IMNI PRECISION trial protocol: a phase II, open-label, non-inferior randomized controlled trial of tailoring omission of internal mammary node irradiation for early-stage breast cancer.

BACKGROUND: Since the publication of MA-20 and EORTC-22922 trials, chest wall (CW)/ whole breast (WB) irradiation + comprehensive regional nodal irradiation (RNI) with internal mammary node irradiation (IMNI) has been the standard adjuvant treatment for early-stage breast cancer (BC). However, one size does not fit all BC, and the risk of recurrence significantly varies among this patient population. In addition, whether all BC patients presented with one to three positive lymph nodes (pN1) could benefit from IMNI remains controversial. Thus, the optimal adjuvant RNI volume for early-stage BC with T1-2N1 remains undetermined. METHODS: The IMNI PRECISION trial is a single institute, open-labeled, non-inferior, randomized controlled trial. A total of 214 clinically "high risk" BC patients which is characterized as having at least two of the five clinically adverse factors (age ≤ 40, three positive LN, T2 stage, grade 3 and Ki-67 index ≥ 14%), but genomic score "low risk" (the genomic score ≤ 44) N1 breast cancers are randomly assigned to omitting IMNI group (experimental group) or with IMNI (control group) with a 1:1 ratio. The primary endpoint of this trial is event-free survival, and secondary endpoints include overall survival and locoregional recurrence-free survival. DISCUSSION: The IMNI PRECISION design allows promising clinical-genomic model to stratify the individualized risk of developing recurrence and guides the optimal RNI treatment for early-stage (pT1-2N1) BC patients. We anticipate that our results would provide high-level evidence to tailor IMNI according to individualized recurrence risk of BC. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT04517266 . Date of registration: August 18, 2020. Status: Recruiting.

[Risk assessment of internal mammary lymph node metastasis and choice of irradiation of internal mammary lymphatic drainage area in breast cancer patients with negative internal breast lymph nodes on imaging].

Objective: To explore the independent risk factors of internal mammary lymph nodes (IMN) metastasis and the risk assessment method of IMN metastasis preoperatively in breast cancer patients with negative IMN in imaging examination, and guide the radiotherapy of IMN in patients with different risk stratification of IMN metastasis. Methods: The clinical and pathological data of 301 breast cancer patients who underwent internal mammary sentinel node biopsy(IM-SLNB) and/or IMN dissection in Shandong Cancer Hospital with negative IMN on CT and/or MRI from January 2010 to October 2019 were analyzed retrospectively. The independent risk factors were analyzed by univariate and multivariate logistic regression, and the independent risk factors of IMN metastasis were used to risk stratification. Results: Among the 301 patients, 43 patients had IMN metastasis, and the rate of IMN metastasis was 14.3%. Univariate analysis showed that vascular tumor thrombus, progesterone receptor (PR) expression, T stage and N stage were associated with IMN metastasis. Multivariate logistic regression analysis showed that tumor located in medial quadrant, positive PR and axillary lymph node metastasis were independent risk factors for IMN metastasis. The risk of IMN metastasis was assessed according to the independent risk factors of the patients: low-risk group is including 0 risk factor, medium-risk group is including 1 risk factor, and high-risk group is including 2-3 risk factors. According to this evaluation criteria, 301 patients with breast cancer were divided into low-risk group (with 0 risk factors), medium-risk group (with 1 risk factor) and high-risk group (with 2-3 risk factors). The IMN metastasis rates were 0 (0/34), 4.3% (6/140) and 29.1% (37/127), respectively. Conclusions: The risk stratification of IMN metastasis according to three independent risk factors of IMN metastasis including tumor located in medial quadrant, positive PR and axillary lymph node metastasis in breast cancer patients can guide the radiotherapy of IMN in newly diagnosed breast cancer patients. For N1 patients, radiotherapy of IMN is strongly recommended when the primary tumor is located in the medial quadrant and/or PR positive.

POstmastectomy radioThErapy in Node-posiTive breast cancer with or without Internal mAmmary nodaL irradiation (POTENTIAL): a study protocol for a multicenter prospective phase III randomized controlled trial.

BACKGROUND: Various randomized trials have demonstrated that postmastectomy radiotherapy (RT) to the chest wall and comprehensive regional nodal areas improves survival in patients with axillary node-positive breast cancer. Controversy exists as to whether the internal mammary node (IMN) region is an essential component of regional nodal irradiation. Available data on the survival benefit of IMN irradiation (IMNI) are conflicting. The patient populations enrolled in previous studies were heterogeneous and most studies were conducted before modern systemic treatment and three-dimensional (3D) radiotherapy (RT) techniques were introduced. This study aims to assess the efficacy and safety of IMNI in the context of modern systemic treatment and computed tomography (CT)-based RT planning techniques. METHODS: POTENTIAL is a prospective, multicenter, open-label, parallel, phase III, randomized controlled trial investigating whether IMNI improves disease-free survival (DFS) in high-risk breast cancer with positive axillary nodes (pN+) after mastectomy. A total of 1800 patients will be randomly assigned in a 1:1 ratio to receive IMNI or not. All patients are required to receive ≥ six cycles of anthracycline and/or taxane-based chemotherapy. Randomization will be stratified by institution, tumor location (medial/central vs. other quadrants), the number of positive axillary nodes (1-3 vs. 4-9 vs. ≥10), and neoadjuvant chemotherapy (yes vs. no). Treatment will be delivered with CT-based 3D RT techniques, including 3D conformal RT, intensity-modulated RT, or volumetric modulated arc therapy. The prescribed dose is 50 Gy in 25 fractions or 43.5 Gy in 15 fractions. Tiered RT quality assurance is required. After RT, patients will be followed up at regular intervals. Oncological and toxilogical outcomes, especially cardiac toxicities, will be assessed. DISCUSSION: This trial design is intended to overcome the limitations of previous prospective studies by recruiting patients with pN+ breast cancer, using DFS as the primary endpoint, and prospectively assessing cardiac toxicities and requiring RT quality assurance. The results of this study will provide high-level evidence for elective IMNI in patients with breast cancer after mastectomy. TRIAL REGISTRATION: ClinicalTrails.gov , NCT04320979 . Registered 25 Match 2020, https://clinicaltrials.gov/ct2/show/NCT04320979.

