CANTO skin: Evaluation of skin toxicity risk factors in patients treated for breast cancer.

Skin reaction is a common toxicity during oncology management, especially followed during the radiotherapy. Its assessment and understanding of the factors influencing its occurrence, is a major issue in the management of patients treated for an early breast cancer (BC). We evaluated 8561 patients during their overall management for a BC. We focus on specific skin toxicities: erythema, fibrosis, telangiectasia and changes of skin colour. These toxicities were assessed at the baseline defined as 0-3-6 (M0), 12 (M12), 36 (M36) and 60 (M60) months. The prevalence of toxicities of interest varied over time, so at M0, 30.4% of patients had erythema while 17.7% of patients had fibrosis. At M60, the prevalence of erythema was 2%, while fibrosis remained stable at about 19%. After adjustments, at M0, there was a significant association between the onset of cutaneous erythema and obesity, the presence of axillary dissection, the type of surgery and the tumour phenotype RH+/HER2+. Concerning fibrosis, a significant association was found, at M12, with the age of the patient, obesity, Charlson score and type of surgery. Concerning the modification of skin colour at M12, we find a link between the age of the patient, obesity, tobacco consumption and alcohol consumption. The prevention of this toxicity is a major issue for the quality of life. Our results allow us to understand the risk of developing skin toxicity in a patient, depending on her intrinsic, tumour or therapeutic characteristics and to implement adapted means of prevention and monitoring.

Comparison of prone and supine positioning for breast cancer radiotherapy using REQUITE data: dosimetry, acute and two years physician and patient-reported outcomes.

OBJECTIVE: Most patients receive whole breast radiotherapy in a supine position. However, two randomised trials showed lower acute toxicity in prone position. Furthermore, in most patients, prone positioning reduced doses to the organs at risk. To confirm these findings, we compared toxicity outcomes, photographic assessment, and dosimetry between both positions using REQUITE data. METHODS: REQUITE is an international multi-centre prospective observational study that recruited 2069 breast cancer patients receiving radiotherapy. Data on toxicity, health-related quality of life (HRQoL), and dosimetry were collected, as well as a photographic assessment. A matched case control analysis compared patients treated prone (n = 268) versus supine (n = 493). Exact matching was performed for the use of intensity-modulated radiotherapy, boost, lymph node irradiation, chemotherapy and fractionation, and the nearest neighbour for breast volume. Primary endpoints were dermatitis at the end of radiotherapy, and atrophy and cosmetic outcome by photographic assessment at two years. RESULTS: At the last treatment fraction, there was no significant difference in dermatitis (p = .28) or any HRQoL domain, but prone positioning increased the risk of breast oedema (p < .001). At 2 years, patients treated in prone position had less atrophy (p = .01), and higher body image (p < .001), and social functioning (p < .001) scores. The photographic assessment showed no difference in cosmesis at 2 years (p = .22). In prone position, mean heart dose (MHD) was significantly lower for left-sided patients (1.29 Gy vs 2.10 Gy, p < .001) and ipsilateral mean lung dose (MLD) was significantly lower for all patients (2.77 Gy vs 5.89 Gy, p < .001). CONCLUSIONS: Prone radiotherapy showed lower MLD and MHD compared to supine position, although the risk of developing breast oedema during radiotherapy was higher. At 2 years the photographic assessment showed no difference in the cosmetic outcome, but less atrophy was seen in prone-treated patients and this seems to have a positive influence on the HRQoL domain of body image.

CANTO-RT: Skin toxicities evaluation of a multicentre large prospective cohort of irradiated patients for early-stage breast cancer.

Skin damage is the most common and most important toxicity during and after radiation therapy (RT). Its assessment and understanding of the factors influencing its occurrence, is a major issue in the management of patients irradiated for an early breast cancer. CANTO is a prospective clinical cohort study of 10 150 patients with stage I-III BC treated from 2012 to 2017 in 26 cancer centres. In our study, we used CANTO-RT, a subcohort of CANTO, including 3480 patients who received RT. We are focus on specific skin toxicities: erythema, fibrosis, telangiectasia and cutaneous pigmentation. The prevalence of toxicities of interest varied over time, so at baseline for early toxicity Month (M) 0-3-6, 41.1% of patients had erythema while 24.8% of patients had fibrosis. At M12 and M36, the prevalence of erythema decreased, respectively, while fibrosis remains stable. The prevalence of telangiectasia increases from 1% to 7.1% from M0-3-6 to M36. After adjustments, we showed an association between the occurrence of skin erythema and obesity; the type of surgery; the presence of axillary dissection; the use of taxane-based CT and the 3D vs IMRT irradiation technique. Regarding fibrosis, an association is found, at M0-3-6, with age at diagnosis, obesity, tobacco and the use of boost. Only obesity and the type of surgery received by the patient remained statistically significant at M12 and M36. In our study we identified several risk factors for acute and late skin reactions. The use of a boost was mainly related to the occurrence of fibrosis while the use of IMRT-type technique decreased the occurrence of skin erythema.

