Strahlentherapie

und Onkologie Original Article

DEGRO Practical Guidelines for Radiotherapy

of Breast Cancer II
Postmastectomy Radiotherapy, Irradiation of Regional Lymphatics,
and Treatment of Locally Advanced Disease
Marie-Luise Sautter-Bihl1, Rainer Souchon2, Wilfried Budach3, Felix Sedlmayer4, Petra Feyer5,
Wolfgang Harms6, Wulf Haase7, Jürgen Dunst8, Frederik Wenz9, Rolf Sauer10

Background and Purpose: The aim of the present paper is to update the practical guidelines for radiotherapy of breast cancer
published in 2006 by the breast cancer expert panel of the German Society for Radiooncology (DEGRO). These recommendations
were complementing the S3 guidelines of the German Cancer Society (DKG) elaborated in 2004. The present DEGRO recommenda-
tions are based on a revision of the DKG guidelines provided by an interdisciplinary panel and published in February 2008.
Methods: The DEGRO expert panel (authors of the present manuscript) performed a comprehensive survey of the literature. Data
from lately published meta-analyses, recent randomized trials and guidelines of international breast cancer societies, yielding
new aspects compared to 2006, provided the basis for defining recommendations referring to the criteria of evidence-based
medicine. In addition to the more general statements of the DKG, this paper emphasizes specific radiooncologic issues relating
to radiotherapy after mastectomy (PMRT), locally advanced disease, irradiation of the lymphatic pathways, and sequencing of
local and systemic treatment. Technique, targeting, and dose are described in detail.
Results: PMRT significantly reduces local recurrence rates in patients with T3/T4 tumors and/or positive axillary lymph nodes
(12.9% with and 40.6% without PMRT in patients with four or more positive nodes). The more local control is improved, the more
substantially it translates into increased survival. In node-positive women the absolute reduction in 15-year breast cancer mor-
tality is 5.4%. Data referring to the benefit of lymphatic irradiation are conflicting. However, radiotherapy of the supraclavicular
area is recommended when four or more nodes are positive and otherwise considered individually. Evidence concerning timing and
sequencing of local and systemic treatment is sparse; therefore, treatment decisions should depend on the dominating risk of
recurrence.
Conclusion: There is common consensus that PMRT is mandatory for patients with T3/T4 tumors and/or four or more positive
axillary nodes and should be considered for patients with one to three involved nodes. Irradiation of the lymphatic pathways and
the optimal time point for onset of radiotherapy are still under debate.
Key Words: Radiotherapy of breast cancer · Postmastectomy radiotherapy · Locally advanced disease · Lymph node irra-
diation · Sequencing of local and systemic treatment

Strahlenther Onkol 2008;184:347–53

DOI 10.1007/s00066-008-1901-8

1
Municipal Hospital Karlsruhe, Germany,
2
Allgemeines Krankenhaus Hagen, Germany,
3
University Hospital Duesseldorf, Germany,
4
University Hospital, Salzburger Landeskliniken, Salzburg, Austria,
5
Klinikum Neukölln, Berlin, Germany,
6
St. Clara Hospital, Basel, Switzerland,
7
formerly St.-Vincentius-Kliniken, Karlsruhe, Germany,
8
University Hospital Schleswig-Holstein, Luebeck, Germany,
9
University Hospital Mannheim, Germany,
10
University Hospital Erlangen, Germany.

Update: October 2007

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Sautter-Bihl M-L, et al. DEGRO Guidelines for Radiotherapy after Mastectomy and/or in LABC

