Uterine Cancer: Part 2

Uterine Cancer
Written By Sydney Oesch

Episode Notes

  1. Surgical Approach

    1. Standard of care: total hysterectomy with bilateral salpingo-oophorectomy via a minimally invasive approach

    2. Add omental biopsy or infra-colic omentectomy in specific histologic subtypes such as serous and undifferentiated endometrial carcinoma and carcinosarcoma

    3. GOG-LAP2 trial established minimally invasive surgery as standard of care for early-stage endometrial cancer

      1. Results corroborated with LACE trial (international RCT)

  2. Lymph Nodes Considerations

    1. Why does lymph node positivity matter?

      1. Patients with clinical stage I-II disease are upstaged to stage III disease due to positive lymph nodes found surgically

      2. GOG-33

        1. Demonstrated that a lot of patients with clinical stage I disease actually have extrauterine spread including lymph node involvement

        2. Tumor limited completely to the endometrium had a risk of lymph node metastases of <3%, but this group was only about 14% of all cases

        3. 22% of patients with clinical uterus-confined disease had extrauterine spread on final pathology. 

        4. Established surgical staging (not clinical stage) as standard of care

      3. Mayo Criteria

        1. Mariani et al, 2000

          1. Retrospective study of 328 patients w/ grade 1-2 endometrioid histology, ≤ 50% myometrial invasion, no intraoperative evidence of change

          2. In patients whose primary tumor was ≤ 2 cm, there were zero patients with positive lymph nodes and zero deaths

          3. Proposed “Mayo Criteria”

            1. <50% myometrial invasion

            2. Tumor ≤ 2 cm

            3. Well or moderately differentiated histology

        2. Mariani et al, 2008

          1. Prospective study of 422 patients using the “Mayo Criteria”

          2. 20% of these low risk endometrioid cases underwent a lymphadenectomy and all had completely negative nodes.  Of the 67% not meeting the low risk criteria and undergoing lymphadenectomy, 22% had nodal metastases

          3. affirmed the previously proposed Mayo criteria as a way to identify patients intraoperatively who may not need a lymphadenectomy

      4. Benefits of full lymphadenectomy?

        1. CONSORT 2008

          1. randomized patients with preoperative clinical stage I (excluding low risk) disease to Hysterectomy/BSO +/- bilateral pelvic LN dissection

          2. demonstrated improved staging accuracy but no improvement in overall or disease free survival

        2. ASTEC

          1. randomized patients with preoperative stage I-IIa disease to hysterectomy with or without pelvic lymphadenectomy (+/- paraaortic lymphadenectomy at discretion of the surgeon)

          2. did not see any difference in PFS or OS between patients who had or didn’t have a systematic lymphadenectomy

        3. Criticisms of these studies (CONSORT and ASTEC) was that there was no systemic para-aortic lymphadenectomy, and no systematic approach to using the nodal disease status to guide adjuvant treatment

        4. Disadvantages of systematic lymphadenectomy

          1. overall risk of nodal disease in “all-comers” with endometrial cancer is ~9%, so the vast majority of patients will not have positive nodes

          2. Patients who undergo full lymphadenectomy have a much higher rate of lymphedema and lymphocyst formation and have increased surgical and postoperative morbidity. 

  3. Sentinel Lymph Nodes

    1. SENTI-endo, 2011

      1. evaluated patients with stage I-II endometrial cancer

      2. had a sentinel lymph node dissection followed by systematic pelvic lymph node dissection.

