v. budach – statements on h&n cancer - 1 discussion panel on quality of life and radiotherapy...

V. Budach – Statements on H&N Cancer - 1

Discussion Panel on Quality of Life and Radiotherapy in Head and Neck Cancer

Volker Budach, MD, PhD Head Department

for Radiation OncologyCharité Campus-Mitte

Berlin

Interdisciplinary Workshop on Modern Treatment Options

Statements on Head and Neck CanerFrankfurt, 27-28 of January 2006


Most of the studies addressing chemoradiation of locally advanced H&N cancer report increased acute and in some instances also late morbidities!

Is this a valid observation which can be supported by published literature results?

Are the data sufficient to address this question?

Quality of Life Issues and Acute Toxicity/Late Morbidity Items in Chemoradiation of Locally

Advanced Head and Neck Cancer


Toxicity in random. head & neck trials: RT vs. RT-CHX(grade >=III)

Concurrent RT-CHX (“older studies“)drug(s) %-diff. n end point referenceBLM +54.0%* 199 acute Eschwege et al. 1987

BLM/MTX +50.0%* 96 acute Fu et al. 1987

MTX +9.0%* 313 acute Gupta et al. 1990

5-FU +11.7%* 282 acute Sanchiz et al. 1990

5-FU +20.5%* 175 acute Bowman et al. 1994

mean +23.7% 1065 acute

5-FU grade 4:+4.4% 136 late Collin et al. 1972 BLM/MTX +5.0% 96 late Fu et al. 1987MTX “not enhanced“ 313 late Gupta et al. 1990

*= significantly more pat. with severe mucosa and/or skin toxicityW. Budach, personell communicationW. Budach, personell communication


Toxicity in random. head & neck. trials: RT vs. RT-CHX(Concurrent RT-CHX: grade >=III)

drug(s) %-diff. n end point referenceMMC (adj) +0.2% 113 acute Haffty et al. 1983MMC -12.0% 117 acute Weissberg et al. 1989

P/5-FU +22.0%* 270 acute Wendt et al. 1998P-P/5-F +9.2% 147 acute Al-Sarraf et al. 1998

P/5-FU +30.0%* 222 acute Calais et al. 1999P (daily) +13.8% 130 acute Jeremic et al. 2000

mean +16.6% 999 acute

MMC +2.0% 117 late Weissberg et al. 1989P/5-FU +3.6% 270 late Wendt et al. 1998

P/5-FU +12.0%** 222 late Calais et al. 1999P (daily) +17.0% 130 late Jeremic et al. 2000

mean +8.2% 739 late *= significantly more pat. with severe mucosa and/or skin toxicity

**= significantly more severe late toxicityW. Budach, personell communicationW. Budach, personell communication


Toxicity in random. head & neck. trials: RT vs. RT-CHX(Concurrent or alternating RT-CHX: grade >=III)

Studies with 5-14% less RT-dose in CHX-arm RT dose end

drug(s) with CHX %-diff. n point referenceP/5-FU alt. -14% -2.5% 157 acute Merlano et al. 1991P/5-FU -5% -2.0% 116 acute Brizel et al. 1998MMC/5-FU -10% -9.5%* 384 acute Budach et al. 2000

mean -5.2% 774 acute

P/5-FU alt. -14% -9.1%** 157 late Merlano et al. 1991 P/5-FU -5% +2.0% 116 late Brizel et al. 1998

MMC/5-FU -10% -3.8% 384 late Budach et al. 2000

mean -3.1% 774 late

*= significantly less pat. with severe mucosa toxicity **= significantly less severe late toxicity

W. Budach, personell communicationW. Budach, personell communication


No Correlation between acute and late CHX excess toxicity (Evidence from 18 randomized clinical trials)

NSCLC

Head&Neck-Ca. Cervical-Ca. Rectal-Ca.

