Transcript Impact of gap duration on local control in anal carcinoma

Post-mastectomy radiotherapy
Sabine Balmer Majno
Radiation Oncology
Geneva University Hospital
SRO Tutorial 20/09/2006
Post-mastectomy radiotherapy
(PMRT)
• RT as post-operative «adjuvant» to total
mastectomy (usually with axillary surgery)
• Historically (clinical trials), PMRT refers to
comprehensive loco-regional RT:
–
–
–
–
chest wall
axilla
supraclavicular
internal mammary
PMRT technical requirements
• Megavoltage photon and electron beams
of appropriate energies (linear accelerator)
• Beam simulation (conventional or CT)
• Computer-assisted dose optimisation
• «Adjuvant» dose prescription (EORTC):
50 Gy in 25 2-Gy fractions, 5 weeks*
*Other schedules may have comparable therapeutic ratios
Set-up of the patient on the breast
board
Breast board
SINMED BV Posiboard-2
Patient with radio-opaque markers on the
skin
Red crosses (initial position for the scan) are drawn
on the skin to check the position of the patient
before marking the isocenters of the different
fields.
CT Parameters
130 kV - 200 mA
Pitch 2.00
Index 4 - Thickness 4
Pilot scan
Transfer of the data set to ACQSIM.
Outline of the superior border slice of the breast = inferior border
of the SC field. Determining the isocenter for the SC field. SSD= 100 cm.
Rotation of the gantry to avoid the spinal cord.
A modification of the isocenter is possible.
ESTRO
ESTRO
MARCONI
MARCONI
Add
shifts if
necessar
y
Coordinates of the isocenter - Add shifts if
necessary.
Determination of the central slice for the tangential
beams.
Drawing the box
Automatic set-up of the isocenter.
Displacement of isocenter, if needed.
Virtual simulation software.
The negative side of PMRT
• Cost, inconvenience, and transient acute
reactions
• Chronic functional impairments: arm
oedema, rib fractures, shoulder stiffness,
brachial plexus injury, lung fibrosis
• Increased second neoplasms
• Increased cardiovascular morbidity
The negative side of PMRT
• Almost all serious complications of PMRT
relate to irradiation of specific nodal fields
(e.g., arm oedema from axillary RT, brachial
plexus injury from supraclavicular RT, cardiac
injury from left-sided IMC RT)
• Properly conducted chest-wall RT has little
serious morbidity
The negative side of PMRT
• Functional complications of PMRT can be
reduced by:
– improved RT technique
– more restrictive indications for nodal RT
• Potentially fatal consequences of PMRT
essentially limited to:
– cardiac (and other vascular?) events
– secondary neoplasms
EBCTCG 1995 Overview
Lancet 2000
• Analysed long-term results from ~20,000
women randomised in 40 adjuvant RT trials
• Statistically powerful, but heterogeneous
regarding tumour stage, surgical approach,
and RT technique
• Purports to provide conclusions relevant to
contemporary practice
EBCTCG 1995 Overview
Lancet 2000
• Non-vascular non-breast-cancer mortality
slightly, but not significantly, greater with
RT (2p = 0.08)
• Deaths from second non-breast cancers:
– with RT:
– without RT:
213/10,021 (2.1%)
173/10,154 (1.7%)
2p > 0.1
EBCTCG 1995 Overview
Lancet 2000
• Increased non-breast cancer mortality
essentially due to excess of vascular deaths
in irradiated patients
– with RT:
– without RT:
437/10,021 (4.3%)
322/10,154 (3.2%) 2p = 0.0007
• Predominant effect thought to result from
cardiac irradiation in left-sided tumours
EBCTCG 1995 Overview
Lancet 2000
• Increased non-breast-cancer mortality
observed in irradiated patients
• Significant only in trials started before 1975
– < 1975:
– >1975:
6.4% absolute increase in non-BC
deaths with RT
0.8% absolute increase in non-BC
deaths with RT
Randomised trials of the local
management of early breast
cancer by various types of surgery
and/or radiotherapy
Meta-analyses: 42,000 women in 79 trials from
the year 2000 EBCTCG meeting
Richard Peto, Sarah Darby & Paul McGale,
on behalf of the Early Breast Cancer Trialists’
Collaborative Group (EBCTCG)
EBCTCG 2000: trials of local therapy
Treatment comparison
Available for the EBCTCG
year 2000 meta-analyses
Trials
Women
Deaths
Radiotherapy (RT) versus no RT
46
24,000
12,000
More surgery v less surgery
16
9,000
4000
More surgery v RT + less surgery
17
9,000
5000
TOTAL
79
42,000
21,000
Crude example:
any RT versus no RT
Meta-analysis putting together the results from
all (old or new) trials of radiotherapy
Shows that breast cancer mortality can be
affected by better local disease control
Isolated local recurrence in the trials of
any type of radiotherapy (RT) versus no
RT
Isolated local recurrence
Absolute difference in risk of
isolated local recurrence: 20%,
mostly within the first 5 years.
