endometrial cancer - astro · when utilizing imrt in the post-operative treatment of endometrial...
TRANSCRIPT
Endometrial Cancer
William Small Jr., MD Professor of Radiation Oncology
The Robert H. Lurie Comprehensive Cancer Center of Northwestern University
Learning Objectives:
•Discuss the role of radiation therapy in early stage and advanced stage endometrial cancer. •Review controversies in Radiation Techniques. Explain the role of surgery and surgical staging in the management of endometrial cancer. •Review the role of chemotherapy in the management of early and advanced stage endometrial cancer.
When utilizing IMRT in the post-operative treatment of endometrial cancer the MOST
important aspect of treatment is? 1. Daily image guidance. 2. Asking the patient to have a full bladder on a
daily basis. 3. Assuring that bone and bowel are excluded
from the CTV. 4. Carful attention to an ITV.
Who will win the Super Bowl this Year ?
1. The Chicago Bears. 2. The NFL team from Chicago. 3. I don’t care as long as the Packers are not in
the Super Bowl.
Endometrial Cancer
Incidence Deaths
All 848,170 301,820
Prostate 241,740 28,170
Lung 116,470 87,750
Colon/Rectum 73,420 26,470
Bladder 55,600 10,510
Incidence Deaths
All 790,740 275,370
Breast 226,870 39,510
Lung 109,690 75,590
Colon/Rectum 70,040 25,220
Uterine 47,130 8,010
American Cancer Society, Surveillance Research, 2012
Estimated New Cancer Cases and Deaths by Sex, 2012
Men Women
“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
All Patients Receive Adjuvant RT
Even Low Grade Minimally Invasive
Tumors
Center A
No Patients Receive adjuvant RT
Even High Grade Deeply Invasive
Tumors
Center B
Very contentious Disease
In intermediate risk endometrial cancer, the risk of recurrence with and without pelvic RT is approximately?
1. 3% vs. 12 %. 2. 3% vs. 20% 3. 1% vs. 5% 4. 10% vs. 30%.
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
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% P<0.0001 11% P<0.0001
MI None 1% 1% Superficial 5% 3%
Middle 6% 1% Deep 25% P<0.0001 17% P<0.0001
More useful to combine grade & MI
Positive Pelvic LNs
Invasion G1 G2 G3
None 0% 3% 0%
Inner 3% 5% 9%
Middle 0% 9% 4%
Deep 11% 19% 34%
Invasion G1 G2 G3
None 0% 3% 0%
Inner 1% 4% 4%
Middle 5% 0% 0%
Deep 6% 14% 23%
Positive PA LNs
Creasman WT et al, Cancer 1987;60:2035
Cervical involvement and also CSI are correlated with Positive LNs
Positive Pelvic LNs
Positive PA LNs
Site Fundus 8% 4%
Isthmus - cervix
16% P = 0.01 14% P= 0.0001
Capillary Space involvement
Negative 7% 4%
Positive 27% P=0.0001 19% P= 0.0001
Rationale also provided by the correlation between adverse pathologic factors and vaginal
failure
• Price 1965 41 clinical stage I patients undergoing surgery alone Unfortunately Grade and Myometrial invasion not combined in the analysis Price et al. Am J Obstet Gynecol 1965; 91:1060
Vaginal Recurrence All Patients 14%
Grade 1 4.4 2 5.7 3 13.6
MI None 3.7 < half 4.7
> half 15.1
What evidence supports the use of Adjuvant Radiation Therapy is
Stage I & II Endometrial Carcinoma ?
