Regional Lymph Node Radiation Is Not the Main Risk Factor for Breast Cancer Related Lymphedema: Stop Chasing Radiation Doses, Fractionation or Techniques-Focus on Axillary Surgery De-escalation or Prevention.

For patients with breast cancer with positive-lymph-nodes (LNs), the goal of axillary management is to balance optimum tumor control through axillary surgery/regional lymph-nodes radiation (RLNR) with minimizing treatment's side effects; mostly breast cancer related lymphedema (BCRL). Hence, the subject of axillary management de-escalation has been the focus of many trials to achieve this balance. In the articles that accompany this editorial, radiation oncologists seek different RLNR approaches and their relation with BCRL. Healy et al1Healy E. Beyer S. Jhawar S. White J..R. Bazan J.G. The axillary lateral vessel thoracic junction is not an organ at risk for breast cancer-related lymphedema.Int J Radiat Oncol Biol Phys. 2023; 117: 452-460Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar shed the light on a developing area of research defining axillary-lateral thoracic vessel juncture (ALTJ) as an organ at risk for BCRL for patients undergoing RLNR. Spiegel et al2Spiegel D.Y. Willcox J. Friedman R. Kinney J. Singhal D. A prospective study of radiation therapy after immediate lymphatic reconstruction: Analysis of the dosimetric implications.Int J Radiat Oncol Biol Phys. 2023; 117: 446-451Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar evaluate the radiation dose distribution to the immediate lymphatic reconstruction (ILR) anastomosis. Yet, there remains gaps between RLNR and BCRL in the literature which we aim to delve into. Today, after decades of research there is still no universal definition for BCRL as an endpoint.3McLaughlin SA Brunelle CL Taghian A. Breast cancer-related lymphedema: Risk factors, screening, management, and the impact of locoregional treatment.J Clin Oncol. 2020; 38: 2341-2350Crossref PubMed Scopus (56) Google Scholar Majority of studies use tape measurements for arm circumferences or volume, others use clinical judgment, patients’ symptoms and surveys. Those are subjective to wide inter/intrarater variability and lack of reproducibility. Few groups use objective arm volume considering preoperative-baseline- measurement to avoid misdiagnosis of BCRL in 48% to 57% of the times.4Sun F Skolny MN Swaroop MN et al.The need for preoperative baseline arm measurement to accurately quantify breast cancer-related lymphedema.Breast Cancer Res Treat. 2016; 157: 229-240Crossref PubMed Scopus (57) Google Scholar Consequently, with such wide variation in BCRL definition between studies and lack of interchangeability between measurements-methods, caution should be taken when interpreting any results and comparing different studies with the goal of generalization. In the past decade, the NCIC clinical trials group MA.20 trial (MA.20)5Whelan TJ Olivotto IA Parulekar WR et al.Regional nodal irradiation in early-stage breast cancer.New Engl J Med. 2015; 373: 307-316Crossref PubMed Scopus (704) Google Scholar and European organisation for research and treatment of cancer trial (EORTC)6Poortmans PM Collette S Kirkove C et al.Internal mammary and medial supraclavicular irradiation in breast cancer.New Engl J Med. 2015; 373: 317-327Crossref PubMed Scopus (782) Google Scholar trials showed that RLNR improves the tumor-control for patients with positive-LNs. Despite such benefit, those trials showed RLNR increased BCRL-rate; where MA.20 reported BCRL-rate of 4.5% with no-RLNR and 8.4% with RLNR; the EORTC reported 10.5% without and 12% with RLNR. A metanalysis showed that pooled rates of adding different fields of RLNR yields a BCRL risk between 10% to 15% (according to RLNR fields) compared with 8% with no-RLNR.7Shaitelman SF Chiang YJ Griffin KD et al.Radiation therapy targets and the risk of breast cancer-related lymphedema: A systematic review and network meta-analysis.Breast Cancer Res Treat. 2017; 162: 201-215Crossref PubMed Scopus (81) Google Scholar The difference in rates between all those studies is attributed to lack of a universal BCRL definition and methodology; where EORTC was unclear on BCRL assessment, MA20 used clinical assessment and the metanalysis had pooled rates of all different studies. Collectively looking at those numbers and despite the wide gap in BCRL definition, it is safe to say that RLNR adds 3% to 5% absolute-risk-increase in lymphedema. Another pitfall in MA.20 and EORTC is the lack of stratification by axillary surgery, as only 3.7% and 7.1% of MA.20 and EORTC cohorts included sentinel nodal biopsy (SLNB), respectively. The metanalysis by Shaitelman et al7Shaitelman SF Chiang YJ Griffin KD et al.Radiation therapy targets and the risk of breast cancer-related lymphedema: A systematic review and network meta-analysis.Breast Cancer Res Treat. 