Endometrial Cancer: Current Status of Radiation

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

Review the patterns of recurrence for endometrial cancer. Review the role and techniques of radiation for early stage endometrial cancer. Review the role of radiation in advanced stage endometrial cancer. Endometrial Cancer Estimated New Cancer Cases and Deaths by Sex, 2017 Women

American Cancer Society, Surveillance Research, 2017 “The reports of my death have been greatly exaggerated.” -Mark Twain “There are three kinds of lies: Lies, Damned Lies, and Statistics.” -Benjamin Disraeli -Mark Twain FIGO 1988 Surgical staging System Early stage disease Stage I IA Limited to the endometrium IB < half of the endometrium IC > half of the endometrium Stage II Corpus and cervix IIA Endocervical glands only IIB Endocervical stromal invasion FIGO 1988 Surgical staging System Late stage disease Stage III IIIA Tumor Involves the serosa and/or adenexa (direct extension or metastasis) and/or cancer cells in ascites or peritoneal washings IIIB Vaginal Involvement III C Metastasis to Pelvic or Para-aortic Lymph Nodes Stage IV IVA Tumor Involves the bladder or bowel mucosa IVB Distant Metastasis FIGO 2009 Surgical staging System Early stage disease Stage I IA No or < half of the endometrium IB = or > half of the endometrium Stage II Corpus and cervix Endocervical stromal invasion

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

All Patients 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 Predicting Lymph Node Metastasis

Unclear what these number would be in the face of negative imaging GOG 33 Surgical Pathologic study of 621 stage I pts

Positive 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

Invasio G1 G2 G3 Invasion G1 G2 G3 n None 0% 3% 0% None 0% 3% 0%

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

Middle 0% 9% 4% Middle 5% 0% 0%

Deep 11% 19% 34% Deep 6% 14% 23%

Creasman WT et al, Cancer 1987;60:2035 Tumor Size and Lymph Node Metastasis multivariate p-0.01 40%

35% 30%

20%

Metastasis Metastasis 15%

% Lymph% Node 10%

4% 0% <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;1991 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

Bendifallah et al/Am J. Obstet Gyncol 2012; 207:197.e1-8.

What evidence supports the use of Adjuvant Radiation Therapy in Stage I & II Endometrial Carcinoma ? Rationale also provided by the correlation between adverse pathologic factors and vaginal failure Price 1965 41 clinical stage I patients undergoing surgery alone Vaginal Recurrence All Patients 14% Grade 1 4.4 2 5.7 3 13.6 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 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 Vagina

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 Brachytherapy Clinical Stage I LDR 60 Gy @vaginal 540 Patients surface TAH + BSO without LN Sampling Arm 1 Arm 2 No assessment of Pelvic RT 40 Gy No further peritoneal cytology Midline block therapy after 20 Gy

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 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 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 histologies HIR Definition

Age > 60 Grade 3 Invasion >50% HIR defined as: 2 of those 3 factors present (except for grade 3 with deep invasion = high risk, eligible for PORTEC3) Fig. 3

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 ( 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) Regimen 1 Pap/Serous-Clear Cell 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 lymphadenectomy 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 48 (5%) (11%) 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 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 +/- 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 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) Acute and Late Toxicity

No EBRT EBRT N=453 N=452

Acute toxicity (post surgery and 121 (27%) 258 (57%) radiotherapy)

Worst score Mild 77 (17%) 143 (32%) Moderate 38 (8%) 100 (22%) Severe/Life threatening 3 (<1%) 14 (3%)

Late Toxicity 3% 8% Severe/Life threatening

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

Only includes 42/123 total recurrences Cumulative incidence Cumulative

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) Meta-analysis: overall survival

Study EBRT No EBRT Peto OR (IPD) N Peto OR (IPD) n/N n/N 95% CI 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% 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? 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 pelvic radiotherapy Holland

R Flevoland Overijssel

Gelderland Zuid Holland Utrecht

vaginal brachytherapy Noord Brabant

Zeeland Limburg PORTEC-2

Randomized Between:

Pelvic Radiotherapy – 46 Gy in 23 fractions

Vaginal Brachytherapy – 21 Gy HDR or 30 Gy LDR

PORTEC-2 Author Conclusions

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

PORTEC- 4 and Patient Preference PORTEC-4 HIR endometrial carcinoma Vaginal brachytherapy vs no further treatment 21 Gy in 3 fractions vs 15 Gy in 3 fractions

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

Kunneman, et.al/British Journal of Cancer, 2014, 1-6 Kunneman, et.al/British Journal of Cancer, 2014, 1-6 How should you treat – so called – intermediate risk patients?

