Download Thoughts on Toxicity and Radiation in Endometrial Cancer

Endometrial Cancer: Current Status of
Radiation
William Small Jr., MD
Professor and Chairman
Loyola University, Chicago
Learning Objectives
Review the patterns of recurrence for
endometrial cancer.
Review the role and techniques of radiation for
early stage endometrial cancer.
Review the role of radiation in advanced stage
endometrial cancer.
Endometrial Cancer
Estimated New Cancer Cases and Deaths by Sex, 2017
Women
American Cancer Society, Surveillance Research, 2017
“The reports of my death have
been greatly exaggerated.”
-Mark Twain
“There are three kinds of lies: Lies,
Damned Lies, and Statistics.”
-Benjamin Disraeli
-Mark Twain
FIGO 1988
Surgical staging System
Early stage disease
Stage I
IA
Limited to the endometrium
IB
< half of the endometrium
IC
> half of the endometrium
Stage II Corpus and cervix
IIA
Endocervical glands only
IIB
Endocervical stromal invasion
FIGO 1988
Surgical staging System
Late stage disease
Stage III
IIIA Tumor Involves the serosa and/or adenexa
(direct extension or metastasis) and/or cancer
cells in ascites or peritoneal washings
IIIB Vaginal Involvement
III C Metastasis to Pelvic or Para-aortic Lymph Nodes
Stage IV
IVA Tumor Involves the bladder or bowel mucosa
IVB Distant Metastasis
FIGO 2009
Surgical staging System
Early stage disease
Stage I
IA
No or < half of the endometrium
IB
= or > half of the endometrium
Stage II Corpus and cervix
Endocervical stromal invasion
Int J Obs Gyn, May 2009,
FIGO 2009
Surgical staging System
Late stage disease
Stage III
IIIA
Tumor Involves the serosa and/or adenexa
(direct extension or metastasis)
IIIB Vaginal and/or parametrial Involvement
III C1 Metastasis to Pelvic Lymph Nodes
IIIC2 Metastasis to Para-aortic +/- pelvic Lymph Nodes
Stage IV
IVA Tumor Involves the bladder or bowel mucosa
IVB Distant Metastasis and/or inguinal metastasis
Post Operative Radiotherapy
Early Stage Disease
Very contentious Disease
All Patients
Receive Adjuvant RT
Even Low Grade
Minimally Invasive
Tumors
No Patients
Receive adjuvant RT
Even High Grade
Deeply Invasive
Tumors
Center A
Center B
Postoperative RT Rationale
Early stage patient with adverse pathologic features
are at risk for extra uterine disease and recurrence
Most commonly cited pathologic factors
-Myometrial Invasion (MI)
-Tumor Grade
-Cervical involvement
- Age
- LVSI
Importance demonstrated in GOG33
Predicting Lymph Node
Metastasis
Unclear what these number would
be in the face of negative imaging
GOG 33
Surgical Pathologic study of 621 stage I pts
Positive
Pelvic LNs
Positive
PA LNs
Grade
1
3%
2%
2
9%
5%
3
18%
None
1%
1%
Superficial
5%
3%
Middle
6%
1%
Deep
25%
P<0.0001
11%
P<0.0001
MI
P<0.0001
17%
P<0.0001
More useful to combine grade & MI
Positive Pelvic LNs
Positive PA LNs
Invasio
n
G1
G2
G3
Invasion
G1
G2
G3
None
0%
3%
0%
None
0%
3%
0%
Inner
3%
5%
9%
Inner
1%
4%
4%
Middle
0%
9%
4%
Middle
5%
0%
0%
Deep
11%
19%
34%
Deep
6%
14%
23%
Creasman WT et al, Cancer 1987;60:2035
Tumor Size and Lymph Node
Metastasis
multivariate p-0.01
% Lymph Node
Metastasis
40%
35%
30%
20%
15%
10%
0%
4%
<2 cm
> 2 cm
Tumor Size
Schink Cancer 67:279;1991
Entire Cavity
Prevalence of Lymph Node Metastasis
in Endometrial Cancer by Tumor Size
and Depth of Myometrial Invasion
Tumor size
Depth of invasion
< 2 cm
diameter (%)
> 2 cm
diameter (%)
Entire Surface (%)
None
0/17 (0)
0/8 (0)
0/7 (0)
>½
2/9 (22)
6/23 (26)
4/8 (50)
Schink Cancer 67:279;1991
Prevalence of Lymph Node Metastasis
in Endometrial Cancer by Tumor Size
and Grade
Tumor size
Tumor Grade
< 2 cm
diameter (%)
> 2 cm
diameter (%)
I
II
III
1/27 (4)
0/19 (0)
1/7 (14)
1/26 (4)
5/28 (18)
5/18 (28)
Entire Surface (%)
0/7 (0)
2/4 (50)
4/6 (67)
Schink Cancer 67:279;1991
Cervical involvement and also CSI are
correlated with Positive LNs
Positive
Pelvic LNs
Positive
PA LNs
Site
Fundus
8%
Isthmus cervix
16%
Negative
7%
Positive
27%
4%
P = 0.01
14%
P= 0.0001
Capillary Space
involvement
4%
P=0.0001
19%
P= 0.0001
Bendifallah et al/Am J. Obstet Gyncol 2012; 207:197.e1-8.
What evidence supports the use of
Adjuvant Radiation Therapy in
Stage I & II Endometrial
Carcinoma ?
Rationale also provided by the correlation
between adverse pathologic factors and vaginal
failure
Price 1965
41 clinical stage I patients undergoing surgery alone
Vaginal Recurrence
All Patients
14%
Grade
1
4.4
2
5.7
3
13.6
None
3.7
< half
4.7
> half
15.1
MI
Unfortunately Grade and Myometrial invasion not combined in the analysis
Price et al. Am J Obstet Gynecol 1965; 91:1060
Retrospective studies also suggest benefit
of Adjuvant RT in patients with adverse
pathologic factors
Pelvic
Recurrence
with RT
Pelvic
Recurrence
without RT
Carey 1995
High Risk pts
Deep MI, G3,
+Cx, Adenos.
