Exclusive intraoperative radiotherapy for invasive breast cancer in elderly patients (>70 years): proportion of eligible patients and local recurrence-free survival
Lambaudie et al. BMC Surgery
Exclusive intraoperative radiotherapy for invasive breast cancer in elderly patients (>70 years): proportion of eligible patients and local recurrence-free survival
Eric Lambaudie 1 3 10
Gilles Houvenaeghel 1 3 10
Amira Ziouèche 1 3 10
Sophie Knight 1 3
François Dravet 0
Jean Remy Garbay 7
Sylvie Giard 6
Hélène Charitansky 5
Monique Cohen 1 3 10
Christelle Faure 4
Delphine Hudry 9
Paul Azuar 8
Richard Villet 2
Pierre Gimbergues 11
Christine Tunon de Lara 12
Agnès Tallet 1 3 10
Marie Bannier 1 3 10
Mathieu Minsat 1 3 10
Michel Resbeut 1 3 10
0 Institut René Gauducheau , Nantes , France
1 CRCM , Marseille , France
2 Hôpital des Diaconesses , Paris , France
3 Institut Paoli Calmettes , 232 Boulevard de Sainte-Marguerite, 13009 Marseille , France
4 Centre Léon Bérard , Lyon , France
5 Centre Claudius Regaud , Toulouse , France
6 Centre Oscar Lambret , Lille , France
7 Institut Gustave Roussy , Villejuif , France
8 Hôpital de Grasse , Grasse , France
9 Centre Georges François Leclerc , Dijon , France
10 Aix Marseille Université , Marseille , France
11 Centre Jean Perrin , Clermont Ferrand , France
12 Institut Bergonié , Bordeaux , France
Background: To estimate the proportion of elderly patients (>70 years) with breast cancer eligible for an Exclusive IntraOperative RadioTherapy (E-IORT) and to evaluate their local recurrence-free survival rate. Methods: This retrospective study examining two cohorts focuses on patients over 70 years old: a multi-centric cohort of 1411 elderly patients and a mono-centric cohort of 592 elderly patients. All patients underwent conservative surgery followed by external radiotherapy for T0-T3 N0-N1 invasive breast cancer, between 1980 and 2008. Results: Within each cohort two groups were identified according to the inclusion criteria of the RIOP trial (R group) and TARGIT E study (T group). Each group was divided into two sub-groups, patients eligible (E) or non-eligible (nE) for IORT. The population of patients that were eligible in the TARGIT E study but not in the RIOP trial were also studied in both cohorts. The proportion of patients eligible for IORT was calculated, according to the eligibility criteria of each study. A comparison of the 5-year local or locoregional recurrence-free survival rate between eligible vs non-eligible patients was made. In both cohorts, the proportion of patients eligible according to the RIOP trial's eligibility criteria was 35.4 and 19.3%, and according to the TARGIT E study criteria was 60.9 and 45.3%. The 5-year locoregional recurrence-free survival rate was not significantly different between RE and RnE groups, TE and TnE groups. In both cohorts RE and (TE-RE) groups were not significantly different. Conclusions: Our results encourage further necessary studies to define and to extend the eligibility criteria for per operative exclusive radiotherapy.
Breast cancer; Elderly patients; Intraoperative radiotherapy
The objective of this retrospective study was to estimate,
in a cohort of 12,025 patients managed conventionally,
the proportion of elderly patients (>70 years) eligible for
exclusive intra-operative radiotherapy (IORT) and to
evaluate local recurrence-free survival rates.
The results of this study suggest that up to 50% of
patients presenting with a cN0, T0-2 tumor could be
eligible for exclusive IORT with expected 7-year local
recurrence-free survival rates ranging from 93 to 96%.
These results suggest the possible extension of the
eligibility criteria for intra-operative exclusive radiotherapy.
