Cervix Part 1

Oct 15

Episode Notes

Epidemiology
1. 3rd most common gynecologic malignancy in US
2. 1st most common worldwide
  1. 350,000 deaths in 2022, 94% occurred in low and middle-income countries
3. Incidence of squamous cell cervical cancer (SCC) is decreasing, largely due to effective screening and Human Papillomavirus (HPV) vaccination
4. Rates of adenocarcinoma and adenosquamous carcinoma of the cervix are increasing
Risk Factors
1. By far: persistent HPV infection
2. Related to increased risk of HPV: early onset of sexual activity, higher numbers of sexual partners, history of STI, early and increasing parity, immunosuppression.
3. Not related to increased risk of HPV: smoking history, low socioeconomic status (likely related to decreased access to vaccination and screening)
Prognosis
1. Stage is most important factor
2. LN status independent prognostic factor
3. LVSI - controversial
4. HPV status - HPV-independent disease has worse OS
Histologies
1. 80% SCC, ~20% adenocarcinoma (AC)
2. DOI in AC difficult to measure so pathologists use:
  1. Silva classification system
    1. Pattern A: non-destructive invasion
    2. Pattern B: localized or early destructive stromal invasion
    3. Pattern C: diffuse destructive stromal invasion
Work Up at Diagnosis
1. H&P, CBC, renal and liver function tests; consider HIV testing and smoking cessation counseling
2. Staging determined by clinical exam, surgery, and/or imaging
  1. No longer requires cystoscopy or proctoscopy
  2. Apparent stage I disease -> Pelvic MRI
  3. Stage IB+ -> PET/CT to assess for nodal disease and distant spread
  4. If greater than microscopic disease -> assess upper urinary tract
3. If colposcopic biopsy performed ->
  1. Cone biopsy to determine invasion or accurate assessment of DOI
    1. Path report should include margin and LVSI status
Staging - FIGO 2018
1. Early stage: IA1, IA2, IB1, 1B2
  1. IA1: DOI <= 3 mm
  2. IA2: DOI 3-5 mm
  3. 1B1: DOI > 5 mm, tumor <= 2 cm
  4. 1B2: DOI > 5 mm, tumor 2-4 cm
2. IIA1 disease not technically early stage, but can be offered the same treatment
Pelvic Lymph Nodes
1. GOG49
  1. N = 645
  2. Apparent stage I disease -> PPaLND
    1. Those w/ extrauterine disease including paraaortic metastases were excluded
  3. Those w/ stage I disease (> 3 DOI by staging at that time) followed to determine prognosis factors for recurrence and pelvic LN positivity
  4. Risk factors on multivariate analysis: LVSI, DOI, parametrial involvement, age
  5. 3 yr DFI 86% if node negative, 74% if node positive
2. Based on stage
  1. IA1, <=1% risk of LN mets; not needed unless LVSI
  2. IA2-IIA1 LN evaluation recommended
3. SLNB
  1. Detection rates 89-92% w/ sensitivity of 89-90% on meta-analyses
  2. Sensitivity better when tumors <4 cm in size (and even better with <2 cm)
  3. Should use ultrastaging
4. SENTICOL-1, 2011
  1. Prospective, non-randomized
  2. Included up to FIGO 1994 stage IB1 (up to 4 cm disease)
  3. SLNB in all pts using blue dye and radiotracer, followed by PLND and resection of all other sites that had SLN map
  4. Nodes mapped 98% of time, 76% bilaterally
    1. In those w/ bilateral SLN detection, zero false negatives
  5. Sensitivity 92% and negative predictive value 98%
5. SENTICOL-2, 2021
  1. RCT
  2. Similar inclusion criteria, combined detection method
  3. Randomized to SLNB vs SLNB + PLND
    1. Only randomized if successful mapping of SLN bilaterally and if nodes were negative during frozen section
    2. If final path w/ positive nodes -> reoperation with full LND
  4. Primary endpoint: morbidity related to LN dissection
    1. Improved with SLNB: postop neurologic symptoms, lymphatic morbidity
    2. Rates of lymphedema not different
  5. 3-yr RFS did not differ
  6. No difference in DFS at 4 year follow-up
6. SENTICOL-3, ongoing
  1. Ongoing international RCT, enrollment completed in 5/2024