3.9%
14.3%
Pitson 2002
Stage II (55%
IIA)
5.6%
22.2%
Carey et al, Gynecol Oncol 1995; 57:138
Piston et al, Int J Radiation Oncol Bio Phys 2002; 53:862
Retrospective studies also suggest
benefit of Adjuvant RT in patients with
adverse pathologic factors
In a retrospective review of 927 patients Stage I&II pts
Vaginal Recurrence
with RT – either Vault
or Total Vagina
Vaginal Recurrence
without RT
Stage I Low Risk
G 1 – 2, <1/3 MI
1%
3.2%
Stage I High Risk
G3 &/Or >1/3 MI
1.3%
11.7%
Stage II
5.2 %
12.8%
Elliot at al., Int J Gyne cancer 1994; 4 : 84
Post operative RT Stage I & II Disease
Five prospective randomized trials have been
conducted to evaluate post operative
radiotherapy in early stage disease
Norwegian Trial
PORTEC 1
GOG 99
ASTEC/EN 5
PORTEC 2
Norwegian Trial
Clinical Stage I
540 Patients
TAH + BSO without
LN Sampling
No assessment of
peritoneal cytology
Vaginal Brachytherapy
LDR 60 Gy @vaginal
surface
Arm 1
Arm 2
Pelvic RT 40 Gy
Midline block
after 20 Gy
No further
therapy
Aalders et al, Obstet Gynecol 1980; 56(4);419
Norwegian Trial
Pelvic RT reduces vaginal / pelvic failures in patients with
high risk features (deep MI & G3 Tumors)
Vaginal/Pelvic recurrence
Grade 1 – < ½ MI
2 Tumors > ½ MI
No RT
4%
9.8%
With RT
2.3%
9.4%
Grade 3
Tumors
5.6%
19.6%
2.1%
4.5 %
< ½ MI
> ½ MI
Aalders et al, Obstet Gynecol 1980; 56(4);419
Norwegian Trial
No Overall survival benefit with Radiotherapy
5 Years Survival Rate
Pelvic RT
89%
No Pelvic RT
91%
Only in Patients with deeply invasive Grade 3
Tumors
Death from Cancer
Pelvic RT
18.2%
No Pelvic RT
27.5%
Aalders et al, Obstet Gynecol 1980; 56(4);419
LVSI
LVSI was evaluated in the last 151 patients on
trial.
Vessel invasion seen in 19.9 % of the patients.
Local recurrence 21 % in the no Pelvic RT group
versus none in the Pelvic RT group.
Aadlers Trial: Conclusions
Grade 3> 50 % invasion – pelvic RT.
All patients with LVSI receive pelvic RT
All other patients with invasion receive
VBT.
PORTEC Trial
Post Operative Radiation Therapy in
Endometrial Carcinoma
Selected Clinical Stage I
Grade 1 > ½ MI
Grade 2 any MI
Grade 3 < ½ MI
715 Patients
TAH + BSO without LN
Sampling
All histologies
Regimen 1
Pelvic radiotheraoy
46 Gy / 23 Fractions
No Vaginal Brachytherapy
• Regimen 2
No further Treatment
HIR Definition
Age > 60
Grade 3
Invasion >50%
HIR defined as: 2 of those 3 factors present
(except for grade 3 with deep invasion = high
risk, eligible for PORTEC3)
Fig. 3
Source: International Journal of Radiation Oncology * Biology * Physics (DOI:10.1016/j.ijrobp.2011.04.013 )
Copyright © Elsevier Inc. Terms and Conditions
PORTEC – 10-year outcome with PA review
Locoregional recurrence (actuarial rates)
All pts
5-yr
10-yr
p
RT
No RT
3%
13%
5%
14%
<0.001
Exclusion of IB grade 1 (n=134):
RT
No RT
4%
15%
5%
17%
<0.001
Creutzberg, Lancet 2000; Scholten, IJROBP 2005
PORTEC – 15-year outcome
( Median f/u: 13.3 Years)
Locoregional recurrence (actuarial rates)
5.8 % in the Radiotherapy Arm
15.5 % in the NAT Arm
Nout et al; JCO, 2011
Site of Loco-regional Recurrences
74% of the locoregional recurrences were isolated
vaginal recurrences.
Nout et al; JCO, 2011
GOG 99 Trial
Stage IB - II (Occult)
Pap/Serous-Clear Cell
Excluded
392 Patients
TAH + BSO with
selective Bilateral
Pelvic & Para- aortic
lymphadenectomy
Assessment of
peritoneal cytology
Regimen 1
Pelvic radiotheraoy
50.4 Gy / 1.8 Gy/ Fraction
No Vaginal Brachytherapy
• Regimen 2
No further Treatment
Keys et al. Gynecol Oncol 2004; 92;744
Overall Results
Median follow-up of surviving patients – 68 months.
The 24-month cumulative incidence of recurrence
(CIR) rate was 3% in the RT group and 12 % in the
no additional therapy group.
13 of the 18 loco-regional recurrences in the NAT
arm were in the vaginal vault (72%)
Overall Results
CIR at 24 months of isolated local (vagina or pelvic)
1.6% versus 7.4%
48 month Kaplan-Meier estimates for survival –
86% in the NAT group, 92 % in RT group (p=0.55).
The GI, GU, Cutaneous and Hematological side
effects were significantly higher in the RT group.
HIR group (GOG-99)
Prognostic factors:
› advanced age
› high grade (2 or 3)
› outer 33% myometrial invasion
› lymph-vascular space invasion (LVI)
HIR (high intermediate risk):

at least 70 yr with any other risk factor

at least 50 yr with any 2 other risk factor

any age with all 3 other factors
Keys, Gynecol Oncol 2004
GOG-99: recurrence
HIR, NAT: 27%
HIE, RT: 13%
Relative hazard RT: 0.42 (58% hazard reduction)
HIR: 33% of patients, 67% of recurrences
Keys, Gynecol Oncol 2004
GOG 99: Survival
LIR: 92 - 94%
HIR, RT: 88%
HIR, no RT: 74%
Relative hazard for RT: 0.86 (ns); HIR: 0.73
Keys, Gynecol Oncol 2004
MRC ASTEC Radiotherapy and
NCIC EN.5 Trial
Adjuvant external beam radiotherapy (EBRT) in the treatment of
endometrial cancer: results of the randomized MRC ASTEC and
NCIC CTG EN.5 trials
ASTEC ISRCTN 16571884
EN.5 clinicaltrials.gov NCT 00002807
Presented by
Jane Orton
On behalf of all ASTEC and EN.5 Collaborators
Trial Design
Surgery
High risk pathology and no macroscopic disease
RANDOMIZE
No external beam RT
External beam RT
Inclusion Criteria ASTEC and EN.5
FIGO
Stage
Grade 1
Grade 2
Grade 3
Papillary
Serous/cle
ar cell
IA
1 (<1%)
1 (<1%)
8 (1%)
15 (2%)
IB
1 (<1%)
5 (1%)
99
(11%)
48 (5%)
IC
213 (24%)
337
(37%)
100
(11%)
27 (3%)
IIA
9 (1%)
19 (2%)
6 (1%)
3 (<1%)
IIB
2 (<1%)
0
0
1 (<1%)
Eligibility Criteria
Brachytherapy allowed if
centre policy
stated before randomisation
used in both arms
Positive para-aortic nodes an exclusion
Positive pelvic lymph nodes
Eligible for ASTEC
Ineligible for EN.5
Brachytherapy
In the ASTEC trial HDR: Two fractions of 4 Gy at
0.5 cm from the vaginal mucosa over 3-7 days
or LDR: 15 Gy – upper third of the vagina.
In the EN-5: Given in accordance with local
practice.
