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The association of internal mammary and medial supraclavicular lymph node radiation technique with clinical outcomes: Results from the EORTC 22922/10925 randomised trial

      Highlights

      • Radiotherapy to internal mammary and supraclavicular nodes improves disease outcomes with limited toxicity.
      • A more individualised radiation technique seems associated with higher rates of oncological improvements without increased risks for late side effects.

      Abstract

      Background and purpose

      The multicentre EORTC 22922/10925 trial (ClinicalTrials.gov, NCT00002851) was conducted between 1996 and 2004. The trial evaluated the effect of irradiation of the internal mammary and medial supraclavicular lymph node chains (IM-MS) vs no further radiation therapy (RT) on survival and cause of death in breast cancer stage I-III patients. At 15.7 years of median follow-up, a significant reduction of breast cancer specific mortality (BCSM) and any recurrence, not translating in improved overall survival (OS), and low absolute rates of side effects were found. The aim of the current analysis was to evaluate the association of RT techniques of IM-MS lymph node irradiation with long-term outcomes.

      Patients and methods

      Three RT techniques were used for IM-MS: a standard technique using a fixed set-up combining photon/electron beams to the IM and tangential fields to the breast or chest wall vs a standard-modified technique with minor adaptation for beam settings vs a more individualised technique based on individual localisation of the IM. Techniques used were fixed per institution over the duration of the trial. We performed an exploratory and descriptive analysis of the outcomes after 15 years follow-up for the three RT techniques.

      Results

      Between July 1996 and January 2004, 46 radiation oncology departments from 13 countries accrued 4004 patients. Median follow-up was 15.7 years. The number of patients treated by each technique was 2440 (61%) by standard vs 635 (16%) by standard-modified vs 929 (23%) patients by individualised technique. The absolute improvements of oncological outcomes in terms of disease-free survival (DFS), OS and BCSM with IM-MS RT compared to no IM-MS RT were 6.8%, 4.9% and −5.8% for the individualised technique, vs 1.6%, 2.9% and −4.3% for modified standard and −1.4%, 1.1% and −3% for standard technique, respectively. The increase in 15-year rates of side effects due to IM-MS RT, both scored longitudinally and cross-sectionally, were similar among the techniques.

      Conclusion

      Even though a straightforward comparison by technique is not possible because of variations in baseline characteristics between institutions, our findings suggest that the use of more individualised RT techniques is associated with higher rates of oncological improvements without increased risks for late side effects.

      Keywords

      The internal mammary nodes (IMN) receive lymphatic drainage from all quadrants of the breast [
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      • Estourgie S.H.
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      • Estourgie S.H.
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      • Estourgie S.H.
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      Impact of locoregional treatment on the early-stage breast cancer patients: a retrospective analysis.
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      • Povel J.A.C.M.
      • Stroeken H.J.G.
      • Hoofwijk A.G.M.
      Halsted revisited: internal mammary sentinel lymph node biopsy in breast cancer.
      ,
      • Vendrell-Torne E.
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      • Domenech-Torne F.M.
      Study of normal mammary lymphatic drainage using radioactive isotopes.
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      ]. IMN dissection was not shown to provide survival benefit [
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      ]. For many years thereafter, elective IMN irradiation was controversial, as data were conflicting for disease outcome benefits vs potential detrimental effects of radiation therapy (RT) [
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      ]. An overview of randomised trials conducted in the 1950s to 1970s by Cuzick et al. [
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      ] was the standard bearer for this approach, suggesting that RT increases the rate of non-breast cancer deaths, which nullifies the RT-derived benefits in reducing locoregional recurrences and increasing overall survival [
      • Cuzick J.
      • Stewart H.
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      • Baum M.
      • Fisher B.
      • Host H.
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      • Cuzick J.
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      Cause-specific mortality in long-term survivors of breast cancer who participated in trials of radiotherapy.
      ]. This warning signal that the benefits of RT might be jeopardised by serious late side effects, especially cardiovascular disease, led to much research to evaluate causes and find risk-reducing solutions [
      • Harris J.R.
      • Hellman S.
      Put the “hockey stick” on ice.
      ,
      • Cuzick J.
      • Stewart H.
      • Peto R.
      • Baum M.
      • Fisher B.
      • Host H.
      • et al.
      Overview of randomized trials of postoperative adjuvant radiotherapy in breast cancer.
      ,
      • Cuzick J.
      • Stewart H.
      • Rutqvist L.
      • Houghton J.
      • Edwards R.
      • Redmond C.
      • et al.
      Cause-specific mortality in long-term survivors of breast cancer who participated in trials of radiotherapy.
      ,
      • Clarke M.
      • Collins R.
      • Darby S.
      • Davies C.
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      Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials.
      ,

      Thorsen LBJ, Overgaard J, Matthiessen LW, Berg M, Stenbygaard L, Pedersen AN, et al. Internal mammary node irradiation in patients with node-positive early breast cancer: fifteen-year results from the Danish Breast Cancer Group Internal Mammary Node Study. J Clin Oncol. 2022:Jco2200044.

      ]. Tumour laterality (left vs right), IMN-RT and radiation technique (represented also by year of RT) were found to be significant predictors for RT-related cardiac toxicity [
      • Harris J.R.
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      Put the “hockey stick” on ice.
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      • Clarke M.
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      • Evans V.
      • et al.
      Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials.
      ,
      • Darby S.C.
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      • McGale P.
      • Bennet A.M.
      • Blom-Goldman U.
      • Brønnum D.
      • et al.
      Risk of ischemic heart disease in women after radiotherapy for breast cancer.
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      • Darby S.C.
      • McGale P.
      • Taylor C.W.
      • Peto R.
      Long-term mortality from heart disease and lung cancer after radiotherapy for early breast cancer: prospective cohort study of about 300,000 women in US SEER cancer registries.
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      • Bengtsson N.-O.
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      • et al.
      Incidence of heart disease in 35,000 women treated with radiotherapy for breast cancer in Denmark and Sweden.
      ,
      • Taylor C.W.
      • Nisbet A.
      • McGale P.
      • Darby S.C.
      Cardiac exposures in breast cancer radiotherapy: 1950s–1990s.
      ,
      • Taylor C.W.
      • Wang Z.
      • Macaulay E.
      • Jagsi R.
      • Duane F.
      • Darby S.C.
      Exposure of the heart in breast cancer radiation therapy: a systematic review of heart doses published during 2003 to 2013.
      ]. All this stressed the need to re-evaluate the role of nodal irradiation, mainly internal mammary nodes and medial supraclavicular nodes (IM-MS)-RT. This formed the rationale for the EORTC 22922/10925 trial (Clinicaltrials.gov NCT00002851) in patients with stage I-III breast cancer. At a median follow up of 15.7 years, a significant reduction of breast cancer mortality and breast cancer recurrence, which was not converted into improved overall survival, was shown [
      • Poortmans P.M.
      • Weltens C.
      • Fortpied C.
      • Kirkove C.
      • Peignaux-Casasnovas K.
      • Budach V.
      • et al.
      Internal mammary and medial supraclavicular lymph node chain irradiation in stage I-III breast cancer (EORTC 22922/10925): 15-year results of a randomised, phase 3 trial.
      ,
      • Poortmans P.M.
      • Collette S.
      • Kirkove C.
      • Van Limbergen E.
      • Budach V.
      • Struikmans H.
      • et al.
      Internal mammary and medial supraclavicular irradiation in breast cancer.
      ]. A detailed analysis of RT-related toxicity revealed more pulmonary and cardiac side effects after IM-MS irradiation, with cumulative incidence rates of lung fibrosis being 2.9% vs 5.7% (P < 0.0001), and of any cardiac disease of 9.4% vs 11.1% (p = 0.044). However, at 15-years follow-up, the cumulative incidence probabilities of cross-sectionally reported side effects grade 2 and more remained low: 0.1% vs 0.8% for pulmonary fibrosis (P = 0.017), and 1.8% vs 2.6% for any cardiac disease (P = 0.154) [
      • Poortmans P.M.
      • Struikmans H.
      • De Brouwer P.
      • Weltens C.
      • Fortpied C.
      • Kirkove C.
      • et al.
      Side effects 15 years after lymph node irradiation in breast cancer: randomized EORTC trial 22922/10925.
      ]. No significant differences were noted between left- and right-sided breast cancer. Furthermore, no difference was observed in the incidence of second malignancies and contralateral breast cancer. Cardiovascular death rates were similar (1.4%) between the study groups [
      • Poortmans P.M.
      • Struikmans H.
      • De Brouwer P.
      • Weltens C.
      • Fortpied C.
      • Kirkove C.
      • et al.
      Side effects 15 years after lymph node irradiation in breast cancer: randomized EORTC trial 22922/10925.
      ].
      As data clearly links organs at risk RT dose to toxicity, with doses being highly dependent on RT-techniques [
      • Darby S.C.
      • Ewertz M.
      • McGale P.
      • Bennet A.M.
      • Blom-Goldman U.
      • Brønnum D.
      • et al.
      Risk of ischemic heart disease in women after radiotherapy for breast cancer.
      ,
      • Taylor C.W.
      • Nisbet A.
      • McGale P.
      • Darby S.C.
      Cardiac exposures in breast cancer radiotherapy: 1950s–1990s.
      ,
      • Taylor C.W.
      • Wang Z.
      • Macaulay E.
      • Jagsi R.
      • Duane F.
      • Darby S.C.
      Exposure of the heart in breast cancer radiation therapy: a systematic review of heart doses published during 2003 to 2013.
      ,
      • Taylor C.W.
      • Nisbet A.
      • McGale P.
      • Goldman U.
      • Darby S.C.
      • Hall P.
      • et al.
      Cardiac doses from Swedish breast cancer radiotherapy since the 1950s.
      ], we aim in the current analysis to evaluate the association of the RT techniques applied in EORTC 22922/10925 for elective nodal irradiation on disease control and toxicity outcomes.

