Endometrial and Ovarian

William Small Jr., MD Professor and Chairman Loyola University, Chicago

Learning Objectives: •Discuss the role of in early stage and advanced stage .

•Review controversies in Radiation Techniques.

Explain the role of and surgical staging in the management of endometrial cancer.

•Review the role of in the management of early and advanced stage endometrial cancer.

•Review the role of Radiation in .

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 Estimated New Cancer Cases and Deaths by Sex, 2014 Women

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

“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 IB < half of the endometrium IC > half of the endometrium • Stage II Corpus and 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 ) and/or cancer cells in or peritoneal washings IIIB Vaginal Involvement III C Metastasis to Pelvic or Para-aortic Lymph Nodes • Stage IV IVA Tumor Involves the bladder or bowel mucosa IVB Distant Metastasis FIGO 2009 Surgical staging System Early stage disease • Stage I IA No or < half of the endometrium IB = or > half of the endometrium • Stage II Corpus and cervix Endocervical stromal invasion

Int J Obs Gyn, May 2009, FIGO 2009 Surgical staging System Late stage disease • Stage III IIIA Tumor Involves the serosa and/or adenexa (direct extension or metastasis) IIIB Vaginal and/or parametrial Involvement III C1 Metastasis to Pelvic Lymph Nodes IIIC2 Metastasis to Para-aortic +/- pelvic Lymph Nodes • Stage IV IVA Tumor Involves the bladder or bowel mucosa IVB Distant Metastasis and/or inguinal metastasis Post Operative Radiotherapy Early Stage Disease Very contentious Disease

All Patients No Patients Receive Adjuvant RT Receive adjuvant RT Even Low Grade Even High Grade Minimally Invasive Deeply Invasive Tumors Tumors

Center A Center B Postoperative RT Rationale

• Early stage patient with adverse pathologic features are at risk for extra uterine disease and recurrence • Most commonly cited pathologic factors -Myometrial Invasion (MI) -Tumor Grade -Cervical involvement - Age - LVSI • Importance demonstrated in GOG33 GOG 33 • Surgical Pathologic study of 621 stage I pts Positive Positive Pelvic LNs 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 Positive PA LNs

Invasion G1 G2 G3 Invasion G1 G2 G3

None 0% 3% 0% None 0% 3% 0%

Inner 3% 5% 9% Inner 1% 4% 4%

Middle 0% 9% 4% Middle 5% 0% 0% Creasman WT et al, Cancer 1987;60:2035 Deep 11% 19% 34% Deep 6% 14% 23% Tumor Size and Metastasis multivariate p-0.01

40%

35% 30%

20%

Metastasis 15%

% Lymph Node 10%

0% 4%

<2 cm > 2 cm Entire Cavity Tumor Size Schink Cancer 67:279;1991 Prevalence of Lymph Node Metastasis in Endometrial Cancer by Tumor Size and Depth of Myometrial Invasion

Tumor size < 2 cm > 2 cm Entire Surface (%) Depth of invasion diameter (%) diameter (%)

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

> ½ 2/9 (22) 6/23 (26) 4/8 (50)

Schink Cancer 67:279;1991 Prevalence of Lymph Node Metastasis in Endometrial Cancer by Tumor Size and Grade

Tumor size < 2 cm > 2 cm Entire Surface (%) Tumor Grade diameter (%) diameter (%)

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)

Schink Cancer 67:279;199 Cervical involvement and also CSI are correlated with Positive LNs

Positive Positive Pelvic LNs PA LNs Site Fundus 8% 4%

Isthmus - 16% P = 0.01 14% P= 0.0001 cervix 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 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

Unfortunately Grade and Myometrial invasion not combined in the analysis

Price et al. Am J Obstet Gynecol 1965; 91:1060 What evidence supports the use of Adjuvant Radiation Therapy is Stage I & II Endometrial ? Retrospective studies also suggest benefit of Adjuvant RT in patients with adverse pathologic factors Pelvic Pelvic Recurrence Recurrence with RT without RT Carey 1995 3.9% 14.3% High Risk pts Deep MI, G3, +Cx, Adenos. Pitson 2002 5.6% 22.2% Stage II (55% IIA)