Trial Profile
905 Randomized
453
No EBRT
452
EBRT
98% No EBRT
2% received EBRT
92% received EBRT
8% No EBRT
51% Brachytherapy
52% Brachytherapy
453 assessed
for primary outcome
measure
452 assessed
for primary outcome
measure
Patient Characteristics
Baseline characteristics balanced between treatment groups
median age 65 years
98 % performance status 0-1
83% endometrioid histology
25% lymphovascular space invasion
4% positive peritoneal cytology
Surgery received
71% TAH/BSO
29% TAH/BSO plus lymphadenectomy
4% of patients (with nodes harvested) had positive pelvic
nodes
Radiotherapy Details
EBRT
N=452
80
Distribution of EBRT dose used
45
25
34
40
20
2
60
24 (5%)
0
Median:
Total Dose (Gy)
Fractions
Duration in days
416 (92%)
10 (3%)
Percentage (%)
EBRT +/brachytherapy
Brachytherapy
alone
None
Missing
5
Treatment
compliance
(% of patients who
received total dose
of 40-46 Gy in 20-25
fractions)
82%
10
15
20
25
30 35 40 45
Total dose (Grays)
50
55
60
65
70
Acute and Late Toxicity
Acute toxicity (post surgery and
radiotherapy)
Worst score
Mild
Moderate
Severe/Life threatening
Late Toxicity
Severe/Life threatening
No EBRT
N=453
EBRT
N=452
121 (27%)
258 (57%)
77 (17%)
38 (8%)
3 (<1%)
143 (32%)
100 (22%)
14 (3%)
3%
8%
Isolated Vaginal or Pelvic Initial
Recurrence (ASCO Presentation)
1.0
Events
28
14
No EBRT
EBRT
0.9
Totals
453
452
0.8
Cumulative incidence
0.7
0.6
3% difference in 5 year cumulative incidence rate
(4% in EBRT to 7% in no EBRT)
0.5
HR=0.53, 95% CI=0.29-0.97, p=0.038
0.4
Only includes 42/123 total recurrences
0.3
0.2
0.1
0.0
0
PATIENTS at Risk
No EBRT
EBRT
1
2
3
4
5
6
7
81
78
35
32
Years from randomisation
453
452
425
420
366
376
282
281
211
212
142
142
Isolated Vaginal or Pelvic Initial Recurrence
5-year cumulative incidence 6.1 % versus 3.2 %
(p=0.02)
Overall Survival: by centre
brachytherapy policy (ASCO
Presentation)
[no. events/no. entered]
EBRT
No EBRT
O-E
Variance
Hazard Ratio (Fixed)
Brachytherapy
Yes
23/196
29/190
-3.99
12.98
0.74 (0.43-1.27) p=0.268
No
30/181
25/184
3.96
13.69
1.34 (0.79-2.27) p=0.284
0
0.5
EBRT Better
Interaction Test: chi-square=2.37, df=1, p=0.123
1
2
5
No EBRT Better
Recurrence-Free Survival: by
centre brachytherapy policy
(ASCO Presentation)
Meta-analysis: overall survival
Study
EBRT
n/N
No EBRT
n/N
Peto OR (IPD)
95% CI
PORTEC
GOG
ASTEC + EN5
57/354
30/190
65/452
48/360
36/202
66/453
Total (95% CI)
152/996
150/1015
N
Peto OR (IPD)
95% CI
714
392
905
1.22 [0.83, 1.79]
0.86 [0.57, 1.29]
1.00 [0.71, 1.41]
2011
1.02 [0.82, 1.27]
Test for heterogeneity: Chi² = 1.51, df = 2 (P = 0.47), I² = 0%
Test for overall effect: Z = 0.20 (P = 0.84)
0.1
0.2
0.5
Favours EBRT
1
2
5
10
Favours No EBRTl
0.2% difference in 5-year OS (87.8% in EBRT and 88% in no EBRT)
95% CI of difference = -2.0% to 3.0%
The “Myth” that Isolated Vaginal
Recurrences are Easily Salvageable
Accompanying editorial to GOG 99 by Michael
Berman noted: “Yet vaginal recurrences usually are
treated successfully with radiotherapy in patient not
previously treated with adjunctive radiation”
The data from GOG 99 noted that 12 of 13 patients
in the NAT arm were treated with salvage
radiotherapy – crude observations noted 5 of these
thirteen died of endometrial cancer.
Immediate versus delayed RT
Salvage rate may not be as high as those
commonly quoted.
> 70% results are typically quoted.
Most studies do not support this even in isolated
vaginal recurrences.
Survival typically range around 40 – 50 %.
Poorer outcomes in non-vaginal pelvic recurrences.
Salvage RT Series
Locally Recurrent Endometrial Cancer
Author
Number
Local Control
5 Years
Survival
Kuten (1989)
51
35%
18%
Jereczek(2000)
73
48%
25%
Curran (1988)
47
48%
31%
Jhingran (2003)
91
75%
43%
Hoekstra (1993)
26
84%
44%
Sears (1994)
45
54%
44%
Hart (1998)
26
65%
53%
Wylie (2000)
58
65%
53%
Lin (2005)
50
74%
53%
Creutzberg
(2003)
35
77%
66%
Salvage treatment with high-dose-rate
brachytherapy for isolated vaginal endometrial
cancer recurrence
And the risk of toxicity should NOT be ignored
22 isolated vaginal recurrences
18 EBRT + HDR, 4 HDR alone
Median follow-up 32 month
18% grade 3-4 GI toxicity
50% grade 3 vaginal sequelae
Petignat et al. Gynecol Oncol 2006; 101:445
Population Based Data
SEER analysis: efficacy of RT
• SEER program (NCI), 10% US population
• 21.249 patients, 1988-2001
• 19% of patients had RT (82% EBRT)
• 43% had surgical node sampling
Lee et al, JAMA 295, 389-97, 2006
Multivariate Analysis
Table 2. Cox regression analysis with relative survival endpoint
Covariates
Stage 1A, Grade I
Stage 1B, Grade I
Stage 1C, Grade I
Stage 1A, Grade II
Stage 1B, Grade II
Stage 1C, Grade II
Stage 1A, Grade III/IV
Stage 1B, Grade III/IV
Stage 1C, Grade III/IV
Race/ethnicity=Black
Pathologic Node Negative at TAH-BSO
Age at Diagnosis (per decade, base age 65)
Radiation + Stage 1A, Grade I
Radiation + Stage 1B, Grade I
Radiation + Stage 1C, Grade I
Radiation + Stage 1A, Grade II
Radiation + Stage 1B, Grade II
Radiation + Stage 1C, Grade II
Radiation + Stage 1A, Grade III/IV
Radiation + Stage 1B, Grade III/IV
Radiation + Stage 1C, Grade III/IV
HR (95% CI)
1.000
1.13 (0.97-1.31)
2.06 (1.63-2.61)
1.38 (1.14-1.67)
1.47 (1.27-1.72)
2.04 (1.64-2.54)
2.47 (1.97-3.11)
2.64 (2.21-3.16)
5.09 (4.09-6.32)
0.54 (0.46-0.63)
0.90 (0.83-0.98)
1.79 (1.73-1.86)
0.85 (0.40-1.80)
0.91 (0.64-1.29)
0.45 (0.32-0.64)
1.37 (0.82-2.28)
1.00 (0.81-1.24)
0.96 (0.76-1.21)
1.02 (0.66-1.57)
0.98 (0.80-1.19)
0.74 (0.58-0.93)
*Baseline reference group= no radiation, stage 1A, grade 1 cohort.
p value
reference
.13
<.001
<.001
<.001
<.001
<.001
<.001
<.001
<.001
<.001
<.001
.67
.59
<.001
.23
.97
.75
.93
.82
.009
What is the “best” RT
It is clear that radiotherapy is indicated in high risk
early stage endometrial cancer.