Longitudinal analysis of health-related quality of life in cancer clinical trials: methods and interpretation of results.

PURPOSE: Health-related quality of life (HRQoL) is assessed by self-administered questionnaires throughout the care process. Classically, two longitudinal statistical approaches were mainly used to study HRQoL: linear mixed models (LMM) or time-to-event models for time to deterioration/time until definitive deterioration (TTD/TUDD). Recently, an alternative strategy based on generalized linear mixed models for categorical data has also been proposed: the longitudinal partial credit model (LPCM). The objective of this article is to evaluate these methods and to propose recommendations to standardize longitudinal analysis of HRQoL data in cancer clinical trials. METHODS: The three methods are first described and compared through statistical, methodological, and practical arguments, then applied on real HRQoL data from clinical cancer trials or published prospective databases. In total, seven French studies from a collaborating group were selected with longitudinal collection of QLQ-C30. Longitudinal analyses were performed with the three approaches using SAS, Stata and R software. RESULTS: We observed concordant results between LMM and LPCM. However, discordant results were observed when we considered the TTD/TUDD approach compared to the two previous methods. According to methodological and practical arguments discussed, the approaches seem to provide additional information and complementary interpretations. LMM and LPCM are the most powerful methods on simulated data, while the TTD/TUDD approach gives more clinically understandable results. Finally, for single-item scales, LPCM is more appropriate. CONCLUSION: These results pledge for the recommendation to use of both the LMM and TTD/TUDD longitudinal methods, except for single-item scales, establishing them as the consensual methods for publications reporting HRQoL.

Clinical Correlations of Programmed Cell Death Ligand 1 Status in Liquid and Standard Biopsies in Breast Cancer.

BACKGROUND: Data regarding the prognostic value of programmed cell death ligand 1 (PD-L1) expression on circulating tumor cells (CTCs) are lacking. However, CTCs could represent an alternative approach to serial biopsies, allowing real-time monitoring of cancer phenotype. METHODS: We evaluated, in a dedicated prospective clinical trial, the clinicopathological correlations and prognostic value of PD-L1(+)-CTCs in 72 patients with metastatic breast cancer (MBC). RESULTS: Eighteen of 56 patients with available archival tissue presented at least one positive (≥1%) PD-L1 tumor sample. Baseline CTCs and PD-L1(+)-CTCs were detected in 57 (79.2%) and 26 (36.1%) patients. No significant correlation was found between PD-L1 tumors and CTC expression. In univariate analysis, triple negative (TN) phenotype, number of metastatic treatments, >2 metastatic sites, ≥5 CTCs and PD-L1(+)-CTCs were significantly associated with progression-free survival, while tissue PD-L1 expression was not. In multivariate analysis, TN phenotype, number of metastatic treatments and of metastatic sites were the only 3 variables independently associated with progression-free survival. Progesterone receptor negativity, TN phenotype, >2 metastatic sites and ≥5 CTCs were significantly associated with overall survival in univariate analysis. In multivariable analysis, TN phenotype and >2 metastatic sites were the only 2 independent variables. CONCLUSIONS: Unlike PD-L1(+)-tumor, PD-L1(+)-CTCs correlate to survival in MBC. Reappraisal of the role of PD-L1 expression by tumor tissue and by CTCs under anti-PD-1/PD-L1 treatment is necessary to evaluate its predictive value and potential role as a stratifying factor in strategies and trials for MBC patients with MBC. CLINICAL TRIAL REGISTRATION: NCT02866149.

