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Which target volume should be considered when irradiating the regional nodes in breast cancer? Results of a network-meta-analysis

Which target volume should be considered when irradiating the regional nodes in breast cancer?... Purpose/objective(s): Radiation treatment to the regional nodes results in an improvement in survival in breast cancer according to a meta-analysis of randomized trials. However, different volumes were targeted in these studies: breast or chestwall only (WBI/CWI), inclusion of the medial supraclavicular region and axillary apex (MS + WBI/CWI) or additional inclusion of the internal mammary chain (IM + MS + WBI/CWI). The benefit of treating the medial supraclavicular region and axillary apex compared to tangential breast or chestwall irradiation only remains unclear. Materials/methods: A literature search was conducted identifying trials for adjuvant radiation volumes in nodal irradiation after breast surgery and axillary treatment. Events and effect sizes were extracted from the publications for the endpoints of overall survival (OS), breast cancer-specific survival (BCSS), disease-free survival (DFS), distant metastasis-free survival (DMFS) and loco-regional control (LRC). A network meta-analysis was performed using MetaXL V5.3 with the inverse variance heterogeneity model. Results: We found two randomized studies (n = 5836) comparing comprehensive nodal irradiation to sole breast treatment as well as one randomized (n = 1407) and one prospective cohort study (n = 3377) analysing the additional treatment of the internal mammary chain against sole local and supraclavicular and axillary apex radiation. Compared to WBI/CWI alone the treatment of IM + MS + WBI/CWI (HR = 0.88; CI:0.78-0.99; p = 0.036) results in improved OS unlike MS + WBI/CWI (HR = 0.99; CI:0.86-1.14; p = 0,89). These results are confirmed in BCSS: IM + MS + WBI/CWI (HR = 0.82; CI: 0.72-0.92; p = 0.002) and MS + WBI/CWI (HR = 0.96; CI:0.79-1.18; p = 0.69). PFS is significantly improved with the treatment of MS + WBI/CWI (OR = 0.83; CI:0.71-0.97; p = 0.019). Both nodal treatment volumes improve LRC (MS + WBI/CWI OR = 0.74; CI:0.62-0.87; p = 0.004 and IM + MS + WBI/CWI OR = 0.60; CI:0.43-0.86; p < 0,001). Yet only the internal mammary nodes provide a benefit in DMFS (MS + WBI/CWI HR = 0.97; CI:0.81-1.16; p = 0.74 and IM + MS + WBI/CWI HR = 0.84; CI:0.75-0.94; p = 0.002). Conclusion: Expanding the radiation field to the axillary apex and supraclavicular nodes after axillary node dissection reduced loco-regional recurrences without improvement in overall and cancer-specific survival. A prolongation in survival due to regional nodal irradiation is achieved when the internal mammary chain is included. This derives from a reduction in distant metastasis. Keywords: Breast cancer, Radiation therapy, Regional lymph nodes, Radiation volumes * Correspondence: boelke@med.uni-duesseldorf.de Department of Radiation Oncology, Heinrich Heine University, Dusseldorf, Germany Full list of author information is available at the end of the article © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Haussmann et al. Radiation Oncology (2019) 14:102 Page 2 of 14 Introduction wide tangents, intensity-modulated RT techniques or Radiation therapy is a key component in the multidiscip- protons [15]. linary approach of breast cancer treatment after breast Due to the aforementioned difficulties, nodal irradi- conserving surgery and achieves equal oncologic results ation is often limited to the supraclavicular nodes and to mastectomy alone [1]. Over the last decades, surgical the axillary region at risk. This analysis was conducted and radiation treatment to the lymphatic drainage of to evaluate the additional benefit of supraclavicular and breast tumors have also been implemented as standard axillary apex radiation compared to whole breast or of care. Traditionally, axillary lymph node dissection was chest wall irradiation alone, as well as comprehensive performed to determine the accurate tumor stage and nodal irradiation in clinical practice. eliminate nodal metastasis. Recently, the paradigm has shifted to do less extensive surgery, such as sentinel Methods node biopsy alone. Regarding supraclavicular radiation A literature research according to PRISMA guidelines therapy, anterior/posterior opposing fields were matched was performed using the MEDLINE as well as EMBASE to the tangential fields of the breast to treat the axillary and EBM review platforms [16]. Moreover, we screened apex as well as the supraclavicular nodes to cover the major meetings for published abstracts. micro-metastatic spread into these regions. A second Search criteria were randomized or prospective obser- lymphatic drainage system is located parasternal along vational trials reporting on regional nodal irradiation the internal mammary vessels coalescing with the axil- compared to no regional radiotherapy with a median lary chain at the intersection with the subclavian vein. follow-up of more than five years and trial publication Extended radical mastectomies including a dissection of after the year 2009. The study population had to consist the internal mammary nodes (IMN) have been aban- of patients suffering from non-metastatic breast cancer doned due to high complication rates and dubious onco- treated with regional irradiation in least one trial arm. logical benefits [2, 3]. Radiotherapy (RT) was also used The exclusion criteria and time range were chosen to to cover this lymphatic drainage site and resulted in ensure a relatively homogeneous radiation technique, as equivocal results with reports of a potential benefits [4, well as systemic therapies mimicking current standard of 5] as well as no advantage [2, 6] or even harmful effects care. We excluded patients undergoing surgical dissec- [7]. However, a meta-analysis by the EBCTCG, based on tion of the internal mammary lymph nodes, preoperative individual patient data, identified the role of postmastec- radiation therapy and studies that used non-standard tomy radiation (PMRT) including a comprehensive systemic therapies. nodal irradiation, and reported significant benefits for All available data were extracted as hazard ratios or local control, disease-free and overall survival. In fact, event rates. Assessment of toxicities in the included tri- the vast majority of the 22 studies included radiation of als was attempted. The definition of the analyzed end- the internal mammary chain [8]. points was adopted from the published trials. If hazard Contemporarily breast cancer surgery is often per- ratios were not reported an attempt was made to calcu- formed using an organ preservation approach followed late the hazard ratios and their corresponding 95% confi- by adjuvant radiation therapy [1]. It has been a matter of dence intervals according to the method published by debate whether nodal irradiation provides any benefit Parmar et al. [17]. If both effect measures were available, after axillary node dissection (AND) in the era of effect- we elected to compare hazard ratios as they are regarded ive systemic therapies. Additionally, the regions of high- as most appropriate in analyzing time-to-event data. est risk in the axilla might already be covered by Visual analysis of publication bias by creating funnel standard tangential field irradiation, as whole breast plots was available but is not presented here due to the radiation therapy applies substantial doses to the lower low number of included trials. Endpoints of the axilla and might provide equal control to dissection in comparison included overall survival (OS), breast clinically node negative but sentinel node positive cancer-specific survival (BCSS), disease-free survival patients [9, 10]. (DFS), distant metastasis-free survival (DMFS) and Moreover, inclusion of the internal mammary nodes loco-regional control (LRC). proves to be a challenging task for radiation oncologists, Data were analyzed using the Microsoft Excel plug-in because it subsequently leads to higher lung and heart MetaXl V5.3 and the included network meta-analysis doses, which increase the risks for late adverse events function. Due to possible heterogeneity of the study pop- like ischemic heart events, secondary lung cancers or ulations the inverse variances of heterogeneity model pulmonary fibrosis [11–14]. Furthermore, no consensus (ivhet) by Doi et al. was chosen as the comparison was reached on the optimal treatment application. method [18]. This method favors larger trials, uses a Current techniques range from anterior electron fields more conservative estimation of the confidence limits to mixed electron and photon beam techniques, partial and produces lesser observed variances compared to the Haussmann et al. Radiation Oncology (2019) 14:102 Page 3 of 14 random effects model. Zero event correction was ap- Results plied, where appropriated [19]. An intended analysis of The literature search depicted in Fig. 1 identified four heterogeneity was not feasible because not enough stud- randomized or prospective trials matching the search ies were available to form a closed loop. Subgroup ana- criteria [20–23]. The EORTC trial was recently pre- lysis of