. 2019 Jun 12;8:F1000 Faculty Rev-849. [Version 1] doi: 10.12688/f1000research.17408.1

Table 1. Key trials guiding adjuvant therapy in high-intermediate and high-risk endometrial cancer.

Trial Years of accrual Number of patients assessed First author Publication year	Eligibility		LN assessed	Arms	Aims	Outcomes		Conclusions
PORTEC 1990–1997 N = 714 Creutzberg et al. (2000) ²²	Stage I: IB ^a G2–3 ^b IC G1–2 S/CC		No	Observation versus WPRT (46 Gy)	Primary: Locoregional recurrence and death Secondary: Treatment- related morbidity and survival after relapse	-5-year locoregional recurrence: 14% obs versus 4% WPRT ( P <0.001) -5-year OS: 85% obs versus 81% WPRT ( P = 0.31) -Cancer-related death: 6% obs versus 9% WPRT ( P = 0.37) -Treatment-related complications: 6% obs versus 25% WPRT ( P <0.0001) -2-year survival after recurrence: 79% after vaginal versus 21% after pelvic/distant recurrence -15-year follow-up: locoregional recurrence 15.5% obs versus 6% WPRT ²³		-Adjuvant RT improves locoregional control, not OS -Limit adjuvant RT to patients age > 60 with G3 and less than half myometrial invasion or any grade with outer half myometrial invasion -Avoid adjuvant RT if age < 60 or G2 with superficial invasion (risk locoregional recurrence < 5%) -15-year follow-up study: confirms. Limit adjuvant pelvic RT to HIR cohort ²³
GOG 99 1987–1995 N = 392 Keys et al. (2004) ¹⁹	“Intermediate risk:” IB IC II (occult) ^a		Yes	Observation versus WPRT (50.4 Gy)	Primary: Toxicity, date and location of recurrence, OS	-Authors defined a HIR group by age and number of RFs: RF: grade 2–3, LVSI, and outer 1/3		-Adjuvant radiation decreases risk of recurrence, but not OS -Limit adjuvant pelvic radiation to patients who fit HIR group
						Age	# RF
						<50	3
						50–69	2
						>70	1
						In all patients: -2-year cumulative incidence of recurrence: 12% obs versus 3% WPRT (RH: 0.42, P = 0.007) -18 versus 3 vaginal recurrences -OS: 86% obs versus 92% WPRT (RH: 0.86, P = 0.557) In the HIR group: -2-year recurrence: 26% obs versus 6% WPRT
PORTEC-2 2002–2006 N = 427 Nout et al. (2010) ²⁷	Age > 60 IB G3 IC G1 or 2 ^a IIA (any age, exclude G3 with outer half invasion) Excluded S/CC		No	EBRT (46 Gy in 23 fx) versus VCB (21 Gy HDR in 3 fx or 30 Gy LDR)	Non-inferiority trial Primary: Vaginal recurrence	-5-year vaginal recurrence rate: 1.8% VCB versus 1.6% EBRT (HR 0.78, 95% CI 0.17–3.49, P = 0.74) -5-year locoregional relapse: 5.1% VCB versus 2.1% EBRT (HR 2.08, 95% CI 0.71–6.09, P = 0.17) -OS: 84.8% VCB versus 79.6% EBRT (HR 1.17, 95% CI 0.69–1.98; P = 0.67) -Rates grade 1–2 gastrointestinal toxicity: 12.6% VCB versus 53.8% WPRT		-VCB is non-inferior to WPRT in this HIR group, with fewer gastrointestinal toxic effects -Of note, LVSI not considered
GOG 249 2009–2013 N = 601 Randall et al. (2019) ²⁴	I with HIR criteria: RF: Outer 1/2, Grade 2 or 3, LVSI		Optional: 89% assessed If not assessed, required imaging (CT or MRI) to rule out enlarged lymph nodes	Pelvic RT (4 field or IMRT, 45 to 40.5 Gy over 5–6 weeks) Additional VCB optional for S/CC or II) versus VCB (HDR 6–7 Gy at 0.5 cm depth x 3 fx, HDR 10–10.5 Gy at vaginal surface ×3 fx, or 6 Gy at vaginal surface × 5 fx or LDR 65–70 Gy at vaginal surface in 1–2 fx), followed by carboplatin AUC 6/ paclitaxel 175 mg/m ² Q 21 days × 3 cycles (VCB/C)	Primary: RFS Secondary: OS, patterns of failure, toxicity	-60-month RFS: 0.76 RT (95% CI 0.70–0.81) versus 0.76 VCB/C (95% CI 0.70–0.81) -60-month OS: 0.87 RT (95% CI 0.83–0.91) versus 0.85 VCB/C (95% CI 0.81–0.90) -No difference in vaginal or distant failures -5-year pelvic and para-aortic nodal failures: 9% VCB/C versus 4% RT, HR 0.47 -5-year vaginal recurrence: 2.5% versus 2.5% -5-year distant recurrence: 18% versus 18% -Toxicity: > Grade 3 acute toxicity: 11% RT versus 64% VCB/C > Grade 3 late toxicity: 13% RT versus 12% VCB/C -At 11 weeks, VCB/C arm had 3.7 points lower (98.3% CI -5.9–1.6, P <0.001) on FACIT fatigue subscale score than RT arm. RT arm returned to baseline at 11 weeks and VCB/C arm returned to baseline at 8 months -VCB/C arm reported more neurotoxicity than RT arm, however returned to baseline at 14 months		-VCB/C did not improve RFS or OS compared with RT -In subgroup analysis (including serous and clear cell), VCB/C did not improve RFS or OS -Pelvic and para-aortic nodal failures more common in VCB/C -Acute mild/moderate toxicities greater in VCB/C arm, while late toxicities similar versus RT -Pelvic radiation preferred for high-risk, early-stage endometrial carcinoma
	Age	# RF
	<50	3
	50–69	2
	>70	1
	II I–II serous or clear cell with negative washings (15% serous, 5% CC)
Locally advanced
GOG 122 1992–2000 N = 396 Randall et al. (2006) ⁶	III/IV (post- op residual disease <2 cm)		Optional: 86% assessed	WART (30 Gy in 20 fx, with a 15-Gy boost) versus doxorubicin 60 mg/m ² and cisplatin 50 mg/m ² Q 3 weeks × 7 cycles, followed by 1 cycle of cisplatin (AP)	Primary: PFS Secondary: OS	Stage-adjusted progression: HR 0.71, 95% CI 0.55 to 0.91; P <0.01 Local recurrence: 13% WART versus 18% AP Distant recurrence: 38% WART versus 32% AP 5-year stage-adjusted disease-free survival: 50% CT versus 38% WART 5-year stage-adjusted OS: 55% AP versus 42% WART		-Chemotherapy improved PFS and OS compared with WART
PORTEC-3 2006–2013 N = 660 de Boer et al. (2018) ²⁶	IA G3 with LVSI IB G3 II III I–III S or CC (IA S or CC required to have myometrial invasion)		Optional: 58% assessed	Pelvic RT (48.6 Gy in 1.8 Gy fx) versus combination chemotherapy and radiation (CTRT) (cisplatin 50 mg/m ² weeks 1 and 4 of RT, followed by carboplatin AUC 5 and paclitaxel 175 mg/m ² Q 3 weeks × 4 cycles)	Primary: OS and FFS	-5-year OS: 81.8% CTRT versus 76.7% RT (HR 0.76, 95% CI 0.54–1.06; P = 0.11) -5-year FFS: 75.5% CTRT versus 68.8% RT (HR 0.71, 95% CI 0.53–0.95; P = 0.022) > Grade 3 adverse events: 60% CTRT versus 12% RT Subgroup analysis of stage III patients: -5-year FFS 69.3% CTRT versus 58% RT (HR 0.66, 95% CI 0.45–0.97) -5-year OS 78.7% CTRT versus 69.8% RT (HR 0.71, 95% CI 0.45–1.11)		-CTRT did not improve OS, although it did increase FFS -Subgroup analysis of stage III: improved 5-year FFS (HR 0.66) and trend toward improved OS
GOG 258 2009–2014 N = 733 Matei et al. (2017) (abstract) ²⁵	III–IVA (<2 cm residual disease) I–II S/CC with positive washings		Optional: (% N/A)	Cisplatin 50 mg/m ² intravenous D1 and D29 plus volume- directed RT (45 Gy ± brachytherapy) followed by carboplatin AUC 5/ paclitaxel 175 mg/m ² Q 21 days × 4 cycles with G-CSF support (CRT) versus Carboplatin AUC 6/ Paclitaxel 175 mg/m ² Q 21 days × 6 cycles (CT)	Primary: RFS Secondary: survival, toxicity, quality of life	-Vaginal recurrence: 3% CRT versus 7% CT (HR = 0.36, 95% CI 0.16–0.82) -Pelvic and para-aortic node recurrence: 10% CRT versus 21% CT (HR 4.2, 95% CI 0.28–0.66) -Distant recurrence: 28% CRT versus 21% CT, HR 1.36, 95% CI 1–1.86) -6-year recurrence-free survival: 35.7% CRT versus 38.0% (HR 0.9, 95% CI 0.74–1.1) > Grade 3 toxicity: 58% CRT versus 63% CT -Survival and quality of life endpoints not yet reported		-Chemoradiation did not improve RFS compared with chemotherapy (HR = 0.9, 95% CI 0.74–1.1) -More acute toxicities in CRT versus CT -Fewer vaginal, pelvic, and para- aortic failures in CRT versus CT -Distant recurrences more common in CRT than CT