R2 = 0.074-10

-5

0

5

10

15

20

-20 0 20 40 60

excess acute >=grade III toxicity [%]

exce

ss la

te >

=g

r. II

I to

xcit

y [%

]

W. Budach, personell communicationW. Budach, personell communication


Developments in Safety, Toxicity and QOL Reporting

in Oncology Clinical Trials

Dimtrios Colevas MDSenior Investigator,Investigational Drug

Branch, CTEP, National Cancer InstituteBethesda, MD

ASTRO Education SessionOctober 20,2005Denver, Colorado

Andy Trotti MDAndy Trotti MDDirector of Clinical Trials,Director of Clinical Trials,

Radiation OncologyRadiation OncologyH. Lee Moffitt Cancer H. Lee Moffitt Cancer

CenterCenterTampa, FLTampa, FL

Deborah Watkins-Bruner RN PhD

Director of Outcomes Research, Fox Chase Cancer Center

Philadelphia, PA


• Provide background on how safety data is generated, analyzed and published.

•We will highlight areas in need of better methods, standards and guidelines in patient screening/data collection, data analysis, presentation, publication, and interpretation.

•Target audience: Primarily directed at the investigator (or the practitioner with a keen interest in toxicity/QOL) who wants to have a deeper understanding of toxicity profiles and QOL outcomes.

•Highlight opportunities for research questions.

Objectives

Research opportunity…


•Understand the strengths and limitations of the current toxicity reporting process for multimodality clinical trials

•Understand changes in the new NCI-Common Terminology Criteria system for adverse events (CTCAE)

•Understand the role of QOL and symptom tools in specific investigations of adverse effects

Educational Objectives


References and Sources

Adverse Effects of Cancer Treatment:

Metrics, Management and Investigations

Seminars Radiation Oncology

Volume 13, No 3, July 2003

Andy Trotti MDAndy Trotti MDDirector of Clinical Trials,Director of Clinical Trials,

Radiation OncologyRadiation OncologyH. Lee Moffitt Cancer CenterH. Lee Moffitt Cancer Center

Tampa, FLTampa, FL


How should we evaluate the adverse effects of

cancer treatment on health status in oncology?


Patient Relevance

Sp

ecif

icit

y

* Bentzen et al (Sem Rad Onc July 03)* Bentzen et al (Sem Rad Onc July 03)

Adverse Effects Domains*

ANALYTIC (Lab)

SYMPTOMS

OBJECTIVE (Exam)

QUALITY OF LIFE &PATIENT REPORTED OUTCOMES

Common Toxicity Criteria

Research opportunity:Develop and use PROsto improve quality of symptom capture.


•QOL and symptoms scales are wholly subjective metrics--a highly

individual personal perception.

•QOL scores are affected by one’s ability to cope/adapt to adversity

•QOL scores are influenced by cancer status

•QOL correlates with toxicity in some studies, not in others

•QOL may include diverse domains of social support, spirituality

QOL = Toxicity

•QOL (assessed by patients) may be complimentary to, and may

help to inform the clinician about adverse effects, but is

not a substitute for adverse event reporting (as assessed by

clinicians).


Safety

Efficacy

Balancing Risk and Benefit

This gap constrains our ability to make informed judgments about the balance of risks and benefits.

Well develop endpoints and reporting methods

Underdeveloped and lacking standards…


“Toxicity profile”

• Data verification (audits; monitoring)

The Safety Reporting Process in Oncology

• Schedule of required evaluations

• Evaluation/Screening (interview + exam + testing)

• Clinical documentation

• Assign toxicity terms and grades (coding)

• Data display and analysis

• Scientific Publication

• Data submission (CRFs/sponsor)

Terminology and Grading System

• SAE/AE determination & reporting

Adapted from Gwede, JOM 2002


•Schedule of required evaluations

•Evaluation/Screening (interview + exam + testing)

•Clinical documentation

•Interpret and apply a grade (coding)

•Data display and analysis

•Scientific Publication

•Data submission (CRFs/sponsor)


Terminology and Grading Criteria

•Data verification (audits; monitoring)

•SAE/AE determination & reporting

Data Genera

tion

Data Submission/A

nalysis

The Safety Reporting Process in Oncology

Variations in data collection practices

Variations in grading systems (# terms; acute/late; modalities)

Variations in reporting methods

Lack of standard summary methods

“Deficiencies in the safety reporting process may lead to under-reporting and bias”

Gwede (2002)


•Schedule of required evaluations

•Evaluation/Screening (interview + exam + testing)

•Clinical documentation

•Interpret and apply a grade (coding)

•Data display and analysis

•Scientific Publication

•Data submission (CRFs/sponsor)


•Grading Criteria

•Data verification (audits; monitoring)