The data on unselected patients consistently shows a reduction in vaginal recurrences. I believe the “best” technique is to look at all the risk factors before deciding on an individual patient. Clinical Outcomes in International Federation of Gynecology and Obstetrics Stage IA Endometrial Cancer With Myometrial Invasion Treated With or Without Postoperative Vaginal Brachytherapy

V. Diavolitsis, M.D.,1 * A. Rademaker, Ph.D.,2 J. Lurain, M.D.,3 A. Hoekstra, M.D., M.P.H.,4 J. Strauss, M.D., M.B.A.,5 and W. Small, Jr., M.D.,*

Departments of Radiation Oncology, Preventive Medicine, and Obstetrics and Gynecology, Division of Gynecologic Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL.

Int J Radiol Oncol Biol Phys,. Volume 84, Number 2 (2012) 415-419. Patient outcomes data Variable 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 Lung 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 adjuvant therapy; VBT = vaginal brachytherapy Data in parentheses are percentages *Several patients had multiple sites of recurrence

Vaginal Brachytherapy Techniques

Aims

• To update the current practice patterns for the treatment of postoperative endometrial cancer from the ABS survey sent in 2003 and published in 2005 (Small et al, IJROBP 2005).

• To present the practice patterns of vaginal brachytherapy (VBT) regarding patient selection, treatment planning, treatment delivery, and quality assurance. Results Patient Evaluation • Lymph Nodes • 90% make treatment recommendations based on whether or not a lymph node dissection was performed • 70% use number of nodes removed to influence treatment decisions

Number of nodes removed 40.7% 41.8% 100% 8.2% 9.3% 50% 0% 0-5 6-10 11-20 20 or more Results

Treatment Planning •26% place radio-opaque (i.e. gold) markers at the vaginal apex •53% report doses at both the surface and 0.5cm •80% document dose to normal tissues •Most common dose rate •96% HDR •3% LDR •1% Both •0% PDR Results

HDR Brachytherapy •83% use single channel and 14% use a multi- channel cylinder •83% perform CT planning •26% for each fraction •74% for first fraction only •Most common dose prescription location •Vaginal surface – 23% •0.5cm depth – 60% •Other – 17% Results

Fixed Length Most Common Prescription of Dose 3% • 60% treat to a fixed length Proximal 3cm 23% 26% Proximal 4cm Proximal 5cm

49% Other

• 37% treat to a fractional length of the vagina 9% Fractional Length

1% Proximal 1/3

26% Proximal 1/2

Entire Vagina 63% Other Results

Treating the entire length of the vagina • 26% treat for CCC/UPSC histology • 11% for grade 3 • 13% for LVSI • 65% never Results

Dose prescription at the surface of the vagina

8% VBT Alone 10% VBT Boost 13% 7% 4.0 Gy x 6 fx 4.0 Gy x 4 fx 10% 6.0 Gy x 5 fx 19% 6.0 Gy x 2 fx 7.5 Gy x 5 fx 31% 6.0 Gy x 3 fx 12% 10.5 Gy x 3 fx 5.0 Gy x 3 fx Other Other 57% 34% Results

Dose prescription at 0.5cm depth of the vagina

VBT Alone VBT Boost

21% 5.0 Gy x 3 fx 7.0 Gy x 3 fx 38% 15% 5.5 Gy x 3 fx 5.5 Gy x 4 fx 4.0 Gy x 3 fx 19% 12% 5.0/5.5/6.0 Gy x 2 fx Other 67% Other 13% 15% Results

Treatment Planning & Delivery •Fractions per week •1 – 34% •2 – 52% •3 – 13% •4 or 5 – 2% •73% place optimization points at the vaginal apex AND lateral to the cylinder •99% perform secondary QA checks Highlights - Similarities

2003 2014

Placement of 21% 26% Radio-opaque Markers

Use of 90%/10% 83%/14% Single/Multi (check all applicable) (check one) Channel Cylinder