Breast cancer has become the most frequent cancer
in both “developed” and “developing” countries
(http://globocan.iarc.fr/). Its management represents a
major concern for public health at therapeutic and
Moreover, robust publications have shown that in the
case of conservative surgery for an invasive cancer,
adjuvant whole-breast irradiation in association with a boost
to the tumor bed significantly increases recurrence-free
survival, without any difference compared to total
mastectomy in terms of overall survival . However, almost
90% of recurrences in the breast are located in the same
Based on this clinical information, and with the aim of
facilitating access to radiotherapy, partial breast
irradiation techniques have been developed over the past
20 years; using brachytherapy, external radiotherapy and
Organized screening combined with these modern
therapeutic approaches enable a less radical and invasive
management of patients.
As suggested by the results of the Targit A trial,
targeted intraoperative radiotherapy appears to be as safe
as whole-breast external beam radiotherapy when the
radiotherapy is delivered at the time of lumpectomy in
selected patients . The potential medico-economic
impact must be considered in order to encourage the
development of this technique as a second objective.
In France, the main objective of the RIOP trial [a French
trial currently in progress conducted under the aegis of
the National Cancer Institute (INCA - Institut National
du Cancer) is medico-economic.
Concerning the elderly population, the future results
of the TARGIT E trial  should give us a better
knowledge of the indications for partial breast irradiation in
this specific population.
Following our previously published study  concerning
eligibility criteria in the general population of patients, the
purpose of this new retrospective analysis focusing on
patients over 70 years old, undergoing conservative
treatment associating conservative surgery and conventional
external radiotherapy for an invasive breast cancer was:
– to estimate the proportion of eligible patients for
exclusive intraoperative radiotherapy (IORT)
according to the criteria of the RIOP trial and the
TARGIT E trial,
– to evaluate and compare using data from these two
cohorts, the local and locoregional recurrence-free
survival rates among patients who were both eligible
and non-eligible for exclusive IORT according to the
eligibility criteria of both trials mentioned above.
This retrospective study analyzed two different cohorts
of patients who underwent conservative surgery followed
by external radiotherapy for invasive, non-metastatic and
non-inflammatory breast cancer (Fig. 1).
The first multi-centric cohort (cohort G3S) included
7580 patients treated in 13 centers between 1999
and 2008, all of which underwent a sentinel node
biopsy followed or not by complementary axillary
dissection for N0, T0 to T2 tumors.
The second monocentric cohort (cohort 2) included
4445 patients treated at Paoli Calmettes Institute
(IPC) between 1980 and 2005 with conservative
surgery for tumors stage T0 to T3, N0 or N1 who
underwent a sentinel node biopsy followed or not by
complementary axillary dissection or alternatively
immediate axillary dissection.
A first analysis concerning eligible patients within these
cohorts was conducted and published recently using the
same methodology . For this task, we focused our study
in both cohorts, on the subgroup of patients over 70 years
old: 1411/7580 patients and 592/4445 patients for cohort
1 and cohort 2 respectively.
This study obtained ethics approval by our Institutional
review board (Paoli Calmettes Institute’s ethical committee)
was obtained and the data were used confidentially for
The pathological analysis of each resected specimen
defined tumor size, histological type, tumor stage, tumor
grade according to the Scarff-Bloom-Richardson
classification (SBR) , presence of lympho-vascular
invasion and lymph node metastasis. Immunohistochemical
techniques determined estrogen receptor (RE) and
progesterone receptor (RP) status with a positive threshold
of >10%. Data relating to the overexpression of the Her2
receptors was too recent in relation to the study period;
therefor Her2 status was only defined for 857 patients
(60.7%) and 89 patients (15%) over 70 years old, in the
G3S cohort and the cohort 2 respectively.
All patients were treated with 50 Gy whole-breast
radiotherapy, most frequently associated with a 10–16 Gy
boost to the tumor bed.
Adjuvant chemotherapy and a 5-year hormonotherapy
in case of hormone-sensitive tumors were delivered
according to institutional guidelines at the time of patient
management. For all the patients with an established
Her2 status, targeted therapy has been administrated
when chemotherapy was indicated.