15-year breast cancer mortality in the trials of
any type of radiotherapy (RT) versus no RT
(total: 24,000 women randomised in 46 trials)
Breast cancer mortality
Absolute difference in risk of
death from breast cancer: 4%,
mostly after the first 5 years.
Little difference in breast cancer
mortality during the first 5 years.
comparisons
(NB Absolute 5-year gain in local recurrence
risk depends on treatment comparison and on
• Radiotherapy (RT) vs no radiotherapy (24,000 women)
nodal
N- AC)or RTN+)
•
Mastectomy
+ Axillarystatus,
Clearance (Mast
•
•
•
Mast  Axillary Sampling / Partial C (AS / PC)  RT
Mast alone (with no routine axillary surgery)  RT
Breast-Conserving Surgery + AC (BCS  AC)  RT
• More surgery vs less surgery (9000 women)
•
•
•
•
•
•
•
Internal mammary node (IMN) removal vs not, neither with RT
Pectoral muscle (PecM) removal l vs not, both with same RT or neither with RT
AC vs not in N disease, both with same RT
AC vs not in N disease, neither with axillary RT
Mast  AC vs BCS  AC, neither with RT (NSABP B-06)
Mast vs BCS, both with AC and RT
More BCS vs less BCS, neither with AC
• More surgery vs radiotherapy and less surgery (9000 women)
•
•
•
Mast  AC vs Mast alone  RT
Mast  AC vs BCS alone  RT (Guy’s Hospital)
Mast vs BCS  RT, both with AC
: 24 meta-analyses
Overall meta-analysis of
24 specific meta-analyses
•
•
Sort the 24 meta-analyses of particular types of local
therapy comparisons into 3 categories,
according to the absolute sizes of their reductions in 5year local recurrence risk (<10%, 10-20%, >20%)
• Example: N- BCS RT yields 10-20% gain,
• but N+ BCS RT yields >20% gain
Danish DBCG Trials 82b & 82c
• Test the effect of 50 Gy loco-regional RT
on survival of high-risk patients receiving
systemic therapy after mastectomy
• RT technique explicitly chosen to avoid
cardiopulmonary toxicity
• Sample size large enough to provide
definitive evidence
Danish DBCG Trials 82b & 82c
(Hojris et al, Lancet 1999)
N=3,083, MFU 122 mo
With RT
Without RT
766 (50%)
627 (41%)
710 (47%)
Dead,
cancer
12 (0.8%)
Dead,
cardiac
Dead, other 37 (2.4%)
836 (55%)
Alive
13 (0.9%)
45 (3%)
Meta-analysis of PMRT in patients
receiving systemic therapy
Whelan et al, JCO 2000
• 6,367 patients randomised in 18 trials
(1973-1984)
• Significant net benefit from PMRT:
– 75% reduction in odds of LRF
– 31% reduction in odds of cancer recurrence
– 17% reduction in odds of death
• Multivariate analysis: significant benefit for
beginning RT<6 months
Superior results with ~2 Gy fractions
EBCTCG 1995 Overview
• better local control:
– risk reduction 73% vs 63%
• less excess non-breast cancer deaths:
– 1.4% versus 3.7%
• more reduction in breast cancer mortality:
– 4.5% versus 2.9%
Which anatomical regions should
be irradiated in PMRT?
• Most clinical trials used comprehensive RT.
• But overview analysis assumes that survival
benefit is proportional to LRF reduction.
• LRF is observed most commonly on chest wall,
less frequently in the supraclavicular area,
uncommonly in the axilla, and rarely in the
internal mammary area.
• It follows that chest wall RT is first priority.