Can VBT replace external beam for the majority of
these patients?
PORTEC - 2 trial (2002-2006)
Stage I-IIA endometrial carcinoma
• age > 60 and IC grade 1-2, or IB grade 3
• stage 2A (except grade 3 > 1/2)
• surgery: TAH-BSO
Groningen
Waddenzee
Friesland
R
pelvic radiotherapy
Noord
Holland
Drenthe
Ijsselmeer
Flevoland
Zuid Holland
vaginal brachytherapy
Overijssel
Gelderland
Utrecht
Noord Brabant
Zeeland
Limburg
PORTEC-2
Randomized Between:
Pelvic Radiotherapy – 46 Gy in 23 fractions
VS
Vaginal Brachytherapy – 21 Gy HDR or 30 Gy LDR
PORTEC-2 Author Conclusions
“Despite the slightly but significantly increased
pelvic failure rate in the VBT arm, DM, RFS and OS
were similar. As patient reported quality of life after
VBT was…better, VBT should be the treatment of
choice for patients with high-intermediate risk
endometrial cancer”
PORTEC- 4 and Patient Preference
PORTEC-4
HIR endometrial carcinoma
Vaginal brachytherapy vs no further
treatment
21 Gy in 3 fractions vs 15 Gy in 3 fractions
2
R
1
1
VBT 3 x 7 Gy at 5 mm
1
VBT 3 x 5 Gy at 5 mm
No further treatment
Close FU; EBRT/VBT for vaginal relapse
4
Kunneman, et.al/British Journal of Cancer, 2014, 1-6
Kunneman, et.al/British Journal of Cancer, 2014, 1-6
How should you treat – so called –
intermediate risk patients?
The data on unselected patients consistently
shows a reduction in vaginal recurrences.
I believe the “best” technique is to look at all the
risk factors before deciding on an individual
patient.
Clinical Outcomes in International Federation of
Gynecology and Obstetrics Stage IA Endometrial Cancer
With Myometrial Invasion Treated With or Without
Postoperative Vaginal Brachytherapy
V. Diavolitsis, M.D.,1 * A. Rademaker, Ph.D.,2 J. Lurain, M.D.,3 A. Hoekstra,
M.D., M.P.H.,4 J. Strauss, M.D., M.B.A.,5 and W. Small, Jr., M.D.,*
Departments of Radiation Oncology, Preventive Medicine, and Obstetrics and
Gynecology, Division of Gynecologic Oncology, Robert H. Lurie Comprehensive
Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL.
Int J Radiol Oncol Biol Phys,. Volume 84, Number 2 (2012) 415-419.
Patient outcomes data
Variable
Disease status (all patients)
Alive without disease
Dead of another cause
Alive with disease
Dead of disease
Recurrence
Interval from surgery
to recurrence (mo)
Median
Range
Recurrence location*
Vagina
Pelvis
Para-aortic
Upper abdomen
Lung
Status after recurrence
Alive without disease
Died of another cause
Alive with disease
Died of disease
VBT
(n = 169)
NAT
(n = 83)
p
.07
145 (85.8)
18 (10.7)
1 (0.6)
5 (3.0)
8 (4.7)
40
9-102
78 (94.0)
2 (2.4)
1 (1.2)
2 (2.4)
6 (7.2)
NS
NS
19
2-49
1
4
1
3
3
3
2
0
1
0
3 (37.5)
1 (12.5)
1 (12.5)
3 (37.5)
3 (50)
0 (0)
1 (16.7)
2 (33.3)
Abbreviations: NAT – no adjuvant therapy; VBT = vaginal brachytherapy
Data in parentheses are percentages
*Several patients had multiple sites of recurrence
Vaginal Brachytherapy Techniques
Aims
• To update the current practice patterns for
the treatment of postoperative endometrial
cancer from the ABS survey sent in 2003 and
published in 2005 (Small et al, IJROBP 2005).
• To present the practice patterns of vaginal
brachytherapy (VBT) regarding patient
selection, treatment planning, treatment
delivery, and quality assurance.
Results
Patient Evaluation
• Lymph Nodes
• 90% make treatment recommendations based
on whether or not a lymph node dissection
was performed
• 70% use number of nodes removed to
influence treatment decisions
Number of nodes removed
100%
50%
0%
40.7%
41.8%
9.3%
8.2%
0-5
6-10
11-20
20 or
more
Results
Treatment Planning
•26% place radio-opaque (i.e. gold) markers at the
vaginal apex
•53% report doses at both the surface and 0.5cm
•80% document dose to normal tissues
•Most common dose rate
•96% HDR
•3% LDR
•1% Both
•0% PDR
Results
HDR Brachytherapy
•83% use single channel and 14% use a multichannel cylinder
•83% perform CT planning
•26% for each fraction
•74% for first fraction only
•Most common dose prescription location
•Vaginal surface – 23%
•0.5cm depth – 60%
•Other – 17%
Results
Most Common Prescription of Dose
• 60% treat to a fixed length
3%
Fixed Length
Proximal 3cm
23%
26%
Proximal 4cm
Proximal 5cm
49%
•
37% treat to a fractional length
of the vagina
9%
1%
Other
Fractional Length
Proximal 1/3
26%
Proximal 1/2
Entire Vagina
63%
Other
Results
Treating the entire length of the vagina
• 26% treat for CCC/UPSC histology
• 11% for grade 3
• 13% for LVSI
• 65% never
Results
Dose prescription at the surface of the vagina
13% 8%
VBT Alone
4.0 Gy x 6 fx
7%
10%
VBT Boost
4.0 Gy x 4 fx
6.0 Gy x 5 fx
10%
7.5 Gy x 5 fx
12%
19%
31%
6.0 Gy x 3 fx
10.5 Gy x 3 fx
57%
Other
6.0 Gy x 2 fx
5.0 Gy x 3 fx
34%
Other
Results
Dose prescription at 0.5cm depth of the vagina
VBT Alone
21%
VBT Boost
7.0 Gy x 3 fx
5.5 Gy x 4 fx
12%
67%
15%
38%
5.5 Gy x 3 fx
4.0 Gy x 3 fx
19%
5.0/5.5/6.0 Gy x 2 fx
Other
13%
5.0 Gy x 3 fx
15%
Other
Results
Treatment Planning & Delivery
•Fractions per week
•1 – 34%
•2 – 52%
•3 – 13%
•4 or 5 – 2%
•73% place optimization points at the vaginal apex
AND lateral to the cylinder
•99% perform secondary QA checks
Highlights - Similarities
2003
2014
Placement of
Radio-opaque Markers
21%
26%
Use of
Single/Multi
Channel Cylinder
90%/10%
(check all applicable)
83%/14%
(check one)
Use of 7Gy x 3 fx at
0.5cm depth
w/o EBRT
42%
(most common)
41%
(most common)
Document dose to
OAR
78% bladder
80% rectum
80%
Highlights - Differences
2003
2014
Response Rate
31.6%
7.3%
# of Nodes Removed
0-5 / 6-20 / 20+
37% / 58% / 5%
8% / 82% / 10%
Use of HDR
69%
97%
Use of 5Gy x 3 fx at
0.5cm depth
w/ EBRT
43%
(most common)
27%
(most common)
Treat entire
vaginal length
4%
0.3%
Conclusions
•Electronic surveys are possible though response rate is lower than
the original study
•In a population of ABS/ASTRO members
•HDR Brachytherapy is the most common delivery modality
•Responders are seeing increased nodal dissections
•Fractionation schedules continue to be highly variable
•Almost all are doing secondary QA checks
•Treatment devices and planning techniques are variable but
they generally align with the ABS recommendations
American Brachytherapy Society consensus
guidelines for adjuvant vaginal cuff
brachytherapy after hysterectomy.
