, the 2025 NCCN guidelines have incorporated this strategy as a new therapeutic option. The guidelines now state that induction chemotherapy with carboplatin/paclitaxel, as given in the INTERLACE protocol, "could be considered" for patients with Stage IB3, IIA2, and IIB-IVA disease.1 The emergence of two successful, yet distinct, strategies for intensifying systemic therapy—concurrent/adjuvant immunotherapy (KEYNOTE-A18) and induction chemotherapy (INTERLACE)—heralds a new era in the management of locally advanced disease. Future research will focus on identifying which patients benefit most from each approach, potentially through the use of clinical and molecular biomarkers.

IV. Management of Metastatic, Persistent, or Recurrent Cervical Cancer

The management of cervical cancer that is metastatic at initial presentation (Stage IVB) or has persisted or recurred following primary treatment presents a significant clinical challenge. In this setting, the therapeutic intent is generally palliative, with goals focused on prolonging survival, controlling symptoms, and maintaining quality of life. The treatment landscape for advanced cervical cancer has been revolutionized in recent years, transforming from an approach reliant on conventional chemotherapy to a sophisticated, biomarker-driven paradigm that incorporates targeted therapies and immune checkpoint inhibitors. This shift has led to unprecedented improvements in survival outcomes for select patient populations.

A. First-Line Systemic Therapy for Stage IVB or Recurrent Disease: Platinum Doublets, Bevacizumab, and Immunotherapy Combinations

The cornerstone of first-line systemic therapy for metastatic or recurrent cervical cancer remains a platinum-based doublet chemotherapy regimen.1 The most commonly used backbones are carboplatin plus paclitaxel or cisplatin plus paclitaxel. The choice between carboplatin and cisplatin is often guided by the patient's prior treatment history and comorbidities; carboplatin is generally preferred for its more favorable toxicity profile, particularly in patients who have previously received cisplatin as a radiosensitizer.1

A major advance in this setting was established by the GOG 240 trial, which demonstrated that the addition of the anti-angiogenic agent bevacizumab to chemotherapy (either cisplatin/paclitaxel or topotecan/paclitaxel) resulted in a statistically significant improvement in median overall survival (17.0 vs. 13.3 months).1 Consequently, the combination of platinum-doublet chemotherapy with bevacizumab became a Category 1 standard of care.1

The most recent and impactful evolution in first-line therapy has been the integration of immune checkpoint inhibitors. The phase 3 KEYNOTE-826 trial evaluated the addition of the anti-PD-1 antibody pembrolizumab to chemotherapy with or without bevacizumab. The study showed that for patients whose tumors expressed PD-L1 (defined as a Combined Positive Score ≥1), the addition of pembrolizumab significantly improved both progression-free survival and overall survival.1 At a median follow-up of 39.1 months, the median overall survival in the PD-L1 positive population was 28.6 months in the pembrolizumab arm versus 16.5 months in the placebo arm.1 Similarly, the BEATcc trial demonstrated a survival benefit with the addition of the anti-PD-L1 antibody atezolizumab to chemotherapy plus bevacizumab.1

Based on this high-level evidence, the NCCN guidelines now recommend that for patients with PD-L1 positive (CPS ≥1) persistent, recurrent, or metastatic cervical cancer, the preferred, Category 1 first-line treatment is a combination of platinum/paclitaxel plus bevacizumab plus an immune checkpoint inhibitor (pembrolizumab or atezolizumab).1 This chemo-immunotherapy combination represents the new standard of care for the majority of patients in this setting.

Table 3: Systemic Therapy Regimens for First-Line Treatment of Metastatic/Recurrent Disease

B. The Critical Role of Biomarker Testing in Advanced Disease

The success of immunotherapy and targeted agents has made comprehensive molecular profiling an essential, standard-of-care component in the management of all patients with recurrent, progressive, or metastatic cervical cancer.1 The results of these tests directly guide the selection of first-line and subsequent therapies.