Retrospective studies also suggest benefit of Adjuvant RT in patients with adverse
pathologic factors
Carey et al, Gynecol Oncol 1995; 57:138 Piston et al, Int J Radiation Oncol Bio Phys 2002; 53:862
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%
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
Elliot at al., Int J Gyne cancer 1994; 4 : 84
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%
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 Pelvic RT 40 Gy Midline block
after 20 Gy
Arm 2 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 No RT With RT
Grade 1 – 2 Tumors
< ½ MI 4% 2.3% > ½ MI 9.8% 9.4%
Grade 3 Tumors
< ½ MI 5.6% 2.1% > ½ MI 19.6% 4.5 %
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 – Recent Publication
• 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
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
Locoregional recurrence (actuarial rates)
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)
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
Prognostic factors: › advanced age › high grade (2 or 3) › outer 33% myometrial invasion › lymph-vascular space invasion (LVI)
Keys, Gynecol Oncol 2004
GOG-99: recurrence
Relative hazard RT: 0.42 (58% hazard reduction)
HIR: 33% of patients, 67% of recurrences
HIR, NAT: 27%
HIE, RT: 13%
Keys, Gynecol Oncol 2004
GOG 99: Survival
Relative hazard for RT: 0.86 (ns); HIR: 0.73
HIR, no RT: 74% HIR, RT: 88% LIR: 92 - 94%
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.
98% No EBRT 2% received EBRT
51% Brachytherapy
453 No EBRT
453 assessed for primary outcome
measure
452 EBRT
92% received EBRT 8% No EBRT
52% Brachytherapy
452 assessed for primary outcome
measure
905 Randomized
Trial Profile
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
EBRT +/-brachytherapy Brachytherapy alone None Missing
416 (92%) 10 (3%)
24 (5%)
2
Median: Total Dose (Gy) Fractions Duration in days
45 25 34
Treatment compliance (% of patients who received total dose of 40-46 Gy in 20-25 fractions)
82%
020
4060
80P
erce
ntag
e (%
)
5 10 15 20 25 30 35 40 45 50 55 60 65 70Total dose (Grays)
Distribution of EBRT dose used
Acute and Late Toxicity No EBRT
N=453 EBRT N=452
Acute toxicity (post surgery and radiotherapy) Worst score Mild Moderate Severe/Life threatening Late Toxicity Severe/Life threatening
121 (27%)
77 (17%) 38 (8%) 3 (<1%)
3%
258 (57%)
143 (32%) 100 (22%) 14 (3%)
8%
Isolated Vaginal or Pelvic Initial Recurrence (ASCO Presentation)
28 45314 452
Events Totals
PATIENTS at RiskNo EBRTEBRT
453 425 366 282 211 142 81 35452 420 376 281 212 142 78 32
No EBRT EBRT
Cum
ulat
ive
inci
denc
e
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Years from randomisation
0 1 2 3 4 5 6 7
HR=0.53, 95% CI=0.29-0.97, p=0.038
3% difference in 5 year cumulative incidence rate (4% in EBRT to 7% in no EBRT)
Only includes 42/123 total recurrences
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)
Brachytherapy
Yes 23/196 29/190 -3.99 12.98
No 30/181 25/184 3.96 13.69
[no. events/no. entered]EBRT No EBRT O-E Variance Hazard Ratio (Fixed)
EBRT Better No EBRT Better0 1 50.5 2
0.74 (0.43-1.27) p=0.268
1.34 (0.79-2.27) p=0.284
Interaction Test: chi-square=2.37, df=1, p=0.123
Recurrence-Free Survival: by centre brachytherapy policy
(ASCO Presentation)
Meta-analysis: overall survival
Study EBRT No EBRT Peto OR (IPD) Peto OR (IPD) n/N n/N 95% CI
N 95% CI
PORTEC 57/354 48/360 714 1.22 [0.83, 1.79] GOG 30/190 36/202 392 0.86 [0.57, 1.29]
ASTEC + EN5 65/452 66/453 905 1.00 [0.71, 1.41]
Total (95% CI) 152/996 150/1015 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 1 2 5 10
Favours EBRT 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%