2017; 162: 201-215Crossref PubMed Scopus (81) Google Scholar delved into such stratification showing that RLNR in SLNB only patients did not significantly increase BCRL-risk. On the contrary, for patients with ALND, RLNR significantly increased BCRL-risk. Those findings suggest and highlight a complex relation between RLNR effect and type of axillary surgery. This was elaborated by Naoum et al8Naoum GE Roberts S Brunelle CL et al.Quantifying the impact of axillary surgery and nodal irradiation on breast cancer-related lymphedema and local tumor control: Long-term results from a prospective screening trial.J Clin Oncol. 2020; 38: 3430-3438Crossref PubMed Scopus (57) Google Scholar in prospectively screened 1815 patients with preoperative baseline and objective whole-arm-measurements using perometer in follow-up for at least 5 years. Stratification by axillary surgery and RLNR showed 5-years cumulative BCRL incidence of 8% for SLNB only, 11% SLNB + RLNR, 25% ALND alone, and 30% ALND + RLNR. This reflects that RLNR effect varies by surgery type and yet ranges between 3% to 5% absolute-risk-increase within the same axillary surgery group. The 10-years results from the AMAROS study9Bartels SAL Donker M Poncet C et al.Radiotherapy or surgery of the axilla after a positive sentinel node in breast cancer: 10-year results of the randomized controlled EORTC 10981-22023 AMAROS trial.J Clin Oncol. 2023; 41: 2159-2165Crossref PubMed Scopus (32) Google Scholar confirmed those findings where BCRL rates were identical 11.9% and 24.5% in SLNB + RLNR and ALND alone groups, respectively. Those findings confirm that the main driving risk-factor for BCRL is the extent of axillary surgery (ALND vs SLNB) not the RLNR. Moreover, safe oncological substitution of ALND by SLNB + RLNR for patients with 1 to 2 positive-LNs, has been showed in AMAROS and OTOASOR10Sávolt Á Péley G Polgár C et al.Eight-year follow up result of the OTOASOR trial: The optimal treatment of the axilla surgery or radiotherapy after positive sentinel lymph node biopsy in early-stage breast cancer: A randomized, single centre, phase III, non-inferiority trial.Eur J Surg Oncol. 2017; 43: 672-679Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar trials. Minimal surgery with RLNR yielded same tumor-control with lower BCRL-rates in those trials. Therefore, future BCRL-reducing-strategy should focus mostly on ALND de-escalation or prophylactic sleeves11Paramanandam VS Dylke E Clark GM et al.Prophylactic use of compression sleeves reduces the incidence of arm swelling in women at high risk of breast cancer-related lymphedema: A randomized controlled trial.J Clin Oncol. 2022; 40: 2004-2012Crossref PubMed Scopus (20) Google Scholar or possibly preventive surgery (although no randomizes trials results are available yet), not on squeezing RLNR approaches that yields 3% to 5% BCRL absolute-risk-increase. In 3-dimensional (3D) conformal era of radiation therapy, an anterior field delivering radiation to the supraclavicular (SCV) LNs and level 3 axilla with a half-beam block to the breast/chest wall is commonly used. The lateral-border of this field can be stretched or trimmed (in relation to the humoral head) to include upper parts of level 1 and 2. In some clinical scenarios, supplemental field posteriorly (posterior-axillary-boost [PAB]) could be complementarily added to ensure adequate coverage to the undissected axillary LNs, although, it has been perceived as an extra radiation dose, potentially leading to more tissue damage. Warren et al12Warren AG Brorson H Borud LJ et al.Lymphedema: A comprehensive review.Ann Plast Surg. 2007; 59: 464-472Crossref PubMed Scopus (503) Google Scholar showed that addition of PAB to the SCV field did not significantly increase BCRL risk. Shaitelman et al7Shaitelman SF Chiang YJ Griffin KD et al.Radiation therapy targets and the risk of breast cancer-related lymphedema: A systematic review and network meta-analysis.Breast Cancer Res Treat. 