TWENTY-FIVE-YEAR FOLLOW-UP OF A

RANDOMIZED TRIAL COMPARING RADICAL

MASTECTOMY, TOTAL MASTECTOMY, AND TOTAL
MASTECTOMY FOLLOWED BY IRRADIATION

N Engl J Med, Vol. 347, No. 8 August 22, 2002

BACKGROUND
In women breast cancer radical
mastectomy as compared with less
extensive surgery has been debated
1971 : determine whether less
extensive
surgery
(with/without
radiation) was as effective as Halsted
radical mastectomy

INTRODUCTION
Halsted radical mastectomy (removed of the
breast, muscle of the chest, contents of the
axilla)
standardized operation for breast
cancer all of stage
Mid-1960s : dissatisfaction with result after
radical mastectomy
New information about tumor metastase
sugessted less radical surgery as effective as
the more extensive operation
August 1971 :To resolve controversy NSABP
initiated the B-04 clinical trial
3

AIM of the study is,

to determine whether..

SAME
OUTCO
ME ????
?

Previous finding (25 years)

Demonstrated differences in control
of local disease
But failed to show a signifcant
difference in either survival free of
distant disease or overall survival
among the groups of women with (-)
nodes or between with (+) nodes

Metode

Statistical Analysis
End points for the comparisons among
treatment groups were
Disease-free survival
relapse-free survival
Distant-diseasefree survival
Overall survival

Statistical Analysis
The KaplanMeier method was used to estimate
their curves for each treatment group.
Comparisons of the treatments were made with
the use of log-rank tests
The nonparametric method was used to estimate
the cumulative incidence curves
Grays K-sample test statistic was used to test
the statistical significance of differences in
cumulative incidence among the treatments.
Analyses are based on all follow-up information
received at the NSABP Biostatistical Center as of
March 31, 2001.
9

Result

10

Result

13
20
%
% and event-free after 25 years of
Alive

11

Result
Negative nodes
Radic Total Mastectomy +
al
Irradiation

Total Mastectomy

95% CI

95% CI

Disease Free

19
2

13
2

0,9 1,25

0,49

19
2

0,91 1,27

0,39

Relapse Free

53
3

52
4

0,76
1,21

0,74

50
3

0,91 1,42

0,27

Distand
Free 46
38
0,88
0,44
Positive
nodes
3
3
1,34
Radic
Total
+
Overall
25 19
Mastectomy
0,91
0,38
al3
Irradiation
Survival
2
1,28

43
3

0,89 1,35

0,39

26
3

0,87 1,23

0,72

95% CI

Disease Free

11
2

10
2

0,99
1,33

0,20

Relapse Free

36
3

33
3

0,89
1,35

0,40
12

13

14

Result
Pts Death
Positive nodes :
Total mastectomy +
Irrradiation

Hazard
Ratio

95% CI

P Value

1,06

0,89
1,27

0,49

Negative nodes :
1. Total mastectomy +
1,08
Irrradiation
1,03
* Dibandingkan
dengan Radical Mastectomy
2. Total mastectomy

0,91
0,38
1,28
0,72
0,87
1,23
No significant differences were observed among the three
groups of women with negative nodes or between the two
groups of women with positive nodes with respect to
disease-free survival, relapse-free survival, distantdiseasefree survival, or overall survival.

15

16

17

18

19

POPULATION

20

POPULATION
1079 Women with clinically negative
axillary nodes
586 women with clinically positive
axillary nodes

