Important Studies

Question 1

IMRT

Answer 1

TIME-C (NRG RTOG 1203). Yeung et al, JCO, 2020. “→3DCRT vs. →IMRT
“patients reported less diarrhea, frequency of incontinence, and interference of incontinence with IMRT

“Interestingly, clinicians under reported adverse events compared to patients.

Bowel space V40<30%
Rectum V40<80%
Bladder V45<35%
Bone marrow: V40<37%, V10<90%”

PARCER

RTCMIENDOMETRE French: Barillot et al, Radiother Oncol, 2014. 49 Endometrial Stage IB grade 3, IC, or II.
“Phase II.
WPRT IMRT 45 Gy
HDR VC boost of 6-10Gy in 1-2 fx given in 75%”

"27% grade 2 GI toxicity
No grade 3 or greater toxicity
19% grade 2 GU
No grade 2 events at week 15
20% with grade 1 events at week 15"

Question 2

Predictors of LN involvement

Answer 2

GOG 33. Creasman et al, Cancer, 1987. Stage I endometrial CA who had TAH/BSO, lymphadenectomy, peritoneal cytology:

Increased grade and invasion correlates with probability of nodal mets. Low-risk: Gr 1, endometrium only. Mod-risk: Gr2-3 and/or inner-middle invasion. High-risk: deep invasion and/or intraperitoneal disease”

"Risk of pelvic nodes
                 Grade
              1     2     3
inner 1/3   | <5% | 5%  | 10%
middle 1/3  | 5%  | 10% | 10%
outer 1/3   | 10% | 20% | 35%

Risk of PA nodes
                 Grade
              1     2     3
inner 1/3   |<5%  | 5%  | 5%
middle 1/3  | 5%  | 5%  | 5%
outer 1/3   | 5%  | 15% | 25%
[nonscientific interpolation 
shown; for original see paper]"

Question 3

VCB then WPRT vs. obs

Answer 3

Norwegian Radium Hospital: “Aalders et al, Obstet Gynecol, 1980. Stage I adeno with TAH/BSO”→WPRT 40 Gy vs. 60 Gy VC brachy
Brachy was 40 Gy LDR to vaginal surface plus about 25 Gy HDR to 0.5 cm. Cobalt and betatron

"9-yr LR 2% WPRT vs. 7%
9-yr DM 10% vs. 5%
9-yr OS 87-90%, not different
In IC G3 tumors: LC 5% WPRT vs. 20%
LVSI LR: 0% without vs. 20% with LVSI
IC Grade 3 9-yr OS 72% vs. 82%
"WPRT improves LC compared to VCB alone. 
This trial shows WPRT+VCB gives a survival benefit in IC Grade 3. 

Orebro University Hospital, Orebro, Sweden: Sorbe et al, IJROBP, 2012. Stage I with at least on risk factor: Grade 3, IB, or DNA aneuploidy

“46 Gy plus VCB vs. VCB alone

Doses: 3.0 Gy x 6, 5.9 Gy x 3, 20 Gy x 1 LDR to 5 mm, 2/3 length vagina”
“5-yr LRF 1.5% vs. 5%
15 pelvic failures in VCB alone arm vs. 1”

The addition of WPRT to VCB reduces LRF in grade 3, IB, or DNA aneuploidy.

Question 4

WPRT vs. obs

Answer 4

GOG 99: Keys et al, Gynecol Oncol, 2004. 392 “IB, IC, occult IIA,B s/p TAH/BSO

Excluded: pap serous/clear cell, cytology

Originally included intermediate risk, then amended to include HIR: age ≥70 with 1 risk factor, ≥50 with 2 risk factors, or any age with 3 risk factors. Factors are grade 2-3, LVI, or IC”
→WPRT 50.4 Gy vs. observation

Nodes:Selective LN dissection of pelvis and PA nodes”

“2-yr LR 3% WPRT vs. 12% obs
LR in vagina 2% vs. 13% (those in the WPRT group had refused RT)
LR in pelvis only 0% vs. 4%
4-yr OS 92% vs. 86% (NS) (not primary endpoint)
In HIR subgroup, 2-yr LR 6% vs. 26%
Most recurrences occur within 18 mos”

“This trial showed that HIR patients benefit from adjuvant therapy. The later PORTEC 2 showed that VC brachy is as effective as WPRT and with less adverse effects.

Note that pelvic recurrence in GOG 99 (which used LND) with no RT is 4%, same as PORTEC-1 (no LND allowed), which is 3.6% (Creutzberg 2000).”