Difference between planned and delivered radiotherapy dose to the internal mammary nodes in high-risk breast cancer patients.

Background and purpose: Chest wall movement during radiotherapy can impact the delivered dose to the internal mammary nodes (IMN) in high-risk breast cancer patients. Using portal imaging and dose reconstruction we aimed to examine the delivered IMN dose coverage. Material and methods: Cine MV images were recorded for 39 breast cancer patients treated with daily image-guided radiotherapy (IGRT) in deep-inspiration breath-hold (DIBH). On the final frame of each cine MV recording the chest wall was matched with the Digitally Reconstructed Radiograph (DRR) from the treatment plan. The geometrical chest wall error was determined in the imager-plane perpendicular to the cranio-caudal direction, rounded to integer millimeters, and binned. For each 1 mm bin, an isocenter-shifted treatment plan was recalculated assuming that the projected error observed in the cine MV image was caused by anterior-posterior chest wall movement in the IMN region. A weighted plan sum yielded the IMN clinical target volume receiving at least 90% dose (V90_CTVn_IMN). Results: The mean number of cine MV observations per patient was 36 (range 26-55). Most patients (67%) had on average a posterior chest wall position at treatment compared to planned. This translated into a change in the delivered median V90_CTVn_IMN of -0.7% (range, -11.9-2.9%; p < 0.001). The V90_CTVn_IMN reduction was greater than 9% in three patients. No clinically relevant differences were found for the mean lung dose or mean heart dose. Conclusion: Using cine MV images, we found that the delivered V90_CTVn_IMN was significantly lower than planned. In 8% of the patients, the V90_CTVn_IMN reduction exceeded 9%.

Internal mammary node irradiation improves 8-year survival in breast cancer patients: results from a retrospective cohort study in real-world setting.

BACKGROUND: Regional nodal irradiation (RNI) improves disease outcome in breast cancer patients, but the contribution of internal mammary node irradiation (IMNI) in the context of modern systemic treatment is still controversial. The aim of our study is to evaluate the effect of IMNI in patients with modern systemic treatment in real-world setting. METHODS: We retrospectively analyzed patients with primary breast cancer treated with surgery followed by adjuvant chemotherapy and adjuvant chestwall/breast irradiation and RNI from 5/2007-12/2010. RNI was delivered to the ipsilateral supraclavicular region and infraclavicular region + / - IMNs. We separated two groups based on the presence and the absence of IMNI. The primary end point was disease-free survival (DFS). DFS and overall survival (OS) were evaluated with Kaplan-Meier method. Differences between two groups were compared with the log-rank test (p < 0.05 considered significant). We used two methods to account for potential confounders: propensity score matching (PSM) and Cox regression analysis. RESULTS: We analyzed 872 patients who received RNI with IMNI (n = 390) or without IMNI (n = 482). Median radiation dose was 50 Gy. Median follow-up was 98 months. IMNI improved 8-year DFS rates versus no IMNI: 75.9% and 64.9% (p < 0.001). After PSM, baseline characteristics were well balanced between the two groups. IMNI significantly improved DFS (p < 0.001) in patients after PSM. IMNI was an independent prognostic factor for DFS. CONCLUSIONS: In this study, we found that IMNI improved DFS and OS in breast cancer patients in the context of modern systemic treatment. These data continue to support that IMNI is a key component of RNI.

Individual case review in a phase 3 randomized trial to investigate the role of internal mammary lymph node irradiation for breast cancer: Korean Radiation Oncology Group 08-06 study.

PURPOSE/OBJECTIVE: This study aimed to assess protocol compliance based on an individual case review (ICR) of the Korean Radiation Oncology Group-0806 trial. METHODS AND MATERIALS: For the ICR, 747 participants were divided into eight subgroups based on internal mammary node irradiation (IMNI), tumor laterality, and surgery type. Next, 15% of patients were randomly selected within each subgroup, and corresponding hospitals were subsequently requested to upload information related to radiation therapy (RT) planning. We reviewed the dose distributions of targets and organs at risk to determine protocol compliance. RESULTS: Data of 102 patients were collected. Overall, RT plans were found to be mostly protocol-compliant, with acceptability rates of 60-80% despite deviations in the ipsilateral lung in Arm 2 (IMNI group). However, despite few deviations, a subgroup analysis revealed significant differences in protocol compliance. Among RT techniques, plans using standard and partial wide tangents were most compliant in both Arms. In this ICR, the estimated survival benefits based on IMN doses were 7.7%, 8.4%, and 7.2% for all, breast-conserving surgery, and mastectomy cases, respectively. CONCLUSION: This ICR demonstrated overall protocol compliance, despite significant differences with regard to IMN irradiation and organs at risk according to subgroups and adopted field arrangements.