      Patients and methods

      The trial design of the EORTC trial 22922/10925 prospective multicentre, randomised, phase 3 was previously reported [
      • Poortmans P.M.
      • Weltens C.
      • Fortpied C.
      • Kirkove C.
      • Peignaux-Casasnovas K.
      • Budach V.
      • et al.
      Internal mammary and medial supraclavicular lymph node chain irradiation in stage I-III breast cancer (EORTC 22922/10925): 15-year results of a randomised, phase 3 trial.
      ,
      • Poortmans P.M.
      • Collette S.
      • Kirkove C.
      • Van Limbergen E.
      • Budach V.
      • Struikmans H.
      • et al.
      Internal mammary and medial supraclavicular irradiation in breast cancer.
      ]. In summary, eligibility criteria included breast cancer stage I–III with a primary tumour located centrally or medially in the breast, irrespective of axillary node involvement, or a primary tumour located in the external quadrants combined with axillary lymph node involvement. Surgery included breast conserving surgery (BCS) or mastectomy. Sentinel lymph node procedure was added to the protocol during the last years of the trial, followed by an axillary dissection in case of sentinel lymph node tumour involvement. Primary axillary lymph node dissection remained an option even after the sentinel lymph node concept was introduced. After written informed consent, patients were centrally randomised to irradiation or not of the IM-MS lymph nodes. The prescribed total dose was 50 Gy in 25 fractions of 2 Gy over 5 weeks. The interval between randomisation and last surgery (whatever this was on the primary tumour or the axilla) could not be more than 8 weeks. RT was aimed to start within 8 weeks after the last surgical intervention or as soon as reasonably possible after randomisation, but the interval should never exceed 11 weeks. In cases chemotherapy was given, RT was started not later than 6 weeks after the last cycle and within 8 months after surgery. A minimization algorithm with 1:1 ratio was used for the randomisation with the following stratification factors: centre, menopausal status, site of the primary tumour within the breast, type of breast surgery, type of axillary dissection, pathological T-stage, pathological N-stage. Sample sizes were calculated based on the primary endpoint, overall survival, originally estimated at 52.5% at 10 years, which was later adapted to 77%. After completion of RT, patients were seen annually for the first five years and then every 2 years or upon recurrence or death. All data were analysed using observed cumulative rates or cumulative incidence curves. Results on the 15-years primary and secondary tumour-outcome related endpoints, overall survival, disease-free survival, distant metastases-free survival, and breast cancer mortality were published recently, as well as a detailed analysis concerning side effects [
      • Poortmans P.M.
      • Weltens C.
      • Fortpied C.
      • Kirkove C.
      • Peignaux-Casasnovas K.
      • Budach V.
      • et al.
      Internal mammary and medial supraclavicular lymph node chain irradiation in stage I-III breast cancer (EORTC 22922/10925): 15-year results of a randomised, phase 3 trial.
      ,
      • Poortmans P.M.
      • Struikmans H.
      • De Brouwer P.
      • Weltens C.
      • Fortpied C.
      • Kirkove C.
      • et al.
      Side effects 15 years after lymph node irradiation in breast cancer: randomized EORTC trial 22922/10925.
      ].

      EORTC RT quality assurance

      The trial was subjected to the EORTC Radiation Oncology Group quality assurance programme, predefined and done by a centralised multidisciplinary RT quality assurance team (RTQA team). The RTQA team initially verifies the overall ability of institutes that are participating in clinical trials involving RT whether they can adhere to the required protocol guidelines [
      • Grant W.
      • Hurkmans C.W.
      • Poortmans P.M.
      • Maingon P.
      • Monti A.F.
      • van Os M.J.H.
      • et al.
      Quality assurance standards drive improvements in the profile of radiation therapy departments participating in trials of the EORTC Radiation Oncology Group.
      ]. Subsequently, RTQA evaluations allow for uncertainties in the protocol to be detected at an early stage of the trial and potentially corrected to reduce systematic protocol deviations.
      The EORTC trial 22922/10925, had a specific pre-planned QA programme and the RTQA evaluations were published at early phases of the trial [
      • Lievens Y.
      • Poortmans P.
      • Van den Bogaert W.
      A glance on quality assurance in EORTC study 22922 evaluating techniques for internal mammary and medial supraclavicular lymph node chain irradiation in breast cancer.
      ,
      • Poortmans P.
      • Kouloulias V.E.
      • Venselaar J.L.
      • Struikmans H.
      • Davis J.B.
      • Huyskens D.
      • et al.
      Quality assurance of EORTC trial 22922/10925 investigating the role of internal mammary–medial supraclavicular irradiation in stage I-III breast cancer: the individual case review.
      ,
      • Poortmans P.M.P.
      • Venselaar J.L.M.
      • Struikmans H.
      • Hurkmans C.W.
      • Davis J.B.
      • Huyskens D.
      • et al.
      The potential impact of treatment variations on the results of radiotherapy of the internal mammary lymph node chain: a quality-assurance report on the dummy run of EORTC Phase III randomized trial 22922/10925 in Stage I-III breast cancer(1).
      ]. Near the end of accrual, in December 2013, the RTQA team distributed a case report form (CRF) containing questions concerning the “Statement on IM-MS Chain Irradiation Policy”, including information on individual localisation of the IMNs; the treatment technique used for most of the included patients and whether these have been changed during the course of the trial. This information was used to verify and update the information obtained with the RTQA procedures.

      EORTC trial 22922/10925 RT protocol

      The treatment techniques to be used were not fixed, as long as they were approved by the RTQA team. Thereby, a variation of technical set-ups was used, as described before [
      • Lievens Y.
      • Poortmans P.
      • Van den Bogaert W.
      A glance on quality assurance in EORTC study 22922 evaluating techniques for internal mammary and medial supraclavicular lymph node chain irradiation in breast cancer.
      ,
      • Poortmans P.
      • Kouloulias V.E.
      • Venselaar J.L.
      • Struikmans H.
      • Davis J.B.
      • Huyskens D.
      • et al.
      Quality assurance of EORTC trial 22922/10925 investigating the role of internal mammary–medial supraclavicular irradiation in stage I-III breast cancer: the individual case review.
      ,
      • Poortmans P.M.P.
      • Venselaar J.L.M.
      • Struikmans H.
      • Hurkmans C.W.
      • Davis J.B.
      • Huyskens D.
      • et al.
      The potential impact of treatment variations on the results of radiotherapy of the internal mammary lymph node chain: a quality-assurance report on the dummy run of EORTC Phase III randomized trial 22922/10925 in Stage I-III breast cancer(1).
      ]. Patients were treated in supine position. The RT protocol encouraged determining IMN location by CT, ultrasound (US) or lymph node scintigraphy. Basically, all 3 techniques were field-based. The IMN clinical target volume (CTV) included the first 3 intercostal spaces, indicating that approximately 85% of the lymph nodes lie within 4 cm lateral to the midline, and to a depth of up to 4 cm. For medial lower quadrant tumours, the CTV was recommended to be extended to the 5th intercostal space, also taking into account the location of the primary tumour and the specific anatomy of the individual patient. Using these guidelines, the protocol intentionally aimed to lower exposure to the heart. The protocol did not allow for irradiation of the opposite IM lymph node chain. In order to be able to avoid high doses to the underlying lung and heart, electron irradiation facilities were required.
      The protocol defined a “standard” RT technique but allowed for “alternative” RT techniques (modified standard and individualised). Contrary to the “standard” technique, alternative RT techniques mandated individual localisation of the IM lymph node chain in an aim to adapt the beam shapes and energies, prescription depths and relative beam weights (Fig. 1, Fig. 2).
      Figure thumbnail gr1
      Fig. 1Field borders of the standard radiation technique. The lateral border of the field is defined at the middle of the clavicle, and the upper border is 3 cm above the head of the clavicle. The medial field border lies 1 cm across the midline, and the lateral field border of the internal mammary part of the field is 5 cm lateral from the midline. The lower border of the fourth rib defines the lower field border; in medial inferior quadrant lesions the inferior border may have to be lowered in order to include the fifth intercostal space. Adapted from Lievens et al., Radiotherapy and Oncology 60 (2001) 257–265.
      Figure thumbnail gr2
      Fig. 2All of the figures (A, B, C) are original dosimetric illustration from the trial of the basics 3 RT techniques (A) Standard radiation technique. The absolute maximal dose can exceed 180% at the overlap of the tangential with the mixed photon/electron IM field, leading to “match line fibrosis”. (B) Modified standard technique: Left mastectomy plan with direct electron beam to chest wall (B1) and right breast conserving surgery (B2). The slip zone reduces the doses at the match line. (C) Individualised radiation technique. Left mastectomy plan C1) central slice, C2) caudal slice. The dose distribution is more conformally following the target volumes.