DEGRO-Leitlinien für die Radiotherapie des Mammakarzinoms II. Indikationen nach Mastektomie, für die Bestrahlung
der Lymphabflussgebiete und bei lokal fortgeschrittenen Situationen
Hintergrund und Ziel: Ziel der Arbeit ist eine Aktualisierung der 2006 publizierten Leitlinie der „Expertengruppe Mammakarzi-
nom“ der Deutschen Gesellschaft für Radioonkologie (DEGRO). Diese war seinerzeit in Ergänzung zur interdisziplinären S3-Leitli-
nie der Deutschen Krebsgesellschaft (DKG) von 2004 verfasst worden. Zwischenzeitlich erfolgten eine Überarbeitung und Aktua-
lisierung der S3-Leitlinie der DKG, die im Februar 2008 publiziert wurde.
Methodik: Die Expertengruppe (identisch mit den Autoren dieses Manuskripts) führte eine umfassende Literaturrecherche durch.
Aktuelle Metaanalysen und randomisierte Studien, die neue Aspekte gegenüber 2006 ergaben, sowie Empfehlungen internationa-
ler Fachgesellschaften wurden in die Bewertung von Therapieindikationen einbezogen. Diese orientieren sich an den Kriterien
evidenzbasierter Medizin. In Ergänzung zu den eher allgemeinen Statements der DKG 2008 werden spezielle radiotherapeutische
Fragestellungen behandelt, die eine Strahlentherapie nach Mastektomie (PMRT) und/oder bei fortgeschrittenen Tumoren, die
Bestrahlung der Lymphabflusswege und die Sequenz von Radio- und Systemtherapie betreffen. Zielvolumendefinition und Dosie-
rung werden im Detail beschrieben.
Ergebnisse: Die PMRT senkt die Lokalrezidivrate bei Patientinnen mit hohem Rückfallrisiko (T3/T4-Tumoren und/oder befallene
axilläre Lymphknoten; 12,9% mit und 40,6% ohne PMRT). Je ausgeprägter die durch die Radiotherapie bewirkte lokale Tumor-
kontrolle ist, desto stärker wirkt sich dies auf die Überlebenswahrscheinlichkeit aus. Bei lymphonodal positiven Patientinnen
ergab sich eine absolute Verminderung der tumorspezifischen Sterblichkeit um 5,4% nach 15 Jahren. Hinsichtlich des Nutzens
einer Strahlentherapie der Lymphabflusswege ist die Datenlage widersprüchlich. Eine Bestrahlung der Supraklavikularregion ist
jedoch bei vier oder mehr befallenen axillären Lymphknoten stets indiziert und sollte bei ein bis drei positiven Lymphknoten
erwogen werden. Bezüglich der Sequenz von Radio- und Systemtherapie gibt es keine richtungweisenden Evidenzen zugunsten
einer Therapiemodalität. Postoperativ sollte die Sequenz vom dominierenden Risiko abhängig gemacht werden.
Schlussfolgerung: Nach Mastektomie ist die PMRT bei T3/T4-Tumoren, Resttumor und/oder axillären Lymphknotenmetastasen
obligat. Die Bestrahlung der regionalen Lymphabflusswege und die Sequenz von Radio- und Systemtherapie bleiben bei unzurei-