  2. Comparing SLNB alone to SLNB + PLND
  3. Primary outcome: DFS, health-related QOL
  4. Secondary outcome: OS
7. SENTIX, 2025
  1. Single arm prospective noninferiority trial
  2. N = 731 pts w/ FIGO 2018 stage IA1 with LVSI to stage IB2 cervical cancer
  3. SLNB followed by either hysterectomy or trachelectomy, radical or simple
  4. Those w/ failed mapping, unilateral detection, or intraoperative SLN metastases excluded from ITT
  5. 2-yr RR 6.1%, meeting noninferiority compared to benchmark (7%)
  6. 2-year DFS: 93.3%
  7. 2-year OS: 97.9%
  8. Ultrastaging identified ~44% of node-positive cases that would have been otherwise missed by conventional pathology
8. PHENIX-1, 2025
  1. Randomized, open-label, noninferiority trial
  2. N = 838 pts w/ FIGO 2018 stage IA1 w/ LVSI, IA2, IB1, IIA1 disease, tumors <= 3 cm
  3. SLNB -> intraop path assessment
    1. If negative -> full LND vs no LND followed by rad hyst (or simple hyst if stage IA1)
  4. 3-yr DFS: 94.6% in LND group vs. 96.9% in SLNB group
9. SENTIREC, 2021
  1. Prospective, nonrandomized study
  2. N = 245
  3. SLN mapping w/ ICG
    1. If side didn’t map -> full PLND
    2. All tumors > 2 cm -> full bilat PLND
  4. All surgeries MIS
  5. 15% of patients had nodal mets; in patients w/ tumors > 2 cm, 27% had metastatic disease
  6. PET CT was not very helpful for metastatic nodes - PPV of only 27%, sensitivity of 15%
Paraaortic Lymph Nodes
1. Higher rates if positive pelvic or common iliac LN or tumors > 2 cm
2. If pelvic nodes suspicious → recommend para-aortic LND
3. PAROLA trial ongoing to evaluate whether PALND can be used to tailor chemoRT to improve survival; results expected in 2030
Surgical Management
1. Fertility Sparing
  1. Microinvasive disease - stage 1A1 w/o LVSI
    1. Sufficient treatment w/ conization
    2. CKC > LEEP d/t ability to orient specimen and non-charred margins
  2. CONCERV, 2021
    1. Single-arm, multicenter trial, N = 100
    2. CKC w/ lymph node evaluation vs simple hyst w/ lymph node evaluation
    3. Inclusion: SCC or AC, tumors < 2 cm, no LVSI, DOI < 10 mm, negative imaging for metastatic disease
    4. LN assessment: full LND OR SLNB -> full LND OR SLNB (only 4%)
    5. 44 CKC + LND, 40 CKC → simple hyst + LND, 16 simple hyst → LND
    6. Pos nodes in 5% of patients, recurrence rate 3.5% at 2 years
    7. Criteria for conservative surgery: negative margins on CKC, tumor size <= 2 cm, DOI <= 10 mm, negative imaging for locoregional disease
      1. Negative LVSI, SCC or usual type AC g1-2 preferred/recommended criteria
  3. Radical trachelectomy
    1. Option for up to stage IB2 disease
    2. If tumor 2-4 cm → abdominal approach preferred by NCCN (improved parametrial resection)
    3. SLNB and/or PLND recommended to assess nodes
      1. Stage IB1 and select stage IB2: consider paraaortic LND
    4. Pregnancy rates appear to be >50%; pts more likely to experience miscarriage and preterm labor
  4. SHAPE, CONCERV, and GOG 278 collectively demonstrate that fertility-sparing conization with pelvic lymph node assessment is oncologically safe for carefully selected patients with early-stage cervical cancer achieving low recurrence rates and successful pregnancy outcomes
2. Hysterectomy - Which Type?
  1. SHAPE, 2024
    1. Randomized non-inferiority trial of simple vs radical hysterectomy in pts w/ low-risk cervical cancer (tumor <= 2 cm w/ DOI <10 mm and negative margins on CKC or <=50% cervical stromal tissue invasion on MRI)
    2. Published before LACC → most rad hysts were MIS
    3. N = 700
    4. 90% had stage IB1 disease
    5. 3 year recurrence rate 2.2% in rad hyst vs 2.5% in simple hyst
    6. Simple hyst group w/ less urinary incontinence and urinary retention
  2. What’s the difference?
    1. Radical (type C1) hyst involves 1-2 cm vaginal margin, ureters/bladder/rectum are mobilized further, parametrial and uterosacral ligaments are resected 1-2 cm off the cervix
