Benjamin Movsas, M.D.
This presentation is the property of its rightful owner.
Sponsored Links
1 / 57

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


  • 220 Views
  • Uploaded on
  • Presentation posted in: General

Benjamin Movsas, M.D. Chairman, Radiation Oncology Henry Ford Health System Herndon Chair in Oncology Research. Lessons from RTOG 9801. Lesson #1: Being PI of a study in not all fun and games!. RTOG 9801. Amifostine (500 mg IV) InductionBID RT4x/week) P/C X 2+ weekly P/C

Download Presentation

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

An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -

Presentation Transcript


Benjamin movsas m d chairman radiation oncology henry ford health system herndon chair in oncology research

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

Lessons from RTOG 9801


Benjamin movsas m d chairman radiation oncology henry ford health system herndon chair in oncology research

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


Rtog 9801

RTOG 9801

Amifostine

(500 mg IV)

InductionBID RT4x/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: 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

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

RTOG 98-01:Lesson #2

“The worst result of a clinical trial……


Rtog 98 01 lesson 21

RTOG 98-01:Lesson #2

“The worst result of a clinical trial……

is no result at all!”


Rtog phase iii 98 01

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 98 011

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

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 protection1

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

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

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 no1

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 no2

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

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

RTOG 9801: Patient Accrual

Total Patients Entered243

Average Monthly Accrual5.7


Benjamin movsas m d chairman radiation oncology henry ford health system herndon chair in oncology research

RTOG 9801:

Survival and PFS (in months)

Median f/u = 31 months

Amifostine No-AM

Median Surv 17.3 17.9

Median PFS9.2 9.2

p = NS


Lesson 4 the disconnect

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

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


Esophagitis evaluation by mds

Esophagitis Evaluation by MDs


Severe acute esophagitis primary endpoint

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


Esophagitis evaluation by patient swallowing log 2nd method

Esophagitis Evaluation by Patient Swallowing Log(2nd method)


Area under the curve during ct rt at least 15 assessments performed

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

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

Lesson: Continue to collect PRO data over time!


Qol endpoint

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

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.


Rtog 98011

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


Rtog 98012

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


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)

METHODS

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

AM = amifostine


Methods1

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


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!

RESULTS


Results1

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


Benjamin movsas m d chairman radiation oncology henry ford health system herndon chair in oncology research

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


Results2

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


Results3

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


Benjamin movsas m d chairman radiation oncology henry ford health system herndon chair in oncology research

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


Conclusions1

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

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 significance1

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


Conclusions2

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


Conclusions3

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

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 considerations1

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.


Benjamin movsas m d chairman radiation oncology henry ford health system herndon chair in oncology research

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


Benjamin movsas m d chairman radiation oncology henry ford health system herndon chair in oncology research

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


Benjamin movsas m d chairman radiation oncology henry ford health system herndon chair in oncology research

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


Benjamin movsas m d chairman radiation oncology henry ford health system herndon chair in oncology research

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”


Benjamin movsas m d chairman radiation oncology henry ford health system herndon chair in oncology research

Templatized Study Management

Study templates auto-deliver versioned forms, and reminders


Benjamin movsas m d chairman radiation oncology henry ford health system herndon chair in oncology research

QOL Study Forms for Online Completion

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

EQ5D_html.htm


Benjamin movsas m d chairman radiation oncology henry ford health system herndon chair in oncology research

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


Benjamin movsas m d chairman radiation oncology henry ford health system herndon chair in oncology research

CONCLUSION


Benjamin movsas m d chairman radiation oncology henry ford health system herndon chair in oncology research

CONCLUSION


Benjamin movsas m d chairman radiation oncology henry ford health system herndon chair in oncology research

CONCLUSION


Benjamin movsas m d chairman radiation oncology henry ford health system herndon chair in oncology research

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


  • Login