21

INTERVENTION
WOMEN WITH CLICALLY NEGATIVE NODES

22

COMPARE
DFS

23

HR = 1.06
95% CI 0.901.25
P= 0.49

HR =1.07
95% CI0.911.27
P = 0.39

HR = 1.02
95% CI 0.871.21

P = 0.78

HR = 1.21
95% CI 0.941.33
P =0.20

24

HR = 0.96
95% CI 0.761.72
P= 0.74

HR = 1.14
95% CI 0.911.42
P = 0.27

HR = 1.18
95% CI 0.941.48

P = 0.15

HR = 1.09
95% CI 0.891.35
P = 0.40

25

HR = 1.38
95% CI 0.881.34
P= 0.44

HR = 1.10
95% CI 0.891.35
P = 0.39

HR = 1.02
95% CI 0.831.25

P = 0.85

HR = 1.07
95% CI 0.871.32
P = 0.51

26

HR = 1.08
95% CI 0.911.28
P= 0.38

HR = 1.03
95% CI 0.871.23
P = 0.72

HR = 0.96
95% CI 0.811.13

P = 0.60

HR = 1.06
95% CI 0.891.27
P =0.49

27

CUMMULATIVE DEATH

28

POSSITIVE AXILLARY NODES AFTER TOTAL

MASECTOMY WITHOUT RADIATION THERAPY
365WOMEN
(-)NODES

68 WOMEN
IDENTIFIED(+)
IPSATERAL NODES
SURGERY

297 WOMEN
NOT

29

OUTCOME
NO SIGNIFICANT DIFFERENCES WERE
OBSERVED AMONG 3 GROUPS OF
WOMEN WITH NEGATIVE NODES OR
BETWEEN THE TWO GROUPS OF
WOMEN WITH POSITIVE NODES WITH
RESPECT TO DFS, RFS, DDFS OR OS
NO ADVANTAGE FROM RADICAL
MASECTOMY
30

CRITICAL APPRAISAL

V.I.A

31

VALID

32

1. Was the assignment of patients

to treatment randomized?
Yes
Method : 1765 women with primary operable breast
cancer were randomly assignment to treatment. One
third of those with clinically negative axillary nodes
underwent Halsted radical mastectomy and axillary
dissection. One third underwent total mastectomy with
out axillary dissection but with regional irradiation, and
one third underwent total mastectomy alone. One half
of the women with clinically positive nodes underwent
radical mastectomy the other half underwent total
mastectomy and regional irradiation.
(It was mentioned clearly in the method of the journal)

33

2. Was the randomization

concealed?
No
from trial protocol it was mentioned that
after randomisation the patient were divided into
treatmen groups
One third of those with clinically negative axillary
nodes underwent Halsted radical mastectomy and
axillary dissection. One third underwent total
mastectomy with out axillary dissection but with
regional irradiation, and one third underwent total
mastectomy alone.
One half of the women with clinically positive nodes
underwent radical mastectomy the other half
underwent total mastectomy and regional irradiation.
34

3.Were the groups similar at

the start of the trial?
No
From method it was mentioned that
Clinically negative axillary nodes: One third
underwent Halsted radical mastectomy and
axillary dissection, one third underwent total
mastectomy without axillary dissection but with
regional irradiation, and one third underwent
total mastectomy alone
Clinically positive nodes: One half of the women
with clinically positive nodes underwent radical
mastectomy; the other half underwent total
mastectomy and regional irradiation.
(It was mentioned in table 1, page 570)
35

4.Was follow-up of patients

sufficiently long and complete?
Yes
1665 patients were followed up until 25
years
18% (293) of 1665 patients were
followed up until the trial ended
82% (1372) were lost to follow up
(It was mentioned in table 1, page 570)
36

5.Were all patients analyzed in the

groups to which they were randomized?

Yes

37

6.Were patients, clinicians, and study

personnel kept blind to treatment?

No
Tidak ada keterangan yang menyatakan hal
tersebut.

38

7. Were groups treated equally, apart

from the experimental therapy?

Yes
both groups were treated equal.
None of the women received
adjuvant systemic therapy

(It was mentioned clearly in the method of the journal)

39

Important ??

40

1.What is the magnitude of the ?

ILLUSTRATION A randomized trial comparing Radical

mastectomy, Total mastectomy, and Total mastectomy followed
by Irrradiation

25 years follow-up, terdapat 2 kategori mastectomy yang

dilakukan yakni pada woman with Negative nodes dan woman
with Positive nodes

Control Event Rate = CER

Radical mastectomy yang dilakukan pada kejadian Positive
nodes yang mengalami kegagalan perawatan 87%
Radical mastectomy yang dilakukan pada kejadian Negative
nodes yang mengalami kegagalan perawatan 78%

Experimental Event Rate = EER

Total mastectomy + Irrradiation yang dilakukan pada kejadian
Positive nodes yang mengalami kegagalan perawatan 88%
Total mastectomy + Irrradiation yang dilakukan pada kejadian
Negative nodes yang mengalami kegagalan perawatan 83% (1)
Total mastectomy yang dilakukan pada kejadian Negative
nodes yang mengalami kegagalan perawatan 79% (2)
41

1.What is the magnitude of the ?