  3. GOG 278, Nov 2024
    1. Prospective cohort study
    2. Physical function and QOL before and after nonradical surgery for pts w/ stage IA1 w/ LVSI, IA2, IB1
      1. Included DOI <=10 mm and negative margins on excisional specimen
    3. N = 224
    4. Simple hyst or CKC + full PLND
    5. 75% live birth rate among achieved pregnancies
    6. RFS 94.8% in CKC and 100% in simple hyst group
    7. Provided valuable data on conservative surgery for patients with stage IA1 w/ LVSI
  4. Updated NCCN guidelines for non-fertility sparing conservative management
    1. Stage IA1 w/o LVSI → simple hyst
    2. Stage IA1 w/ LVSI
      1. Negative margins → simple hyst, nodal evaluation
      2. Positive margins → either
        Repeat CKC to r/o stage IA2/IB1 disease
        Modified radical hysterectomy, nodal evaluation
3. Which approach?
  1. LACC, 2018
    1. Phase III RCT
    2. Inclusion: SCC, AC, or AS up to stage 1B1 to rad hyst via MIS (lsc or robotic) vs abdominal approach
    3. MIS had inferior 4.5 year DFS (91.2 vs. 97.1%) and 3-year overall survival (93.8 vs. 99%)
    4. Has been validated retrospectively
    5. Has not been prospectively validated in other patient populations or countries
  2. LACC OS analysis, 2024
    1. Confirmed detriment in MIS
  3. ROCC/GOG-3043
    1. Ongoing - evaluating robotic vs open radical hysterectomy
Adjuvant Treatment
1. Intermediate Risk
  1. Sedlis criteria, based on review of GOG 92
    1. GOG 92 randomized patients to pelvic XRT vs no further therapy after rady hyst w/ PLND
    2. Used for node-, margin-, and parametria-negative cases to determine intermediate risk for recurrence
  2. GOG 263, 2025
    1. Evaluated addition of weekly cisplatin to RT for intermediate risk cervical cancer
    2. Negative trial
      1. Increased toxicity w/o significant oncologic benefit
2. High Risk
  1. Peters criteria, based on GOG 109
    1. Determines who require adjuvant chemoRT after radical hysterectomy
    2. Study compared RT vs chemoRT w/ cisplatin and fluorouracil
      1. PFS and OS improved with chemoRT
    3. High risk criteria: positive surgical margins, pathologically confirmed involvement of the pelvic lymph nodes, microscopic involvement of the parametrium
  2. STARS, 2021
    1. Phase 3 RCT
    2. N = 1048
    3. Stage IB-IIA cervical cancer with “adverse pathological factors” after rad hyst randomized to adjuvant sequential chemoradiation (SCRT) vs concurrent chemoradiation (CCRT) or radiation alone (RT)
    4. Adverse factors: lymph node mets, positive parametrium, positive margins, LVSI, deep stromal invasion
    5. Protocol
      1. Adjuvant RT: total dose to 45-50 Gy
      2. CCRT: weekly cisplatin at 30-40 mg/m2 + RT
      3. SCRT: cisplatin 60-75 mg/m2 plus paclitaxel 135-175 mg/m2 in a 21 day cycle given 2 cycles before and 2 cycles after RT
    6. SCRT w/ better disease-free survival (HR 0.52 vs RT, HR 0.65 vs CCRT)
  3. GOG 0724, 2024
    1. Phase III RCT
    2. Adjuvant chemoRT vs chemoRT + 4 cycles carbo/taxol in pts w/ high risk features after rad hyst
    3. N = 212, 56% w/ open rad hyst
    4. 4-year DFS not different between arms, but toxicity higher w/ addition of chemotherapy
Neuroendocrine Cervical Cancer
1. High grade NEC most common - but still only 1-1.5% of cervical cancers
  1. Small cell most common of high grade
2. Most will receive cisplatin + etosoposide at some point based on lung and cervical cancer data
  1. Timing?
    1. If <=4 cm -> hyst followed by chemo or chemoRT
    2. If >= 4 cm -> usually chemo or chemoRT before surgery
Surveillance
1. H&P every 2-6 months x 2 years
2. Recurrence symptoms: discharge weight loss, pain, persistent cough
3. Radiation? → referrals for sexual health
4. Imaging?
  1. Stage I → based on symptoms/clinical suspicion
  2. Stage II+ → PET/CT w/i 3-6 months following completion of therapy