An auristatin-based antibody-drug conjugate targeting HER3 enhances the radiation response in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer characterized by poor response to chemotherapy and radiotherapy due to the lack of efficient therapeutic tools and early diagnostic markers. We previously generated the nonligand competing anti-HER3 antibody 9F7-F11 that binds to pancreatic tumor cells and induces tumor regression in vivo in experimental models. Here, we asked whether coupling 9F7-F11 with a radiosensitizer, such as monomethylauristatin E (MMAE), by using the antibody-drug conjugate (ADC) technology could improve radiation therapy efficacy in PDAC. We found that the MMAE-based HER3 antibody-drug conjugate (HER3-ADC) was efficiently internalized in tumor cells, increased the fraction of cells arrested in G2/M, which is the most radiosensitive phase of the cell cycle, and promoted programmed cell death of irradiated HER3-positive pancreatic cancer cells (BxPC3 and HPAC cell lines). HER3-ADC decreased the clonogenic survival of irradiated cells by increasing DNA double-strand break formation (based on γH2AX level), and by modulating DNA damage repair. Tumor radiosensitization with HER3-ADC favored the inhibition of the AKT-induced survival pathway, together with more efficient caspase 3/PARP-mediated apoptosis. Incubation with HER3-ADC before irradiation synergistically reduced the phosphorylation of STAT3, which is involved in chemoradiation resistance. In vivo, the combination of HER3-ADC with radiation therapy increased the overall survival of mice harboring BxPC3, HPAC cell xenografts or patient-derived xenografts, and reduced proliferation (KI67-positive cells). Combining auristatin radiosensitizer delivery via an HER3-ADC with radiotherapy is a new promising therapeutic strategy in PDAC.

Prognostic value of androgen receptor and FOXA1 co-expression in non-metastatic triple negative breast cancer and correlation with other biomarkers.

BACKGROUND: In luminal androgen receptor (AR) tumours, FOXA1 may direct AR to sites occupied by ER in luminal tumours, thus stimulating proliferation. METHODS: AR and FOXA1 expression were evaluated by immunohistochemistry in 333 non-metastatic triple-negative breast cancers (TNBC). Positivity threshold was set at ≥ 1% staining. Lymphocytic infiltration, PD-L1expression, PIK3CA mutations, PTEN defects and BRCA1 promoter methylation were assessed. RESULTS: AR + /FOXA1 + tumours (42.4%) were more frequently: found in older patients, lobular, of lower nuclear grade, with more frequently PIK3CA mutations; exhibited less frequently BRCA1 promoter methylation, defects of PTEN and PD-L1 expression than others. Recurrence-free and overall survivals were significantly lower for AR + /FOXA1 + TNBC (median follow-up: 7.8 years). CONCLUSIONS: AR + /FOXA1 + expression defines a luminal-like TNBC subgroup affected with a worse outcome compared to other TNBC and a higher risk of late recurrences. This subgroup appears enriched in PIK3CA mutations, suggesting a role for PI3K inhibitors in this subgroup.

Clinicopathological and Treatment-Associated Prognostic Factors in Patients with Breast Cancer Leptomeningeal Metastases in Relation to Tumor Biology.