•SAE/AE determination & reporting

Data Genera

tion

Data Submission/A

nalysis

4 Initiatives to Improve Safety Reporting

Safety ProfilerElectronic data capture and reporting tools

CTCAE v 3.0Wide Adoption of Uniform Terminology and Grading

TAMETreatment Risk Classification System

AERO(Safety Endpoint Data Collection & Reporting Standards)

Adverse Events Reporting in Oncology


Common Understanding of Toxicity Burden

Common Data Collection,Display & Analysis

Common Methods of Data Capture

Common TerminologyAnd Grading

4 Initiatives to Improve Safety Reporting….

Safety ProfilerElectronic reporting methods & tools

AEROAdverse Events Reporting in Oncology (Endpoint collection, Analysis & Reporting Standards)

TAMETreatment Risk Classification System

CTCAE v 3.0Wide Adoption of Uniform Grading System


The Evolution of Adverse Events Grading Systems

System # Terms #Organs Modality Phase

WHO (1979) 28 9 Chemo AcuteCTC (1984) 48 13 Chemo AcuteRTOG-A (1984) 14 13 RT AcuteRTOG-L (1984) 16 13 RT LateSOMA (1995) 152 22 RT LateCTC v 2.0 (1998) 260 24 All* Acute

CTCAE v 3.0 (2003) 1058* All All Acute & Late

“The first comprehensive grading system for all modalities.”

V. Budach – Statements on H&N Cancer - 33ctep.info.nih.gov/CTC3/ctc.htm

A comprehensive terminology and grading system for acute and late effects for all modalities, for use in NCI

supported clinical trials.

NCI-CTCAE

Common Toxicity Criteria for Adverse Events

2003

Terminology


CTC GradingGeneral guidelines

1 2 3 4 Mild

Asymptomatic;No intervention

indicated

Moderate

Symptomatic; interventions such as local treatment or meds may be indicated;

Some interfere with function, but no impact on ADLs.

Severe

Very undesirable; multiple, disruptive

symptoms;more serious interventions,

including surgery or hospitalization may

be indicated.

Life threatening

life threatening, catastrophic,

disabling, or resultin loss of organ, organ function,

or limb

High grade Low grade


The Need for Adverse Effects Reporting

Standards in OncologyTrotti & Bentzen

Journal of Clinical Oncology: 22 (1) January 2004

Adverse Events Reporting in Oncology(AERO Committee)


AERO-H&N Working GroupRochester NY, April, 2004

Soren Bentzen (Chair)Andy Trotti (Co-Chair)Volker Budach (EORTC/DEGRO)A. Dimitrios Colevas (NCI/CTEP)David Pfister (MSKCC)Barbara Murphy (ECOG)Ann Setser (NCI/CTEP)Susan Davidson (Christie NHS Trust)Howard Fingert (Pfizer)Jay Cooper (RTOG)Jens Overgaard (DAHANCA) Drew Ridge (RTOG/ECOG/ACOSOG)

Tom Pajak (RTOG)Ozlem Ataman (ESTRO-REACT)Brian O’Sullivan (NCIC/ACOSOG/CARO)Stanley Dische (ESTRO)MichelleSaunders (ESTRO)Kian Ang (RTOG)Arlene Forastiere (ECOG/RTOG)Gareth Griffith (MRC)Clement Gwede (RTOG/Moffitt)Cai Grau (DAHANCA)Stephen Edge (AJCC/ACOSOG)John Ioannides (CONSORT)

25 members; 13 organis.; 7 countries; 6 coop groups; 17 MDs(10 rad onc; 5 med onc; 2 surg); 3 stat; 2 NCI; 1 Industry; 2 clin. scient.

Mahmut Oszahin (EORTC)


1) Protocol Development Safety Endpoint

Data Collection Guidelines

2) AERO Safety Reporting Standards (for scientific end-results and publications)

AERO-H&N Committee

Committee Aims:


CTCAE v3.0 Multimodality H&N Criteria

Bone marrowDiarrheaFatigueFebrile neutropeniaHearingInfectionLab/metabolicMucositisNeuropathyN&VOtitisRenal functionTinnitusWeight loss

Airway obstructionBone necrosisDental lossFibrosisLarynx dysfunctionLymphedemaNeuropathySkin atrophySoft tissue necrosisStricture (tube dependence)

Taste alterationThryoid functionTrismusVoice and speechXerostomia

Cranial nerve injuryFistulaFlap failureHemorrhageLarynx dysfunctionLymphaticsPerforationShoulder dysfunctionSpeechStrictureSwallowing dysfunctionTrismusVascular injuryWound complicationWound infection

Acute toxicity Late effects Surgical effects

Needed: standardized templates for collection of acute and late effects


TAMEInitiative #4

Development of a concise adverse event summary and treatment risk classification system


TAME: Dimensions of Risk in Oncology

Dimension

• Short Term

• Long Term

• Mortality from treatment

How “TAME” is this treatment?

