Treatment/Prognosis

Question 1

What is the primary Tx modality for endometrial cancer?

Answer 1

Sg is the primary Tx modality for endometrial cancer.

Question 2

What is resected in a TAH?

Answer 2

TAH removes the uterus and a small rim of vaginal cuff.

Question 3

What is resected in a modified radical hysterectomy?

Answer 3

Modified radical hysterectomy:

Removal of uterus and 1–2 cm of vaginal cuff
Wide excision of parametrial and paravaginal tissues (including median one-half of cardinal and uterosacral ligaments)
Ligation of uterine artery at ureter

Question 4

What is resected in a radical hysterectomy?

Answer 4

Radical hysterectomy:

Resection of uterus and upper vagina
Dissection of paravaginal and parametrial tissues to pelvic sidewalls
Ligation of uterine artery at its origin at internal iliac artery

Question 5

Pelvic and P-A lymphadenectomy is recommended in which pts with endometrial cancer?

Answer 5

Although controversial, LNs are commonly assessed at the time of initial Sg for endometrial cancer. Pelvic lymphadenectomy may not be indicated in women with Dz clinically confined to the uterus. The ASTEC (A Study in the Treatment of Endometrial Carcinoma) trial randomized 1,408 pts with endometrial cancer that was clinically confined to the uterus to standard Sg (TAH + BSO, peritoneal washing, palpation of P-A nodes) vs. standard Sg + pelvic lymphadenectomy. Those at intermediate or high risk for recurrence (independent of nodal status) were further randomized to rcv pelvic RT or not. There was no benefit to pelvic lymphadenectomy in terms of OS or RFS; however pts had increased morbidity. (ASTEC Study Group et al., Lancet 2009)

Question 6

What is the risk of lymphedema following Sg for uterine malignancies?

Answer 6

According to an MSKCC retrospective review of 1,289 pts, the rate of lymphedema at a median f/u of 3 yrs was 1.2%. When ≥10 LNs were removed, the rate of symptomatic lymphedema was 3.4%. (Abu-Rustum NR et al., Gyn Oncol 2006)

Question 7

What are considered negative prognostic factors for endometrial cancer?

Answer 7

Negative prognostic indicators for endometrial cancer:

LVSI
Age >60 yrs
Grade 3/nonendometrioid histology
Deep myometrial invasion (>50% based on GOG 249)
Tumor size
Lower uterine segment involvement
Anemia
Poor KPS

Question 8

What adj therapy is indicated for completely surgically staged endometrial cancers limited to the endometrium?

Answer 8

No adj therapy is indicated for endometrial cancers limited to the endometrium, except for grade 3, where vaginal cuff brachytherapy is considered. In grade 3 tumors with adverse risk factors and incomplete surgical staging, adj therapy should be considered.

Question 9

Which endometrioid endometrial cancers can be treated with vaginal brachytherapy (VBT) alone?

Answer 9

Surgically staged pts with true high-intermediate–risk Dz, namely stage IA tumors, grades 2–3 without LVSI; Stage IB tumors, grade 1–2 without LVSI; and 1B tumors, grade 1–2 with LVSI. Stage 1B grade 3 tumors are controversial as they were not included in the PORTEC randomization, however, in well-staged pts, this may be an acceptable Tx option.

Question 10

Which endometrioid endometrial cancers should be managed with pelvic RT é VBT?

Answer 10

Stage IB, grade 3 or other higher-grade histology with multiple adverse prognostic factors.
Incompletely surgical staging—low LN count, only 1-side sampled, etc. For incompletely staged grade 3 tumors, chemo may be considered as well.
If LVSI is present without LND, strongly consider with whole pelvis (WP) RT.

Question 11

Which clinical situations should VBT be added to pelvic RT?

Answer 11

The overall benefit of adding VBT to pelvic RT is currently under question. Several retrospective series have suggested there to be small/negligible benefit. Currently accepted situations include:

Adj pelvic RT and VBT is indicated for endometrial cancers that invade the cervical stroma. If grade 3, consider chemo.
Tumors with the combination of deep myometrial invasion (>50%) and LVSI.

Question 12

When is chemo indicated for endometrial cancer?

Answer 12

Adj chemo should be considered for grade 3, nonendometrioid histology (serous and clear cell), and in pts with stage III–IV Dz.

Question 13

Describe the whole pelvic RT field for endometrial cancer. What total doses are typically prescribed?

Answer 13

Borders of the WP RT field for endometrial cancer:

Superior: L4–5 or L5/S1

Inferior: bottom of obturator foramen

Lateral: 1.5–2.0 cm lat to pelvic brim

Anterior: front of pubic symphysis

Posterior: split sacrum to S3

Treat to 45–50.4 Gy.

