- Young age is a risk factor for local recurrence after breast-conserving therapy, and adding a boost dose reduces the 5-year local recurrence rate from 26% to 8.5% for patients aged 35 or younger, compared to from 3.9% to 2.1% for patients older than 60. - Post-mastectomy radiotherapy reduces locoregional recurrences by 70% and prevents one breast cancer death within 15 years for every four recurrences prevented at 5 years. PMRT is generally recommended for stage pT3/pN2a or higher. - While radiotherapy decreases in-field recurrences, significant excess non-breast cancer mortality from heart disease and lung cancer was

2. Evidence based radiation oncology: Breast
cancer by Philip Poortmans
Dr. Bernard Verbeeten Instituut, Radiotherapy,
Tilburg, Netherlands
 Materials and methods: Based on a review of the
literature the level of evidence that is available for
the indications for radiotherapy is summarised, as
well as the main clinical questions that are
unanswered today.

3. Breast-conserving therapy
• BCT offers equal results as compared to mastectomy in appropriately
selected patients (1a).
• The majority of breast cancer patients can be offered BCT.
• After lumpectomy, postoperative radiotherapy is always required (1a).
• Their exists a dose–effect relationship that is independent of age (1b).
• As young age is an independent risk factor for local relapses, especially
younger patients benefit from a boost dose (1b).
• The higher local recurrence risk for younger patients is much reduced if
adjuvant systemic treatment is given (2a).
• As margins are an important prognostic factor for local control, a
microscopically complete lumpectomy should be aimed at (1a).
• Patients with infiltrating lobular carcinoma are eligible for BCT, even if
the resection margins are not microscopically complete (2b).

4.  The meta-analysis of the Early Breast Cancer Trialists’
Collaborative Group (EBCTCG) confirmed the equivalence of
those two approaches with survival as endpoint and the need for
radiotherapy following lumpectomy to reduce the 5-year local
recurrence rate from 26% to 7% (Lancet 2005;366:2087–106).
 So in summary, despite the higher risk of an incomplete tumour
excision, patients with lobular cancer do not have a higher local
recurrence risk after BCT than patients with ductal cancer and
should be offered this treatment even after a (focally)
microscopically incomplete tumour excision [Silverstein MJ
Infiltrating lobular carcinoma. Is it different from infiltrating duct
carcinoma? Cancer 1994;73:1673–7.].

5.  Young age is demonstrated to being an unfavourable
prognostic factor for local control after breast-
conserving therapy. The analysis at 5 years showed that
for patients 35 years of age or less the addition of a
boost resulted in a reduction of the 5-year local
recurrence rate from 26% to 8.5%, while for patients
older than 60 years this reduction was only from 3.9%
to 2.1%.

6.  The authors noted that the 5-year local recurrence rate was
significantly higher in patients treated with adjuvant
radiotherapy more than 8 weeks after surgery, compared
with those who started treatment within 8 weeks of surgery
(OR 1.6). They noted also that radiotherapy given after
completion of adjuvant chemotherapy resulted in a higher
local recurrence rate compared to patients who received
early onset radiotherapy (OR 2.3). In a comprehensive
review dealing with prospective and retrospective studies
in BCT it appeared that early initiation of radiotherapy
might be of benefit to patients with positive, close or
unknown microscopic margins, whereas those with wider
tumour free margin widths did not benefit clearly Recht A
Clin Breast Cancer 2003;4:104–13.

7.  In a single large (n = 7800) retrospective study it was
suggested that delaying the initiation of RT for 20–26
weeks after surgery is associated with a decreased survival
after BCT (Mikeljevic JS Br J Cancer 2004;90:1343–8).
 In an editorial accompanying a report of a retrospective
study on the timing of radiotherapy in the prospective
randomised trial CALGB 9344 that evaluated three dose
levels of anthracyclines and the addition of paclitaxel,
Bellon and Harris concluded that with the available
evidence radiotherapy should be given after completion of
all chemotherapy (diminished blood flow and a relative
hypoxia in the postoperative region).

8.  A four fold increased risk of cardiac events after
anthracycline containing chemotherapy (>450 mg/m2 )
regimens was observed. Of note, cardiac events occurred
as long as 10 years after treatment.
 Forward-planned IMRT techniques and techniques that
mix step-and-shoot IMRT with open fields have been
proposed as a class solution by several authors, on one
hand because of the time constraints and simplicity, but
on the other hand because the much lower dose outside
of the treatment volume than with ‘‘conventional’’
inverse IMRT techniques.

9. Unresolved questions and controversies:
• The best approach to offer patients after a
microscopically incomplete lumpectomy is not clear.
• Patient subgroups, with a low risk for a local relapse
after surgery alone or after a lower dose/ smaller
volume of radiotherapy, still need to be properly
defined.
• The integration of adjuvant systemic treatment with
surgery and radiotherapy to optimise local control
needs to be worked out.