matching endpoints and cohorts was intended. sented in an updated version, hence we used the avail- However, subgroups were only analyzed when two or able recent results in this analysis [20]. For non-updated more trials reported results in the specific subgroup. endpoints the fully-published results were used [20]. Furthermore we performed a subgroup analysis Additionally, the EBCTCG meta-analysis was also con- according to the radiation volume of the EBCTCG indi- sidered to provide valuable information on the volumes vidual patient meta-analysis on the effect of postmastec- used in PMRT compared to no adjuvant radiation tomy radiation [8]. We identified two studies that did therapy. not include the internal mammary region in the regional An overview of the included trials is presented in irradiation volumes. We extracted the numbers under Table 1. Overall 10,620 patients with nodal positive or risk and events from the different nodal disease sub- nodal negative with risk factors for lymphatic spread groups from these two studies and compared them to were randomized in the studies. The majority of in- the remaining trials in that specific subgroup. To avoid cluded patients had pT1 or pT2 tumors with pN0 or bias of analysis only subgroups with more than five pN1 disease. The surgical approach consisted of mastec- patients per comparison were analyzed. Afterwards, we tomy (MTX) or breast-conservation surgery (BCS) and performed two comparisons (Comparison 1: chest wall planned axillary lymph node dissection. The sentinel irradiation + comprehensive nodal irradiation vs. no node approach only was used in fewer than 3% of the PMRT; Comparison 2: chest wall irradiation without patients. Chemotherapy was regularly administered in IMN irradiation vs. no PMRT) using the same methods the majority of trial participants. Median follow-up was as described above. In the EBCTCG Analysis we in- above 8 years in all included trials. Table 2 shows an cluded any first locoregional and any first recurrence in overview in which trials overall survival was analyzed be- addition to overall survival as endpoints. tween different subgroups. Fig. 1 The PRISMA flowchart of the included trials Haussmann et al. Radiation Oncology (2019) 14:102 Page 4 of 14 Table 1 Overview of included trials. n.r. = not reported, FU = follow up, HR + = hormone receptor positive, N+/− = lymph node positive/negative, RN = regional nodes, IMN = internal mammary nodes, TV = target volume; ICS = intercostal space; BCS = breast conserving surgery; MTx = Mastectomy; AND = axillary node dissection Trial Synonym Years trial N total med. FU (y) Post meno- HR+ CTx N+ N- T1 T2 Lateral Surgery Dose Dose RN RT IMN TV Main trial Age pausal Location Breast Boost group Hennequin French 1991–1997 1407 n.r. 8.6 n.r. 52% 61% 75% 25% 33% 52% 36% MTx 100 AND 50Gy 18 × 2.5 Gy none ICS 1–5N0 2013 100% =45Gy med/ central or N+ Thorsen DBCG- 2003–2007 3377 56 8.9 60% 80% 53% 100% 0% 41% 52% 60% BCS 35% MTx 65 24x2Gy 24x2Gy 13% ICS 1–4N+ 2016 IMN AND 100% =48Gy =48Gy Poortmans EORTC 1996–2004 4004 54 15.7 59% 78% 55% 56% 45% 60% 36% n.r. BCS 76,1% MTx 25x2Gy 25x2Gy 85% ICS 1–3 N0 2015/2018 22922 23,9% =50Gy =50Gy (−4) med/ AND 100% central or N+ Whelan Ma.20 2000–2007 1832 54 9.5 nr 75% 91% 90% 10% 52% 46% 62% BCS 100 AND 96% 25x2Gy 25 × 1.8–2Gy 33% ICS 1–3 N0 (high 2015 SNB 4% =50Gy =45-50Gy risk) or N+ Haussmann et al. Radiation Oncology (2019) 14:102 Page 5 of 14 Table 2 Overview of subgroups analysed for overall survival by trial. a) Subgroup analysis based on (Poortmans et al. [20]) Subgroups Thorsen Hennequin Poortmans Whelan Primary Tumor Size -T1 + – + – -T2 + – + – -T3 + – + – Nodal Stage -N+ ++ + + -N0 – ++ + -N1 + – ++ -N2+ + – ++ Tumor Location -Medial / central ++ – + -Lateral ++ – + Hormonal Status -Premenopausal + – + – -Postmenopausal + – + – Type of Surgery -Mastectomy + – + – -Breast conservation + – + – Receipt of Chemotherapy – ++ – In Fig. 2 we present the resulting network for compari- breast−/chest wall-irradiation + supraclavicular / axillary son. Two trials (EORTC 22922 and Ma.20) compared apex (MS + WBI/CWI-RT). comprehensive regional nodal radiation (IMN + MS + According to Fig. 3, comprehensive RNI improved the WBI/CWI-RT) to whole breast−/chest wall-irradiation rate of locoregional recurrence (OR = 0.80 CI95%: 0.68– only (WBI/CWI-RT). The other two trials compared 1.11; p = 0.182). This effect was mainly based on the in- nodal radiotherapy with (IMN + MS + WBI/CWI-RT) clusion of the MS (OR = 0.74 CI95%: 0.62–1.05; p = and without (MS + WBI/CWI-RT) the parasternal lymph 0.092) and not the IMN (OR = 0.99 CI95%: 0.70–1.39; nodes (French and DBCG-IMN). Subsequently we were p = 0.946) target volume. However, the endpoint of able to perform an indirect analysis of the comparison disease-free survival (Fig. 4) was not significantly im- breast−/chest wall irradiation only (WBI/CWI-RT) vs. proved by any components of the regional radiation Fig. 2 Overview of analyzed network according to target volume of regional irradiation Haussmann et al. Radiation Oncology (2019) 14:102 Page 6 of 14 Fig. 3 Forest plot of direct and indirect comparison of locoregional recurrence according to extend of regional radiation (+/− IMN: OR = 0.90 CI95%: 0.80–1.01; p = 0.081; +/− 0.71–1.03; p = 0.094), whereas MS-radiation had no im- MS: OR = 0.85 CI95%: 0.70–1.03; p = 0.101; +/− RNI: pact (OR = 0.97 CI95%: 0.82–1.16; p = 0.745) (Fig. 5). As OR = 0.85 CI95%: 0.62–1.17; p = 0.331). This numeric depicted in Fig. 6 this resulted in a significant improve- improvement resulted from a significant reduction of ment in breast-cancer specific survival in IMN-RT (HR = distant metastasis from RNI (OR = 0.80 CI95%: 0.70– 0.85 CI95%: 0.73–0.98; p = 0.031) and RNI (HR = 0.81 0.91; p = 0.001). IMN radiation showed a trend for an CI95%: 0.71–0.92; p = 0.001). MS-RT had no significant improvement in distant recurrence (OR = 0.85 CI95%: effect (HR = 0.94 CI95%: 0.69–1.28; p = 0.700). Fig. 4 Forest plot of direct and indirect comparison of disease-free survival according to extend of regional radiation Haussmann et al. Radiation Oncology (2019) 14:102 Page 7 of 14 Fig. 5 Forest plot of direct and indirect comparison of distant metastasis according to extend of regional radiation Fig. 6 Forest plot of direct and indirect comparison of cancer-specific survival according to extend of regional radiation Haussmann et al. Radiation Oncology (2019) 14:102 Page 8 of 14 Subsequently, overall survival was equally improved by 20 years results are depicted inn Figs. 9 and 10 compar- IMN-RT (HR = 0.86 CI95%: 0.76–0.99; p = 0.031). After ing comprehensive PMRT and PMRT without IMN to the inclusion of the 2018 update of the EORTC trial RNI no PMRT at all. PMRT with the inclusion of the IMN did no longer significantly improve overall mortality significantly improved the rate of any first recurrence (HR = 0.94 CI95%: 0.85–1.04; p = 0.253). Again MS-RT after 10 years (OR = 0.68 CI95%: 0.62–0.74; p < 0.001) had no effect on survival (HR = 1.03 CI95%: 0.89–1.18; but did not improve the rate of any death after 20 years p = 0.708) (Fig. 7). (OR = 0.84 CI95%: 0.65–1.07; p = 0.160). PMRT without Subgroup analysis on overall mortality was feasible in the treatment of the IMN in the two included studies a subset of trials (Table 2). Figure 8 shows the effect of showed a significant improvement in the recurrence rate comprehensive regional therapy compared to no re- after ten years (OR = 0.60 CI95%: 0.40–0.90; p = 0.014). gional RT as well as the indirect effect of MS + WBI/ However, this did not translate into better survival (OR = CWI-RT compared to WBI/CW-RT. We identified a sig- 1.13 CI95%: 0.58–2.20; p = 0.722). As the analysis of nificant improvement in overall survival by IMN + MS + locoregional recurrence showed equal results to any first WBI/CWI-RT in patients with T2 stage cancers. A stat- recurrence it was not reported in detail. istical trend was seen in node negative, postmenopausal Figure 11 shows the analysis of cardiac events. We and patients treated with BCS. The relative effectiveness found no significant differences between the radiation analysis revealed no subgroup that significantly profited volumes. However the point estimates imply that the in terms of overall mortality from MS + WBI/CWI-RT non-significant increase in cardiac events derive mainly alone. Importantly, in all subgroups the estimated effect from the parasternal radiation. sizes were superior in patients treated with comprehen- sive nodal radiation therapy. Discussion Furthermore we analyzed the effect of the sub-volumes Regional nodal irradiation in presumed intermediate risk in PMRT radiation compared to no PMRT in the indi- breast cancer patients in stages I-III results in a small vidual patient meta-analysis by the EBCTCG published improvement in breast cancer specific and overall sur- in 2014 [8]. We identified two trials that specifically did vival due to a reduction in distant metastasis [24]. This not include the internal mammary nodes in the post- network meta-analysis supports the role of internal mastectomy radiation volumes and compared them to mammary radiation as the critical sub-volume to achieve the included trials treating matching