The guidelines recommend a panel of tests that should be performed on tumor tissue. This includes immunohistochemistry (IHC) for PD-L1 expression, reported as a CPS, which is required to determine eligibility for first-line pembrolizumab.1 Testing for mismatch repair deficiency (dMMR) by IHC or microsatellite instability (MSI) by PCR is also mandatory, as MSI-High (MSI-H)/dMMR tumors are highly responsive to immune checkpoint inhibitors.1 Additionally, HER2 expression should be assessed by IHC, with reflex to fluorescence in situ hybridization (FISH) for equivocal (IHC 2+) cases, to identify candidates for HER2-targeted antibody-drug conjugates.1

Beyond these specific tests, the guidelines recommend consideration of broader comprehensive molecular profiling, such as next-generation sequencing (NGS), to assess for Tumor Mutational Burden (TMB) and to detect rare but actionable genomic alterations, including NTRK gene fusions and RET gene fusions.1 The identification of these biomarkers is no longer an academic exercise; it is a critical step in the clinical pathway that unlocks access to highly effective, FDA-approved therapies for patients who have exhausted standard options.

C. Second-Line and Subsequent Systemic Therapies: A Biomarker-Driven Approach

The therapeutic options for patients whose disease has progressed on or after first-line platinum-based therapy are increasingly guided by the results of molecular testing.1

The guidelines list two preferred regimens in the second-line setting. Tisotumab vedotin-tftv, an antibody-drug conjugate that targets Tissue Factor (which is highly expressed on cervical cancer cells) and delivers a potent microtubule-disrupting agent, is a Category 1 recommendation based on its significant activity in previously treated patients.1 Pembrolizumab monotherapy is also a preferred option for patients whose tumors are identified as being PD-L1 positive, MSI-H/dMMR, or TMB-High (TMB-H), provided they have not previously received a checkpoint inhibitor.1

A growing list of therapies are recommended as "useful in certain circumstances," almost all of which are tied to a specific molecular biomarker. This highlights the rapid transition to a personalized medicine approach in refractory disease. These options include:

• For HER2-positive (IHC 3+ or IHC 2+/FISH+) tumors: The antibody-drug conjugate fam-trastuzumab deruxtecan-nxki has shown significant activity in the DESTINY-PanTumor02 trial.1

• For tumors with an activating HER2 mutation: The tyrosine kinase inhibitor neratinib is an option.1

• For tumors harboring an NTRK gene fusion: The TRK inhibitors larotrectinib, entrectinib, or repotrectinib are highly active, tumor-agnostic therapies.1

• For tumors with a RET gene fusion: The RET inhibitor selpercatinib is recommended.1

For patients without an actionable biomarker or who are not candidates for these targeted agents, other single-agent chemotherapies such as topotecan, gemcitabine, or vinorelbine remain as options, although response rates are modest.1

Table 4: Biomarker-Directed Therapies for Second-Line and Subsequent Treatment

D. Management of Locoregional Recurrence: Salvage Surgery vs. Re-irradiation

While many recurrences involve distant metastases, a subset of patients will present with an isolated locoregional recurrence within the pelvis. For these patients, aggressive local therapy may still offer a chance for long-term control or cure. The choice of salvage modality depends heavily on the patient's primary treatment.1

For a patient who was initially treated with surgery and develops an isolated pelvic recurrence without having received prior radiation, the standard approach is definitive chemoradiotherapy, similar to the treatment for primary locally advanced disease.1

The more challenging scenario is a patient who develops an isolated central pelvic recurrence (in the cervix, uterus, or vagina) after having previously received definitive radiation therapy. In this setting, further radiation is often not feasible due to normal tissue tolerance. For these highly selected patients, the only potentially curative option is a pelvic exenteration. This is an ultra-radical, highly morbid surgical procedure that involves the en bloc removal of the central pelvic organs, including the bladder, rectum, uterus, and vagina, with the creation of urinary and fecal diversions.1 Due to its complexity and impact on quality of life, pelvic exenteration should only be performed at high-volume centers for patients with no evidence of disease outside the central pelvis who are medically fit and well-counseled.1 In very select cases of a small (<2 cm) central recurrence, a radical hysterectomy may be considered as a less morbid alternative to exenteration.1