Use of 7Gy x 3 fx at 42% 41% 0.5cm depth (most common) (most common) w/o EBRT Document dose to 78% bladder 80% OAR 80% rectum Highlights - Differences 2003 2014

Response Rate 31.6% 7.3%

# of Nodes Removed 37% / 58% / 5% 8% / 82% / 10% 0-5 / 6-20 / 20+

Use of HDR 69% 97%

Use of 5Gy x 3 fx at 43% 27% 0.5cm depth (most common) (most common) w/ EBRT Treat entire 4% 0.3% vaginal length Conclusions

•Electronic surveys are possible though response rate is lower than the original study

•In a population of ABS/ASTRO members •HDR Brachytherapy is the most common delivery modality •Responders are seeing increased nodal dissections •Fractionation schedules continue to be highly variable •Almost all are doing secondary QA checks •Treatment devices and planning techniques are variable but they generally align with the ABS recommendations American Brachytherapy Society consensus guidelines for adjuvant vaginal cuff brachytherapy after hysterectomy.

William Small, Jr., M.D.,1*, Sushil Beriwal, M.D., 2 D. Jeffrey Demanes, M.D.,3 Kathryn E. Dusenbery, M.D., 4 Patricia Eifel, M.D.,5 Beth Erickson, M.D., 6 Ellen Jones, M.D., 7 Jason J. Rownd, M.D.,8 Jennifer F. De Los Santos, M.D., 9Akila N. Viswanathan, M.D.,10 and David Gaffney, M.D.11

Brachytherapy 11(2012) 58-47. Pretherapy Evaluation

Pay particular attention to healing – especially on the current proliferation of robotic surgery. Choose the applicator that is correct for the clinical situation. Cylinders most common which range in size from 2 – 4 cm. Brachytherapy Technique

Placement of a radio-opaque seed or clip(s) at the vaginal apex should be considered. Place the largest cylinder that fits comfortably. Minimize movement from placement, planning and treatment. Dose Fractionation

7 Gy X 3 to 0.5 cm is the most commonly prescribed fractionation scheme. Many sites use different fractionation schemes. I use 5.5 Gy X 4 to 0.5 cm. Prescription

Diameter Size Vaginal Surface @ 5 mm (cm)

2 100% 60%

3 100% 68%

4 100% 71% External Beam Techniques Dosimetric Studies

IMRT versus conventional Pelvic RT

Small Bowel Bladder Rectum

Decreases the volume receiving the prescription dose by

Roeske 50% 23% 23% Heron 51% 31% 66% Chen 70% NS NS Ahamad 40 – 63% NS NS

Wong 95% NS NS Clinical outcome studies Adjuvant IMRT in Endometrial Cancer

Number Follow DF Pelvic Chronic up S Contro Toxicity l 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 A RANDOMIZED PHASE III STUDY (NRG Oncology’s RTOG 1203) OF STANDARD VS. IMRT PELVIC RADIATION FOR POST-OPERATIVE TREATMENT OF ENDOMETRIAL AND CERVICAL CANCER (TIME-C)

Ann H. Klopp MD, PhD MD Anderson Cancer Center Ann Klopp, Anamaria Yeung, Snehal Deshmukh, Karen M Gil, Lari Wenzel, Shannon Westin, Kent Gifford, David Gaffney, William Small, Jr., Spencer Thompson, Desiree Doncals, Guilherme Cantuaria, Brian Yaremko, Amy Chang, Vijayananda Kundapur, Dasarahally Mohan, Michael Haas, Yong Bae Kim, Catherine Ferguson, Deborah W.Bruner IMRT for post-operative pelvic RT

Concave target allows IMRT to reduce dose to small bowel in center of pelvis.

Retrospective studies show lower rates of acute and chronic GI toxicity.

RTOG 0418 found IMRT to be feasible with a favorable rate of acute 2+ GI toxicity (25%) Objectives

Determine if acute GI toxicity is reduced with IMRT in week 5 of RT Primary endpointusing: Determine patient reported if acute measure GI toxicity of toxicity is reduced with IMRT in week 5 on RT using patient reported measure of toxicity.