patient populations. these benefits. The supraclavicular irradiation appears to Any first recurrence after 10 years and any death after provide a benefit in locoregional control but does not, in Fig. 7 Forest plot of direct and indirect comparison of overall survival according to extend of regional radiation Haussmann et al. Radiation Oncology (2019) 14:102 Page 9 of 14 Fig. 8 Forest plot of direct and indirect comparison of overall survival between different subgroups according to extend of regional irradiation. Direct comparison is depicted as diamonds, indirect comparison as squares contrast to the internal mammary nodal radiation, re- rates of pulmonary fibrosis and pneumonitis, as well as duce the distant recurrence rate and subsequently mor- lymphedema [20, 22]. Additional treatment of the IMN tality. This interpretation is supported by the additional did not resulted in a significant increase of Grade 3–4ad- investigation of the PMRT meta-analysis, showing a verse events [21]. A more thorough analysis of side effects comparable reduction in any first recurrence with supra- separated by sub-volumes would be desirable but is cur- clavicular radiation. However, a trend towards improved rently not feasible, due to a lack of reported data. mortality is only observed when the IMN are included The applied radiation techniques in the included trials in the radiation plan. ranged from 2D to early computer tomography-based Despite the advantage in reducing metastases, the approaches. However, modern techniques to reduce treatment of the internal mammary nodes is technically doses at organs at risk, like deep inspiration breath hold, challenging and is accompanied by a significantly higher field in field treatments or volumetric modulated arc dose to the heart and lungs. Hence, the possible gain in therapy were not used [25]. The use of these techniques survival has to be weighed against its harms, especially has been shown to further improve the therapeutic gain in patients with a history of smoking or other cardiovascu- in RT. [26] Particularly the decreased benefit of regional lar risk factors. These patients might not benefit from re- radiation in the EORTC 22922 trial due to currently un- gional radiation at all, due to the higher absolute risks for explained deaths raises some questions [27]. Efforts are secondary lung cancer or cardiac events [12, 13]. Our ana- currently being made to explain these unexpected lysis demonstrates that, although not statistically signifi- events. Speculatively, late vascular side effects leading to cant, especially the increase in cardiac risks derive mainly cardiac disease (IMN fields) or cerebrovascular disease from the parasternal radiation. RNI was reported to cause (supraclavicular fields) may have contributed to these a small increase in pulmonary toxicity with higher event observations [27–29]. Haussmann et al. Radiation Oncology (2019) 14:102 Page 10 of 14 Fig. 9 Forest plot of direct comparison of overall survival according to extend of regional radiation in the 2014 EBCTCG Meta-Analysis. Here, the comparisons are PMRT (IMN + MS + CWI) vs. no radiation and PMRT without IMN (MS + CWI) vs. no radiation It has been hypothesized that the benefit of any treated with chemotherapy [20, 23]. In the French local treatment is dependent on the benefit resulting trial around 60% were treated with mainly from systemic therapies [30]. The administered anthracycline-based chemotherapy [21]. The effective- chemo- and hormone therapy in the included trials ness of regional irradiation in the Ma.20 trial, where were heterogeneous. In the Ma.20 trial 90% of pa- the highest rate and closest to the current standard tients received adjuvant chemotherapy, mostly chemotherapy was offered, does not appear to differ anthracycline-based, with about 25% receiving also substantially from the other trials. This is why we taxanes [22]. In contrast, only around 55% of patients thinkthatevenmodernsystemic therapiesdo not in the EORTC trial and in the Danish trial were mitigate the effectiveness of regional radiation. Fig. 10 Forest plot of direct comparison of any first recurrence according to extend of regional radiation in the 2014 EBCTCG Meta-Analysis. Here, the comparisons are PMRT (IMN + MS + CWI) vs. no radiation and PMRT without IMN (MS + CWI) vs. no radiation Haussmann et al. Radiation Oncology (2019) 14:102 Page 11 of 14 Fig. 11 Forest plot of direct and indirect comparison of cardiac events according to extend of regional radiation. Cardiac events varied between studies and included acute myocardial infarction, ischemic heart disease, congestive heart failure, supraventricular arrhythmias and pericardial effusion Since the publication of the ACOSOG Z0011 trial, the Furthermore, since the publication of the ACOSOG routine use of axillary lymph node dissection (ALND) Z0011 trial, it has been well established that a small for the clinically node negative axilla has been declining tumor burden in the axilla can safely remain [9]. However, the role of radiation therapy in this con- un-dissected and treated with systemic therapy [9]. text is not well established [31]. The AMAROS and Radiation therapy to the breast or chest wall might OTOASOR trials showed that radiation could replace additionally contribute to this favorable outcome. It is axillary surgery and achieve equivalent effectiveness possible that the two regions may be differently af- [10, 32]. With the routine omission of ALND, it is fected by these “incidental” treatments. Hormone- or certainly possible that the RT treatment of the axilla chemotherapy might affect a postoperative region dif- and the supraclavicular region could regain more im- ferently than a solely irradiated one. Moreover, the in- portance in the future. cidental radiation doses to the axillary levels I and II What are possible explanations for the proposed dif- were reported to be larger than respectively to the ferential oncologic effects of RT to the two components IMNs [36–38]. of the lymphatic chain? Obviously, the therapeutic ap- The difference in locoregional control rates between proaches to both regions in the included studies were MS- and IMN-RT fields could also be explained by the very different, since the axillary chain was dissected way recurrences are diagnosed in the clinical follow-up. followed by irradiation and the internal mammary nodal As recurrences in both regions are usually subclinical chain was solely treated with radiation. The effect of MS and routine diagnostic imaging is often not included in radiation was investigated in large retrospective series the routine follow-up, the diagnosis of a regional recur- demonstrating an impairment in DMFS and OS when rence is often delayed and accompanied by distant meta- supraclavicular recurrences occur during follow-up. static disease. Furthermore, regional relapses in the However, on multivariate analysis RNI to the MS was internal mammary nodes are very difficult to distinguish not associated with an improvement in BCSS or OS, radiologically from mediastinal lymph nodes, leading to which reflects the results of the present analysis [33]. the diagnosis of metastatic disease. This influences the This deviation might be explained by alterations in the relative effects on locoregional recurrence and distant trial populations. The highest risk of supraclavicular in- metastasis, but does not explain the impact on overall volvement has been reported in patients with multiple mortality. axillary nodes, large nodal size, lymphovascular invasion, The effectiveness of the IMN radiation is currently higher grading and extracapsular extension [33–35]. mainly explained by two hypotheses. IMN irradiation re- This high-risk population might be underrepresented in duces the spread of micrometastases along this drainage the present analysis, as less than 10% of the patients had site and subsequently lowers the risk for distant metasta- pN2+ axillary staging. ses. Furthermore, also an abscopal response, with a Haussmann et al. Radiation Oncology (2019) 14:102 Page 12 of 14 tumoricidal effect on non-target tumor cells, has also an adequate ALND to the breast tissue and the internal been postulated [24, 39]. One might expand this ap- mammary lymph nodes. To our knowledge, there have proach concluding that only IMN and not MS treatment been no attempts to restrict the treatment to these vol- can generate this effect, which explains our results. Cur- umes. An omission of MS-RT might decrease early and rently the systemic effects of RNI and its clinical impli- late toxicities, including esophagitis and radiation cations are insufficiently understood. dermatitis, as well as hypothyroidism, pulmonary events This network meta-analysis has several strengths and and cardiac side effects [45]. Subgroups where this might limitations we need to address. It includes high-quality be considered appropriate are patients with favorable trials with a considerable number of participants. Fur- biology as well as low axillary nodal burden. thermore, the observed effects are relatively consistent This analysis should be viewed as hypothesis-generat- among the subgroups, supporting the general conclu- ing for future investigations. Additionally, it