Endometrial and Ovarian Cancer

William Small Jr., MD Professor and Chairman

Loyola University, Chicago

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. •Review the role of Radiation in Ovarian Cancer.

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 810,320 275,710

Breast 232,670 40,000

Lung 108,210 72,330

Colon/Rectum 65,002 24,040

Uterine 52,630 8,590

American Cancer Society, Surveillance Research, 2012

Estimated New Cancer Cases and Deaths by Sex, 2014 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

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

Tumor Size and Lymph Node Metastasis multivariate p-0.01

4%

15%

35%

0%

10%

20%

30%

40%

% L

ymph

Nod

e M

etas

tasi

s

Tumor Size <2 cm > 2 cm Entire Cavity

Schink Cancer 67:279;1991

Tumor size

Depth of invasion

None 0/17 (0) 0/8 (0) 0/7 (0)

> ½ 2/9 (22) 6/23 (26) 4/8 (50)

Prevalence of Lymph Node Metastasis in Endometrial Cancer by Tumor Size

and Depth of Myometrial Invasion

< 2 cm diameter (%)

> 2 cm diameter (%)

Schink Cancer 67:279;1991

Entire Surface (%)

Tumor size

Tumor Grade

I 1/27 (4) 1/26 (4) 0/7 (0) II 0/19 (0) 5/28 (18) 2/4 (50) III 1/7 (14) 5/18 (28) 4/6 (67)

< 2 cm diameter (%)

> 2 cm diameter (%) Entire Surface (%)

Schink Cancer 67:279;199

Prevalence of Lymph Node Metastasis in Endometrial Cancer by Tumor Size

and Grade

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

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)

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

An Update Survey is Currently Being

Distributed

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 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

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

86

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.

87

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.

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

89

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)

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.

Should IMRT be A Standard Therapy

In the Post-operative

Treatment of Endometrial Cancer

For Post-Operative Pelvic Treatment of Gynecologic Malignancies what Technique do you use?

1. IMRT 2. 3-D Conformal 3. Depends on the patient

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

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

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.

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

What About Chemotherapy? Is it the next step to improving

overall survival?

GOG 122 Schema

GOG 122

Dox/CDDP

WART

p=.01

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.

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.

Ovarian Cancer

William Small Jr., MD Professor and chairman

Loyola University Medical Center

Learning Objectives:

• Discuss current Radiation treatment options with ovarian cancer.

• Role of RT as primary vs. adjuvant therapy

• Role of Radioisotopes, External beam, whole abdominal RT, IMRT, radiochemotherapy, and stereotactic radiotherapy.

• Discuss future of ovarian RT

FIGO Staging for Carcinoma of the Ovary

Stage Description

I Growth limited to the ovaries.

IA Growth limited to one ovary; no ascites containing malignant cells. No tumor on the external surface; capsule intact.

IB Growth limited to both ovaries; no ascites containing malignant cells. No tumor on the external surface; capsule intact.

IC

Tumor either state IA or IB but with tumor on the surface of one or both of the ovaries; or with capsule(s) ruptured; or with ascites present containing malignant cells or with positive peritoneal washings.

FIGO Staging for Carcinoma of the Ovary

Stage Description

II Growth involving one or both ovaries with pelvic extension.

IIA Extension and/or metastases to the uterus and/or fallopian tubes.

IIB Extension to other pelvic tissues.

IIC Tumor either stage IIA or IIB but with tumor on the surface of one or both of the ovaries; or with capsule(s) ruptured; or with ascites present containing malignant cells or with positive peritoneal washings.

FIGO Staging for Carcinoma of the Ovary Stage Description

III

Tumor involving one or both ovaries with peritoneal implants outside the pelvis and/or positive retroperitoneal or inguinal nodes. Superficial liver metastases equals stage III. Tumor is limited to the true pelvis, but with histologically proven malignant extension to small bowl or omentum.

IIIA Tumor grossly limited to the true pelvis with negative nodes but with histologically confirmed microscopic seeding of abdominal peritoneal surfaces.

IIIB Tumor of one or both ovaries with histologically confirmed implants of abdominal peritoneal surfaces, none >2 cm in diameter. Nodes negative.

IIIC Abdominal implants >2 cm in diameter or positive retroperitoneal or inguinal lymph nodes or both.

IV

Growth involving one or both ovaries with distant metastases. If pleural effusion is present, there must be positive cytologic test results to allot a case to stage IV. Parenchymal liver metastasis equals stage IV.

Standard Therapy • Optimal debulking surgery followed by

chemotherapy in patient’s at risk for recurrence.

Radiophosphorus • Intraperitoneal instillation of colloidal suspensions of

radio isotopes of gold and phosphorus have long been theoretical means of treatment. Due to partial emission of gold and its concerns of over exposure it is no longer used.