Secondary endpoints • Acute urinary toxicity with EPIC tool • Acute GI toxicity with PRO-CTCAE • Quality of life (FACT) • LRC, DFS, OS • Health utilities analysis Time points for evaluation

Time Point Purpose Before RT Baseline 3 weeks after RT Compare early acute start toxicity End of RT (5 weeks Maximum difference after RT start) in acute toxicity 4-5 weeks after RT Compare resolution of acute toxicity 1 year from start of Early chronic toxicity RT 3 years from the Long term toxicity start of RT Schema

Eligibility

IMRT pelvic Women with endometrial or cervical radiation treatment cancer requiring post-op pelvic RT or chemoRT

Stratification Factors

XRT Dose: 45 Gy, 50.4 Gy

4-field pelvic

Chemo: No chemo, 5 cycles of weekly RANDOMIZE radiation treatment cisplatin at 40mg/m2

Disease Site: Endometrial, Cervix Sample size

• Primary endpoint: change in acute GI toxicity – EPIC bowel domain – baseline to 5 weeks after the first fraction of radiation is delivered • No prior data → effect size of 0.4 • Two-sample t-test, one interim look and an overall 2-sided α = 0.05 – alpha = 0.049 for final analysis • 85% power • 225 evaluable patients • 20% inflation due to attrition, non-compliance, ineligibility → 281 patients IMRT Planning

Contouring per RTOG atlas - Nodal CTV - Vaginal ITV using full and empty bladder CT sim scans - 7mm PTV expansion - OARs: Bone marrow, bowel space, bladder, rectum

Rapid review of contours and plans required on the first case on each arm for a site.

All cases not rapidly reviewed were QA’d after treatment. Patient Characteristics

IMRT 4 Field (n=129) (n=149) Age Median 62 62 (yrs) Race Black 12 (10%) 12 (8%) White 96 (74%) 114 (77%) Zubrod 0 101 103 (78%) (69%) 1 27 (21%) 42 (28%) Radiation 45 Gy 76 (59%) 84% Dose (56%) 50.4 Gy 53 (41%) 65 (44%) Site Endometri 108 125 EPIC Bowel Questions

Bowel Function: - rectal urgency? How often have you had… - uncontrolled leakage of stool? - stools that were loose? - bloody stools? - your bowel movements been painful?

How many bowel movements have you had on a typical day? How often have you had crampy pain in your abdomen or pelvis?

Bowel Bother:

How big - has each of these issues been for you? of a problem… - have your bowel habits been for you? EPIC Bowel Answers – Patient Reported

IMRT 4 Field p-value (n=107) (n=126) Bowel Mean -18.6 -23.6 Summary Std. Dev. 18.7 19.4 0.0476 Median -17.9 -22.3 Mean -14.8 -21.0 0.02 Bowel Std. Dev. 19.0 19.3 Function Median -14.3 -17.9 Mean -22.3 -26.1 Bowel Std. Dev. 22.0 22.2 0.19 Bother Median -21.4 -21.4 EPIC Bowel Score

90 p-value = 0.0476

IMRT 70

4-field

50 Baseline Week 3 of RT Week 5 of RT 4-6 weeks post-RT

IMRT 128 113 111 102 4 Field 148 132 130 125 Pro-CTCAE Questions

Bowel Function: - Did you have loose or watery stools(diarrhea)? In the last 7 days, how - Did you lose control of bowel movements? often… - Have you taken an anti-diarrhea medication?

Bowel Bother: - What was the severity of your pain in the abdomen (belly area) at its worst? - How much did pain in the abdomen (belly area) interfere In the with your usual or daily activities? last 7 days… - How much did loss of control of bowel movements interfere with your usual or daily activities? Acute GI Toxicity – Patient Reported

Symptomatic Adverse IMRT 4 Field Event PRO-CTCAE Score p-value (n=92) (n=108) ≥3 at 5 weeks Severity 11 (11.9%) 22 (20.4%) 0.11 Abdominal Pain Interference 10 (10.9%) 17 (15.7%) 0.32

Diarrhea Frequency 31 (33.7%) 56 (51.9%) 0.01

Fecal Frequency 1 (1.1%) 10 (9.3%) 0.01 Incontinenc e Interference 4 (4.4%) 14 (12.9%) 0.04 Use of Anti-Diarrheal medications

