Tolerance of Concurrent Adjuvant Radiation Therapy and Pembrolizumab for Triple Negative Breast Cancer: Real Life Experience.

Purpose: The current standard-of-care management of locally advanced triple negative breast cancer (TNBC) is based on neoadjuvant chemo-immunotherapy with pembrolizumab, surgery, radiation therapy (RT), and adjuvant pembrolizumab. However, the safety of combining pembrolizumab with adjuvant breast RT has never been evaluated. This study evaluated the tolerance profile of concurrent pembrolizumab with adjuvant RT in patients with locally advanced TNBC. Methods and Materials: This bicentric ambispective study included all the patients with early and locally advanced TNBC who received neoadjuvant chemo-immunotherapy with pembrolizumab and adjuvant RT as part of their treatment. The tolerance profile of adjuvant RT was evaluated and compared in patients who received concurrent pembrolizumab and in patients for whom pembrolizumab was withheld. Results: Fifty-five patients were included between July 2021 and March 2023. Twenty-eight patients received adjuvant RT with concurrent pembrolizumab (RT+P group), and 27 patients had pembrolizumab withheld while receiving adjuvant RT (RT-only group). Two patients developed grade ≥3 toxicity (1 grade 3 pain in the RT+P group and 1 grade 3 radiodermatitis in the RT-only group), and there were no differences in terms of toxicity between the RT-only and the RT+P groups. No cardiac or pulmonary adverse event was reported during RT. With a median follow-up of 12 months (10-26), no patient relapsed. Conclusions: In this study of limited size, the authors did not find a difference between the RT-only and RT+P groups in terms of toxicity. More studies and longer follow-up may add to the strength of this evidence.

Systematic review for deep inspiration breath hold in proton therapy for mediastinal lymphoma: A PTCOG Lymphoma Subcommittee report and recommendations.

PURPOSE: To systematically review all dosimetric studies investigating the impact of deep inspiration breath hold (DIBH) compared with free breathing (FB) in mediastinal lymphoma patients treated with proton therapy as compared to IMRT (intensity-modulated radiation therapy)-DIBH. MATERIALS AND METHODS: We conducted a systematic review in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline using the PubMed database to identify studies of mediastinal lymphoma patients with dosimetric comparisons of proton-FB and/or proton-DIBH with IMRT-DIBH. Parameters included mean heart (MHD), lung (MLD), and breast (MBD) doses, among other parameters. Case reports were excluded. Absolute differences in mean doses > 1 Gy between comparators were considered to be clinically meaningful. RESULTS: As of April 2021, eight studies fit these criteria (n = 8), with the following comparisons: proton-FB vs IMRT-DIBH (n = 5), proton-DIBH vs proton-FB (n = 5), and proton-DIBH vs IMRT-DIBH (n = 8). When comparing proton-FB with IMRT-DIBH in 5 studies, MHD was reduced with proton-FB in 2 studies, was similar (<1 Gy difference) in 2 studies, and increased in 1 study. On the other hand, MLD and MBD were reduced with proton-FB in 3 and 4 studies, respectively. When comparing proton-DIBH with proton-FB, MHD and MLD were reduced with proton DIBH in 4 and 3 studies, respectively, while MBD remained similar. Compared with IMRT-DIBH in 8 studies, proton-DIBH reduced the MHD in 7 studies and was similar in 1 study. Furthermore, MLD and MBD were reduced with proton-DIBH in 8 and 6 studies respectively. Integral dose was similar between proton-FB and proton-DIBH, and both were substantially lower than IMRT-DIBH. CONCLUSION: Accounting for heart, lung, breast, and integral dose, proton therapy (FB or DIBH) was superior to IMRT-DIBH. Proton-DIBH can lower dose to the lungs and heart even further compared with proton-FB, depending on disease location in the mediastinum, and organ-sparing and target coverage priorities.

Neoadjuvant Concurrent Radiotherapy and Chemotherapy in Early Breast Cancer Patients: Long-Term Results of a Prospective Phase II Trial.

