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%