      3. sentinel lymph nodes mapped 88% of the time, and bilaterally in 62% of cases

      4. False negative rate of 16%

    2. FIRES, 2017

      1. all patients with clinical stage I disease, including all grades and histologic types

      2. mapped 86% of the time, but only 52% bilaterally

      3. SLN correctly picked up lymph node metastases in 35 of the 36 patients (97%), for a false negative rate of <3% among patients whose nodes mapped and a negative predictive value of 99.6%

    3. SENTOR, 2020

      1. clinical stage I, intermediate risk and high grade endometrial cancer

      2. Patients with grade 2 endometrioid endometrial cancer underwent sentinel lymph node biopsy followed by pelvic lymphadenectomy, and patients with high-grade endometrial cancer additionally underwent periaortic lymphadenectomy

      3. study had a lot of histologic heterogeneity; the patient population was comprised of 33% serous carcinoma, 10.9% carcinosarcoma, 8% mixed histologies, and 1.9% clear cell carcinomas

      4. Negative predictive value of 99%

    4. SLN Ultra-staging

      1. Ultra-staging is a pathology technique that involves 2 components: serial sectioning with review of multiple H&E stained slides with or without cytokeratin IHC staining

      2. Ultra-staging is key, because it leads to upstaging in about 5-15% of patients when compared to traditional H&E.

  4. Categories for Recurrence Risk

    1. Low-risk: low-grade disease without LVSI which is limited to the endometrium or is <50% myometrial invasion

      1. Cured w/ surgery - do not need adjuvant therapy

    2. High-risk: stage ≥ III disease, regardless of histology or grade OR serous or clear cell carcinoma OR grade III deeply invasive endometrioid adenocarcinoma

      1. Always require adjuvant treatment

    3. Intermediate

      1. Grade I or II disease with >50% myometrial invasion OR disease with occult cervical stromal invasion OR grade I-II disease with <50% myometrial invasion with LVSI

    4. “High Intermediate Risk”

      1. GOG 99

        1. Compared observation versus whole pelvic radiation for the intermediate-risk group

        2. In a post-hoc analysis, the study established risk factors for recurrence, when combined with age: >2/3 myometrial invasion, grade II-III disease, and/or presence of LVSI.  In their “high intermediate risk” group, for whom recurrence risk was higher, adjuvant radiation had a significant improvement in recurrence rate. This group includes patients who are : age ≥70 with 1 risk factor, age 50-69 with 2 risk factors, and age < 50, with all three risk factors

      2. PORTEC criteria

        1. PORTEC I and II also identified a high-intermediate risk group

        2. must have ≥2 of 3 of the following risk factors to be considered to have high-intermediate risk disease:

          1. age > 60

          2. >50% myometrial invasion

          3. and/or grade III histology

  5. Adjuvant Therapy

    1. To date, no randomized control trial has demonstrated an overall survival benefit for any adjuvant therapy in the overall study population or in a pre-specified subgroup for early stage endometrial cancer.

    2. GOG 99

      1. observation versus 50.4 Gy EBRT

      2. 2 year recurrence rate was 2% vs 12% in the radiotherapy vs observation group, respectively

      3. One-third of the study patients were high-intermediate risk, and importantly, were responsible for two-thirds of the cancer related deaths.  Among the patients with high-intermediate risk disease (by GOG criteria) randomized to observation, recurrence risk at 2 years was 27% (compared to 6% in the radiation group).

    3. PORTEC I

      1. All patients had a total abdominal hysterectomy without lymph node assessment and were included if their disease was: grade I with >50% myometrial invasion, grade II with any invasion, or grade III with <50% myometrial invasion

      2. 46 Gy EBRT vs observation

      3. radiotherapy significantly reduced locoregional recurrence from 14% in the observation group to 4% in the EBRT group

    4. PORTEC II

      1. Non-inferiority trial to evaluate vaginal recurrence risk after treatment with vaginal brachytherapy versus EBRT

      2. found that vaginal brachytherapy is equivalent to EBRT in terms of reducing risk of vaginal recurrence.  It additionally found that EBRT does reduce the risk of pelvic recurrence from 3.8% vs 0.5%, but there is additional GI toxicity with EBRT

      3. Thus, PORTEC-2 established vaginal brachytherapy as the new standard of care for adjuvant treatment of early stage high-intermediate risk endometrial cancer.  

