Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials

1
Effects of radiotherapy and of differences in
the extent of surgery for early breast cancer on
local recurrence and 15-year survival an
overview of the randomised trials
Early Breast Cancer Trialists Collaborative
Group (EBCTCG)
EBCTCG Lancet 2005 366 2087-2106
2
Background
In early breast cancer, variations in local
treatment that substantially affect the risk of
locoregional recurrence could also affect
long-term breast cancer mortality. To examine
this relationship, collaborative meta-analyses
were undertaken, based on individual patient
data, of the relevant randomised trials that
began by 1995.
3
Data available

• Information was available on 42 000 women in 78
• randomised treatment comparisons
• radiotherapy vs no radiotherapy, 23 500
• more vs less surgery, 9300
• more surgery vs radiotherapy, 9300

4
Availability of data from unconfounded randomised
trials of local therapy that began by 1995
5
Breast-conserving surgery (BCS)

• There were 7300 women with BCS in trials of ? RT
• RT was generally just to the conserved breast
• 5-year local recurrence risks (mainly in the
  conserved breast)
• 7 vs 26 (reduction 19)
• 15-year breast cancer mortality risks
• 30.5 vs 35.9 (reduction 5.4, SE 1.7,
  2p0.002)
• 15-year overall mortality risks
• 35.2 vs 40.5 (reduction 5.3, SE 1.8, 2p0.005)

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Effect of radiotherapy after breast-conserving
surgery (10 trials of BCS ? RT) on local
recurrence
7
Effect of radiotherapy after breast-conserving
surgery (10 trials of BCS ? RT) on breast cancer
mortality
8
Effect of radiotherapy after breast-conserving
surgery (10 trials of BCS ? RT) on local
recurrence and on breast cancer mortality 6097
women with node-negative disease
9
Effect of radiotherapy after breast-conserving
surgery (10 trials of BCS ? RT) on local
recurrence and on breast cancer mortality 1214
women with node-positive disease
10
Mastectomy and axillary clearance N-ve

• There were 1400 women with mastectomy, axillary
  clearance,
• and N-ve disease in trials of ?RT
• RT was generally to the chest wall and regional
  lymph nodes
• 5-year local recurrence risks
• 2 vs 6 (reduction 4)
• 15-year breast cancer mortality risks
• 31.3 vs 27.7 (increase 3.6, SE 3.6, 2p0.01)
• 15-year overall mortality risks
• 42.4 vs 38.2 (increase 4.2, SE 2.7, 2p0.0002)

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Mastectomy and axillary clearance Nve

• There were 8500 women with mastectomy, axillary
  clearance,
• and Nve disease in trials of ?RT
• RT was generally to the chest wall and regional
  lymph nodes
• 5-year local recurrence risks
• 6 vs 23 (reduction 17)
• 15-year breast cancer mortality risks
• 54.7 vs 60.1 (reduction 5.4, SE 1.3,
  2p0.0002)
• 15-year overall mortality risks
• 59.8 vs 64.2 (reduction 4.4, SE 1.2, 2p0.0009)

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Effect of radiotherapy after mastectomy and
axillary clearance (25 trials of MastAC ? RT)
on local recurrence and on breast cancer
mortality1428 women with node-negative disease
13
Effect of radiotherapy after mastectomy and
axillary clearance (25 trials of MastAC ? RT)
on local recurrence and on breast cancer
mortality8505 women with node-positive disease
14
Methods

• About three-quarters of the eventual local
  recurrence risk occurred during the first 5
  years.
• To help relate the effect on local recurrence
  to that on breast cancer mortality, the 24 types
  of local treatment comparison were grouped
  according to whether or not the 5-year local
  recurrence risk was lt 10 (17 000 women), 10-20
  (20 000 women), gt20 (5000 women).

15
Absolute reduction in 5-year local recurrence
risk 78 trials grouped into 24 types of local
treatment comparison, based on treatments
compared and nodal status
16
Breast cancer mortality risks by time since
randomisation and by category of absolute
reduction in 5-year local recurrence risk
(a) 16 804 women, 43 Nve, (bc) 25 276 women,
51 Nve
17
Local recurrence and breast cancer mortality for
12 treatment comparisons that produce lt10
absolute reduction in 5-year local recurrence
risk16 804 women, 43 with node-positive disease
18
Local recurrence and breast cancer mortality for
12 treatment comparisons that produce gt10
absolute reduction in 5-year local recurrence
risk25 276 women, 51 with node-positive disease
19
Proportional and absolute reductions produced
by radiotherapy

• Radiotherapy produced similar proportional
  reductions in
• local recurrence in all women (irrespective of
  age or tumour
• characteristics) and in all major trials of ?RT
  (recent or older
• with or without systemic therapy), so large
  absolute reductions
• in local recurrence were seen only if the control
  risk was large.

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Effects of age and tumour characteristics on
5-year risks of local recurrence in trials of
radiotherapy (a) after breast-conserving surgery
in women with node-negative disease (BCSRT) and
(b) after mastectomy and axillary clearance in
women with node-positive disease (MastACRT)
21
Radiotherapy side-effects

• Trials of ?RT were combined with those of RT vs
  more surgery.
• There was an excess incidence of contralateral
  breast cancer (rate ratio 1.18, SE 0.06,
  2p0.002).
• There was also an excess of non-breast-cancer
  mortality (rate ratio 1.12, SE 0.04, 2p0.001),
  heart disease (rate ratio 1.27, SE 0.07,
  2p0.0001) and lung cancer (rate ratio 1.78, SE
  0.22, 2p0.0004).
• Both excesses were slight during the first 5
  years, but continued after year 15.

