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 Pilot scan

130 kV - 200 mA

Pitch 2.00

Index 4 - Thickness 4

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.

Add shifts if necessary

ESTRO MARCONIESTRO MARCONI

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 OverviewLancet 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 OverviewLancet 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: 213/10,021 (2.1%)– without RT: 173/10,154 (1.7%) 2p > 0.1

EBCTCG 1995 OverviewLancet 2000

• Increased non-breast cancer mortality essentially due to excess of vascular deaths in irradiated patients– with RT: 437/10,021 (4.3%)– without RT: 322/10,154 (3.2%) 2p = 0.0007

• Predominant effect thought to result from cardiac irradiation in left-sided tumours

EBCTCG 1995 OverviewLancet 2000

• Increased non-breast-cancer mortality observed in irradiated patients

• Significant only in trials started before 1975– < 1975: 6.4% absolute increase in non-BC

deaths with RT– >1975: 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

RTIsolated local recurrence

Absolute difference in risk of isolated local recurrence: 20%, mostly within the first 5 years.

Breast cancer mortality

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)

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.

EBCTCG local treatment comparisons

(NB Absolute 5-year gain in local recurrence risk depends on treatment comparison and on

nodal status, N- or N+)• Radiotherapy (RT) vs no radiotherapy (24,000 women)• Mastectomy + Axillary Clearance (Mast AC) RT• 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 5-year 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

Alive 766 (50%) 627 (41%)

Dead,cancer

710 (47%) 836 (55%)

Dead,cardiac

12 (0.8%) 13 (0.9%)

Dead, other 37 (2.4%) 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 fractionsEBCTCG 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 radicalmastectomy 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 non-breast 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 positiveaxillary nodes, randomised in ECOG Trials and receiving appropriate chemotherapy (with orwithout 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?