chender Datenlage Gegenstand interdisziplinärer Diskussionen.
Schlüsselwörter: Strahlentherapie bei Mammakarzinom · Lokal fortgeschrittenes Mammakarzinom · Mastektomie ·
Strahlentherapie der Lymphabflusswege · Sequenz der Radio- und Systemtherapie

Introduction Postmastectomy Radiotherapy (PMRT) – Rationale

The present paper completes the first part of the practi- and Indications
cal guidelines for radiotherapy of breast cancer [39] of the
German Society of Radiooncology (DEGRO) which was • PMRT of the chest wall decreases the local recurrence
restricted to breast-conserving treatment. The following rate (LOE 1a)
recommendations are an update of the guidelines for ra- • In patients with a high risk of local recurrence, PMRT
diotherapy of breast cancer compiled by the breast cancer improves survival (LOE 1a)
expert panel of the DEGRO; these were based on the re- • PMRT of the chest wall is indicated in patients with
vised interdisciplinary guidelines for breast cancer diagnosis, – T3/T4 tumors (LOE 2a, GR A)
therapy and follow-up of the German Cancer Society, pub- – R1/R2 resection (LOE 2a, GR A)
– pN+ (> 3) (LOE 1a, GR A)
lished in March 2008 [8]. The respective statements, the level
• Patients with 1–3 positive axillary nodes may profit from
of evidence (LOE), and the grade of recommendation (GR)
PMRT (LOE 1a, GR 0)
are depicted at the beginning of each chapter. In addition
• After primary systemic treatment, the indication for PMRT
to these more general statements, the present recommenda-
should be based on the preoperative tumor stage (T- and
tions are further specified with regard to radiotherapeutic
N-status) irrespective of response to systemic treatment
aspects, problems, and techniques. The aim of the paper was
(LOE 2a, GR A)
to give a summary of the most important issues of postmast-
Statement RT-4 of the German Cancer Society
ectomy radiotherapy (PMRT), locally advanced disease,
regional irradiation of the lymphatics, and sequencing of
different treatment modalities. Therefore, a comprehensive While there is common consensus regarding whole breast ra-
survey of the literature was performed, comprising lately diotherapy after breast-conserving surgery (BCS), some indi-
published meta-analyses, data from recent randomized con- cations for PMRT continue to be an issue of debate.
trolled trials, and guidelines of international breast cancer Several meta-analyses and randomized controlled trials
societies. have provided clear evidence that PMRT substantially re-