22
Effect of radiotherapy on contralateral breast
cancer incidence and on non-breast-cancer
mortality (46 trials of adding radiotherapy, and
17 trials of radiotherapy vs more surgery)
(29 623 women)
23
Effect of radiotherapy on incidence of second
cancers before recurrence of breast cancer(23
500 women in 46 trials of adding radiotherapy,
and 9300 in 17 trials of radiotherapy vs more
surgery)
24
Effect of radiotherapy on mortality from causes
other than breast cancer (23 500 women in 46
trials of adding radiotherapy, and 9300 in 17
trials of radiotherapy vs more surgery)
25
Interpretation

• In these trials, avoidance of a local recurrence
  in the conserved
• breast after BCS and avoidance of a local
  recurrence
• elsewhere (eg, the chest wall or regional nodes)
  after
• mastectomy were of comparable relevance to
  15-year breast
• cancer mortality.
• Differences in local treatment that substantially
  affect local
• recurrence rates would, in the hypothetical
  absence of any
• other causes of death, avoid about one breast
  cancer death
• over the next 15 years for every four local
  recurrences avoided,
• and should reduce 15-year overall mortality.

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Effect of radiotherapy on breast cancer mortality
and on all-cause mortality after
breast-conserving surgery (BCS?RT)7311 women
(17 with node-positive disease)
27
Effect of radiotherapy on breast cancer mortality
and on all-cause mortality after mastectomy with
axillary clearance (MastAC?RT)8505 women with
node-positive disease
28
Conclusions (1)

• In early breast cancer, local treatments that
  substantially
• improve local control have little effect on
  breast cancer mortality during the first few
  years, but have definite,
• although moderate, effects by 15 years, and
  avoidance of local recurrence in a conserved
  breast and elsewhere are of comparable relevance
  to 15-year breast cancer mortality.

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Conclusions (2)

• These trials of radiotherapy and of the extent of
  surgery
• show that, in the hypothetical absence of other
  causes of
• death, about one breast cancer death over the
  next 15 years
• would be avoided for every four local recurrences
  avoided.
• Although the management of early breast cancer
  continues
• to change, it is reasonable to assume that this
  approximate
• four-to-one relationship will continue to apply
  and will still be
• of relevance to future treatment choices.

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Conclusions (3)

• The evidence as to what will happen after year 15
  is still
• limited.
• Longer follow-up will help assess the additional
  benefits
• and risks after year 15.

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Webfigures
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Radiotherapy after breast-conserving surgery,
generally with axillary clearance (BCS?RT) in
all women (node-negative or node-positive)(7311
women, 17 with node-positive disease)
33
Radiotherapy after breast-conserving surgery,
generally with axillary clearance (BCS?RT) in
women with node-negative disease (6097 women)
34
Radiotherapy after breast-conserving surgery,
generally with axillary clearance (BCS?RT) in
women with node-positive disease (1214 women)
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Radiotherapy after mastectomy with axillary
clearance (MastAC?RT) in all women (9933
women, 86 with node-positive disease)
36
Radiotherapy after mastectomy with axillary
clearance (MastAC?RT) in women with
node-negative disease(1428 women)
37
Radiotherapy after mastectomy with axillary
clearance (MastAC?RT) in all women with
node-positive disease (8505 women, many with
the actual number of involved nodes unknown)
38
Radiotherapy after mastectomy with axillary
clearance (MastAC?RT) in women with 1-3
involved lymph nodes (pN1-3) (1890 women)
39
Radiotherapy after mastectomy with axillary
clearance (MastAC?RT) in women with 4 or more
involved lymph nodes (pN4) (1868 women)
40
12 types of treatment comparison that yield lt10
isolated local recurrence risk reduction (16
804 women, 43 with node-positive disease)
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12 types of treatment comparison that yield gt10
isolated local recurrence risk reduction (25 276
women, 51 with node-positive disease)
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Breast cancer mortality rate ratio by time since
randomisation and by category of absolute
reduction in 5-year local recurrence risk
43
Homogeneity of 24 breast cancer mortality rate
ratios, given the category (lt10, 10-20, or
gt20) of absolute reduction in 5-year local
recurrence risk
44
Radiotherapy after breast conserving surgery in
node-negative disease
Isolated local recurrence Breast cancer
mortality Any death
45
Radiotherapy after mastectomy and axillary
clearance in node-positive disease
Isolated local recurrence Breast cancer
mortality Any death
46
12 types of treatment comparison that yield gt10
isolated local recurrence risk reduction
Isolated local recurrence Breast cancer
mortality Any death
47
Effect of radiotherapy on contralateral breast
cancer incidence and on non-breast-cancer
mortality (46 trials of adding radiotherapy, and
17 trials of radiotherapy vs more surgery)
(29 623 women)
48
Radiotherapy versus not, in women with
node-negative disease
Isolated local recurrence Breast cancer
mortality Any death
49
Radiotherapy versus not, in women with
node-positive disease
Isolated local recurrence Breast cancer
mortality Any death
50
More surgery versus less surgery, in women
with node-negative disease
Isolated local recurrence Breast cancer
mortality Any death
51
More surgery versus less surgery, in women
with node-positive disease
Isolated local recurrence Breast cancer
mortality Any death
52
Surgery versus less surgery plus radiotherapy,
in women with node-negative disease
Isolated local recurrence Breast cancer
mortality Any death
53
Surgery versus less surgery plus radiotherapy,
in women with node-positive disease
Isolated local recurrence Breast cancer
mortality Any death