Background: Neoadjuvant concurrent radiochemotherapy makes it possible to increase the breast conservation rate. This study reports the long term outcome of this treatment. Methods: From 2001 to 2003, 59 women with T2-3 N0-2 M0 invasive breast cancer (BC) not amenable to upfront breast conserving treatment (BCS) were included in this prospective, non-randomized phase II study. Chemotherapy (CT) consisted of four cycles of continuous 5-FU infusion and Vinorelbine. Starting concurrently with the second CT cycle, normofractionated RT was delivered to the breast and LN. Breast surgery was then performed. Results: Median follow-up (FU) was 13 years [3-18]. BCS was performed in 41 (69%) patients and mastectomy in 18 patients, with pathological complete response rate of 27%. Overall and distant-disease free survivals rates at 13 years were 70.9% [95% CI 59.6-84.2] and 71.5% [95% CI 60.5-84.5] respectively. Loco regional and local controls rates were 83.4% [95% CI 73.2-95.0] and 92.1% [95% CI 83.7-100], respectively. Late toxicity (CTCAE-V3) was assessed in 51 patients (86%) with a median follow-up of 13 years. Fifteen presented grade 2 fibrosis (29.4%), 8 (15.7%) had telangiectasia, and 1 had radiodermatitis. Conclusions: This combined treatment provided high long-term local control rates with limited side-effects.

Eribulin combined with radiation therapy in a young patient re-irradiated for a new lesion of breast cancer.

Eribulin is widely used in the treatment of metastatic breast cancer, with a manageable toxicity profile. This aggressive disease often requires systemic and local treatments, comprising surgery or radiotherapy. However, eribulin is usually discontinued during radiation therapy due to the lack of data concerning the safety of this combination, especially in the setting of repeat locoregional radiation therapy. Our patient was diagnosed with ER positive invasive ductal carcinoma of the left breast initially treated by surgery, radiation therapy, chemotherapy, and hormone therapy. She then received various lines of chemotherapy for multiple triple-negative relapses in the left axillary region. Since October 2020, she has been treated by eribulin. In order to improve local control, it was decided to add local radiation therapy to the region of recurrence in addition to systemic therapy. She underwent radiation therapy concomitantly with eribulin from February to March 2021. Treatment was very well tolerated, and no acute toxicity was reported. This is the first published case of repeat locoregional radiation therapy in combination with eribulin.

Proton Therapy for Breast Cancer: A Consensus Statement From the Particle Therapy Cooperative Group Breast Cancer Subcommittee.

Radiation therapy plays an important role in the multidisciplinary management of breast cancer. Recent years have seen improvements in breast cancer survival and a greater appreciation of potential long-term morbidity associated with the dose and volume of irradiated organs. Proton therapy reduces the dose to nontarget structures while optimizing target coverage. However, there remain additional financial costs associated with proton therapy, despite reductions over time, and studies have yet to demonstrate that protons improve upon the treatment outcomes achieved with photon radiation therapy. There remains considerable heterogeneity in proton patient selection and techniques, and the rapid technological advances in the field have the potential to affect evidence evaluation, given the long latency period for breast cancer radiation therapy recurrence and late effects. In this consensus statement, we assess the data available to the radiation oncology community of proton therapy for breast cancer, provide expert consensus recommendations on indications and technique, and highlight ongoing trials' cost-effectiveness analyses and key areas for future research.

Selection criteria for early breast cancer patients in the DBCG proton trial - The randomised phase III trial strategy.