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Sautter-Bihl M-L, et al. DEGRO Guidelines for Radiotherapy after Mastectomy and/or in LABC

duces the locoregional failure rate in all patients except those meta-analyses and made up for only 3.5% of all patients [6, 9,
with small tumors and node-negative disease, indicating that 46]. In a recent retrospective evaluation of the SEER Medicare
the benefit is proportional to the stage-dependent risk of lo- database, a survival benefit was described for patients whose
cal relapse [6, 10, 32, 40, 50, 51, 56]. Consequently, the greater risk of local recurrence was high (T3/4, N2/3) [44].
the reduction of local recurrence rates, the more it translates
into increased survival [11, 56]. In the latest meta-analysis Conclusion of the DEGRO Panel
of the Early Breast Cancer Trialists’ Collaborative Group • Patients should not be precluded from PMRT on the basis of
(EBCTCG) encompassing data from trials up to 2000 [6], formal age criteria alone.
patients with positive nodes had a benefit in cancer-specific • When PMRT is indicated according to TMN stage [49], it
survival of 5.4% and in overall survival of 4.4% after 15 years. should only be omitted in case of poor clinical condition or
The survival benefit was greatest (6.2%) in patients with four comorbidities substantially reducing life expectancy.
or more positive nodes whose 5-year local recurrence rate was
reduced from 40.6% to 12.9%. Therefore, PMRT is interna- PMRT and Other Risk Factors
tionally recommended for patients with a large tumor size The significance of other risk factors such as age < 40 years,
(pT3–4), incomplete resection, and/or four or more positive blood or lymphatic vessel invasion, infiltration of the pec-
axillary nodes [8, 26, 27, 42, 48]. toral fascia, or close resection margins < 1 mm has not been
definitely assessed, therefore, the respective benefit of PMRT
PMRT for Patients with One to Three Positive Nodes is not yet quantifiable on a high LOE [29]. As radiotherapy
Recently, the benefit of PMRT has also been demonstrated may prevent secondary distant spread by reducing local recur-
for patients with one to three positive axillary lymph nodes. rence [15], the panel recommends to consider PMRT in these
In the latest meta-analysis of the EBCTCG [6], patients with situations, especially in patients with several of the above-
one to three positive axillary nodes experienced an absolute mentioned risk factors.
reduction of breast cancer mortality of 4.4% after 15 years.
The local recurrence rate amounted to only 5.3% with radio- Radiotherapy of the Regional Lymph Node Areas
therapy versus 24.3% without. In a subgroup analysis of the
• The benefit of postoperative irradiation of the lymphatic
Danish Breast Cancer Study Group, the survival gain after 15
pathways has not been proven in prospective randomized
years was 9% for patients with four or more positive nodes
trials, therefore, the decision has to be made individually
(21% vs. 12%). Interestingly, the subgroup with one to three
(LOE 3b)
affected nodes had the same absolute survival gain of 9%
• There is no indication for radiotherapy of the axilla, when
(57% vs. 48%), while the rate of overall survival was higher
sentinel node biopsy was tumor-negative (LOE 1b, GR A)
[31]. The 20-year analysis of the British Columbia trial pro-
• Radiotherapy of the axilla is indicated
vided similar results [34]. On the basis of these data, several
– in presence of residual tumor in the axilla (LOE 2b,
guidelines recommend that PMRT should be considered for
GR A)
patients with one to three positive nodes as well [26, 27, 32,
– in case of clinically apparent tumor spread to the axilla
48]. Results from the UK Medical Research Council/EORTC
or in case of positive sentinel node biopsy without or
22052-10051 SUPREMO trial to answer this question are still
after incomplete axillary dissection (LOE 3b, GR A)
pending. However, in a recently published editorial, Marks et
There are no sufficient data supporting irradiation of the
al. explicitly state that the distinction between one to three
axilla in case of extracapsular tumor spread
versus four or more positive nodes is arbitrary and that it is
• Radiotherapy of the supra-/infraclavicular nodes is rec-
therefore “time to end the debate” [23].
ommended
– when more than three nodes are positive (LOE 2a,
Conclusion of the DEGRO Panel
GR B)
• For patients with one to three positive axillary nodes bearing
– in case of tumor spread to level III (LOE 3b, GR B)
an intermediate risk for locoregional recurrence after mast-
– when radiotherapy of the axilla is indicated (LOE 3b,
ectomy, PMRT should no longer be considered optional
GR B)
only, but an indication based on strong evidence (LOE 1).
• Radiotherapy of the internal mammary nodes is generally
As a consequence, in the next update of the German Can-
no longer recommended except in clinical trials
cer Society the respective recommendation should be modi-
Statement RT-5 of the German Cancer Society
fied accordingly.