    5. ASTEC

      1. In the second phase of this study, patients with high or intermediate risk of recurrence were randomized to radiation vs. observation

      2. The results of this second phase of the ASTEC trial were combined with the results of another trial, EN.5 (due to low recruitment in each individual study)

      3. takeaway from this study was that there was no benefit to postop RT in intermediate or high risk endometrial cancer, and pelvic RT had more side effects

    6. GOG-249

      1. sought to answer whether chemotherapy + vaginal brachytherapy improves recurrence free survival compared with EBRT in patients with high-intermediate and high-risk early stage endometrial cancer

      2. No evidence that vaginal brachytherapy with chemotherapy was superior to EBRT in terms of recurrence free survival or overall survival

      3. higher pelvic and pera-aortic recurrence in the vaginal brachytherapy/chemotherapy group (9%) vs EBRT group (4%) and no differences in distant or vaginal recurrences

      4. suggested that pelvic RT should remain standard of care in patients with high-risk early stage endometrial cancer and addition of chemotherapy may not improve outcomes.

  6. PORTEC III

    1. compared adjuvant chemoradiation versus radiation alone in patients with high-risk endometrial cancer

    2. primary outcome was overall survival and “failure free survival”, meaning time from randomization to any relapse or death related to endometrial cancer or treatment.  The 5-year overall survival was not significant, but the failure-free survival was, in favor of the chemoradiation group: 76 vs 67 months with radiation alone

    3. The takeaway here is that chemoradiation improves “failure free survival” when compared to radiotherapy alone for patients with high risk endometrial cancer, and that patients with stage III disease and serous cancers have the most benefit.  Chemoradiation should not be recommended for stage I or II disease.

  7. Fertility Preservation

    1. To consider fertility sparing or non-surgical management of endometrial cancer, certain criteria must be met.  The biopsy must be consistent with grade I endometrioid endometrial cancer confirmed by expert pathology with a specimen preferably obtained via D&C.  The disease must be limited to the endometrium on imaging.  MRI is preferred, but ultrasound is acceptable.  There must be an absence of suspicious or metastatic disease on imaging.  There must not be any contraindications to medical therapy or pregnancy.  And, lastly, the patient must be counseled extensively to understand that this is not the standard of care treatment.

    2. Progesterone IUD is listed in NCCN guidelines as “preferred” for fertility preservation

Episode Takeaways

  1. Endometrial cancer is surgically staged and early endometrial cancer (stage I-II disease) is surgically treated (with or without adjuvant therapy.)  Based on results from the GOG-LAP2 and LACE trials, minimally invasive hysterectomy has been established as the standard of care for endometrial cancer, due to improved quality of life (QOL), less surgical morbidity, and equivalent oncologic outcomes when compared to open surgery. Open surgery should be reserved for patients in whom a minimally invasive approach is not feasible or safe. Vaginal hysterectomy can be considered for patients at high risk of surgical morbidity and at low risk of metastasis or advanced disease.

  2. Complete surgical staging for endometrial cancer includes hysterectomy, BSO, assessment for lymph node metastasis, and in high risk histologies (serous, clear cell, carcinosarcoma), an omental biopsy or infracolic omentectomy. Assessment of lymph node status is crucial as it is an important prognostic factor. Patients at low risk of lymph node metastasis can be predicted with the Mayo Criteria.  With publication of the FIRES trial and SENTOR trial, sentinel lymph node biopsy, compared with complete pelvic and para-aortic lymphadenectomy, has been shown to be safe and effective, with false negative rates of 1-3%, and reduced surgical morbidity.

  3. Endometrial cancer is stratified as low risk, intermediate (low or high), and high risk disease, based on risk of disease recurrence postoperatively. Low risk disease includes patients with : low grade, limited to <50% myoinvasion, and no LVSI. Intermediate risk disease is a heterogeneous group split into low- and high-intermediate risk; GOG-99 and PORTEC I established risk factors to define a high intermediate risk group, using a combination of age, grade, DOI, and, in GOG, LVSI. If meeting high intermediate risk criteria by either schema, patients should be categorized as high intermediate risk. High risk disease includes ≥ stage III, serous, clear cell, or grade III deeply invasive endometrioid adenocarcinoma.

