Benjamin Movsas, M.D.Chairman, Radiation OncologyHenry Ford Health SystemHerndon Chair in Oncology Research

Lessons from RTOG 9801

Lesson #1: Being PI of a study in not all fun and games!

RTOG 9801RTOG 9801

AmifostineAmifostine(500 mg IV)(500 mg IV)

InductionInduction BID RTBID RT 4x/week)4x/week)P/C X 2P/C X 2 ++

weekly P/Cweekly P/C

NoNoAmifostineAmifostine

P P = paclitaxel (225 mg/m= paclitaxel (225 mg/m22 d1, 22; 50 d1, 22; 50 mg/mmg/m22 d43, 50, 57, 64, 71, 78) d43, 50, 57, 64, 71, 78)C C = carboplatin (AUC 7.5 d1, 22; AUC 2 = carboplatin (AUC 7.5 d1, 22; AUC 2 d43, 50, 57, 64, 71, 78)d43, 50, 57, 64, 71, 78)RT RT = 1.2 Gy BID to 69.6 Gy= 1.2 Gy BID to 69.6 Gy

Capizzi RL. Oncology. 1999;13:47-59.

Amifostine: Mechanism of Amifostine: Mechanism of ActionAction

NH2-(CH2)3-NH-(CH2)2-SH

WR-1065

NH2-(CH2)3-NH-(CH2)2-S-PO3H2

Amifostine (WR-2721)

RTOG 98-01RTOG 98-01

-- Largest phase III trial of Largest phase III trial of

amifostine (n=243)amifostine (n=243)

-- In the setting of intensive In the setting of intensive

chemoRTchemoRT

-- Collected prospective QOL Collected prospective QOL

datadata

RTOG 98-01:RTOG 98-01:Lesson #2Lesson #2

““The worst result of a clinical The worst result of a clinical

trial……trial……

RTOG 98-01:RTOG 98-01:Lesson #2Lesson #2

““The worst result of a clinical The worst result of a clinical

trial……trial……

is no result at all!”is no result at all!”

RTOG Phase III 98-01RTOG Phase III 98-01

- Early on, the accrual was lower than Early on, the accrual was lower than

projectedprojected

- While there were many issues (eg, While there were many issues (eg,

activation issues, intensity of tx), one activation issues, intensity of tx), one

concern surfaced over time……………concern surfaced over time……………

RTOG 98-01RTOG 98-01

- Early on, the accrual was lower than Early on, the accrual was lower than

projectedprojected

- While there were many issues (eg, While there were many issues (eg,

activation issues, intensity of tx), one activation issues, intensity of tx), one

concern surfaced over time……………concern surfaced over time……………

- POTENTIAL FOR TUMOR PROTECTIONPOTENTIAL FOR TUMOR PROTECTION

TUMOR TUMOR PROTECTION?PROTECTION?

- To date, there is no clinical evidence that To date, there is no clinical evidence that

amifostine protects tumorsamifostine protects tumors

- In many RCTs, a sig diff has not been seen In many RCTs, a sig diff has not been seen

in RRs, TTP, or OS in RRs, TTP, or OS

TUMOR TUMOR PROTECTION?PROTECTION?

- Yet, this debate has a life of its own…..Yet, this debate has a life of its own…..

- In In Lancet OncologyLancet Oncology (Vol 4, June 2003), (Vol 4, June 2003),

there was a debate bwn Dr. Brizel and Dr. there was a debate bwn Dr. Brizel and Dr.

OvergaardOvergaard

TUMOR PROTECTION?TUMOR PROTECTION?Dr. Overgaard: YESDr. Overgaard: YES

- ““There are insufficient data to establish There are insufficient data to establish

whether the use of AM decreases the rate whether the use of AM decreases the rate

of cure”of cure”

- ““We should not forget that absence of We should not forget that absence of

evidence is not evidence of absence”evidence is not evidence of absence”

TUMOR PROTECTION?TUMOR PROTECTION?Dr. Brizel: NoDr. Brizel: No

- In his RCT for H&N (N=303), 2 yr OS was In his RCT for H&N (N=303), 2 yr OS was

81% (AM arm) vs. 73% (no-AM)81% (AM arm) vs. 73% (no-AM)

- OR 1.12 (95% CI 0.98-1.27)OR 1.12 (95% CI 0.98-1.27)

- ““Critics argue that this trial was not Critics argue that this trial was not

sufficiently powered to detect a very small sufficiently powered to detect a very small

diff in survival. This argument is diff in survival. This argument is

technically correct, but overlooks the technically correct, but overlooks the

realities of clinical trials and practice”realities of clinical trials and practice”

TUMOR PROTECTION?TUMOR PROTECTION?Dr. Brizel: NoDr. Brizel: No

- ““In order to absolutely refute the claims In order to absolutely refute the claims

that antitumor efficacy is compromised by that antitumor efficacy is compromised by

AM, an equivalence trial would have to be AM, an equivalence trial would have to be

done.done.