      The standard RT technique

      Fig. 1 shows the field borders. Using mixed beams, 26 Gy is delivered with photons (minimum energy of Co-60 and maximum energy of 10 MV), and 24 Gy with electrons, to a total of 50 Gy in 25 fractions. To cover the CTV with at least the 95% isodose line for photons and 85% for electrons, the prescription point for photons is defined at 3 cm depth and the electron energy is chosen between 12 and 14 MeV. This standard set-up aimed to obtain adequate coverage of the planning target volume (PTV) of the IMNs [
      • Lievens Y.
      • Poortmans P.
      • Van den Bogaert W.
      A glance on quality assurance in EORTC study 22922 evaluating techniques for internal mammary and medial supraclavicular lymph node chain irradiation in breast cancer.
      ].

      Modified standard RT technique

      In case of individual localisation of the position of the IM lymph node chain, starting from the standard technique, individualisation by minor adaptations for beam size and gantry angle; match line setting; proportion and energy of electrons was allowed (see Fig. 2 for dosimetric illustration).

      Individualised RT technique

      Individualised RT techniques also mandated an individual localisation of IM lymph node chain for each patient. However, here all beam settings, including number and shapes, energies, prescription points and relative beam weights could be individualised (see Fig. 2 for dosimetric illustration).

      Data analysis

      This is an exploratory analysis of the association of RT techniques, as used by the participating institutions, of the primary and secondary endpoints at a median follow up of 15.7 years. Outcomes were analysed descriptively by RT-technique subgroup and treatment arm in the intention-to treat population (all 4004 randomized patients) for efficacy endpoints and in the per-protocol population (3866 eligible patients treated per protocol) for toxicity endpoints. P-values were calculated to assess the heterogeneity of baseline characteristics across the RT-technique subgroups. No inferential tests were conducted for outcomes, because of the potential confounding between RT-technique and institution effects. Descriptive statistics consisted of frequencies and percentages for categorical variables and Kaplan-Meier or Cumulative Incidence Rates at 15 years for time-to-event endpoints. Additional analyses were conducted by side treated (left vs right breast/chest-wall) and by tumour location within the breast (lateral vs central or medial).
      We arbitrarily defined absolute differences of 2–4.9% as “potentially clinically relevant” and ≥5% difference as “clinically relevant”.

      Results

      Between July 1996 and January 2004, 46 radiation oncology departments from 13 countries accrued a total of 4004 patients. Thirty-seven departments, accruing 3674 patients, participated in the RTQA procedures. Only two centres stated that they modified the technical aspects of their approach during the trial: one introducing computerised tomography (CT)-based adaptation of the prescription point for the IMNs and another replacing lymphoscintigraphy by CT-scan for IMN localisation as well as a modification of the standard technique in some patients, based on individual anatomy. In summary, 33 centres, randomising 2440 patients, used the standard technique; 8 centres (635 patients) used the standard modified technique, and 5 centres (929 patients) used an individualised technique. The median age for all groups was 54 years (range 19–75 years). Overall, the patients’ characteristics were different between three RT-technique groups: Table 1 shows heterogeneity in baseline characteristics for most categories as patients were not stratified according to RT technique. The “standard” group had less patients who underwent BCS; less pN2-3 and less patients with breast cancer stage III; less patients received chemotherapy and more patients received endocrine therapy. The “standard modified” group included less patients who underwent sentinel lymph node procedure; T-stage and N-stage were more advanced; and more patients received systemic therapy. The “individualised” group included more pre-menopausal patients; had more BCS; less patients underwent partial-axillary dissection; more patients had hormone-receptor negative cancers; and less patients received adjuvant systemic therapy (Table 1).
      Table 1Characteristics according to the RT techniques.
      Baseline characteristics (ITT)p-value (Chi-square test)
      RT TechniqueTotal

      (N = 4004)
      Standard

      (N = 2440)
      Standard

      modified

      (N = 635)
      Individualised

      (N = 929)
      N (%)N (%)N (%)N (%)
      Menopausal statusP = 0.2710
       Pre-menopausal991 (40.6)249 (39.2)400 (43.1)1640 (41.0)
       Post-menopausal1449 (59.4)386 (60.8)529 (56.9)2364 (59.0)
      Type of breast surgeryP < 0.0001
       Mastectomy663 (27.2)136 (21.4)156 (16.8)955 (23.9)
       Breast conserving1777 (72.8)499 (78.6)773 (83.2)3049 (76.1)
      Type of axillary dissectionP < 0.0001
       Total1276 (52.3)303 (47.7)618 (66.5)2197 (54.9)
       Partial1016 (41.6)304 (47.9)203 (21.9)1523 (38.0)
       SLNB only148 (6.1)28 (4.4)108 (11.6)284 (7.1)
      Pathological T stageP = 0.0025
       pT11502 (61.6)338 (53.2)568 (61.1)2408 (60.1)
       pT2834 (34.2)269 (42.4)327 (35.2)1430 (35.7)
       pT390 (3.7)23 (3.6)28 (3.0)141 (3.5)
       Missing14 (0.6)5 (0.8)6 (0.6)25 (0.6)
      Pathological N stage (axillary LN)P < 0.0001
       pN01150 (47.1)206 (32.4)422 (45.4)1778 (44.4)
       pN11023 (41.9)335 (52.8)367 (39.5)1725 (43.1)
       pN2204 (8.4)79 (12.4)113 (12.2)396 (9.9)
       pN362 (2.5)14 (2.2)27 (2.9)103 (2.6)
       Missing1 (0.0)1 (0.2)0 (0.0)2 (0.0)
      Tumour stageP < 0.0001
       Stage I878 (36.0)136 (21.4)330 (35.5)1344 (33.6)
       Stage IIa779 (31.9)236 (37.2)280 (30.1)1295 (32.3)
       Stage IIb467 (19.1)153 (24.1)157 (16.9)777 (19.4)
       Stage III303 (12.4)105 (16.5)156 (16.8)564 (14.1)
       Missing13 (0.5)5 (0.8)6 (0.6)24 (0.6)
      Combination of ER/PG statusP = 0.0003
       ER+,PR+1326 (54.3)313 (49.3)541 (58.2)2180 (54.4)
       ER+,PR−,unkn509 (20.9)124 (19.5)131 (14.1)764 (19.1)
       PR+,ER−,unkn93 (3.8)24 (3.8)40 (4.3)157 (3.9)
       ER−,PR−371 (15.2)106 (16.7)172 (18.5)649 (16.2)
       Missing141 (5.8)68 (10.7)45 (4.8)254 (6.3)
      Adjuvant treatmentP < 0.0001
       No adj. therapy351 (14.4)68 (10.7)206 (22.2)625 (15.6)
       Chemotherapy543 (22.3)183 (28.8)268 (28.8)994 (24.8)
       Endocrine therapy830 (34.0)148 (23.3)207 (22.3)1185 (29.6)
       Both (CT&ET)716 (29.3)236 (37.2)248 (26.7)1200 (30.0)
      ITT = intention to treat; SLNB = sentinel lymph node biopsy; ER = Oestrogen Receptor; PR = Progesterone Receptor.; PR-unkn or ER-unkn- status of receptor unknown; CT&ET = chemotherapy & Endocrine therapy; The type of axillary surgery (total or partial) is according to the statement of the surgeon and the local investigator.
      At 15 years, out of the total population (4004), 72% were alive, the main cause of death was breast cancer for all groups (17.3% from the total population) (Table 2).
      Table 2Survival/follow-up status and cause of death per RT-technique and per treatment arm at 15-years.
      Standard techniqueStandard modified techniqueIndividualised techniqueTotalTotal
      NoIM-MSNoIM-MSNoIM-MSNoIM-MS(N = 4004)
      IM-MS(N = 1218)IM-MS(N = 319)IM-MS(N = 465)IM-MS(N = 2002)
      (N = 1222)(N = 316)(N = 464)(N = 2002)
      N (%)N (%)N (%)N (%)N (%)N (%)N (%)N (%)N (%)
      Survival status
       Alive895 (73.2)894 (73.4)225 (71.2)231 (72.4)313 (67.5)323 (69.5)1433 (71.6)1448 (72.3)2881 (72.0)
       Dead327 (26.8)324 (26.6)91 (28.8)88 (27.6)151 (32.5)142 (30.5)569 (28.4)554 (27.7)1123 (28.0)
      Cause of death
       Breast Cancer209 (17.1)179 (14.7)64 (20.3)52 (16.3)105 (22.6)83 (17.8)378 (18.9)314 (15.7)692 (17.3)
       Other cancer35 (2.9)35 (2.9)11 (3.5)12 (3.8)15 (3.2)14 (3.0)61 (3.0)61 (3.0)122 (3.0)
       Toxicity
      Any toxicity.
      1 (0.1)1 (0.1)0 (0.0)0 (0.0)0 (0.0)0 (0.0)1 (0.0)1 (0.0)2 (0.0)
       Infection6 (0.5)11 (0.9)2 (0.6)0 (0.0)0 (0.0)3 (0.6)8 (0.4)14 (0.7)22 (0.5)
       Cardiovascular disease15 (1.2)17 (1.4)2 (0.6)5 (1.6)12 (2.6)7 (1.5)29 (1.4)29 (1.4)58 (1.4)
       Other chronic disease10 (0.8)7 (0.6)0 (0.0)0 (0.0)0 (0.0)3 (0.6)10 (0.5)10 (0.5)20 (0.5)
       Other cause27 (2.2)37 (3.0)5 (1.6)6 (1.9)9 (1.9)13 (2.8)41 (2.0)56 (2.8)97 (2.4)
       Unknown23 (1.9)35 (2.9)7 (2.2)13 (4.1)10 (2.2)19 (4.1)40 (2.0)67 (3.3)107 (2.7)
       Missing1 (0.1)2 (0.2)0 (0)0 (0)0 (0)0 (0)1 (0.0)2 (0.1)3 (0.1)
      * Any toxicity.
      The improvements of oncological outcomes in terms of disease-free survival (DFS), overall survival (OS) and breast cancer specific mortality (BCSM) with IM-MS RT compared to no IM-MS RT was calculated as the absolute difference between the treatment arms per treatment technique. This absolute difference was larger for patients treated with an individualised technique for each oncological outcome (Table 3: absolute benefits between 4.9 and 6.8% compared to ≤4.3% difference), suggesting a clinically relevant difference of IM-MS RT on disease outcome related endpoints for patients treated with an individualised RT technique. Overall survival curves according to RT-technique showed least benefit in case of standardized IM-MS irradiation compared to no-IM-MS irradiation (Fig. 3).
      Table 3Disease-related outcome rates at 15 years, per RT-technique and per treatment arm.
      Standard techniqueStandard modified techniqueIndividualised techniqueTotal
      (n = 2440)(n = 635)(n = 929)(n = 4004)
      no IM-MS (%; 95% CI)IM-MS (%; 95% CI)Percentage points difference relative to no IM-MSno IM-MS (%; 95% CI)IM-MS (%; 95% CI)Percentage points difference relative to no IM-MSno IM-MS (%; 95% CI)IM-MS (%; 95% CI)Percentage points difference relative to no IM-MSno IM-MS (%; 95% CI)IM-MS (%; 95% CI)Percentage points difference relative to no IM-MS
      DFS62.7