BACKGROUND: Breast cancer (BC) is one of the solid tumors most commonly associated with leptomeningeal disease (LMD). LMD carries a devastating prognosis; however, disease presentation and prognostic factors are uncertain. SUBJECTS, MATERIALS, AND METHODS: In order to describe patient characteristics, treatment patterns, and factors associated with survival in a contemporary multicentric cohort, 153 consecutive BC patients diagnosed with LMD at two European institutions (2002-2017) were included. Time to LMD and overall survival (OS) after LMD diagnosis were evaluated using the Kaplan-Meier method and Cox proportional hazards models. RESULTS: Median age at LMD diagnosis was 58 years (25-84). Tumor phenotype distribution was as follows: hormone receptor (HR) positive (HR+)/human epidermal growth receptor 2 (HER2) negative 51.0%, triple-negative 15.0%, HR+/HER2 positive (HER2+) 13.1% and HR negative/HER2+ 7.2%. Most patients received active anticancer treatments (radiation therapy [RT] n = 42, systemic therapy n = 110, intrathecal treatment n = 103).Median OS was 3.9 months (95% confidence interval [CI] 2.4-5.5). Eastern Cooperative Oncology Group performance status (ECOG PS) >2, high white blood cells count, low glucose, and high protein in cerebrospinal fluid (CSF) were poor prognostic factors. Having received RT or systemic treatment was associated with better prognosis. In multivariate analysis, ECOG PS (hazard ratio 2.22, 95% CI 1.25-3.94), CSF glucose levels (hazard ratio 1.74, 95% CI 1.05-2.88), and having received systemic treatment (hazard ratio 0.17, 95% CI 0.09-0.32) were confirmed as independent prognostic factors. In HER2+ BC patients, having received systemic HER2-targeted therapy was the only factor maintaining independent prognostication (hazard ratio 0.12, 95% CI 0.02-0.67) in multivariate analysis. CONCLUSION: Despite being limited by their retrospective nature, these results highlight the need for clinical trials in BC LMD, stratified on tumor biology. IMPLICATIONS FOR PRACTICE: Leptomeningeal disease (LMD) is a devastating complication of breast cancer (BC), and its optimal therapy is still not defined. Here, patient characteristics, treatment patterns, and prognostic factors from a contemporary cohort of 153 BC-related LMD patients are reported. In multivariate analysis, Eastern Cooperative Oncology Group performance status, cerebrospinal fluid glucose levels, and having received systemic treatment were confirmed as independent prognostic factors in the overall population, whereas in human epidermal growth receptor 2 (HER2) positive BC patients, having received systemic HER2-targeted therapy was the only factor maintaining independent prognostication in multivariate analysis. These results highlight the need to consider stratification on tumor biology in the treatment of BC LMD.

Early onset breast cancer: differences in risk factors, tumor phenotype, and genotype between North African and South European women.

PURPOSE: This report compares the risk factors, the tumor phenotypes, and the BRCA1/BRCA2 genotype of early onset breast cancer (EOBC) patients between Southern Europe and North Africa. METHODS: Four hundred and fifty six women with invasive EOBC (≤40 years) were prospectively included from four centers in France (n = 270) and four centers in North Africa (Algeria, Egypt, Morocco, Tunisia; n = 186). Life style, tumor phenotype, familial history, BRCA1/BRCA2 genotype were compared between the two populations. RESULTS: We found an older age at menarche, a higher number of childbearing, a more frequent breastfeeding, a higher body mass index, a lower use of oral contraceptives in North African women compared to French women. TNM stage at diagnosis was higher in North African women than in French women. North African women had a lower incidence of triple negative and proliferative (Ki 67 index > 20%) tumors. There was a lower rate of BRCA1 mutation in North Africa (7 vs. 15%, P = 0.02). Three putative BRCA1/2 founder mutations were identified in North Africa. CONCLUSIONS: In EOBC, we found significant differences in risk factors, phenotype and a higher incidence of BRCA1 mutations in Southern Europe as compared to North Africa. The worst prognosis previously reported for EOBC in North Africa is more likely due to a higher stage at diagnosis than to a more aggressive phenotype, since triple negative tumors are more common in Southern Europe and advanced tumors in North Africa.

Randomized phase 2 neoadjuvant trial evaluating anastrozole and fulvestrant efficacy for postmenopausal, estrogen receptor-positive, human epidermal growth factor receptor 2-negative breast cancer patients: Results of the UNICANCER CARMINA 02 French trial (UCBG 0609).

BACKGROUND: Treatment strategies for locally advanced breast cancer in elderly patients too frail to receive neoadjuvant chemotherapy and the introduction of new classes of drugs in the early 2000s have led to the consideration of endocrine therapy as a neoadjuvant treatment for younger hormone receptor (HR)-positive, postmenopausal patients not eligible for primary breast-conserving surgery (BCS). METHODS: This was a multicenter, phase 2, randomized trial designed to evaluate as its primary objective the clinical response rate after up to 6 months of neoadjuvant endocrine therapy (NET) alone in HR-positive/human epidermal growth factor receptor 2 (HER2)-negative patients with 1 mg of anastrozole (arm A) or 500 mg of fulvestrant (arm B). Secondary objectives included the BCS rate, tumor response assessment (breast ultrasound and magnetic resonance imaging), pathological response (Sataloff classification), safety profile, relapse-free survival (RFS), and predictive markers of responses and outcomes. RESULTS: From October 2007 to April 2011, 116 women (mean age, 71.6 years) with operable infiltrating breast adenocarcinoma (T2-T4, N0-N3, M0) were randomized to receive anastrozole or fulvestrant. The clinical response rates at 6 months were 52.6% (95% confidence interval [CI], 41%-64%) in arm A and 36.8% (95% CI, 25%-49%) in arm B. BCS was performed for 57.6% of arm A patients and 50% of arm B patients. The RFS rates at 3 years were 94.9% in arm A and 91.2% in arm B. The Preoperative Endocrine Prognostic Index status was significantly predictive of RFS. Both treatments were well tolerated. CONCLUSIONS: Both drugs are effective and well tolerated as NET in postmenopausal women with HR-positive/HER2-negative breast cancer. NET could be considered a treatment option in this subpopulation. Cancer 2016;122:3032-3040. © 2016 American Cancer Society.