Sites of LRF after mastectomy
(Recht et al, 1999)
Sites of LRF at 10 years in 2016 node-positive patients treated in ECOG Trials by modified radical
mastectomy and adjuvant chemotherapy (with or without tamoxifen), without PMRT
Site of LRF
N (%)
chest wall
244 (12%)
supra/infraclavicular
158 (8%)
axilla
82 (4%)
internal mammary
4 (0.2%)
Axillary irradiation
• Axillary RT increases risk of arm lymphoedema
after axillary clearance.
• Axillary failure is rare after adequate clearance.
• Axillary RT should be avoided after clearance,
unless residual axillary disease is suspected.
• Axillary RT is recommended after axillary
sampling in case of positive nodes.
• Other indications: undissected axilla? positive
sentinel node?
Supraclavicular irradiation
• Risk of brachial plexus injury <1% if dose does
not exceed 50 Gy in 2 Gy fractions.
• Cerebro-vascular risk of supraclavicular RT?
• After axillary clearance, risk of supraclavicular
recurrence <10% in patients with less than 4
positive nodes.
• Supraclavicular RT generally recommended for 4
or more positive nodes.
Supraclavicular recurrence
10-year rate of supra/infraclavicular recurrence after
modified radical mastectomy and chemotherapy in N+ patients
(ECOG Trials, Recht 1999)
n
% failure
1-3 N+
1011
4%
4-7 N+
562
9%
> 7 N+
436
16%
Internal mammary irradiation (1)
• IM nodes frequently involved when axillary
nodes positive (particularly for medial T).
• Clinically, IM recurrence is rare.
• No direct evidence that IM treatment
improves survival.
• IM RT (particularly left-sided) contributes
to cardiac morbidity.
Internal mammary irradiation (2)
• Benefits vs risks of IM irradiation under
study in randomised trials.
• Major importance of RT technique:
– CT-based treatment planning
– use of electron beams
• Future role for sentinel node techniques for
planning IM RT?
Which patients need PMRT?
• In appropriate patients PMRT reduces LRF
and increases overall survival.
• EBCTCG Overview: 5 fewer breast cancer
deaths for every 20 LRF prevented by RT
(more favourable estimates in newer trials).
• With modern RT techniques, excess nonbreast cancer deaths assumed to be <1%,
but longer follow-up needed in recent trials.
Which patients need PMRT?
• The quality of both surgery and systemic
therapy is important in reducing LRF risk
• But it is a fallacy to believe
– that correct surgical technique makes PMRT
unnecessary
– that systemic therapy can totally replace PMRT
Which patients need PMRT?
• PMRT should be recommdended for
patients whose 10-year LRF risk remains
«unacceptable» despite optimal surgery and
appropriate systemic therapy.
• What is «unacceptable» is arbitrary, but a
threshold of 20% is proposed, as PMRT in
such patients will reduce breast cancer
mortality by ~5% (absolute).
LRF after modified radical mastectomy
and optimal systemic therapy
(Recht et al, 1999)
10-year loco-regional recurrence rates in 2,016 patients with T1-3 tumours and positive
axillary nodes, randomised in ECOG Trials and receiving appropriate chemotherapy (with or
without tamoxifen) after modified radical mastectomy, but without PMRT.
% LRF
Positive nodes
T1
T2
T3
1-3
12%
12%
31%
4-7
20%
27%
45%
> 7
33%
33%
33%
Which patients need PMRT?
• PMRT strongly recommended for
– T1-2 tumours with 4 or more N+.
– T3-4 tumours with N+.
• For T1-2 tumours with < 4 N+, high-risk
subgoups remain to be defined
– larger tumours, close margins, < 10 nodes
examined, extracapsular extension?
– unfavourable morphology (LV invasion, etc.)?
PMRT: Conclusions (1)
• 50 Gy PMRT reduces LRF by factor of 4.
• This reduction in LRF leads to a decrease
in breast-cancer mortality.
• In appropriate high-risk patients, overall
survival will also be improved if excess
cardiovascular mortality is minimised.
• Meticulous planning and execution of
PMRT is of major importance.
PMRT: Conclusions (2)
• Future questions:
–
–
–
–
–
–
indications for T1-2, N1-3+?
role of internal mammary nodal RT?
role of axillary RT after sentinal node biopsy?
safety of PMRT with anthracyclines, taxanes?
optimal sequencing?
optimisation of RT technique?