Cervix Part 1

 Episode Notes

1. 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

2. 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)

3. 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

4. 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

5. 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 

6. 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 

7. 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

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. Size Limitations?

1. SENTICOL included up to 4 cm; some studies suggest improved sensitivity and NPV in tumors <=2 → NCCN guideline for this

2. SENTIREC, 2021

1. Evaluated efficacy of SLNB in early stage cervical cancer w/ planned subgroup analysis of tumors between 2-4 cm

2. n=245

3. SLN mapping w/ ICG -> removal of any suspicious nodes; if side didn’t map -> PLND

4. All done via MIS

5. If >2 cm -> pelvic LND regardless of mapping 

6. 15% had nodal mets overall; in pts w/ tumors 2-4 cm, 27% w/ nodal mets

7. PET CT not very helpful for detection of metastatic nodes; PPV of only 27% and sensitivity of 15%

8. Overall takeaway: no long-term safety or survival data for SLNB in cervical cancer → varying practice patterns and rates of adoption of SLNB in US

8. 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

9. 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. CKC w/ lymph node evaluation vs simple hyst w/ lymph node evaluation in early stage cervical cancer

2. Inclusion: SCC or AC, tumors < 2 cm, no LVSI, DOI < 10 mm, negative imaging for metastatic disease

3. N = 100 

4. 44 CKC + LND, 40 CKC → simple hyst + LND, 16 simple hyst → LND

5. Pos nodes in 5% of patients, recurrence rate 3.5% at 2 years

3. Radical trachelectomy

1. Option for up to stage IB2 disease

2. If tumor 2-4 cm → abdominal approach preferred by NCCN

3. Pregnancy rates appear to be >50%; pts more likely to experience miscarriage and preterm labor

2. Hysterectomy - Which Type?

1. SHAPE

1. Randomized non-inferiority trial of simple vs radical hysterectomy in pts w/ low-risk cervical cancer (<= 2 cm w/ limited stromal involvement)

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. 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. ROCC/GOG-3043

1. Ongoing - evaluating robotic vs open radical hysterectomy

10. 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

1. Ongoing trial assessing whether pelvic RT vs chemoRT should be recommended for patients with intermediate risk disease

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)

11. 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 -> hysterectomy followed by chemo or chemoRT

2. If ≥ 4 cm -> usually chemo or chemoRT before surgery

12. 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

References

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