- To show AM reduced survival from a To show AM reduced survival from a

hypothetical 45% to 40% (alpha=0.05, hypothetical 45% to 40% (alpha=0.05,

80% power) would require >1200 pts per 80% power) would require >1200 pts per

armarm

- Yet, the largest H&N RCT took 8 yrs to Yet, the largest H&N RCT took 8 yrs to

accrue 1100 pts”accrue 1100 pts”

TUMOR PROTECTION?TUMOR PROTECTION?Dr. Brizel: NoDr. Brizel: No

- ““Tumor protection will always be a Tumor protection will always be a

potential risk of any cytoprotective potential risk of any cytoprotective

strategy, pharmacological or physical” strategy, pharmacological or physical”

(including, eg, IMRT)(including, eg, IMRT)

- ““Risks are inherent in the adoption of any Risks are inherent in the adoption of any

new treatment paradigm. The greatest new treatment paradigm. The greatest

risk, however, is to simply ignore the tools risk, however, is to simply ignore the tools

available to us.”available to us.”

Lesson #3:Lesson #3:TUMOR PROTECTIONTUMOR PROTECTION

- In designing clinical trials for RT In designing clinical trials for RT

mitigators, we need to be aware of this mitigators, we need to be aware of this

ongoing debate, especially as we embark ongoing debate, especially as we embark

on studying relatively new agents.on studying relatively new agents.

RTOG 9801: Patient RTOG 9801: Patient AccrualAccrual

Total Patients EnteredTotal Patients Entered 243 243

Average Monthly AccrualAverage Monthly Accrual 5.75.7

RTOG 9801:RTOG 9801:Survival and PFS (in months)Survival and PFS (in months)

Median f/u = 31 monthsMedian f/u = 31 months

Amifostine Amifostine No-AMNo-AM

Median Surv 17.3Median Surv 17.3 17.917.9

Median PFSMedian PFS 9.29.2 9.2 9.2p = NSp = NS

Lesson #4: The Lesson #4: The “disconnect”“disconnect”

- Once your symptom management study is Once your symptom management study is

completed…..how do you interpret the completed…..how do you interpret the

results?results?

- What endpoint/perspective matters most? What endpoint/perspective matters most?

That measured by the healthcare That measured by the healthcare

provider (MD) or reported by the patient provider (MD) or reported by the patient

(Patient Reported Outcome or PRO)?(Patient Reported Outcome or PRO)?

Two Methods of Assessing Two Methods of Assessing OutcomeOutcome

Maximum Esophagitis Grade (CTC)Maximum Esophagitis Grade (CTC)…..measured by the MD (the “classic” primary …..measured by the MD (the “classic” primary endpoint)endpoint)

Patient Swallowing QuestionnairePatient Swallowing Questionnaire (patients (patients were asked to assign a were asked to assign a dailydaily swallowing score swallowing score 0-5 based on their symptoms; allows for Area 0-5 based on their symptoms; allows for Area Under The Curve calculation) + validated QOL Under The Curve calculation) + validated QOL instrument (EORTC QLQC30 + lung module)instrument (EORTC QLQC30 + lung module)….ie, the PROs….ie, the PROs

Esophagitis Evaluation Esophagitis Evaluation by MDsby MDs

Severe Acute EsophagitisSevere Acute Esophagitis(Primary Endpoint)(Primary Endpoint)

P P = 0.9= 0.9

0033

(3%)(3%)3737

(31%)(31%)

0022

(2%)(2%)3434

(28%)(28%)

554433554433

Amifostine (n = 120)Grade

No Amifostine (n = 122)Grade

Esophagitis Evaluation by Esophagitis Evaluation by Patient Swallowing LogPatient Swallowing Log(2nd method)(2nd method)

Area Under the Curve During Area Under the Curve During CT/RT CT/RT At Least 15 Assessments At Least 15 Assessments PerformedPerformed

Amifostine Amifostine

(n = 96) (n = 96) No Amifostine No Amifostine

(n = 96)(n = 96)

AverageAverage 2.192.19 2.342.34

1–3.51–3.51–3.761–3.76Range

p = 0.025

Patient Self-Assessment–AUCPatient Self-Assessment–AUC(solid line: amifostine)(solid line: amifostine)

Lesson: Continue to collect PRO data over time!