      (59.6–65.5)
      61.3

      (58.1–64.3)
      −1.459.1

      (52.5–65.0)
      60.7

      (54.2–66.6)
      1.653

      (48.0–57.7)
      59.8

      (54.8–64.5)
      6.859.9

      (57.5–62.2)
      60.8

      (58.4–63.2)
      0.9
      OS72.7

      (69.9–75.3)
      73.8

      (71.0–76.4)
      1.169.2

      (63.1–74.4)
      72.1

      (66.3–77.1)
      2.967.2

      (62.4–71.5)
      72.1

      (67.5–76.2)
      4.970.9

      (68.6–72.9)
      73.1

      (71.0–75.2)
      2.2
      BCSM18

      (15.8–20.4)
      15

      (13.0–17.2)
      −321.5

      (16.9–26.6)
      17.2

      (13.1–21.8)
      −4.323.3

      (19.4–27.5)
      17.5

      (14.0–21.3)
      −5.819.8

      (18.0–21.7)
      16

      (14.3–17.7)
      −3.8
      DFS-Disease free survival; OS-Overall survival; BCSM- Breast Cancer Specific Mortality. Estimates at 15 years are based on Kaplan-Meier for DFS and OS, and on cumulative incidence rates for BCSM. Qualification of differences: 2–4.9%: “potentially clinically relevant”; ≥5% difference: “clinically relevant”.
      Figure thumbnail gr3
      Fig. 3Kaplan–Meier curves for overall survival according to RT-technique (a) Standard radiation technique (b) Modified standard technique (c) Individualised radiation technique.
      The association of the IM-MS irradiation techniques with lung and cardiac long-term toxicity, both scored longitudinally and cross-sectionally, were very similar among the techniques (presented in percentage points difference, Table 4).
      Table 4Lung and cardiac long-term toxicity cumulative incidence rates at 15 years, per RT-technique and per treatment arm.
      Standard techniqueStandard modified techniqueIndividualised techniqueTotal
      (n = 2360)(n = 599)(n = 907)(n = 3866)
      no IM-MS (%)IM-MS (%)Percentage points difference relative to no IM-MSno IM-MS (%)IM-MS (%)Percentage points difference relative to no IM-MSno IM-MS (%)IM-MS (%)Percentage points difference relative to no IM-MSno IM-MS (%)IM-MS (%)Percentage points difference relative to no IM-MS
      Side effects longitudinal:
      Any clinical evidence of lung fibrosis1.15.44.32.752.37.48.30.92.95.72.8
      Any clinical evidence of cardiac fibrosis0.81.70.91.40.7−0.73.35.11.81.11.90.8
      Any evidence of cardiac disease8.610.625.18.33.213.114.71.69.411.11.7
      Side effects cross-sectional at 15 years
      Late cardiac morbidity ≥ grade 21.22.10.90.40.60.23.84.50.71.82.60.8
      Late cardiac morbidity ≥ grade 30.810.20.40−0.421.5−0.51.11−0.1
      Late lung morbidity ≥ grade 200.50.50110.310.70.10.80.7
      Late lung morbidity ≥ grade 300.10.100000.40.400.20.2
      IM-MS = Internal Mammary – Medial Supraclavicular irradiation. Qualification of differences: 2–4.9%: “potentially clinically relevant”; ≥5% difference: “clinically relevant”.
      The side of the treated breast cancer (left vs right breast/chest-wall) did not influence the rates of significant lung and cardiac long-term toxicity, except for lung fibrosis in right sided-RT treated with the standard technique (5.2% difference) (Table 5).
      Table 5The association of the RT techniques with toxicity and local/regional control according to the side treated (left vs. right breast/chest-wall).
      RT technique and Left/right treated breast sideTotal

      (N = 1944)
      Standard-LeftStandard-RightStandard

      modified-Left
      Standard

      modified-Right
      Individualised-LeftIndividualised-Right
      N/Total N (%)N/Total N (%)N/Total N (%)N/Total N (%)N/Total N (%)N/Total N (%)N (%)
      Any clinical evidence of lung fibrosis?
      IM-MS RT28/579

      (4.8)
      35/592

      (5.9)
      6/157

      (3.8)
      9/146

      (6.2)
      23/251

      (9.2)
      14/197

      (7.1)
      115/1922 (6)
      No-IM-MS RT9/628

      (1.4)
      4/561

      (0.7)
      4/135

      (3)
      4/161

      (2.5)
      18/229

      (7.9)
      16/230

      (7)
      55/1944 (2.8)
      Percentage difference IM-MS vs. no-IM-MS RT3.45.20.83.71.30.1
      Percentage difference left vs. right IM-MS RT−1.1−2.42.1
      Any clinical evidence of cardiac fibrosis?
      IM-MS8/579 (1.4)12/592

      (2)
      2/157

      (1.3)
      0/146(0)13/251

      (5.2)
      10/197

      (5.1)
      45/1922 (2.3)
      No-IM-MS7/628

      (1.1)
      3/561

      (0.5)
      3/135

      (2.2)
      1/161

      (0.6)
      8/229

      (3.5)
      7/230

      (3)
      29/1944

      (1.5)
      Percentage difference IM-MS vs. no-IM-MS RT0.31.5−0.9−0.61.72.1
      Percentage difference left vs. right IM-MS RT−0.61.30.1
      Any evidence of cardiac diseases?
      IM-MS65/579 (11.2)59/592 (10)15/157 (9.6)10/146 (6.8)31/251

      (12.4)
      35/197

      (17.8)
      215/1922 (11.2)
      No-IM-MS63/628

      (10)
      39/561

      (7)
      10/135

      (7.4)
      5/161

      (3.1)
      26/229

      (11.4)
      34/230

      (14.8)
      177/1944 (9.1)
      Percentage difference IM-MS vs. no-IM-MS RT1.232.23.713
      Percentage difference left vs. right IM-MS RT1.22.8−5.4
      Cardiac toxicity grade ≥ 3
      IM-MS5/579

