PART.01 Overview of Recurrent and Metastatic Cervical Cancer

Global and Chinese Incidence

Improved Survival Rate

High Recurrence Risk

PART.02 Definition and Classification of Recurrent and Metastatic Cervical Cancer

1. Recurrence of Cervical Cancer

• Recurrence after radiotherapy: Complete disappearance of cervical tumors after radiotherapy, with tumor recurrence in the irradiated area ≥6 months after radiotherapy completion. "Uncontrolled disease after radiotherapy" refers to persistent obvious tumors in the irradiated area 3~6 months after adequate radiotherapy.
• Recurrence after surgery: Tumor recurrence in the surgical area after surgery. Pelvic recurrence is further divided into central recurrence (cervix, vagina, uterine body) and non-central recurrence (pelvic wall, pelvic lymph nodes).

2. Metastasis of Cervical Cancer

• Oligometastasis: ≤5 metastatic lesions with limited locations, and the primary tumor is controllable or controlled. Potential cure or long-term control can be achieved through local treatment.
• Other classifications: According to whether recurrent lesions have received radiotherapy, they are divided into in-field lesions and out-of-field lesions.

3. Recurrence and Metastasis Characteristics of Different Stages

• Early-stage cervical cancer: Low recurrence and metastasis rate. For example, the recurrence and metastasis rate of FIGO 2009 stage ⅠB1 cervical cancer is approximately 9% (53% local recurrence, 39% distant metastasis); the rate for stages ⅠB2/ⅡA2 is approximately 14.3% (5.6% local recurrence, 7.3% distant metastasis).
• Locally advanced cervical cancer: High recurrence and metastasis rate. The treatment failure rate of patients receiving radical radiotherapy is approximately 18.3%, including 77.5% distant metastasis rate and 36.9% local recurrence rate. Local recurrence is mainly central, with common sites including the cervix, pelvic lymph nodes, and vagina; distant metastasis commonly occurs in the lungs, para-aortic region, left supraclavicular lymph nodes, and bones.
• Changes in treatment failure patterns: Under precise radiotherapy, the treatment failure of locally advanced cervical cancer has shifted from "pelvic recurrence-dominant" to "distant metastasis-dominant". The overall treatment failure rate and isolated pelvic recurrence rate have decreased from 35% and 16% to 30% and 6%, respectively.

PART.03 Diagnosis of Recurrent and Metastatic Cervical Cancer

1. Diagnostic Principles

• Gold standard: Histopathological examination, with the principle of "comprehensive sampling". For patients who cannot undergo puncture or have negative puncture results but high clinical suspicion, diagnosis should be made after multidisciplinary team (MDT) discussion, combining clinical symptoms, imaging findings, tumor markers, and short-term follow-up.

2. Clinical Symptoms and Signs

3. Examination Methods

• Superficial lymph node examination: B-ultrasound is the preferred method.
• Deep lesion examination: CT or MRI is the main method for detecting deep lesions in the lungs, brain, liver, pelvic cavity, and abdominal cavity. PET-CT has higher diagnostic sensitivity (85.7%~96.1%) and specificity, and can detect lesions earlier than anatomical changes, helping to clarify ambiguous imaging results. FAPI PET-CT is more effective in distinguishing recurrent lesions after radiotherapy.
• Tumor marker monitoring: SCC-Ag elevation in recurrent cervical squamous cell carcinoma often precedes clinical symptoms or imaging findings by 2~7.8 months, and 46%~92% of squamous cell carcinoma recurrences first present with SCC-Ag elevation. Adenocarcinoma recurrence may be accompanied by elevated CEA, CA125, or CA19-9; combined detection of multiple markers is recommended to improve accuracy.

4. Biopsy Requirements

• For positive cervical cytology or clinically suspected central recurrence, further cervical histopathological examination is required.
• For suspected metastatic lesions such as pelvic masses, lung, liver, and lymph nodes, puncture biopsy under B-ultrasound/CT guidance should be attempted. The safety of puncture should be evaluated when lesions are adjacent to important organs or blood vessels.
• PD-L1, human epidermal growth factor receptor 2 (HER2), P16, and mismatch repair (MMR) testing are recommended for tissue sections of recurrent and metastatic lesions; next-generation sequencing (NGS) should be performed if necessary to identify therapeutic targets.