BACKGROUND AND PURPOSE: Adjuvant radiotherapy of internal mammary nodes (IMN) improves survival in high-risk early breast cancer patients but inevitably leads to more dose to heart and lung. Target coverage is often compromised to meet heart/lung dose constraints. We estimate heart and lung dose when target coverage is not compromised in consecutive patients. These estimates are used to guide the choice of selection criteria for the randomised Danish Breast Cancer Group (DBCG) Proton Trial. MATERIALS AND METHODS: 179 breast cancer patients already treated with loco-regional IMN radiotherapy from 18 European departments were included. If the clinically delivered treatment plan did not comply with defined target coverage requirements, the plan was modified retrospectively until sufficient coverage was reached. The choice of selection criteria was based on the estimated number of eligible patients for different heart and lung dose thresholds in combination with proton therapy capacity limitations and dose-response relationships for heart and lung. RESULTS: Median mean heart dose was 3.0 Gy (range, 1.1-8.2 Gy) for left-sided and 1.4 Gy (0.4-11.5 Gy) for right-sided treatment plans. Median V17Gy/V20Gy (hypofractionated/normofractionated plans) for ipsilateral lung was 31% (9-57%). The DBCG Radiotherapy Committee chose mean heart dose ≥ 4 Gy and/or lung V17Gy/V20Gy ≥ 37% as thresholds for inclusion in the randomised trial. Using these thresholds, we estimate that 22% of patients requiring loco-regional IMN radiotherapy will be eligible for the trial. CONCLUSION: The patient selection criteria for the DBCG Proton Trial are mean heart dose ≥ 4 Gy and/or lung V17Gy/V20Gy ≥ 37%.

Risk of Lymphedema Following Contemporary Treatment for Breast Cancer: An Analysis of 7617 Consecutive Patients From a Multidisciplinary Perspective.

OBJECTIVE: The aim of this study was to identify the comprehensive risk factors for lymphedema, thereby enabling a more informed multidisciplinary treatment decision-making. SUMMARY BACKGROUND DATA: Lymphedema is a serious long-term complication in breast cancer patients post-surgery; however, the influence of multimodal therapy on its occurrence remains unclear. METHODS: We retrospectively collected treatment-related data from 5549 breast cancer patients who underwent surgery between 2007 and 2015 at our institution. Individual radiotherapy plans were reviewed for regional nodal irradiation (RNI) field design and fractionation type. We identified lymphedema risk factors and used them to construct nomograms to predict individual risk of lymphedema. Nomograms were validated internally using 100 bootstrap samples and externally using 2 separate datasets of 1877 Asian and 191 Western patients. RESULTS: Six hundred thirty-nine patients developed lymphedema during a median follow-up of 60 months. The 3-year lymphedema incidence was 10.5%; this rate increased with larger irradiation volumes (no RNI vs RNI excluding axilla I-II vs RNI including axilla I-II: 5.7% vs 16.8% vs 24.1%) and when using conventional fractionation instead of hypofractionation (13.5% vs 6.8%). On multivariate analysis, higher body mass index, larger number of dissected nodes, taxane-based regimen, total mastectomy, larger irradiation field, and conventional fractionation were strongly associated with lymphedema (all P < 0.001). Nomograms constructed based on these variables showed good calibration and discrimination internally (concordance index: 0.774) and externally (0.832 for Asian and 0.820 for Western patients). CONCLUSIONS: Trimodality breast cancer treatment factors interact to promote lymphedema. Lymphedema risk can be decreased by deintensifying node dissection, chemotherapy regimen, and field and dose of radiotherapy. Deescalation strategies on a multidisciplinary basis might minimize lymphedema risk.

Adjuvant Trastuzumab Emtansine (T-DM1) and Concurrent Radiotherapy for Residual Invasive HER2-positive Breast Cancer: Single-center Preliminary Results.

OBJECTIVES: The treatment of nonmetastatic HER2-positive breast cancer with residual invasive disease using concurrent Trastuzumab emtansine (T-DM1) and radiotherapy appears to be an effective option. Our aim was to evaluate the acute side effects of this treatment regime. METHODS: Fourteen patients were treated between March 2019 and April 2020 concurrent T-DM1 and radiotherapy. Left ventricular ejection fraction was assessed at baseline, before and after radiotherapy. All toxicities were evaluated using Common Terminology Criteria of Adverse Events (CTCAE) version 3.0. RESULTS: The median age was 55 years (range 36 to 72). All patients received total dose of 50 Gy for the breast/ chest wall, 10 patients got lymph node irradiation, 4 patients received an additional tumor bed boost. The most common side effect was grade 1 radiodermatitis. A reversible grade 2 left ventricular ejection fraction decrease occurred in 2 patients. During our examination 3 patients showed alanine aminotransferases increase after the cycle 4 of T-DM1, 1 patient had grade 1, 1 patient grade 2, and 1 patient grade 3 alanine aminotransferase increases. CONCLUSIONS: The acute toxicity rate especially focusing on skin and cardiac toxicity were assumed acceptable in our cohort. To safely administer this concomitant treatment, further examination and prospective data are needed.