2017; 162: 201-215Crossref PubMed Scopus (81) Google Scholar in the meta-analysis showed that the pool rates of PAB usages yielded lower rates of BCRL than SCV alone (SCV + PAB: 12.2% vs SCV alone: 15%). Chandra et al13Chandra RA Miller CL Skolny MN et al.Radiation therapy risk factors for development of lymphedema in patients treated with regional lymph node irradiation for breast cancer.Int J Radiat Oncol Biol Phys. 2015; 91: 760-764Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar showed that both PAB and the extent of the lateral border of SCV-field (including axillary level 1 and 2) did not increase BCRL risks. On the contrary, Gross et al14Gross JP Sachdev S Helenowski IB et al.Radiation therapy field design and lymphedema risk after regional nodal irradiation for breast cancer.Int J Radiat Oncol Biol Phys. 2018; 102: 71-78Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar showed that extending the lateral border of the SCV-field or adding a PAB significantly increased BCRL. Unlike Chandra et al controlling for breast and axillary surgery type in the multivariable model, Gross et al did not control for neither. Moreover, the EORTC trial did not allow the lateral extension of the SCV field to include level 1 and 2 and yielded 12% risk of BCRL in the RLNR arm. On the contrary, MA20 allowed such extension of SCV fields (if <10 LNs were removed or >3 positive-LNs) and the RLNR arm had 8% risk of BCRL. All those discordant results clearly show that RLNR techniques have very little effect on the risk of BCRL. If technique mattered, then why adding PAB in the metanalysis7Shaitelman SF Chiang YJ Griffin KD et al.Radiation therapy targets and the risk of breast cancer-related lymphedema: A systematic review and network meta-analysis.Breast Cancer Res Treat. 2017; 162: 201-215Crossref PubMed Scopus (81) Google Scholar pooled rates yielded lower BCRL rates? Moreover, why EORTC not allowing lateral extension of SCV field had higher BCRL-rates in the RLNR arm compared with the MA20, which allowed extension and radiation to the dissected axilla? It could be difference of BCRL-assessment and statistical modeling; regardless, these discordant results do not support changing radiation techniques to reduce the 3% to 5% BCRL-absolute-risk-increase from radiation. This brings us to the focus of the accompanying study by Healey et al aiming to validate if the radiation dose to the ALTJ is associated with increased BCRL risk. In 2019, Gross et al15Gross JP Lynch CM Flores AM et al.Determining the organ at risk for lymphedema after regional nodal irradiation in breast cancer.Int J Radiat Oncol Biol Phys. 2019; 105: 649-658Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar reported in a series of 256 patients with both lumpectomy or mastectomy and SLNB or ALND treated with RLNR, that radiation dose to the ALTJ area matters. The multivariable model by Gross et al15Gross JP Lynch CM Flores AM et al.Determining the organ at risk for lymphedema after regional nodal irradiation in breast cancer.Int J Radiat Oncol Biol Phys. 2019; 105: 649-658Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar controlling for number of LNs removed not for axillary surgery type nor radiation-technique used (3D vs intensity modulated radiotherapy (IMRT)), concluded that delivering ≥38.6 Gy to this area increases BCRL risk. Such approach is important especially as our field starts seeing an increasing trend of using IMRT; where dose painting and anatomic dose-constraints can be applied directly to the planning algorithms. Therefore, directly underdosing areas of the axilla is risky jeopardizing tumor control. However, Gross et al15Gross JP Lynch CM Flores AM et al.Determining the organ at risk for lymphedema after regional nodal irradiation in breast cancer.Int J Radiat Oncol Biol Phys. 2019; 105: 649-658Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar showed that ALTJ <38.6 Gy, did not increase locoregional-failure compared with ALTJ ≥38.6 Gy. The median number of positive-LNs in Gross et al. Table 1, was 2, reflecting low nodal-disease involvement, with a median removed-LNs of 11, reflecting appropriate surgical control. Probably that is the reason there was no correlation between ALTJ underdosing and local control. On the other hand, more data are pointing out that locoregional-failures happen outside the current atlases contours and calling for more expansion of the current RTOG-nodal-contours for more tumor control.16Beaton L Nica L Tyldesley S et al.PET/CT of breast cancer regional nodal recurrences: An evaluation of contouring atlases.Radiat Oncol. 