The 2016 Assisi Think Tank Meeting on breast cancer: white paper.

PURPOSE: To identify weak points in daily routine use of radiation therapy (RT) for non-metastatic breast cancer patients, particularly when data are lacking or equivocal, a "think tank" of experts met in Assisi. METHODS: Before the meeting, controversial issues on non-metastatic breast cancer were identified and reviewed, and clinical practice investigated by means of an online questionnaire. During the 3-day meeting, topics were discussed in-depth with attendees and potential sponsors that are involved in breast cancer treatment. RESULTS: Three issues were identified as needing further investigation: (1) Regional lymph node treatment in early-stage breast cancer; (2) Combined post-mastectomy RT and breast reconstruction; (3) RT in patients treated with primary systemic therapy. Future research proposals included the following: (1) Participating in appropriately selected on-going clinical trials; (2) Designing new randomized controlled clinical trials and prospective population cohort studies; (3) Setting-up large database(s) to generate predictive response models and detect biomarkers for tailored loco-regional treatments. CONCLUSIONS: It is hoped that the ATTM findings, as described in the present white paper, will stimulate a new generation of radiation oncologists to focus on research in these areas, and that the white paper will become a tool for multidisciplinary groups to help them design research proposals and strategies.

Loco-regional control after neo-adjuvant chemotherapy and conservative treatment for locally advanced breast cancer patients.

Breast-conserving treatment (BCT) has been validated for breast cancer patients receiving adjuvant chemotherapy. Our objective was to evaluate the difference in loco-regional recurrence (LRR) rates between BCT and mastectomy in patients receiving radiation therapy after neo-adjuvant chemotherapy (NCT). A retrospective data base was used to identify all patients with breast cancer undergoing NCT from 2002 to 2007. Patients with initial metastatic disease were excluded from this analysis. LRR was compared between those undergoing BCT and mastectomy. Individual variables associated with LRR were evaluated. Two hundred eighty-four patients were included, 111 (39%) underwent BCT and 173 (61%) mastectomy. Almost all patients (99%) in both groups received postoperative radiation. Pathologic complete response was seen in 37 patients, of which 28 underwent BCT (p < 0.001). Patients receiving mastectomy had more invasive lobular carcinoma (p = 0.007) and a higher American Joint Committee on Cancer (AJCC) stage (p < 0.001) at diagnosis than those with BCT. At a median follow-up of 6.3 years, the loco-regional control rate was 91% (95% CI: 86-94%). The 10-year LRR rate was similar in the BCT group (9.2% [95% CI: 4.9-16.7%]) and in the mastectomy group (10.7% [95% CI: 5.9-15.2%]; p = 0.8). Ten-year overall survival (OS) rates (63% [95% CI: 46-79%] in the BCT group; 60% [95% CI: 47-73%] in the mastectomy group, p = 0.8) were not statistically different between the two patient populations. Multivariate analysis showed that AJCC stage ≥ III (HR: 2.6; 95% CI: 1.2-5.8; p = 0.02), negative PR (HR: 6; 95% CI: 1.2-30.6, p = 0.03), and number of positive lymph nodes ≥3 (HR: 2.5; 95% CI: 1.1-5.9; p = 0.03) were independent predictors of LRR. Ten-year OS was similar in the BCT and in the mastectomy group (p = 0.1). The rate of LRR was low and did not significantly differ between the BCT and the mastectomy group after NCT. Randomized trials assessing whether mastectomy can be safely omitted in selected breast cancer patients (nonstage III tumors or those which do not require adjuvant hormone suppression) which respond to NCT are required.