Question 5

WPRT vs. obs

Answer 5

PORTEC-1. “Creutzberg et al, Lancet, 2000. 715 “Stage I (no IC Gr 3 or IB Gr 1) with TAH/BSO (any histo allowed, but vast majority endo)

HIR group (established post-hoc): need 2/3 factors of age >60, invasion >50%, or grade 3, or inv >50% plus grade 3 any age.”

→WPRT 46 Gy vs. observation

Nodes: Sampling of suspicious LN. Routine LN dissection not done”

"5-yr LRR 4% WPRT vs. 14% obs
5-yr LR in vaginal vault 1.6% vs. 6.4%
in vagina 0.7% vs. 3.9%
in pelvis 2.0% vs. 3.4%
in HIR group, LRR 4% vs. 23%
73% of first recurrences at vagina
5-yr LRR as first failure 13% with obs
10-yr LRR results identical
Not different: 5-yr DM 7%, 5-yr OS ~82%

Nomogram in Creutzberg et al, IJROBP, 2015
If vaginal recurrence, long term control 68% (most treated with radiation and brachy), and 2-yr OS 79%

Late complications 26% vs. 4%
Late grade 3-4 toxicity 3% vs. 0% (all GI)
At 15 years, WPRT group had more urinary incontinence, diarrhea, fecal leakage, and limits on daily activities”

“This trial showed that WPRT resulted in LC benefit in HIR patients. Later PORTEC-2 trial showed that VCB in these patients gives similar benefit with less toxicity (Nout 2010).

Note that pelvic recurrence in GOG 99 (which used LN dissection) with no RT is 4%, similar to in PORTEC-1 (no LN dissection allowed), which is 3.4% (Keys 2004). The addition of RT decreases pelvic recurrence rate, but absolute values of recurrences in any treatment combination are still low, which raises the question of the value of WPRT.

PORTEC = ““Post operative radiation therapy in Endometrial Carcinoma””

An analysis by Witlink (2014) showed no increase in 2nd cancers after RT in PORTEC 1, PORTEC 2, and patients who received pelvic RT for rectum after TME.”

Question 6

VC brachy in grade 1-2 vs. obs

Answer 6

Orebro University Hospital, Orebro, Sweden. Sorbe et al, Int J Gynecol Cancer, 2009. 645 Stage IA, grade 1-2, post-op “→VCB 3-8 Gy/ 3-6 fx to 5 mm depth vs. obs”.

“Vaginal cuff recurrences 1.2% vs. 3.1%, p=0.114
Recurrence rate 4.0% overall (2.6% LRR and 1.4% DM)”

Question 7

VCB vs. WPRT

Answer 7

PORTEC-2. “Nout et al, Lancet, 2010. 427 “HIR: age >60 and IC grade 1-2, or IB grade 3. Stage IIA any age
(grade 3 and >1/2 invasion excluded) Adenocarcinoma only”
→WPRT 46 Gy vs. VCB to proximal 1/2 of vagina, HDR 7 Gy x 3 or LDR 30 Gy Rx to 5mm depth

Nodes: Suspicious pelvic or PA lymph nodes removed. Routine LN dissection not allowed”

“Pelvic recurrences reduced with WPRT. Most pelvic recurrences occur with DM
5-yr VR 1.6% WPRT vs. 1.8% VCB, noninferior
10-yr VR 2.4-3.4%, not different
5-yr pelvic recurrence 0.5% vs. 3.8%
10-yr pelvic recurrence 1% vs. 6%
10-yr pelvic recurrence first failure 0.5% vs. 2.5%, p=0.10

Not different: 5-yr OS ~84%, 10-yr OS ~68%, 10-yr CSS ~90%, 10-yr DM ~10%

Nomogram in Creutzberg et al, IJROBP, 2015

QOL better with VBT: WBRT had 11% fecal leakage, 8% diarrhea, 10.5% bowel limitations, 23% bowel urgency, 39% urinary urgency. More vaginal mucosal toxicity with VBT”

“This trial set a standard of VC brachytherapy for HIR patients.

These patients were also included as eligible for GOG 249, which concluded WPRT to be standard (Randall 2019). However eligibility in the study may have been to broad.

An analysis by Witlink (2014) showed no increase in 2nd cancers after RT in PORTEC 1, PORTEC 2, and patients who received pelvic RT for rectum after TME.”