Symptomatic Adverse IMRT 4 Field p- Event PRO-CTCAE at 5 (n=90) (n=108) value weeks 0-1 times daily 59 (65.6%) 59 (54.6%) 0.04

2-3 times daily 24 (26.7%) 27 (25.0%)

4+ times daily 7 (7.8%) 22 (20.4%) Acute Urinary Toxicity – Patient Reported

Change in EPIC Urinary IMRT 4 Field p- Score from Baseline to 5 (n=107) (n=126) value Weeks Urinary Summary

Mean -5.6 -10.4 0.03

Std. Dev. 15.3 17.5

Median -2.1 -4.5

Min - Max -57.0 - 27.8 -83.3 - 36.1 QOL: Trial Outcome Index (TOI)

Change in FACT-Cx IMRT 4 Field p- (n=110) (n=125) value Trial Outcome Index (n=86) (n=106) Mean -8.8 -12.8 0.06 Std. Dev. 14.4 14.3 Physical Well-Being (n=86) (n=106) Mean -4.2 -6.1 0.03 Std. Dev. 6.0 6.1 Add’l Concerns/Cervix (n=87) (n=104) Mean -2.7 -4.9 0.01 Std. Dev. 6.1 6.5 TOI: Functional, Physical and adnl concerns Conclusions

Pelvic IMRT reduces acute patient reported GI and GU toxicity compared to standard pelvic RT.

Pelvic IMRT reduces need for anti-diarrheal medications as compared to standard pelvic RT.

Pelvic IMRT improves quality of life metrics during treatment as compared to standard pelvic RT.

Longer term follow up will determine if these differences in acute toxicity result in lower rates of late toxicity. Atlas Update In Progress

• Utilize patterns of recurrence data from RTOG 0418. • Better define obturator nodal region. • Eliminate all reference to boney landmarks. • Give recommendations regarding rectal distention. • Included recommendations for common iliacs and para-aortic CTV. RTOG 0418 – Endometrial Arm RTOG 0418 – Endometrial Arm RTOG 0418 – Endometrial Arm RTOG 0418 – Endometrial Arm RTOG 0418 – Endometrial Arm RTOG 0418 – Endometrial Arm CASE STUDY

The patient was treated with pelvic IMRT on RTOG 0418 with concurrent weekly cisplatin. An ITV was accomplished to determine the CTV. The consensus contouring guidelines were utilized to draw the CTV. Full and Empty Bladder Full and Empty Bladder Full and Empty Bladder Post-Treatment Complications PORTEC 1 : Long Term QOL SF-36 Scores EBRT NAT

Remain close to the 26 10 toilet related to urinary control

Urinary Incontinence 30 16

Limitations of daily 26 15 activity 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 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

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 Cumulative Risk of Bladder Cancer

Bladder Cancer Risk PORTEC 1

At a median follow-up of 13.3 years 19% of the patients had a second primary. 22% in the EBRT group, 16% in the no additional treatment group P=0.10 Can Chemotherapy Replace Pelvic Radiotherapy? A randomized phase III trial of pelvic radiation therapy (PXRT) versus vaginal cuff brachytherapy followed by paclitaxel/carboplatin chemotherapy (VCB/C) in patients with high risk (HR), early stage endometrial cancer (EC): a Gynecologic Oncology Group trial.

McMeekin DS, Filiaci VL, Aghajanian C, et al. Proceedings of the 45th Annual Meeting on Women's Cancer, Society of Gynecologic Oncology; 2014, March 22; Tampa, FL. GOG 249

Primary objective: To determine if treatment with VCB/C reduces the rate of recurrence or death (RFS) when compared to PXRT Secondary objectives: Compare OS, patterns of failure, toxicity/functioning between arms – All patients underwent hysterectomy +/- staging CT/MRI required if no LND – Endometrioid histology- risk criteria > 70 + 1, age >50 +2, age > 18 + 3 Factors: LVSI, Gr 2-3, outer ½ invasion – Serous/Clear cell- stage I-II – Stage II any histology GOG 249