2020; 15: 136Crossref PubMed Scopus (12) Google Scholar, 17Loganadane G Truong PT Taghian AG et al.Comparison of nodal target volume definition in breast cancer radiation therapy according to RTOG versus ESTRO atlases: A practical review from the TransAtlantic Radiation Oncology Network (TRONE).Int J Radiat Oncol Biol Phys. 2020; 107: 437-448Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar, 18Almahariq MF Maywood MJ Levitin RB et al.Mapping of metastatic level I axillary lymph nodes in patients with newly diagnosed breast cancer.Int J Radiat Oncol Biol Phys. 2020; 106: 811-820Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar, 19Gentile MS Usman AA Neuschler EI et al.Contouring guidelines for the axillary lymph nodes for the delivery of radiation therapy in breast cancer: Evaluation of the RTOG breast cancer atlas.Int J Radiat Oncol Biol Phys. 2015; 93: 257-265Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar Furthermore, with the AMAROS update,9Bartels SAL Donker M Poncet C et al.Radiotherapy or surgery of the axilla after a positive sentinel node in breast cancer: 10-year results of the randomized controlled EORTC 10981-22023 AMAROS trial.J Clin Oncol. 2023; 41: 2159-2165Crossref PubMed Scopus (32) Google Scholar we will likely see more ALND de-escalation for patients with 1 to 2 positive-LNs. Therefore, adequate/full coverage of the axilla should be pursued. According to AMAROS, not completing ALND can leave 33% chance of additional positive-LNs, hence good safe RT coverage is a must. With more shift toward surgery de-escalation, the ALTJ concept and avoiding dissected axilla shouldn't be considered. A recent study from Park et al20Park Y-I Chang JS Ko H et al.Development and validation of a normal tissue complication probability model for lymphedema after radiotherapy in breast cancer.Int J Radiat Oncol Biol Phys. 2023; 116: 1218-1225Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar aimed to validate ALTJ-concept in a cohort of 1345 patients from 2 hospitals. The study had significant limitations: including patients without RLNR (Park et al.20Park Y-I Chang JS Ko H et al.Development and validation of a normal tissue complication probability model for lymphedema after radiotherapy in breast cancer.Int J Radiat Oncol Biol Phys. 2023; 116: 1218-1225Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar Table 1) leading to heterogonous populations, loose BCRL-definitions, lack of controlling for institutional confounding in BCRL assessment and treatment planning -uncertainties, lack of data about tumor characteristics and local control and no stratification by axillary surgery type. Additionally, including multiple fractionations with equivalent dose in 2-Gy fractions (EQD2) conversion assumes homogenous response of normal tissues to different dose per fractions. Therefore, such ALTJ concept validation with many analytical, clinical, and radiobiological uncertainties is questionable. Healy et al1Healy E. Beyer S. Jhawar S. White J..R. Bazan J.G. The axillary lateral vessel thoracic junction is not an organ at risk for breast cancer-related lymphedema.Int J Radiat Oncol Biol Phys. 2023; 117: 452-460Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar aimed to overcome these shortcomings in larger cohort where all patients received RLNR and used a similar BCRL methodology as Gross et al. In (Healy et al1Healy E. Beyer S. Jhawar S. White J..R. Bazan J.G. The axillary lateral vessel thoracic junction is not an organ at risk for breast cancer-related lymphedema.Int J Radiat Oncol Biol Phys. 2023; 117: 452-460Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar Table 3), authors replicated Gross's multivariable model but controlling for technique, showing that ALTJ-V45 yields a hazard ratio of 0.99 (0.94-1.04; P = .54). This null association with a HR almost 1 remained after stratifying by axillary surgery (Supplementary Materials). Arguments could be made that this discordance was due to higher median LNs removed (18 Hayley et al vs 11 Gross et al). Here, this confirms that the main risk factor for BCRL is rather the extent of axillary surgery and not RLNR. Moreover, if higher ALTJ doses mattered, the mean ALTJ dose was higher here (49.9 Gy in Hayley et al vs 44.6 Gy in Gross et al), then we would expect significant association between ALTJ dose and BCRL not a plateau HR of 0.99. Stratifying by axillary surgery: SLNB and ALND (Healy et al.1Healy E. Beyer S. Jhawar S. White J..R. Bazan J.G. The axillary lateral vessel thoracic junction is not an organ at risk for breast cancer-related lymphedema.Int J Radiat Oncol Biol Phys. 2023; 117: 452-460Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar Supplementary Tables) showed the same result with no correlation between the ALTJ dose and BCRL, and ALND had significant higher BCRL odds compared with SLNB. All these results reiterate over and over the same obvious fact: “The key in reducing BCRL incidence is surgical de-escalation or any preventive techniques rather than radiation techniques.” That brings us to the focus of the second article by Spiegel et al2Spiegel D.Y. Willcox J. Friedman R. Kinney J. Singhal D. A prospective study of radiation therapy after immediate lymphatic