Regional Nodal Irradiation Research Articles

Tumor Contact With Internal Mammary Perforator Vessels as Risk Factor for Gross Internal Mammary Lymph Node Involvement in Patients With Breast Cancer

ImportanceThe identification of internal mammary lymph node metastases and the assessment of associated risk factors are crucial for adjuvant regional lymph node irradiation in breast cancer patients. The current study aims to investigate if tumor contact with internal mammary perforator vessels is associated with gross internal mammary lymph node involvement. MethodsWe included 297 patients with primary breast cancer and gross internal mammary (IMN+) and/or axillary metastases (AXN+) as well as 230 patients without lymph node metastasis. Based on pre-treatment dynamic contrast-enhanced magnetic resonance imaging (DE-MRI), we assessed contact of the tumor to the internal mammary perforating vessels (IMPV). Results59 patients had ipsilateral IMN+ (iIMN+), 10 patients contralateral IMN+ (cIMN+) and 228 patients had ipsilateral axillary metastases without IMN. 230 patients had node negative breast cancer. In patients with ipsilateral IMN+, 100% of tumors had contact with ipsilateral IMPV with 94.9% (n=56) classified as major contact. In iIMN- patients on the other hand, major IMPV contact was observed in only 25.3% (n=116) and 36.2% (n=166) had no IMPV contact at all. Receiver operating characteristic (ROC) analysis revealed that “major IMPV contact” was more accurate in predicting ipsilateral IMN+ (AUC 0.85) compared to a multivariate model combining grade of differentiation, tumor site, size and molecular subtype (AUC 0.65). Strikingly, among patients with contralateral IMN+ (cIMN+), 100% of tumors had contact to a crossing contralateral IMPV, whereas in contralateral IMN- (cIMN-) patients, IMPVs to the contralateral side were observed in only 53.4% (iIMN+) and 24.8% (iIMN-), respectively. ConclusionTumor contact with the IMPV is highly associated with risk of gross IMN involvement. Further studies are warranted to investigate whether this identified risk factor is also associated with microscopic IMN involvement and whether it can assist in the selection of breast cancer patients for IMNI.

Lymphocytopenia following adjuvant radiotherapy for breast cancer

AbstractObjectiveWe retrospectively analyzed breast cancer patients who received adjuvant radiotherapy to determine the incidence of lymphocytopenia and its risk factors.MethodsWe reviewed 812 patients with breast cancer who received postoperative radiotherapy. Patients were divided into two groups based on the use of chemotherapy, and a generalized linear regression model was used to explore predictive factors for grade 2 or higher lymphocytopenia. We also examined the effect of lymphocytopenia on overall survival.ResultsGrade 2 or higher lymphocytopenia was observed in 19.4% of patients who did not receive chemotherapy and 45.1% of patients who received chemotherapy. In multivariate analysis, bilateral disease, regional lymph node irradiation, and baseline lymphocytopenia were associated with lymphocytopenia in patients who did not receive cytotoxic chemotherapy. Regional lymph node irradiation, baseline lymphocytopenia, use of antimetabolites, and use of molecular‐targeted agents were associated with lymphocytopenia in patients treated with chemotherapy. In the survival analysis, lymphocytopenia was associated with worse overall survival only in patients treated with cytotoxic chemotherapy (p = 0.039), and not in patients who did not receive chemotherapy (p = 0.77).ConclusionThe analysis revealed the incidence and risk factors of lymphocytopenia after postoperative radiotherapy in patients with breast cancer.

Assessment of Postmastectomy Radiation Therapy Receipt by Age and Association With Outcomes in Women With Breast Cancer

PurposePostmastectomy radiation therapy (PMRT) reduces locoregional recurrence (LRR) and improves overall survival (OS) in patients with breast cancer. Young age has been recognized as a risk factor for LRR. The primary objective of this study was to determine if recommendations for PMRT differed among patients younger than 50 years as compared to women aged 50 years or older. MethodsWe reviewed medical records of patients with breast cancer who underwent mastectomy with or without PMRT from 2010 through 2018. Univariable and multivariable models were used to estimate the association of age with PMRT. ResultsOf 2471 patients, 839 (34%) were <50 years; 1632 (66%) were ≥50 years. Patients <50 years had a higher percentage of grade 3 tumors, hormone receptor (HR) negative and/or Her-2/neu positive tumors, clinical stage T2/T3 tumors, and nodal involvement. Compared with patients ≥50 years, patients <50 years were more likely to undergo PMRT (OR 1.57; P = .001) and regional node irradiation (RNI) to the internal mammary nodes. Advanced clinical and pathologic stage, invasive tumor histology, the presence of lymphovascular invasion, and treatment with systemic chemotherapy were predictors of PMRT receipt for patients <50 years (P < .05). PMRT was associated with improved OS and recurrence free survival (RFS) among all patients (P < .01). ConclusionPatients <50 years were more likely to undergo PMRT and to receive RNI to the internal mammary nodes but were also more likely to have other risk factors for recurrence that would warrant a PMRT recommendation. PMRT improved OS and RFS for all patients.

The Role of Adjuvant Radiotherapy in the Treatment of Breast Cancer.