Carey et al, Gynecol Oncol 1995; 57:138 Piston et al, Int J Radiation Oncol Bio Phys 2002; 53:862 Retrospective studies also suggest benefit of Adjuvant RT in patients with adverse pathologic factors • In a retrospective review of 927 patients Stage I&II pts

Vaginal Recurrence Vaginal Recurrence with RT – either Vault without RT or Total Stage I Low Risk 1% 3.2% G 1 – 2, <1/3 MI

Stage I High Risk 1.3% 11.7% G3 &/Or >1/3 MI Stage II 5.2 % 12.8% Elliot at al., Int J Gyne cancer 1994; 4 : 84 Post operative RT Stage I & II Disease

• Five prospective randomized trials have been conducted to evaluate post operative radiotherapy in early stage disease – Norwegian Trial – PORTEC 1 – GOG 99 – ASTEC/EN 5 – PORTEC 2

Norwegian Trial

Vaginal • Clinical Stage I • 540 Patients LDR 60 Gy @vaginal • TAH + BSO surface without LN Arm 1 Arm 2 Sampling Pelvic RT 40 Gy No further Midline block therapy • No assessment of after 20 Gy peritoneal cytology 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 – < ½ MI 4% 2.3% 2 Tumors > ½ MI 9.8% 9.4% Grade 3 < ½ MI 5.6% 2.1% Tumors > 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 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 • Regimen 1 Grade 1 > ½ MI Pelvic radiotheraoy Grade 2 any MI 46 Gy / 23 Fractions Grade 3 < ½ MI No Vaginal Brachytherapy • 715 Patients • TAH + BSO without LN • Regimen 2 Sampling No further Treatment • All 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 * Biology * Physics (DOI:10.1016/j.ijrobp.2011.04.013 ) Copyright © Elsevier Inc. Terms and Conditions PORTEC – 10-year outcome with PA review

Locoregional recurrence (actuarial rates)

All pts 5-yr 10-yr p

RT 3% 5% No RT 13% 14% <0.001

Exclusion of IB grade 1 (n=134):

RT 4% 5% No RT 15% 17% <0.001

Creutzberg, Lancet 2000; Scholten, IJROBP 2005 PORTEC – 15-year outcome ( 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) • Regimen 1 • Pap/Serous-Clear Pelvic radiotheraoy Excluded 50.4 Gy / 1.8 Gy/ Fraction • 392 Patients No Vaginal Brachytherapy • TAH + BSO with selective Bilateral • Regimen 2 Pelvic & Para- aortic No further Treatment • Assessment of Keys et al. Gynecol Oncol 2004; 92;744 peritoneal cytology

Overall Results

• Median follow-up of surviving patients – 68 months. • The 24-month cumulative incidence of recurrence (CIR) rate was 3% in the RT group and 12 % in the no additional therapy group. • 13 of the 18 loco-regional recurrences in the NAT arm were in the vaginal vault (72%) Overall Results

• CIR at 24 months of isolated local (vagina or pelvic) 1.6% versus 7.4% • 48 month Kaplan-Meier estimates for survival – 86% in the NAT group, 92 % in RT group (p=0.55). • The GI, GU, Cutaneous and Hematological side effects were significantly higher in the RT group. HIR group (GOG-99) Prognostic factors: › advanced age › high grade (2 or 3) › outer 33% myometrial invasion › lymph-vascular space invasion (LVI) HIR (high intermediate risk): • at least 70 yr with any other risk factor

• at least 50 yr with any 2 other risk factor

• any age with all 3 other factors

Keys, Gynecol Oncol 2004 GOG-99: recurrence

HIR, NAT: 27%

HIE, RT: 13%

Relative hazard RT: 0.42 (58% hazard reduction) HIR: 33% of patients, 67% of recurrences Keys, Gynecol Oncol 2004 GOG 99: Survival

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

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

Keys, Gynecol Oncol 2004 MRC ASTEC Radiotherapy and NCIC EN.5 Trial

Adjuvant external beam radiotherapy (EBRT) in the treatment of endometrial cancer: results of the randomized MRC ASTEC and NCIC CTG EN.5 trials

