Cosmetic Results and Side Effects of Accelerated Partial-Breast Irradiation Versus Whole-Breast Irradiation for Low-Risk Invasive Carcinoma of the Breast: The Randomized Phase III IRMA Trial.

PURPOSE: The results in terms of side effects vary among the published accelerated partial-breast irradiation (APBI) studies. Here, we report the 5-year results for cosmetic outcomes and toxicity of the IRMA trial. METHODS: We ran this randomized phase III trial in 35 centers. Women with stage I-IIA breast cancer treated with breast-conserving surgery, age ≥ 49 years, were randomly assigned 1:1 to receive either whole-breast irradiation (WBI) or external beam radiation therapy APBI (38.5 Gy/10 fraction twice daily). Patients and investigators were not masked to treatment allocation. The primary end point was ipsilateral breast tumor recurrence. We hereby present the analysis of the secondary outcomes, cosmesis, and normal tissue toxicity. All side effects were graded with the Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer Radiation Morbidity Scoring Schema. Analysis was performed with both intention-to-treat and as-treated approaches. RESULTS: Between March 2007 and March 2019, 3,309 patients were randomly assigned to 1,657 WBI and 1,652 APBI; 3,225 patients comprised the intention-to-treat population (1,623 WBI and 1,602 APBI). At a median follow-up of 5.6 (interquartile range, 4.0-8.4) years, adverse cosmesis in the APBI patients was higher than that in the WBI patients at 3 years (12.7% v 9.2%; P = .009) and at 5 years (14% v 9.8%; P = .012). Late soft tissue toxicity (grade ≥ 3: 2.8% APBI v 1% WBI, P < .0001) and late bone toxicity (grade ≥ 3: 1.1% APBI v 0% WBI, P < .0001) were significantly higher in the APBI arm. There were no significant differences in late skin and lung toxicities. CONCLUSION: External beam radiation therapy-APBI with a twice-daily IRMA schedule was associated with increased rates of late moderate soft tissue and bone toxicities, with a slight decrease in patient-reported cosmetic outcomes at 5 years when compared with WBI, although overall toxicity was in an acceptable range.

Hippocampal-sparing radiotherapy and neurocognitive impairment: A systematic literature review.

INTRODUCTION: Whole-brain radiation therapy (WBRT) is an effective therapeutic modality in patients with brain metastases. However, nearly 90% of patients undergoing WBRT suffer from a neurocognitive function (NCF) impairment at diagnosis, and up to two-thirds will experience a further decline within 2-6 months after WBRT. Focal-dose reduction on bilateral hippocampus is thought to improve NCF preservation. The aim was to present a systematic review of clinical results on NCF after hippocampal-sparing (HS) WBRT. MATERIALS AND METHODS: A systematic review of published literature was performed on PubMed and the Cochrane Library. Only prospective clinical trials reporting NCF outcome in patients treated with HS-WBRT have been analyzed. RESULTS: A total of 165 patients from three studies were included. These studies are characterized by small sample size and different methods in terms of WBRT technique but with similar planning analysis and NCF assessment tests. No significant changes in NCF (i.e., verbal and nonverbal learning memory, executive functions, and psychomotor speed) between baseline and 4-month follow-up after RT and only a mean relative decline in delayed recall at 4 months (7% compared to 30% of historical control) were observed. CONCLUSIONS: Considering preliminary results on NCF preservation, further studies seem justified in patients undergoing brain irradiation for brain metastases or referred for prophylactic cranial irradiation to evaluate long-term effects on NCF and quality of life.

Intensity-Modulated Radiotherapy with Concomitant Boost After Breast Conserving Surgery: A Phase I-II Trial.

PURPOSE: A concomitant boost (CB) in patients treated with postoperative radiotherapy after conservative surgery of invasive breast cancer (BC) has been suggested for treatment time reduction and therapy intensification. The aim of this analysis was to assess long-term tolerability of a CB in patients treated with postoperative intensity Modulated Accelerated RAdiotherapy (MARA). PATIENTS AND METHODS: In this phase I-II trial, 321 patients with intermediate-high risk BC (pT1-4 with at least one of the following characteristics: pre or perimenopausal status, pN2-3, positive or close margins) were enrolled. Patients were treated with forward-planned intensity modulated radiotherapy (IMRT) and CB. A total dose of 50 Gy (2 Gy/fraction) and 60 Gy (2.4 Gy/fraction) was prescribed to the whole breast and the tumor bed, respectively. The potential impact of hypertension, diabetes, smoking habit, alcohol consumption, chemotherapy, and hormone therapy on both skin and subcutaneous late toxicity-free survival (LTFS) was evaluated. Survival curves were calculated using the Kaplan-Meier method. RESULTS: Median follow-up was 52 months (range: 3-115). Regional node irradiation, adjuvant chemotherapy and hormonal therapy were prescribed to 29.3%, 65.4% and 81.0% of patients, respectively. Five-year G2 and G3 skin LTFS were 95.6% and 100.0%, respectively. Five-year G2 and G3 subcutaneous LTFS were 80.0% and 98.6%, respectively. Only diabetes showed a significant correlation with worse G3 subcutaneous LTFS (p: 0.024). Five-year loco-regional control, metastasis-free survival, disease-free survival, and overall survival were 98.0%, 91.8%, 89.7% and 96.3%, respectively. CONCLUSION: IMRT combined with CB was associated with a low risk of > G2 late toxicities (0.0% and 1.4% for skin and subcutaneous tissue, respectively). The cumulative actuarial incidence of local recurrences was 2.0% despite the exclusion of low-risk patients. Our results suggest that CB is safe and effective in patients with intermediate-high risk BC. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03471741.

Brachytherapy boost after chemoradiation in anal cancer: a systematic review.