The role of postmastectomy radiotherapy and regional nodal irradiation after radical mastectomy is defined in high-risk patients with locally advanced tumors, positive margins, and unfavorable biology. The benefit of postmastectomy radiotherapy in intermediate-risk patients (T3N0 tumors) remains a matter of controversy. It has been demonstrated that radiotherapy after breast-conserving surgery lowers the locoregional recurrence rate compared with surgery alone and improves the overall survival rate. In patients with four or more positive lymph nodes or extracapsular extension, regional lymph node irradiation is indicated regardless of the surgery type (breast-conserving surgery or mastectomy). Despite the consensus that patients with more than three positive lymph nodes should be treated with radiotherapy, there is controversy regarding the recommendations for patients with one to three involved lymph nodes. In patients with N0 disease with negative findings on axillary surgery, there is a trend to administer regional lymph node irradiation in patients with a high risk of recurrence. In patients treated with neoadjuvant systemic therapy and mastectomy, adjuvant radiotherapy should be administered in cases of clinical stage III and/or ≥ypN1. In patients treated with neoadjuvant systemic therapy and breast-conserving surgery, postoperative radiotherapy is indicated irrespective of pathological response.

Neoadjuvant SBRT plus regional nodal irradiation with concurrent capecitabine for patients with resectable pancreatic cancer: Survival analysis of prospective phase 1 trial.

652 Background: Radiation may have a role in management of patients with early-stage pancreatic cancer. However, the role of regional nodal irradiation (RNI) is not well defined despite the high frequency of occult nodal disease. The goal of this trial was to evaluate the safety and feasibility of stereotactic body radiation therapy (SBRT) to primary disease with RNI, combined with capecitabine as a neoadjuvant approach for patients with resectable pancreatic cancer. Updated survival analysis will be presented here. Methods: This is a prospective, single institution, phase IA/B dose-escalation trial that enrolled patients with biopsy-proven, resectable, pancreatic adenocarcinoma between 2014 – 2019 (NCT1918644). Patients were enrolled into one of the 3 cohorts with escalating dose levels. Neoadjuvant SBRT to the primary tumor was delivered in 5 fractions of 5, 6, or 7 Gy with concomitant capecitabine. All patients received RNI 5 Gy x 5 fractions. Our initial report found no dose-limiting toxicities (Witt et al IJROBP 2020). Clinicopathologic features were summarized using descriptive statistics. Kaplan-Meier curves were employed for survival analysis. Results: Seventeen patients were enrolled on the protocol with sixteen evaluable (94.1%). Thirteen (76.5%) patients proceeded to surgery. Median follow up was 31.1 months (2.0 – 73.2). Among the evaluable patients, 63% were male, median age at diagnosis was 73 years (63 – 84), pre-treatment CA 19-9 149.5 U/mL (2.0 – 19358.0). The majority of patients had cT2-3 (94%) and cN0 (87.5%) disease. In patients who underwent resection, median time from radiation to surgery was 19.7 days (14.8 – 42.4), with median of 18 lymph nodes removed (11 – 27). Pathologically involved nodes were present in 69.2% of patients with a median of 2 nodes (1 – 10). Five patients (31.3%) received neoadjuvant chemotherapy, and ten (62.5%) received adjuvant chemotherapy. At the time of data cutoff, median overall survival was 31.1 months (2.3 – 73.6), and median locoregional control and distant metastasis free survivals were 32.8 months (4.0 – 59.5) and 15.3 months (0.4 – 73.6), respectively. No further radiation related toxicities were noted since the prior report. Conclusions: Neoadjuvant chemoradiation with SBRT and capecitabine to primary disease with RNI is feasible and provided a promising signal of durable local control in our study, despite high rates of pathological nodal involvement. Further investigation of this strategy is warranted in a larger cohort of patients. Clinical trial information: NCT1918644 .

Establishing a risk stratification model to identify clinically high-risk N0 breast cancer who could benefit from regional nodal irradiation: a single institute analysis.

The purpose of this real-world study was to investigate the risk factors for developing recurrence among patients with pathological T1-3N0 breast cancer (BC) treated with breast-conserving surgery (BCS) followed by whole breast irradiation alone (WBI) and identify those clinically high-risk BCs who could benefit from regional nodal irradiation (RNI). Female BC patients treated at Shanghai Ruijin hospital from 2009 to 2016 were retrospectively reviewed. The disease-free survival (DFS), breast cancer specific survival (BCSS) and overall survival (OS) were estimated by the Kaplan-Meier method, and survival differences were compared with the log-rank test. Univariate and multivariate analysis was performed using Cox proportional hazards regression analysis. An external validation was conducted by using SEER database. A total of 622 BC patients treated with BCS+WBI alone were included. With a median follow-up of 82 months, the 7-year OS, BCSS and DFS for the entire cohort was 97%, 99% and 91%, respectively. Multivariable Cox analysis indicated that tumor size (p=0.006), tumor location (p=0.033), lymphovascular invasion (LVI) status (p=0.0028) and Ki-67 index (p=0.051) were independent risk factors for DFS. A scoring system was developed using these four factors and the 7-year DFS and OS were 97% and 96% for patients with 0-1 risk factors, 95% and 82% for patients with ≥2 risk factors (p<0.0001 for DFS, and p=0.0063 for OS). Based on tumor size and tumor location, an external validation by demonstrated that the 7-year OS was 90% and 88% for patients with 0-1 risk factor, which was significantly better than those defined as high-risk BC patients (82%, p<0.0001). By using our institute database, we establish a risk stratification system for identifying sub-group of pN0 BC patients, who are at high risk for developing recurrence. The results of our study support tailored RT decision-making according to individual risks, which needed to be confirmed in further studies.

