Benjamin Movsas, M.D. Chairman, Radiation Oncology Henry Ford Health System Herndon Chair in Oncology Research

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Benjamin Movsas, M.D.Chairman, Radiation
OncologyHenry Ford Health SystemHerndon Chair
in Oncology Research
Lessons from RTOG 9801
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Lesson 1 Being PI of a study in not all fun and
games!
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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

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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. 19991347-59.
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RTOG 98-01

• - Largest phase III trial of amifostine (n243)
• - In the setting of intensive chemoRT
• - Collected prospective QOL data

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RTOG 98-01Lesson 2

• The worst result of a clinical trial

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RTOG 98-01Lesson 2

• The worst result of a clinical trial
• is no result at all!

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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

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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

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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

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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

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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

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TUMOR PROTECTION?Dr. Brizel No

• In his RCT for HN (N303), 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

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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 (alpha0.05, 80 power) would require
  gt1200 pts per arm
• Yet, the largest HN RCT took 8 yrs to accrue
  1100 pts

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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.

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Lesson 3TUMOR 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.

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RTOG 9801 Patient Accrual

• Total Patients Entered 243
• Average Monthly Accrual 5.7

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• 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

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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)?

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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

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Esophagitis Evaluation by MDs
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Severe Acute Esophagitis(Primary Endpoint)
Amifostine (n 120)Grade
No Amifostine (n 122)Grade
5
4
3
5
4
3
2 (2)
34 (28)
0
0
3 (3)
37 (31)
P 0.9
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Esophagitis Evaluation by Patient Swallowing
Log(2nd method)
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Area Under the Curve During CT/RT At
Least 15 Assessments Performed
Amifostine (n 96) Amifostine (n 96) No Amifostine (n 96) No Amifostine (n 96)
Average 2.19 2.19 2.34 2.34

Range
13.5
13.76
p 0.025
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Patient Self-AssessmentAUC(solid line
amifostine)
Lesson Continue to collect PRO data over time!
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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 (p0.003)

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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.

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RTOG 9801

• 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).

Movsas et. al. J. Clin. Oncol. 23 2145-54, 2005
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RTOG 9801

• Which begs a fundamental question
• WHAT IS THE (ADDED) VALUE OF PATIENT-REPORTED
  OUTCOME DATA, SUCH AS QUALITY OF LIFE?

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

• 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)

Note Only pts with lt5 weight loss within 3
months were eligible for
enrollment AM amifostine
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METHODS

• A multivariate Cox proportional hazard model
  was performed.
• The model was built using a backwards selection
  process, eliminating variables that have p-values
  gt0.05.

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RESULTS

• 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!

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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 (p0.002)

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RESULTS
log rank p 0.001
5 yr OS For all pts 17 27 11
QOL median
QOL median
QOL lt median
QOL lt median
same 5 yr OS with carbo/taxol/RT as with
cisplat/RT regimens
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RESULTS

• Patients who were married or had a partner had
  higher QOL scores than those who were not
  (p0.004).
• 43 of married/partnered pts had QOLgtmedian
• vs.
• 21 of single/widowed/divorced patients.

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RESULTS

• In particular, married females had higher QOL
  scores than single males (p0.008).
• 48 of married females had QOLgtmedian
• vs.
• 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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CONCLUSIONS

• 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 (p0.002)

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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).

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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 gt10 points.
• 1 Osoba et.al. J Clin Oncol 16 139-144, 1998

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CONCLUSIONS

• A clinically meaningful increase in the QOL score
  (of 10 points) corresponded to a decrease in the
  hazard of death by 10 (p0.002)!

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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)

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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 91166-172, 1999

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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.

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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

• 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 RAs) 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

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System Workflow
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Information Delivery Engine (IDE)
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Templatized Study Management
Study templates auto-deliver versioned forms,
and reminders
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QOL Study Forms for Online Completion
All study forms are provided to the patient for
completion as they are on paper EQ5D_html.htm
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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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CONCLUSION
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CONCLUSION
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CONCLUSION
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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

• End of thoracic radiotherapy

Esophagitis Index (EI) 01 11 x 4 12 23 30 x 4 14.5
Esophagitis Index (EI) 2 2 x 4 2 2 2 x 4 14.5