A RANDOMIZED PHASE III STUDY (NRG Oncology’s RTOG 1203) OF STANDARD VS. IMRT PELVIC RADIATION FOR POST-OPERATIVE TREATMENT OF ENDOMETRIAL AND CE CERVICAL CA CANCER (T (TIME-C) 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
IMRT for post-operative pelvic RT IMRT reduces the dose delivered to small bowel in center of pelvis. 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%).
Schema Eligibility IMRT pelvic Women with endometrial or cervical radiation treatment cancer requiring post-op pelvic RT or chemoRT RANDOMIZE Stratification Factors XRT Dose: 45 Gy, 50.4 Gy 4-field pelvic Chemo: No chemo, 5 cycles of weekly radiation treatment cisplatin at 40mg/m 2 Disease Site: Endometrial, Cervix
Objectives Primary endpoint: Determine if acute GI toxicity is reduced with IMRT after 5 weeks of treatment using a patient reported measure of toxicity . Secondary endpoints: • Acute urinary toxicity with patient reported outcome • Quality of life (FACT) • Local control, disease-free survival, overall survival • Health utilities analysis
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
Sample size • 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.
Treatment planning IMRT planning Standard RT 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.
Enrollment: 2012-2015 IMRT 4 Field 289 enrolled, 278 eligible (n=129) (n=149) Age Median (yrs) 62 62 Black 12 (10%) 12 (8%) Race White 96 (74%) 114 (77%) 0 101 (78%) 103 (69%) PS (Zubrod) 1 27 (21%) 42 (28%) 45 Gy 76 (59%) 84% (56%) Radiation Dose 50.4 Gy 53 (41%) 65 (44%) Endo 108 (84%) 125 (84%) Site Cervix 21 (16%) 24 (16%) Chemotherapy No 95 (74%) 112 (75%)
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: - has each of these issues been for you? How big of a problem… - have your bowel habits been for you?
EPIC Bowel Score 90 IMRT 70 p-value = 0.048 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
EPIC Bowel Results IMRT 4 Field p-value (n=107) (n=126) Mean -18.6 -23.6 Bowel Summary Std. Dev. 18.7 19.4 0.048 Median -17.9 -22.3 Mean -14.8 -21.0 0.02 Bowel Function Std. Dev. 19.0 19.3 Median -14.3 -17.9 Mean -22.3 -26.1 0.19 Bowel Bother Std. Dev. 22.0 22.2 Median -21.4 -21.4
Pro-CTCAE Questions Bowel Function: - Did you have loose or watery stools? In the - Did you lose control of bowel movements? last 7 days, how - What was the severity of your pain in the abdomen (belly often… area) at its worst? Bowel Bother: - Have you taken an anti-diarrhea medication? - How much did pain in the abdomen (belly area) interfere with your usual or daily activities? In the last 7 days… - How much did loss of control of bowel movements interfere with your usual or daily activities?
Pro-CTCAE Results * 60 standard IMRT Percent of patients with PRO- 50 CTCAE Score ≥3 at 5 weeks 40 30 * * 20 10 0 Frequency Interference Frequency Interference *, p <0.05 Abdominal pain Diarrhea Fecal incontinence
Use of Anti-Diarrheal Medications 70% Percentage of patients 60% 50% 40% standard IMRT 30% 20% p <0.05 10% 0% 0 or 1 2 or 3 4 or more Number of anti-diarrheal medications daily
EPIC Urinary Results Change in EPIC Urinary Score from IMRT 4 Field p-value Baseline to 5 Weeks (n=107) (n=126) 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 Trial Outcome Index 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
Quality of Life: FACT-Cx Change in FACT-Cx IMRT 4 Field p-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 treatment concerns (n=87) (n=104) Mean -2.7 -4.9 0.01 Std. Dev. 6.1 6.5
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 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.
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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