What is the most common outcome after a vaginal cuff relapse when no previous radiotherapy has
been delivered? 1. Patients are salvaged without complications 2. Patients are salvaged with complications 3. No patients are salvage
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 HR (95% CI) p valueStage 1A, Grade I 1.000 referenceStage 1B, Grade I 1.13 (0.97-1.31) .13Stage 1C, Grade I 2.06 (1.63-2.61) <.001Stage 1A, Grade II 1.38 (1.14-1.67) <.001Stage 1B, Grade II 1.47 (1.27-1.72) <.001Stage 1C, Grade II 2.04 (1.64-2.54) <.001Stage 1A, Grade III/IV 2.47 (1.97-3.11) <.001Stage 1B, Grade III/IV 2.64 (2.21-3.16) <.001Stage 1C, Grade III/IV 5.09 (4.09-6.32) <.001Race/ethnicity=Black 0.54 (0.46-0.63) <.001Pathologic Node Negative at TAH-BSO 0.90 (0.83-0.98) <.001Age at Diagnosis (per decade, base age 65) 1.79 (1.73-1.86) <.001Radiation + Stage 1A, Grade I 0.85 (0.40-1.80) .67Radiation + Stage 1B, Grade I 0.91 (0.64-1.29) .59Radiation + Stage 1C, Grade I 0.45 (0.32-0.64) <.001Radiation + Stage 1A, Grade II 1.37 (0.82-2.28) .23Radiation + Stage 1B, Grade II 1.00 (0.81-1.24) .97Radiation + Stage 1C, Grade II 0.96 (0.76-1.21) .75Radiation + Stage 1A, Grade III/IV 1.02 (0.66-1.57) .93Radiation + Stage 1B, Grade III/IV 0.98 (0.80-1.19) .82Radiation + Stage 1C, Grade III/IV 0.74 (0.58-0.93) .009
*Baseline reference group= no radiation, stage 1A, grade 1 cohort.
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?
An American Brachytherapy Society Survey Regarding the
Practice Patterns of Post-Operative Irradiation for
Endometrial Cancer William Small Jr., M.D.
Beth Erickson, M.D. Francis Kwakwa, M.A.
Has there been an increasing trend for referrals for vaginal
brachytherapy?
YES 54.2
NO 31.8
NO OPINOIN
12.8
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
R pelvic radiotherapy
vaginal brachytherapy Utrecht
Ijsselmeer
Groningen
DrentheNoordHolland
Gelderland
Limburg
Flevoland
Zuid Holland
Noord Brabant
Zeeland
Overijssel
FrieslandWaddenzee
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”
• HIR endometrial carcinoma
• Vaginal brachytherapy vs no further treatment
• 21 Gy in 3 fractions vs 15 Gy in 3 fractions
PORTEC-4
1
1
R
VBT 3 x 7 Gy at 5 mm
VBT 3 x 5 Gy at 5 mm
No further treatment Close FU; EBRT/VBT for vaginal relapse
2 1
4
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.
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 and tumor characteristics (n = 252)
Characteristic VBT NAT p
Patients (n) 169 83
Follow-up (mo) Median Range
104 1-330
61 0-328
<0001
Age (y) Median Range
61 29-89
60 33-85
.71
Type of surgery TAH/BSO without LN biopsy TAH/BSO with LN biopsy Pelvic LNs removed Median Range Para-aortic LNs removed (n) Median Range
28 (16.6) 141 (83.4) 10 0-36 3 0-19
18 (21.7) 66 (79.5) 8 0-32 2 0-12
.39 .49 .03 .002
Patient and tumor characteristics (n = 252)
Characteristic VBT NAT p Tumor histologic grade 1 2 3
96 (56.8) 64 (37.9) 9 (5.3)
63 (75.9) 17 (20.5) 3 (3.6)
.01
Depth of invasion (cm) Median Range
0.30 0.07-2.40
0.22 0.02-0.90
.0006
Lymphatic or vascular space invasion
19/153 (12.4)
4/72 (5.6)
.16
Interval from surgery to RT (d) Median Range
41 8.257
NA
Patient outcomes data Variable VBT
(n = 169) NAT (n = 83)
p
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
145 (85.8) 18 (10.7) 1 (0.6) 5 (3.0) 8 (4.7) 40 9-102 1 4 1 3 3 3 (37.5) 1 (12.5) 1 (12.5) 3 (37.5)
78 (94.0) 2 (2.4) 1 (1.2) 2 (2.4) 6 (7.2) 19 2-49 3 2 0 1 0 3 (50) 0 (0) 1 (16.7) 2 (33.3)
.07 NS NS
Abbreviations: NAT – no adjuvant therapy; VBT = vaginal brachytherapy Data in parentheses are percentages *Several patients had multiple sites of recurrence
Vaginal Brachytherapy
Techniques
When delivering Vaginal Brachytherapy in a patient with endometroid histology – what is your typical
target?
