Benjamin Movsas, M.D.Chairman, Radiation OncologyHenry Ford Health SystemHerndon Chair in Oncology Research Lessons from RTOG 9801
RTOG 9801 Amifostine (500 mg IV) Induction BID RT 4x/week) P/C X 2 + weekly P/C No Amifostine P = paclitaxel (225 mg/m2 d1, 22; 50 mg/m2 d43, 50, 57, 64, 71, 78) C = carboplatin (AUC 7.5 d1, 22; AUC 2 d43, 50, 57, 64, 71, 78) RT = 1.2 Gy BID to 69.6 Gy
Amifostine: Mechanism of Action Amifostine (WR-2721) NH2-(CH2)3-NH-(CH2)2-S-PO3H2 WR-1065 NH2-(CH2)3-NH-(CH2)2-SH Capizzi RL. Oncology. 1999;13:47-59.
RTOG 98-01 - Largest phase III trial of amifostine (n=243) - In the setting of intensive chemoRT - Collected prospective QOL data
RTOG 98-01:Lesson #2 “The worst result of a clinical trial……
RTOG 98-01:Lesson #2 “The worst result of a clinical trial…… is no result at all!”
RTOG Phase III 98-01 Early on, the accrual was lower than projected While there were many issues (eg, activation issues, intensity of tx), one concern surfaced over time……………
RTOG 98-01 Early on, the accrual was lower than projected While there were many issues (eg, activation issues, intensity of tx), one concern surfaced over time…………… POTENTIAL FOR TUMOR PROTECTION
TUMOR PROTECTION? To date, there is no clinical evidence that amifostine protects tumors In many RCTs, a sig diff has not been seen in RRs, TTP, or OS
TUMOR PROTECTION? Yet, this debate has a life of its own….. In Lancet Oncology (Vol 4, June 2003), there was a debate bwn Dr. Brizel and Dr. Overgaard
TUMOR PROTECTION?Dr. Overgaard: YES “There are insufficient data to establish whether the use of AM decreases the rate of cure” “We should not forget that absence of evidence is not evidence of absence”
TUMOR PROTECTION?Dr. Brizel: No In his RCT for H&N (N=303), 2 yr OS was 81% (AM arm) vs. 73% (no-AM) OR 1.12 (95% CI 0.98-1.27) “Critics argue that this trial was not sufficiently powered to detect a very small diff in survival. This argument is technically correct, but overlooks the realities of clinical trials and practice”
TUMOR PROTECTION?Dr. Brizel: No “In order to absolutely refute the claims that antitumor efficacy is compromised by AM, an equivalence trial would have to be done. To show AM reduced survival from a hypothetical 45% to 40% (alpha=0.05, 80% power) would require >1200 pts per arm Yet, the largest H&N RCT took 8 yrs to accrue 1100 pts”
TUMOR PROTECTION?Dr. Brizel: No “Tumor protection will always be a potential risk of any cytoprotective strategy, pharmacological or physical” (including, eg, IMRT) “Risks are inherent in the adoption of any new treatment paradigm. The greatest risk, however, is to simply ignore the tools available to us.”
Lesson #3:TUMOR PROTECTION In designing clinical trials for RT mitigators, we need to be aware of this ongoing debate, especially as we embark on studying relatively new agents.
RTOG 9801: Patient Accrual Total Patients Entered 243 Average Monthly Accrual 5.7
RTOG 9801: Survival and PFS (in months) Median f/u = 31 months Amifostine No-AM Median Surv 17.3 17.9 Median PFS 9.2 9.2 p = NS
Lesson #4: The “disconnect” Once your symptom management study is completed…..how do you interpret the results? What endpoint/perspective matters most? That measured by the healthcare provider (MD) or reported by the patient (Patient Reported Outcome or PRO)?
Two Methods of Assessing Outcome • Maximum Esophagitis Grade (CTC)…..measured by the MD (the “classic” primary endpoint) • Patient Swallowing Questionnaire (patients were asked to assign a daily swallowing score 0-5 based on their symptoms; allows for Area Under The Curve calculation) + validated QOL instrument (EORTC QLQC30 + lung module)….ie, the PROs
Severe Acute Esophagitis(Primary Endpoint) Amifostine (n = 120)Grade No Amifostine (n = 122)Grade 3 4 5 3 4 5 34 (28%) 2 (2%) 0 37 (31%) 3 (3%) 0 P = 0.9
Area Under the Curve During CT/RT At Least 15 Assessments Performed Range 1–3.76 1–3.5 p = 0.025
Patient Self-Assessment–AUC(solid line: amifostine) Lesson: Continue to collect PRO data over time!
QOL Endpoint • In global assessment and subscales no significant differences between arms were seen. • However, there was significantly less deterioration in clinically meaningful pain scores on the amifostine arm (compared to the other arm)-- 21% vs. 35% (p=0.003)
Conclusions • Amifostine did not reduce severe esophagitis in patients with lung cancer receiving concurrent chemotherapy and hyperfractionated RT. • However, based on patient swallowing diaries, area under the curve of esophagitis was significantly lower with amifostine.