William Small, Jr., M.D.,1*, Sushil Beriwal, M.D., 2 D. Jeffrey Demanes,
M.D.,3 Kathryn E. Dusenbery, M.D., 4 Patricia Eifel, M.D.,5 Beth Erickson,
M.D., 6 Ellen Jones, M.D., 7 Jason J. Rownd, M.D.,8 Jennifer F. De Los Santos,
M.D., 9Akila N. Viswanathan, M.D.,10 and David Gaffney, M.D.11
Brachytherapy 11(2012) 58-47.
Pretherapy Evaluation
Pay particular attention to healing – especially
on the current proliferation of robotic surgery.
Choose the applicator that is correct for the
clinical situation.
Cylinders most common which range in size
from 2 – 4 cm.
Brachytherapy Technique
Placement of a radio-opaque seed or clip(s) at
the vaginal apex should be considered.
Place the largest cylinder that fits comfortably.
Minimize movement from placement, planning
and treatment.
Dose Fractionation
7 Gy X 3 to 0.5 cm is the most commonly
prescribed fractionation scheme.
Many sites use different fractionation schemes.
I use 5.5 Gy X 4 to 0.5 cm.
Prescription
Diameter Size
(cm)
Vaginal Surface
@ 5 mm
2
100%
60%
3
100%
68%
4
100%
71%
External Beam Techniques
Dosimetric Studies
IMRT versus conventional Pelvic RT
Small Bowel
Bladder
Rectum
Decreases the volume receiving the prescription dose by
Roeske
50%
23%
23%
Heron
51%
31%
66%
Chen
70%
NS
NS
Ahamad
40 – 63%
NS
NS
Wong
95%
NS
NS
Clinical outcome studies
Adjuvant IMRT in Endometrial Cancer
Number Follow
up
DF
S
Pelvic Chronic
Contro Toxicity
l
31
24m
84
%
100%
No ≥ Grade 2
Beriwal 47
20m
100%
2.1% at 3
years
≥ Grade 2
Knab
Knab et al, Int J Radiat Oncol Biol Phys 2004 ; 60:303
Beriwal et al, Int J Radiat Oncol Biol Phys 2006 ; 66:S41
A RANDOMIZED PHASE III STUDY (NRG Oncology’s RTOG 1203) OF STANDARD VS. IMRT
PELVIC RADIATION FOR POST-OPERATIVE TREATMENT OF ENDOMETRIAL AND CERVICAL
CANCER (TIME-C)
Ann H. Klopp MD, PhD
MD Anderson Cancer Center
Ann Klopp, Anamaria Yeung, Snehal Deshmukh, Karen M Gil, Lari Wenzel, Shannon Westin,
Kent Gifford, David Gaffney, William Small, Jr., Spencer Thompson, Desiree Doncals,
Guilherme Cantuaria, Brian Yaremko, Amy Chang, Vijayananda Kundapur, Dasarahally
Mohan, Michael Haas, Yong Bae Kim, Catherine Ferguson,
Deborah W.Bruner
IMRT for post-operative pelvic RT
Concave target allows IMRT to reduce dose to small bowel in center of
pelvis.
Retrospective studies show lower rates of acute and chronic GI toxicity.
RTOG 0418 found IMRT to be feasible with a favorable rate of acute 2+ GI
toxicity (25%)
Objectives
Determine if acute GI toxicity is reduced with IMRT in week 5 of RT
Primary endpoint:
Determine
if acute
GI toxicity
using
patient reported
measure
of toxicityis reduced with
IMRT in week 5 on RT using patient reported measure of toxicity.
Secondary endpoints
• Acute urinary toxicity with EPIC tool
• Acute GI toxicity with PRO-CTCAE
• Quality of life (FACT)
• LRC, DFS, OS
• Health utilities analysis
Time points for evaluation
Time Point
Purpose
Before RT
Baseline
3 weeks after RT
start
Compare early acute
toxicity
End of RT (5 weeks
after RT start)
Maximum difference
in acute toxicity
4-5 weeks after RT
Compare resolution
of acute toxicity
1 year from start of
RT
Early chronic toxicity
3 years from the
start of RT
Long term toxicity
Schema
Eligibility
IMRT pelvic
radiation treatment
Women with endometrial or cervical
cancer requiring post-op pelvic RT or
chemoRT
XRT Dose: 45 Gy, 50.4 Gy
Chemo: No chemo, 5 cycles of weekly
cisplatin at 40mg/m2
Disease Site: Endometrial, Cervix
RANDOMIZE
Stratification Factors
4-field pelvic
radiation treatment
Sample size
• Primary endpoint: change in acute GI toxicity
– EPIC bowel domain
– baseline to 5 weeks after the first fraction of radiation is delivered
• No prior data → effect size of 0.4
• Two-sample t-test, one interim look and an overall 2-sided α = 0.05
– alpha = 0.049 for final analysis
• 85% power
• 225 evaluable patients
• 20% inflation due to attrition, non-compliance, ineligibility → 281
patients
IMRT Planning
Contouring per RTOG atlas
- Nodal CTV
- Vaginal ITV using full and empty bladder CT sim scans
- 7mm PTV expansion
- OARs: Bone marrow, bowel space, bladder, rectum
Rapid review of contours and plans required on the first case on each arm
for a site.
All cases not rapidly reviewed were QA’d after treatment.