“T” (Toxicity, acute)

“A” (Adverse late effects)

“M” (Mortality)

• End Results Reporting “E” (End-Results)

Proposed Reporting System


Thank you

Acute Toxicity (Safety) Profile: RTOG 90-03

“Worst grade” summary: STD HFX AF-S AF-C Gr 1-2: 63% 42% 36% 40% Gr 3-4: 35% 56% 51% 59%


Summary Reporting Methods

Worst Grade Summary Method (WGSM)

• Did the patient experience at least one high grade

(e.g., grade 3+) toxicity?

T-score

• How many high grade toxicities did the

patient experience?


# high grade events in a patient cohort

# patients in a patient cohort

T-Score includes all acute CTC (and/or RTOG) grade 3-4 events

for all toxicity items measured.

T-Score =

“T-Score” (Acute Toxicity)


Thank you

GR 3-4 ACUTE

WORST # UTILIZED # COLLECTED

# GRADE GRADE 3-4 GRADE 3-4

PATIENTS INCIDENCE EVENTS EVENTS T-SCORE

95-01* RT ALONE 174 29% 51 81 0.4790-03+ CONVENT 268 35% 94 140 0.5290-03+ CONCOM BST 274 51% 138 194 0.7091-11 ^ RT ALONE 171 47% 80 133 0.7790-03+ HYPERFRAC 263 55% 144 230 0.8790-03+ SPLIT COURSE 268 59% 157 258 0.9691-11 ^ RT/PLAT 171 77% 131 388 1.9797-03 $ RT/Plat-5Fu 78 65% 51 156 2.0199-14 CB-RT/Plat 84 88% 68 161 2.1291-11 ^ INDUC--RT 168 66% 190 349 2.1695-01* RT/PLAT 176 72% 126 415 2.3697-03 $ RT/HU-5Fu 76 78% 59 200 2.6397-03 $ RT/Plat-Taxol 77 87% 67 242 3.14

T Scores (include ALL Gr 3-4 events) in 5 RTOG H&N Trials

>5 fold (500%) difference in toxicity burden across programs

“T-score uses ALL events and corrects for multiplicity”


Thank you

RELATIVE Toxicity Burden (or Risk) T-scores, Worst Grade Incidence

0

1

2

3

4

5

6

7

Worst Grade

T-Score

95-01 90-0390-03

91-1190-03

90-03

91-11

97-03 99-1491-11 95-01

97-03

97-03

Increasing Toxicity in RTOG H&N TrialsT-Score (ALL events): 500% increase in high grade toxicity

Worst grade summary method: 200% increase in high grade toxicity

Systematic bias: high toxicity programs appear less toxic

Re

lati

ve

dif

fere

nc

e

Reporting GAP= 300%


TAME reporting in RTOG 91-11

T A MRT alone 0.77 0.59 3%

Induction CT/RT

2.16 0.43 5%

Concurrent CT-RT

1.97 0.48 3%

“Approximately 2.5 TIMES more acute toxicity burden with chemotherapy”


Summary• The current safety reporting process has strengths and

limitations.

• The “new” CTC system (CTCAE) is more specific and

comprehensive, promising to provide more information

rich data.

• Current deficiencies may result in systematic under-

reporting of toxicity.

• Additional guidance and standards are needed to improve

the reliability and utility of safety data.


Design of the ARO 95-6 StudyDesign of the ARO 95-6 Study

HARTHART (77.6 Gy/6 wks.)(77.6 Gy/6 wks.)

Stages III/IV*Stages III/IV* RRC-HART + MMC/5-C-HART + MMC/5-

FUFU(70.6 Gy/6 wks.)(70.6 Gy/6 wks.)