      (0.9)
      6/592

      (1)
      0/157

      (0)
      0/146

      (0)
      8/251

      (3.2)
      2/197

      (1)
      21/1922 (1.1)
      No-IM-MS6/628

      (1)
      2/561

      (0.4)
      1/135

      (0.7)
      0/161

      (0)
      6/229

      (2.6)
      5/230

      (2.2)
      20/1944 (1)
      Percentage difference IM-MS vs. no-IM-MS RT−0.10.6−0.700.6−1.2
      Percentage difference left vs. right IM-MS RT−0.102.2
      Local recurrence
      IM-MS40 (6.6)40 (6.5)12 (7.2)5 (3.3)18 (6.9)18 (8.7)133 (6.6)
      No-IM-MS33 (5.1)40 (7)9 (6.3)9 (5.2)22 (9.6)15 (6.4)128 (6.4)
      Percentage difference IM-MS vs. no-IM-MS RT1.5−0.50.9−1.9−2.7−2.3
      Percentage difference left vs. right IM-MS RT0.13.9−1.8
      Regional recurrence
      IM-MS21 (3.5)20 (3.2)10 (6)4 (2.6)6 (2.3)4 (1.9)65 (3.2)
      No-IM-MS29 (4.5)27 (4.7)5 (3.5)9 (5.2)16 (7)14 (6)100 (5)
      Percentage difference IM-MS vs. no-IM-MS RT−1−1.52.5−2.6−4.7−4.1
      Percentage difference left vs. right IM-MS RT0.33.40.4
      Local recurrence: breast/chest wall; regional recurrence: breast lymphatic drainage; IM-MS: Internal mammary nodes-medial supraclavicular nodes; RT: radiation therapy. Qualification of differences: 2–4.9%: “potentially clinically relevant”; ≥5% difference: “clinically relevant”.
      The addition of IM-MS irradiation had the largest impact on reducing local and regional recurrences in the individualised IM-MS irradiation (Table 5). Per technique, the percentage difference of local recurrence between left-side vs right-side IM-MS RT was largest in the standard modified technique and showed potentially clinically relevant differences of less recurrences in left-sided breast cancer (Table 5).
      Analysing the association of the RT techniques with lung and cardiac long-term toxicity and local control according to the tumour location within the breast (central portion or medial quadrants vs lateral quadrants) showed significant differences in the individualised technique compared to the other two in the group that did not undergo IM-MS irradiation (Table 6). The percentage differences for lung fibrosis in central/medial vs lateral tumour location for no IM-MS irradiation was 0% for the standard technique, 0.7% for the standard modified and −6.8 % for the individualised technique. No clinically relevant differences were noted for IM-MS irradiation (-0.5% for the standard technique, −1% for the standard modified and 0.1% for the individualised technique). The percentage differences for any cardiac toxicity in central/medial vs lateral tumour location for no IM-MS irradiation was −0.7% for the standard technique, 1% for the standard modified and −1.9 % for the individualised technique and −0.5% for the standard technique, 1.1% for the standard modified and 4.1% for the individualised technique including IM-MS irradiation. Potentially clinically relevant differences for local and regional recurrences were noted only in the individualised IM-MS group, indicating fewer local recurrences in case of a central/medially located tumour compared to lateral tumour location. Regional recurrence rate was lower in the individualised IM-MS irradiation group for both central/medially and laterally located tumours with a larger impact if the tumour was located laterally within the breast (6.7% vs 3.1% difference).
      Table 6The association of the RT techniques with toxicity and local/regional control according to the tumour location within the breast (lateral vs. central or medial).
      RT technique and Location of primary tumourTotal
      Standard-LateralStandard-Central/MedialStandard

      modified-Lateral
      Standard

      modified-Central/Medial
      Individualised-LateralIndividualised-Central/Medial
      N/Total N (%)N/Total N (%)N/Total N (%)N/Total N (%)N/Total N (%)N/Total N (%)N (%)
      Any clinical evidence of lung fibrosis?
      IM-MS21/369

      (5.7)
      42/802

      (5.2)
      5/116

      (4.3)
      10/187

      (5.3)
      13/158

      (8.2)
      24/290

      (8.3)
      115/1922 (6.0)
      No-IM-MS4/374

      (1.1)
      9/815

      (1.1)
      3/128

      (2.3)
      5/168

      (3)
      18/150

      (12)
      16/309

      (5.2)
      55/1944

      (2.8)
      Percentage difference IM-MS vs. no-IM-MS RT4.64.122.3−3.83.1
      Percentage difference central/medial vs. lateral IM-MS T−0.51.00.1
      Any clinical evidence of cardiac fibrosis?
      IM-MS7/369

      (1.9)
      13/802

      (1.6)
      0/116

      (0)
      2/187

      (1.1)
      4/158

      (2.5)
      19/290

      (6.6)
      45/1922

      (2.3)
      No-IM-MS4/374

      (1.1)
      6/815

      (0.7)
      1/128

      (0.8)
      3/168

      (1.8)
      3/150

      (2)
      12/309

      (3.9)
      29/1944

      (1.5)
      Percentage difference IM-MS vs. no-IM-MS RT0.80.9−0.8−0.70.52.7
      Percentage difference central/medial vs. lateral IM-MS RT−0.31.14.1
      Cardiac toxicity grade ≥ 3
      IM-MS3/369

      (0.8)
      8/802

      (1)
      0/116

      (0)
      0/187

      (0)
      2/158

      (1.3)
      8/290

      (2.8)
      21/1922

      (1.2)
      No-IM-MS3/374

      (0.8)
      5/815

      (0.6)
      0/128

      (0)
      1/168

      (0.6)
      2/150

      (1.3)
      9/309

      (2.9)
      20/1944

      (1)
      Percentage difference IM-MS vs. no-IM-MS RT00.40−0.60−0.9
      Percentage difference central/medial vs. lateral IM-MS RT0.201.5
      Local Recurrence
      IM-MS16 (4.2)64 (7.7)8 (6.5)9 (4.6)16 (9.8)20 (6.6)133 (6.6)
      No-IM-MS18 (4.6)55 (6.6)9 (6.6)9 (5.0)10 (6.5)27 (8.7)128 (6.4)
      Percentage difference IM-MS vs. no-IM-MS RT−0.41.1−0.1−0.43.3−2.1
      Percentage difference central/medial vs. lateral IM-MS RT3.5−1.9−3.2
      Regional recurrence
      IM-MS14 (3.7)27 (3.2)8 (6.5)6 (3.1)5 (3)5 (1.7)65 (3.2)
      No-IM-MS22 (5.6)34 (4.1)8 (5.8)6 (3.4)15 (9.7)15 (4.8)100 (5)
      Percentage difference IM-MS vs. no-IM-MS RT−1.9−0.90.7−0.3−6.7−3.1
      Percentage difference central/medial vs. lateral IM-MS RT−0.5−3.41.3
      Local recurrence: breast/chest wall; regional recurrence: breast lymphatic drainage; IM-MS: Internal mammary nodes-medial supraclavicular nodes; RT: radiation therapy. Qualification of differences: 2–4.9%: “potentially clinically relevant”; ≥5% difference: “clinically relevant”.
      A further analysis according to systemic therapy (no adjuvant therapy vs endocrine and/or chemotherapy) and RT technique for late cardiac toxicity grade 3–4 confirms low rates of toxicity for all three techniques: overall 1% events (out of 1944 patients) in all patients who did not undergo IM-MS RT compared to 1.1% (out of 1922 patients) who underwent IM-MS RT. A similar analysis performed for late lung toxicity grade 3–4, according to systemic therapy and RT technique indicated also overall very low rates: 0.6% (out of 1944 patients) without IM-MS RT compared to 0.2% (out of 1922 patients) who underwent IM-MS RT, without differences related to the RT technique used.