Outcomes of exclusive radiation therapy for older women with breast cancer according to age and comorbidity status: An observational retrospective study.

The management of older patients with breast cancer, a public health issue, remains a highly topical subject. Among this heterogeneous population, only few studies have focused on outcomes of older women treated with exclusive radiation therapy for localized BC. This retrospective study provides data concerning the efficacy and safety of exclusive RT, as well as the impact of comorbidities according to the Charlson Comorbidity Index on survival in this subset of women not suitable for surgery or who have refused it. This analysis demonstrates that this treatment is well-tolerated; however, the prognosis is strongly impacted by age and comorbidities.

Prospective results of concurrent radiation therapy and weekly paclitaxel as salvage therapy for unresectable locoregionally recurrent breast cancer.

PURPOSE: To investigate the efficacy and toxicity of concurrent radiation therapy (RT) and paclitaxel in the treatment of unresectable locoregionally recurrent breast cancer (RBC) after mastectomy as primary treatment. METHODS: This was a prospective monocentric study of 51 patients (pts) diagnosed with unresectable locoregionally RBC after mastectomy and treated between 2008 and 2012. Radiotherapy (RT) was delivered at 60 Gy in 30 treatment fractions to recurrent sites. Chemotherapy was weekly paclitaxel of 50 mg/m2 for 5 weeks. All pts. underwent clinical examination, CT or PET/CT every 3 months in first 2 years and then every 6 months. Tumor response was evaluated clinically and by CT using the RECIST criteria. Toxicity was assessed weekly during RT by the NCI common toxicity criteria (version 3.0). RESULTS: Fifty-one pts. with 61 recurrent sites were studied. The median age was 49 years. Sites of RBC were chest wall in 20 patients (32.8%), supraclavicular in 19 (31.1%), axilla in 11 (18.0%), and internal mammary lymph nodes in the remaining 11 (18.0%). RBC presented as single in 25 pts., multiple in 20 pts. and diffuse growth in 6 pts. Clinical response was observed in 47 pts. (92.2%), with 36 (70.6%) complete and 11 (21.6%) partial responses. Two patients (3.9%) presented with stable disease and 2 progressive disease. The cumulative local progression-free survival rate was 62.8% at 2 year and 53.0% at 5 years after treatment. No grade 4 toxicity was observed. Grade 3 radiation dermatitis and leukocytopenia were observed in 10 (19.6%) and 12 (23.5%) pts., respectively. One patient experienced grade 2 pneumonitis. CONCLUSIONS: Concurrent RT and weekly paclitaxel could be an effective therapeutic option for unresectable locoregionally recurrent breast cancer after mastectomy with an acceptable toxicity profile.

Competing risk nomogram predicting initial loco-regional recurrence in gastric cancer patients after D2 gastrectomy.