PART.04 Differential Diagnosis

1. Differentiation between Post-Radiotherapy Reaction and Recurrence

• The cytological degeneration of cervical tumor tissue after radiotherapy takes time, and fibrosis may occur, making it difficult to distinguish uncontrolled disease/recurrence from local radiotherapy reactions. Excessively high radiotherapy doses may lead to non-healing wounds for more than half a year, with necrotic substances on the cervical surface; tumor tissue may be buried under necrotic tissue, and pathology may be misdiagnosed as inflammation or necrosis.
• Differentiation methods: Strengthen local vaginal and cervical irrigation, conduct close follow-up, and perform multiple biopsies if necessary. MRI and PET-CT are preferred for differentiating parametrial fibrosis from parametrial recurrence; puncture biopsy is recommended if necessary.

2. Differentiation between Distant Metastasis and Double Primary Cancer

PART.05 Treatment of Recurrent and Metastatic Cervical Cancer

General Recommended Principles

01 Local Treatment

1. Surgical Treatment

Pelvic Recurrence after Radical Hysterectomy

• Limited pelvic recurrence without prior radiotherapy: Surgery + postoperative adjuvant chemoradiotherapy is recommended (Category 2A).
• Multiple or extensive pelvic recurrence: Complete resection is not feasible, with poor surgical efficacy and short survival; surgery is not the first choice (Category 2A).
• Clinical data: For patients with postoperative central pelvic recurrence receiving surgery + adjuvant chemoradiotherapy, the 5-year overall survival (OS) rate is 6%~77%; among 16 domestic patients who underwent surgical treatment, the 2-year OS rate was 37.5% and the 5-year OS rate was 18.8%.

Uncontrolled Disease/Recurrence in the Pelvis after Radiotherapy

• Central uncontrolled disease/recurrence (lesions not invading the bladder/rectum, completely resectable): Radical hysterectomy or total hysterectomy is recommended (Category 2A). Clinical data: The 5-year and 10-year OS rates of 50 patients after surgery were 72% and 60%, respectively; the 5-year OS rate was 90% for tumors <2cm (64% for tumors >2cm), and 28% of patients developed vesicovaginal fistula or rectovaginal fistula.
• Central uncontrolled disease/recurrence (lesions invading the bladder/rectum, no pelvic wall involvement/pelvic extrapelvic metastasis, completely resectable): Pelvic exenteration (PE) is the first choice (Category 2A). PE is divided into anterior, posterior, and total types. The overall postoperative complication rate is nearly 70%, and the 5-year OS rate is 20%~73%. Negative surgical margins and no lymph node metastasis are important prognostic factors; the median OS time is 73.2 months for patients without lymph node metastasis (17.8 months for those with metastasis).
• Non-central uncontrolled disease/recurrence (pelvic wall or pelvic wall lymph node metastasis): Most cases have unresectable or residual tumors, with poor surgical efficacy. Laterally extended endopelvic resection (LEER) can expand the resection range, but the complication rate is high (nearly half of patients have grade ≥Ⅱ complications), and its pros and cons are controversial; it is only suitable for patients with limited lesions.
• Rectovaginal fistula/vesicovaginal fistula: Surgical management is required to relieve symptoms. Early intestinal or urinary diversion is recommended to avoid deterioration such as septic shock. The surgical plan should balance the possibility of repair and the patient's overall prognosis.

Surgical Treatment for Distant Metastasis

• Recommendation: Suitable for isolated or oligometastatic lesions (≤5) and lesions requiring symptom relief (Category 2B).
• Clinical application: Isolated para-aortic lymph node, lung, and brain metastases can be surgically resected for potential cure. Among 29 patients with lung metastasis who underwent surgical resection, the 5-year survival rate was 32.9% (42.2% for 1~2 lesions, 0% for 3~4 lesions). For brain metastasis (incidence 1%~2%, median OS time 3~6 months), surgery can relieve symptoms and improve survival in patients with Karnofsky Performance Status ≥70, stable primary lesions, single lesions (or 2~3 adjacent lesions), and symptoms/space-occupying effects; local radiotherapy should be supplemented after surgery. For bone metastasis (commonly occurring in the spine, pelvis, and long bones), surgery is suitable for confirmation of diagnosis, fracture risk/established fracture, and nerve compression; combined use of bisphosphonates or denosumab can reduce skeletal-related events.