Patient Characteristics
IMRT
(n=129)
4 Field
(n=149)
Age
Median
(yrs)
62
62
Race
Black
12 (10%)
12 (8%)
White
96 (74%)
114
(77%)
0
101
(78%)
103
(69%)
Zubrod
1
Radiation
Dose
45 Gy
50.4 Gy
27 (21%) 42 (28%)
76 (59%)
84%
(56%)
53 (41%) 65 (44%)
EPIC Bowel Questions
Bowel Function:
How often have you had…
- rectal urgency?
- uncontrolled leakage of stool?
- stools that were loose?
- bloody stools?
- your bowel movements been painful?
How many bowel movements have you had on a typical day?
How often have you had crampy pain in your abdomen or pelvis?
Bowel Bother:
How big
of a problem…
- has each of these issues been for you?
- have your bowel habits been for you?
EPIC Bowel Answers – Patient Reported
Bowel
Summary
Bowel
Function
Bowel
Bother
IMRT
(n=107)
4 Field
(n=126)
p-value
Mean
Std. Dev.
Median
-18.6
18.7
-17.9
-23.6
19.4
-22.3
0.0476
Mean
Std. Dev.
Median
-14.8
19.0
-14.3
-21.0
19.3
-17.9
Mean
-22.3
-26.1
Std. Dev.
22.0
22.2
Median
-21.4
-21.4
0.02
0.19
EPIC Bowel Score
90
p-value = 0.0476
IMRT
70
4-field
50
Baseline
IMRT
4 Field
128
148
Week 3 of RT
113
132
Week 5 of RT
111
130
4-6 weeks post-RT
102
125
Pro-CTCAE Questions
Bowel Function:
In the
last 7 days, how
often…
- Did you have loose or watery stools(diarrhea)?
- Did you lose control of bowel movements?
- Have you taken an anti-diarrhea medication?
Bowel Bother:
In the
last 7 days…
- What was the severity of your pain in the abdomen (belly
area) at its worst?
- How much did pain in the abdomen (belly area) interfere
with your usual or daily activities?
- How much did loss of control of bowel movements
interfere with your usual or daily activities?
Acute GI Toxicity – Patient Reported
Symptomatic Adverse
Event PRO-CTCAE Score
≥3 at 5 weeks
Abdominal
Pain
Diarrhea
Severity
IMRT
(n=92)
4 Field
(n=108)
p-value
11 (11.9%) 22 (20.4%)
0.11
Interference 10 (10.9%) 17 (15.7%)
0.32
Frequency
0.01
Frequency
Fecal
Incontinenc
e
Interference
31 (33.7%) 56 (51.9%)
1 (1.1%)
10 (9.3%)
0.01
4 (4.4%)
14 (12.9%)
0.04
Use of Anti-Diarrheal medications
Symptomatic Adverse
Event PRO-CTCAE at 5
weeks
IMRT
(n=90)
4 Field
(n=108)
0-1 times daily
59 (65.6%) 59 (54.6%)
2-3 times daily
24 (26.7%) 27 (25.0%)
4+ times daily
7 (7.8%)
22 (20.4%)
pvalue
0.04
Acute Urinary Toxicity – Patient Reported
Change in EPIC Urinary
Score from Baseline to 5
Weeks
IMRT
(n=107)
4 Field
(n=126)
pvalue
Mean
-5.6
-10.4
0.03
Std. Dev.
15.3
17.5
Median
-2.1
-4.5
Urinary Summary
Min - Max
-57.0 - 27.8 -83.3 - 36.1
QOL: Trial Outcome Index (TOI)
4 Field
(n=125)
(n=106)
pvalue
Trial Outcome Index
IMRT
(n=110)
(n=86)
Mean
Std. Dev.
-8.8
14.4
-12.8
14.3
0.06
Physical Well-Being
Mean
Std. Dev.
(n=86)
-4.2
6.0
(n=106)
-6.1
6.1
0.03
Add’l Concerns/Cervix
Mean
Std. Dev.
(n=87)
-2.7
6.1
(n=104)
-4.9
6.5
0.01
Change in FACT-Cx
TOI: Functional, Physical and adnl concerns
Conclusions
Pelvic IMRT reduces acute patient reported GI and GU toxicity
compared to standard pelvic RT.
Pelvic IMRT reduces need for anti-diarrheal medications as
compared to standard pelvic RT.
Pelvic IMRT improves quality of life metrics during treatment as
compared to standard pelvic RT.
Longer term follow up will determine if these differences in acute
toxicity result in lower rates of late toxicity.
Atlas Update In Progress
• Utilize patterns of recurrence data from RTOG
0418.
• Better define obturator nodal region.
• Eliminate all reference to boney landmarks.
• Give recommendations regarding rectal
distention.
• Included recommendations for common iliacs
and para-aortic CTV.
RTOG 0418 – Endometrial Arm
RTOG 0418 – Endometrial Arm
RTOG 0418 – Endometrial Arm
RTOG 0418 – Endometrial Arm
RTOG 0418 – Endometrial Arm
RTOG 0418 – Endometrial Arm
CASE STUDY
The patient was treated with pelvic IMRT on
RTOG 0418 with concurrent weekly cisplatin.
An ITV was accomplished to determine the CTV.
The consensus contouring guidelines were
utilized to draw the CTV.
Full and Empty Bladder
Full and Empty Bladder
Full and Empty Bladder
Post-Treatment Complications
PORTEC 1 : Long Term QOL
SF-36 Scores
EBRT
NAT
Remain close to the
toilet related to urinary
control
26
10
Urinary Incontinence
30
16
Limitations of daily
activity related to bowel
symptoms
26
15
Nout et al; JCO, 2011
PORTEC 1: EBRT Technique
52% Four Field (5-year comp rate 21%)
18 % Three Field (5-year comp rate 36%)
30 % AP/PA (5-year comp rate 30%)
5 Yr actuarial rate of toxicity 26 % vs. 4 %
Grade 3 or 4: 3 % vs 0 % - 67 % of complications
Grade 1, Grade 2: 7 % vs 1%.
P=0.06 for technique and complication rate.
Creutzberg, In J Rad Oncol Biol Phys, 2001
Vaginal Length after Intracavitary
Radiotherapy
Looked at 90 patients with intracavitary RT
after treatment for cervical or endometrial
CA (48).
Measurements were taken at 6 and 12
months and then yearly.
The vaginal dilator compliance rate was 68
% of using 1 o more times per week.
Bruner et al,
Second Primaries
Treatment delivered
Observed/Expected
No Radiation
0.92
Brachytherapy Alone
0.97
EBRT Alone
1.1
EBRT and Brachy
1.22
Any Radiation
1.09
Brown et al., Int J Radiol Biol
Phys, 2010.