PMRT and Age The impact of radiotherapy of the regional lymph node areas
For patients > 70 years there is limited level I evidence on the on outcome in breast cancer has not been ultimately proven
effects of PMRT. Therefore, its benefit is not ultimately proven in prospective randomized studies; therefore, the indication
as this group has, so far, been underrepresented in the published for regional lymphatic irradiation remains an individual de-

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Sautter-Bihl M-L, et al. DEGRO Guidelines for Radiotherapy after Mastectomy and/or in LABC

cision [26–28, 35, 42, 48]. On the other hand, in those stud- guidelines [48] refrain from giving a definite recommenda-
ies that showed improved survival in the irradiated patients, tion for IMC irradiation due to the inconsistency of data. The
the regional lymphatic pathways were mostly included [6, 32]. NCCN guidelines representatively demonstrate the contro-
However, the contribution of lymph node irradiation to the versial views taken by different scientists on the issue of IMC
improvement of outcome cannot yet be quantified. The re- irradiation: “There is considerable disagreement, some panel
sults of ongoing clinical trials clarifying the impact of adjuvant members believe that irradiation of the internal mammary
radiotherapy of regional lymphatics are still pending. It seems nodes is unnecessary and produces possible morbidity. Others
noteworthy that most of the data referring to radiotherapy believe IMC should be included as used in those studies that
with additional lymphatic irradiation were evaluated in PMRT demonstrated an advantage of radiotherapy.” The panel’s
patients, whereas lymph node irradiation was performed only compromise is reflected by the statement that “the treatment
in a minority of studies with BCS [6]. This may be explained of the internal mammary nodes is left to the discretion of the
by the restriction of BCS studies to patients with small tumors treating radiooncologist”. Moreover, the NCCN does recom-
and favorable prognostic factors in whom additional lymphat- mend consideration of IMC radiation (and supraclavicular
ic irradiation did not seem to be beneficial. fossa) even for patients with one to three positive nodes after
mastectomy [27]. Clarification of the issue whether the benefit
Radiotherapy of the Supraclavicular Fossa outweighs potential risks of IMC irradiation is expected from
Radiotherapy of the supraclavicular fossa is regarded as man- the EORTC 22922/10925 trial that is currently investigating
datory when more than three axillary nodes are positive [42]. the impact of IMC radiotherapy in patients with medial/cen-
The National Comprehensive Cancer Network (NCCN) rec- tral location and/or axillary lymph node involvement [33].
ommends to consider radiotherapy of the supraclavicular fossa More than 4,000 patients have been randomized; results are
even for patients with one to three positive nodes, though with expected in 2011.
a lower GR [26, 27]. The Canadian guidelines recommend in-
clusion of the supra-/infraclavicular nodes in all patients who Conclusion of the DEGRO Panel
receive PMRT [48]. • No routine use of IMC radiotherapy.
• However, IMC irradiation should not be regarded as obso-
Conclusion of the DEGRO Panel lete for patients with four or more positive axillary nodes
Supra-/infraclavicular irradiation is and large tumors, especially those with medial/central loca-
• mandatory when four or more axillary nodes are positive, tion. Any decision has to be made individually considering
• an individual decision in patients with one to three positive the patient’s specific risk pattern.
axillary nodes.
Radiotherapy of Locally Advanced Breast Cancer
Radiotherapy of the Axilla and Primarily Inoperable Tumors
Radiotherapy of the axilla is only recommended for patients
• For patients with tumors that are irresectable at diagnosis
with residual tumor after axillary dissection or in case of clinical
(stage IIIB) primary systemic treatment is recommended,
involvement and inadequate axillary clearance [26, 27, 42, 47,
followed by surgery and radiotherapy (LOE 1b, GR A)
48]. Positive sentinel node biopsy (SNB) without consecutive
• If primary systemic treatment fails to achieve operability,
axillary dissection is another indication [22, 27, 42, 48], whereas
radiotherapy is recommended, possibly in combination
radiotherapy should be omitted after negative SNB [52, 53].
with concomitant systemic treatment (GR B)
Data supporting a benefit of irradiation of the axilla in case
Statement RT-6 of the German Cancer Society
of extracapsular extension (ECE) are inconsistent. Therefore,
ECE is not regarded as indication [12, 25, 45, 54, 55].
Generally accepted criteria for the definition of locally ad-
Conclusion of the DEGRO Panel vanced breast cancer (LABC) are tumors of a size > 5 cm in
Radiotherapy of the axilla is performed only in patients diameter or with either skin or chest wall involvement. Fur-
• without axillary dissection or with residual tumor thereafter, ther criteria are fixed (matted) axillary lymph node masses or
• in case of clinical involvement and inadequate axillary clear- spread to the ipsilateral supraclavicular or IMC nodes. Inflam-
ance as defined in the guidelines of the German Cancer So- matory carcinomas are regarded as a subgroup of LABC [2,
ciety, 7, 43].
• with positive SNB without consecutive axillary dissection. LABC is currently treated with primary systemic therapy,
i.e., chemo- or endocrine therapy with the aim of tumor shrink-
Radiotherapy of the Internal Mammary Chain ing and consecutive resectability (mastectomy or in a breast-
Radiotherapy of the internal mammary chain (IMC) is gener- conserving setting). Preoperative radiotherapy may increase
ally no more recommended as a routine treatment unless these the rate of breast conservation and seems to have no negative
nodes are clinically or pathologically positive. The Canadian impact on cosmetic outcome. However, radiotherapy should

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Sautter-Bihl M-L, et al. DEGRO Guidelines for Radiotherapy after Mastectomy and/or in LABC