Question 14

What is the border of an extended RT field for endometrial cancer, and when should extended fields be used?

Answer 14

The sup border of an extended RT field for endometrial cancer depends on the upper extend of the para-aortic nodes to be treated. If only pelvic LNs are involved, the upper border can be placed at the level of the renal vessels, or L2–3. In situations where the entire para-aortic LN chain is being treated (for positive P-A LNs), then the upper border should be T10–11 or T11–12.

Question 15

According to the American Brachytherapy Society (ABS), what are the Tx site and depth for vaginal cuff brachytherapy for endometrial cancer?

Answer 15

According to the ABS, for endometrioid carcinoma of the endometrium, the proximal 3–5 cm of the vagina (appx one-half) should be treated. For CCC, UPSC, or stage IIIB, the target is the entire vaginal canal up to the urethra. Rx is typically vaginal surface or 0.5 cm beyond the vaginal mucosa. (Small W, Brachytherapy 2012)

Question 16

What LDR and HDR dose/fractionation schemes are typically used for adj intracavitary RT alone for stage 1 endometrial cancer?

Answer 16

For adj intracavitary RT therapy alone, the LDR is 50–60 Gy over 72 hrs (0.7–0.8 Gy/hr). The HDR Rx in PORTEC-2 was 21 Gy (7 Gy × 3) at 0.5 cm depth; alternatively 6 Gy × 5 prescribed to the surface can also be used. The proximal 1/2 or 4 cm at 2 fx per wk is commonly used for endometrioid histology. (Harkenrider M et al., Brachytherapy 2016)

Question 17

What LDR and HDR dose/fractionation schemes are commonly used for adj intracavitary RT given with WP RT for endometrial cancer?

Answer 17

When given in combination with WP RT, LDR doses of 30–40 Gy and HDR doses of 15 Gy (5 Gy × 3) prescribed to the vaginal surface is commonly used.

Question 18

How are nonbulky vaginal cuff recurrences managed in endometrial cancer pts?

Answer 18

For nonbulky vaginal cuff recurrences in pts with no prior RT, a combination of pelvic RT and brachytherapy is typically used. Treat to 45 Gy pelvic RT and assess the response. If the residual is ≤0.5 cm, add HDR VBT at 7 Gy × 3 to 0.5-cm depth beyond the vaginal mucosa. (Nag S et al., IJROBP 2000)

For endometrial cancer pts with vaginal cuff recurrences that are bulky (>0.5 cm thickness) or in a previously irradiated field, interstitial brachytherapy may be employed (salvage LC ranges from 50%–75%).

Question 19

When do inguinal nodes need to be included in the RT fields for endometrial cancer?

Answer 19

In cases with distal vaginal involvement, the entire vagina and inguinal nodes need to be included in EBRT fields.

Question 20

How should inoperable endometrial cancer be treated with RT?

Answer 20

Consider pelvic RT to 45 Gy → intracavitary RT boost using 1–3 tandem intrauterine applicators to 6.3 Gy × 3 prescribed to 2-cm depth (serosal surface). If pelvic RT is contraindicated, consider definitive intracavitary RT alone (7.3 Gy × 5 prescribed to 2-cm depth). (Nag S et al., IJROBP 2000)

Question 21

Describe the design and results of PORTEC-1 (Post Operative Radiation Therapy in Endometrial Carcinoma).

Answer 21

In PORTEC-1, 714 pts grade 1 with ≥50% myometrial invasion, grade 2 with any invasion, or grade 3 <50% myometrial invasion underwent TAH/BSO with washings with no lymphadenectomy and were randomized to adj EBRT (46 Gy) vs. observation. EBRT reduced LRR from 14% to 5% at 10 yrs. 74% of LRs were in the vaginal vault. There was no difference in 10-yr OS. Note that with central pathology review, there was a significant shift from grade 2 to grade 1. (Creutzberg CL et al., Lancet 2000; Scholten AN et al., IJROBP 2005)

Question 22

Describe the design and results of GOG 99.

Answer 22

In GOG 99, 392 endometrial cancer pts with myometrial and/or occult cervical invasion underwent TAH/BSO, pelvic and P-A LN sampling, and peritoneal cytology and then were randomized to observation vs. WP RT (50.4 Gy). Inclusion criteria were revised during the trial to include only high-intermediate–risk pts defined as: (1) age >70 yrs with 1 risk factor (grade 2 or 3, LVI, outer one-third myometrial invasion), (2) age >50 yrs with 2 risk factors, and (3) any age with 3 risk factors. RT improved LR from 12% to 3%. The greatest benefit in LR was in high-intermediate–risk pts from 26% to 6% vs. low-intermediate–risk pts from 6% to 2%. There was no change in OS, but the study was not powered to detect this. Conclusion: Limit pelvic RT to high-intermediate–risk pts. The major flaw of this study is that grade 2 was grouped with grade 3 even though grade 2 Dz tends to behave more similarly to grade 1. (Keys HM et al., Gyn Oncol 2004)

Question 23

Describe the design and results of PORTEC-2.