For patients with non-central (e.g., pelvic sidewall) or unresectable locoregional recurrences in a previously irradiated field, treatment options are limited and generally palliative. They may include systemic therapy or, in carefully selected cases, highly conformal re-irradiation using techniques like stereotactic body radiation therapy (SBRT) or IMRT to deliver a focused dose while minimizing overlap with the prior radiation field.1

V. Special Considerations in Cervical Cancer Management

Beyond the standard treatment pathways for the common histologic subtypes, the comprehensive management of cervical cancer requires an understanding of several special clinical scenarios. These include the distinct biology and treatment of rare but aggressive histologies, the complex management of cancer discovered incidentally after a simple hysterectomy, and the critical importance of long-term survivorship care to address the sequelae of treatment.

A. Small Cell Neuroendocrine Carcinoma of the Cervix (NECC): A Distinct Therapeutic Approach

Small Cell Neuroendocrine Carcinoma of the Cervix (NECC) is a rare and highly aggressive malignancy that constitutes less than 5% of all cervical cancers.1 Its clinical behavior is characterized by rapid growth, early and widespread metastatic dissemination, and a generally poor prognosis. Due to its distinct biology and clinical course, the treatment paradigm for NECC differs significantly from that of squamous cell carcinoma and adenocarcinoma and is largely adapted from the management principles for small cell lung cancer, a more common neuroendocrine tumor.1

For early-stage disease (FIGO Stage IA1-IB2, tumor ≤4 cm), a multimodality approach is standard. One option is primary surgery, consisting of a radical hysterectomy with pelvic lymphadenectomy and para-aortic lymph node sampling, followed by mandatory adjuvant chemotherapy.1 The preferred chemotherapy regimen is a platinum agent (cisplatin or carboplatin) combined with etoposide. Alternatively, definitive chemoradiation with a platinum-etoposide regimen can be used as the primary treatment.1

For locally advanced disease (Stage IB3-IVA), the preferred primary treatment is definitive chemoradiation, using a platinum-etoposide chemotherapy backbone, followed by a brachytherapy boost. This is typically followed by additional cycles of adjuvant systemic chemotherapy to address the high risk of micrometastatic disease.1 Neoadjuvant chemotherapy followed by either surgery or chemoradiation is another acceptable strategy.1

For metastatic (Stage IVB) or recurrent NECC, the first-line systemic therapy is a platinum-etoposide combination.1 Based on data from extensive-stage small cell lung cancer trials (e.g., CASPIAN, IMpower133), the addition of an immune checkpoint inhibitor (atezolizumab or durvalumab) to first-line platinum-etoposide is a recommended option.1 Second-line therapy options are limited but include regimens such as topotecan/paclitaxel/bevacizumab or single-agent topotecan or irinotecan.1

B. Management of Incidental Findings Post-Simple Hysterectomy

Occasionally, an invasive cervical cancer is discovered incidentally on the pathology specimen after a simple (extrafascial) hysterectomy has been performed for what was presumed to be a benign condition. This presents a complex management challenge, as the initial surgery was suboptimal from an oncologic perspective (i.e., it lacked the wide parametrial margins and nodal dissection of a radical hysterectomy). The NCCN guidelines provide a detailed algorithm to guide the subsequent management of these cases, which is based on the pathologic findings from the hysterectomy specimen and a thorough post-operative re-staging workup, including advanced imaging.1

The management strategy is highly stratified. For patients with the lowest-risk findings, such as a Stage IA1 cancer without LVSI and with negative surgical margins, observation or a pelvic lymphadenectomy alone may be sufficient.1 For patients with higher-risk features, such as LVSI, Stage IA2 or IB1 disease, or positive surgical margins, more aggressive therapy is required. Options may include a second surgery to complete the staging and achieve adequate local control (e.g., a parametrectomy, upper vaginectomy, and pelvic lymphadenectomy) or definitive pelvic radiation with concurrent chemotherapy.1 The choice between these modalities depends on the specific pathologic findings, the results of post-operative imaging, and patient-specific factors. For any patient with positive margins or gross residual disease, definitive chemoradiation is the standard approach.1