Therapy initiated within 12 weeks after surgery Arm I- Pelvic Radiation (PXRT) – 180cGy/day X 25-28 fractions 4500-5040 in 5-6 weeks – Standard or IMRT permitted – VCB allowed for stage II or Stage I S/CC Arm II- Vaginal Cuff Brachytherapy + Chemotherapy (VCB/C) – LDR or HDR – HDR 6-7 Gy X 3 or 10-10.5 X 3 or 6 Gy X 5 – Chemotherapy to start within three weeks of VCB – Carboplatin AUC 6 + Paclitaxel 175mg/m2 every 21 days X 3 Statistical Design

1:1 Randomization Stratification: – Lymphadenectomy – Intent to use VCB in Arm I Assumptions: – 85% of patients treated with PXRT alive, recurrence – free at three years – Relative decrease in recurrence/death hazard of 49% increases three year RFS to 92% important – Required 77 failures (90% power, type 1 error= 0.05 (one tailed) sample size 562 patients Outcome: Recurrence-Free Survival

– Median follow-up 24 months – 87 events – HR 0.97 (VCB/C relative to PXRT) – (CI 0.635-1.47, p=0.44) – Effect size of 0.51 (i.e. 49% decrease in hazard) not contained within these CI RFS at 24 months: 82% PXRT vs. 84% VCB/C OS at 24 months: 93% PXRT vs. 92% VCB/C

Permission to reuse given by Dr. Scott McMeekin GOG0249 A Randomized Phase III Trial of Pelvic Radiation Therapy versus Vaginal Cuff Brachytherapy followed by Paclitaxel/Carboplatin Chemotherapy in Patients with High- Risk, Early Stage Endometrial Cancer

Vaginal cuff brachytherapy followed Pelvic radiation by Paclitaxel/Carboplatin Chemotherapy Progression-free 82% 84% Survival Overall Survival 93% 92%

87 events Median follow-up 24 months Hazard ratio 0.97 Patterns of Failure

Site of Recurrence PXRT (N=301) VCB/C (N=300)

Vaginal 5 (1.6%) 3 (1%)

Pelvic 2 (0.6%) 19 (6.3%) Para-aortic 2 (0.6%) 3 (1%) Distant 32 (10.6%) 24 (8%) Subgroup Analysis

There is no statistically significant evidence of heterogeneity of the treatment effect with respect to recurrence-free survival among the variables tested above and displayed in the forest plot.

Permission to reuse given by Dr. Scott McMeekin Toxicity

AE Gr 2 Gr 3 Gr 4 PXRT VCB/C PXRT VCB/C PXRT VCB/C Constitutional Fatigue 25 60 1 9 0 1 Weight Loss 0 2 0 0 0 0 GI Nausea 7 17 0 4 0 0 Vomiting 3 8 0 4 0 0 Diarrhea/Constipation 33/1 16/21 8/0 5/1 0/0 0/0 Dehydration 3 6 0 3 0 0 Heme ANC 8 46 0 73 0 94 Hb 3 62 0 5 0 2 PLT 0 11 0 4 0 5 Febrile Neutropenia 0 0 0 6 0 1 Neurologic Sensory 2 20 0 5 0 0 Locally Advanced Disease

In general, most reports have used “involved field” radiotherapy for patients with Stage III disease. Whole Abdominal Radiotherapy

GOG 122 noted a significant worse outcome in advanced patients with WAR (38% 5-year survival) as compared to chemotherapy. GOG 122 delivered 30 Gy to the whole abdomen and 15 Gy to the pelvis – 25 % of patients with stage IV. Our series of WAR patients noted a 86 % 5-year survival, Smith et al noted a 77 % 3-year survival. Pelvic Recurrence Advanced Disease

Author Stage Radiothera Chemothera Observatio py py n Patel et al, III 13% - 33% - 77 % 2007 non Vag Vault Mundt et al, I-IV - 39.5 % – - 2001 53% non Vag Small et al, I-IV 10 % - - 2000 Randall et III-IV 13% (Initial) 18% (Initial) al, 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) Sarcoma 44.9 vs 46.3 % (p=0.51) The data remained significant on multivariate analysis Pelvic Lymphadenopathy ASTEC Survival and sites of recurrence Cause No LN’s Of Death LN removed

Total 88 103 13% 15%

Disease 65% 63%

Treatment 5% 7% related Disease & 0 2% Treatment 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

