Endometrial Cancer - ASTRO

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


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


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,


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 %


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%


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

http://www.redjournal.org/article/S0360-3016(11)00530-X/abstract

http://www.redjournal.org/misc/terms

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.


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%


GOG 99: Survival

Relative hazard for RT: 0.86 (ns); HIR: 0.73

HIR, no RT: 74% HIR, RT: 88% LIR: 92 - 94%


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%)


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.

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

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


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

http://www.redjournal.org/article/S0360-3016(09)02797-7/abstract




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.

Endometrial Cancer - ASTRO

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