[Onco'sport testing by patients: Lived experience of patients with cancer practicing adapted physical activity as part of the Onco'sport program, a qualitative study]. / Onco'sport à l'épreuve des patients : expérience vécue des patients atteints d'un cancer pratiquant de l'activité physique adaptée dans le cadre du programme Onco'sport, une étude qualitative.

INTRODUCTION: Physical activity is a major determinant in the prevention of chronic diseases, equally on the side effects of treatments and the consequences of the disease. It improves quality of life, but also reduces morbidity and mortality, and therefore health expenses. A sedentary lifestyle is the fourth cause of premature death in the world, in the context of chronic non-communicable diseases. In France, the prescription for adapted physical activity (APA) has been included in the law since 2016. With the development of "Maisons Sport santé", the Onco'sport program was developed to enable people affected by cancer to participate in adapted physical activity. The objective of our work is to explore the lived experience of cancer patients practicing adapted physical activity as part of the Onco'sport program. METHODS: This is a qualitative study of 10 semi-directed individual interviews with patients participating in the Onco'sport program, recruited from the "Maison Sport Santé" from Nîmes and the association "Les Roses du Gard". A phenomenological analysis was carried out with a semiopragmatic approach. RESULTS: For all participants, the APA through a program provides professional supervision of Physical Activity, influences adherence and builds confidence. This program is at the origin of changes in lifestyle habits and improves the relationship with illness and their cancer thanks to the physical and psychological benefits felt. Thus, APA appears as a full-fledged supportive care which requires informing patients and promoting it so that access is facilitated and becomes a standard. Health professionals including general practitioners do not currently have an important place in the promotion of APA, and patients most often obtain documentation on their own or through associations of patient. CONCLUSION: An APA program like Onco'sport is often the cause of a return to physical activity in patients, brings overall well-being and changes lifestyle habits. It seems important to promote physical activity to patients but also to the general population, given the benefits. This promotion involves easier access to this type of supervised program, financial support and better training of health professionals.

Pharmacological strategies to spare normal tissues from radiation damage: useless or overlooked therapeutics?

Half of all the patients with a solid malignant tumor will receive radiation therapy (RT) with a curative or palliative intent during the course of their treatment. Deleterious effects may result in acute and chronic toxicities that reduce the long-term health-related quality of life of these patients. High-tech RT enables precise beam delivery that conforms closely to the shape of tumors yielding an improved efficacy/toxicity ratio. However, sophisticated RT will not completely prevent toxicity in the irradiated field, especially as normal tissue constraints are offset by dose escalation or concurrent chemotherapy. Pharmacological agents can be used before or after RT to reduce side effects and are classified based on the timing of RT delivery. "Radioprotectors," used as a molecular prophylactic strategy before RT, are mostly based on antioxidant properties. Currently, amifostine is the only radioprotector approved for use in the clinic. "Mitigators," given during or shortly after RT, reduce the action of cellular ionizing radiation on normal tissues before the emergence of symptoms. Lastly, a "treatment" is the administration of an agent once symptoms have developed in order to reverse those that are mostly due to fibrosis. This review presents the major known physiopathological mechanisms involved in radiation response and tissue damage for which potential pharmacological candidates are emerging. We discuss the potential clinical relevance of such therapeutics in the era of high-precision radiotherapy.

Clinical benefit for patients with non-small cell lung cancer enrolled in phase I trials.

AIM: To analyze the clinical features and outcomes of advanced non-small cell lung cancer (NSCLC) patients treated in phase I trials. PATIENTS AND METHODS: The clinical characteristics, efficacy and toxicity data of 70 pretreated NSCLC patients enrolled in 17 phase I trials between January 2005 and June 2010 were analyzed at our institution. RESULTS: The histological types were: adenocarcinoma (79%), squamous cell carcinoma (13%), and others. Patients received a median number of 3 prior lines of treatment before inclusion. 1 complete response (CR), 11 (16%) partial responses (PRs), and 29 (41%) stable diseases (SDs) were observed (according to Response Evaluation Criteria in Solid Tumors (RECIST)). The median overall survival (OS) time was 18 months and the median progression-free survival (PFS) time was 4.1 months. The median PFS of these patients within their prior therapy line before phase I inclusion was 4.3 months. A performance status score of 0 and the number of prior lines of treatment were significant for OS and PFS in multivariate analysis, respectively. Grade 3/4 toxicities were observed in 20 (27%) patients, and there was 1 treatment-related death. CONCLUSION: Patients in good general condition and with limited pretreatment derived an improved benefit, suggesting that phase I studies may be a valid option for pretreated NSCLC patients.

