nasopharyngeal cancer
TRANSCRIPT
NPC-9902 Trial on Therapeutic Gain by Concurrent Chemotherapy and/or
Accelerated Fractionation for Locally-Advanced Nasopharyngeal Cancer
Estimation on Sample & Eligible Patients
Incidence in Incidence in Hong KongHong Kong: CT-staged patients: CT-staged patients
Trial
Gain in FFS
Target sample
Eligible pt. / yr
Accrual time
NPC-9902
45 -> 55%
464
186
3 – 5 yr
NPC-9901
40 -> 55%
340
160
3 – 4 yr
NPC-990NPC-99022: Eligibility Criteria: Eligibility Criteria
NNon-keratinizing / on-keratinizing / UUndifferentiatedndifferentiated typetype
T3-4T3-4 NN0-10-1 M0 M0 (UI(UICC CC 55thth))
Staging Ix:Staging Ix: CT / MRCT / MRX-ray / CT thoraxX-ray / CT thorax++ metastatic work-up metastatic work-up
Eligibility CriteriaEligibility Criteria
AgeAge
Performance Status Performance Status
Marrow:Marrow: WBCWBCPlateletPlatelet
Creatinine ClearanceCreatinine Clearance
<70 years<70 years
<<2 2 (ECOG)(ECOG)
>>4,000 4,000 // μμLL>>100,000100,000 / / μμLL
>>60 ml 60 ml // min min
CFCF CFCF++CC
SStratificationtratification
by center, N-stage, T-stageby center, N-stage, T-stage
RRandomizationandomization (equal proportion)(equal proportion)
AFAF AFAF+C+C
CF = conventional fractionation; AF = accelerated fractionation; +C = plus chemotherapy
RT: Same for RT: Same for allall Arms Arms
RT techniqueRT technique
Total doseTotal dose
Additional boostAdditional boost
Individual center policyIndividual center policy
Gross tumor Gross tumor >> 66 Gy 66 GyElective sites Elective sites >> 50 Gy 50 Gy
Not exceed 20 GyNot exceed 20 Gy
RT: RT: FractionationFractionation
Fractionation doseFractionation dose: : 2 Gy/ Fr2 Gy/ Fr
ConventionalConventional: : 55 Fr/ wk Fr/ wkCCF F ArmsArms
AF AF ArmsArms Accelerated: Accelerated: 66 Fr/ w Fr/ wkkQD Monday - Saturday orQD Monday - Saturday orBID on 1 weekday (BID on 1 weekday (>>6 Hr interval) 6 Hr interval)
Treatment in CRT ArmTreatment in CRT Arm
ChemotherapyChemotherapy (IGS regimen) (IGS regimen)
←← →→2 Gy/ Fr,2 Gy/ Fr, 5 5 - - 66 Fr/ wkFr/ wk
Radiotherapy Radiotherapy >>6666 Gy Gy
ConcurrentConcurrent
P P 100100
↓↓
P P 100100
↓↓
P P 100100
↓↓
AdjuvantAdjuvant
P P 80 +80 +5FU 5FU 1000 x 4d1000 x 4d
(q4 wk (q4 wk x 3 cycles)x 3 cycles)
Statistical ConsiderationStatistical Consideration
Target accrual = 4Target accrual = 46464 patients patients
HypothesisHypothesis
Improve Failure-FreeImprove Failure-Free Survival Survival (FFS) (FFS)[[Time to failure (any site)Time to failure (any site)]]
from 45% to 55% (5-year)from 45% to 55% (5-year)
(alpha = 0.05, power = 90%)(alpha = 0.05, power = 90%)
Other End PointsOther End Points
Progression-Free Progression-Free SSurvival (PFS)urvival (PFS)[Time to first failure or death (any cause)][Time to first failure or death (any cause)]
Failure-Free RateFailure-Free Rate• LocoregionalLocoregional• Distant Distant
OOverall verall SSurvivalurvival
•Acute Acute • LLateateToxicity Toxicity (Grade (Grade >>3)3)
Participating CentersPamela Youde Nethersole E. HospitalPamela Youde Nethersole E. Hospital
Tuen Mun HospitalTuen Mun Hospital
Princess Margaret HospitalPrincess Margaret Hospital
19991999 Hong KongHong Kong
Hong KongHong Kong
CanadaCanada
Prince of Wales HospitalPrince of Wales Hospital
20022002 SingaporeSingapore
20032003 ChinaChina
National Cancer Center
Sun Yat Sen University
20002000 Hong KongHong Kong
Queen Elizabeth HospitalQueen Elizabeth Hospital
Queen Mary HospitalQueen Mary Hospital
20012001 Hong KongHong Kong
Hong KongHong Kong
Accrual RateAccrual Rate
020
406080
100120140
160180200
1999 2000 2001 2002 2003 2004
July 1999 – April 2004: 189 patients
Premature Termination
due to
Slow Accrual
Recommendation by Data Monitoring Committee
ResultsResults
Period: Period: JulJul 1999 1999 – – AprApr 2004 2004
Total No. randomized: Total No. randomized: 118899 pt. pt.