Question 8

RT vs. VCB/C in HR and HIR

Answer 8

GOG 249. Randall et al, JCO, 2019. 601 “Stage I endometrial HIR, Stage II endo, Stage I-II serous or clear cell with negative cytology
[74% stage I, 15% serous, 5% clear cell]

HIR defined as: age ≥70 + 1 risk factor, age ≥50 + 2 risk factors, age ≥18 + 3 factors.
Risk factors: grade 2 or 3, LVI, >50% myometrium”

“→WPRT 45-50 Gy + optional VC for serous, pap or Stage II vs. VC brachy then carbo/paclitaxel x3

pelvic LND encouraged [used in 89%]”

“Similar outcomes but worse acute toxicity and more pelvic/PA relapse with VCB/C

5-yr OS ~86%, RFS 76%, not different
pelvic or PA recurrence 4% vs. 9%
VCR 2.5%, not different
DM 18%, not different

On interactions analysis there is no favoring of treatment in any subgroup
Worse neurotoxicity and fatigue with chemo
Acute toxicity worse with chemo. Late toxicity similar”

“Why weren’t 6 cycles of chemo used? The investigators had concern for overtreatment and toxicity with 6 cycles.

Results are similar to PORTEC 3, which shows no benefit to chemo added to WPRT in this population. Also compare to PORTEC 2, where VCB had more pelvic recurrences but these were simultaneous with DM. Note in GOG 249 that even DM are not reduced with chemo. VCB alone may still be sufficient in HIR per PORTEC 2 (de Boer 2019, Nout 2010).”

Question 9

VBT dose

Answer 9

PORTEC 4 (ongoing). Dutch Cancer Society, ongoing protocol. 500 “Intermediate risk
IA, any age, grade 3, no LVSI
IB, age ≥60, grade 1-2
IB, any age, grade 1-2, LVSI “

“obs vs. 21 or 15 Gy /3 fx VCB”

Question 10

Molecular profiling

Answer 10

PORTEC 4a (ongoing). Leiden University Medical Center., ongoing protocol. 500
"IA, grade 3, any age, ± LVSI
IB, grade 1-2, age >60
IB, grade 1-2, LVSI
IB, grade 3, no LVSI
II (microscopic), grade 1"

Question 11

Adjuvant whole pelvis RT

Answer 11

ASTEC/EN.5: Lancet, 2009. 905”Stage IA to IIB, Grade 1-3. Pap serous and clear cell allowed. Positive pelvic nodes allowed in ASTEC, but not in EN.5. PA nodes are excluded”

“→WPRT (median 45 Gy) vs. obs

The int and high risk patients from ASTEC LND trial were forwarded to this trial

~30% had pelvic LND

VCB allowed if stated before randomization and used in both arms
ASTEC: 2x4 Gy HDR, or 15 Gy LDR
EN.5: VCB by local practice

~50% brachy given in both arms”

“Isolated pelvic or vag recurrence improved: 3.2% WPRT vs. 6.1%
No change in OS or DSS

Toxicity worse with EBRT: 57% WPRT vs. 27%, moderate toxicity 22% vs. 8%, late tox 8% vs. 3%”

“Criticisms: If node+ after pelvic LND, randomization was not impacted. Node positive could enter no RT arm.

50% VCB
82% EBRT compliance
4% of all had positive nodes

Groups are well balanced: median age 65, 83% endometrial histology, 25% LVSI, 29% with LND

Note that pelvic recurrences rates are low in GOG 99 (LND allowed) and PORTEC-1 (no LND) both with and without RT. However vaginal recurrences were higher in GOG and PORTEC-1 than in ASTEC (Keys 2004, Creutzberg 2000).”

Question 12

Pelvic LN dissection

Answer 12

ASTEC. ASTEC study group et al, Lancet, 2009. 1408 disease limited to uterus body”→pelvic LND vs. no PLND. Patients int/high risk (33%) further randomized to ASTEC RT trial”. “No change in RFS or OS with lymphadenectomy
9% positive nodes detected
5% crude rate of lymphedema
On subanalysis, no difference with depth, histology, grade, age, or performance status”

Criticisms: If LND resulted in positive nodes, no adjuvant therapy was required. N dissection does provide staging information and guides therapy that could result in increased OS.

Question 13

SLN biopsy

Answer 13

FIRES: Rossi et al, Lancet Oncol, 2017. 385 Clinical Stage I endometrial cancer of all histologies and grades undergoing robotic staging.
“Prospective cohort.
→SLN mapping with cervical injection of indocyanine green → pelvic LND ± PA LND
Negative SLNs were ultrastaged with immunohistochemistry for cytokeratin”

“SLN detected nodal mets in 97% of LNDs (in 12% with positive nodes on dissection)
Sensitivity 97%, NPV 99.6%

PA node dissection in 58%
86% had successful mapping of at least one node
Post-op stage:
66% IA, 14% IB, 4% II, 3% IIA, 12% IIIC, 1% IV
82% endometrial, 43% grade 1, 29% grade 2, 11% grade 3, 12% serous, 4% carcinosarcoma, 2% clear cell, 1% other”

Results might not apply to high grade or higher stage tumors. Note entry criteria is clinical stage I and entry criteria cannot be the post op stage. Few high grade and higher stage patients were diagnosed on pathology.