SHARE: a French multicenter phase III trial comparing accelerated partial irradiation versus standard or hypofractionated whole breast irradiation in breast cancer patients at low risk of local recurrence.

The standard treatment for breast cancer patients at low risk of recurrence is based on conservative surgery followed by radiation therapy delivered to the whole breast. The accelerated partial breast irradiation (APBI) concept, developed more than 15 years ago, could be an option in selected patients. However, the ideal patient profile for APBI is still not clearly identified. Recent reports from the American Society for Radiation Oncology (ASTRO) and the Groupe Européen de Curiethérapie-European Society for Therapeutic Radiology and Oncology (GEC-ESTRO) have suggested selection criteria for "suitable patients" who could receive APBI outside of clinical trials. Currently, there are 6 ongoing phase III trials. All are characterized by a significant heterogeneity regarding inclusion criteria and stratification factors. The French UNICANCER trial (SHARE; ClinicalTrials.gov identifier NCT01247233) will randomize 2,800 patients in 3 arms: APBI (1 week) using 3-dimensional (3D) conformal radiotherapy, standard radiotherapy (6.5 weeks), and hypofractionated radiotherapy (3 weeks). In this article, we review the reported retrospective studies as well as older randomized trials. We will also describe the differences between the 6 ongoing phase III trials and the particularities of the French SHARE trial.

Robustness of Breast Margins with Volumetric Modulated Arc Therapy without a Six-Degrees-of-Freedom Couch: A Dosimetric Evaluation.

In our hospital, a TrueBeam linear accelerator and the PerfectPitch 6-degrees-of-freedom (6-DOF) couch (Varian), with 7 mm margins, are used for volumetric modulated arc therapy (VMAT) of breast cancer (BC). This study tested whether a 3-degrees-of-freedom (3-DOF) couch, i.e., without rotation compensation (such as the Halcyon couch), affected dose metrics. A total of 446 daily extended cone beam computed tomography (CBCT) data of 20 patients who received VMAT for BC were used to recalculate the treatment plans with the session registration (6-DOF) and a simulated matching with 3-DOF. The initial plan provided significantly better coverage for internal mammary chain and clavicular lymph node clinical target volumes (CTVs) than the 6-DOF and 3-DOF CBCT plans. The volumes receiving 110% of the prescribed dose (V110%) were increased for all CTVs with the 6-DOF and 3-DOF CBCT plans, but the difference was significant only for the breast/chest wall CTV (p < 0.05; paired samples t-test). Protection of the heart and lungs was comparable among plans. The dose volume histograms based on the 6-DOF and 3-DOF data were similar for CTVs and organs at risk. Therefore, with a 7 mm margin, VMAT and a 3-DOF couch can be used for BC treatment without any compromise in delivery accuracy.

Feasibility study of adaptive radiotherapy with Ethos for breast cancer.