Regular follow-upRegular follow-up:: 97% 97%
Median follow-up: 2.Median follow-up: 2.99 (0.1 – 5.5)(0.1 – 5.5) yryr
Patient CharacteristicsPatient Characteristics
Age: meanAge: mean
Sex: maleSex: male
PPS S (ECOG): (ECOG): 00
LDH: meanLDH: mean
Comparison by Arm
AFAF(n = 51)(n = 51)
48 48 yryr
9090%%
8181%%
221221
CFCF(n = 42)(n = 42)
49 49 yryr
6969%%
8181%%
232232
CFCF+C+C(n = 52)(n = 52)
47 47 yryr
7878%%
7878%%
238238
AAFF+C+C(n = 44)(n = 44)
50 50 yryr
7171%%
9595%%
205205
p = 0.046 p = 0.067
Tumor StagingTumor Staging
Staging Staging byby MR MR
T-T-categorycategory: T4: T4
N-N-categorycategory: N: N11
Comparison by Arm
AFAF
79%79%
4848%%
6969%%
CFCF
76%76%
5050%%
6464%%
CFCF+C+C
75%75%
4747%%
59%59%
AFAF+C+C
77%77%
5050%%
80%80%
p = 0.18
RadiotherapyRadiotherapy
Technique: 3DTechnique: 3D
Total doseTotal dose to NP to NP
Overall timeOverall time
BoostBoost to NP/ PPS to NP/ PPS
CFCF
45%45%
69 Gy69 Gy
48 d48 d
3333%%
CFCF+C+C
46%46%
68 Gy68 Gy
47 d47 d
2828%%
AFAF
45%45%
69 Gy69 Gy
41 d41 d
2525%%
AFAF+C+C
49%49%
69 Gy69 Gy
42 d42 d
4141%%
Comparison of Prognostic Factors
RT vs CRT All balanced
CF vs AF All balanced
Arm Balanced except AF Arm vs other Arms:
Male: 90% vs 70% (p = 0.046)
PS 2: 4% vs 0%Non-Chinese: 4% vs 0%
Major Major Violation ofViolation of Protocol Protocol
RT - Incomplete doseRT - Incomplete dose
Delay >7dDelay >7d
ChemotherapyChemotherapy
CFCF
--
--
+ 2%+ 2%
CFCF+C+C
2%2%
--
- 2%- 2%
AFAF+C+C
--
5%5%
- 2%- 2%
AFAF
2%2%
2%2%
+ 2%+ 2%
Compliance to CCompliance to Chemotherapyhemotherapy
AFAF+C+C
84%84%
73%73%
Concurrent cycles: Concurrent cycles: >> 2 2
Adjuvant cycles: > 3
CFCF+C+C
92%92%
64%64%
Total dose of CisplatinTotal dose of Cisplatin 427 427 mg/mmg/m22 418 418 mg/mmg/m22
Complete 6 cyclesComplete 6 cycles 55%55% 57%57%
Acute Toxicity Acute Toxicity (Grade (Grade >>3)3)
MucositisMucositis
Skin reactionSkin reaction
Any RT toxicityAny RT toxicity
CFCF
50%50%
1919%%
55%55%
CFCF+C+C
64%64%
1818%%
66%66%
AFAF+C+C
80%80%
4040%%
80%80%
AFAF
65%65%
1919%%
69%69%
ChemotherapyChemotherapy Toxicity Toxicity in CRT Armin CRT Arm
LeukopeniaLeukopeniaAnemiaAnemiaThrombocytopeniaThrombocytopenia
VomitingVomitingStomatitisStomatitis
Hearing lossHearing loss
Renal impairmentRenal impairment