1. Upper 2 cm of the vaginal. 2. Upper 3 cm of the vaginal 3. Upper one third of the vagina. 4. Upper one half of the vagina. 5. The entire vagina.
When delivering Vaginal Brachytherapy in a patient with endometroid histology – what is your typical
dose?
1. 6 Gy times 5 to the vaginal mucosa. 2. 4 Gy times 6 to the vaginal mucosa. 3. 7 Gy times 3 to 0.5 cm from the vaginal
mucosa. 4. 5.5 Gy times 4 to 0.5 cm from the vaginal
mucosa. 5. Other.
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.
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.
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.
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.
Diameter Size (cm)
Vaginal Surface @ 5 mm
2 100% 60%
3 100% 68%
4 100% 71%
Intensity Modulated Radiation Therapy
• IMRT may decreases the risk of severe sequelae • Dosimetric studies demonstrate significant sparing
of small bowel, bladder and rectum • Preliminary outcome studies have noted low toxicity
rates and excellent Pelvic Control.
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.
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
DFS Pelvic Control
Chronic Toxicity
Knab 31 24m 84% 100% No ≥ Grade 2
Beriwal 47 20m 100% 2.1% at 3 years ≥ Grade 2
Knab et al, Int J Radiat Oncol Biol Phys 2004 ; 60:303 Beriwal et al, Int J Radiat Oncol Biol Phys 2006 ; 66:S41
89
Efficacy and safety of IMRT after surgery in patients with endometrial cancer: RTOG 0418 phase II study
Anuja Jhingran, Kathryn Winter, Lorraine Portelance, Brigitte Miller, Mohammad Salehpour, Rakesh Gaur, Louis Souhami, William Small, and
David Gaffney
Supported by RTOG U10 CA21661, CCOP U10 CA37422, and ATC U24 CA 81647 NCI grants.
90
RTOG 0418
• Objectives: – Primary – to determine the transportability
of pelvic IMRT for patients with endometrial carcinoma to a multi-institutional setting.
– Secondary • To assess adverse events related to this
regimen. • To test the hypothesis that there is a reduction
in short-term bowel injury with this regimen compared to standard treatments.
• To estimate the rates of local-regional control, distant metastasis, disease-free and overall survival.
91
RTOG 0418 – Endometrial Arm Protocol
• Chemotherapy was not allowed in the endometrial arm. • Guidelines for contouring were detailed in protocol as well as
a web-base atlas. • Dose/volume constraints for targets and normal tissue were
outlined. • Patients were simulated with a both empty and full bladder
scan and a vaginal ITV was contoured encompassing contours from both scans. Pts. were treated on full bladder scan.
• Dose to nodal PTV and vaginal PTV (ITV with margin) was 50.4 Gy in 28 fractions.
• Vaginal brachytherapy was allowed at the discretion of the physician.
92
RTOG 0418 – Endometrial Arm Protocol
• Central quality assurance was performed – the first case from each institution was reviewed by one of the two PIs prior to treatment and the second case could be reviewed at the discretion of the PIs.
• Adverse events (AEs) were assessed using the CTCAE v. 3.0.
• Primary endpoint - if <5 of 42 treatments delivered 50.4 Gy to the nodal PTV and to vaginal PTV, then the protocol is considered reproducible.