      Discussion

      In the current study we evaluated the association of the RT techniques applied in EORTC 22922/10925 trial for elective nodal irradiation, mainly IM-MS nodes, with disease control and toxicity outcomes. Our findings suggest that the use of more individualised RT technique is associated with higher rates of oncological improvements without increased risks for late side effects. As patients’ characteristics were unbalanced between the RT technique groups (Table 1), we derived our conclusions from the percentage differences between IM-MS RT and no IM-MS RT within each of the RT techniques, rather than comparing the oncological outcomes between the techniques. The “standard” group had less advanced N-stage, less stage III, more mastectomies and systemic therapy, which may explain the overall slightly better outcomes. The “standard modified” group included less sentinel lymph node procedures; larger tumours and more stage IIA-IIB disease; and received more systemic therapy while the “individualised” group included more pre-menopausal patients; had more BCS; more hormone-negative cancers; and received less adjuvant systemic therapy, all of which combined may explain the slightly worse oncological outcome results. Data from the Danish Breast Cancer Group (DBCG 82b&c) suggest that the benefit of RT is irrespective of the risk group, thus we can assume that in our report the larger absolute clinical benefit shown in the “individualised” group is mostly attributable to the benefits of a more individualised RT-technique [
      • Overgaard M.
      • Nielsen H.M.
      • Tramm T.
      • Højris I.
      • Grantzau T.L.
      • Alsner J.
      • Offersen B.V.
      • Overgaard J.
      DBCG Radiotherapy Group. Postmastectomy radiotherapy in high-risk breast cancer patients given adjuvant systemic therapy. A 30-year long-term report from the Danish breast cancer cooperative group DBCG 82bc trial.
      ]. Moreover, our results also confirm that, at least for RT, the relative benefit is not constant: the BCSM reduction as shown in Table 3 translates into relative mortality reductions of 16.7%, 20% and 24.8%, respectively (19.2% for the entire population) [
      • Ebctcg M.P.
      • Taylor C.
      • Correa C.
      • Cutter D.
      • Duane F.
      • et al.
      Effect of radiotherapy after mastectomy and axillary surgery on 10-year recurrence and 20-year breast cancer mortality: meta-analysis of individual patient data for 8135 women in 22 randomised trials.
      ].
      It is important to emphasize that the EORTC 22922/10925 trial recruited patients between the years 1996 and 2004, at a time that concerns of radiation toxicity, resulting in mainly cardiac morbidity and mortality, were a significant consideration to avoid elective IM-MS irradiation in early-stage breast cancer patients [
      • Harris J.R.
      • Hellman S.
      Put the “hockey stick” on ice.
      ,
      • Cuzick J.
      • Stewart H.
      • Peto R.
      • Baum M.
      • Fisher B.
      • Host H.
      • et al.
      Overview of randomized trials of postoperative adjuvant radiotherapy in breast cancer.
      ,
      • Cuzick J.
      • Stewart H.
      • Rutqvist L.
      • Houghton J.
      • Edwards R.
      • Redmond C.
      • et al.
      Cause-specific mortality in long-term survivors of breast cancer who participated in trials of radiotherapy.
      ,
      • Clarke M.
      • Collins R.
      • Darby S.
      • Davies C.
      • Elphinstone P.
      • Evans V.
      • et al.
      Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials.
      ]. Common practice for RT planning at that time followed bony landmarks and the use of individualised RT-techniques and imaging-based treatment planning were not practiced in most centres. All 3 techniques in the EORTC 22922/10925 trial were field-based RT and not volume-based, with dose distributions and calculations performed on a limited number of transversal slices [
      • Grant W.
      • Hurkmans C.W.
      • Poortmans P.M.
      • Maingon P.
      • Monti A.F.
      • van Os M.J.H.
      • et al.
      Quality assurance standards drive improvements in the profile of radiation therapy departments participating in trials of the EORTC Radiation Oncology Group.
      ]. Thereby, dose-volume-histograms as we use today were not available and the estimations of OARs doses were done based on measurements of limited imaging, such as mean lung-distance and maximal heart distance within the tangential fields, providing a limited ability to produce dose-volume estimations [
      • Lievens Y.
      • Poortmans P.
      • Van den Bogaert W.
      A glance on quality assurance in EORTC study 22922 evaluating techniques for internal mammary and medial supraclavicular lymph node chain irradiation in breast cancer.
      ]. The evaluation and analysis presented in this report was obtainable as the participating centres were subjected to a centralized QA, performed by the EORTC-RTQA team, and as the RT protocol defined the irradiation techniques and captured the technique used per individual centre [
      • Poortmans P.
      • Kouloulias V.E.
      • Venselaar J.L.
      • Struikmans H.
      • Davis J.B.
      • Huyskens D.
      • et al.
      Quality assurance of EORTC trial 22922/10925 investigating the role of internal mammary–medial supraclavicular irradiation in stage I-III breast cancer: the individual case review.
      ].
      The initial QA evaluation of the EORTC 22922/10925 trial [
      • Lievens Y.
      • Poortmans P.
      • Van den Bogaert W.
      A glance on quality assurance in EORTC study 22922 evaluating techniques for internal mammary and medial supraclavicular lymph node chain irradiation in breast cancer.
      ] identified the individualised IM-MS irradiation as being at risk of irradiating a substantial volume of lung and heart up to a significant dose (50 ± 70% of the prescribed dose) [
      • Lievens Y.
      • Poortmans P.
      • Van den Bogaert W.
      A glance on quality assurance in EORTC study 22922 evaluating techniques for internal mammary and medial supraclavicular lymph node chain irradiation in breast cancer.
      ]. A recent RT planning study, aiming to better understand the EORTC 22922/10925 trial results [
      • Lievens Y.
      • Poortmans P.
      • Van den Bogaert W.
      A glance on quality assurance in EORTC study 22922 evaluating techniques for internal mammary and medial supraclavicular lymph node chain irradiation in breast cancer.
      ] in the context of modern RT, analysed target volume coverage and OAR doses for whole breast irradiation with vs without IMN RT between 3 RT techniques including a 2D-RT as used during the era of the EORTC trial (free-breathing) [
      • Bogers S.L.C.P.A.
      • Penninkhof J.J.
      • Mast M.E.
      • Poortmans P.M.
      • Hoogeman M.S.
      • Struikmans H.
      Target volume coverage and organ at risk doses for left-sided whole breast irradiation with or without internal mammary chain irradiation: A comparison between 3 techniques representing the past and the present.
      ]. A prescribed dose of 40.05 Gy in 15 fractions was used for the analysis. The mean heart dose for whole breast irradiation-only was <2 Gy for all techniques compared to a mean heart dose of 15.3 Gy in case the IMN were also targeted using a 2D-RT technique, which is nowadays considered as unacceptable with currently available innovative RT methods such as breathing control [
      • Borm K.J.
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      ,
      • Reckhow J.
      • Kaidar-Person O.
      • Ben-David M.A.
      • Ostrovski A.
      • Ilinsky D.
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      Continuous positive airway pressure with deep inspiration breath hold in left-sided breast radiation therapy.
      ,
      • Zagar T.M.
      • Kaidar-Person O.
      • Tang X.
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      • Matney J.
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      • et al.
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      ]. Therefore, at the time of the EORTC trial, a major concern was that individualising RT to limit doses to OARs and thereby toxicity might lead to under-dosing of the target volume and thereby reduce disease control, diminishing the potential benefit of IM-MS irradiation [
      • Poortmans P.M.P.
      • Venselaar J.L.M.
      • Struikmans H.
      • Hurkmans C.W.
      • Davis J.B.
      • Huyskens D.
      • et al.
      The potential impact of treatment variations on the results of radiotherapy of the internal mammary lymph node chain: a quality-assurance report on the dummy run of EORTC Phase III randomized trial 22922/10925 in Stage I-III breast cancer(1).
      ].
      In the current analysis we observed that the increase in 15-year rates of side effects due to IM-MS irradiation, both scored longitudinally and cross-sectionally, were relatively similar among the RT techniques used, except for potential clinically relevant differences (2–4.9%) in any cardiac disease and lung fibrosis that were only seen for the “standard” and “modified standard” techniques for IM-MS irradiation. It is inevitable that the addition of IM-MS irradiation increases the dose to OARs, which may lead to an increase in toxicity. By not individualizing IM-MS irradiation, we can assume that the “standard” and to a lesser extent the “modified standard” IM-MS techniques had more impact on the dose distribution compared to the technique that accounted more for the individual patient’s anatomy [
      • Taylor C.W.
      • Wang Z.
      • Macaulay E.
      • Jagsi R.
      • Duane F.
      • Darby S.C.
      Exposure of the heart in breast cancer radiation therapy: a systematic review of heart doses published during 2003 to 2013.
      ,
      • Kaidar-Person O.
      • Offersen B.V.
      • Boersma L.
      • Meattini I.
      • Dodwell D.
      • Wyld L.
      • et al.
      Tricks and tips for target volume definition and delineation in breast cancer: Lessons learned from ESTRO breast courses.
      ].
      The adjuvant systemic therapies used at the time of the EORTC 22922/10925 trial were tamoxifen as endocrine therapy and mainly CMF-based chemotherapy (cyclophosphamide, methotrexate, fluorouracil) [
      • Bonadonna G.
      • Brusamolino E.