  4. Adjuvant therapy for early stage endometrial cancer has not shown an overall survival benefit in any RCT; any adjuvant therapy given is in an effort to decrease recurrence risk. Radiation therapy reduces the risk of local recurrence and is recommended for high-intermediate risk disease, with VBT preferred over EBRT.  High risk disease requires adjuvant therapy, and in high risk histology groups, chemotherapy is often given to reduce the risk of distant recurrence. With the new FIGO 2023 guidelines, molecular subtypes of POLEmut and P53 can also be used to help guide adjuvant therapy decisions.

  5. To meet criteria for fertility sparing management, patients must have endometrioid disease, grade I, stage IA. They should also have imaging which confirms disease is limited to the endometrium. Options include ovarian preservation, hormonal management (with progesterone IUD recently being upgraded to the preferred method). If undergoing hormonal treatment, surveillance with endometrial biopsy should be performed every 3-6 months.

References

1.       Walker JL, Piedmonte MR, Spirtos NM, et al. Laparoscopy compared with laparotomy for comprehensive surgical staging of uterine cancer: Gynecologic Oncology Group Study LAP2. J Clin Oncol. 2009;27(32):5331-5336. doi:10.1200/JCO.2009.22.3248

2. Walker JL, Piedmonte MR, Spirtos NM, et al. Recurrence and Survival After Random Assignment to Laparoscopy Versus Laparotomy for Comprehensive Surgical Staging of Uterine Cancer: Gynecologic Oncology Group LAP2 Study. Journal of Clinical Oncology. 2012;30(7):695. doi:10.1200/JCO.2011.38.8645

3. Janda M, Gebski V, Davies LC, et al. Effect of Total Laparoscopic Hysterectomy vs Total Abdominal Hysterectomy on Disease-Free Survival Among Women With Stage I Endometrial Cancer: A Randomized Clinical Trial. JAMA. 2017;317(12):1224-1233. doi:10.1001/JAMA.2017.2068

4. Panici PB, Basile S, Maneschi F, et al. Systematic pelvic lymphadenectomy vs. no lymphadenectomy in early-stage endometrial carcinoma: randomized clinical trial. J Natl Cancer Inst. 2008;100(23):1707-1716. doi:10.1093/JNCI/DJN397

5. Barton DPJ, Naik R, Herod J. Efficacy of systematic pelvic lymphadenectomy in endometrial cancer (MRC ASTEC Trial) A Randomized Study. International Journal of Gynecological Cancer. 2009;19(8):1465. doi:10.1111/IGC.0B013E3181B89F95

6. Creasman WT, Morrow CP, Bundy BN, Homesley HD, Graham JE, Heller PB. Surgical pathologic spread patterns of endometrial cancer. A Gynecologic Oncology Group Study. Cancer. 1987;60(8 Suppl):2035-2041. doi:10.1002/1097-0142(19901015)60:8+<2035::aid-cncr2820601515>3.0.co;2-8

7. Mariani A, Webb MJ, Keeney GL, Haddock MG, Calori G, Podratz KC. Low-risk corpus cancer: is lymphadenectomy or radiotherapy necessary? Am J Obstet Gynecol. 2000;182(6):1506-1519. doi:10.1067/MOB.2000.107335

8. Mariani A, Dowdy SC, Cliby WA, et al. Prospective assessment of lymphatic dissemination in endometrial cancer: A paradigm shift in surgical staging. Published online 2008. doi:10.1016/j.ygyno.2008.01.023

9. Ballester M, Rouzier R, Daraï E, et al. Detection rate and diagnostic accuracy of sentinel-node biopsy in early stage endometrial cancer: a prospective multicentre study (SENTI-ENDO). www.thelancet.com/oncology. 2011;12:469-476. doi:10.1016/S1470

10. Emma C Rossi, Lynn D Kowalski, Jennifer Scalici, et al. A comparison of sentinel lymph node biopsy to lymphadenectomy for endometrial cancer staging (FIRES trial): a multicentre, prospective, cohort study | Elsevier Enhanced Reader. Accessed September 7, 2021. https://reader.elsevier.com/reader/sd/pii/S1470204517300682?token=28BD4371F5CE678C9DEE7558FAE9710893B9F6BBB611CA5DFAF5553990830EF5EE30A44D3B51A711D729421C9D702C3D&originRegion=us-east-1&originCreation=20210908130614