**Locally advanced H&N-cancer of the oral cavity, oro- and hypopharynx stratified Locally advanced H&N-cancer of the oral cavity, oro- and hypopharynx stratified according to centres, tumor sites, N-stage and gradingaccording to centres, tumor sites, N-stage and grading


T2 1 21 5 27

T3 5 15 46 3 69

T4 14 17 207 44 282

T1 3 3 6

Total

Stage III: 5.5% (n=21)Stage IV: 94.5% (n=363)

N0 TotalN1 N2 N3

TNM-Matrix

19 33 277 55 384

Multicentric Phase-III Trial “Accelerated Hyperfractionation ± 5-Fluorouracil / Mitomycin C

for locally advanced head & neck cancer (ARO 95-6)


0.0

0.2

0.4

0.6

0.8

1.0

0 12 24 36 48 60

Month from Entry

Lo

core

gio

na

l Co

ntr

ol

Numberat risk

Numberat risk

Numberat risk

Numberat risk

Numberat risk

Sum ofeventsSum ofeventsSum ofeventsSum ofeventsSum ofevents

188 118 82 67 60 37

50 69 75 77 78

193 89 63 50 45 32

75 96 100 102 102

Arm B - CRT

Arm A - RT

p=0.004(early) p=0.002(late)

ARO 95-06


0.0

0.2

0.4

0.6

0.8

1.0

0 12 24 36 48 60

Month from Entry

Ove

rall

Surv

iva

l

Numberat risk

Numberat risk

Numberat risk

Numberat risk

Numberat risk

Sum ofeventsSum ofeventsSum ofeventsSum ofeventsSum ofevents

188 131 93 75 65 42

55 93 110 120 125

193 115 78 57 51 36

77 113 133 138 141

Arm B - CRT

Arm A - RT

p=0.017(early) p=0.020(late)

ARO 95-06


ARO 95-06Acute Toxicity (EORTC / RTOG)

(n = 348)

Erythema Epithelio- Pigmen- Mucositis Dysphagia Xerostomia Dysgeusia lysis tation

Brunner* p=0.30**p=0.30** p=0.24***p=0.24*** p=0.30 p=0.30 p=0.65 p=0.65 p=0.82 p=0.82 p=0.60 p=0.60 p=0.98 p=0.98

14.08.2001*non-parametric analysis of variance for repeated measures

**isolated significance at 5th and 6th time points (Mann-Whitney-U-test)***isolated significance at 6th time point (Mann-Whitney-U-test)


Late Morbidity Late Morbidity (EORTC/RTOG)(EORTC/RTOG)(n=331)(n=331)

Brunner* Xero-** Dys- Dys-*** Tele- Fibrosis Trismus Plexo- Osteorad. Pigmen- Lymph- Mucosal Neurol. analysis stomia geusia phagia angiect. pathy necrosis tation edema necrosis sympt.

@ 5 yrs. p=0.58 p=0.79 p=0.24 p=0.43 p=0.95 p=0.82 p=0.29 p=0.96 p=0.74 p=0.75 p=0.26 p=0.93

19.06.2003

*non-parametric analysis of variance for repeated measures

**isolated significance at 11th observation (Mann-Whitney-U-test)

***isolated significance at 2nd, 3th, 5th and 9th observation (Mann-Whitney-U-test)


0.0

0.2

0.4

0.6

0.8

1.0

0 12 24 36 48 60

Month from Entry

Ove

rall

Sur

viva

l

FATIGUE (LOW)

FATIGUE (HIGH)

p=0.005(early) p=0.001(late)

i.t.t.(01.08.01) 12 / 01Months from Entry

ARO 95-06


0.0

0.2

0.4

0.6

0.8

1.0

0 12 24 36 48 60

Month from Entry

Ove

rall

Sur

viva

l

FUNCTIONALITY (HIGH)

FUNCTIONALITY (LOW)

p=0.001(early) p=0.001(late)

i.t.t.(01.08.01) 12 / 01Months from Entry

ARO 95-06


How to improve the therapeutic ratio by optimizing the risk – benefit ratio?

Do we have to address an improvement of the treatment results at the same level of toxicities and morbidities?

How closely are quality of life measures related to acute and late radiation effects?

Open Questions for the design of clinical trials in Locally Advanced Head and Neck Cancer

involving chemoradiation

v. budach – statements on h&n cancer - 1 discussion panel on quality of life and radiotherapy...

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