Medical Archive

2023 ASTRO Guideline – Endometrial Cancer

https://www.practicalradonc.org/article/S1879-8500(22)00273-9/fulltext

KQ1 : Adjuvant RT indication

Stage I-II Endometrioid carcinoma

Figure 1 Stage I to II endometroid carcinoma.
*Intermediate-risk factors include age ≥60 years and focal LVSI. †High-risk factors include substantial LVSI, especially without surgical nodal staging.

Stage I-II High-Risk Histologies

Figure 2 High-risk histologies.
*Serous carcinoma, clear cell carcinoma, carcinosarcoma, mixed histology carcinoma, dedifferentiated, or undifferentiated carcinoma.
†Molecular profiling may influence alternate treatment pathway selection.

Stage III-IVA (All Histologies)

GOG 122

  • FIGO III-IVA, <2 cm of residual post-surgery
  • WAI vs CTx alone (cisplatin+doxo)

Other 2 RCTs

  • EBRT alone vs. CTx alone
  • No difference in PFS or OS

PORTEC-III

KQ2 : RT techniques, regimen

EBRT technique

  • IMRT is strongly recommended
  • RTOG 1203(TIME-C) demonstrated that IMRT (vs 3D-CRT) was associated with significantly lower rates of acute patient-reported GI, GU toxicity with improved QOL.

Targeting volume

  • Vaginal ITV with daily IGRT is strongly recommended
    • Vaginal ITV
      • by merging scans taken with a full and an empty bladder.
      • include vagina, residual parametria, and paravaginal tissues (if distended rectum, include anterior rectum in case of empty rectum)
    • Daily Image Guided RT (IGRT): CBCT every day.

Dose fractionation (based on major prospective studies)

  • The strongly recommended standard dose for adjuvant EBRT
    • 4500–5040 cGy, delivered in daily fractions of 180–200 cGy to vaginal ITV
    • EQD2 of 5500-6500cGy, either sequential or simultaneous to residual nodal diseases

Normal Tissue Dose Limits

  • Insufficient evidence to make formal recommendations
  • RTOG 1203 (TIME-C) trial as “reasonable to follow”

Brachytherapy

  • Traditional 6000-6500cGy LDR dose equivalent used.
    • Contemporary lower dose regimens can be used.
    • Refer to American Brachytherapy Society for more complete options
  • Adj VBT Alone (Monotherapy)
    • Strongly recommends treating the proximal third to half (3~5cm) of the vagina.
    • The predominant location for recurrence. Treating the entire length of the vagina increases the risk of vaginal stenosis) (Retrospective analysis)
    • -> LVSI or high-risk histology: longer length can be considered
  • VBT Boost After EBRT
    • Conditionally recommended in close or positive vaginal margins, cervical stromal involvement (With limited evidence)

KQ3 : Systemic therapy indication

Stage I-II Endometrioid carcinoma

Systemic therapy is not recommended.

Stage I-II High-Risk Histologies

Systemic therapy is conditionally recommended

Stage III-IVA (All Histologies)

Systemic therapy is strongly recommended.

  • GOG 122
  • PORTEC-3
  • GOG 258

KQ4 : Appropriate sequencing of systemic therapy with RT

Stage III-IVA

Stage I-II with high-risk histologies

  • For FIGO Stage I-II with High-Risk Histologies
    • When both EBRT and chemotherapy are given, either sequential or concurrent treatment is strongly recommended. (as with PORTEC-3 and GOG 258 regimen)
  • For Vaginal Brachytherapy (VBT) and Chemotherapy
    • No RCT for optimal sequencing, but VBT is low-morbidity therapy: either sequential or concurrent treatment is strongly recommended.
    • To avoid unnecessary risk, it is better not to administer VBT and chemotherapy on the same day

KQ5 : Adjuvant RT decisions based on LN assessment

Bilateral sentinel lymph node (SLN) mapping is strongly recommended over standard pelvic lymphadenectomy. (Several retrospective and prospective studies (e.g. SENTOR))

  • Increased Accuracy: Surgical precision by removing fewer but mor relevant nodes, more detailed analysis with “pathologic ultrastaging”
  • Decreased Morbidity: Significantly lower rates of lower extremity lymphedema, compared to a full lymphadenectomy.
  • Isolated Tumor Cells (ITC): <0.2mm or fewer than 200 cells found during ultrastaging -> pN0(i+), associated with other uterine risk factors but no prognostic value independantly
  • Micrometastases: 0.2–2 mm or Macrometastases: >2 mm -> N+ -> stage IIIC

ITC

  • Adjuvant therapy decisions is conditionally recommended based on uterine risk factors (like grade, histology, and LVSI), not on the presence of ITCs alone.
  • Large center retrospective study shows that the prognosis for ITC is similar to node-negative patients. (Further verification of the importance of ITC is warranted.)

Micrometastases or Macrometastases

  • Adjuvant therapy is strongly recommended.
  • Multiple RTCs: micrometastases are associated with worse survival, which is improved with adjuvant therapy.
  • Locoregional control important -> EBRT is recommended than chemo alone

No nodal assessment (Hysterectomy without nodal assessment)

  • Surgical restaging or pelvic RT is conditionally recommended for patients with “any myoinvasion with LVSI or >50% myoinvasion“
  • With an approximately 10% or greater risk of having positive lymph nodes

KQ6 : Adjuvant Therapy Decision

  • This is one of the most significant updates in the guideline
    • based on a molecular analysis of the PORTEC-3 trial, which originally compared EBRT alone vs. EBRT plus chemotherapy for high-risk endometrial cancer.
  • Universal Testing using immunohistochemistry (IHC) to check for mismatch repair (MMR) proteins and p53, along with gene sequencing to identify POLE mutations
    • Molecular testing is strongly recommended for patients with endometrial cancer who are considering adjuvant therapy
    • The Cancer Genome Atlas (TCGA) classification (4 subsets identified)
      • POLE ultramutated: Best prognosis.
      • Mismatch Repair Deficient (MMR-d) or Microsatellite Instability Hypermutated (MSI-H): Intermediate prognosis.
      • Copy Number Low or No Specific Molecular Profile (NSMP): Intermediate prognosis.
      • Copy Number High (high rate of TP53 mutation (p53 abnormal)): Worst prognosis.

TP53 Mutated Tumors:

  • Chemotherapy and RT are conditionally recommended.
  • This was the only molecular subgroup in the PORTEC-3 trial that showed a significant and substantial benefit from the addition of chemotherapy. RT+Chemo (vs RT alone) improved the 5-year RFS from 36% to 59%.

MMR-d/MSI-H Tumors:

  • RT without chemotherapy is conditionally recommended.
  • The PORTEC-3 analysis showed no difference in 5yr RFS for MMR-d patients.
  • May be treated with adjuvant immunotherapy (NRG-GY020 ongoing).

POLE Mutant Tumors:

  • RT without chemotherapy is conditionally recommended.
  • Excellent prognosis: PORTEC-3 study, only 1 out of 51 patients (EBRT only) had a disease recurrence.
  • Single modality (RT only) may be sufficient. Ongoing trials of eliminating adjuvant therapy (PORTEC-4a, TAPER)