2. Radiation Therapy

Pelvic Recurrence after Radical Surgery

• Recommendation: Concurrent chemoradiotherapy (CCRT) containing cisplatin and/or paclitaxel is the first choice for patients without adjuvant radiotherapy and no distant metastasis (Category 2A).
• Clinical data: Among 72 patients receiving IMRT-based salvage CCRT, the 5-year OS rate was 65.9% and the 5-year progression-free survival (PFS) rate was 57.6%. For central recurrence, CCRT + brachytherapy (dose 80~90Gy) can achieve similar efficacy to that of newly diagnosed locally advanced cervical cancer.

Radiation Therapy for Oligometastatic Lesions

• Recommendation: For oligometastatic lesions with controlled primary tumors, local radiotherapy is the first choice, and SBRT is an optional technique; priority is given to patients with a long disease-free interval (Category 2A).
• Para-aortic lymph node (PALN) metastasis: 27% of patients with isolated PALN metastasis survive more than 5 years. The 5-year OS rates of CCRT, radiotherapy alone, and palliative chemotherapy are 40%, 30%, and 0%, respectively. Among 67 Korean patients, the 3-year OS rate of patients with isolated PALN metastasis was 60.8% (lower in those with combined metastasis). Squamous cell carcinoma, asymptomatic recurrence, isolated metastasis, and long disease-free interval are favorable prognostic factors.
• Other oligometastatic lesions: The median PFS time of 38 patients receiving radical radiotherapy (≥50.4Gy) was 21.7 months, with 2-year and 3-year OS rates of 74% and 65%, respectively. Among 85 patients receiving SBRT, the median OS time was 32.7 months, and the 2-year OS rate was 57.5%. SABR has good local control and low adverse reactions, and is the first choice; combination with systemic therapy is needed to reduce the risk of extensive recurrence.
• Lung metastasis: SBRT/SABR is the appropriate technique. The selection criteria include lesions ≤5cm, number ≤3, no extrapulmonary metastasis/controlled extrapulmonary metastasis, and no obvious interstitial lung disease. Palliative radiotherapy can be performed for extensive metastasis to relieve symptoms such as cough and hemoptysis.

Management of Newly Diagnosed Stage ⅣB Cervical Cancer

• Recommendation: Systemic therapy is the main treatment. For patients with isolated lymph node metastasis, combination with radical radiotherapy is recommended; for patients with hematogenous metastasis who respond well to systemic therapy, local treatment (radiotherapy, surgery, thermal ablation, etc.) can be performed for oligometastatic/active lesions (Category 2A).
• Clinical data: The 5-year OS rate of stage ⅣB cervical cancer is 14.7%. Propensity score matching analysis shows that chemotherapy combined with radiotherapy (external beam ± brachytherapy) has a longer median OS time than chemotherapy alone. Among 25 patients with left supraclavicular lymph node metastasis receiving CCRT, the 3-year OS rate was 49% and the disease-free survival (DFS) rate was 33%; the 3-year OS rate was 68% for patients with controlled primary lesions (29% for those with uncontrolled primary lesions).

Reirradiation

• Recommendation: Irradiation should only target the involved lesion area; lymphatic drainage areas without evidence of disease should not be irradiated (Category 2A).
• Precautions: Comprehensive evaluation of patient status, prior radiotherapy history (dose, range, normal tissue dose), tumor characteristics, and radiotherapy interval is required. Adverse reactions are more severe than those of the first radiotherapy; the dose to organs at risk must be strictly controlled to avoid complications such as bleeding and fistula. The longer the interval, the higher the feasibility and safety.

Palliative Symptom-Relief Radiation Therapy

• Advantages: Non-invasive with definite efficacy. It can relieve increased intracranial pressure (nausea, vomiting), esophageal compression (dysphagia), vascular compression (venous return disorders), and pain caused by bone metastasis, pleural metastasis, and pelvic wall metastasis. It is the preferred local palliative treatment for symptom relief.

Intraoperative Radiation Therapy (IORT)

• Application scenario: During surgical resection of recurrent lesions in the pelvic wall or lymphatic drainage area, supplementary radiotherapy to the surgical field with a dose of 10~20Gy is performed while avoiding normal tissues, when the safety margin is insufficient or the surgical margin is positive.
• Clinical data: The 5-year OS rate of patients with microscopic residual lesions after IORT was 37% (10% for those with gross residual lesions). Among 17 patients receiving surgery + HDR IORT, the 3-year local control (LC) rate was 67%, and the 3-year LC rate was 83% for patients with complete resection (25% for those with residual lesions).