Study groups and parameters studied
Two groups were identified within each cohort using the
inclusion criteria of the RIOP and TARGIT-E trials. Each
group was divided into two sub-groups, separating
patients who were eligible for exclusive IORT from those
who were not eligible: the RIOP trial with sub-groups
R1E and R1nE for the G3S cohort, R2E and R2nE for
the cohort 2 and the TARGIT E trial with the
subgroups T1E and T1nE for the G3S cohort, T2E and
T2nE for the cohort 2. The sub-group of patients eligible
in the TARGIT E study but not eligible in the RIOP
study (TE-RE) were also analyzed in each cohort.
In each trial the eligibility criteria were based on
preoperative clinical, radiological and histological data.
Patients’ eligibility (inclusion criteria) according to
TARGIT E and RIOP trials are summarized in Table 1.
Patients eligible for the TARGIT E study were at least
70 years old and had a unifocal invasive ductal carcinoma.
Three post-operative criteria indicated the requirement
for additional external irradiation of the mammary gland:
discrepancies concerning histologic type (invasive lobular
carcinoma), the presence of an extensive intraductal
carcinoma in situ and positive margins. The presence of
lymph node involvement, lympho-vascular invasion, a
tumor size above 35 mm and a proven multifocality or
multicentricity could indicate an additional external
irradiation. The results of this study are not yet available.
The eligibility criteria for an exclusive IORT according
to the RIOP trial were: age ≥55 years, tumor size ≤ 2 cm,
an unifocal invasive ductal carcinoma, tumor grade 1 or 2,
positive hormone receptors (HR), the absence of
lymphovascular invasion and the absence of clinically involved
lymph nodes. Her2 overexpression was considered an
exclusion criterion. The presence of post-operative nodal
invasion, of an extensive intraductal carcinoma in situ,
positive excision margins and the failure to meet all the
criteria stated above at the preoperative stage rendered
complementary external radiotherapy necessary.
In our study, all the patients were menopausal and
none of them have been referred for BRCA mutation’s
For each cohort we calculated the proportion of patients
eligible for exclusive IORT according to the criteria of
each trial. We then compared, after conventional
treatment combining breast conservative surgery and external
radiotherapy, the 5-year and 7-year local recurrence-free
survival rates of the following groups: RE groups versus
Table 1 Inclusion criteria for TARGIT E and RIOP trials
No vascular invasion
SBR grade 1 and 2,
positive, HER 2 negative
All of these criteria
No known BRCA mutation
the RnE groups, the TE groups versus the TnE groups and
finally the RE groups versus (TE-RE).
All local recurrences have been confirmed by biopsy.
Locoregional recurrences included axillary recurrences,
supra and infraclavicular recurrences or intra-mammary
recurrences. Concerning nodal recurrences, literature
review indicates that it represents only a marginal number
of locoregional recurrences; thus, recurrence-free
survival can be considered as local recurrence-free survival
in almost all cases [7–9].
This retrospective evaluation has limitations
concerning clinical characteristics and follow-up; some criterions
are missing in the description of each population.
All statistical tests were two-sided. Comparisons were
performed using the Chi-square test for percentages
Student’s t-test for means (statistical significance was set
at 0.05 for both tests) and log-rank test for survival
(statistical significance set at 0.1). Statistical analyses
were performed using SPSS version 16.0.
For the total population studied (12,025 patients for the
two cohorts) the average age at diagnosis was 58
(median 58, range 22–101) in the G3S cohort and
55.6 years (median 55, range 20–91) in the IPC cohort.
Within this population, all patients underwent
conservative surgery and axillary lymph node staging (sentinel
lymph node biopsy or complete axillary lymph node
dissection). Adjuvant treatments were the following in the
G3S and cohort 2 respectively: 36.7% (2784/7580) and
43.6% (1938/4445) patients received adjuvant
chemotherapy and 84.3% (6373/7556) and 54.6% (2417/4422)
patients were treated with adjuvant hormonal therapy.
All patients received adjuvant radiotherapy with a
whole-breast 50 Gy irradiation completed in most case
with a 16 Gy boost to the tumor bed.
