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 Posiboard-2 The Posiboard-2 breast board is a complete solution for the positioning of breast patients. It is made of a low density foam core covered with an ultra thin layer of carbon fiber. This allows the beam to transfer the Posiboard-2 from any angle with minimal attenuation. For arm positioning, several comfortable and adjustable supports are available. To prevent the patient from sliding down, an adjustable bottom stop is integrated. The Posiboard-2 is compact, lightweight and can be positioned on any couch top with the aid of specifically designed couch top fixation pieces. For additional support, a breast mask can be mounted using a quick release system. When the Posiboard-2 is not in use, it is hung on the wall with the supplied wall mount plate. 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 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 necessar y ESTRO 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 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: 213/10,021 (2.1%) –without RT: 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: 437/10,021 (4.3%) –without RT:322/10,154 (3.2%) 2p = 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: 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 TrialsWomenDeaths Radiotherapy (RT) versus no RT4624,00012,000 More surgery v less surgery169, More surgery v RT + less surgery179, TOTAL7942,00021,000

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.

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 ( 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

Meta-analysis of PMRT in patients receiving systemic therapy Whelan et al, JCO ,367 patients randomised in 18 trials ( ) 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)

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

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)

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?