RTOG 0418 – Endometrial Arm GI Toxicity (n=40)
Grade 0/1 Grade 2+
n % n %
Overall 29 73 11 28
Adverse Event
# days from start
Grade
A Enteritis 38 2
B Diarrhea 37 2
C Diarrhea 41 2
Enteritis 41 2
D Enteritis 40 2
E Enteritis 55 2
F Stricture 139 2
Diarrhea 35 2
Enteritis 35 2
Proctitis 35 2
G Diarrhea 24 3
H Diarrhea 41 2
I Diarrhea 35 2
J Diarrhea 51 2
K Diarrhea 23 3
94
RTOG 0418 Purpose – Secondary Endpoints
• To estimate the rates: – Local-regional recurrence – Distant recurrence – Disease-free survival – Overall survival
• Assess adverse events
95
RTOG 0418 – Endometrial Arm
• Study period – March 2006 – June 2007 • 58 patients enrolled, 43 eligible patients • Median age – 57 (min-max: 36-73) • Median FU – 3.5 years (min-max: 1.0-4.4) • OS and DFS rates estimated using the Kaplan-
Meier method. • Local-regional and distant recurrence rates
estimated with the cumulative incidence method.
96
RTOG 0418 – Endometrial Arm Tumor Stage and Grade
IC, G1-3 IIB
IIA
IIIC
IB, G2-3
97
RTOG 0418 – Endometrial Arm Outcomes
Endpoint
Number of
Failures
Estimated 2-Year Rate
(95% CI)
Estimated 3-Year Rate
(95% CI)
Overall Survival 4 95.2% (82.3, 98.8)
92.4% (78.0, 97.5)
Disease-Free Survival 5 90.6%
(76.8, 96.4) 90.6%
(76.8, 96.4) Local-Regional Failure 3 7.0%
(0, 14.8) 7.0%
(0, 14.8) Para-aortic nodes 2 4.8%
(0, 11.3) 4.8%
(0, 11.3) Distant (excluding para-aortic nodes)
3 7.1%
(0, 14.9) 7.1%
(0, 14.9)
98
RTOG 0418 – Endometrial Arm Cause of Death
Cause of Death n (%)
Treated Cancer 2 (50%) Intracranial hemorrhage 1 (25%)
Unknown 1 (25%) Total 4 (100%)
RTOG 0418 – Endometrial Arm
Conclusions • IMRT in the post-operative setting is feasible across multiple
institutions using a detailed protocol and centralized Q/A and may be used in phase III protocols.
• G2 and higher small bowel toxicity was reduced from 40% in traditional XRT to 28% with IMRT (p = 0.13) – not powered to detect a 12% decrease.
• Contouring of OARs were all within minor deviations except for small bowel which needs a better definition.
• Contouring of nodal and vaginal tissue had some major deviations and will need continued monitoring with good Q/A in a protocol setting.
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
The Practice of Post Operative Pelvic IMRT in Gynecological Malignancies
1) The CTV needs to be as accurate as possible. 2) Internal target motion MUST be accounted for -
simple daily cone beam CT’s are inadequate because the nodal volumes will follow boney landmarks – whereas the vaginal volumes are influenced by bladder and rectal filling.
3) Therefore a ITV is critical unless daily bladder and rectal volume is regulated.
Should IMRT be A Standard Therapy
In the Post-operative
Treatment of Endometrial Cancer
C O - P I S A N N K L O P P M D , P H D
A N A M A R I A Y E U N G M D
P R O A N D Q O L C O - C H A I R L A R I W E N Z E L , P H . D .
K A R E N G I L , P H . D .
C O S T A N A L Y S I S C O - C H A I R A N D R E K O N S K I , M D , M B A , M A , F A C R
S T A T I S T I C I A N
S T E P H A N I E S H O O K
A RANDOMIZED PHASE III STUDY OF STANDARD VS. IMRT PELVIC RADIATION FOR
POST-OPERATIVE TREATMENT OF ENDOMETRIAL AND CERVICAL CANCER
(TIME-C)
TIME-C: Objectives
Primary Objective: oTo determine if acute gastrointestinal toxicity is reduced with IMRT using patient reported measure of toxicity
Secondary Objective:
oTo determine if acute grade 2 gastrointestinal toxicity (CTCAE v. 3.0) is reduced with IMRT compared to conventional WPRT.
oTo determine if acute grade 3+ hematologic toxicity (CTCAE v. 3.0) is reduced with IMRT compared to conventional WPRT.
oTo determine if acute urinary toxicity is reduced with IMRT using a patient reported measure of toxicity.
oTo assess the impact of pelvic IMRT on quality of life using patient reported outcomes.