Colon Cancer
Source: International Journal of Radiation Oncology * Biology * Physics 2010; 78:127-135 (DOI:10.1016/j.ijrobp.2009.07.1692 )
Copyright © 2010 Elsevier Inc. Terms and Conditions
Vaginal Cancer
Source: International Journal of Radiation Oncology * Biology * Physics 2010; 78:127-135 (DOI:10.1016/j.ijrobp.2009.07.1692 )
Copyright © 2010 Elsevier Inc. Terms and Conditions
Cumulative Risk of Bladder Cancer
Bladder Cancer Risk
PORTEC 1
At a median follow-up of 13.3 years 19% of the
patients had a second primary.
22% in the EBRT group,
16% in the no additional treatment group
P=0.10
Can Chemotherapy Replace
Pelvic Radiotherapy?
A randomized phase III trial of pelvic radiation therapy
(PXRT) versus vaginal cuff brachytherapy followed by
paclitaxel/carboplatin
chemotherapy
(VCB/C)
in
patients with high risk (HR), early stage endometrial
cancer (EC): a Gynecologic Oncology Group trial.
McMeekin DS, Filiaci VL, Aghajanian C, et al. Proceedings of the 45th
Annual Meeting on Women's Cancer, Society of Gynecologic
Oncology; 2014, March 22; Tampa, FL.
GOG 249
Primary objective: To determine if treatment with VCB/C
reduces the rate of recurrence or death (RFS) when
compared to PXRT
Secondary objectives: Compare OS, patterns of failure,
toxicity/functioning between arms
– All patients underwent hysterectomy +/- staging
CT/MRI required if no LND
– Endometrioid histology- risk criteria
> 70 + 1, age >50 +2, age > 18 + 3
Factors: LVSI, Gr 2-3, outer ½ invasion
– Serous/Clear cell- stage I-II
– Stage II any histology
GOG 249
Therapy initiated within 12 weeks after surgery
Arm I- Pelvic Radiation (PXRT)
– 180cGy/day X 25-28 fractions 4500-5040 in 5-6 weeks
– Standard or IMRT permitted
– VCB allowed for stage II or Stage I S/CC
Arm II- Vaginal Cuff Brachytherapy + Chemotherapy
(VCB/C)
–
–
–
–
LDR or HDR
HDR 6-7 Gy X 3 or 10-10.5 X 3 or 6 Gy X 5
Chemotherapy to start within three weeks of VCB
Carboplatin AUC 6 + Paclitaxel 175mg/m2 every 21 days X 3
Statistical Design
1:1 Randomization
Stratification:
– Lymphadenectomy
– Intent to use VCB in Arm I
Assumptions:
– 85% of patients treated with PXRT alive, recurrence –
free at three years
– Relative decrease in recurrence/death hazard of 49%
increases three year RFS to 92% important
– Required 77 failures (90% power, type 1 error= 0.05
(one tailed) sample size 562 patients
Outcome: Recurrence-Free Survival
– Median follow-up 24 months
– 87 events
– HR 0.97 (VCB/C relative to
PXRT)
– (CI 0.635-1.47, p=0.44)
– Effect size of 0.51 (i.e. 49%
decrease in hazard) not
contained within these CI
RFS at 24 months: 82% PXRT vs. 84% VCB/C
OS at 24 months: 93% PXRT vs. 92% VCB/C
Permission to reuse given by Dr. Scott McMeekin
GOG0249
A Randomized Phase III Trial of Pelvic Radiation Therapy
versus Vaginal Cuff Brachytherapy followed by
Paclitaxel/Carboplatin Chemotherapy in Patients with HighRisk, Early Stage Endometrial Cancer
Pelvic radiation
Vaginal cuff
brachytherapy followed
by Paclitaxel/Carboplatin
Chemotherapy
Progression-free
Survival
82%
84%
Overall Survival
93%
92%
87 events
Median follow-up 24 months
Hazard ratio 0.97
Patterns of Failure
Site of Recurrence
PXRT (N=301)
VCB/C (N=300)
Vaginal
5 (1.6%)
3 (1%)
Pelvic
2 (0.6%)
19 (6.3%)
Para-aortic
2 (0.6%)
3 (1%)
Distant
32 (10.6%)
24 (8%)
Subgroup Analysis
There is no statistically
significant evidence of
heterogeneity of the
treatment effect with respect
to recurrence-free survival
among the variables tested
above and displayed in the
forest plot.
Permission to reuse given by Dr. Scott McMeekin
Toxicity
AE
Constitutional
Fatigue
Weight Loss
Gr 2
PXRT VCB/C
Gr 3
PXRT VCB/C
Gr 4
PXRT VCB/C
25
0
60
2
1
0
9
0
0
0
1
0
7
3
33/1
3
17
8
16/21
6
0
0
8/0
0
4
4
5/1
3
0
0
0/0
0
0
0
0/0
0
ANC
Hb
PLT
8
3
0
46
62
11
0
0
0
73
5
4
0
0
0
94
2
5
Febrile Neutropenia
0
0
0
6
0
1
2
20
0
5
0
0
GI
Nausea
Vomiting
Diarrhea/Constipation
Dehydration
Heme
Neurologic
Sensory
Locally Advanced Disease
In general, most reports have used “involved field”
radiotherapy for patients with Stage III disease.
Whole Abdominal Radiotherapy
GOG 122 noted a significant worse outcome in
advanced patients with WAR (38% 5-year survival)
as compared to chemotherapy.
GOG 122 delivered 30 Gy to the whole abdomen
and 15 Gy to the pelvis – 25 % of patients with
stage IV.
Our series of WAR patients noted a 86 % 5-year
survival, Smith et al noted a 77 % 3-year survival.
Pelvic Recurrence Advanced
Disease
Author
Stage
Radiothera
py
Chemothera
py
Observatio
n
Patel et al,
2007
III
13%
-
33% - 77 %
non Vag
Vault
Mundt et al,
2001
I-IV
-
39.5 % –
53% non Vag
Small et al,
2000
I-IV
10 %
-
Randall et
al, 2008
III-IV
13% (Initial)
18% (Initial)
Hoekstra et
al,
2009
IIIC
0%
-
EBRT and outcome
Pelvic relapse
Disease-specific survival
Overall survival
Klopp et al Gyn Oncology 2009
SEER DATA
Schmid et al (Gyn Onc, 2009) reviewed the
SEER data base from 1988 – 2001
5-year disease specific survival (DSS) with RT
67.9% vs 53.4% without RT (p<0.001).
Single lymph node DSS 74.3 vs. 54.4 %
(p<0.001), 2-5 lymph nodes DSS 59.7 vs. 52.7
% (p=0.089).
SEER DATA
Endometroid 73.7 vs 61.9% (p=0.007)
Clear Cell 77.1 vs. 39.2% (p=0.046)
Papillary Serous 44 vs. 45.5 % (p=0.48)
Sarcoma 44.9 vs 46.3 % (p=0.51)
The data remained significant on multivariate analysis
Pelvic Lymphadenopathy
ASTEC Survival and sites of
recurrence
Cause
Of Death
No
LN
LN’s
removed
Total
88
13%
103
15%
Disease
65%
63%
Treatment
related
5%
7%
Disease &
Treatment
0
2%
Not Disease
30%
28%
What About Chemotherapy?