Answer 23

PORTEC-2 randomized 427 pts with intermediate-high–risk endometrial cancer defined as:

Age >60 yrs and inner 1/3 (IA) myometrial invasion and grade 3
Age >60 yrs and outer 2/3 (IB and IC) myometrial invasion and grades 1–2
Invasion of cervical glandular epithelium and grades 1–2 except grade 3 with > 1/2 myometrial invasion.

All pts were s/p TAH/BSO without pelvic LND and were randomized to EBRT (46 Gy) vs. VBT alone (21 Gy in 3 fx or 30 Gy). At median f/u at 3.8 yrs, VBT was similar to EBRT with respect to 5-yr outcomes: vaginal relapse (1.8% vs. 1.6%), isolated pelvic relapse (1.5% vs. 0.5%), LRR (5.1% vs. 2.1%), or OS (85% vs. 80%). However, there were significantly higher rates of acute grades 1–2 GI toxicity in the EBRT group. The authors concluded that VBT should be standard in intermediate-high–risk endometrial cancer. (Nout RA et al., Lancet 2010)

Question 24

What is the strongest predictor for LR, DM, and OS based off the PORTEC studies?

Answer 24

Substantial LVSI is the strongest independent prognostic factor for LR, DM, and OS based off pooled analysis of PORTEC 1 and 2. Only EBRT reduced the risk of pelvic recurrence. (Bosse T et al., Eur J Cancer 2015)

Question 25

Describe the design and results of GOG 122.

Answer 25

In GOG 122, 388 pts with endometrial tumors invading beyond the uterus (all histologies) underwent TAH/BSO and surgical staging with <2-cm residual tumor. P-A LNs were allowed, but mets to the chest or SCV nodes were not allowed. Pts were randomized to whole abdomen irradiation (30 Gy AP/PA +15 Gy boost to pelvic +/– P-A LNs) vs. chemo (doxorubicin/cisplatin q3wks × 8 cycles). At 5 yrs, chemo had improved stage-adjusted OS (55% vs. 42%) and PFS (38% vs. 50%). Chemo had increased grades 3–4 heme toxicity (88% vs. 14%) and increased GI, cardiac, and neurologic toxicity. (Randall ME et al., JCO 2006)

Question 26

Describe the design of GOG 249.

Answer 26

GOG 249 comparing EBRT alone vs. VBT + carbo/taxol in early stage high-intermediate–risk pts. Initial reports show similar rates of RFS, PFS, and OS with higher toxicity and poorer QOL in the VB + chemo arm. (59th Annual ASTRO Meeting presentation, 2017)

Question 27

Describe the design and results of the TIME-C trial.

Answer 27

Time-C trial compared 3D vs. IMRT for postop endometrial and cervical pts evaluating GU and GI outcomes. Initial reports show improved GI and GU toxicity with IMRT. (58th Annual ASTRO Meeting presentation, 2016)

Question 28

Describe the design and results of the Nordic Society of Gynaecological Oncology (NSGO)–EORTC trial that evaluated adj RT é chemo in high-risk endometrial cancer.

Answer 28

The NSGO–EORTC trial enrolled 367 endometrial cancer pts with surgical stages I–II, positive peritoneal fluid cytology or positive pelvic LNs. Most had ≥2 risk factors: grade 3, deep myometrial invasion, or DNA nondiploidy. Pts with serous, clear cell, or anaplastic carcinomas were eligible regardless of risk factors. Pts were randomized to RT vs. RT + chemo (various regimens allowed). RT was pelvic EBRT (44 Gy) +/– VBT. 5-yr PFS favored the RT + chemo arm (82% vs. 75%). (Hogberg T et al., ASCO 2007 abstract)

Question 29

Which major prospective trials for endometrial cancer are currently forthcoming?

Answer 29

PORTEC-3 trial comparing pelvic RT vs. Pelvic RT + chemo in high-risk pts.
PORTEC-4 trial comparing VBT and Observation after Sg in pts with endometrial cancer and high-intermediate–risk features.
GOG 258 trial in stage 3 and 4 pts comparing RT + cisplatin (concurrent) f/b carbo/taxol vs. carbo/taxol alone.