BACKGROUND: Lacking quantitative evaluations of clinicopathological features and the risk factors for loco-regional recurrence (LRR) in gastric cancer after D2 gastrectomy, we aimed to develop a competing risk nomogram to identify the risk predictors for initial LRR. METHODS: We retrospectively analysed 1105 patients who underwent radical gastrectomy with D2 resection for stage I-III gastric cancer. A nomogram predicting initial LRR of gastric cancer was conducted based on Fine and Grey's competing risk analysis. The predictive accuracy and discriminative ability of the model were determined using the concordance index (C-index) and calibration curve. Decision tree analysis was performed for patient grouping. RESULTS: At a median follow-up of 28.4 months, 274 patients developed 373 first recurrence events (local, regional, and distant disease). The median recurrence-free survival (RFS) was 16.7 months. Multivariate competing risk analysis showed that age (SHR, 1.72; 95% CI, 1.10-2.83, p = 0.031), CEA (SHR, 1.94; 95% CI, 1.09-3.46, p = 0.024), pT4 (SHR, 2.77; 95% CI, 1.01-7.57, p = 0.047), lymph node metastasis (SHR 1.92, 95% CI: 1.09-3.38, p = 0.024) and LVI (SHR, 1.84; 95% CI, 1.06-3.20, p = 0.028) were independent risk factors for LRR (all p < 0.05). The nomogram incorporating these factors achieved good agreement between prediction and actual observation with a concordance index of 0.738 (95% CI, 0.767 to 0.709). In a subgroup analysis of node-positive patients, pN3b was associated with increased peritoneal and distant metastasis (p = 0.048). The para-aortic lymph nodes were the most frequent sites (n = 71) of LRR, and among them, the 16a2 and 16b1 nodes exhibited even more prevalence (90.1 and 81.7%). CONCLUSIONS: Adjuvant radiotherapy might be recommended in gastric cancer patients ≥65 years old or those with pN+, pT4, LVI, or increased CEA levels, particularly in high-risk or pN1-3a patients. The competing risk nomograms may be considered as convenient and individualized predictive tools for LRR in gastric cancer after D2 gastrectomy. It is also recommended that the clinical target volume (CTV) include 16a2 and 16b1 regions of para-aortic lymph nodes.

Salvage Treatment and Survival for Relapsed Follicular Lymphoma Following Primary Radiation Therapy: A Collaborative Study on Behalf of ILROG.

PURPOSE: We previously reported that ∼30% of patients with localized follicular lymphoma (FL) staged by 18F-fluorodeoxyglucose positron emission tomography-computed tomography receiving primary radiation therapy (RT) will relapse within 5 years. We sought to report outcomes for those who relapsed. METHODS AND MATERIALS: We conducted a multicenter, retrospective study of patients aged ≥18 years who received RT ≥ 24 Gy for stage I to II, grade 1 to 3A FL, staged with 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography-computed tomography. Observation was defined as >6 months without treatment from relapse. Overall survival (OS) and freedom from progression (FFP) were estimated with Kaplan-Meier analysis and univariable and multivariable analyses with Cox regression. RESULTS: Of 512 patients with median follow-up of 52 months, 149 (29.1%) developed recurrent lymphoma at a median of 23 months (range, 1-143) after primary RT. Median follow-up was 33 months after relapse. Three-year OS was 91.4% after recurrence. OS was significantly worse for those with relapse ≤12 months from date of diagnosis versus all others-88.7% versus 97.6%, respectively (P = .01)-and remained significantly worse on multivariable analyses (follicular lymphoma international prognostic index-adjusted hazard ratio, 3.61; P = .009). Histology at relapse included 93 indolent (grade 1-3A), 3 FL grade 3B/not otherwise specified, and 18 diffuse large B-cell lymphoma; 35 patients did not undergo biopsy. Of those with follow-up ≥3 months who underwent biopsy (n = 74) or had presumed (n = 23) indolent recurrence, 58 patients (59.8%) were observed, 19 (19.6%) had systemic therapy, 16 (16.5%) had RT, and 4 (4.1%) had systemic therapy + RT. For patients with indolent recurrences that were observed, 3-year FFP or freedom from treatment was 56.6% (median, 48 months). For all patients with biopsied/presumed indolent recurrence receiving salvage treatment (n = 59, including 20 initially observed) 3-year FFP was 73.9%. CONCLUSIONS: Prognosis for patients with relapsed FL after primary radiation therapy is excellent, supporting the role of primary radiation in the management of early stage disease. Patients with localized FL treated with primary RT who experience early relapse (<12 months) have inferior survival compared with those with longer disease-free interval.