could also sions of the analysis. One limitation is that we did not provide a helpful guide for prioritization in the clinical identify any trial addressing the effect of supraclavicular practice, for example when dose constraints cannot be radiotherapy alone after surgical dissection. Conse- met or attempts to de-escalate radiation volumes are quently, the estimation of this comparison is only indir- intended. ect and therefore hypothesis generating. Moreover, the inclusion of a prospective non-randomized trial in- Conclusion creased the number of patients, but may add potential Expanding the radiation field to the axillary apex and biases to the analysis [23]. However, restriction of the in- supraclavicular nodes after axillary node dissection re- vestigated endpoints to only randomized trials, showed duced loco-regional recurrences without improvement no difference in outcome, providing support for the ro- in overall and cancer-specific survival. A prolongation in bustness of this analysis. The median follow-up between survival due to regional nodal irradiation is achieved 8 and 15 years is relatively long but might still be inad- when the internal mammary chain is included. This de- equate to capture long-term side effects, like cardiac rives from a reduction in distant metastasis. events or secondary carcinomas impacting mortality. Abbreviations Unfortunately, the analysis of adverse events was re- ALND: Axillary lymph node dissection; AND: Axillary node dissection; stricted to the cardiac event rates as the reporting was BCSS: Breast cancer-specific survival; CI: Confident interval; CWI: Chest wall irradiation; DFS: Disease free survival; DMFS: Distant metastasis-free survival; inconsistent in the included trials. EORTC: European Organisation for Research and Treatment of Cancer; The comparison of multiple randomized trials in a FU: Follow up; HR: Hazard ratio; HR-: Hormone receptor negative; network meta-analysis offers an intriguing option to HR + : Hormone receptor positive; IMN: Internal mammaria node; Ivhet: Inverse variance of heterogeneity model; LCR: Loco-regional control; investigate previously not directly compared treat- MTX: Mastectomy; N-: Lymph node negative; n.r: Not reported; N + : Lymph ment options. Like any meta-analysis the homogen- node positive; OS: Overall survival; PFS: Progression free survival; eity of the included population, trial arms and PMRT: Postmastectomy radiation; RT: Radiotherapy; WBI: Whole breast irradiation investigated endpoints are central to a robust, mean- ingful analysis. Beyond the “classical” comparison of Acknowledgements the pooled effect sizes, a network meta-analysis also This work was presented as an oral presentation in the plenary session at the allows a ranking of the groups by using the point Joint Scientific Meeting of the Canadian Association of Radiation Oncology in Montreal 2018. estimates. In view of the small benefit of nodal irradiation with Funding an equally small but substantial risk of adverse events in There was no funding for this investigation. an unselected patient population, it is of enormous im- Availability of data and materials portance to predict the benefit for different subgroups. All data and materials can be found in “Patient, materials and methods” section Numerous attempts have succeeded in predicting which or can be accessed via JH and CM. groups are at higher risk for local or distant relapse. Authors’ contributions However, to date there is no predictive test to estimate JH, CM and WB, participated in collecting data, and drafted the manuscript. the benefit of radiotherapy. Subdivision by classical JH and KK performed the statistical analysis and participated in its design. EB, subtypes (hormone receptor, Her2, triple negative) BT, FJD, SC and CM helped to draft the manuscript. All authors read and approved the final manuscript. produced varying results [40, 41]. Currently, tumor cells in the blood or bone marrow, as well as cellular Ethics approval and consent to participate markers scoring for intrinsic radiation sensitivity, are There was no ethics approval necessary because in this meta-analysis we were pulling numbers from the published manuscripts and pooling results. being studied to improve our understanding of the benefit of radiation [42–44]. Consent for publication Possible consequences and further topics of investiga- This is a network-meta-analysis which does not contain any individual tion might be a de-escalation of radiation volumes after persons data, therefore not applicable. Haussmann et al. Radiation Oncology (2019) 14:102 Page 13 of 14 Competing interests 16. Moher D, Liberati A, Tetzlaff J, Altman DG, Group P. Preferred reporting The authors declare that they have no competing interests. items for systematic reviews and meta-analyses: the PRISMA statement. BMJ. 2009;339:b2535. 17. Parmar MK, Torri V, Stewart L. Extracting summary statistics to perform Publisher’sNote meta-analyses of the published literature for survival endpoints. Stat Med. Springer Nature remains neutral with regard to jurisdictional claims in published 1998;17:2815–34. maps and institutional affiliations. 18. Doi SA, Barendregt JJ, Khan S, Thalib L, Williams GM. 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Ten-year survival results of a randomized trial of irradiation of internal mammary nodes after Received: 29 December 2018 Accepted: 22 April 2019 mastectomy. Int J Radiat Oncol Biol Phys. 2013;86:860–6. 22. Whelan TJ, Olivotto IA, Levine MN. Regional nodal irradiation in early-stage breast Cancer. N Engl J Med. 2015;373:1878–9. References 23. Thorsen LB, Offersen BV, Dano H, et al. DBCG-IMN: a population-based 1. Fisher B, Anderson S, Bryant J, et al. Twenty-year follow-up of a randomized cohort study on the effect of internal mammary node irradiation in early trial comparing total mastectomy, lumpectomy, and lumpectomy plus node-positive breast Cancer. J Clin Oncol. 2016;34:314–20. irradiation for the treatment of invasive breast cancer. N Engl J Med. 2002; 24. Budach W, Bolke E, Kammers K, Gerber PA, Nestle-Kramling C, 347:1233–41. Matuschek C. Adjuvant radiation therapy of regional lymph nodes in 2. Fisher B, Jeong JH, Anderson S, Bryant J, Fisher ER, Wolmark N. Twenty-five- breast cancer - a meta-analysis of randomized trials- an update. Radiat year follow-up of a randomized trial comparing radical mastectomy, total Oncol. 2015;10:258. mastectomy, and total mastectomy followed by irradiation. N Engl J Med. 25. Pazos M, Fiorentino A, Gaasch A, et al. Dose variability in different lymph 2002;347:567–75. node levels during locoregional breast cancer irradiation: the impact of 3. Horino T, Fujita M, Ueda N, et al. Efficacy of internal mammary node deep-inspiration breath hold. Strahlenther Onkol. 2018. dissection in the treatment of breast cancer. Jpn J Clin Oncol. 1991;21: 26. Jagsi R, Griffith KA, Moran JM, et al. A randomized comparison of 422–7. radiation therapy techniques in the Management of Node-Positive 4. Arriagada R, Le MG, Mouriesse H, et al. Long-term effect of internal Breast Cancer: primary outcomes analysis. Int J Radiat Oncol Biol Phys. mammary chain treatment. Results of a multivariate analysis of 1195 2018;101:1149–58. patients with operable breast cancer and positive axillary nodes. Radiother 27. Poortmans P, Collette S, Struikmans H, et al. Fifteen-year results of the Oncol. 1988;11:213–22. randomised EORTC trial 22922/10925 investigating internal mammary and 5. Courdi A, Chamorey E, Ferrero JM, Hannoun-Levi JM. Influence of internal medial supraclavicular (IM-MS) lymph node irradiation in stage I-III breast mammary node irradiation on long-term outcome and contralateral breast cancer. J Clin Oncol. 2018;36:504. cancer incidence in node-negative breast cancer patients. Radiother Oncol. 28. Killander F, Anderson H, Kjellen E, Malmstrom P. Increased cardio and 2013;108:259–65. cerebrovascular mortality in breast cancer patients treated with 6. Fowble B, Hanlon A, Freedman G, et al. Internal mammary node irradiation postmastectomy radiotherapy--25 year follow-up of a randomised trial from neither decreases distant metastases nor improves survival in stage I and II the South Sweden breast Cancer group. Eur J Cancer. 2014;50:2201–10. breast cancer. Int J Radiat Oncol Biol Phys. 2000;47:883–94. 29. Stokes EL, Tyldesley S, Woods R, Wai E, Olivotto IA. Effect of nodal irradiation 7. Cuzick J, Stewart H, Rutqvist L, et al. Cause-specific mortality in long-term and fraction size on cardiac and cerebrovascular mortality in women with survivors of breast cancer who participated in trials of radiotherapy. J Clin breast cancer treated with local and locoregional radiotherapy. Int J Radiat Oncol. 1994;12:447–53. Oncol Biol Phys. 2011;80:403–9. 8. Ebctcg MGP, Taylor C, et al. Effect of radiotherapy after mastectomy and 30. Punglia RS, Morrow M, Winer EP, Harris JR. Local therapy and survival in axillary surgery on 10-year recurrence and 20-year breast cancer mortality: breast cancer. N Engl J Med. 2007;356:2399–405. meta-analysis of individual patient data for 8135 women in 22 randomised 31. Jagsi R, Chadha M, Moni J, et al. Radiation field design in the ACOSOG trials. Lancet. 2014;383:2127–35. Z0011 (Alliance) trial. J Clin Oncol. 