Sedlis’ (Intermediate risk) and Peters’ (High risk) criteria for early stage cervical cancer.

*Source: Fleischmann et al. Molecular Markers to Predict Prognosis and Treatment Response in Uterine Cervical Cancer. Cancers. 2021, 13, 5478. https://doi.org/10.3390/cancers13225748*

Reference List

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2. Jhingran A. Adjuvant chemotherapy following concurrent chemoradiation (CRT) in patients with high-risk early-stage cervical carcinoma following radical hysterectomy: Results of NRG oncology/RTOG 0724/GOG-0724. Journal of Clinical Oncology. 2024;42(16_suppl):5504-5504. doi:10.1200/jco.2024.42.16_suppl.5504

3. Covens A, Huang H, Kim YB, et al. Evaluation of physical function and quality of life before and after non-radical surgical therapy (extra fascial hysterectomy or cone biopsy with pelvic lymphadenectomy) for stage IA1 (LVSI+) and IA2–IB1 cervical cancer (GOG-278). Gynecol Oncol. 2024;190:S58-S59. doi:10.1016/j.ygyno.2024.07.088

4. Tu H, Huang H, Li Y, et al. Sentinel-Lymph-Node Biopsy Alone or with Lymphadenectomy in Cervical Cancer. New England Journal of Medicine. 2025;393(15):1463-1474. doi:10.1056/NEJMoa2506267

5. Leath CA, Monk BJ. Twenty-first century cervical cancer management: A historical perspective of the gynecologic oncology group/NRG oncology over the past twenty years. Gynecol Oncol. 2018;150(3):391-397. doi:10.1016/J.YGYNO.2018.06.023

6. Sedlis A, Bundy BN, Rotman MZ, Lentz SS, Muderspach LI, Zaino RJ. A Randomized Trial of Pelvic Radiation Therapy versus No Further Therapy in Selected Patients with Stage IB Carcinoma of the Cervix after Radical Hysterectomy and Pelvic Lymphadenectomy: A Gynecologic Oncology Group Study. Gynecol Oncol. 1999;73(2):177-183. doi:10.1006/GYNO.1999.5387

7. Plante M, Kwon JS, Ferguson S, et al. Simple versus Radical Hysterectomy in Women with Low-Risk Cervical Cancer. New England Journal of Medicine. 2024;390(9):819-829. doi:10.1056/nejmoa2308900

8. Peters WA, Liu PY, Barrett RJ, et al. Concurrent chemotherapy and pelvic radiation therapy compared with pelvic radiation therapy alone as adjuvant therapy after radical surgery in high-risk early-stage cancer of the cervix. J Clin Oncol. 2000;18(8):1606-1613. doi:10.1200/JCO.2000.18.8.1606

9. Nitecki R, Ramirez PT, Frumovitz M, et al. Survival After Minimally Invasive vs Open Radical Hysterectomy for Early-Stage Cervical Cancer: A Systematic Review and Meta-analysis. JAMA Oncol. 2020;6(7):1019-1027. doi:10.1001/JAMAONCOL.2020.1694

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Updated as of March 2026

cervical cancerOctober 2024Updated 2026part 1

Sydney Oesch

Cervix Part 1

Episode Notes

Reference List

Cervix Part 2

Chemotherapy: HIPEC and IPC