Hypofractionated irradiation in 794 elderly breast cancer patients: An observational study.

To assess the efficacy, and the acute and late toxicity of hypofractionated radiotherapy (Hypo-RT), and the impact of age and comorbidities on disease progression and death in elderly breast cancer (BC) patients. Women aged ≥65 years who received Hypo-RT (42.4 Gy in 16 fractions, plus a boost for high-risk patients) were considered for the present analysis. Competing risk analysis was used to estimate the 5-year cumulative incidence of BC progression and BC-related death, calculating the adjusted subhazard ratios (SHR) with 95% confidence intervals (95%CI) in relation to age, hypertension-augmented Charlson Comorbidity Index (hCCI), tumor characteristics, and chemotherapy. The sample included 794 patients with a median age of 74 years (range 65-91 years). At the baseline, 70% of these patients had at least one comorbidity. With a median follow-up of 48.3 months, the 5-year cumulative incidence of BC progression and BC-related death was 6.7% (95%CI 4.8%-9.2%) and 2.3% (95%CI 1.2%-3.9%), respectively. Old age (≥80 years) and a high burden of comorbidity (hCCI ≥ 2) were independently associated with BC progression. Hypo-RT is safe in elderly BC patients, but age and comorbidities influence BC progression. Further studies are warranted.

Preemptive treatment with Xonrid®, a medical device to reduce radiation induced dermatitis in head and neck cancer patients receiving curative treatment: a pilot study.

PURPOSE: The purpose of this study was to investigate efficacy, safety and tolerability of Xonrid®, a new medical device, in preventing radiation dermatitis associated with head and neck cancer (HNC) radiotherapy (RT). METHODS: In this monocentric, prospective pilot study, adult consecutive HNC patients who were planned to receive curative RT with or without chemotherapy were enrolled. Patients were instructed to apply Xonrid® on the irradiated area during treatment continuing until 2 weeks after the completion of RT or the development of severe skin toxicity. Toxicity was assessed using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 scale. The patient reported outcome measures included the Skindex-16 questionnaire and patient satisfaction. Skin reflectance spectra were analyzed to objectively evaluate dermatitis. RESULTS: In total, 41 subjects were enrolled (30 males, median age 60 years). No skin adverse events were recorded either in the skin area where the product was applied or in the nearby skin over the entire period of administration. At the end of RT, nine patients (22%) presented G1, 31 (76%) G2, and one patient (2%) G3 skin toxicity (after 5 weeks). Seven and 20 patients reached skin maximum toxicity at the fourth week and after the seventh week, respectively. An increasing trend of median spectrophotometry scores along with skin toxicity grades was observed. A correlation between Skindex-16 scores and skin toxicity grade during treatment was found. CONCLUSIONS: Our study results suggest that Xonrid® is well tolerated, safe, and effective in minimizing and delaying high-grade radiation dermatitis in HNC patients.

Hypofractionated whole-breast radiotherapy in large breast size patients: is it really a resolved issue?

The purpose of this study was to evaluate the impact of breast size on acute and late side effects in breast cancer (BC) patients treated with hypofractionated radiotherapy (Hypo-RT). In this study we analyzed patients over 50 years with a diagnosis of early BC, candidate for Hypo-RT after conservative surgery. Acute and late skin toxicities were evaluated in accordance with the RTOG scale. Multivariable logistic analysis was performed using dosimetric/anatomical factors resulted associated with toxicity outcome in univariable analysis. Among patients treated between 2009 and 2015, 425 had at least 5 years of follow-up. At RT end, acute skin toxicity ≥ G2 and edema ≥ G2 occurred in 88 (20.7%) and 4 (0.9%) patients, respectively. The multivariable analysis showed association of skin toxicity with boost administration (p < 0.01), treated skin area (TSA) receiving more than 20 Gy (p = 0.027) and breast volume receiving 105% of the prescription dose (V105%) (p = 0.016), but not breast size. At 5 years after RT, fibrosis ≥ G1 occurred in 89 (20.9%) patients and edema ≥ G1 in 36 (8.5%) patients. Fibrosis resulted associated with breast volume ≥ 1000 cm3 (p = 0.04) and hypertension (p = 0.04). As for edema, multivariable logistic analysis showed a correlation with hypertension and logarithm of age, but not with boost administration. Breast volume had an unclear impact (p = 0.055). A recurrent association was found between acute and late toxicities and breast V105%, which is correlated with breast size. This may suggest that a more homogenous RT technique may be preferred for patients with larger breast size.