2014;32:3600–6. 9. Giuliano AE, Ballman KV, McCall L, et al. Effect of axillary dissection vs no 32. Savolt A, Peley G, Polgar C, et al. Eight-year follow up result of the OTOASOR trial: axillary dissection on 10-year overall survival among women with invasive the optimal treatment of the axilla - surgery or radiotherapy after positive breast Cancer and sentinel node metastasis: the ACOSOG Z0011 (Alliance) sentinel lymph node biopsy in early-stage breast cancer: a randomized, single randomized clinical trial. JAMA. 2017;318:918–26. Centre, phase III, non-inferiority trial. Eur J Surg Oncol. 2017;43:672–9. 10. Donker M, van Tienhoven G, Straver ME, et al. Radiotherapy or surgery of 33. Yates L, Kirby A, Crichton S, et al. Risk factors for regional nodal relapse in the axilla after a positive sentinel node in breast cancer (EORTC 10981- breast cancer patients with one to three positive axillary nodes. Int J Radiat 22023 AMAROS): a randomised, multicentre, open-label, phase 3 non- Oncol Biol Phys. 2012;82:2093–103. inferiority trial. Lancet Oncol. 2014;15:1303–10. 34. Grills IS, Kestin LL, Goldstein N, et al. Risk factors for regional nodal failure 11. Boekel NB, Jacobse JN, Schaapveld M, et al. Cardiovascular disease after breast-conserving therapy: regional nodal irradiation reduces rate of incidence after internal mammary chain irradiation and anthracycline-based axillary failure in patients with four or more positive lymph nodes. Int J chemotherapy for breast cancer. Br J Cancer. 2018. Radiat Oncol Biol Phys. 2003;56:658–70. 12. Darby SC, Ewertz M, McGale P, et al. Risk of ischemic heart disease in 35. Yu JI, Park W, Huh SJ, et al. Determining which patients require irradiation women after radiotherapy for breast cancer. N Engl J Med. 2013;368:987–98. of the supraclavicular nodal area after surgery for N1 breast cancer. Int J 13. Taylor C, McGale P, Bronnum D, et al. Cardiac structure injury after Radiat Oncol Biol Phys. 2010;78:1135–41. radiotherapy for breast Cancer: cross-sectional study with individual patient 36. Reed DR, Lindsley SK, Mann GN, et al. Axillary lymph node dose with data. J Clin Oncol. 2018;36:2288–96. tangential breast irradiation. Int J Radiat Oncol Biol Phys. 2005;61:358–64. 14. van den Bogaard VA, Ta BD, van der Schaaf A, et al. Validation and modification of a prediction model for acute cardiac events in patients with 37. Reznik J, Cicchetti MG, Degaspe B, Fitzgerald TJ. Analysis of axillary coverage breast Cancer treated with radiotherapy based on three-dimensional dose during tangential radiation therapy to the breast. Int J Radiat Oncol Biol distributions to cardiac substructures. J Clin Oncol. 2017;35:1171–8. Phys. 2005;61:163–8. 15. Jagsi R, Moran J, Marsh R, Masi K, Griffith KA,PierceLJ. Evaluation of four techniques 38. Thorsen LB, Thomsen MS, Berg M, et al. CT-planned internal mammary using intensity-modulated radiation therapy for comprehensive locoregional node radiotherapy in the DBCG-IMN study: benefit versus potentially irradiation of breast cancer. Int J Radiat Oncol Biol Phys. 2010;78:1594–603. harmful effects. Acta Oncol. 2014;53:1027–34. Haussmann et al. Radiation Oncology (2019) 14:102 Page 14 of 14 39. Jatoi I, Benson JR, Kunkler I. Hypothesis: can the abscopal effect explain the impact of adjuvant radiotherapy on breast cancer mortality? NPJ Breast Cancer. 2018;4:8. 40. Sjostrom M, Lundstedt D, Hartman L, et al. Response to radiotherapy after breast-conserving surgery in different breast Cancer subtypes in the Swedish breast Cancer group 91 radiotherapy randomized clinical trial. 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Which target volume should be considered when irradiating the regional nodes in breast cancer? Results of a network-meta-analysis

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Springer Journals
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Copyright © 2019 by The Author(s).
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Biomedicine; Cancer Research; Oncology; Radiotherapy; Imaging / Radiology
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10.1186/s13014-019-1280-6
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Abstract

Purpose/objective(s): Radiation treatment to the regional nodes results in an improvement in survival in breast cancer according to a meta-analysis of randomized trials. However, different volumes were targeted in these studies: breast or chestwall only (WBI/CWI), inclusion of the medial supraclavicular region and axillary apex (MS + WBI/CWI) or additional inclusion of the internal mammary chain (IM + MS + WBI/CWI). The benefit of treating the medial supraclavicular region and axillary apex compared to tangential breast or chestwall irradiation only remains unclear. Materials/methods: A literature search was conducted identifying trials for adjuvant radiation volumes in nodal irradiation after breast surgery and axillary treatment. Events and effect sizes were extracted from the publications for the endpoints of overall survival (OS), breast cancer-specific survival (BCSS), disease-free survival (DFS), distant metastasis-free survival (DMFS) and loco-regional control (LRC). A network meta-analysis was performed using MetaXL V5.3 with the inverse variance heterogeneity model. Results: We found two randomized studies (n = 5836) comparing comprehensive nodal irradiation to sole breast treatment as well as one randomized (n = 1407) and one prospective cohort study (n = 3377) analysing the additional treatment of the internal mammary chain against sole local and supraclavicular and axillary apex radiation. Compared to WBI/CWI alone the treatment of IM + MS + WBI/CWI (HR = 0.88; CI:0.78-0.99; p = 0.036) results in improved OS unlike MS + WBI/CWI (HR = 0.99; CI:0.86-1.14; p = 0,89). These results are confirmed in BCSS: IM + MS + WBI/CWI (HR = 0.82; CI: 0.72-0.92; p = 0.002) and MS + WBI/CWI (HR = 0.96; CI:0.79-1.18; p = 0.69). PFS is significantly improved with the treatment of MS + WBI/CWI (OR = 0.83; CI:0.71-0.97; p = 0.019). Both nodal treatment volumes improve LRC (MS + WBI/CWI OR = 0.74; CI:0.62-0.87; p = 0.004 and IM + MS + WBI/CWI OR = 0.60; CI:0.43-0.86; p < 0,001). Yet only the internal mammary nodes provide a benefit in DMFS (MS + WBI/CWI HR = 0.97; CI:0.81-1.16; p = 0.74 and IM + MS + WBI/CWI HR = 0.84; CI:0.75-0.94; p = 0.002). Conclusion: Expanding the radiation field to the axillary apex and supraclavicular nodes after axillary node dissection reduced loco-regional recurrences without improvement in overall and cancer-specific survival. A prolongation in survival due to regional nodal irradiation is achieved when the internal mammary chain is included. This derives from a reduction in distant metastasis. Keywords: Breast cancer, Radiation therapy, Regional lymph nodes, Radiation volumes * Correspondence: boelke@med.uni-duesseldorf.de Department of Radiation Oncology, Heinrich Heine University, Dusseldorf, Germany Full list of author information is available at the end of the article © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Haussmann et al. Radiation Oncology (2019) 14:102 Page 2 of 14 Introduction wide tangents, intensity-modulated RT techniques or Radiation therapy is a key component in the multidiscip- protons [15]. linary approach of breast cancer treatment after breast Due to the aforementioned difficulties, nodal irradi- conserving surgery and achieves equal oncologic results ation is often limited to the supraclavicular nodes and to mastectomy alone [1]. Over the last decades, surgical the axillary region at risk. This analysis was conducted and radiation treatment to the lymphatic drainage of to evaluate the additional benefit of supraclavicular and breast tumors have also been implemented as standard axillary apex radiation compared to whole breast or of care. Traditionally, axillary lymph node dissection was chest wall irradiation alone, as well as comprehensive performed to determine the accurate tumor stage and nodal irradiation in clinical practice. eliminate nodal metastasis. Recently, the paradigm has shifted to do less extensive surgery, such as sentinel Methods node biopsy alone. Regarding supraclavicular radiation A literature research according to PRISMA guidelines therapy, anterior/posterior opposing fields were matched was performed using the MEDLINE as well as EMBASE to the tangential fields of the breast to treat the axillary and EBM review platforms [16]. Moreover, we screened apex as well as the supraclavicular nodes to cover the major meetings for published abstracts. micro-metastatic spread into these regions. A second Search criteria were randomized or prospective obser- lymphatic drainage system is located parasternal along vational trials reporting on regional nodal irradiation the internal mammary vessels coalescing with the axil- compared to no regional radiotherapy with a median lary chain at the intersection with the subclavian vein. follow-up of more than five years and trial publication Extended radical mastectomies including a dissection of after the year 2009. The study population had to consist the internal mammary nodes (IMN) have been aban- of patients suffering from non-metastatic breast cancer doned due to high complication rates and