Regarding our study, patients over 70 years old
represented 18.6% (1411/7580) of the G3S cohort 1 and
13.3% (592/4445) of the IPC cohort 2.
Characteristics of patients over 70 years old are shown
in Table 2. There was a significant difference between
both cohorts for the following characteristics: age, tumor
size, hormonal receptor (HR) status, nodal status, grade,
lympho-vascular invasion, and local recurrences with a
population showing more unfavorable characteristics in
the IPC cohort 2. These differences are confirmed when
the eligible groups for RIOP (RE) and TARGIT E (TE)
trials are considered, with fewer eligible patients in the
IPC cohort 2 than in the G3S cohort 1.
Table 3 presents in each cohort the eligible patients
for the RIOP study (R1E and R2E) and the TARGIT-E
study (T1E and T2E). Table 4 shows that in both cohorts
eligible patients for RIOP trial had significantly different
characteristics from the eligible patients in the TARGIT
E trial and non eligible in the RIOP study (TE-RE).
Proportion of eligible patients and locoregional
In the G3S cohort the proportion of patients over 70 years
old eligible for exclusive IORT was 35.4% (499/1411) and
60.9% (859/1411) when using eligibility criteria of the
RIOP and TARGIT E studies respectively. 5-year and
7-year locoregional recurrence-free survival rates were
94.2 and 94.2% respectively for the R1E group versus 93.7
and 89% for the R1nE group; 94.1 and 92.3% for the T1E
group versus 93.4 and 89.8% for the T1nE group.
Locoregional recurrence-free survival was not significantly
different between the T1E and T1nE (log rank = 0,266) groups
and between the R1E and R1nE (log rank = 0,136) groups.
We did not observe any significant difference between
the R1E and (T1E-R1E), log rank = 0,210 (Table 5).
In the entire G3S cohort overexpression of Her2 was
not related to a higher rate of locoregional recurrences
log rank = 0.894.
The study of the sub-populations showed that the
eligible patients both in the TARGIT-E and the RIOP
studies with tumors overexpressing Her2 did not present
locoregional recurrence significantly more frequently
than patients without overexpression of Her2. In the
IPC cohort the proportion of patients over 70 years old
eligible for exclusive IORT was 19.3% (114/592) and
45.3% (268/592) when using eligibility criteria of the
RIOP and TARGIT E trials respectively. The 5-year and
7-year local recurrence-free survival rates were 98.6 and
98.6% respectively for the R2E group versus 97 and
96.6% for the R2nE group; 97.7 and 97.7% for the T2E
group versus 97 and 96.3% for the T2nE group. There was
no significant difference in local recurrence-free survival
between the T2E and T2nE groups (log rank = 0.319) and
between the R2E and R2nE groups, (log rank = 0.314).
Eligible patients RIOP (RE)
Eligible patients TARGIT E (TE)
Nor was there a significant difference in local
recurrencefree survival between the R2E and T2E-R2E groups
(log rank = 0.322), (Table 6).
Although conservative surgery followed by post-operative
adjuvant radiotherapy, associating whole-breast irradiation
followed by a boost to the tumor bed is considered the
standard care of early stage breast cancer , a current
aim is to reduce treatment duration and associated costs.
Though this option could benefit the entire population of
patients treated for breast cancer, elderly patients, who are
generally more fragile, represent an excellent target
population. For this reason partial and accelerated breast
irradiation techniques by means of brachytherapy, external
radiotherapy and intra-operative radiotherapy have been
Certain advantages of these techniques should be
underlined: such as radiobiological benefits enabling a
reduction in the time lapse between surgery and
radiotherapy and an increase in the dose of equivalent
Additionally, irradiation techniques such as IORT
delivered during the surgical procedure also seem to act
favorably on the tumor microenvironment .