Is it the next step to improving
overall survival?
GOG 122 Schema
GOG 122
Dox/CDDP
WART
p=.01
Adjuvant chemotherapy versus radiotherapy
in high-risk endometrial carcinoma: result of
a randomised trial
Stage IC G3
STAGE II G3
>50% MI
Stage III
Regimen 1:
Pelvic RT (45-50 gy)
Regimen 2:
CDDP, Adriamycin, Cytoxan
5 cycles
R Maggi et al, BJC,2006;95:266
Adjuvant chemotherapy versus radiotherapy
in high-risk endometrial carcinoma: result of
a randomised trial
Median follow up 95.5 months
No difference in 5 Year DFS or OS
RT
locoregional initial recurrence: 7 %,
Distant: 21 %,
Both:5
Chemotherapy
locoregional initial recurrence: 11%,
Distant: 16 %,
Both:5 %
RT reduced local recurrence, chemotherapy reduced
distant failure
R Maggi et al, BJC,2006;95:266
Chemotherapy
Such results suggest that a more
prudent approach would be to combine
chemotherapy and RT
Published trials, however, have reported
mixed results
GOG 34
Chemotherapy did not improve outcome
3 Years Survival
Extra-Pelvic
Failure
RT Alone
75%
22.5%
RT + Adriamycin
68%
16.3%
P = NS
P = NS
Moreover, 12 (7%) of these surgically staged
patients developed a SBO after pelvic +/- PART
Maybe adriamycin alone is not enough
To test a more aggressive regimen, the
RTOG launched RTOG 9708
Stage I – III
TAH – BSO
+/- Nodal Surgery
Grade 2-3 > ½ MI
+ cervical stroma
Extra-uterine
(Pelvic only)
disease +
washings
Pelvic RT 45
Gy +VB
CDDP
50 mg/m2
Days 1,28
Four cycles
Chemo
CDDP
50 mg/m2
+
Paclitaxel
175 mg/m2
Kathryn Greven et al., Gynecol Oncol 2006;103:155
Concurrent and adjuvant chemotherapy
Phase II trial RTOG (46 pts):
stage I-II high risk or stage III (66%)
 Concurrent: cisplatin 50 mg/m2 days 1, 28
 Adjuvant: 4x cisplatin 50 mg/m2 and paclitaxel 175 mg/m2
4-yr locoregional relapse 4%, distant 19%
4-yr DFS 81%, OS 85% (stage III: 77 and 72%)
No recurrences in stage IC, IIA, IIB
 promising data, phase III needed – attempted in
RTOG 9901 – closed for lack of accrual. Only highrisk early stage in that trial related to competing
Phase III GOG randomized trial for Stage III
patients,
Greven et al, Gynecol Oncol 2006
NSGO EC-9501/EORTC-55991
May 1996 to January 2007
Randomization
n=382
RT
≥ 44 Gy XRT ±
n=196
optional VBT (39%)
Radical surgery
TAH+BSO (+PLA)
RT+CT
Surgical stage I, II,
IIIA (positive peritoneal fluid
cytology only), or IIIC (positive
pelvic lymph nodes only) with high
risk for micro-metastatic disease
Patients with serous, clear cell, or anaplastic
carcinomas were eligible regardless of other risk
factors
OR
(VBT 44%)
n=186
CT+RT
CT : intially AP
Later AP, TcP, TAP, TEcP
Primary endpoint
Progression-free survival (PFS)
Thomas Hogberg, Lund Univ Hosp Oct 2009
NSGO EC-9501/EORTC-55991
PFS progression-free survival (PFS)
1.00
PFS NSGO-EC-9501/EORTC-5591
0.79
0.75
Chemo/RT
0.50
RT alone
0.72
0.00
0.25
HR 0.63 (95 % CI 0.41 - 0.98) p = 0.04
0
1
2
3
4
5
123
143
110
119
84
82
years
Number at risk
random = 0 191
random = 1 186
170
175
149
158
random = 0
random = 1
Thomas Hogberg, Lund Univ Hosp Oct 2009
NSGO EC-9501/EORTC-55991
PFS progression-freee survival (PFS) serous/clear cell ca
1.00
PFS serous/cc carcinoma NSGO-EC-9501/EORTC-55991
0.75
0.73
0.50
0.71
0.00
0.25
HR 0.81 (95 % CI 0.41 - 1.61) p=0.55
0
1
2
3
analysis time
4
5
Number at risk
random = 0 76
random = 1 65
70
62
59
55
43
43
35
27
random = 0
47
48
random = 1
Thomas Hogberg, Lund Univ Hosp Oct 2009
Combined Modality Trials
Several new combined modality trials are underway or in the
planning stages
PORTEC-3 comparing pelvic RT versus pelvic RT +
chemotherapy in high risk pts
GOG 258 compares chemotherapy alone versus
chemotherapy plus volume directed RT in advanced stage
patients.
GOG 258:Phase III Randomized Study of Adjuvant
Chemoradiotherapy Comprising Cisplatin and Tumor
Volume-Directed Radiotherapy Followed by
Carboplatin and Paclitaxel Versus Carboplatin and
Paclitaxel Alone in Patients With Stage III or IVA
Endometrial Carcinoma
Objective:Compare the recurrence-free survival of
patients with stage III or IVA endometrial carcinoma
treated with adjuvant chemoradiotherapy
comprising cisplatin and tumor volume-directed
radiotherapy followed by carboplatin and paclitaxel
vs carboplatin and paclitaxel alone.
GOG 258 Submitted to ASCO 2017 as
a late breaking abstract!
PORTEC-3
pelvic radiotherapy (48.6 Gy)
R
RT plus concurrent and
adjuvant chemotherapy
Concurrent: 2 courses cisplatin 50 mg/m2
Adjuvant: 4 courses of carboplatin AUC 5 and
paclitaxel 175 mg/m2
Brachytherapy boost if cervical invasion
a.
c.
e.
Stage IB grade 3 with documented lymph-vascular space invasion
(LVSI); b. Stage IC or IIA grade 3;
Stage IIB; d. Stage IIIA* or IIIC *IIIA based on peritoneal cytology
alone is only eligible if grade 3;
Stage IB, IC, II or III with serous or clear cell histology
Medically Inoperable Endometrial
Cancer
Schwartz, J., Beriwal, S., Esthappan, J, Erickson, B., Feltmate, C.,
Fyles, A., Gaffney, D., Jones, E., Klopp, A., Small, Jr., W.,
Thomadsen, B., Yashar, C., Viswanathan, A., Consensus
statement for brachytherapy for the treatment of medically
inoperable entometrial cancer, Brachytherapy, Sept-Oct 2015;
14(5): 587-599.
Conclusions
RT continues to play an important role in endometrial
cancer
Its optimal role is still evolving
Attention turning to combined modality approaches in
high risk patients following surgery