OthersOthers
CFCF+C+C
34%34%**1010%% 44%%
1188%%14%14%
4%4%
4%4%
2%2%
AFAF+C+C
26%26%1616%% 00%%
2323%%21%21%
5%5%
2%2%
12%12%
Overall Acute Toxicity Overall Acute Toxicity (Grade (Grade >>3)3)
0
20
40
60
80
100
CF AF CF+C AF+C
Gd 3 Gd 4 Gd 5
69
55
84 86
Overall Acute Toxicity (Grade (Grade >>3)3)
Comparison
RT vs CRT
CF vs AF
Arm
Incidence rate (%)
63 vs 85
71 vs 77
55 vs 69 vs 84 vs 86
P value
0.001
0.315
0.002
Failure-FreeFailure-Free Survival Survival (3-year)(3-year)
RTRT vsvs CRTCRT66%66% vsvs 83%83% ((pp = 0.05) = 0.05)
AFAF vs vs AFAF7272%% vsvs 77%77% ((pp = 0. 31) = 0. 31)
CRTCRT*AF*AF
HR = 0.11 (0.02-0.57)HR = 0.11 (0.02-0.57)
P = 0.01P = 0.01
((Event: any Event: any failure)failure)
0 1 2 3 4 5 6
0.0
0.2
0.4
0.6
0.8
1.0
AF+C
CF
AF
AF+C
Year
Pro
babi
lity
P=0.01
Failure-FreeFailure-Free Survival Survival (3-year)(3-year)
CRTCRT*AF*AF
HR = 0.11 (0.02-0.57)HR = 0.11 (0.02-0.57)
P = 0.01P = 0.01
CF
• This represents a significant interaction effect.
• What does it mean?• Effects of CRT and AF are non-additive:• Effect of CRT is enhanced in presence of AF and• Effect of AF is enhanced in presence of CRT.
• Is it real? Is CRT useless without AF? Is AF useless without CRT?
Hazard Ratio = .11 = 1/9
⇒ Nine-fold decrease in failure with AF + CRT together rather than separately.
But the decrease is a product of three effects:
RT + AF
CRT + CF
RT + CF ------------------------------------------------
CRT + AF
CRT alone,HR × 1.1
AF alone,HR × 1.4
CRT + AF,HR ÷ 6
1.1 × 1.4 × 6 = 9, the total effect
That is, the benefit due to CRT + AF being delivered in tandem vs. separately is due to:
• The apparent disadvantage of CRT + CF over RT + CF (1.1 increase);
• The apparent disadvantage of RT + AF over RT + CF (1.4 increase); and
• The advantage of CRT + AF over RT + CF (six-fold reduction):
1.1 × 1.4 × 6 = 9, the total interaction effect.
A clinically important question:
• Suppose we don’t believe the first two effects – we don’t believe that acceleration or adding chemotherapy can cause failures, and fix their hazard ratios at 1.0:
• What is the significance of the “restricted interaction effect”, the hazard ratio of 6?
• Answer: p = ????.
• Modest evidence that AF and CRT do seem to work better together.