Feasibility of Intraoperative Radiotherapy Tumor Bed Boost in Patients with Breast Cancer after Neoadjuvant Chemotherapy.

This study aimed to assess the feasibility and safety of administering intraoperative radiotherapy (IORT) as a boost during breast-conserving surgery (BCS) following neoadjuvant chemotherapy for patients at high risk of breast cancer recurrence. Patients who underwent neoadjuvant chemotherapy received a single 20-Gy dose of IORT during BCS, followed by external beam radiotherapy 4-6 weeks after surgery. The median follow-up duration was 31.0 months (range, 18.0-59.0 months). Initial tumor sizes had a median of 2.6 cm (range: 0.8-5.3 cm), reducing to 0.3 cm (range: 0-4.0 cm) after neoadjuvant chemotherapy. The most common neoadjuvant chemotherapy regimen was doxorubicin and cyclophosphamide, followed by paclitaxel (n=42, 73.7%). Among 57 patients who received neoadjuvant chemotherapy before BCS and IORT, 2 patients (3.5%) required secondary surgery to achieve negative resection margins due to initially positive margins. Regional lymph node irradiation was performed in 37 (64.9%) patients. There was no grade 3 or higher adverse events, with 4 patients (7.0%) experiencing grade 2 acute radiation dermatitis and 3 (5.3%) having less than grade 2 breast edema. Binary correlation analysis did not reveal statistically significant associations between applicator size or radiation therapy modality and the risk of treatment-related toxicity. Furthermore, chi-square analysis showed that the grade of treatment-related toxicity was not associated with the fractionated regimen (p=0.375). Most patients successfully received IORT as a tumor bed boost after neoadjuvant chemotherapy. Thus, IORT may be a safe and feasible option for patients with advanced-stage breast cancer receiving neoadjuvant chemotherapy.

Prevalence of Lymphedema and Associated Risk Factors Following Multimodal Breast Cancer Treatment

Background: Breast cancer related Lymphedema (BCRL) in the respective arm is a common but serious negative sequel of breast cancer management. Risk factors include dissection of Axillary lymph nodes and irradiation of Regional lymph nodes. Nearly 20% of patients receiving treatment of breast cancer develop this complication and it has a negative impact on quality of life of the patient. Objective: Current study aims to equip the medical professionals with all the details needed for prevention, early detection, intervention and management of this hazardous late treatment related complication. Material and Methods: Total 350 breast cancer patients (with their consent) treated at Government Cancer Hospital, Indore in the Radiotherapy and Oncology Department, in period from January 2019till December 2021, with chest wall radiotherapy following subsequent hormonal therapy, as needed. Patients then analysed for occurrence of lymphedema. Subsequently, efforts were given for finding out the correlation between lymphedema and related treatment modality like adjuvant radiotherapy following definitive surgery with number of excised lymph nodes and number of involved lymph nodes, chemotherapy, hormonal therapy, subjective co-morbid condition (obesity, diabetes mellitus and high blood pressure). Results: Current study demonstrate a significant correlation of adjuvant radiotherapy, including progressive involvement of the lymph node stations, with radical or conservative breast surgery with lymph node dissection represents a statistically significant risk factor, with relative risk, RR=1.49 (95% CI=0.72–3.05), p&lt;0.001. Subsequent increase in number of dissected lymph nodes shown a risk factor with statistical significance as relative risk for more than 25 removed lymph nodes, demonstrated significant risk of lymphedema than for 16-25 removed lymph nodes. Other analysed risk factors, which did not influence lymphedema development like, associated chemotherapy, hormonal therapy or presence of co-morbid illnesses. Conclusions: Arm lymphedema is a late sequel associated with carcinoma breast treatment using radiation or surgery, and quite capricious occurrence that can happen years after axillary clearance surgery. With the use of sentinel node sampling, could reduce the need of frank axillary clearance by showing either involvement of lymph node in axilla, so as to manage only by radiotherapy. That significantly reduces the risk of lymphedema from 16% with axillary clearance to 5% without dissection. Keywords: Lymphedema, Breast cancer, Risk factors, Axillary lymph node