ASTEC ISRCTN 16571884 EN.5 clinicaltrials.gov NCT 00002807

Presented by Jane Orton On behalf of all ASTEC and EN.5 Collaborators

Trial Design

Surgery

High risk pathology and no macroscopic disease

RANDOMIZE

No external beam RT External beam RT Inclusion Criteria ASTEC and EN.5

FIGO Grade 1 Grade 2 Grade 3 Papillary Stage 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%) 337 100 27 (3%) (37%) (11%)

IIA 9 (1%) 19 (2%) 6 (1%) 3 (<1%)

IIB 2 (<1%) 0 0 1 (<1%)

Eligibility Criteria

• Brachytherapy allowed if – centre policy – stated before randomisation – used in both arms

• Positive para-aortic nodes an exclusion • Positive pelvic lymph nodes – Eligible for ASTEC – Ineligible for EN.5

Brachytherapy

 In the ASTEC trial HDR: Two fractions of 4 Gy at 0.5 cm from the vaginal mucosa over 3-7 days or LDR: 15 Gy – upper third of the vagina.  In the EN-5: Given in accordance with local practice. Trial Profile

905 Randomized

453 452 No EBRT EBRT

98% No EBRT 92% received EBRT 2% received EBRT 8% No EBRT

51% Brachytherapy 52% Brachytherapy

453 assessed 452 assessed for primary outcome for primary outcome measure measure Patient Characteristics

Baseline characteristics balanced between treatment groups • median age 65 years • 98 % performance status 0-1 • 83% endometrioid • 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 +/- 416 (92%) brachytherapy 10 (3%) Brachytherapy Distribution of EBRT dose used alone 24 (5%) 80 None Missing 2 60 Median: 40 Total Dose (Gy) 45 Percentage (%) Fractions 25 20 Duration in days 34 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 Treatment Total dose (Grays) compliance 82% (% of patients who received total dose of 40-46 Gy in 20-25 fractions)

Isolated Vaginal or Pelvic Initial Recurrence (ASCO Presentation)

1.0 Events Totals No EBRT 28 453 0.9 EBRT 14 452

0.8

0.7

3% difference in 5 year cumulative incidence rate 0.6 (4% in EBRT to 7% in no EBRT)

0.5 HR=0.53, 95% CI=0.29-0.97, p=0.038

0.4

Cumulative incidence Cumulative Only includes 42/123 total recurrences

0.3

0.2

0.1

0.0 0 1 2 3 4 5 6 7

PATIENTS at Risk Years from randomisation No EBRT 453 425 366 282 211 142 81 35 EBRT 452 420 376 281 212 142 78 32 Isolated Vaginal or Pelvic Initial Recurrence

• 5-year cumulative incidence 6.1 % versus 3.2 % (p=0.02) Overall Survival: by centre brachytherapy policy (ASCO Presentation)

[no. events/no. entered] EBRT No EBRT O-E Variance Hazard Ratio (Fixed)