QOL EndpointQOL Endpoint

In global assessment and In global assessment and subscales no significant subscales no significant differences between arms were differences between arms were seen.seen.

However, there was significantly However, there was significantly less deterioration in clinically less deterioration in clinically meaningful pain scores on the meaningful pain scores on the amifostine arm (compared to the amifostine arm (compared to the other arm)--other arm)--

21% vs. 35% 21% vs. 35% (p=0.003)(p=0.003)

ConclusionsConclusions Amifostine did not reduce severe Amifostine did not reduce severe

esophagitis in patients with lung esophagitis in patients with lung cancer receiving concurrent cancer receiving concurrent chemotherapy and hyperfractionated chemotherapy and hyperfractionated RT.RT.

However, based on patient swallowing However, based on patient swallowing diaries, area under the curve of diaries, area under the curve of esophagitis was significantly lower esophagitis was significantly lower with amifostine.with amifostine.

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RTOG 9801RTOG 9801

While the study did not show a decrease in the While the study did not show a decrease in the rate of severe esophagitis (using NCI-CTC rate of severe esophagitis (using NCI-CTC criteria), patients who received amifostine criteria), patients who received amifostine self-reported significantly less swallowing self-reported significantly less swallowing symptoms (on pt diaries) and decreased pain symptoms (on pt diaries) and decreased pain (on their QOL forms).(on their QOL forms).

RTOG 9801 highlighted a critical “disconnect” RTOG 9801 highlighted a critical “disconnect” between physician vs. patient reported between physician vs. patient reported outcomes (PROs).outcomes (PROs).

Movsas et. al. J. Clin. Oncol. 23: 2145-54, 2005

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RTOG 9801RTOG 9801

Which begs a fundamental question:Which begs a fundamental question:

WHAT IS THE (ADDED) VALUE OF WHAT IS THE (ADDED) VALUE OF PATIENT-REPORTED OUTCOME PATIENT-REPORTED OUTCOME DATA, SUCH AS QUALITY OF DATA, SUCH AS QUALITY OF LIFE?LIFE?

Movsas et. al. J. Clin. Oncol. 23: 2145-54, 2005

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METHODSMETHODS

These pre-tx factors were analyzed as predictors for OS:These pre-tx factors were analyzed as predictors for OS:

-KPS -KPS (70-80 vs. 90-100)(70-80 vs. 90-100) - -AJCC stage AJCC stage (II/IIIA vs. IIIB)(II/IIIA vs. IIIB)

-Gender-Gender -Age -Age

-Race-Race -Marital Status -Marital Status

-Histology -Histology (SqCCa vs. other)(SqCCa vs. other) -Tumor location -Tumor location (lower vs. (lower vs. other)other)

-Tx arm -Tx arm [AM vs. no-AM][AM vs. no-AM] -Global QOL score -Global QOL score (via validated EORTC-QLQ-C30)(via validated EORTC-QLQ-C30)

Note: Only pts with <5% weight loss within 3 months were eligible for Note: Only pts with <5% weight loss within 3 months were eligible for enrollment enrollment

AM = amifostineAM = amifostine

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METHODSMETHODS

A multivariate Cox proportional A multivariate Cox proportional hazard model was performed. hazard model was performed.

The model was built using a backwards The model was built using a backwards selection process, eliminating variables selection process, eliminating variables that have p-values >0.05.that have p-values >0.05.

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RESULTSRESULTS

The median baseline global QOL score was The median baseline global QOL score was identical (66.7 out of 100) on both treatment identical (66.7 out of 100) on both treatment arms, further supporting its relevance.arms, further supporting its relevance.

Whether the global QOL score was treated as a Whether the global QOL score was treated as a dichotomized variable (based on the median dichotomized variable (based on the median score of 66.7) or a continuous variable, score of 66.7) or a continuous variable, all all other variables fell out of the MVA for OS (eg, other variables fell out of the MVA for OS (eg, KPS, stage), except for the global QOL score!KPS, stage), except for the global QOL score!