Clinical Experience of Axillary Radiotherapy for Node-positive Breast Cancer

AimsPatients with breast cancer who have positive lymph nodes are currently recommended axillary node clearance (ANC) or regional nodal irradiation (RNI). ANC is associated with complications such as lymphoedema, brachial plexopathy and shoulder stiffness. The AMAROS Group showed RNI to be non-inferior to ANC with regards to survival and recurrence, and with a better quality of life. We conducted a large real-world population study to show our centre's experience with the use of RNI and to contribute to the current discussion around the management of node-positive breast cancer. Materials and methodsWe evaluated patients who received RNI as opposed to ANC between 2006 and 2009 (n = 190). Patients had a range of cancer subtypes/grades. All had positive axillary disease, identified by axillary node sampling or sentinel lymph node biopsy. Systemic therapy was given as per standard protocol. Our data were compared with those of patients who had RNI (n = 681) in AMAROS. Patients were followed up retrospectively and overall survival, breast cancer-specific survival, distant metastasis-free survival, locoregional recurrence and toxicity were recorded, including lymphoedema, brachial plexopathy and shoulder stiffness. Survival analysis was performed on R via the Kaplan–Meier method. Univariate and multivariate analyses were also performed. Toxicity data were reported as percentages. Patients meeting POSNOC trial criteria (one to two positive sentinel lymph nodes, macrometastasis, receiving adjuvant chemotherapy) including if oestrogen receptor-positive (stratified POSNOC) were identified for subgroup analysis in the regression model. ResultsLocoregional recurrence was 3.16% versus AMAROS RNI of 1.82%. Overall survival was slightly lower in our population, but cancer-specific survival was higher than AMAROS. Lymphoedema rates were 5.8% versus AMAROS 11% in RNI and 23% in ANC arms, respectively. Brachial plexopathy was 1.6% and arm/shoulder stiffness 7.4%. AMAROS conducted a quality of life survey pertaining to arm/shoulder stiffness, mobility and function, which seemed to affect about 18% in the RNI arm. Univariate analysis revealed POSNOC status, especially if also oestrogen receptor-positive, to be a low risk group with hazard ratio 0.42 (0.20–0.83, P = 0.015). Extracapsular extension of lymph node metastasis was a poor prognostic factor; hazard ratio 4.39 (1.45–14.0, P = 0.009). ConclusionWe support the conclusion of the AMAROS trial with survival and recurrence following RNI being non-inferior to ANC, and with similarly favourable toxicity data. We support the continuing use of RNI as a treatment option for patients with node-positive breast cancer. Further research is required to answer the key questions regarding personalised management for node-positive breast cancer, with regards to de-escalation and also intensification for the patients exhibiting adverse tumour biology.

Treatment of Internal Mammary Nodes is Associated With Improved Overall Survival in Breast Cancer: A Meta-Analysis.

The role of internal mammary nodal irradiation (IMNI) as a component of regional nodal radiotherapy is a controversial issue in breast radiation oncology with conflicting results presented in recent landmark trials. We thus created a meta-analysis of available data to better ascertain the potential benefit of IMNI. We hypothesize that with the increased power available within a meta-analysis, IMNI will prove to improve overall survival (OS) in breast cancer. Literature search was conducted for prospective studies comparing IMNI to no IMNI. Primary endpoint was OS and secondary endpoints included local recurrence, regional recurrence, disease-free survival (DFS), breast cancer mortality (BCM), distant metastasis-free survival (DMFS), grade 2+ skin toxicity, cardiac events, and pneumonitis events. Subgroup analyses were performed for tumor location (medial/central vs. lateral), and nodal status (pN+ vs. pN0). Fixed-effect model was used if there was no heterogeneity, random-effects model otherwise. Four studies with a total of 5258 patients (IMNI: n=2592; control: n=2666) were included in the study. Pooled results showed IMNI significantly improved OS for all-comers (hazard ratio [HR]=0.89; 95% CI 0.81-0.97; P =0.008), as well as subgroups of pN+ with medial/central tumor location (HR=0.84; 95% CI 0.73-0.96; P =0.01) and pN+ with lateral tumor location (HR=0.87; 95% CI 0.77-0.99; P =0.04). There was no significant difference in OS for subgroups of pN0 and medial/central tumor location. There was no difference in local recurrence, but regional recurrence was significantly improved ( P =0.04). Endpoints of DFS (HR 0.91, 95% CI 0.84-0.99 P =0.03), BCM (HR 0.87, 95% CI 0.77-0.98, P =0.03), and DMFS (HR=0.87; 95% CI, 0.78-0.98; P =0.02) were all improved with IMNI. Grade 2+ skin toxicity, cardiac events and pneumonitis events were not significantly different between patient in the IMNI and no IMNI groups. Inclusion of IMN irradiation improves OS, DFS, BCM, and DMFS in breast cancer. Largest effect on OS was noted in the subgroup of patients with pN+ and medial/central tumor location.

De-escalated radiotherapy for HER2-overexpressing breast cancer patients with 1-3 positive lymph nodes undergoing anti-HER2 targeted therapy.

