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Transcript of V. Budach – Statements on H&N Cancer - 1 Discussion Panel on Quality of Life and Radiotherapy in...
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
V. Budach – Statements on H&N Cancer - 2
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
V. Budach – Statements on H&N Cancer - 3
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
V. Budach – Statements on H&N Cancer - 4
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
V. Budach – Statements on H&N Cancer - 5
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
V. Budach – Statements on H&N Cancer - 6
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
V. Budach – Statements on H&N Cancer - 7
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
V. Budach – Statements on H&N Cancer - 9
• 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…
V. Budach – Statements on H&N Cancer - 10
•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
V. Budach – Statements on H&N Cancer - 11
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
V. Budach – Statements on H&N Cancer - 15
How should we evaluate the adverse effects of
cancer treatment on health status in oncology?
V. Budach – Statements on H&N Cancer - 16
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.
V. Budach – Statements on H&N Cancer - 17
•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).
V. Budach – Statements on H&N Cancer - 24
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…
V. Budach – Statements on H&N Cancer - 25
“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
V. Budach – Statements on H&N Cancer - 26
•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)
“Toxicity profile”
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)
V. Budach – Statements on H&N Cancer - 27
•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)
“Toxicity profile”
•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
V. Budach – Statements on H&N Cancer - 28
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
V. Budach – Statements on H&N Cancer - 32
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
V. Budach – Statements on H&N Cancer - 34
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
V. Budach – Statements on H&N Cancer - 43
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)
V. Budach – Statements on H&N Cancer - 44
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)
V. Budach – Statements on H&N Cancer - 45
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:
V. Budach – Statements on H&N Cancer - 46
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
V. Budach – Statements on H&N Cancer - 49
TAMEInitiative #4
Development of a concise adverse event summary and treatment risk classification system
V. Budach – Statements on H&N Cancer - 50
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
V. Budach – Statements on H&N Cancer - 51
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%
V. Budach – Statements on H&N Cancer - 56
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?
V. Budach – Statements on H&N Cancer - 57
# 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)
V. Budach – Statements on H&N Cancer - 58
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”
V. Budach – Statements on H&N Cancer - 59
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%
V. Budach – Statements on H&N Cancer - 62
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”
V. Budach – Statements on H&N Cancer - 65
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.
V. Budach – Statements on H&N Cancer - 73
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
V. Budach – Statements on H&N Cancer - 74
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)
V. Budach – Statements on H&N Cancer - 75
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
V. Budach – Statements on H&N Cancer - 76
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
V. Budach – Statements on H&N Cancer - 77
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)
V. Budach – Statements on H&N Cancer - 78
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)
V. Budach – Statements on H&N Cancer - 80
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
V. Budach – Statements on H&N Cancer - 81
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
V. Budach – Statements on H&N Cancer - 83
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