Regimen 1: Stage IC G3 Pelvic RT (45-50 gy) STAGE II G3 >50% MI Stage III Regimen 2: CDDP, Adriamycin, Cytoxan 5 cycles

R Maggi et al, BJC,2006;95:266 Adjuvant chemotherapy versus radiotherapy in high-risk endometrial carcinoma: result of a randomised trial Median follow up 95.5 months No difference in 5 Year DFS or OS RT locoregional initial recurrence: 7 %, Distant: 21 %, Both:5 Chemotherapy locoregional initial recurrence: 11%, Distant: 16 %, Both:5 % RT reduced local recurrence, chemotherapy reduced distant failure R Maggi et al, BJC,2006;95:266 Chemotherapy

Such results suggest that a more prudent approach would be to combine chemotherapy and RT

Published trials, however, have reported mixed results GOG 34 Chemotherapy did not improve outcome 3 Years Survival Extra-Pelvic Failure RT Alone 75% 22.5% RT + Adriamycin 68% 16.3% P = NS P = NS

Moreover, 12 (7%) of these surgically staged patients developed a SBO after pelvic +/- PART Maybe adriamycin alone is not enough To test a more aggressive regimen, the RTOG launched RTOG 9708

Stage I – III Four cycles TAH – BSO Pelvic RT 45 Chemo +/- Nodal Surgery Gy +VB CDDP Grade 2-3 > ½ MI CDDP 50 mg/m2 + cervical stroma 50 mg/m2 + Extra-uterine Days 1,28 Paclitaxel (Pelvic only) 175 mg/m2 disease + 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 peritoneal fluid 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 carcinomas 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

probabilitysurvivalof 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 NSGO EC-9501/EORTC-55991

PFS progression-freee survival (PFS) serous/clear cell ca

PFS serous/cc carcinoma NSGO-EC-9501/EORTC-55991 1.00

0.73 0.75 0.71

0.50 HR 0.81 (95 % CI 0.41 - 1.61) p=0.55

0.25 0.00 0 1 2 3 4 5 analysis time Number at risk random = 0 76 70 59 47 43 35 random = 1 65 62 55 48 43 27 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

PORTEC-3 comparing pelvic RT versus pelvic RT + chemotherapy in high risk pts

GOG 258 compares chemotherapy alone versus chemotherapy plus volume directed RT in advanced stage patients. GOG 258:Phase III Randomized Study of Adjuvant Chemoradiotherapy Comprising Cisplatin and Tumor Volume-Directed Radiotherapy Followed by Carboplatin and Paclitaxel Versus Carboplatin and Paclitaxel Alone in Patients With Stage III or IVA Endometrial Carcinoma

Objective:Compare the recurrence-free survival of patients with stage III or IVA endometrial carcinoma treated with adjuvant chemoradiotherapy comprising cisplatin and tumor volume-directed radiotherapy followed by carboplatin and paclitaxel vs carboplatin and paclitaxel alone. GOG 258 Submitted to ASCO 2017 as a late breaking abstract! PORTEC-3

pelvic radiotherapy (48.6 Gy)

R RT plus concurrent and adjuvant chemotherapy Concurrent: 2 courses cisplatin 50 mg/m2 Adjuvant: 4 courses of carboplatin AUC 5 and paclitaxel 175 mg/m2 Brachytherapy boost if cervical invasion a. Stage IB grade 3 with documented lymph-vascular space invasion (LVSI); b. Stage IC or IIA grade 3; c. Stage IIB; d. Stage IIIA* or IIIC *IIIA based on peritoneal cytology alone is only eligible if grade 3; e. Stage IB, IC, II or III with serous or clear cell histology Medically Inoperable Endometrial Cancer Schwartz, J., Beriwal, S., Esthappan, J, Erickson, B., Feltmate, C., Fyles, A., Gaffney, D., Jones, E., Klopp, A., Small, Jr., W., Thomadsen, B., Yashar, C., Viswanathan, A., Consensus statement for brachytherapy for the treatment of medically inoperable entometrial cancer, Brachytherapy, Sept-Oct 2015; 14(5): 587-599. Conclusions

RT continues to play an important role in endometrial cancer

Its optimal role is still evolving

Attention turning to combined modality approaches in high risk patients following surgery