Question 14

Pelvic LN dissection

Answer 14

La Sapienza University, Rome. Panici et al, JNCI, 2008. 514 early stage endometrial cancer “surgery→pelvic LND vs. no PLND”

“LN mets found: 13% with LND vs. 3% without
No change in DFS or OS”

Although it’s not obvious that LND improves outcomes, perhaps the improved staging may help better outcomes if it guides adjuvant therapies such as WPRT for LN+.

Question 15

Definitive radiation for inoperable

Answer 15

McGill University, Montreal, Quebec, Cananda: Niazi et al, IJROBP, 2005. 38 Clinical (not pathologic) Stage I-II endometrial adenocarcinoma, high operative risk

Retrospective eval of definitive endometrial RT. 79% patients treated with HDR alone, 21% treated with EBRT plus HDR. Median EBRT 42 Gy, median HDR 24 Gy in 3 fx

“15-yr DSS 78% for all stages
stage I DSS 90% and stage II DSS 42%
If Stage I by MRI and at least 30 Gy HDR, then 10-yr DSS 100%”

Question 16

CRT vs. RT in HIR and advanced

Answer 16

PORTEC 3: “de Boer et al, Lancet Oncol, 2018. 686 “IA with invasion, G3, and LVSI. IB G3, II, IIIA, IIIC, IIIB if parametrial. IA with invasion, IB, II, or III with serous or clear cell histology”
→WPRT 48.6 Gy + VCB for cervical invasion
vs. WPRT + conc cisplatin x2 and adjuvant carbo/taxol x4”
“•Post-hoc adjusted analysis with longer f/u
5-yr OS 81% vs. 76%, p=0.034
5-yr FFS 77% vs. 69%, p=0.016
Benefits were only in Stage III
Stage I-II OS ~83%, FFS ~80%, not different
5-yr isolated DM 21% vs. 29%
isolated pelvic (0.3%) and vaginal recurrence (0.9%) not different

•Serous
5-yr OS 71% vs. 53%
5-yr FFS 60% vs. 48%
serous had highest risk of recurrence

•Molecular analysis

• RFS benefit in p53abn with chemo but not POLEmut, MMRd, or NSMP
• p53abn was mainly in serous
• p53abn 5-yr RFS 36% vs. 59%
• p53abn 5-yr OS 42% vs. 65%
• Benefit in early stage, but not stage III p53abn, but low power
• MMRD had best RFS and OS with almost no recurrences in both arms

[On the initial publication, OS and FFS were not significantly different. FFS did become significant after adjustment for imbalanced arms. On subanalysis the FFS benefit is only in Stage III. The authors later released a post-hoc analysis with longer f/u.]”

“There is OS and FFS benefit with chemotherapy added to RT for Stage III tumors on post-hoc analysis with longer f/u. (On initial reporting, there was no OS benefit.)

On subgroup analysis, chemo notably does provide OS benefit in serous tumors.

Tumors with p53abn mutations, mainly present in serous, had RFS and OS benefit with chemo. MMRD had the best RFS and OS, with almost no recurrences. “

“FFS benefit in Stage III was present both without and with the adjustment. The authors state that they followed sound statistical methods to adjust the arms for imbalances and cited statistical references in support. Still, something about the process seems very post-hoc. The subanalyses were prespecified.

Compare to GOG 249 which showed no benefit with chemotherapy added to RT in stage I-II (Randall 2019) but had shorter f/u.

On subanalysis there is a nonsignificant, but trend, to benefit with LND, p=0.119.”

Question 17

CRT vs. C

Answer 17

GOG 258. Matei et al, NEJM, 2019. 736 “-advanced endometrial carcinoma

• Stage III-IVA, serous papillary and undifferentiated carcinomas allowed
• Stage I-II clear cell or serous carcinoma
• Lymph node dissection optional”

“→WPRT 45 Gy + cisplatin + VCB (for cervix or vaginal involvement) then carbo/paclitaxel x4 vs. →carbo/taxol x6 alone”

"5-yr RFS 59% RT vs. 58%, p=0.20
OS results are maturing
5-yr VR 2% RT vs. 7%
5-yr Pelvic/PA LN recurrence 11% vs. 20%
5-yr DM 27% vs. 21%
Grade 3-5 toxicity 58% vs. 63%
A subanalysis and sensitivity analysis, no subgroups were favored by either arm"

RT with concurrent and adjuvant chemo did not significantly improve RFS compared to chemo alone. ChemoRT had less VR, LN recurrence, and toxicity. Chemo alone had less DM. OS results are maturing.