dubious onco- treated with regional irradiation in least one trial arm. logical benefits [2, 3]. Radiotherapy (RT) was also used The exclusion criteria and time range were chosen to to cover this lymphatic drainage site and resulted in ensure a relatively homogeneous radiation technique, as equivocal results with reports of a potential benefits [4, well as systemic therapies mimicking current standard of 5] as well as no advantage [2, 6] or even harmful effects care. We excluded patients undergoing surgical dissec- [7]. However, a meta-analysis by the EBCTCG, based on tion of the internal mammary lymph nodes, preoperative individual patient data, identified the role of postmastec- radiation therapy and studies that used non-standard tomy radiation (PMRT) including a comprehensive systemic therapies. nodal irradiation, and reported significant benefits for All available data were extracted as hazard ratios or local control, disease-free and overall survival. In fact, event rates. Assessment of toxicities in the included tri- the vast majority of the 22 studies included radiation of als was attempted. The definition of the analyzed end- the internal mammary chain [8]. points was adopted from the published trials. If hazard Contemporarily breast cancer surgery is often per- ratios were not reported an attempt was made to calcu- formed using an organ preservation approach followed late the hazard ratios and their corresponding 95% confi- by adjuvant radiation therapy [1]. It has been a matter of dence intervals according to the method published by debate whether nodal irradiation provides any benefit Parmar et al. [17]. If both effect measures were available, after axillary node dissection (AND) in the era of effect- we elected to compare hazard ratios as they are regarded ive systemic therapies. Additionally, the regions of high- as most appropriate in analyzing time-to-event data. est risk in the axilla might already be covered by Visual analysis of publication bias by creating funnel standard tangential field irradiation, as whole breast plots was available but is not presented here due to the radiation therapy applies substantial doses to the lower low number of included trials. Endpoints of the axilla and might provide equal control to dissection in comparison included overall survival (OS), breast clinically node negative but sentinel node positive cancer-specific survival (BCSS), disease-free survival patients [9, 10]. (DFS), distant metastasis-free survival (DMFS) and Moreover, inclusion of the internal mammary nodes loco-regional control (LRC). proves to be a challenging task for radiation oncologists, Data were analyzed using the Microsoft Excel plug-in because it subsequently leads to higher lung and heart MetaXl V5.3 and the included network meta-analysis doses, which increase the risks for late adverse events function. Due to possible heterogeneity of the study pop- like ischemic heart events, secondary lung cancers or ulations the inverse variances of heterogeneity model pulmonary fibrosis [11–14]. Furthermore, no consensus (ivhet) by Doi et al. was chosen as the comparison was reached on the optimal treatment application. method [18]. This method favors larger trials, uses a Current techniques range from anterior electron fields more conservative estimation of the confidence limits to mixed electron and photon beam techniques, partial and produces lesser observed variances compared to the Haussmann et al. Radiation Oncology (2019) 14:102 Page 3 of 14 random effects model. Zero event correction was ap- Results plied, where appropriated [19]. An intended analysis of The literature search depicted in Fig. 1 identified four heterogeneity was not feasible because not enough stud- randomized or prospective trials matching the search ies were available to form a closed loop. Subgroup ana- criteria [20–23]. The EORTC trial was recently pre- lysis of matching endpoints and cohorts was intended. sented in an updated version, hence we used the avail- However, subgroups were only analyzed when two or able recent results in this analysis [20]. For non-updated more trials reported results in the specific subgroup. endpoints the fully-published results were used [20]. Furthermore we performed a subgroup analysis Additionally, the EBCTCG meta-analysis was also con- according to the radiation volume of the EBCTCG indi- sidered to provide valuable information on the volumes vidual patient meta-analysis on the effect of postmastec- used in PMRT compared to no adjuvant radiation tomy radiation [8]. We identified two studies that did therapy. not include the internal mammary region in the regional An overview of the included trials is presented in irradiation volumes. We extracted the numbers under Table 1. Overall 10,620 patients with nodal positive or risk and events from the different nodal disease sub- nodal negative with risk factors for lymphatic spread groups from these two studies and compared them to were randomized in the studies. The majority of in- the remaining trials in that specific subgroup. To avoid cluded patients had pT1 or pT2 tumors with pN0 or bias of analysis only subgroups with more than five pN1 disease. The surgical approach consisted of mastec- patients per comparison were analyzed. Afterwards, we tomy (MTX) or breast-conservation surgery (BCS) and performed two comparisons (Comparison 1: chest wall planned axillary lymph node dissection. The sentinel irradiation + comprehensive nodal irradiation vs. no node approach only was used in fewer than 3% of the PMRT; Comparison 2: chest wall irradiation without patients. Chemotherapy was regularly administered in IMN irradiation vs. no PMRT) using the same methods the majority of trial participants. Median follow-up was as described above. In the EBCTCG Analysis we in- above 8 years in all included trials. Table 2 shows an cluded any first locoregional and any first recurrence in overview in which trials overall survival was analyzed be- addition to overall survival as endpoints. tween different subgroups. Fig. 1 The PRISMA flowchart of the included trials Haussmann et al. Radiation Oncology (2019) 14:102 Page 4 of 14 Table 1 Overview of included trials. n.r. = not reported, FU = follow up, HR + = hormone receptor positive, N+/− = lymph node positive/negative, RN = regional nodes, IMN = internal mammary nodes, TV = target volume; ICS = intercostal space; BCS = breast conserving surgery; MTx = Mastectomy; AND = axillary node dissection Trial Synonym Years trial N total med. FU (y) Post meno- HR+ CTx N+ N- T1 T2 Lateral Surgery Dose Dose RN RT IMN TV Main trial Age pausal Location Breast Boost group Hennequin French 1991–1997 1407 n.r. 8.6 n.r. 52% 61% 75% 25% 33% 52% 36% MTx 100 AND 50Gy 18 × 2.5 Gy none ICS 1–5N0 2013 100% =45Gy med/ central or N+ Thorsen DBCG- 2003–2007 3377 56 8.9 60% 80% 53% 100% 0% 41% 52% 60% BCS 35% MTx 65 24x2Gy 24x2Gy 13% ICS 1–4N+ 2016 IMN AND 100% =48Gy =48Gy Poortmans EORTC 1996–2004 4004 54 15.7 59% 78% 55% 56% 45% 60% 36% n.r. BCS 76,1% MTx 25x2Gy 25x2Gy 85% ICS 1–3 N0 2015/2018 22922 23,9% =50Gy =50Gy (−4) med/ AND 100% central or N+ Whelan Ma.20 2000–2007 1832 54 9.5 nr 75% 91% 90% 10% 52% 46% 62% BCS 100 AND 96% 25x2Gy 25 × 1.8–2Gy 33% ICS 1–3 N0 (high 2015 SNB 4% =50Gy =45-50Gy risk) or N+ Haussmann et al. Radiation Oncology (2019) 14:102 Page 5 of 14 Table 2 Overview of subgroups analysed for overall survival by trial. a) Subgroup analysis based on (Poortmans et al. [20]) Subgroups Thorsen Hennequin Poortmans Whelan Primary Tumor Size -T1 + – + – -T2 + – + – -T3 + – + – Nodal Stage -N+ ++ + + -N0 – ++ + -N1 + – ++ -N2+ + – ++ Tumor Location -Medial / central ++ – + -Lateral ++ – + Hormonal Status -Premenopausal + – + – -Postmenopausal + – + – Type of Surgery -Mastectomy + – + – -Breast conservation + – + – Receipt of Chemotherapy – ++ – In Fig. 2 we present the resulting network for compari- breast−/chest wall-irradiation + supraclavicular / axillary son. Two trials (EORTC 22922 and Ma.20) compared apex (MS + WBI/CWI-RT). comprehensive regional nodal radiation (IMN + MS + According to Fig. 3, comprehensive RNI improved the WBI/CWI-RT) to whole breast−/chest wall-irradiation rate of locoregional recurrence (OR = 0.80 CI95%: 0.68– only (WBI/CWI-RT). The other two trials compared 1.11; p = 0.182). This effect was mainly based on the in- nodal radiotherapy with (IMN + MS + WBI/CWI-RT) clusion of the MS (OR = 0.74 CI95%: 0.62–1.05; p = and without (MS + WBI/CWI-RT) the parasternal lymph 0.092) and not the IMN (OR = 0.99 CI95%: 0.70–1.39; nodes (French and DBCG-IMN). Subsequently we were p = 0.946) target volume. However, the endpoint of able to perform an indirect analysis of the comparison disease-free survival (Fig. 4) was not significantly im- breast−/chest wall irradiation only (WBI/CWI-RT) vs. proved by any components of the regional radiation Fig. 2 Overview of analyzed network according to target volume of regional irradiation Haussmann et al. Radiation Oncology (2019) 14:102 Page 6 of 14 Fig. 3 Forest plot of direct and indirect comparison of locoregional recurrence according to extend of regional radiation (+/− IMN: OR = 0.90 CI95%: 0.80–1.01; p = 0.081; +/− 0.71–1.03; p = 0.094), whereas MS-radiation had no im- MS: OR = 0.85 CI95%: 0.70–1.03; p = 0.101; +/− RNI: pact (OR = 0.97 CI95%: 0.82–1.16; p = 0.745) (Fig. 5). As OR = 0.85 CI95%: 0.62–1.17; p = 0.331). This numeric depicted in Fig. 6 this resulted in a significant improve- improvement resulted from a significant reduction of ment in breast-cancer specific survival in IMN-RT (HR = distant metastasis from RNI (OR = 0.80 CI95%: 0.70– 0.85 CI95%: 0.73–0.98; p = 0.031) and RNI (HR = 0.81 0.91; p = 0.001). IMN radiation showed a trend for an CI95%: 0.71–0.92; p = 0.001). MS-RT had no significant improvement in distant recurrence (OR = 0.85 CI95%: effect (HR = 0.94 CI95%: 0.69–1.28; p = 0.700). Fig. 4 Forest plot of direct and indirect comparison of disease-free survival according to extend of regional radiation Haussmann et al. Radiation Oncology (2019) 14:102 Page 7 of 14 Fig. 5 Forest plot of direct and indirect comparison of distant metastasis according to extend of regional radiation Fig. 6 Forest plot of direct and indirect comparison of cancer-specific survival according to extend of regional radiation Haussmann et al. Radiation Oncology (2019) 14:102 Page 8 of 14 Subsequently, overall survival was equally improved by 20 years results are depicted inn Figs. 9 and 10 compar- IMN-RT (HR = 0.86 CI95%: 0.76–0.99; p = 0.031). After ing comprehensive PMRT and PMRT without IMN to the inclusion of the 2018 update of the EORTC trial RNI no PMRT at all. PMRT with the inclusion of the IMN did no longer significantly improve overall mortality significantly improved the rate of any first recurrence (HR = 0.94 CI95%: 0.85–1.04; p = 0.253). Again MS-RT after 10 years (OR = 0.68 CI95%: 0.62–0.74; p < 0.001) had no effect on survival (HR = 1.03 CI95%: 0.89–1.18; but did not improve the rate of any death after 20 years p = 0.708) (Fig. 7). (OR = 0.84 CI95%: 0.65–1.07; p = 0.160). PMRT without Subgroup analysis on overall mortality was feasible in the treatment of the IMN in the two included studies a subset of trials (Table 2). Figure 8 shows the effect of showed a significant improvement in the recurrence rate comprehensive regional therapy compared to no re- after ten years (OR = 0.60 CI95%: 0.40–0.90; p = 0.014). gional RT as well as the indirect effect of MS + WBI/ However, this did not translate into better survival (OR = CWI-RT compared to WBI/CW-RT. We identified a sig- 1.13 CI95%: 0.58–2.20; p = 0.722). As the analysis of nificant improvement in overall survival by IMN + MS + locoregional recurrence showed equal results to any first WBI/CWI-RT in patients with T2 stage cancers. A stat- recurrence it was not reported in detail. istical trend was seen in node negative, postmenopausal Figure 11 shows the analysis of cardiac events. We and patients treated with BCS. The relative effectiveness found no significant differences between the radiation analysis revealed no subgroup that significantly profited volumes. However the point estimates imply that the in terms of overall mortality from MS + WBI/CWI-RT non-significant increase in cardiac events derive mainly alone. Importantly, in all subgroups the estimated effect from the parasternal radiation. sizes were superior in patients treated with comprehen- sive nodal radiation therapy. Discussion Furthermore we analyzed the effect of the sub-volumes Regional nodal irradiation in presumed intermediate risk in PMRT radiation compared to no PMRT in the indi- breast cancer patients in stages I-III results in a small vidual patient meta-analysis by the EBCTCG published improvement in breast cancer specific and overall sur- in 2014 [8]. We identified two trials that specifically did vival due to a reduction in distant metastasis [24]. This not include the internal mammary nodes in the post- network meta-analysis supports the role of internal mastectomy radiation volumes and compared them to mammary radiation as the critical sub-volume to achieve the included trials treating matching patient populations. these benefits. The supraclavicular irradiation appears to Any first recurrence after 10 years and any death after provide a benefit in locoregional control but does not, in Fig. 7 Forest plot of direct and indirect comparison of overall survival according to extend of regional radiation Haussmann et al. Radiation Oncology (2019) 14:102 Page 9 of 14 Fig. 8 Forest plot of direct and indirect comparison of overall survival between different subgroups according to extend of regional irradiation. Direct comparison is depicted as diamonds, indirect comparison as squares contrast to the internal mammary nodal radiation, re- rates of pulmonary fibrosis and pneumonitis, as well as duce the distant recurrence rate and subsequently mor- lymphedema [20, 22]. Additional treatment of the IMN tality. This interpretation is supported by the additional did not resulted in a significant increase of Grade 3–4ad- investigation of the PMRT meta-analysis, showing a verse events [21]. A more thorough analysis of side effects comparable reduction in any first recurrence with supra- separated by sub-volumes would be desirable but is cur- clavicular radiation. However, a trend towards improved rently not feasible, due to a lack of reported data. mortality is only observed when the IMN are included The applied radiation techniques in the included trials in the radiation plan. ranged from 2D to early computer tomography-based Despite the advantage in reducing metastases, the approaches. However, modern techniques to reduce treatment of the internal mammary nodes is technically doses at organs at risk, like deep inspiration breath hold, challenging and is accompanied by a significantly higher field in field treatments or volumetric modulated arc dose to the heart and lungs. Hence, the possible gain in therapy were not used [25]. The use of these techniques survival has to be weighed against its harms, especially has been shown to further improve the therapeutic gain in patients with a history of smoking or other cardiovascu- in RT. [26] Particularly the decreased benefit of regional lar risk factors. These patients might not benefit from re- radiation in the EORTC 22922 trial due to currently un- gional radiation at all, due to the higher absolute risks for explained deaths raises some questions [27]. Efforts are secondary lung cancer or cardiac events [12, 13]. Our ana- currently being made to explain these unexpected lysis demonstrates that, although not statistically signifi- events. Speculatively, late vascular side effects leading to cant, especially the increase in cardiac risks derive mainly cardiac disease (IMN fields) or cerebrovascular disease from the parasternal radiation. RNI was reported to cause (supraclavicular fields) may have contributed to these a small increase in pulmonary toxicity with higher event observations [27–29]. Haussmann et al. Radiation Oncology (2019) 14:102 Page 10 of 14 Fig. 9 Forest plot of direct comparison of overall survival according to extend of regional radiation in the 2014 EBCTCG Meta-Analysis. Here, the comparisons are PMRT (IMN + MS + CWI) vs. no radiation and PMRT without IMN (MS + CWI) vs. no radiation It has been hypothesized that the benefit of any treated with chemotherapy [20, 23]. In the French local treatment is dependent on the benefit resulting trial around 60% were treated with mainly from systemic therapies [30]. The administered anthracycline-based chemotherapy [21]. The effective- chemo- and hormone therapy in the included trials ness of regional irradiation in the Ma.20 trial, where were heterogeneous. In the Ma.20 trial 90% of pa- the highest rate and closest to the current standard tients received adjuvant chemotherapy, mostly chemotherapy was offered, does not appear to differ anthracycline-based, with about 25% receiving also substantially from the other trials. This is why we taxanes [22]. In contrast, only around 55% of patients thinkthatevenmodernsystemic therapiesdo not in the EORTC trial and in the Danish trial were mitigate the effectiveness of regional radiation. Fig. 10 Forest plot of direct comparison of any first recurrence according to extend of regional radiation in the 2014 EBCTCG Meta-Analysis. Here, the comparisons are PMRT (IMN + MS + CWI) vs. no radiation and PMRT without IMN (MS + CWI) vs. no radiation Haussmann et al. Radiation Oncology (2019) 14:102 Page 11 of 14 Fig. 11 Forest plot of direct and indirect comparison of cardiac events according to extend of regional radiation. Cardiac events varied between studies and included acute myocardial infarction, ischemic heart disease, congestive heart failure, supraventricular arrhythmias and pericardial effusion Since the publication of the ACOSOG Z0011 trial, the Furthermore, since the publication of the ACOSOG routine use of axillary lymph node dissection (ALND) Z0011 trial, it has been well established that a small for the clinically node negative axilla has been declining tumor burden in the axilla can safely remain [9]. However, the role of radiation therapy in this con- un-dissected and treated with systemic therapy [9]. text is not well established [31]. The AMAROS and Radiation therapy to the breast or chest wall might OTOASOR trials showed that radiation could replace additionally contribute to this favorable outcome. It is axillary surgery