For selected patients, these techniques enable a
reduction in the volume treated and the duration of the
irradiation without a reduction in survival. In a recent
non-inferiority phase 3 randomized trial, Vaidya et al.
reported no significant difference in terms of local
recurrence with a 4 year follow-up in 2232 randomized patients
between external radiotherapy and intra-operative
radiotherapy with 50kv type intrabeam photons . The
updating of this series has confirmed the efficacy of this
treatment over 5 years for patients who received IORT at
the time of the initial lumpectomy (pre pathology group),
and not after definitive pathology during a second surgical
time (post pathology group) .
Other techniques of accelerated partial breast
irradiation using brachytherapy, external radiotherapy of the
ELIOT system have been studied, confirming the safety
of this type of irradiation [11–13]. The difference in the
proportion of eligible patients for exclusive IORT
observed between the G3S and IPC cohorts for elderly
Table 4 Comparison of patients of the G3S cohort 1 (R1E) and IPC cohort 2 (R2E) eligible for the RIOP trial with patients eligible for
the TARGIT E study and not eligible for RIOP (TE-RE) (Continued)
Radiotherapy boost to tumor bed
NS no significative difference
patients (35.4 and 19.3% eligibility according to the
criteria of the RIOP trial; 60.9 and 45.3% according to the
TARGIT E trial) can be explained by the significantly
greater number of patients presenting with unfavorable
tumor characteristics in the IPC cohort. In the G3S
cohort, the 5-year locoregional recurrence-free survival
rate was 94.2 and 94.1% for patients eligible for IORT
according to the criteria of the RIOP and TARGIT-E
trials respectively and in the IPC cohort of 98.6 and 97.7%
respectively for the both groups. We therefore expect
comparable local recurrence rates if patients are
effectively treated by exclusive IORT.
The eligibility criteria for the TARGIT-E trial were less
restrictive than those of the RIOP trial; for this reason
we compared local and locoregional recurrence-free
survival rates of the group of patients eligible for the RIOP
trial with the patients eligible for the TARGIT-E trial but
not eligible for the RIOP trial (RE versus TE-RE): in both
cohorts we observed no significant difference between
these groups in terms of local or locoregional
recurrencefree survival rate. These results therefore encourage us to
extend the eligibility criteria for exclusive IORT, which
were very restrictive in the RIOP trial. In order to confirm
this state of the art, we are waiting for the results of the
TARGIT E trial. In this study preoperative breast MRI is
not required for inclusion; nevertheless this raises the
question of its value for disqualifying patients with bifocal
or multifocal tumors as in the RIOP trial.
In order to extend the indications for IORT, the
overexpression of Her2 has been screened to confirm or not
Table 5 Loco regional recurrence-free survival in the G3S cohort 1
Exposed to the risk
Exposed to the risk
its negative impact on survival, as it has been considered
as an exclusion criteria; its value as an independent risk
factor compared to other criterions (age, emboli, and
hormonal receptors status) is under discussion [14, 15].
In our study this factor does not compound the risk of
local recurrence among eligible patients and,
consequently, may not be considered as an exclusion factor if
a treatment by exclusive IORT is planned.
Although local recurrence represents the main risk for
patients who are eligible for partial breast radiotherapy,
the team’s decision (surgeon/radiotherapist) could be
guided by different tools that are still in development. In
a study reported by Sanghani et al., significant risk
factors for local recurrence were identified by
developing a model with patients treated in nine randomized
trials. The most significant factors were age < = 40 years
(HR 2.03), positive margins (HR 2.19), positive HRs
(HR 0.73) and grade III tumors (HR 1.55) . In a
metaanalysis, Van Nes et al. developed a prognostic index to
predict the risk of local recurrence by identifying three
risk groups. However, this study compares local
recurrence after conservative surgery and after mastectomy and
does not take into account major factors such as the SBR
grade, the HR status or lympho-vascular invasion .
Finally, the potential economic impact of this
technique is undeniable. Intra-operative radiotherapy
currently provides the best option to reduce hospital stay
and offers the possibility to perform one-day treatment.