Purpose: The aim of this study was to assess the feasibility of online adaptive radiotherapy with Ethos for breast cancer. Materials and methods: This retrospective study included 20 breast cancer patients previously treated with TrueBeam. All had undergone breast surgery for different indications (right/left, lumpectomy/mastectomy) and were evenly divided between these four cases, with five extended cone beam computed tomography (CBCT) scans per patient. The dataset was used in an Ethos emulator to test the full adaptive workflow. The contours generated by artificial intelligence (AI) for the influencers (left and right breasts and lungs, heart) and elastic or rigid propagation for the target volumes (internal mammary chain (IMC) and clavicular lymph nodes (CLNs)) were compared to the initial contours delineated by the physician using two metrics: Dice similarity coefficient (DICE) and Hausdorff 95% distance (HD95). The repeatability of influencer generation was investigated. The times taken by the emulator to generate contours, optimize plans, and calculate doses were recorded. The quality of the scheduled and adapted plans generated by Ethos was assessed using planning target volume (PTV) coverage, homogeneity indices (HIs), and doses to organs at risk (OARs) via dose-volume histogram (DVH) metrics. Quality assurance (QA) of the treatment plans was performed using an independent portal dosimetry tool (EpiQA) and gamma index. Results: On average, the DICE for the influencers was greater than 0.9. Contours resulting from rigid propagation had a higher DICE and a lower HD95 than those resulting from elastic deformation but remained below the values obtained for the influencers: DICE values were 0.79 ± 0.11 and 0.46 ± 0.17 for the CLN and IMC, respectively. Regarding the repeatability of the influencer segmentation, the DICE was close to 1, and the mean HD95 was strictly less than 0.15 mm. The mean time was 73 ± 4 s for contour generation per AI and 80 ± 9 s for propagations. The average time was 53 ± 3 s for dose calculation and 125 ± 9 s for plan optimization. A dosimetric comparison of scheduled and adapted plans showed a significant difference in PTV coverage: dose received by 95% of the volume (D95%) values were higher and closer to the prescribed doses for adapted plans. Doses to organs at risk were similar. The average gamma index for quality assurance of adapted plans was 99.93 ± 0.38 for a 3%/3mm criterion. Conclusion: This study comprehensively evaluated the Ethos® adaptive workflow for breast cancer and its potential technical limitations. Although the results demonstrated the high accuracy of AI segmentation and the superiority of adapted plans in terms of target volume coverage, a medical assessment is still required.

CANTO-RT: One of the Largest Prospective Multicenter Cohort of Early Breast Cancer Patients Treated with Radiotherapy including Full DICOM RT Data.

This article describes the methodology used and provides a characterization of the study population in CANTO-RT (CANcer TOxicities RadioTherapy). CANTO (NCT01993498) is a prospective clinical cohort study including patients with stage I-III BC from 26 French cancer centers. Patients matching all CANTO inclusion and exclusion criteria who received RT in one of the 10 top recruiting CANTO centers were selected. Individual full DICOM RT files were collected, pseudo-anonymized, structured and analyzed on the CANTO-RT/UNITRAD web platform. CANTO-RT included 3875 BC patients with a median follow-up of 64 months. Among the 3797 patients with unilateral RT, 3065 (80.4%) had breast-conserving surgery, and 2712 (71.5%) had sentinel node surgery. Tumor bed boost was delivered in 2658 patients (68.5%) and lymph node RT in 1356 patients (35%), including internal mammary chain in 844 patients (21.8%). Most patients (3691 (95.3%)) were treated with 3D conformal RT. Target volumes, organs at risk contours and dose/volume histograms were extracted after quality-control procedures. CANTO-RT is one of the largest early BC prospective cohorts with full individual clinical, biological, imaging and DICOM RT data available. It is a valuable resource for the identification and validation of clinical and dosimetric predictive factors of RT and multimodal treatment-related toxicities.

Stereotactic MR-Guided Radiotherapy for Liver Metastases: First Results of the Montpellier Prospective Registry Study.

Liver stereotactic body radiotherapy (SBRT) is a local treatment that provides good local control and low toxicity. We present the first clinical results from our prospective registry of stereotactic MR-guided radiotherapy (MRgRT) for liver metastases. All patients treated for liver metastases were included in this prospective registry study. Stereotactic MRgRT indication was confirmed by multidisciplinary specialized tumor boards. The primary endpoints were acute and late toxicities. The secondary endpoints were survival outcomes (local control, overall survival (OS), disease-free survival, intrahepatic relapse-free survival). Twenty-six consecutive patients were treated for thirty-one liver metastases between October 2019 and April 2022. The median prescribed dose was 50 Gy (40-60) in 5 fractions. No severe acute MRgRT-related toxicity was noted. Acute and late gastrointestinal and liver toxicities were low and mostly unrelated to MRgRT. Only 5 lesions (16.1%) required daily adaptation because of the proximity of organs at risk (OAR). With a median follow-up time of 17.3 months since MRgRT completion, the median OS, 1-year OS and 2-year OS rates were 21.7 months, 83.1% (95% CI: 55.3-94.4%) and 41.6% (95% CI: 13.5-68.1%), respectively, from MRgRT completion. The local control at 6 months, 1 year and 2 years was 90.9% (95% CI: 68.3-97.7%). To our knowledge, we report the largest series of stereotactic MRgRT for liver metastases. The treatment was well-tolerated and achieved a high LC rate. Distant relapse remains a challenge in this population.