Locoregional Failure-FreeLocoregional Failure-Free Rate (3-year)(3-year)
RTRT vsvs CRTCRT8181%% vsvs 87%87% ((pp = 0.41) = 0.41)
AFAF vs vs AFAF8383%% vsvs 85%85% ((pp = 0. 63) = 0. 63)
CRTCRT*AF*AF
HR = 0.13 (0.02-0.86)HR = 0.13 (0.02-0.86)
P = 0.03P = 0.030 1 2 3 4 5 6
0.0
0.2
0.4
0.6
0.8
1.0
Pro
babi
lity
Year
P=0.14
AF+C
CFCF+C
AF
Distant Failure-FreeDistant Failure-Free Rate (3-year)(3-year)
RTRT vsvs CRTCRT7979%% vsvs 93%93% ((pp = 0.06) = 0.06)
AFAF vs vs AFAF8585%% vsvs 86%86% ((pp = 0. 55) = 0. 55)
CRTCRT*AF*AF
HR = 0.12 (0.01-1.24)HR = 0.12 (0.01-1.24)
P = 0.08P = 0.080 1 2 3 4 5 6
0.0
0.2
0.4
0.6
0.8
1.0
Year
Probability
AF+C
CF
CF+CAF
P=0.10
CFCF+C+C
6969
66
88
1212
22
22
22
Relapse-freeRelapse-free
Successful salvageSuccessful salvage
WithWith disease disease
NPCNPC
ToxicityToxicity
IncidentalIncidental
UnknownUnknown
AliveAlive
DeadDead
CFCF
7171
55
77
1414
--
--
22
DDisease Status at Last Assessmentisease Status at Last Assessment
AFAF
6767
66
44
1919
--
22
22
AFAF+C+C
8989
--
--
55
--
77
--
Overall SurvivalOverall Survival
RTRT vsvs CRTCRT7777%% vsvs 87%87% ((pp = 0.41) = 0.41)
AFAF vs vs AFAF8585%% vsvs 79 79%% ((pp = 0.73) = 0.73)
CRTCRT*AF*AF
HR = 0.44 (0.11-1.87)HR = 0.44 (0.11-1.87)
P = 0.27P = 0.270 1 2 3 4 5 6
0.0
0.2
0.4
0.6
0.8
1.0
Year
Probability
AF+C
CF
AF
CF+C
P=0.56
Progression-FreeProgression-Free SurvivalSurvival ((Event: Event: failure or death)failure or death)
RTRT vsvs CRTCRT6565%% vsvs 80 80%% ((pp = 0.19) = 0.19)
AFAF vs vs AFAF71%71% vsvs 74 74%% ((pp = 0.34) = 0.34)
CRTCRT*AF*AF
HR = 0.26 (0.07-0.89)HR = 0.26 (0.07-0.89)
P = 0.03P = 0.030 1 2 3 4 5 6
0.0
0.2
0.4
0.6
0.8
1.0
Year
Probability
AF+C
CF+C
CF
AF
P=0.09
Late ToxicityLate Toxicity (Grade (Grade >>3)3)
RTRT vsvs CRTCRT1919%% vsvs 33 33%% ((pp = 0.08) = 0.08)
AFAF vs vs AFAF23%23% vsvs 28 28%% ((pp = 0.32) = 0.32)
CRTCRT*AF*AF
HR = 0.81 (0.24-2.69)HR = 0.81 (0.24-2.69)
P = 0.73P = 0.730 1 2 3 4 5 6
0.0
0.2
0.4
0.6
0.8
1.0
Year
Probability
AF+C
CF+C
AF
CF
P=0.24
LateLate Toxicity Toxicity (Grade (Grade >>3)3)
Subset Analyses – Absolute GainSubset Analyses – Absolute Gain
3-yr Rate 3-yr Rate
LR-FFRLR-FFR
D-FFRD-FFR
FFSFFS
PFSPFS
OSOS
Stage IIIStage III(n = 206)(n = 206)
10%10%
3%3%
13%13%
13%13%
- 1%- 1%
Stage IVStage IV(n = 142)(n = 142)
11%11%
10%10%
10%10%
8%8%
5%5%