Application of failure mode and effects analysis to optimization of linac quality controls protocol.

PURPOSE: To apply Failure Mode and Effects Analysis (FMEA) to optimize linac quality control (QC) protocol in order to ensure patient safety and treatment quality, taking maximum advantage of the available resources. MATERIAL AND METHODS: Each parameter tested by the QC was considered as a potential failure mode (FM). For each FM, likelihood of occurrence (O), severity of effect (S), and lack of detectability (D) were evaluated and corresponding Risk Priority Number (RPN) was calculated from the product of three indexes. The scores were assigned using two methods: (a) A survey submitted to the medical physicists; (b) A semi-quantitative analysis (SQA) performed through: simulation of FMs in the treatment planning system; studies reported in literature; results obtained by the QC data analysis. A weighted RPN for all FMs was calculated taking into account both the methods. For each linac, the tests were then sorted by their frequency and the RPN value. RESULTS: A high variability was found in the scores of the survey, although in many it was reduced in RPN values, highlighting the more relevant tests as on beam output and imaging system. Integrating these results with those obtained by SQA, the RPN-based ranking of tests has been provided considering the specific use of the accelerator: for example, more accurate tests on dose modulation and multileaf collimator speed were required in linacs where intensity-modulated treatment is performed, while, more specific tests on couch and jaw position indicators were necessary where treatments with multiple isocenters and/or junctions between adjacent fields were often delivered. CONCLUSIONS: Failure Mode and Effects Analysis is a useful tool to prioritize the linac QCs, taking into account the specific equipment and clinical practice. The integration of SQA and survey results reduces subjectivity of the FMEA scoring and allows to optimize linac QCs without "losing" the expertise and experience of medical physicists and clinical staff.

Interobserver variability (between radiation oncologist and radiation therapist) in tumor bed contouring after breast-conserving surgery.

PURPOSE: To examine interobserver variability between the radiation oncologist (RTO) and the radiation therapist (RTT) in delineating the tumor bed (TB) in early breast cancer (BC). METHODS: We retrospectively analyzed patients who received a radiotherapy boost to the TB. In a first group, the clinical target volume (CTV) for the boost was the surgical bed, defined by using surgical clips. In a second group, the CTV was defined by identifying a seroma cavity or a metallic find on the scar. These contours were compared in terms of volume, number of slices, and Dice similarity coefficient (DSC). RESULTS: Forty patients were assessed: 20 had surgical clips (group 1) while the other 20 had none (group 2). There was no difference in the number of slices contoured by the 2 operators for group 1, but a statistically significant difference emerged in the volumes: the RTT identified a TB that was a mean 45% smaller than the one identified by the RTO. Random differences were found between the 2 operators for group 2. The TBs delineated for this group were significantly larger (P<0.05) than those identified by the RTT for group 1. The mean Dice value between the RTO's and the RTT's TBs was 0.69±0.07 (range 0.53-0.81) for group 1 and 0.37±0.18 (range 0-0.58) for group 2 (P<0.05). CONCLUSIONS: This study showed that the use of clips coincided with less interoperator variability. With appropriate training, the RTT may play an important part in the multidisciplinary radiotherapy team.

Discontinuation of hormone therapy for elderly breast cancer patients after hypofractionated whole-breast radiotherapy.

The purpose of the study was to examine adherence to hormone therapy (HT) in elderly breast cancer patients (≥ 65 years old) treated with hypofractionated radiotherapy. We analyzed data on 550 ER-positive breast cancer patients given hypofractionated whole-breast radiotherapy from June 2009 to September 2016. Baseline comorbidities considered in the hypertension-augmented Charlson Comorbidity Index (hCCI) were retrospectively retrieved. Total hCCI scores were classified as no comorbidity (hCCI = 0), low burden of comorbidity (hCCI = 1), and high burden of comorbidity (hCCI ≥ 2). Competing risk analysis was used to estimate the 5-year cumulative incidence of HT discontinuation. Fine and Gray models were used to estimate the adjusted subhazard ratio (SHR) of HT discontinuation by hCCI score. HT was initially prescribed for 85.6% of patients and almost all of them (468/471) took it for at least one month. It was subsequently discontinued by 45 patients (9.6%), for an overall 5-year cumulative incidence of 11.7%. The 5-year cumulative incidence of HT discontinuation rose from 3.9% in the youngest age group (65-69 years) to 23.3% in the oldest (≥ 80 years) (p = 0.005). Baseline comorbidity had some effect on the likelihood of discontinuing HT, but only among patients with a low burden of comorbidity (hCCI = 1, SHR 2.00, 95%CI 0.95-4.20). Adherence to HT was better in our sample than in the literature, probably because patients were selected and motivated to continue HT. This confirms the importance of communication with patients to improve adherence to HT. We confirmed the association between HT discontinuation and older age, while comorbidity had a limited influence.