11. Cusimano MC, Vicus D, Pulman K, et al. Assessment of Sentinel Lymph Node Biopsy vs Lymphadenectomy for Intermediate-and High-Grade Endometrial Cancer Staging. JAMA Surg. 2021;156(2):157-164. doi:10.1001/jamasurg.2020.5060

12. Keys HM, Roberts JA, Brunetto VL, et al. A phase III trial of surgery with or without adjunctive external pelvic radiation therapy in intermediate risk endometrial adenocarcinoma: A Gynecologic Oncology Group study. Gynecol Oncol. 2004;92(3):744-751. doi:10.1016/j.ygyno.2003.11.048

13. Creutzberg CL, Van Putten WLJ, Koper PCM, et al. Surgery and postoperative radiotherapy versus surgery alone for patients with stage-1 endometrial carcinoma: Multicentre randomised trial. Lancet. 2000;355(9213):1404-1411. doi:10.1016/S0140-6736(00)02139-5

14. Creutzberg CL, Nout RA, Lybeert MLM, et al. Fifteen-year radiotherapy outcomes of the randomized PORTEC-1 trial for endometrial carcinoma. Int J Radiat Oncol Biol Phys. 2011;81(4). doi:10.1016/J.IJROBP.2011.04.013

15. Nout RA, Smit VTHBM, Putter H, et al. Vaginal brachytherapy versus pelvic external beam radiotherapy for patients with endometrial cancer of high-intermediate risk (PORTEC-2): an open-label, non-inferiority, randomised trial. Lancet. 2010;375(9717):816-823. doi:10.1016/S0140-6736(09)62163-2

16. P B, AM S, J O, et al. Adjuvant external beam radiotherapy in the treatment of endometrial cancer (MRC ASTEC and NCIC CTG EN.5 randomised trials): pooled trial results, systematic review, and meta-analysis. Lancet. 2009;373(9658):137-146. doi:10.1016/S0140-6736(08)61767-5

17. de Boer SM, Powell ME, Mileshkin L, et al. Adjuvant chemoradiotherapy versus radiotherapy alone for women with high-risk endometrial cancer (PORTEC-3): final results of an international, open-label, multicentre, randomised, phase 3 trial. www.thelancet.com/oncology. Published online 2018. doi:10.1016/S1470-2045(18)30079-2

18. Randall ME, Filiaci V, Scott ; D, et al. Phase III Trial: Adjuvant Pelvic Radiation Therapy Versus Vaginal Brachytherapy Plus Paclitaxel/ Carboplatin in High-Intermediate and High-Risk Early-Stage Endometrial Cancer. J Clin Oncol. 2019;37:1810-1818. doi:10.1200/JCO.18

19. Greven K, Winter K, Underhill K, Fontenesci J, Cooper J, Burke T. Final analysis of RTOG 9708: adjuvant postoperative irradiation combined with cisplatin/paclitaxel chemotherapy following surgery for patients with high-risk endometrial cancer. Gynecol Oncol. 2006;103(1):155-159. doi:10.1016/J.YGYNO.2006.02.007

20. Maggi R, Lissoni A, Spina F, et al. Adjuvant chemotherapy vs radiotherapy in high-risk endometrial carcinoma: results of a randomised trial. Br J Cancer. 2006;95(3):266-271. doi:10.1038/SJ.BJC.6603279

21.Horeweg N, Nout RA, Jürgenliemk-Schulz IM, et al. Molecular Classification Predicts Response to Radiotherapy in the Randomized PORTEC-1 and PORTEC-2 Trials for Early-Stage Endometrioid Endometrial Cancer. J Clin Oncol. Published online July 24, 2023:JCO2300062. doi:10.1200/JCO.23.00062

Sydney Oesch
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