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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)
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