      • Valagussa P.
      • Rossi A.
      • Brugnatelli L.
      • Brambilla C.
      • et al.
      Combination chemotherapy as an adjuvant treatment in operable breast cancer.
      ]. During that period, the role of tamoxifen in premenopausal women was not completely understood [
      • Munzone E.
      • Curigliano G.
      • Burstein H.J.
      • Winer E.P.
      • Goldhirsch A.
      CMF revisited in the 21st century.
      ] and in postmenopausal women with ER-positive tumours, tamoxifen was recommended, while women with ER-negative tumours were considered having an advantage from adjuvant CMF. Consequently, per trial protocol, systemic therapy was decided according to physician’s preference, institutional or national guidelines and recorded per patient. This enabled us to further analyse data according to no adjuvant therapy (which is not common practice nowadays) vs adjuvant therapy (endocrine and/or chemotherapy). Our analysis showed, overall, low lung and cardiac toxicity rates for all groups regardless of administration of systemic therapy. However, these findings do not allow to deduce the potential interaction with contemporary risk-adapted systemic therapy approaches. It is well known that anthracyclines may have a synergistic association for cardiac toxicity in case of RT [
      • Livi L.
      • Barletta G.
      • Martella F.
      • Saieva C.
      • Desideri I.
      • Bacci C.
      • et al.
      Cardioprotective strategy for patients with nonmetastatic breast cancer who are receiving an anthracycline-based chemotherapy: a randomized clinical trial.
      ,
      • Meattini I.
      • Poortmans P.M.
      • Aznar M.C.
      • Becherini C.
      • Bonzano E.
      • Cardinale D.
      • et al.
      Association of breast cancer irradiation with cardiac toxic effects: a narrative review.
      ] but attention should be also given to anti-HER2 regimens that are introduced into the adjuvant setting (e.g., DESTINY-Breast05, NCT04622319). Therefore, we recommend that trials evaluating new systemic regimens for breast cancer should record RT data to allow for further analysis of potential toxicity from interaction with these treatment modalities. In addition, in daily clinical practice, the radiation oncologist should be aware of the adjuvant systemic therapy and record any potential toxicity (mainly cardiac and lung), as current literature might not capture all potential toxicity and interactions of the brisk changes in the landscape of systemic therapy for breast cancer.
      Previous studies showed that tumour laterality (left vs right) had a significant impact on cardiac dose and that the addition of IMN irradiation may double the mean heart dose [
      • Darby S.C.
      • Ewertz M.
      • McGale P.
      • Bennet A.M.
      • Blom-Goldman U.
      • Brønnum D.
      • et al.
      Risk of ischemic heart disease in women after radiotherapy for breast cancer.
      ,
      • Taylor C.W.
      • Wang Z.
      • Macaulay E.
      • Jagsi R.
      • Duane F.
      • Darby S.C.
      Exposure of the heart in breast cancer radiation therapy: a systematic review of heart doses published during 2003 to 2013.
      ]. In our analysis per tumour laterality, the addition of IM-MS irradiation did not significantly increase toxicity, except for a clinically relevant increased lung fibrosis rate in right sided-RT treated with the standard technique (5.2% absolute difference). A clinically relevant lower rate of any cardiac disease (5.4% absolute difference) was seen for left- vs right-sided IM-MS for the individualised technique. As a similar trend was seen in the group that did not undergo elective IM-MS irradiation with regards to any cardiac disease, it might be a result of more careful planning in the individualised technique when laterality was a concern (i.e., left-sided irradiation). The significant difference noted for any lung fibrosis for right-sided tumours might be related to a similar planning “bias” of having less concern in case of right-sided tumours, combined with the larger size of the right lung. The potentially clinically relevant improvement in local and regional control as noted in the individualised IM-MS irradiation group for both left- and right-sided tumours without additional toxicity underlines the importance of an individualised approach for optimising the clinical benefit from IM-MS irradiation regardless of the laterality of the tumour. Therefore, breath hold techniques should be considered for right-sided tumours as well in case of IM irradiation to reduce the dose to the lungs and possibly liver [
      • Kaidar-Person O.
      • Offersen B.V.
      • Boersma L.
      • Meattini I.
      • Dodwell D.
      • Wyld L.
      • et al.
      Tricks and tips for target volume definition and delineation in breast cancer: Lessons learned from ESTRO breast courses.
      ].
      Considering the tumour location within the breast (lateral vs central or medial), the individualised IM-MS irradiation group had 3.3% less local control in case of a lateral-located tumour while a 2.1% benefit to RT was shown after individualised IM-MS irradiation in case of a central/medially located tumour. Tumour location had a greater clinically relevant impact on regional control in the individualised IM-MS irradiation group, especially for lateral-located tumours (6.7% absolute difference). Avoiding potential lung (3.8% less any lung toxicity in IM-MS RT vs no RT in the individualised group) or cardiac toxicity may lead to under-dosing high-risk regions, leading to inferior local control in lateral-located tumours. The trial’s initial dosimetric analysis based on the dummy run did note this issue of under-dosing (defined as less than 95% prescribed dose coverage) of the primary target volume more frequently in the individualised technique (71%) than with the standard technique (36%) [
      • Lievens Y.
      • Poortmans P.
      • Van den Bogaert W.
      A glance on quality assurance in EORTC study 22922 evaluating techniques for internal mammary and medial supraclavicular lymph node chain irradiation in breast cancer.
      ].
      A similar concept was demonstrated by a dosimetric analysis in early application of heart blocks in clinical use [
      • Raj K.A.
      • Evans E.S.
      • Prosnitz R.G.
      • Quaranta B.P.
      • Hardenbergh P.H.
      • Hollis D.R.
      • et al.
      Is there an increased risk of local recurrence under the heart block in patients with left-sided breast cancer?.
      ]. In case of BCS with inferiorly located tumours, the rates of local recurrence with and without a heart block were 33% patients vs none, respectively, explained by under-dosing an average percentage of breast tissue due to the heart block of 2.8% (range, 0–11%), which was critical for local control [
      • Raj K.A.
      • Evans E.S.
      • Prosnitz R.G.
      • Quaranta B.P.
      • Hardenbergh P.H.
      • Hollis D.R.
      • et al.
      Is there an increased risk of local recurrence under the heart block in patients with left-sided breast cancer?.
      ]. Correspondingly, less tumour control in a lateral-located tumour could result from consideration of the lung and heart dose, resulting in under-dosing of the high-risk area. Therefore, in a recent publication by the European Society for Radiotherapy and Oncology (ESTRO) Breast Course faculty, we recommended that the high-risk areas (such as the tumour bed) should not be overlooked and properly delineated, even if a boost is not planned, to avoid accidentally under-dosing these regions [
      • Kaidar-Person O.
      • Offersen B.V.
      • Boersma L.
      • Meattini I.
      • Dodwell D.
      • Wyld L.
      • et al.
      Tricks and tips for target volume definition and delineation in breast cancer: Lessons learned from ESTRO breast courses.
      ].
      Finally, the summary of follow-up status and cause of death per technique and per treatment arm did not reveal any significant differences per treatment technique. As we indicated previously, patients baseline characteristics were unbalanced between the groups. However, our analysis illustrated a larger benefit of IM-MS RT on disease outcome for patients treated with an individualised technique (absolute improvement of DFS and OS of 6.8% and 4.9% for the individualised technique, vs 1.6% and 2.9% for modified standard and −1.4% and 1.1% for standard technique, respectively; absolute reduction in BCSM of 5.8%, vs 4.3% for modified standard and 3% for standard technique). This was not associated with an additional, and in some cases even reduced risk of toxicity.
      The overall favourable outcomes of IM-MS irradiation in the EORTC 22922/10925 trial as published for clinical outcomes [
      • Poortmans P.M.
      • Weltens C.
      • Fortpied C.
      • Kirkove C.
      • Peignaux-Casasnovas K.
      • Budach V.
      • et al.
      Internal mammary and medial supraclavicular lymph node chain irradiation in stage I-III breast cancer (EORTC 22922/10925): 15-year results of a randomised, phase 3 trial.
      ,
      • Poortmans P.M.
      • Collette S.
      • Kirkove C.
      • Van Limbergen E.
      • Budach V.
      • Struikmans H.
      • et al.
      Internal mammary and medial supraclavicular irradiation in breast cancer.
      ] and for long-term RT-related toxicity [
      • Poortmans P.M.
      • Struikmans H.
      • De Brouwer P.
      • Weltens C.
      • Fortpied C.
      • Kirkove C.
      • et al.
      Side effects 15 years after lymph node irradiation in breast cancer: randomized EORTC trial 22922/10925.
      ] are most probably attributable to the RT-planning and QA procedures done by the RTQA team and the participating sites.
      This trial demonstrates that clinically relevant outcomes of RT can be refined by prudent RT planning and QA procedures at different levels, including per patient, per plan, per machine. Another example of the importance of RT planning QA procedures in enhancing the benefit from RT for another controversial indication is the former DBCG 82b&c, which pioneered QA procedures [
      • Nielsen H.M.
      • Overgaard J.
      • Grau C.
      • Christensen J.J.
      • Overgaard M.
      Audit of the radiotherapy in the DBCG 82 b&c trials–a validation study of the 1,538 patients randomised to postmastectomy radiotherapy.
      ,