^a1998 FIGO (International Federation of Gynaecology and Obstetrics) surgical staging: IA: tumor limited to endometrium, IB: tumor invasion less than one half of the myometrium, IC: tumor invasion more than half of the myometrium. II: cervical involvement (included endocervical glandular involvement and cervical stromal invasion).

^bGrade 1 (G1) ≤ 5% non-squamous or non-morular solid growth pattern; grade 2 (G2): 6–50% non-squamous or non-morular solid growth pattern; and grade 3 (G3): >50% non-squamous or non-morular solid growth pattern.

AP, doxorubicin/cisplatin; AUC, area under the curve; CC, clear cell; CI, confidence interval; CRT, conformal radiation therapy; CT, computed tomography; CTRT, chemotherapy and radiation therapy; EBRT, external beam radiation therapy; FACIT, Functional Assessment of Chronic Illness Therapy; FFS, failure-free survival; fx, fraction; GOG, Gynecologic Oncology Group; Gy, gray; obs, observation; HDR, high-dose radiation therapy; HIR, high-intermediate risk; HR, hazard ratio; IMRT, intensity-modulated radiation therapy; LDR, low-dose radiation therapy; LN, lymph node; LVSI, lymphovascular space invasion; MRI, magnetic resonance imaging; N/A, not available; OS, overall survival; PFS, progression-free survival; PORTEC, Post-Operative Radiation Therapy in Endometrial Carcinoma; Q, every; RF, risk factor; RFS, recurrence-free survival; RH, relative hazard; RT, radiation therapy; S, serous; VCB, vaginal cuff brachytherapy; WART, whole abdominal radiation therapy; WPRT, whole pelvic radiation therapy.