While the study did not show a decrease in the rate of severe esophagitis (using NCI-CTC criteria), patients who received amifostine self-reported significantly less swallowing symptoms (on pt diaries) and decreased pain (on their QOL forms). RTOG 9801 highlighted a critical “disconnect” between physician vs. patient reported outcomes (PROs). RTOG 9801 Movsas et. al. J. Clin. Oncol. 23: 2145-54, 2005
Which begs a fundamental question: WHAT IS THE (ADDED) VALUE OF PATIENT-REPORTED OUTCOME DATA, SUCH AS QUALITY OF LIFE? RTOG 9801 Movsas et. al. J. Clin. Oncol. 23: 2145-54, 2005
These pre-tx factors were analyzed as predictors for OS: -KPS (70-80 vs. 90-100) -AJCC stage (II/IIIA vs. IIIB) -Gender -Age -Race -Marital Status -Histology (SqCCa vs. other) -Tumor location (lower vs. other) -Tx arm [AM vs. no-AM] -Global QOL score (via validated EORTC-QLQ-C30) METHODS Note: Only pts with <5% weight loss within 3 months were eligible for enrollment AM = amifostine
A multivariate Cox proportional hazard model was performed. The model was built using a backwards selection process, eliminating variables that have p-values >0.05. METHODS
The median baseline global QOL score was identical (66.7 out of 100) on both treatment arms, further supporting its relevance. Whether the global QOL score was treated as a dichotomized variable (based on the median score of 66.7) or a continuous variable, all other variables fell out of the MVA for OS (eg, KPS, stage), except for the global QOL score! RESULTS
Patients with a global QOL score less than the median (66.7) had a 70% higher rate of death than patients with a QOL score ≥ 66.7 (p=0.002) RESULTS
RESULTS log rank p = 0.001 5 yr OS For all pts: 17%* 27% 11% QOL ≥ median QOL ≥median QOL < median QOL < median *same 5 yr OS with carbo/taxol/RT as with cisplat/RT regimens
Patients who were married or had a partner had higher QOL scores than those who were not (p=0.004). 43% of married/partnered pts had QOL>median vs. 21% of single/widowed/divorced patients. RESULTS
In particular, married females had higher QOL scores than single males (p=0.008). 48% of married females had QOL>median vs. 16% of single male patients. RESULTS
Konski, Pajak, Movsas, et.al. J. Clin. Oncol. 24: 4177-83,2006
When added to known prognostic factors, the baseline global QOL score replaced them all as the sole predictor of OS for patients with locally advanced NSCLC. A clinically meaningful increase in the QOL score (of 10 points) corresponded to a decrease in the hazard of death by 10% (p=0.002) CONCLUSIONS
SO WHAT? CLINICAL SIGNIFICANCE How does one interpret the QOL results? What change is clinically meaningful? Symposium on the Clinical Significance of QOL Measures in Cancer Patients, Mayo Clinic Proceedings (Volume 77, April-June 2002).
SO WHAT? CLINICAL SIGNIFICANCE Using the EORTC-QLQ-C30 instrument, Osoba et.al. asked the patients to rate their perception of change since the prior questionnaire.1 - They found that if the scale scores changed from 5 to 10 points, patients considered their condition “a little” better (or worse) vs. “a lot” for a change of >=10 points. 1 Osoba et.al. J Clin Oncol 16: 139-144, 1998
A clinically meaningful increase in the QOL score (of 10 points) corresponded to a decrease in the hazard of death by 10% (p=0.002)! CONCLUSIONS
This highlights the “added value” of PROs and the need to incorporate QOL measures not only into clinical oncology trials….but into the oncology clinic! The significantly lower QOL score for single/divorced/widowed patients requires additional study. RTOG has recently obtained a grant from PA to further explore via focus groups (PIs: Drs. Movsas, Bruner, Coyne) CONCLUSIONS
STATISTICAL CONSIDERATIONS Missing data is a challenge that plagues most QOL studies, particularly those in advanced stage disease trials. - In a study of patients with advanced non-small cell lung cancer, at about 4 months into the trial, the percentage of responses were only 36% and 42% on the two arms of treatment.1 1Italian Study Group. J Natl Cancer Inst 91:166-172, 1999
STATISTICAL CONSIDERATIONS Missing Items - A strategy to check compliance with QOL timepoints using a real time electronic tracking system should be considered. - Unlike traditional endpoints (like survival), QOL data cannot be collected retrospectively.
RTOG 0828 – A Pilot Companion Study To: 0415 A Phase III Randomized Study of Hypofractionated 3D-CRT/IMRT Versus Conventionally Fractionated 3D-CRT/IMRT in Patients With Favorable-Risk Prostate Cancer
RTOG 0828 Study Background • RTOG 0828 Study Background • Benjamin Movsas, PI • Deb Bruner and Robert Lee, co-PIs • RTOG 0828 pilot – a potential solution to help capture missing QOL data • Challenges: • Cannot obtain QOL data retrospectively • Statistical analysis impacted • Web-based system being piloted to allow: • Consenting patients to complete QOL from any location • Remind patients (and RA’s) if a QOL timepoint window is about to close before the data becomes ‘missing’. • Pilot Goal: To improve 6-month QOL data capture from ~50% to 80% (pilot study limited to interested 15 top accruing institutions) N ~ 100
Web-based Access to QOL data Patient Logs On from Home or Clinic (web-based) Integrate Disparate EMR / PM Systems Real-time forms collection Complete Forms and Assessments System Workflow Collect and Manage Outcomes Data Portal Delivers versioned forms/reminders & stores PHR
Information Delivery Engine (IDE) Patient’s portal is auto-populated from RTOG 0828 study template Clinical Trials Management – Deliver outcomes assessments during designated window and interval with related messages Patient Portal – clinical trials forms, consents, messaging and reminders. “Electronic Clipboard”
Templatized Study Management Study templates auto-deliver versioned forms, and reminders
QOL Study Forms for Online Completion All study forms are provided to the patient for completion as they are on paper EQ5D_html.htm