In the era of anti-HER2 targeted therapy, the potential clinical feasibility of considering HER2-overexpressing breast cancer cases presenting with 1-3 positive axillary lymph nodes as low-risk, and thereby contemplating postoperative radiotherapy reduction, remains an important subject for in-depth examination. The aim of this retrospective study was to evaluate the effectiveness of de-escalated radiotherapy in T1-2N1M0 HER2-overexpressing breast cancer patients receiving anti-HER2 targeted therapy. Specifically, omitting regional lymph node irradiation (RNI) after breast-conserving surgery and only performing whole-breast irradiation or omitting postmastectomy radiation therapy. A retrospective analysis was conducted on 429 patients with stage T1-2N1M0 primary invasive HER2-overexpressing breast cancer from our center between 2004 and 2018. Patients who received anti-HER2 targeted therapy were divided into an RNI group and a no RNI group to assess the role of RNI. The prognostic role of RNI was investigated via the Kaplan-Meier method and Cox proportional hazards modeling. The median follow-up time was 46.8 months (range 7.1-225.8 months). In the anti-HER2 targeted therapy group RNI yielded no significant improvements in invasive disease-free survival (IDFS) (p = 0.940), local-regional recurrence-free survival (p = 0.380), distant metastases-free survival (p = 0.698), or overall survival (p = 0.403). Estrogen receptor (ER) status (hazard ratio [HR] 0.105, 95% confidence interval [CI] 0.023-0.749, p = 0.004) and lymph vascular invasion status (LVI) (HR 5.721, 95% CI 1.586-20.633, p = 0.008) were identified as independent prognostic factors for IDFS, and ER-positive and LVI-negative patients exhibited better prognoses. Omitting RNI may be a safe option in T1-2N1 HER2-overexpressing breast cancer patients receiving standardized anti-HER2 targeted therapy; particularly in ER-positive or LVI-negative subgroups.

Effective and safe regional node irradiation in early breast cancer

Effective and safe regional node irradiation in early breast cancer

Benefit of postoperative regional nodal irradiation in patients receiving preoperative systemic therapy with docetaxel/carboplatin/trastuzumab/pertuzumab for HER2-positive breast cancer

AimThe role of regional nodal irradiation (RNI) after preoperative systemic treatment (PST) with targeted therapy for HER2-positive breast cancer remains uncertain. This study aimed to investigate the impact of RNI on locoregional recurrence (LRR) and disease-free survival (DFS) outcomes after docetaxel/carboplatin/trastuzumab/pertuzumab (TCHP) for PST. MethodsWe retrospectively analyzed 255 patients who were treated with six cycles of TCHP between 2016 and 2019. The patients were divided into four groups based on clinical nodal involvement: group A, with no nodal disease; group B, with axillary lymph node (AXL) level I; group C, with AXL level I with II/III; and group D, with supraclavicular or internal mammary nodes. ResultsThe RNI group had more advanced nodal disease (C/D) than the no RNI group (56.9 % vs. 6.8 %). With a median follow-up of 51.3 months, there were two (0.8 %), three (1.2 %), and 15 (5.9 %) local, regional, and distant metastases, respectively. LRR did not differ significantly according to the RNI (2.6 % vs. 1.0 %, p = 0.651). Group D had the most frequent distant metastases (17.5 %; p = 0.005). The 4-year DFS rate was 92.7 %, and DFS did not improve significantly after RNI (p = 0.074). When stratified by clinical nodal groups and pathological axillary response, RNI had no effect on LRR/DFS outcomes. ConclusionWith a rare incidence of LRR, RNI did not significantly affect LRR or DFS in patients with HER2-positive breast cancer after with PST-TCHP. However, intensive systemic treatment is required for advanced diseases (C/D). Selective de-intensified RNI and intensified systemic treatment should be investigated in future studies.

Association Between Symptom Burden and Early Lymphatic Abnormalities After Regional Nodal Irradiation for Breast Cancer

Background: Dermal backflow visualized on near-infrared fluorescence lymphatic imaging (NIRFLI) signals preclinical lymphedema that precedes the development of volumetrically-defined lymphedema. We sought to evaluate whether dermal backflow correlates with patient-reported lymphedema outcomes (PRLO) surveys in breast cancer patients treated with regional nodal irradiation (RNI). Methods and Materials: Breast cancer patients planned for axillary dissection and RNI prospectively underwent perometry, NIRFLI, and PRLOs (the Lymphedema Symptom Intensity and Distress Survey (LSIDS) and QuickDash) at baseline, after surgery, and at 6, 12, and 18 months following radiation. Clinical lymphedema was defined as an arm volume increase ≥ 5% over baseline. Trends over time were assessed using ANOVA testing. The association between survey responses and both dermal backflow and lymphedema was assessed using a linear mixed-effects model. Results: Sixty participants completed at least two sets of measurements and surveys and were eligible for analysis. Fifty-four percent of patients had cT3-T4 disease, 53% cN3 disease, and 75% had a BMI >25. Dermal backflow and clinical lymphedema increased from 10% to 85% and from 0% to 40%, respectively, from baseline to 18mo. In the adjusted model, soft tissue sensation, neurologic sensation, and functional LSIDS subscale scores were associated with presence of dermal backflow (all p<0.05). Both dermal backflow and lymphedema were associated with Quickdash score (p<0.05). Conclusion: In this high-risk cohort, we found highly prevalent early signs of lymphedema, with increased symptom burden from baseline. Presence of dermal backflow correlated with PRLO measures, highlighting a potential NIRFLI use to identify patients for early intervention trials following RNI.