Brachytherapy Yes 23/196 29/190 -3.99 12.98 0.74 (0.43-1.27) p=0.268

No 30/181 25/184 3.96 13.69 1.34 (0.79-2.27) p=0.284

0 0.5 1 2 5 EBRT Better No EBRT Better

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 35 77% 66% (2003) 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 value Stage 1A, Grade I 1.000 reference Stage 1B, Grade I 1.13 (0.97-1.31) .13 Stage 1C, Grade I 2.06 (1.63-2.61) <.001 Stage 1A, Grade II 1.38 (1.14-1.67) <.001 Stage 1B, Grade II 1.47 (1.27-1.72) <.001 Stage 1C, Grade II 2.04 (1.64-2.54) <.001 Stage 1A, Grade III/IV 2.47 (1.97-3.11) <.001 Stage 1B, Grade III/IV 2.64 (2.21-3.16) <.001 Stage 1C, Grade III/IV 5.09 (4.09-6.32) <.001 Race/ethnicity=Black 0.54 (0.46-0.63) <.001 Pathologic Node Negative at TAH-BSO 0.90 (0.83-0.98) <.001 Age at Diagnosis (per decade, base age 65) 1.79 (1.73-1.86) <.001 Radiation + Stage 1A, Grade I 0.85 (0.40-1.80) .67 Radiation + Stage 1B, Grade I 0.91 (0.64-1.29) .59 Radiation + Stage 1C, Grade I 0.45 (0.32-0.64) <.001 Radiation + Stage 1A, Grade II 1.37 (0.82-2.28) .23 Radiation + Stage 1B, Grade II 1.00 (0.81-1.24) .97 Radiation + Stage 1C, Grade II 0.96 (0.76-1.21) .75 Radiation + Stage 1A, Grade III/IV 1.02 (0.66-1.57) .93 Radiation + Stage 1B, Grade III/IV 0.98 (0.80-1.19) .82 Radiation + 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 12.8 OPINOIN 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 Groningen

Waddenzee Friesland

Drenthe Noord Ijsselmeer Holland

pelvic radiotherapy Flevoland Overijssel

Gelderland R Zuid Holland Utrecht

Noord Brabant

Zeeland vaginal brachytherapy Limburg PORTEC-2

Randomized Between:

Pelvic Radiotherapy – 46 Gy in 23 fractions

VS

Vaginal Brachytherapy – 21 Gy HDR or 30 Gy LDR

PORTEC-2 Author Conclusions

• “Despite the slightly but significantly increased pelvic failure rate in the VBT arm, DM, RFS and OS were similar. As patient reported after VBT was…better, VBT should be the treatment of choice for patients with high-intermediate risk endometrial cancer” PORTEC-4

• HIR endometrial carcinoma • Vaginal brachytherapy vs no further treatment • 21 Gy in 3 fractions vs 15 Gy in 3 fractions

1 VBT 3 x 7 Gy at 5 mm

2 1 R VBT 3 x 5 Gy at 5 mm 1 No further treatment Close FU; EBRT/VBT for vaginal relapse 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 and Gynecology, Division of , 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 .01 1 96 63 2 (56.8) (75.9) 3 64 17 (37.9) (20.5) 9 3 (5.3) (3.6) Depth of invasion (cm) .0006 Median 0.30 0.22 Range 0.07- 0.02- 2.40 0.90 Lymphatic or vascular 19/153 4/72 .16 space invasion (12.4) (5.6) Interval from surgery to RT (d) Median 41 NA Range 8.257 Patient outcomes data Variable VBT NAT (n = 169) (n = 83) p Disease status (all patients) .07 Alive without disease 145 (85.8) 78 (94.0) Dead of another cause 18 (10.7) 2 (2.4) Alive with disease 1 (0.6) 1 (1.2) Dead of disease 5 (3.0) 2 (2.4) Recurrence 8 (4.7) 6 (7.2) NS Interval from surgery NS to recurrence (mo) Median 40 19 Range 9-102 2-49 Recurrence location* Vagina 1 3 Pelvis 4 2 Para-aortic 1 0 Upper abdomen 3 1 3 0 Status after recurrence Alive without disease 3 (37.5) 3 (50) Died of another cause 1 (12.5) 0 (0) Alive with disease 1 (12.5) 1 (16.7) Died of disease 3 (37.5) 2 (33.3) Abbreviations: NAT – no ; 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 .

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 Vaginal Surface @ 5 mm (cm)

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 DFS Pelvic Chronic up Control 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 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.

86 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.