and achieve equivalent effectiveness possible that the two regions may be differently af- [10, 32]. With the routine omission of ALND, it is fected by these “incidental” treatments. Hormone- or certainly possible that the RT treatment of the axilla chemotherapy might affect a postoperative region dif- and the supraclavicular region could regain more im- ferently than a solely irradiated one. Moreover, the in- portance in the future. cidental radiation doses to the axillary levels I and II What are possible explanations for the proposed dif- were reported to be larger than respectively to the ferential oncologic effects of RT to the two components IMNs [36–38]. of the lymphatic chain? Obviously, the therapeutic ap- The difference in locoregional control rates between proaches to both regions in the included studies were MS- and IMN-RT fields could also be explained by the very different, since the axillary chain was dissected way recurrences are diagnosed in the clinical follow-up. followed by irradiation and the internal mammary nodal As recurrences in both regions are usually subclinical chain was solely treated with radiation. The effect of MS and routine diagnostic imaging is often not included in radiation was investigated in large retrospective series the routine follow-up, the diagnosis of a regional recur- demonstrating an impairment in DMFS and OS when rence is often delayed and accompanied by distant meta- supraclavicular recurrences occur during follow-up. static disease. Furthermore, regional relapses in the However, on multivariate analysis RNI to the MS was internal mammary nodes are very difficult to distinguish not associated with an improvement in BCSS or OS, radiologically from mediastinal lymph nodes, leading to which reflects the results of the present analysis [33]. the diagnosis of metastatic disease. This influences the This deviation might be explained by alterations in the relative effects on locoregional recurrence and distant trial populations. The highest risk of supraclavicular in- metastasis, but does not explain the impact on overall volvement has been reported in patients with multiple mortality. axillary nodes, large nodal size, lymphovascular invasion, The effectiveness of the IMN radiation is currently higher grading and extracapsular extension [33–35]. mainly explained by two hypotheses. IMN irradiation re- This high-risk population might be underrepresented in duces the spread of micrometastases along this drainage the present analysis, as less than 10% of the patients had site and subsequently lowers the risk for distant metasta- pN2+ axillary staging. ses. Furthermore, also an abscopal response, with a Haussmann et al. Radiation Oncology (2019) 14:102 Page 12 of 14 tumoricidal effect on non-target tumor cells, has also an adequate ALND to the breast tissue and the internal been postulated [24, 39]. One might expand this ap- mammary lymph nodes. To our knowledge, there have proach concluding that only IMN and not MS treatment been no attempts to restrict the treatment to these vol- can generate this effect, which explains our results. Cur- umes. An omission of MS-RT might decrease early and rently the systemic effects of RNI and its clinical impli- late toxicities, including esophagitis and radiation cations are insufficiently understood. dermatitis, as well as hypothyroidism, pulmonary events This network meta-analysis has several strengths and and cardiac side effects [45]. Subgroups where this might limitations we need to address. It includes high-quality be considered appropriate are patients with favorable trials with a considerable number of participants. Fur- biology as well as low axillary nodal burden. thermore, the observed effects are relatively consistent This analysis should be viewed as hypothesis-generat- among the subgroups, supporting the general conclu- ing for future investigations. Additionally, it could also sions of the analysis. One limitation is that we did not provide a helpful guide for prioritization in the clinical identify any trial addressing the effect of supraclavicular practice, for example when dose constraints cannot be radiotherapy alone after surgical dissection. Conse- met or attempts to de-escalate radiation volumes are quently, the estimation of this comparison is only indir- intended. ect and therefore hypothesis generating. Moreover, the inclusion of a prospective non-randomized trial in- Conclusion creased the number of patients, but may add potential Expanding the radiation field to the axillary apex and biases to the analysis [23]. However, restriction of the in- supraclavicular nodes after axillary node dissection re- vestigated endpoints to only randomized trials, showed duced loco-regional recurrences without improvement no difference in outcome, providing support for the ro- in overall and cancer-specific survival. A prolongation in bustness of this analysis. The median follow-up between survival due to regional nodal irradiation is achieved 8 and 15 years is relatively long but might still be inad- when the internal mammary chain is included. This de- equate to capture long-term side effects, like cardiac rives from a reduction in distant metastasis. events or secondary carcinomas impacting mortality. Abbreviations Unfortunately, the analysis of adverse events was re- ALND: Axillary lymph node dissection; AND: Axillary node dissection; stricted to the cardiac event rates as the reporting was BCSS: Breast cancer-specific survival; CI: Confident interval; CWI: Chest wall irradiation; DFS: Disease free survival; DMFS: Distant metastasis-free survival; inconsistent in the included trials. EORTC: European Organisation for Research and Treatment of Cancer; The comparison of multiple randomized trials in a FU: Follow up; HR: Hazard ratio; HR-: Hormone receptor negative; network meta-analysis offers an intriguing option to HR + : Hormone receptor positive; IMN: Internal mammaria node; Ivhet: Inverse variance of heterogeneity model; LCR: Loco-regional control; investigate previously not directly compared treat- MTX: Mastectomy; N-: Lymph node negative; n.r: Not reported; N + : Lymph ment options. Like any meta-analysis the homogen- node positive; OS: Overall survival; PFS: Progression free survival; eity of the included population, trial arms and PMRT: Postmastectomy radiation; RT: Radiotherapy; WBI: Whole breast irradiation investigated endpoints are central to a robust, mean- ingful analysis. Beyond the “classical” comparison of Acknowledgements the pooled effect sizes, a network meta-analysis also This work was presented as an oral presentation in the plenary session at the allows a ranking of the groups by using the point Joint Scientific Meeting of the Canadian Association of Radiation Oncology in Montreal 2018. estimates. In view of the small benefit of nodal irradiation with Funding an equally small but substantial risk of adverse events in There was no funding for this investigation. an unselected patient population, it is of enormous im- Availability of data and materials portance to predict the benefit for different subgroups. All data and materials can be found in “Patient, materials and methods” section Numerous attempts have succeeded in predicting which or can be accessed via JH and CM. groups are at higher risk for local or distant relapse. Authors’ contributions However, to date there is no predictive test to estimate JH, CM and WB, participated in collecting data, and drafted the manuscript. the benefit of radiotherapy. Subdivision by classical JH and KK performed the statistical analysis and participated in its design. EB, subtypes (hormone receptor, Her2, triple negative) BT, FJD, SC and CM helped to draft the manuscript. All authors read and approved the final manuscript. produced varying results [40, 41]. Currently, tumor cells in the blood or bone marrow, as well as cellular Ethics approval and consent to participate markers scoring for intrinsic radiation sensitivity, are There was no ethics approval necessary because in this meta-analysis we were pulling numbers from the published manuscripts and pooling results. being studied to improve our understanding of the benefit of radiation [42–44]. Consent for publication Possible consequences and further topics of investiga- This is a network-meta-analysis which does not contain any individual tion might be a de-escalation of radiation volumes after persons data, therefore not applicable. Haussmann et al. Radiation Oncology (2019) 14:102 Page 13 of 14 Competing interests 16. Moher D, Liberati A, Tetzlaff J, Altman DG, Group P. Preferred reporting The authors declare that they have no competing interests. items for systematic reviews and meta-analyses: the PRISMA statement. BMJ. 2009;339:b2535. 17. Parmar MK, Torri V, Stewart L. Extracting summary statistics to perform Publisher’sNote meta-analyses of the published literature for survival endpoints. Stat Med. Springer Nature remains neutral with regard to jurisdictional claims in published 1998;17:2815–34. maps and institutional affiliations. 18. Doi SA, Barendregt JJ, Khan S, Thalib L, Williams GM. 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Published: Jun 11, 2019

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