not replace consecutive resection [19, 36, 41, 48]. Treatment patient numbers, no increased toxicity was observed when
strategy and indication for radiotherapy should be discussed trastuzumab was applied simultaneously with radiotherapy.
in an interdisciplinary setting prior to the start of primary IMC irradiation was not permitted in this setting [3, 13, 37].
systemic therapy and decisions based on pretreatment tumor There are no contraindications for simultaneous endocrine
stage irrespective of response to treatment [18]. Patients with treatment and radiotherapy [1, 14, 17].
LABC and operable tumors (stage IIIA) should receive che-
motherapy either as primary treatment with consecutive sur- Technique of Radiotherapy – Chest Wall
gery and irradiation or as postoperative treatment. Complete Usually, radiotherapy is performed in supine position with
remission following primary systemic treatment is a favor- abducted arm (≥ 90°) using breast tilt boards with arm rest to
able predictive parameter and especially these patients profit maintain the patients’ daily position. Immobilization devices
from PMRT [24]. For inoperable patients, in whom primary may be used to facilitate daily reproducibility and minimize
systemic treatment fails to achieve operability, concomitant setup errors.
radiochemotherapy may be indicated [21, 27, 41]. In order to achieve optimized dose distribution, three-
Inclusion of the axilla into the target volume depends on dimensional CT planning is mandatory, followed by either
the extent of surgery and histopathologic findings and is rec- conventional or virtual simulation with treatment verification
ommended in case of residual tumor. The value of IMC irra- of each field. The planning target volume (PTV) comprises
diation is unclear [26, 27, 41]. the chest wall including the scar and a safety margin. The cra-
nial and caudal field borders are adapted to the size and posi-
Timing and Sequencing of Radiotherapy tion of the contralateral breast with the inferior extension
about 1.5 cm below the original submammary fold. The maxi-
• The most effective sequencing of radiotherapy and sys-
mum depth of the irradiated lung should not exceed 2 cm. The
temic treatment cannot be defined on the basis of current
dose is 50–50.4 Gy delivered in 1.8–2 Gy per fraction. In areas
data. Postoperative sequencing should be determined ac-
at high risk of local recurrence, a boost may be considered in
cording to the predominant risk of recurrence as the opti-
case of close margins or R1 resection status [5, 27, 38, 41].
mal time point for each treatment is unclear (LOE 1a,
GR B)
Technique of Radiotherapy – Lymph Node Areas
• Consistent data referring to sequencing of radiotherapy
For irradiation of the supraclavicular lymph nodes, three-
and trastuzumab are not yet available
dimensional planning is desirable but not mandatory. The PTV
• Simultaneous application of trastuzumab and radiothera-
comprises the supraclavicular nodes and the axillary nodes of
py does not seem to enhance toxicity and is feasible, pro-
level III (apex axillae) with a safety margin of 1–2 cm. Refer-
vided that no IMC irradiation is performed (LOE 3a).
ence points for supraclavicular nodes are usually chosen in a
Antiestrogen treatment may be performed simultaneously
depth of about 3 cm and for level III nodes in about 5 cm, re-
with radiotherapy or sequentially (LOE 1a)
spectively, depending on the individual anatomy. Care has to
Statement RT-7–9 of the German Cancer Society
be taken to match the field border of the tangential portal [5].
When additional irradiation of the axilla is indicated, this
As currently data do not permit to define an optimal sequence is usually performed by opposing techniques. The PTV com-
of surgery, systemic treatment and radiotherapy, the thera- prises the supraclavicular fossa and the axillary lymph nodes
peutic strategy should be determined in an interdisciplinary in levels I–III with a safety margin of 1–2 cm. In case of includ-
approach, oriented on stage of the disease and individual risk ing the supraclavicular nodes into opposing beam arrange-
factors. ments, the difference in anatomic diameter has to be taken
Basically, sequencing and timing of chemo- and radio- into consideration in order to avoid an overdose in the supra-
therapy should be individually adapted to the predominant clavicular area.
risk of recurrence [4, 16, 18, 20]. An early onset of radiothera- The dose in the reference point is 50/50.4 Gy. In case of
py is indicated when the risk of local relapse is prevailing (e.g. increased risk for supraclavicular metastases, i.e., in the pres-
T4 tumors, gross residual disease, or close margins < 2 mm). ence of massive axillary lymph node involvement, the dose
Radiotherapy should be started 4–6 weeks after surgery may be increased up to 56 Gy. The tolerance dose (TD 5/5)
or after completion of the primary or adjuvant chemotherapy using a daily fraction of 2 Gy is considered to be 56 Gy for the
[30, 42]. Theoretically, it seems tempting to minimize the de- brachial plexus. The daily fraction size should therefore not
lay of local treatment by using concomitant radiochemothera- exceed 1.8/2 Gy per day [27, 38, 41].
py, moreover, an additional radiosensitization of tumor cells For radiotherapy of the internal mammary nodes, three-
might be expected. However, simultaneous radiochemothera- dimensional planning is mandatory. The PTV comprises the
py yields higher toxicity. ipsilateral lymphatic pathway along the ipsilateral internal
Trastuzumab is established for adjuvant treatment of mammary vessels encompassing the first three or four inter-
HER2-neu-positive tumors. In a prospective study with large costal spaces with a safety margin of 1 cm. Although there is

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an anastomotic drainage to the contralateral side, irradiation 19. Huang EH, Tucker SL, Strom EA, et al. Postmastectomy radiation improves
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