87 RTOG 0418 – Endometrial Arm GI Toxicity (n=40) Adverse # days Grade Event from start A Enteritis 38 2 B 37 2 C Diarrhea 41 2 Grade 0/1 Grade 2+ Enteritis 41 2 D Enteritis 40 2 n % n % E Enteritis 55 2 Overall 29 73 11 28 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 RTOG 0418 – Endometrial Arm Outcomes

Number Estimated 2-Year Estimated 3-Year of Rate Rate Endpoint Failures (95% CI) (95% CI) 95.2% 92.4% Overall Survival 4 (82.3, 98.8) (78.0, 97.5) Disease-Free 90.6% 90.6% 5 Survival (76.8, 96.4) (76.8, 96.4) Local-Regional 7.0% 7.0% 3 Failure (0, 14.8) (0, 14.8) Para-aortic 4.8% 4.8% 2 nodes (0, 11.3) (0, 11.3) Distant 7.1% 7.1% (excluding para- 3 (0, 14.9) (0, 14.9) aortic nodes)

89 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 A RANDOMIZED PHASE III STUDY OF STANDARD VS. IMRT PELVIC RADIATION FOR POST-OPERATIVE TREATMENT OF ENDOMETRIAL AND (TIME-C)

CO- PIS ANN KLOPP MD, PHD ANAMARIA YEUNG MD

PRO AND QOL CO- CHAIR LARI WENZEL, PH.D. KAREN GIL, PH.D.

COST ANALYSIS CO- CHAIR ANDRE KONSKI, MD, MBA, MA, FACR

STATISTICIAN STEPHANIE SHOOK

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.

Schema

Stratification factors R IMRT pelvic radiation Eligibility XRT dose A P Women with treatment • 45 Gy N endometrial or • 50.4 Gy cervical cancer D Chemotherapy requiringP post- OP • No ChemotherapyP operative pelvic M • 5 cycles of weekly radiation or I 4-field pelvic radiation at 40mg/m2 P chemoradiation treatment Disease Site Z •Endometrial E •Cervix

Post-Treatment Complications PORTEC 1 : Long Term QOL SF-36 Scores EBRT NAT

Remain close to the toilet 26 10 related to urinary control

Urinary Incontinence 30 16

Limitations of daily activity 26 15 related to bowel symptoms

Nout et al; JCO, 2011 PORTEC 1: EBRT Technique • 52% Four Field (5-year comp rate 21%) • 18 % Three Field (5-year comp rate 36%) • 30 % AP/PA (5-year comp rate 30%) – 5 Yr actuarial rate of toxicity 26 % vs. 4 % – Grade 3 or 4: 3 % vs 0 % - 67 % of complications Grade 1, Grade 2: 7 % vs 1%. – P=0.06 for technique and complication rate.

Creutzberg, In J Rad Oncol Biol Phys, 2001 Vaginal Length after Vaginal Brachytherapy for Endometrial Cancer

William Small Jr., MD Professor The Robert H. Lurie Comprehensive Cancer Center of Northwestern University

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 Radiotherap Chemotherap Observatio y y n Patel et al, III 13% - 33% - 77 % 2007 non Vag Vault Mundt et al, I-IV - 39.5 % – 53% - 2001 non Vag Small et al, I-IV 10 % - - 2000 Randall et al, III-IV 13% (Initial) 18% (Initial) 2008 Hoekstra et IIIC 0 % al, 2009 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) • 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 Stage I – III TAH – BSO Four cycles +/- Nodal Surgery Pelvic RT 45 Chemo Grade 2-3 > ½ MI Gy +VB CDDP + cervical stroma CDDP 50 mg/m2 Extra-uterine 2 + 50 mg/m (Pelvic only) Days 1,28 disease + 175 mg/m2 washings

Kathryn Greven et al., Gynecol Oncol 2006;103:155 Concurrent and adjuvant chemotherapy Phase II trial RTOG (46 pts): • stage I-II high risk or stage III (66%)  Concurrent: cisplatin 50 mg/m2 days 1, 28  Adjuvant: 4x cisplatin 50 mg/m2 and paclitaxel 175 mg/m2 • 4-yr locoregional relapse 4%, distant 19% • 4-yr DFS 81%, OS 85% (stage III: 77 and 72%) • No recurrences in stage IC, IIA, IIB  promising data, phase III needed – attempted in RTOG 9901 – closed for lack of accrual. Only high-risk early stage in that trial related to competing Phase III GOG randomized trial for Stage III patients,