P
P
P P
Eligibility Women with
endometrial or cervical cancer requiring post-operative pelvic
radiation or chemoradiation
RANDOMIZE
IMRT pelvic radiation treatment
4-field pelvic radiation treatment
P
Stratification factors
XRT dose • 45 Gy
• 50.4 Gy Chemotherapy
• No Chemotherapy • 5 cycles of weekly
cisplatin at 40mg/m2
Disease Site •Endometrial
•Cervix
Schema
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
William Small Jr., MD Professor
The Robert H. Lurie Comprehensive Cancer Center of
Northwestern University
Vaginal Length after Vaginal Brachytherapy for
Endometrial Cancer
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, Int J Radiol Bilo Phys, 1993
Objective
Feasibility study to assess changes in vaginal length from pre- to post- vaginal brachytherapy for endometrial cancer in women prescribed vaginal dilators.
Methods Patients randomized to standard vs enhanced education: Standard: • Given smooth plastic vaginal dilator • Dilatation began 2-4 wks post
completion of VBT • Written instructions on dilator use
Encouraged to engage in sexual intercourse with vaginal penetration as per institution standard
• Attention control telephone calls at weeks 1, 4, 12, and 18
Enhanced: • Standard + intensive, theory driven education and counseling
Endpoint – Change in Vaginal Length Metric – Vaginal Sound
Modified plastic vaginal dilator Calibrated in centimeters 15 cms long X 2.85 cms in diameter Inter-rater reliability tested by GOG during two training sessions
with live models - 88 MDs and RNs from over 45 institutions attended a 1/2 hr didactic session followed by a 1- hr clinical practicum - Measurements taken by instructor and student at each insertion
Inter-rater reliability was high with intraclass correlation coefficients of 0.88 among instructors and 0.76 among trainees
For purposes of this study – each individual physician underwent a training session with the study PI and a the investigators ability to reliably measure was confirmed on a patient.
Bruner et al Int J Gynecol Cancer.;16(5):1749-55, 2006
Results Preliminary findings of the first 23/50 women with VL data pre and 6 mo post VBT: PreVBT VL 8.7cm (SD + 1.51) PostVBT VL 8.8cm (SD + 1.58)
Dilator compliance was variable at 6mos:
• 22% using the dilator <1 time/week • 22% using the dilator 1 time/week • 56% using the dilator 2-3 times/week
Conclusions
No difference in VL from before to 6 mos after VBT for the
treatment of endometrial cancer
Increased dilator use may be beneficial in preventing loss of
vaginal length post VBT but requires further study
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
Creutzberg, Int J Radiol Biol Phys, In Press
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 Radiotherapy
Chemotherapy
Observation
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
My Current General Treatment Approach
Stage I Patients Limited*/No Lymph Node Surgery
Given PORTEC/ASTEC Results – Becoming Increasingly Similar to Dissected Patients
• *<10 nodes, limited number of sites (arbitrary definition ) – Radiographic
Imaging for all but Stage 1A Grade1 and 2 • 1 Low risk of vaginal recurrence and nodal involvement • 2 Consider observation for minimal invasion – no high risk features. • 3 Consider pelvic RT instead if +LVI and close to ½ MI +/- advanced age • 4 Consider pelvic RT instead if +LVI, deep invasion, advanced age
Grade I Grade II Grade III
IA (No Inv)
1 1 VB
IA (Inv) VB2,3 VB2,3 VB 3
IB VB4
VB4
Pelvic +/- VBT
In surgically staged patients, VB alone is becoming the preferred adjuvant RT
approach
• Stage I Patients Surgically Staged*
• *>10 nodes, multiple sites (arbitrary cut off) • 1 Consider VB depending on other high-risk features. • 2 Consider observation depending on other high-risk features. • 3 Consider Pelvic Radiotherapy if with high-risk features • 4 Consider VBT if limited invasion and minimal high-risk features.