      Nielsen HM, Overgaard M, Grau C, Jensen AR, Overgaard J. Loco-regional recurrence after mastectomy in high-risk breast cancer--risk and prognosis. An analysis of patients from the DBCG 82 b&c randomization trials. Radiother Oncol. 2006;79:147-55.

      ]. At a 30-years follow up outcomes the trial showed a remarkable benefit from postmastectomy and regional node RT without additional RT-related toxicity such as cardiovascular disease [
      • Cuzick J.
      • Stewart H.
      • Peto R.
      • Baum M.
      • Fisher B.
      • Host H.
      • et al.
      Overview of randomized trials of postoperative adjuvant radiotherapy in breast cancer.
      ,
      • Cuzick J.
      • Stewart H.
      • Rutqvist L.
      • Houghton J.
      • Edwards R.
      • Redmond C.
      • et al.
      Cause-specific mortality in long-term survivors of breast cancer who participated in trials of radiotherapy.
      ,
      • Overgaard M.
      • Nielsen H.M.
      • Tramm T.
      • Højris I.
      • Grantzau T.L.
      • Alsner J.
      • Offersen B.V.
      • Overgaard J.
      DBCG Radiotherapy Group. Postmastectomy radiotherapy in high-risk breast cancer patients given adjuvant systemic therapy. A 30-year long-term report from the Danish breast cancer cooperative group DBCG 82bc trial.
      ].
      Our study holds several limitations. It includes an exploratory unplanned analysis, with an imbalance of patients’ characteristics across the 3 techniques that precluded us from performing a direct comparison of clinical outcomes between the techniques. We took this into account by setting wide margins for “potential clinical relevance” of 2–4.9% and “clinical relevance” as ≥5%. In addition, the RT techniques used, and systemic therapies are not up-to current standards: currently, individualised target volume-based RT planning is done in most (if not all) centres. However, like new systemic therapies, innovative RT-techniques may introduce new risks for toxicity resulting from dose-distributions completely different than the traditional beam arrangements [
      • Kaidar-Person O.
      • Nissen H.D.
      • Yates E.S.
      • Andersen K.
      • Boersma L.J.
      • Boye K.
      • et al.
      Postmastectomy radiation therapy planning after immediate implant-based reconstruction using the European Society for Radiotherapy and Oncology-Advisory Committee in radiation oncology practice consensus guidelines for target volume delineation.
      ,
      • Kaidar-Person O.
      • Kostich M.
      • Zagar T.M.
      • Jones E.
      • Gupta G.
      • Mavroidis P.
      • et al.
      Helical tomotherapy for bilateral breast cancer: clinical experience.
      ]. Nowadays, the work of the radiation team is more complex. The radiation oncologist needs to be involved in the multidisciplinary discussions to properly decide on the indications and volumes for RT and on the potential risks for an individual patient. Correct delineation of volumes (OARs and targets), prescription of dose and fractionation, and methods to reduce OARs doses should be part of routine clinical practice [
      • Kaidar-Person O.
      • Offersen B.V.
      • Boersma L.
      • Meattini I.
      • Dodwell D.
      • Wyld L.
      • et al.
      Tricks and tips for target volume definition and delineation in breast cancer: Lessons learned from ESTRO breast courses.
      ,
      • Kaidar-Person O.
      • Nissen H.D.
      • Yates E.S.
      • Andersen K.
      • Boersma L.J.
      • Boye K.
      • et al.
      Postmastectomy radiation therapy planning after immediate implant-based reconstruction using the European Society for Radiotherapy and Oncology-Advisory Committee in radiation oncology practice consensus guidelines for target volume delineation.
      ,
      • Offersen B.V.
      • Boersma L.J.
      • Kirkove C.
      • Hol S.
      • Aznar M.C.
      • Biete Sola A.
      • et al.
      ESTRO consensus guideline on target volume delineation for elective radiation therapy of early stage breast cancer.
      ,
      • Meattini I.
      • Becherini C.
      • Boersma L.
      • Kaidar-Person O.
      • Marta G.N.
      • Montero A.
      • et al.
      European Society for Radiotherapy and Oncology Advisory Committee in Radiation Oncology Practice consensus recommendations on patient selection and dose and fractionation for external beam radiotherapy in early breast cancer.
      ]. Crucially, an innovative RT technique does not absolve from proper QA procedures. Our reports clearly show that the long-term clinical benefit of RT can be achieved only by individualising RT based on an in-depth understanding per case, QA procedures, follow-up, and reporting. Only then, we can attain the true benefit of long-term disease-free survival and the desired outcome of long-term overall survival [

      Thorsen LBJ, Overgaard J, Matthiessen LW, Berg M, Stenbygaard L, Pedersen AN, et al. Internal mammary node irradiation in patients with node-positive early breast cancer: fifteen-year results from the Danish Breast Cancer Group Internal Mammary Node Study. J Clin Oncol. 2022:Jco2200044.

      ,
      • Poortmans P.M.
      • Struikmans H.
      • De Brouwer P.
      • Weltens C.
      • Fortpied C.
      • Kirkove C.
      • et al.
      Side effects 15 years after lymph node irradiation in breast cancer: randomized EORTC trial 22922/10925.
      ]. The high median number of patients included by the centres that used the individualised technique might partially contribute to the larger benefit, thanks to more experience but also to a higher motivation to participate to the trial and to advance RT for breast cancer patients.

      Conclusions

      Elective IM-MS irradiation improves disease outcomes with limited additional toxicity. Our findings support, even though a rigorous comparison between RT techniques was not possible, the use of more individualised RT techniques as they are associated with higher rates of oncological improvements without increased risks for late side effects. The overall rate of grade 3–4 toxicity was low in all groups. This work also emphasizes the importance of QA protocols.

      Funding

      This study was supported by donations from the La Ligue nationale contre le cancer from France; the KWF Kanker Bestrijding from the Netherlands; and from the Kom op tegen Kanker (Stand up to Cancer), the Flemish Cancer Society from Belgium. Nicolas Sauvé's work as a Fellow at the EORTC Headquarters was supported by a grant from the EORTC Cancer Research Fund .

      Conflicts of interest

      None.
      The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication. None of the authors has a conflict of interest related to this work.

      Acknowledgements

      The authors thank Laurence Collette, Sandra Collette and Nicolas Sauvé from EORTC Headquarters in Brussels (Belgium) for their valuable contribution to the statistical analysis as well as Livia Giurgea for her tremendous support in data collection. Apart from the authors, the following institutions and physicians contributed to the EORTC trial 22922-10925; in decreasing order of available data at the 15-years evaluation: Institute Verbeeten, Tilburg, The Netherlands (Dr. K. De Winter; Dr. S.B. Oei; Dr. L. Scheijmans; Dr. P. De Brouwer); University Hospital Gasthuisberg, Leuven, Belgium (Prof. W. van den Bogaert); University Hospital Saint Luc, Brussels, Belgium (Prof. P. Scalliet); Centre George François Leclerc, Dijon, France (Prof. J.C. Horiot; Prof. P. Maingon); Charite University Medicine, Berlin, Germany (Dr. S. Marnitz); University Medical Centre Utrecht, Utrecht, The Netherlands (Dr. C. Rodenhuis; Dr. L. van de Bunt; Dr. J. Felderhof); Institute for Radiation Oncology Stedendriehoek, RISO, The Netherlands (Dr. J. Immerzeel); University Hospital, Tübingen/Düsseldorf, Germany (Prof. W. Budach; Prof. M. Bamberg); Gustave Roussy Cancer Centre, Villejuif, France (Dr. S. Rivera; Dr. C. Le Pechoux; Dr. H. Marsiglia); Academic Medical Center, Amsterdam, the Netherlands (Dr. G. van Tienhoven; Dr N. Bijker); Institut Curie, Paris, France (Dr. F. Campana); Centre Paul Strauss, Strasbourg, France (Prof. G. Noel; Dr. P. Quetin); Sant Anna Hospital, Como, Italy (Dr. L. Scandolaro); University Hospital, Zurich, Switzerland (Prof. U. Lütolf; Prof. C. Glanzmann); Medical Centre Twente, Enschede, The Netherlands (Dr. J. Jobsen); Centre Leon Bérard, Lyon, France (Dr. S. Racadot; Dr. M.P. Sunyach; Prof. C. Carrie); Rambam Medical Centre, Haifa, Israel (Prof. A. Kuten; Dr. E. Gez; Dr. Roxolyana Abdah-Bortnyak); Nottingham City Hospital, Nottingham, United Kingdom (Dr. D. Morgan); University Hospital La Tronche, Grenoble, France (Pr. M. Bolla); University Hospital Vaudois, Lausanne, Switzerland (Prof. R.O. Mirimanoff; Dr. O. Matzinger); Chaim Sheba Medical Centre, Tel-Hashomer, Israel (Dr. R. Pfeffer); University Hospital Henri Mondor, Creteil, France (Prof. J.L. Lagrange); The Netherlands Cancer Institute-Antoni Van Leeuwenhoek Hospital, Amsterdam, The Netherlands (Dr. N. Russell); Centre Eugene Marquis, Rennes, France (Dr C. Chenal; Dr. M. Benchalal); Institute Bergonie, Bordeaux, France (Dr. J.M. Dilhuydy); Sint-Augustinus Hospital, Wilrijk, Belgium (Dr. P. Huget; Dr. P. Buelens); Hospital of Jolimont, Haine St. Paul, Belgium (Prof. M. Beauduin; Dr. C. Mitine); University Hospital Jean Minjoz, Besancon, France (Prof. J.F. Bosset); Centre Antoine Lacassagne, Nice, France (Dr. A. Courdi); University Hospital, Genève, Switzerland (Prof. J. Kurtz, Dr. S. Balmer-Majno); MAASTRO Clinic, Maastricht, The Netherlands (Dr. J.J. Jager; Dr. J. Borger); Medisch Centrum Haaglanden, Den Haag, The Netherlands (Prof. H. Struikmans); University Medical Center Groningen, Groningen, The Netherlands (Dr. W.V. Dolsma); National Cancer Research Institute, Genova, Italy (Dr. M. Guenzi); Groeninghe Hospital, Kortrijk, Belgium (Dr. K. Stellamans); University Hospital, Gdansk, Poland (Dr. A. Kobierska; Dr. E. Senkus-Konefka); Catalan Institute of Oncology, Barcelona, Spain (Dr S. Villa, Dr. A. Boladeras); University Hospital Charité - Campus Buch, Berlin, Germany (Dr. S. Koswig; Dr. H. Krebs); University Hospital Sarajevo, Sarajevo, Bosnia (Dr. H. Basic); Institute of Radiation Oncology, Santiago, Chile (Prof. A. Arriagada; Dr. R. Baeza); Hospital Clairval, Marseille, France (Dr. F. Amalric); University Hospital, Koeln, Germany (Dr. R. Bongartz). No further data received from: University Hospital, Essen, Germany (Prof. M. Stuschke); German Hospital of Santiago, Santiago, Chile (Dr. L. Badinez); Portuguese Institute of Oncology, Porto, Portugal (Dr. I. Silva); Hospital Gooi-Noord Blaricum, The Netherlands (Dr. H.M. Muller); University Hospital Erlangen-Nurnberg, Erlangen, Germany (Dr. V. Strnad).

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