in clinical journals as
the relative risk reduction (RRR)
= ( |CER EER|/ CER )
Positive nodes RRR: ( | 87% 88% |/ 87% ) = 1,15%
Negative nodes RRR 1: ( | 78% 83% |/ 78% ) = 6,41%
Negative nodes RRR 2: ( | 78% 79% |/ 78% ) = 1,28%
we can say
Positive nodes: terjadi peningkatan angka kejadian*
(recurrence, contralateral, Second primary cancer, Dead)
pada pasien dengan Total mastectomy + Irrradiation
sebesar 1,15% dibandingkan Radical mastectomy
Negative nodes:
1.terjadi peningkatan angka kejadian* pada pasien
dengan Total mastectomy + Irrradiation sebesar 6,41%
dibandingkan Radical mastectomy
2.terjadi peningkatan angka kejadian* pada pasien
dengan Total mastectomy sebesar 1,28% dibandingkan
Radical mastectomy
42

NNT
Number Needed to Treat

The inverse of the ARR =

ARR: CER EER

(1/ARR)

Positive nodes NNT: ( 1/| 87% 88% |) = 100

Negative nodes NNT 1: ( 1/| 78% 83% |) =
20
Negative nodes NNT 2: ( 1/| 78% 79% |) =
100

43

NNT
Number Needed to Treat
is a whole number and has the useful property of telling
us
Conclusion:
Positive nodes: Dibutuhkan 100 orang yang diterapi dengan
Total mastectomy + Irrradiation (dibandingkan dengan
Radical mastectomy) selama 25 years untuk mencegah 1
angka kejadian*

Negative nodes:
1. Dibutuhkan 20 orang yang diterapi dengan Total
mastectomy + Irrradiation (dibandingkan dengan Radical
mastectomy) selama 25 years untuk mencegah 1 angka
kejadian*

2. Dibutuhkan 100 orang yang diterapi dengan Total

mastectomy (dibandingkan dengan Radical mastectomy)
selama 25 years untuk mencegah 1 angka kejadian*
44

2. How precise is the ...?

Positive nodes :
Total mastectomy +
Irrradiation

ARR
(%)

95% CI
ARR
(Calculated
)

P Value
(Overall
Survival)

- 4,61
6,14

0,49

Negative nodes :
1. Total mastectomy +
5
-0,50
0,38
Irrradiation
1
11,15
0,72
The2.95Total
% CI for
the
ARR
is
not
quoted
in
the
paper,
but
we
have
calculated
mastectomy
-5,00
7,02
95% CI for the diff between Experimental & Control group (Radical mastectomy)
No overlap the no effect point result is real
P > 0,05 : not statistically significant result
45

http://www.neoweb.org.uk/Additions/compare.h
tm

46

APPLICABLE

47

1.Is our patient so different from those in the

study that its results cannot apply?
From inclusion criteria our patient could apply it
and reject it if our patient doesnt fit each one.
This is sensible approach there is no
differences (ages, degrees of risk of the outcome
event, responsiveness to the therapy)
A far more appropriate approach is consider
our patients such as sociodemographic features or
pathobiology are so different from those in the study

48

2. Is the treatment feasible in our setting?

This comparing is feasible in our practice setting
because that kind of the treatment already established
in Indonesia.
Our patients or health care system can pay for the
treatment, its administration, and the required
monitoring
The treatment for breast cancer is currently available
in our hospital, and already been covered by social
insurance or patients would be required to pay for it
themselves
49

3.What are our patients potential benefits and

harms from the therapy?

likelihood of being helped and harmed (LHH)

LHH = (1/NNT) : (1/NNH)
Positive Node (Total mastectomy +
irradiation)
LHH = (1/100) : (1/100) = 1
Pembedahan dengan total mastektomi +
irradiasi pada pasien dengan positive
memberikan resiko dan keuntungan yang
sama dibandingkan dengan radikal
mastektomi
50

3.What are our patients potential benefits and

harms from the therapy?

likelihood of being helped and

harmed (LHH)
Negative Node (Total mastectomy
+ irradiation)
LHH = (1/20) : (1/20)
= 1
Pembedahan dengan total
mastektomi + irradiasi pada
pasien dengan negative node

51

3.What are our patients potential benefits and

harms from the therapy?

likelihood of being helped and

harmed (LHH)
Negative Node (Total mastectomy)
LHH = (1/100) : (1/100) = 1
Pembedahan dengan total
mastektomi pada pasien dengan
negative node memberikan resiko
dan keuntungan yang sama
dibandingkan dengan radikal
52

Jurnal

53