Greven et al, Gynecol Oncol 2006 NSGO EC-9501/EORTC-55991

May 1996 to January 2007 Randomization RT n=382 ≥ 44 Gy XRT ± n=196 optional VBT (39%) Radical surgery TAH+BSO (+PLA) RT+CT Surgical stage I, II, OR (VBT 44%) n=186 IIIA (positive CT+RT cytology only), or IIIC (positive pelvic lymph nodes only) with high

risk for micro-metastatic disease CT : intially AP Later AP, TcP, TAP, TEcP Patients with serous, clear cell, or anaplastic were eligible regardless of other risk factors Primary endpoint

Progression-free survival (PFS)

Thomas Hogberg, Lund Univ Hosp Oct 2009 NSGO EC-9501/EORTC-55991

PFS progression-free survival (PFS)

PFS NSGO-EC-9501/EORTC-5591 1.00 Chemo/RT 0.79 0.75 RT alone 0.72

0.50 HR 0.63 (95 % CI 0.41 - 0.98) p = 0.04 0.25 probability of survival 0.00 0 1 2 3 4 5 years Number at risk random = 0 191 170 149 123 110 84 random = 1 186 175 158 143 119 82 random = 0 random = 1

Thomas Hogberg, Lund Univ Hosp Oct 2009 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

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

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

Tumor either state IA or IB but with tumor on the surface of one or both of IC 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 and/or fallopian tubes. IIB Extension to other pelvic tissues. Tumor either stage IIA or IIB but with tumor on the surface of one or both of IIC 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 Tumor involving one or both ovaries with peritoneal implants outside the pelvis and/or positive retroperitoneal or inguinal nodes. Superficial III metastases equals stage III. Tumor is limited to the true pelvis, but with histologically proven malignant extension to small bowl or omentum. Tumor grossly limited to the true pelvis with negative nodes but with IIIA histologically confirmed microscopic seeding of abdominal peritoneal surfaces. Tumor of one or both ovaries with histologically confirmed implants of IIIB abdominal peritoneal surfaces, none >2 cm in diameter. Nodes negative. Abdominal implants >2 cm in diameter or positive retroperitoneal or inguinal IIIC lymph nodes or both. Growth involving one or both ovaries with distant metastases. If pleural IV 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 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 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. 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 . • 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 Pelvic RT + 32P arm 106 61 accrual NCIC/ 1988 I, II closed early Klaassen Pelvic RT + WAI 107 62 due to Pelvic RT + 32P 44 66 toxicity WAI 51 71 <2 cm MDACC/ 1975 I-III residual Smith Melphalan 57 72 disease PMH/ IB, II, III 1979 WAI 76 64 (10-yr) Dembo Asymptomatic p = .007 Pelvic RT ± 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 WAI 60 63 (4-yr) DACOVA/ 1990 IB-IC, II Pelvic RT + Sell 58 65 (4-yr) cyclophosphamide 32p 73 78 6% bowel GOG 95/ 1990 IA-IBG3, IC, II obstruction in Young Melphalan 68 81 32P 32P or WAI 169 83 28 in 32P arm NRH/ 1992 I-III treated with Vergote Cisplatin 171 81 WAI 32P 75 79 32P not given GICOG/ 1995 IA-IB, IC in 20% of Bolis Cisplatin 77 81 patients 32P 110 78 GOG 3% bowel 7602/ 2003 IA-IBG3, IC, II Cyclophosphamide perforation in 119 81 32 Young + cisplatin P Randomized Trials of Consolidative Whole- Abdomen Irradiation (WAI) or 32P Trial/ Bowel Author Stage Study Design # Pts 5-yr OS (%) Obstruction West IIB residual, III, WAI 56 7 9% Midlands/ IV Lawton Chlorambucil 53 8 Italy/ III, IV WAI 20 45 (3-yr) 5% Bruzzone Minimal residual Chemotherapy 21 85 (3-yr) disease NTOG/ IIB-IV WAI 58 25 1.7% Lambert <2 cm residual disease Carboplatin 59 30 Sweden- III WAI 32 56 (PFS) Norway/ Cisplatin + Sorbe / 35 36 (PFS) 10% Observation 31 36 (PFS) PFS, Progression-free survival Other Histologies

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