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RESULTSRESULTS

Patients with a global QOL score Patients with a global QOL score less than the median (66.7) had a less than the median (66.7) had a 70% higher rate of death than 70% higher rate of death than patients with a QOL score ≥ 66.7 patients with a QOL score ≥ 66.7

(p=0.002)(p=0.002)

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RESULTSRESULTS

5 yr OS

For allpts: 17%*

27%

11%

QOL ≥ median

QOL < median

*same 5 yr OS with carbo/taxol/RT as with cisplat/RT regimens

Pts. at Risk>= 66.7< 66.7

Pts. at Risk80137

Pts. at Risk80135

Pts. at Risk80134

Pts. at Risk79132

Pts. at Risk79129

Pts. at Risk75125

Fail / Total56 / 80

120 / 137 p=0.0011 (log-rank)>= 67.7< 66.7

% A

LIV

E

0

25

50

75

100

MONTHS FROM RANDOMIZATION0 12 24 36 48 60

QOL ≥ median

QOL < median

log rank p = 0.001

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RESULTSRESULTS

Patients who were married or had a Patients who were married or had a partner had higher QOL scores partner had higher QOL scores than those who were not (p=0.004).than those who were not (p=0.004).

43% of married/partnered pts had QOL>median43% of married/partnered pts had QOL>median vs.vs.21% of single/widowed/divorced patients.21% of single/widowed/divorced patients.

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RESULTSRESULTS

In particular, married females had In particular, married females had higher QOL scores than single higher QOL scores than single males males (p=0.008).(p=0.008).

48% of married females had QOL>median48% of married females had QOL>median

vs.vs.

16% of single male patients.16% of single male patients.

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Konski, Pajak, Movsas, et.al. J. Clin. Oncol. 24: 4177-83,2006

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CONCLUSIONSCONCLUSIONS

When added to known prognostic factors, the When added to known prognostic factors, the baseline global QOL score replaced them all baseline global QOL score replaced them all as the sole predictor of OSas the sole predictor of OS for patients with for patients with locally advanced NSCLC. locally advanced NSCLC.

A clinically meaningful increase in the QOL A clinically meaningful increase in the QOL score (of 10 points) corresponded to a score (of 10 points) corresponded to a decrease in the hazard of death by 10% decrease in the hazard of death by 10% (p=0.002)(p=0.002)

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

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CONCLUSIONSCONCLUSIONS

A clinically meaningful increase in the QOL A clinically meaningful increase in the QOL score (of 10 points) corresponded to a score (of 10 points) corresponded to a decrease in the hazard of death by 10% decrease in the hazard of death by 10% (p=0.002)!(p=0.002)!

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CONCLUSIONSCONCLUSIONS

This highlights the “added value” of PROs and This highlights the “added value” of PROs and the need to incorporate QOL measures not the need to incorporate QOL measures not only into clinical oncology trials….but into only into clinical oncology trials….but into the oncology clinic!the oncology clinic!

The significantly lower QOL score for The significantly lower QOL score for single/divorced/widowed patients requires single/divorced/widowed patients requires additional study.additional study.

RTOG has recently obtained a grant from PA to RTOG has recently obtained a grant from PA to further explore via focus groups further explore via focus groups (PIs: Drs. Movsas, Bruner, Coyne)(PIs: Drs. Movsas, Bruner, Coyne)

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 CONSIDERATIONSSTATISTICAL 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.

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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

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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

RTOG 0828 Study Background

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Patient Logs On from Home or Clinic (web-based)

Portal Delivers versioned forms/reminders & stores PHR

Real-time formscollection

Complete Forms and Assessments

Collect and Manage Outcomes Data

Integrate DisparateEMR / PM Systems

Web-based Access toQOL data

System Workflow

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Clinical Trials Management – Deliver outcomesassessments during designated windowand interval with related messages

Patient Portal – clinical trials forms, consents, messaging and reminders.“Electronic Clipboard”

Patient’s portal is auto-populated from RTOG 0828 study template

Information Delivery Engine (IDE)

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Study templates auto-deliver versioned forms, and reminders

Templatized Study Management

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All study forms are provided to the patient for completion as they are on paper

EQ5D_html.htm

QOL Study Forms for Online Completion

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RTOG 0828 Reports and Data Filters

• Data entered by patients is De-identified and aggregated

• Custom reports may be generated

• Data exported to Excel, XML, PDF

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CONCLUSIONCONCLUSION

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CONCLUSIONCONCLUSION

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CONCLUSIONCONCLUSION

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An Example of a Plot of Acute Esophagitis Grade Vs. Time for a Single Patient, Allowing Us to Calculate Esophagitis Index (EI), Using the Trapezoidal Rule

0

1

2

3

4

1 2 3 4 5 6 7* 8 9 10 11 12 13 14 15 16 17

Weeks

Acu

te E

soph

agiti

s G

rade

(R

TO

G) *End of

thoracic radiotherapy

Esophagitis Index (EI) Esophagitis Index (EI) ==

0+10+1++

1+11+1x 4 x 4 ++

1+21+2++

2+32+3++

3+03+0x 4 = x 4 = 14.514.522 22 22 22 22