02 Pharmacotherapy

1. Traditional Pharmacotherapy

• Single-agent cisplatin: OS time 6.1~7.1 months, response rate 17%~38%. There was no significant difference in response rate between 50mg/m² and 100mg/m² (20.7% vs 31.4%), and no significant improvement in PFS and OS.
• Combination chemotherapy (TP/TC): Cisplatin + paclitaxel (TP) has a higher response rate (36% vs 19%) and longer PFS (4.8 months vs 2.8 months) than single-agent cisplatin. Among cisplatin-based combination regimens, cisplatin + paclitaxel has the longest 3-year median OS time (12.87 months) and the highest overall response rate (ORR) (29.1%) compared with other regimens (such as cisplatin + vinorelbine). Carboplatin + paclitaxel (TC) is non-inferior to TP and is suitable for patients intolerant to cisplatin.
• TP/TC ± bevacizumab: The GOG240 study showed that the median OS time of TP + bevacizumab reached 17.5 months, which was approved by the FDA as a first-line regimen in 2014.

2. Immunotherapy

Second-Line Treatment

• Pembrolizumab: Indicated for patients with PD-L1 positivity (CPS ≥1) and disease progression after chemotherapy, with ORR 14.6%~17%, approved by the FDA.
• Cemiplimab: OS is superior to chemotherapy regardless of PD-L1 status (12.0 months vs 8.5 months), with ORR 16.4%, and is the preferred second-line regimen in NCCN guidelines.
• Nivolumab: ORR 26.3%; balstilimab: ORR 15%.
• Bispecific antibodies: Cadonilimab (PD-1/CTLA-4): ORR 32.3% (42.9% in PD-L1-positive patients), 12-month OS rate 59.9%; epalrestat vorolimab: ORR 33.8%, median PFS time 5.4 months, 12-month OS rate 65.4%.

First-Line Treatment

• Pembrolizumab + TP/TC ± bevacizumab: The KEYNOTE-826 study showed that the median OS time of PD-L1-positive (CPS ≥1) patients reached 28.6 months (16.5 months in the placebo group), and the 24-month OS rate was 52.1% (38.7% in the placebo group). It was approved by the FDA as the standard first-line regimen for PD-L1-positive patients in 2021.
• Atezolizumab + TP/TC + bevacizumab: The BEATcc study showed that the median PFS time was 13.7 months (10.4 months in the non-atezolizumab group) and the median OS time was 32.1 months (22.8 months in the non-atezolizumab group).
• Cadonilimab + TP/TC ± bevacizumab: The domestic COMPASSION-16 trial showed that the median OS of the total population was significantly better than that of the placebo group (P=0.001).

3. Post-Immunotherapy Drugs (ADC)

• Tisotumab vedotin (TV): Targeting tissue factor (TF). The innovaTV 301 study showed that the median OS time was 11.5 months (9.5 months in the chemotherapy group), the median PFS time was 4.2 months (2.9 months in the chemotherapy group), and the ORR was 17.8% (5.2% in the chemotherapy group). It was approved by the FDA in 2024 for patients with disease progression after first-line platinum-based chemotherapy. Attention should be paid to ocular adverse reactions, peripheral neuropathy, and bleeding.
• Trastuzumab deruxtecan (DS-8201): Targeting HER2. In the DESTINY-PanTumor02 study, the ORR of 40 patients with HER2 expression was 50% (75% for HER2 3+ patients, 40% for HER2 2+ patients). It was granted accelerated approval by the FDA in 2024 for HER2 3+/2+ solid tumors.

03 Comprehensive Treatment Strategies

• The treatment of r/mCC should be adjusted according to the patient's status (oligometastasis/oligorecurrence, extensive metastasis): Local treatment is emphasized for patients with oligometastasis/oligorecurrence, and systemic treatment is emphasized for those with extensive metastasis. If patients convert to oligometastasis/oligorecurrence after systemic treatment, local treatment should be initiated.
• Palliative supportive care should be provided throughout the treatment process, and the treatment strategy should be dynamically adjusted according to the trend of disease progression, improvement, or resolution.

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