C. Principles of Survivorship and Management of Long-Term Treatment Sequelae

With high cure rates for early and locally advanced cervical cancer, a large and growing population of survivors requires long-term, comprehensive follow-up care. The NCCN guidelines dedicate a section to the principles of survivorship, emphasizing that care extends beyond simple surveillance for cancer recurrence to include the proactive management of the long-term and late effects of treatment.1

Surveillance for recurrence involves a schedule of regular history and physical examinations, typically every 3-6 months for the first 2 years, every 6-12 months for years 3-5, and annually thereafter.1 Routine surveillance imaging is generally not recommended for asymptomatic patients with early-stage disease but is indicated for higher-risk patients or those with advanced disease at diagnosis.1

A critical component of survivorship care is the management of treatment-induced sequelae. Both surgery and radiation can have a significant impact on pelvic health. Patients should be educated about and screened for issues such as lymphedema, urinary or gastrointestinal dysfunction, and sexual health problems.1 Pelvic radiation frequently causes vaginal atrophy, dryness, and stenosis. The guidelines recommend counseling patients on the regular use of vaginal moisturizers, lubricants, and vaginal dilators to maintain vaginal patency and function.1 For women who experience treatment-induced menopause, hormone therapy should be considered to manage symptoms and mitigate long-term health risks like osteoporosis.1

Finally, survivorship care must address the psychosocial needs of patients, including managing fear of recurrence, anxiety, depression, and altered body image. Patient education on the symptoms of potential recurrence, as well as counseling on healthy lifestyle choices such as smoking cessation, nutrition, and exercise, are integral parts of a comprehensive survivorship care plan.1

VI. Conclusion

The contemporary management of cervical cancer, as delineated in the 2025 NCCN guidelines, reflects a dynamic and rapidly evolving field characterized by three overarching themes: evidence-based de-escalation of therapy for low-risk disease, intensification of multimodality treatment for locally advanced disease, and the transformative impact of personalized medicine in the recurrent and metastatic setting.

For early-stage cervical cancer, the integration of data from the SHAPE trial has established a new paradigm. A well-defined population of patients with low-risk disease can now be safely and effectively treated with less radical surgery, such as simple hysterectomy or even conization, thereby minimizing the significant long-term morbidity associated with traditional radical hysterectomy without compromising oncologic outcomes. This shift underscores a mature understanding of the disease, where the goal is not simply to cure, but to do so with the least possible impact on a patient's quality of life. This is paralleled by the refinement of sentinel lymph node mapping, which has become the standard of care for nodal staging, offering reduced morbidity and enhanced pathologic accuracy.

In the management of locally advanced disease, while definitive chemoradiotherapy remains the backbone of curative-intent treatment, the primary challenge has shifted from achieving local control to preventing distant metastatic relapse. The landmark results of the KEYNOTE-A18 and INTERLACE trials have ushered in a new era of therapeutic intensification. The successful integration of concurrent and adjuvant immunotherapy (pembrolizumab) and the proven benefit of induction chemotherapy now provide powerful new strategies to address micrometastatic disease. These advances promise to improve survival for patients with the highest-risk, non-metastatic presentations.

Finally, the treatment of advanced, recurrent, or metastatic cervical cancer has been fundamentally transformed from a palliative chemotherapy-based approach to a sophisticated, biomarker-driven field. The establishment of chemo-immunotherapy as the first-line standard for PD-L1 positive patients and the expanding arsenal of effective targeted therapies for second-line treatment—including antibody-drug conjugates and agents directed at specific molecular alterations like HER2, NTRK, and RET—have created unprecedented opportunities for durable responses and improved survival. This progress has made comprehensive molecular profiling a mandatory component of care, cementing the role of personalized medicine in the routine management of advanced cervical cancer.

Collectively, these advancements highlight the critical importance of a multidisciplinary, evidence-based, and patient-centered approach. Accurate staging, detailed pathologic and molecular characterization, and careful consideration of individual patient goals are essential to navigating the increasingly complex and hopeful landscape of cervical cancer therapy.

Nguồn trích dẫn

1. NCCN_cervical.pdf

2. Current Standards in the Management of Early and Locally ..., truy cập vào tháng 9 16, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC9139662/