Trastuzumab and Hypofractionated Whole Breast Radiotherapy: A Victorious Combination?

INTRODUCTION: The purpose of this study was to examine the impact of trastuzumab on acute skin and cardiac toxicity in patients with breast cancer treated with chemotherapy with or without trastuzumab and adjuvant whole breast hypofractionated radiotherapy (hypo-RT). MATERIALS AND METHODS: The study was conducted on 727 patients treated from April 2009 to October 2016. Patients received 42.4 Gy in 16 daily fractions (2.65 Gy per fraction). A boost was only administered in cases with grade (G) 3 primary tumor and close or positive margins. Acute and late toxicity was assessed prospectively during and after hypo-RT, based on the Radiation Therapy Oncology Group scale. Multivariable logistic regression models were used to examine the onset of acute skin toxicity (≥ G2) in the whole study population, and the impact of trastuzumab on the onset of acute skin (≥ G2) or cardiac toxicity in the subgroup of 176 patients given chemotherapy. RESULTS: A total of 176 patients received chemotherapy with anthracycline and taxane, and 51 (29%) of them were also treated with trastuzumab. Acute G1, G2, and G3 skin toxicity occurred, respectively, in 56.8%, 27.3%, and 1.1% of the patients given chemotherapy alone, and in 64.7%, 19.6%, and 0% of those given trastuzumab as well. Among the patients given chemotherapy, left ventricular ejection fraction (LVEF) toxicity developed with a severity of G1 (LVEF < 60%-50%) in 12 (6.8%) patients, G2 (LVEF < 50%-40%) in 2 (1.1%) patients, and G3 (LVEF < 40%) in 1 (0.6%) patient. Among the patients also given trastuzumab, 7 (13.7%) patients had G1 LVEF toxicity, and 1 (2%) patient had G2 LVEF toxicity. We found that patients given trastuzumab were at higher risk of cardiac toxicity ≥ G1 (odds ratio, 4.3; P = .01), and at lower risk of acute skin toxicity ≥ G2 (odds ratio, 0.4; P = .03) than patients given chemotherapy alone. CONCLUSIONS: This analysis showed that trastuzumab with adjuvant hypo-RT for patients with breast cancer was generally well-tolerated in routine clinical practice. A longer follow-up will be necessary to assess late cardiac toxicity.

Partial breast irradiation with CyberKnife after breast conserving surgery: a pilot study in early breast cancer.

BACKGROUND: Local recurrences after breast conserving treatment are mainly close to the original tumor site, and as such shorter fractionation strategies focused on and nearest mammary gland, i.e. accelerated partial breast irradiation (APBI), have been developed. Stereotactic APBI has been attempted, although there is little experience using CyberKnife (CK) for early breast cancer. METHODS: This pilot study was designed to assess the feasibility of CK-APBI on 20 evaluable patients of 29 eligible, followed for 2 years. The primary endpoint was acute/sub-acute toxicity; secondary endpoints were late toxicity and the cosmetic result. RESULTS: Mean pathological tumor size was 10.5 mm (±4.3, range 3-18), 8 of these patients were classified as LumA-like, 11 as LumB-like, and 1 as LumB-HER2-enriched. Using CK-APBI with Iris, the treatment time was approximately 60 min (range~ 35 to ~ 120). All patients received 30 Gy in five fractions delivered to the PTV. The median number of beams was 180 (IQR 107-213; range:56-325) with a median PTV isodose prescription of 86.0% (IQR 85.0-88.5; range:82-94). The median PTV was 88.1 cm3 (IQR 63.8-108.6; range:32.3-238.8). The median breast V100 and V50 was 0.6 (IQR 0.1-1.5; range:0-13) and 18.6 (IQR 13.1-21.7; range:7.5-37), respectively. The median PTV minimum dose was 26.2 Gy (IQR 24.7-27.6; range 22.3-29.3). Mild side effects were recorded during the period of observation. Cosmetic evaluations were performed by three observers from the start of radiotherapy up to 2 years. Patients' evaluation progressively increase from 60% to 85% of excellent rating; this trend was similar to that of external observer. CONCLUSIONS: These preliminary results showed the safe feasibility of CK-APBI in early breast cancer, with mild acute and late toxicity and very good cosmetic results. TRIAL REGISTRATION: The present study is registered at Clinicaltrial.gov ( NCT02896322 ). Retrospectively egistered August 4, 2016.