“Only 75% in CRT arm completed therapy. There was 85% completion for chemo alone. 18% serous, 3% clear cell.

Concurrent chemo was used in GOG 258 based on favorable outcomes with this method in RTOG 9708 (Greven 2006). An alternative approach is ““sandwich”” chemo –> RT –> chemo as outlined in other trials here. This approach might warrant further testing in the future.”

Question 18

Whole Abdominal RT

Answer 18

GOG 122. Randall et al, JCO, 2006. 396 Stage III or IV with ≤2cm residual post-opdisease”→cisplatin/doxorubcin vs. Whole abdomen RT (30 Gy/ 20 fx with 15 Gy boost)”

“5-yr PFS 38% RT vs. 42% chemo
5-yr OS 42% vs. 53%. P value not provided

Arms were imbalanced, so stage adjustment was done:
5-yr PFS 38% vs. 50%
5-yr OS 42% vs. 52%
With chemo, more grade 3-4 heme and GI toxicity
63% completed chemo”

Chemotherapy improves PFS and OS compared with WART.

Residual disease was allowed - the RT dose might not have been sufficient. Relapse rates were high in both arms. Significance came only after adjustment for stage imbalance in the arms. A later more rigorous trial, GOG 258, was performed to re-evaluate this question.

Question 19

chemo vs. RT

Answer 19

JGOG. Susumu et al, Gynecol Oncol, 2008. 385 Stage IC - IIIC s/p surgery. "→WPRT vs. Cyclo/doxo/cis x3". 
"No difference in OS or PFS
5-yr PFS 83% vs. 82%
5-yr OS 85% vs. 87%
On subanalysis, benefit in high risk
High risk (IC and age>70, IC G3, II, IIIA from +cytology): 
PFS 66% vs. 84% chemo
High risk OS 74% vs. 90%

Overall there was no difference in OS or PFS. On subanalysis OS and PFS were improved in high risk tumors.

Università degli Studi di Milano, Milano, Italy. Maggi et al, Br J Cancer, 2006. 345 High risk endometrial: IC grade 3, II grade 3 and >50% invasion, stage III. “→WPRT 45-50 Gy vs. cis/doxo/cyclo x5 “ No differences in OS or PFS

Question 20

RT->chemo vs. RT

Answer 20

NSGO / EORTC / MaNGO ILIADE-III. Hogberg et al, Eur J Cancer, 2010. 534 Operable endometrial Stage I-III with no residual tumor and presence of high risk factors. Serous and clear cell also allowed “→WPRT 45 Gy → chemo vs. WPRT alone
EFRT and VCB allowed”

“RT vs. chemo-RT
5-yr PFS 69% vs. 78%
5-yr OS 75% vs. 82%, p=0.07
Subanalysis: benefit only for serous/clear cell, not endometriod”

The addition of adjuvant chemotherapy after RT improves PFS compared to RT alone.

Question 21

“Sandwich” chemoRTchemo

Answer 21

University of Western Ontario, Canada. Lupe et al, Gynecol Oncol, 2009. 43 Stage III or IV endometrial adeno, 49% serous. “Prospective.
Carbo/paclitaxel x4 → 45 Gy RT → carbo/taxol x2. EFRT and VCB allowed”

“DFS 53%, OS 68%
Median DFS 50 mos, median OS not reached
6 cycles of chemo completed in 81%
Only 3 local recurrences: 2 in pelvis and 1 in vagina/vulva”

Adjuvant carboplatin and paclitaxel interposed with RT has low LR and favorable OS in this prospective study.

Given the mixed results of PORTEC 3 and GOG 258 in which neither chemo or RT improved OS, sequential chemo RT regimens may warrant investigation in phase III trials (de Boer 2018, Matei 2019).

Duke University. Secord et al, Gynecol Oncol, 2009. 109 Endometrial cancer s/p TAH-BSO, selective LN dissection. Multi-institutional retrospective analysis. “Sandwich chemoRTchemo 3-yr OS 88%, PFS 69%
RT chemo 3-yr OS 54%, PFS 47%
chemoRT 3-yr OS 57%, PFS 52%
OS benefit with chemoRTchemo remained on adjustment for stage, age, grade, race, histology and cytoreduction status”.

Sequential chemo–>RT–>chemo is associated with improved OS in this retrospective analysis.