Is it the Type of Axillary Surgery or the Number of Removed Lymph Nodes That Increases the Risk of Breast Cancer Related Lymphedema (BCRL)? Results from a Prospective Screening Trial

Axillary surgery has been identified as the main risk factor for BCRL regardless the delivery of regional nodal radiation (RLNR). Yet it remains unknown if it is the type of axillary surgery or the number of removed lymph nodes (LN) that increases BCRL risks. Between 2008 and 2021, 3,350 patients (pts) who received surgery for breast cancer were enrolled in a lymphedema screening trial. Patients with bilateral breast cancer or without axillary surgery were excluded. Perometry was used to assess limb volume preoperatively in all patients. BCRL was defined as a ≥10% relative arm-volume increase arising >3 months postoperatively. The cohort was divided by axillary surgery type: axillary lymph node dissection (ALND) and sentinel lymph node biopsy (SLNB). Radiation was delivered using 3D conformal technique and RLNR was defined as the usage of anterior supraclavicular field. No hypofractionation was used and doses ranged between 50 and 50.4 Gy in 25-28 fractions. Multivariable Cox proportional hazard models compared the cumulative incidence of BCRL and local failure between different patient groups. After applying inclusion criteria, 2,623 pts were available with overall median follow-up s of 6.1 years. Of the entire cohort, 709 (27%) had ALND with a median of 16 LN removed, while 1,914 (73%) received SLNB only with a median of 2 LN removed. The median number of malignant LN and patients receiving RLNR was higher in ALND group compared to SLNB only group. Frequency distribution analysis showed that the main overlap between ALND and SLNB only groups happen in the range of 3-11 LN removed. Therefore, the primary analysis focused only on pts with 3-11 LN across both groups (n = 690: ALND n = 140, SLNB n = 550). The multivariable model adjusted for BMI, RLNR, age and breast surgery showed that in this group with 3-11 LN removed in both cohorts, ALND remained significantly associated with BCRL (HR: 4.2, p<0.0001). Separate analyses for the entire SLNB only group and ALND groups were conducted to evaluate if the BCRL risk increases per each removed LN within the same axillary surgery group. The multivariable analysis for SLNB only pts(N = 1,914) showed that for each LN removed the risk of BCRL did not increase significantly (HR:1.06, p = 0.3), similarly for ALND group (N = 709) for each LN removed (HR:1.02, p = 0.08). For pts with pathologic N2-N3 disease and clinical node negative without neoadjuvant chemotherapy receiving ALND, the number of LN removed did not significantly improve neither Local control (HR:1.02, p = 0.8) nor distant disease survival (HR:1.01, p = 0.6). ALND procedure per se is the main risk factor for BCRL not the number of LNs removed. For high-risk pts with >N2 disease, aggressive ALND did not improve tumor outcome. De-escalation with targeted axillary sampling followed by RLNR should be evaluated. Future lymphedema research should account for type of axillary surgery instead of number of LNs removed as a factor. (NCT01521741).

Largest Real-World Data of Regional Nodal Irradiation Using Ultra-Hypofractionated 5-Fraction Adjuvant Radiation Therapy for Breast Cancer from a Single Institute in India

Safety data for ultra-hypofractionated (UHFRT) 5-daily fractions of the supraclavicular fossa (SCF) radiation therapy (RT) have been reported only on 384 patients treated in trial setting in UK-FAST-Forward (n = 286) and HYPORT study (n = 98). Internal Mammary nodal (IMN) RT has been reported only in 6 patients from HYPORT study. We report acute and late toxicities in largest real world regional nodal irradiation (RNI) cohort of not only with 5-daily but also with 5-weekly once RT regimen. Of 1435 patients (1463 breasts) who received 5-fraction RT in an IEC approved registry and prospectively followed, we report 999 consecutive cases receiving RNI with a median age of 49 years (IQR:42-56years). During pandemic all patients were treated with 5-fr regimens only to limit hospital visits whereas prior to and subsequently only in patients with advanced age or with issues precluding daily 15-20 treatments. Of these, 431 (43.1%) had locally advanced BC, and 280 (28%) patients presented with ≥cN2 disease. Median cT and pT sizes were 4cm (IQR:3-6cm) and 2.8cm (IQR:1.5-4cm) respectively. Tumor was Her2 positive in 290(29%) and TNBC in 220(22%). Of these 999 cases, 611 received NACT, 647 had mastectomy and 351 had breast conserving surgery (BCS). Simultaneous integrated tumor bed boost (SIB) was given in 341 (97.1%) of BCS cases. The fractionation used was 26 Gy/5-daily fractions (SIB = 32 Gy) in 762 and 28.5 Gy/ 5 once weekly fractionation (SIB = 33 Gy) in 232 cases. RNI included SCF in all 999 and IMN in 168 patients. Of the 831 cases not requiring IMN RT, 573 (70.4%) had 3D conformal RT (n = 573/831,70.4%) whereas Inverse-planned intensity modulated RT was used in 152/168 (90.4%) patients requiring IMN RT. All Mono-isocentric technique was used for all RNI cases treated with 3D CRT. Nearly half of the patients treated with SIB received additional boost dose with electrons (50.5%) and the remaining with IMRT. In these 999 patients treated with UHFRT the peak RTOG grade ≥II skin and pharyngeal toxicity was 7.2% and 8.1% respectively. Among the 341 BCS cases who received SIB with UHFRT, the RTOG acute grade II and III skin toxicity was seen in 6.6% and 0.3% cases respectively. The maximum skin toxicity at 2 weeks after completion of RT of grade ≥II was significantly higher with 5-weekly compared to daily regimen (16.1 vs 4.6, p<0.01). In contrast, the maximum pharyngeal toxicity of grade ≥II was significantly higher with 5-daily compared to weekly fractionation (8.8% vs 5.2%, p = 0.04). At median follow-up of 25 months (CI:23.6-26.3 months), none of our patients had developed symptomatic radiation pneumonitis, brachial plexopathy or any major cardiac event. Five-fraction adjuvant breast cancer RT is well tolerated with low acute toxicity burden even among patients requiring regional nodal irradiation. No brachial plexopathy was observed in cases treated with mono-isocentric RNI but longer follow-up is required to inform about the late toxicities and locoregional control rates.