• Phosphorous is now the radioisotope of choice: – Low complication rate. – Pure-beta – Max penetration 8 mm

• Conflicting therapeutic benefits and the high risk of bowel complications have led to platinum based chemotherapy combinations as the preferred adjuvant therapy for ovarian cancer.

GOG-0095 • Patients with early-stage high risk disease (1A

or 1B Grade 3, IC or II with no macroscopic residual).

• P32 vs. cyclophosphamide and cisplatin. • Relapse rate was 29% lower with

chemotherapy (p=0.15) and death rate 17% lower (p=0.43).

• 3% small bowel perforation with p32. Young et al. J Clin Oncol 2003 (21)

4350- 4355

External Radiation

• Historically, whole or partial abdominal external radiation has been used as 1st line therapy following surgical resection with Stage 1, 2, or 3 ovarian cancers.

• Today, most patients are treated with chemotherapy first line post surgery because chemotherapy will prolong survival without bowel injury or obstruction.

• Radiotherapy is now primarily used in isolated relapses and palliative measures only.

Whole Abdominal Radiotherapy

• Encompass the entire peritoneal cavity. • Whole abdominal dose traditionally 25 – 30

Gy with a boost to the pelvis to a total dose of approximately 45 Gy.

Northwest Oncologic Cooperative Group of Italy (NOCGI)

• Prospective randomized trial of high-risk early stage disease.

• Cisplatin and cyclophosphamide vs. WAI • 5-Yr OS 71 % for chemotherapy arm vs. 53%

for WAI (p=0.16). • More complications in the WAR arm.

Early-Stage Ovarian Cancer: Randomized Trials of Whole-Abdomen Irradiation or 32P

Trial/ Author Year Stage Study Design # Pts 5-yr OS (%) Comments

NCIC/ Klaassen 1988 I, II

Pelvic RT + melphalan 106 61

32P arm accrual closed early due to toxicity

Pelvic RT + WAI 107 62

Pelvic RT + 32P 44 66

MDACC/ Smith 1975 I-III

WAI 51 71 <2 cm residual disease Melphalan 57 72

PMH/ Dembo 1979 IB, II, III

Asymptomatic WAI 76 64 (10-yr) p = .007

Pelvic RT ± Chlorambucil 71 40 (10yr)

Early-Stage Ovarian Cancer: Randomized Trials of Whole-Abdomen Irradiation or 32P

Trial/ Author Year Stage Study Design # Pts 5-yr OS (%) Comments

DACOVA/ Sell 1990 IB-IC, II

WAI 60 63 (4-yr)

Pelvic RT + cyclophosphamide 58 65 (4-yr)

GOG 95/ Young 1990 IA-IBG3, IC, II

32p 73 78 6% bowel obstruction in 32P Melphalan 68 81

NRH/ Vergote 1992 I-III

32P or WAI 169 83 28 in 32P arm treated with WAI Cisplatin 171 81

GICOG/ Bolis 1995 IA-IB, IC

32P 75 79 32P not given in 20% of patients Cisplatin 77 81

GOG 7602/ Young

2003 IA-IBG3, IC, II

32P 110 78 3% bowel perforation in 32P

Cyclophosphamide + cisplatin 119 81

Randomized Trials of Consolidative Whole-Abdomen Irradiation (WAI) or 32P

Trial/ Author Stage Study Design # Pts 5-yr OS (%)

Bowel Obstruction

West Midlands/ Lawton

IIB residual, III, IV

WAI 56 7 9%

Chlorambucil 53 8

Italy/ Bruzzone

III, IV Minimal residual disease

WAI 20 45 (3-yr) 5%

Chemotherapy 21 85 (3-yr)

NTOG/ Lambert

IIB-IV <2 cm residual disease

WAI 58 25 1.7%

Carboplatin 59 30

Sweden-Norway/ Sorbe

III WAI 32 56 (PFS)

10% Cisplatin + doxorubicin/ epirubicin

35 36 (PFS)

Observation 31 36 (PFS)

PFS, Progression-free survival

Other Histologies

• Some evidence suggests that non-serous histologies – especially clear cell – may benefit from radiotherapy.

Clear Cell Carcinoma • Suggestion of more loco-regional recurrences. • Nagai compare platinum chemotherapy vs

WAI. – 5-yr DFS 81.2% vs. 25% in favor of WAI(p=0.006). – 5-yr OS 81.8% vs. 33.3% in favor of WAI (p=0.31).

Clear Cell Carcinoma • Hoskins in2012 looked at 241 patients treated

in the carbo/taxol and radiotherapy vs. chemotherapy alone. – British Columbia study were all early patients

were to be offered RT. – In patients with stage IC negative cytology and

stage not based on rupture and staII improved DFS by 20%.

Hoskins et al, J Clin Oncol, 2012; (30) 1656-62.

Questions??