Radio-chemotherapy (RCT) is the primary treatment of anal cancer (AC). However, the role and the optimal total dose of a radiation boost is still unclear. No randomized controlled trials nor systematic reviews have been performed to analyze the efficacy of brachytherapy (BRT) as boost in AC. Therefore, we performed this systematic review based on PRISMA methodology to establish the role of BRT boost in AC. A systematic search of the bibliographic databases: PubMed, Scopus, and Cochrane library from the earliest possible date through January 31, 2018 was performed. At least one of the following outcomes: local control (LC), loco-regional control (LRC), overall survival (OS), disease-free survival (DFS), or colostomy-free survival (CFS) had to be present for inclusion in this systematic review in patients receiving a BRT boost. Data about toxicity and sphincter function were also included. Ten articles fulfilled the inclusion criteria. All the studies had retrospective study design. All studies were classified to provide a level of evidence graded as 3 according to SIGN classification. Median 5-year LC/LRC, CFS, DFS, and OS were: 78.6% (range, 70.7-92.0%), 76.1% (range, 61.4-86.4%), 75.8% (range, 65.9-85.7%), and 69.4% (63.4-82.0%), respectively. The reported toxicities were acceptable. RCT is the treatment cornerstone in AC. High-level evidences from studies on BRT boost in AC are lacking. Further studies should investigate: efficacy of BRT boost in comparison to no boost and to external beam boost, patients who can benefit from this treatment intensification, and optimal radiation dose.

Oncocytic modifications in rectal adenocarcinomas after radio and chemotherapy.

The purpose of the study is to highlight oncocytic modifications in rectal adenocarcinomas and evaluate a possible correlation with preoperative radiochemotherapy (RCT). Twenty-eight cases of advanced rectal carcinoma, treated preoperatively by 5-fluorouracil (200-225 mg/m(2)) and 44-46 Gy in 22-23 fractions, were studied. All patients underwent biopsy before RCT. Surgery was performed within 6 weeks after RCT. In all cases oncocytic modifications were searched for on hematoxylin and eosin (H&E) and at immunohistochemistry using an antimitochondrial antibody. In addition, in two cases, both pre- and post-RCT tissues were examined at electron microscopy. All tumors were adenocarcinomas. In pre-RCT biopsies, oncocytic changes were difficult to find on H&E, while the antimitochondrial antibody strongly stained numerous neoplastic cells (mean 48.4%). In post-RCT surgical specimens, oncocytic changes were detected in 24 out of 28 cases on H&E and the antimitochondrial antibody stained most of the residual neoplastic cells (mean 76.7%). Ultrastructural examination revealed large and bizarre mitochondria inside tumor cells both in pre- and post-RCT tissues. In conclusion, the present data suggest that rectal adenocarcinomas are "mitochondrion-rich" tumors. After preoperative RCT, residual neoplastic cells acquire a definite oncocytic phenotype.

Pattern of p63 expression in squamous cell carcinoma of the oral cavity.

P63 is a recently discovered gene harbouring different isoforms by alternate splicing. The two main isoforms, TAp63 and Delta Np63, have opposite functions, being responsible for cell-cycle arrest and cell proliferation, respectively. In addition, new isoforms have been described with the same sequence as TAp63 and Delta Np63, but lacking exon 4 (Delta 4Tap63 and Delta Np73L). P63 as detected using immunohistochemistry is present in squamous cell carcinomas. To better define the role of p63 in squamous cell carcinomas of the oral cavity (OSCC), 39 patients were investigated using immunohistochemical analysis with a monoclonal antibody recognising all p63 isoforms and an anti-Ki67 antibody. Reverse-transcription polymerase chain reaction (PCR) and nested PCR were also performed using isoform-specific primers to evaluate the p63 mRNA expression pattern. Using immunohistochemistry, p63 was always present in OSCC, and its distribution was similar to that of Ki67. The percentage of positive cells increased from normal to neoplastic mucosa, but there was no relationship between the number of p63 positive cells and prognosis. P63 mRNA was found in all patients. The truncated isoforms Delta 4TAp63 and Delta Np73L were more frequently expressed in patients presenting with metastases. Delta Np73L was found in 66.6% of tumours with lymph-node metastases, but in only 33.3% of those devoid of lymph-node metastases at presentation. An impaired expression of the p63 isoforms might favour cell proliferation and indirectly enhance the metastasising capacity of OSCC.

High MUC2 immunohistochemical expression is a predictor of poor response to preoperative radiochemotherapy (RCT) in rectal adenocarcinoma.

The purpose of this study is to establish if mucoid differentiation is associated with responsiveness to preoperative radiochemotherapy (RCT) in rectal adenocarcinomas. Thirty-two patients with rectal adenocarcinomas were preoperatively treated with 44 to 46 Gy in 22 to 23 fractions and with 5-fluorouracil (200 to 225 mg/m) before surgery. Mucoid differentiation was searched for both in pre-RCT biopsies with anti-MUC2 antiserum and in postoperative specimens. To evaluate the responsiveness to preoperative RCT, a regression grading was used (grades 0 to 4). Statistical analysis showed a significant negative correlation between immunohistochemical expression of MUC2 in pre-RCT biopsies and regression grade in postoperative specimens (r=-0.529; P=0.002). A significant cutoff value of 60% of MUC2 positive neoplastic cells in pre-RCT biopsies was observed (P=0.018): 13 cases with more than 60% exhibited a poor response to RCT (grade 0 in 5/13, grade 1 in 4/13, grade 2 in 4/13), whereas 19 cases with less than 60% showed a better response to RCT (grade 1 in 6/19, grade 2 in 9/19, grade 3 in 3/19, grade 4 in 1/19).