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

Conflicts of Interest

Research funding from

• American Cancer Society

• Cancer Prevention Research Institute of Texas

Retrospective studies show lower rates of acute and chronic GI toxicity

with IMRT as compared to standard 4-field RT.

RTOG 0418 found IMRT to be feasible with a favorable rate of acute 2+ GI

toxicity (25%).

IMRT for post-operative pelvic RTIMRT reduces the dose delivered to small bowel in center of pelvis.

Eligibility

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

Stratification Factors

Disease Site: Endometrial, Cervix

XRT Dose: 45 Gy, 50.4 Gy

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

RA

ND

OM

IZE

IMRT pelvic

radiation treatment

4-field pelvic radiation treatment

Schema

Objectives

Secondary endpoints:

• Acute urinary toxicity with patient reported outcome

• Quality of life (FACT)

• Local control, disease-free survival, overall survival

• Health utilities analysis

Primary endpoint: Determine if acute GI toxicity is reduced with IMRT after 5 weeks of treatment using a patient reported measure of toxicity.

Time points for evaluation

Time Point Purpose

Before RT Baseline

3 weeks after RT start Compare early acute toxicity

End of RT (5 weeks after RT start) Maximum difference in acute toxicity

4-5 weeks after RT Compare resolution of acute toxicity

1 year from start of RT Early chronic toxicity

3 years from the start of RT Long term toxicity

• Primary endpoint: change in acute GI toxicity using EPIC (expanded prostate cancer index composite) bowel domain

– Change from baseline to 5 weeks of RT

• Effect size of 0.4

• Two-sample t-test with one interim analysis

p= 0.049 for final analysis

• 225 evaluable patients needed

– Expanded by 20% for attrition,

non-compliance or ineligibility

resulting goal of 281 patients.

Sample size

Nodal CTV

-RTOG atlas

Vaginal

-ITV w bladder full and empty

7mm PTV expansion

OARs: Bone marrow, bowel,

bladder, rectum

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

Treatment planning

IMRT planning Standard RT

Enrollment: 2012-2015289 enrolled, 278 eligible

IMRT(n=129)

4 Field(n=149)

Age Median (yrs) 62 62

RaceBlack 12 (10%) 12 (8%)

White 96 (74%) 114 (77%)

PS (Zubrod)0 101 (78%) 103 (69%)

1 27 (21%) 42 (28%)

Radiation Dose45 Gy 76 (59%) 84% (56%)

50.4 Gy 53 (41%) 65 (44%)

SiteEndo 108 (84%) 125 (84%)

Cervix 21 (16%) 24 (16%)

Chemotherapy No 95 (74%) 112 (75%)

EPIC Bowel QuestionsBowel Function:

- rectal urgency?

- uncontrolled leakage of stool?

- stools that were loose?

- bloody stools?

- your bowel movements been painful?

How often have you had…

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:

- has each of these issues been for you?

- have your bowel habits been for you?How big of a problem…

50

70

90

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

IMRT 128 113 111 1024 Field 148 132 130 125

EPIC Bowel Score

p-value = 0.048

IMRT

4-field

EPIC Bowel Results

Bowel Summary

IMRT (n=107)

4 Field (n=126)

p-value

Mean -18.6 -23.6

Std. Dev. 18.7 19.4 0.048

Median -17.9 -22.3

Bowel Bother

Mean -22.3 -26.1 0.19

Std. Dev. 22.0 22.2

Median -21.4 -21.4

Bowel Function

Mean -14.8 -21.0 0.02

Std. Dev. 19.0 19.3

Median -14.3 -17.9

Pro-CTCAE QuestionsBowel Function:

- Did you have loose or watery stools?

- Did you lose control of bowel movements?

- What was the severity of your pain in the abdomen (belly area) at its worst?

- Have you taken an anti-diarrhea medication?

In the last 7 days, how often…

Bowel Bother:

In the last 7 days…

- How much did pain in the abdomen (belly area) interfere with your usual or daily activities?

- How much did loss of control of bowel movements interfere with your usual or daily activities?

0

10

20

30

40

50

60 standard

IMRT

Pe

rce

nt

of

pat

ien

ts w

ith

PR

O-

CTC

AE

Sco

re ≥

3 a

t 5

we

eks

Abdominal pain Diarrhea Fecal incontinence

Frequency Interference Frequency Interference

*

* *

*, p <0.05

Pro-CTCAE Results

0%

10%

20%

30%

40%

50%

60%

70%

0 or 1 2 or 3 4 or more

standard

IMRT

Pe

rce

nta

ge o

f p

atie

nts

Use of Anti-Diarrheal Medications

Number of anti-diarrheal medications daily

p <0.05

EPIC Urinary Results

Change in EPIC Urinary Score from Baseline to 5 Weeks

IMRT (n=107)

4 Field (n=126)

p-value

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

Quality of Life: FACT-Cx

Physical well-being

Energy, pain, feeling ill, time in bed, nausea, meeting needs of family

Social well-being

Emotional well-being

Functional well-being

Work, enjoy life, accept illness, sleep well

Additional treatment related concerns

Vaginal symptoms, interest in sex, body appearance, urinary fxn, appetite

Trial Outcome Index

Quality of Life: FACT-Cx

Change in FACT-Cx IMRT 4 Field p-value

Physical Well-Being (n=86) (n=106)

Mean -4.2 -6.1 0.03

Std. Dev. 6.0 6.1

Add’l treatment concerns (n=87) (n=104)

Mean -2.7 -4.9 0.01

Std. Dev. 6.1 6.5

Trial Outcome Index (n=86) (n=106)

Mean -8.8 -12.8 0.06

Std. Dev. 14.4 14.3

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

Pelvic IMRT improves quality of life with regard to physical

functioning and other treatment effects during treatment .

Longer term follow up will be needed to determine if these

differences in acute toxicity result in lower rates of late toxicity.

Pelvic IMRT reduces need for anti-diarrheal medications as

compared to standard pelvic RT.

Conclusions

Acknowledgements

Patients and physicians enrolling on study.

NRG team

Funding

U10CA180868 (NRG Oncology Operations)

U10CA180822 (NRG Oncology SDMC)

UG1CA189867 (NCORP) from the National Cancer Institute (NCI)