Hypofractionated Whole-Breast Irradiation With or Without Boost in Elderly Patients: Clinical Evaluation of an Italian Experience.

PURPOSE: To examine local control, disease-free survival (DFS), and toxicity in elderly (≥ 65 years) breast cancer patients treated with hypofractionated radiotherapy (hypo-RT) with or without a boost to the tumor bed. PATIENTS AND METHODS: The study was conducted on 752 patients treated from April 2009 to February 2017. Patients received 42.4 Gy in 16 daily fractions (2.65 Gy per fraction). A boost was only administered in cases of grade 3 primary tumor and close or positive margins. Acute and late toxicity was prospectively assessed during and after hypo-RT, based on the Radiation Therapy Oncology Group scale. DFS and local recurrence-free survival were estimated by the Kaplan-Meier method for cumulative probability. Log-rank tests were used to identify differences by subtype. Cox proportional hazard models were used to investigate the impact of various factors on the risk of disease progression. RESULTS: Among the 752 patients treated, 41 (5.5%) experienced disease progression, including 7 (17.1%) exclusively local recurrences; 1 (2.4%) local and nodal recurrence; 1 (2.4%) local and nodal recurrence plus metastasis; 7 (17.1%) nodal recurrences plus metastases; and 25 (61%) exclusively distant metastases. The 5-year DFS, local recurrence-free survival, breast cancer-specific survival, and overall survival rates were 91.8% (95% confidence interval [CI], 88.6-94.2), 98.0% (95% CI, 96.1-99.1), 98.2% (95% CI, 96.5-99.1), and 87.5% (95% CI, 83.8-90.5), respectively. On univariate analysis, the administration of a boost, disease grade (grades 1 and 2 vs. 3), and molecular subtype (triple negative or human epidermal growth factor receptor 2 [HER2] positive, or luminal B vs. luminal A) significantly affected disease progression (P < .01). These findings were confirmed by multivariate analysis. CONCLUSION: Hypo-RT is effective and well tolerated in the elderly population, and the routine use of a boost for patients over 65 years is not justified. Further studies on the boost issue are strongly advocated.

Axillary coverage by whole breast irradiation in 1 to 2 positive sentinel lymph nodes in breast cancer patients.

PURPOSE: To evaluate the dosimetric coverage of axillary levels I, II, and III obtained with standard whole breast irradiation in 1 to 2 positive sentinel lymph nodes (SLNs) patients not submitted to axillary lymph nodes dissection (ALND), and to compare the lymph nodes areas coverage obtained with 3D conformal radiation therapy, intensity-modulated radiotherapy (IMRT), and volumetric modulated arc therapy (VMAT). METHODS: Patients with 1 to 2 positive SLNs undergoing breast-conserving therapy, without ALND, were included in the analysis. For each patient, 3 treatment plans were performed: a 3D conventional tangential plan, a static IMRT plan, and a volumetric IMRT, designed to encompass the entire breast parenchyma. The volumes of axillary levels I, II, and III receiving 90% and 95% (V90, V95) of the whole breast prescribed dose were evaluated. Dose-volume histograms were compared by means of the Friedman test. RESULTS: Ten patients were enrolled. All defined breast volumes received >95% of the prescribed dose with the 3 techniques. Median V95 for axillary level I was 26.4% (range 4.7%-61.3%) for 3D plans, 8.6% (range 0.64%-19.1%) for static IMRT plans, and 2.6% (range 0.4%-4.7%) for volumetric IMRT plans (p<0.001). Median V95 for axillary level II was 5.4% (range 0%-14.6%), 1.9% (range 0%-15%), and 2.6% (range 0.4%-4.7%) for 3D, static IMRT, and volumetric IMRT, respectively (p<0.001). CONCLUSIONS: Results of our analysis showed that standard 3D tangential whole breast irradiation failed to deliver a therapeutic dose to axillary levels I and II. The coverage was even lower using static and volumetric IMRT techniques.