reconstruction: Analysis of the dosimetric implications.Int J Radiat Oncol Biol Phys. 2023; 117: 446-451Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar accompanying this editorial, examining radiation dose distribution to the ILR anastomosis. During the past decade, ILR has been an attracting venue for many plastic surgeons as well as patients undergoing ALND. In nutshell, the whole concept of ILR is to microscopically reconnect the damaged yet viable lymphatic vessels after ALND to a nearby tributary vein.21Coriddi M Mehrara B Skoracki R et al.Immediate lymphatic reconstruction: Technical points and literature review.Plast Reconstr Surg Glob Open. 2021; 9: e3431Crossref PubMed Scopus (20) Google Scholar,22Chang EI Skoracki RJ Chang DW. Lymphovenous anastomosis bypass surgery.Semin Plast Surg. 2018; 32: 22-27Crossref PubMed Scopus (47) Google Scholar This anastomosis facilitates keeping the lymphatic circulation patent, preventing lymphatic fluid accumulation and eventually BCRL. Although this concept is appealing, it has not yet been tested in any randomized controlled trial. Moreover, in practical world, ILR can be challenged by its complexity needing a certain level of training and length of time in the operating room. Almost all the evidence and metanalyses published comparing ILR patients to non-ILR patients used historical controls.23Chun MJ Saeg F Meade A et al.Immediate lymphatic reconstruction for prevention of secondary lymphedema: A meta-analysis.J Plast Reconstr Aesthet Surg. 2022; 75: 1130-1141Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar Therefore, one can easily contend if ILR truly prevents BCRL or it slows the time to event which is destined to happen with/without ILR. The only ongoing trial is a phase II (NCT04241341) at Memorial Sloan Kettering randomizing 174 subjects to ALND and ALND + ILR. Until this question is answered in this trial and other trials, we caution the readers to provide their patients full reassurance that they are BCRL proof once the ILR is done. Spiegel et al2Spiegel D.Y. Willcox J. Friedman R. Kinney J. Singhal D. A prospective study of radiation therapy after immediate lymphatic reconstruction: Analysis of the dosimetric implications.Int J Radiat Oncol Biol Phys. 2023; 117: 446-451Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar provide a proof-of-concept analysis studying the location of ILR in relation to radiation fields. In 13 patients, authors have shown that the ILR site lies mainly in axillary level 1 in 12 patients and in axillary level 2 in 1 patient. Although this is anticipated as axillary level 1 is the main site of ALND, the authors highlight that the site of this anastomosis can still receive radiation which in theory can lead to fibrosis and anastomosis stenosis or obstruction. Authors did illustrate different doses of radiation to the anastomosis without any correlation to BCRL. The small number mainly hindered such correlation. They also state “though the intended radiation therapy target was the undissected axilla in the majority of patients, the ILR anastomosis within level 1 of the axilla was still included in the radiation field for 5 of these patients.” Herein, we circle back to all the arguments made above and reiterate that creating avoidance structures in RT planning such as ALTJ or ILR anastomosis and setting arbitrary dosage and coverage to those structures will unlikely results in any reduction of BCRL. Switching from 3D conformal techniques to IMRT, only to avoid parts of level 1 axilla that would have been encompassed in the breast/chest wall tangential field, may increase lung or heart dosage. Even if acceptable plans and low lung/heart dosage were achieved using IMRT, avoidance structure concepts like ALTJ and ILR anastomosis may jeopardize tumor control by underdosing certain areas with microscopic disease with uncertain gain. All these discordant results we reviewed above do not support changing RLNR techniques, field borders, dose per fraction or chasing organ at risk-concepts such as ALTJ. Therefore, radiation trials comparing different fractionations used in RLNR will not yield any significant difference in reducing the risk of BCRL. For radiation planning and research purposes, switching techniques and avoidance structure concepts (ALTJ and ILR anastomosis) may increase radiation exposure of other organs at risk as lung and heart or jeopardize tumor control by underdosing certain areas with microscopic disease. Instead of focusing on RLNR yielding 3% to 5% BCRL absolute risk increase, axillary surgery de-escalation or BCRL preventative measures remain the key strategy for preventing lymphedema.