Cervix Part 1

Cervical Cancer
Written By Sydney Oesch

 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

Lymphovascular Space Invasion (LVSI) definitions

References

1. Schmeler KM, Pareja R, Blanco AL, et al. ConCerv: a prospective trial of conservative surgery for low-risk early-stage cervical cancer GYNECOLOGICAL CANCER. Int J Gynecol Cancer. 2021;31:1317-1325. doi:10.1136/ijgc-2021-002921

2. Plante M, Gregoire J, Renaud MC, Roy M. The vaginal radical trachelectomy: an update of a series of 125 cases and 106 pregnancies. Gynecol Oncol. 2011;121(2):290-297. doi:10.1016/J.YGYNO.2010.12.345

3. Wethington SL, Cibula D, Duska LR, et al. An international series on abdominal radical trachelectomy: 101 patients and 28 pregnancies. Int J Gynecol Cancer. 2012;22(7):1251-1257. doi:10.1097/IGC.0B013E318263EEE2

4. WU Y, LI Z, WU H, YU J. Sentinel lymph node biopsy in cervical cancer: A meta-analysis. Mol Clin Oncol. 2013;1(6):1025-1030. doi:10.3892/MCO.2013.168

5. Kadkhodayan S, Hasanzadeh M, Treglia G, et al. Sentinel node biopsy for lymph nodal staging of uterine cervix cancer: a systematic review and meta-analysis of the pertinent literature. Eur J Surg Oncol. 2015;41(1):1-20. doi:10.1016/J.EJSO.2014.09.010

6. Lécuru F, Mathevet P, Querleu D, et al. Bilateral Negative Sentinel Nodes Accurately Predict Absence of Lymph Node Metastasis in Early Cervical Cancer: Results of the SENTICOL Study. Published online 2011. doi:10.1200/JCO.2010.32.0432

7. Lecuru FR, McCormack M, Hillemanns P, et al. Clinical Trial. Int J Gynecol Cancer. 2019;29:829-834. doi:10.1136/ijgc-2019-000332

8. Favre G, Guani B, Balaya V, Magaud L, Lecuru F, Mathevet P. Sentinel Lymph-Node Biopsy in Early-Stage Cervical Cancer: The 4-Year Follow-Up Results of the Senticol 2 Trial. Front Oncol. 2021;10(2):621518. doi:10.3389/FONC.2020.621518/BIBTEX

9. Frumovitz M, Plante M, Lee PS, et al. The FILM Trial: A randomized phase III multicenter study assessing near infrared fluorescence in the identification of sentinel lymph nodes (SLN). Gynecol Oncol. 2018;149:7. doi:10.1016/J.YGYNO.2018.04.023

10. Bats AS, Mathevet P, Buenerd A, et al. The Sentinel Node Technique Detects Unexpected Drainage Pathways and Allows Nodal Ultrastaging in Early Cervical Cancer: Insights from the Multicenter Prospective SENTICOL Study. Oncol. 2013;20:413-422. doi:10.1245/s10434-012-2597-7

11. Mathevet P, Lécuru F, Uzan C, et al. Clinical Trial Sentinel lymph node biopsy and morbidity outcomes in early cervical cancer: Results of a multicentre randomised trial (SENTICOL-2) * Anne-Sophie Bats i on behalf of the Senticol 2 group. Eur J Cancer. 148:307-315. doi:10.1016/j.ejca.2021.02.009

12. Sponholtz SE, Mogensen O, Grubbe Hildebrandt M, et al. Sentinel lymph node mapping in early-stage cervical cancer-A national prospective multicenter study (SENTIREC trial). Gynecol Oncol. 2021;162:546-554. doi:10.1016/j.ygyno.2021.06.018

13. Huang H, Liu J, Li Y, et al. Metastasis to deep obturator and para-aortic lymph nodes in 649 patients with cervical carcinoma. Eur J Surg Oncol. 2011;37(11):978-983. doi:10.1016/J.EJSO.2011.08.128

14. Gold MA, Tian C, Whitney CW, Rose PG, Lanciano R, Mackey D. Surgical versus radiographic determination of para-aortic lymph node metastases before

chemoradiation for locally advanced cervical carcinoma: a Gynecologic Oncology Group Study. Cancer. 2008;112(9):1954-1963. doi:10.1002/CNCR.23400

15. Gouy S, Morice P, Narducci F, et al. Prospective multicenter study evaluating the survival of patients with locally advanced cervical cancer undergoing laparoscopic para-aortic lymphadenectomy before chemoradiotherapy in the era of positron emission tomography imaging. J Clin Oncol. 2013;31(24):3026-3033. doi:10.1200/JCO.2012.47.3520

16. De Vivar AD, Roma AA, Park KJ, et al. Invasive endocervical adenocarcinoma: Proposal for a new pattern-based classification system with significant clinical implications: A multi-institutional study. International Journal of Gynecological Pathology. 2013;32(6):592-601. doi:10.1097/PGP.0B013E31829952C6

17. Landoni F, Maneo A, Colombo A, et al. Randomised study of radical surgery versus radiotherapy for stage Ib-IIa cervical cancer. Lancet. 1997;350(9077):535-540. doi:10.1016/S0140-6736(97)02250-2

18. Levinson K, Beavis AL, Purdy C, et al. Beyond Sedlis—A novel histology-specific nomogram for predicting cervical cancer recurrence risk: An NRG/GOG ancillary analysis. Gynecol Oncol. 2021;162(3):532-538. doi:10.1016/J.YGYNO.2021.06.017

19. 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

20. 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

21. Plante M, Kwon JS, Ferguson S, et al. Simple versus Radical Hysterectomy in Women with Low-Risk Cervical Cancer. N Engl J Med. 2024;390(9):819-829. doi:10.1056/NEJMOA2308900

22. 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

23. 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

Sydney Oesch
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Chemotherapy: HIPEC and IPC