Reducing Racial Disparities in Breast Cancer Treatment

Racial disparities in breast cancer screening, treatment, and outcomes are well established. A recent multi-institutional paper showed a higher mean heart dose (MHD) in Black women and other minorities compared to White women who underwent left-sided breast or chest wall irradiation. We evaluated the MHD of women treated in our institution and investigated whether institution-wide measures can mitigate disparities. We identified 509 consecutively treated female patients from 2012 to 2021 who received left-sided breast or chest wall irradiation (with or without regional nodal irradiation). Medical records were queried to report cardiac dosimetry across various racial groups. Details regarding the use of active breathing control (ABC), breast size, internal mammary nodal irradiation, and whether the patient's treatment plan met the departmental boarding pass requirement and was prospectively presented at departmental peer review were noted. MHD were noted in absolute values and 2-Gy equivalent doses (EQD2). Kruskal-Wallis test was used to analyze differences in MHD between racial groups. Univariate and multivariable Cox regression analyses were performed to determine association of MHD with other factors. MHD was similar across racial groups; 1.38 Gy (1.12, 2.02) in Black women, 1.35 Gy (1.02, 1.97) in White women, and 1.39 Gy (1.07, 2.01) in others with an EQD2 of 0.71, 0.70 and 0.72 (P = 0.6). Rates of the use of hypofractionation, a cavity boost, regional nodal irradiation, internal mammary nodal irradiation, meeting departmental boarding pass requirement, and peer review of treatment plan before starting treatment were similar across all racial groups. The use of ABC was 83% in White women, 75% in Black women and 62% in other races (P = 0.005). The difference in ABC use was attributed to a higher rate of volumetric modulated arc therapy treatment in other races (33%). Median breast size was 1904 cc in Black women, 1504 cc in White women, and 1331 cc in other racial groups (P = 0.001). On univariate and multivariate analysis, MHD differed with IMN treatment, boost and use of ABC but remained similar across racial groups and varying breast size. Despite anatomical differences such as breast size, achieving similar cardiac dose is feasible across racial groups by uniformly utilizing ABC for left sided breast or chest wall irradiation, applying standardized boarding pass constraints and peer review of all cases. Further studies to identify factors that may lead to differences in the rates of cardiac morbidity among racial groups are warranted.

A Phase II Randomized Clinical Trial to Assess Toxicity and Quality of Life of Breast Cancer Patients with Hypofractionated vs. Conventional Fractionation Radiotherapy with Regional Nodal Irradiation

To compare acute toxicity between conventional fractionated radiation therapy (CFRT) and hypofractionated radiation therapy (HFRT) for patients undergoing breast-conserving surgery or mastectomy with breast or chest wall and regional nodal irradiation (RNI). The secondary endpoints were acute and subacute toxicity, cosmesis, quality of life, and lymphedema features. Unblinded randomized trial with a total of 86 patients treated with CFRT (n = 33; 50 Gy/25 fractions ± sequential boost [10 Gy/5 fractions]) versus HFRT (n = 53; 40 Gy/15 fractions ± concomitant boost [8 Gy/15 fractions]). Women included for enrollment were 18 years or older and diagnosed with breast carcinoma, staging T1-4, with at least one positive lymph node (American Joint Committee on Cancer - AJCC 8th). The surgery performed was mastectomy or breast-conservative surgery with the investigation of sentinel lymph node or axillary dissection. Toxic effects and cosmesis evaluation used the Common Terminology Criteria for Adverse Events version 4.03 (CTCAE) and the Harvard/NSABP/RTOG scale. Patients-reported QoL was determined using the European Organization for Research and Treatment of Cancer quality of life questionnaire (EORTC QLQ-C30) and the breast cancer-specific supplementary questionnaire (QLQ-BR23). The comparative analysis of categorical variables between the control and experimental groups used the Chi-square test and Fisher's exact test, while numerical variables basing on the Mann-Whitney U test. The intergroup comparison of the EORTC QLQ-C30 used the Generalized Equations Estimating method. All analyses used 2-sided α = 0.05 with R software version 4.1.2. Lymphedema determination compared volume differences between the affected and contralateral arms using the Casley-Smith volume formula. Grade 2 and grade 3 skin rash dermatitis were lower with HFRT than with CF-RT (28% vs. 52%, 0% vs. 6%; p = 0.022, respectively). HFRT vs. CFRT had lower rate of grade 2 hyperpigmentation (23% vs. 55%; p = 0.005). Overall rates of any physician-assessed grade ≥ 2 and grade ≥ 3 acute toxicities were no different between HFRT vs. CFRT arms. There was no statistical difference between the CFRT and the HFRT regarding cosmesis, lymphedema rate (13% vs. 12% HFRT vs. CFRT; p = 1.000, respectively), and functional and symptom scales during irradiation and after six months of treatment. HF-RT showed lower rates of acute toxicity, with no changes in quality-of-life outcomes.