10. B. Regional and post mastectomy
radiotherapy

11. Indication for irradiation of the different target volumes
after mastectomy and axillary clearance as well as for
regional RT in the framework of BCT.

12. Attaining maximal initial locoregional tumour control is necessary to
achieve the highest possible ultimate survival rate... but above all, do
not harm the patient!
• Radiotherapy reduces the in-field recurrences by 70% (1a).
• For every 4 locoregional recurrences prevented at 5 years, 1 life at 15
years will be saved (1a).
• PMRT and regional RT is a generally accepted standard from tumour
stage pT3 and/or pN2a on (1a).
• There are enough data available to advise this also to patients from pN1a
stage on (1a).
• The indications for PMRT and regional RT are independent from the
amount of surgery and the administration of adjuvant systemic
treatments (1a).
• The target volumes are under discussion, but quite some arguments
exist for comprehensive locoregional RT.
• There exists, after proper surgery, no indication for irradiation of the
axilla (2a).

13. Decrease LRR
 (PMRT) for patients with 4 or more invaded axillary
lymph nodes, T3 and T4 tumour stage and invasion of
the pectoral muscle or the surgical margins. About 3/4
of the locoregional recurrences occur within 5 years
after the initial treatment. This meta-analysis also
demonstrated that one breast cancer death during the
15 years after randomisation will be avoided for every
four local recurrences at 5 years that are prevented.
Therefore, a gain in local control obtained with
postoperative radiotherapy of 20% at 5 years will result
in an improvement in overall survival at 15 years of 5%.

14. Significant increase in non-breast-cancer mortality in irradiated
women. The excess mortality was mainly from heart disease and lung
cancer. This late toxicity did not yet completely fade out even 15 years.
The cut-off point of 4 involved axillary lymph nodes is thoroughly
challenged by a recent paper from Overgaard et al. [Radiother Oncol
2007;82:247–53]. Based on the well known DBCG (Danish Breast
Cancer Cooperative Group) trials [Overgaard M, N Engl J Med
1997;337:949–55. Lancet 1999;353:1641–8.], they demonstrate that the
number of involved nodes should not be used as a threshold to advice
PMRT. This adds to the growing level of evidence that PMRT should be
offered to all patients with involved axillary lymph nodes.
Upcoming Intergroup SUPREMO (Selective Use of Postoperative
Radiotherapy after Mastectomy) that randomises patients with 1–3
involved lymph nodes, and pT2pN0 tumours with grade 3 tumours
and/or lymphovascular invasion between chest wall irradiation and
follow up, irrespective of regional radiotherapy will attempt to answer
this question.

15.  Strom et al. confirmed that the risk of a local relapse in
the low-mid axilla after surgery alone is only 3%
actuarial at 10 years, independent from the extent of
the axillary involvement Strom EA Int J Radiat Oncol
Biol Phys 2005;63:1508–13. Postoperative axillary
radiotherapy more than doubles the risk for arm
oedema and other symptoms related to axillary
fibrosis Leer JW Eur J Surg 1997;163:815–22.
 With 4 or more nodes invaded and especially when
level 3 of the axilla is invaded, the risk exceeds 15–20%

16. In Situ
 Many similarities exist between invasive and in situ breast
cancer as far as it concerns local tumour behaviour after
treatment. The local recurrence rate is, similar to invasive
breast cancer, too high after lumpectomy alone.
 After lumpectomy, radiotherapy halves the risk for local
recurrence to about 1% a year (in half of them DCIS and in
the other half invasive cancer) with a disease specific
survival identical to mastectomy at nearly 100%. Age and
margins are the most significant prognostic factors for local
recurrence.
 Therefore, we should aim with our treatment at tumour-
free resection margins and in the case of very extensive
DCIS, a mastectomy should be considered.

18. Many parallels do seem to exist between DCIS
and invasive breast cancer.
• DCIS is a local disease and should primarily be treated with local approaches
only.
• BCT offers an acceptable local control rate for many patients with DCIS (1b).
• After lumpectomy, postoperative radiotherapy is always required (1b).
• No influence on survival from the treatment can be detected (1b).
• Their exists a probable dose–effect relationship (4).
• As young age is an independent risk factor for local relapses, especially younger
patients might benefit from a boost dose (4).
• As margins are an important prognostic factor for local control, a
microscopically complete lumpectomy should be aimed at (1b).
Unresolved questions and controversies:
• Patient subgroups, with a low risk for a local relapse with surgery alone or with a
lower dose/smaller volume of radiotherapy, still need to be properly defined.
• The role of adjuvant systemic treatment, if any, needs to be evaluated.