Grade 1 Grade 2 Grade 3
IA ( No Inv) -- -- VB
IA (Inv) -- 1 VB 2 VB 2
IB VB 3 VB 3 Pelvic +/- VB4
Stage II Patients
• In general, I deliver pelvic radiotherapy followed by a VBT boost – depends on the surgery that is accomplished.
Stage III Patients
• I generally deliver tumor directed radiotherapy.
What About Lymph Node Dissection
GOG 33- Creasman A surgical/pathologic study of 621 patients with clinically stage I
endometrial cancer Percent of patients with positive pelvic LN’s
Invasion Grade 1 Grade 2 Grade 3
None 0 3 0
Inner 3 5 9
Middle 0 9 4
Deep 11 19 34
Efficacy of systematic pelvic lymphadenectomy in endometrial
cancer (MRC ASTEC trial): a randomised trial.
• 85 Centres, 4 Countries, 1408 women • Hysterectomy and BSO +/- pelvic
lymphadenectomy • Intermediate or high risk early stage disease
– FIGO (1988) IA or IB with high grade pathology – FIGO (1988) IC or IIA
• Controversial point: “To control for post-surgical treatment…randomized (independent of lymph node status) into the ASTEC radiotherapy trial
Lancet 2009; 373: p125-36
In GOG 33 % positive LN’s
5-9% 10-34%
ASTEC Tx Randomization
• Because women were randomized to adjuvant radiotherapy without regard to the results of the pelvic lymph node dissection: – This is a study of the surgical benefit to removing
lymph nodes. – It does not answer the question of whether
detecting occult nodal metastasis in low and intermediate risk patients better directs adjuvant tx and thus improves survival.
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
R Maggi et al, BJC,2006;95:266
Stage IC G3 STAGE II G3 >50% MI Stage III
Regimen 1: Pelvic RT (45-50 gy)
Regimen 2: CDDP, Adriamycin, Cytoxan 5 cycles
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
• Moreover, 12 (7%) of these surgically staged patients
developed a SBO after pelvic +/- PART • Maybe adriamycin alone is not enough
3 Years Survival Extra-Pelvic Failure
RT Alone 75% 22.5% RT + Adriamycin 68% 16.3%
P = NS P = NS
To test a more aggressive regimen, the RTOG launched RTOG 9708
Kathryn Greven et al., Gynecol Oncol 2006;103:155
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
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 high-risk early stage in that trial related to competing Phase III GOG randomized trial for Stage III patients,
Concurrent and adjuvant chemotherapy
Greven et al, Gynecol Oncol 2006
Radical surgery TAH+BSO (+PLA)
RT+CT
RT
CT+RT OR
Randomization
Primary endpoint
Progression-free survival (PFS)
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
≥ 44 Gy XRT ± optional VBT (39%)
CT : intially AP Later AP, TcP, TAP, TEcP
n=196
n=186
n=382
May 1996 to January 2007
(VBT 44%)
NSGO EC-9501/EORTC-55991
Thomas Hogberg, Lund Univ Hosp Oct 2009
NSGO EC-9501/EORTC-55991
PFS progression-free survival (PFS)
Thomas Hogberg, Lund Univ Hosp Oct 2009
HR 0.63 (95 % CI 0.41 - 0.98) p = 0.04
0.72
0.790.
000.
250.
500.
751.
00
prob
abili
ty o
f sur
viva
l
186 175 158 143 119 82random = 1191 170 149 123 110 84random = 0
Number at risk
0 1 2 3 4 5years
random = 0 random = 1
PFS NSGO-EC-9501/EORTC-5591
RT alone
Chemo/RT
Combined Modality Trials • Several new combined modality trials are underway or in the
planning stages • GOG 249 compares pelvic RT versus VB + chemotherapy in
intermediate risk Stage I and IIa patients
• 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.
When utilizing IMRT in the post-operative treatment of endometrial cancer the MOST
important aspect of treatment is? 1. Daily image guidance. 2. Asking the patient to have a full bladder on a
daily basis. 3. Assuring that bone and bowel are excluded
from the CTV. 4. Carful attention to an ITV.
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 • Novel approaches, notably IMRT and in the future IGRT,
should help improve the quality and delivery of RT in these women.