Establishing a Risk Stratification Model to Identify Clinically High-Risk N0 Breast Cancer Who Could Benefit from Regional Nodal Irradiation: A Single Institute Analysis

The adverse clinical features for pN0 BC patients significantly varies and there is no established clinical risk stratification system to identify those "high-risk" pN0 BC patients who might benefit from RNI. The purpose of this real-world study was to investigate the risk factors for developing recurrence among patients with pathological T1-3N0 breast cancer (BC) treated with breast-conserving surgery (BCS) followed by whole breast irradiation alone (WBI) and identify those clinically high-risk BCs who could benefit from regional nodal irradiation (RNI). Female BC patients treated from 2009 to 2016 were retrospectively reviewed. The disease-free survival (DFS) and overall survival (OS) were estimated by the Kaplan-Meier method, and survival differences were compared with the log-rank test. Univariate and multivariate analysis was performed using Cox logistic regression analysis. An external validation was conducted by using SEER database. A total of 622 BC patients treated with BCS+WBI alone were included. With a median follow-up of 82 months, the 7-year OS and DFS for the entire cohort was 97% and 91%, respectively. Multivariable Cox analysis indicated that tumor size (p = 0.006), tumor location (p = 0.033), lymphovascular invasion (LVI) status (p = 0.0028) and Ki-67 index (p = 0.051) were independent risk factors for DFS, while only tumor size was the only independent risk factors for OS (p = 0.029). A scoring system was developed using these four factors and the 7-year DFS and OS were 97% and 96% for patients with 0-1 risk factors, 95% and 82% for patients with ≥2 risk factors (p<0.0001 for DFS, and p = 0.0063 for OS). Based on tumor size and tumor location, an external validation by demonstrated that the 7-year OS was 90% and 88% for patients with 0-1 risk factor, which was significantly better than those defined as high-risk BC patients (82%, p<0.0001). By using our institute database, we establish a risk stratification system for identifying sub-group of pN0 BC patients, who are at high risk for developing recurrence. The results of our study support tailored RT decision-making according to individual risks, which needed to be confirmed in further studies.

Identification and Dosimetric Analysis of Axillary Substructures Associated with Breast Cancer Related Lymphedema

It has been hypothesized that substructures in the axillary region may be involved in the development of upper limb lymphedema in breast cancer patients. We aimed to compare dosimetric parameters of different substructures to identify risk regions and dose indicators related to the development of lymphedema. A total of 486 patients with breast cancer treated with axillary node dissection (ALND) and regional node irradiation (RNI) between 2017 and 2020 were analyzed. Ten axillary substructures were retrospectively contoured, and dose-volume histogram (DVH) parameters (maximum dose [Dmax], Dmean, Dmin, V5 Gy, V10 Gy, V15 Gy, V20 Gy, V25 Gy, V30 Gy, V35 Gy, V40 Gy, V45 Gy and V50 Gy) were evaluated. EQD2 using α/β = 3 was applied for hypofractionation. The cumulative incidence of lymphedema was 32.5% during the median follow-up of 25 month (IQR 15-35). Higher BMI (≥21.77 kg/m2, hazard ratio [HR]1.6, 95% CI 1.1-2.3, p = 0.019) and higher number of dissected lymph nodes (≥13, HR 1.8, 95% CI 1.1-3.0, p = 0.026) were baseline risk factors associated with breast cancer related lymphedema (BCRL). A cohort of 196 patients was obtained by 1:1 propensity score matching based on the above two factors (154 treated with 50 Gy/25 fractions [Fx] and 42 with 40.05 Gy/15Fx). The optimal metric was axillary-lateral thoracic vessel juncture (ALTJ) Dmean ≥36.84 Gy (HR 3.7, 95% CI 1.6-8.6, p = 0.002). Other significant risk factors are Medial of Axillary Nodes level I(ALN-I-M) Dmin <9.19 Gy (HR 2.3, 95% CI 1.4-3.7, p = 0.001) and Posterior of Axillary Nodes level II(ALN-II-P) Dmax <52.75 Gy (HR 2.0, 95% CI 1.2-3.5, p = 0.015). A nomogram incorporated the above three parameters was created to predict the risk of lymphedema with reasonable accuracy confirmed by both self-training (area under curve [AUC], 0.76; 95% CI, 0.67-0.84) and internal validation (AUC 0.66; 95% CI, 0.50-0.80). A mean dose of 36.84 Gy of ALTJ may be a suggested dose limit for patients indicated RNI after ALND, especially when patients with higher BMI and higher dissected nodes. Ideally, avoidance of ALTJ may be realized without compromising dose coverage to high-risk nodal region. Confirmation of this finding in future prospective studies is needed.