This advantage is particularly interesting in elderly
patients, who usually present more comorbidity, in order
Table 6 Loco regional recurrence-free survival in the IPC cohort 2
Exposed to the risk
Exposed to the risk
R2E vs (T2E-R2E)
to limit the impact of the treatment. In our study
and according to the sub-groups of elderly patients
(≥70 years), the outermost percentages of patients who
could have benefited from exclusive IORT were 19.3 and
60.9%: These are so many patients in whom external
radiotherapy could be avoided. The savings entailed by
such a procedure have been estimated: in the United
Kingdom this treatment would shorten the waiting lists
for post-operative radiotherapy, saving an estimated 23
million dollars. In the USA, IPAS has already been
proposed as an alternative to standard irradiation among
patients of the most favorable ASTRO group in order to
reduce time and costs of journeys for post-operative
external radiotherapy . ESTRO also provided a
classification to guide the selection of patients suitable for partial
accelerated irradiation of the breast . A recent study of
a cohort of 59,396 patients has shown an increase in the
use of partial accelerated irradiation of the breast from
3.4% in 2003 to 12.8% (p < 0.001) in 2008 . On this
matter, the RIOP trial is ongoing in France to study the
economic impact of this technique in our country.
The next step if we want to decrease cost and
morbidity in relation with adjuvant treatment and
particularly external beam radiation therapy, is to select a
subset of patients who did not benefit of breast radiation
after lumpectomy. This is aim of the CALGB 9343 trial
where patients older than 70 years old with a clinical
stage 1 breast cancer ER positive, have been randomised
between adjuvant radiation therapy followed by
tamoxifene (Tam RT group n = 317) or tamoxifene alone
(Tam group n = 319). Hughes et al.  has reported the
results of this study, with no difference in term of overall
survival but a significantly longer time to local
recurrence in the TamRT group (observed HR, 0.18; 95% CI,
0.07 to 0.42; P.001). Long-term follow-up of CALGB
9343 confirms and extends that in women age >70 years
with clinical stage I, ER-positive breast cancer treated
with lumpectomy followed by tamoxifen, irradiation
adds no significant benefit in terms of survival: the place
of exclusive IORT has to be discuss to reduce
locoregional recurrence in this low risk population. But to date,
external beam radiotherapy after lumpectomy remains
the standard of care in Europe, even in case of elderly
patients with a low risk of locoregional recurrence.
Recent data from the TARGIT A trial are encouraging in
terms of effectiveness, safety and toxicity, although a
more extensive follow-up is necessary. Considering
IORT’s potential advantages in terms of cost/efficiency,
our study shows that its potential is underestimated.
The selection of patients remains an important issue
but, given the frequency of breast cancer, a significant
number of treatments could be carried out in this way.
Our results suggest that when considering RIOP or
TARGIT E’s inclusions criterions, 19.3 to 60.9% T0-2 N0
patients could be eligible for exclusive IORT even in
case of Her2 overexpression, with no difference
concerning recurrence-free survival compared to non-eligible
If intra operative radiotherapy must be done at the
time of surgery as demonstrated in the TARGIT A trial,
our results encourage further necessary studies to define
and to extend the eligibility criteria for per operative
ASTRO: American Society for Radiotherapy & Oncology; E: Eligible;
ESTRO: European Society for Radiotherapy & Oncology; Her2: Human Epidermal
Growth Factor Receptor-2; HR: Hormone receptor; IORT: Intra-operative
radiotherapy; IPC: Paoli Calmettes Institute; MRI: Magnetic resonance imaging;
nE: Non-eligible; RE: Estrogen receptor; RP: Progesterone receptor; SBR:
ScarffBloom-Richardson classification; T group: TARGIT E study
Availability of data and materials
All data generated or analysed during this study are included in this
All authors were responsible for date collection and analysis, interpretation
of the results, and writing the manuscript. EL, GH and MR were responsible
for conducting the study design, data analysis and interpretation. All authors
have read and approved the final manuscript.
The authors declare that they have no competing interests.
Ethics approval and consent to participate
Due the nature of this study, ethics approval by our Institutional review
board (Paoli Calmettes Institute’s ethical committee) was obtained and the
data were used confidentially for research work.
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