Phase II study of preoperative radiation plus concurrent daily tegafur-uracil (UFT) with leucovorin for locally advanced rectal cancer

<p>Abstract</p> <p>Background</p> <p>Considerable variation in intravenous 5-fluorouracil (5-FU) metabolism can occur due to the wide range of dihydropyrimidine dehydrogenase (DPD) enzyme activity, which can affect both tolerability and efficacy. The oral fluoropyrimidine tegafur-uracil (UFT) is an effective, well-tolerated and convenient alternative to intravenous 5-FU. We undertook this study in patients with locally advanced rectal cancer to evaluate the efficacy and tolerability of UFT with leucovorin (LV) and preoperative radiotherapy and to evaluate the utility and limitations of multicenter staging using pre- and post-chemoradiotherapy ultrasound. We also performed a validated pretherapy assessment of DPD activity and assessed its potential influence on the tolerability of UFT treatment.</p> <p>Methods</p> <p>This phase II study assessed preoperative UFT with LV and radiotherapy in 85 patients with locally advanced T3 rectal cancer. Patients with potentially resectable tumors received UFT (300 mg/m/²/day), LV (75 mg/day), and pelvic radiotherapy (1.8 Gy/day, 45 Gy total) 5 days/week for 5 weeks then surgery 4-6 weeks later. The primary endpoints included tumor downstaging and the pathologic complete response (pCR) rate.</p> <p>Results</p> <p>Most adverse events were mild to moderate in nature. Preoperative grade 3/4 adverse events included diarrhea (n = 18, 21%) and nausea/vomiting (n = 5, 6%). Two patients heterozygous for dihydropyrimidine dehydrogenase gene (<it>DPYD</it>) experienced early grade 4 neutropenia (variant IVS14+1G > A) and diarrhea (variant 2846A > T). Pretreatment ultrasound TNM staging was compared with postchemoradiotherapy pathology TN staging and a significant shift towards earlier TNM stages was observed (p < 0.001). The overall downstaging rate was 42% for primary tumors and 44% for lymph nodes. The pCR rate was 8%. The sensitivity and specificity of ultrasound for staging was poor. Anal sphincter function was preserved in 55 patients (65%). Overall and recurrence-free survival at 3 years was 86.1% and 66.7%, respectively. Adjuvant chemotherapy was administered to 36 node-positive patients (mean duration 118 days).</p> <p>Conclusion</p> <p>Preoperative chemoradiotherapy using UFT with LV plus radiotherapy was well tolerated and effective and represents a convenient alternative to 5-FU-based chemoradiotherapy for the treatment of resectable rectal cancer. Pretreatment detection of DPD deficiency should be performed to avoid severe adverse events.</p

Online control of reaching is impaired in adults with developmental coordination disorder- DCD

Event Abstract: ACNS-2012 Australasian Cognitive Neuroscience Conference, Brisbane, Australia, 29 Nov - 2 Dec, 201

Use of myocardial strain imaging by echocardiography for the early detection of radiotherapy-induced cardiotoxicity in breast cancer patients (BACCARAT Study)

International audienceBackground: Radiotherapy (RT) is a major component of breast cancer treatment . However, breast RT is associated with long-term cardiac toxicity with clinical detection only relevant 10 to 15 years after RT. Early surrogate endpoints, predictive for the development of later cardiac events, would be useful. Purpose : To evaluate echocardiographic strain imaging for the detection of subclinical myocardial dysfunction arising after breast cancer RT.Methods: BACCARAT is a monocentric prospective cohort study of unilateral breast cancer patients treated with RT but without chemotherapy. They are followed for 2 years with repeated cardiac imaging examinations, including 2-dimensional speckle strain imaging for the detection of subclinical left ventricular abnormalities.Results : Between October 2015 and December 2017, this study prospectively included 114 women (95 left-sided and 19 right-sided) aged 58±8 years. Cardiac evaluations with strain imaging are performed before RT, 6 months and 24 months after RT. At this stage of the study, strain imaging measurements before RT and RT+6 months are available for 65 patients. Mean heart and left ventricle doses were 2.9 ± 1.3 Gy and 6.1 ± 2.9 Gy for the left-sided patients , 0.4 ± 0.1 Gy and 0.1 ± 0.04 Gy , respectively, for the right-sided patients. A decrease in global longitudinal strain was observed at 6 months post-RT for left-sided patients (-14.1% ±3.6% at 6 months after RT vs -15.4% ± 3.2% before RT, percentage of change 9.2%, P=0.02) but not for right-sided patients. No significant change was observed with conventional echocardiography left ventricular ejection fraction measurement.Conclusion : These preliminary results demonstrate a statistically significant reduction of global longitudinal strain 6 months after RT. Further investigation of BACCARAT study could illustrate strain imaging may have a potential role for screening and identification of patients at risk to develop cardiac complications

Early detection of left ventricular dysfunction after breast cancer radiotherapy using speckle tracking echocardiography: association between cardiac exposure and myocardial strain changes (BACCARAT study)

International audienceBackground: Breast radiotherapy (RT) is associated with long-term cardiac toxicity with clinical detection only relevant 10 to 15 years after RT. For early detection of left ventricular dysfunction, it has been shown that detecting a decreased LVEF after RT may be too late for treatment. Use of strain as a more sensitive parameters of LV dysfunction has been suggested, but little is known on the impact of RT-induced cardiac exposure on strain.Purpose: To analyze the relationship between cardiac exposure and myocardial strain changes after RT in breast cancer patients from the BACCARAT (BreAst Cancer and CArdiotoxicity Induced by RAdioTherapy) study. Methods: BACCARAT is a monocentric prospective cohort study that included left or right unilateral breast cancer patients treated with RT without chemotherapy between 2015 and 2017. Each patient was included at baseline before RT and is followed for 2 years with repeated cardiac imaging examinations, including Siemens 2-dimensional speckle strain imaging for the detection of subclinical left ventricular abnormalities with measurement of global longitudinal strain (GLS). Individual dosimetric evaluation provided information on RT-induced absorbed doses for whole heart, left ventricle (LV), left main coronary artery (LM), left anterior descending artery (LAD), left circumflex artery (LCX) and right coronary artery (RCA). For clinically meaningful purpose, the event “decreased GLS” was defined as ≥10% reduction, ie. % change, in GLS compared to baseline measurement.Results: This analysis was based on 94 patients (15 right-sided BC, 79 left-sided BC) aged 58±8 years with a follow-up of 6 months post RT. Mean doses to the heart, LV and LAD were respectively: 3.0 Gy, 6.7 Gy and 16.6 Gy for the left-sided patients; 0.6 Gy, 0.2 Gy and 0.3 Gy for the right-sided patients. Considering BC laterality as a raw index of exposure, an altered GLS was observed for left sided BC patients (-15.5±3.7% before RT vs. -14.1±4.0% at RT+6 months, p=0.02), but not for right sided BC patients (-15.0±4.2% vs. -15.0±4.2%, p=0.99). Half of the population (48%) had “decreased GLS” (38% among right-sided patients, 50% among left sided patients). Considering cardiac doses for the whole population, both mean dose to the heart and LV were significantly associated with “decreased GLS”: OR/1Gy=1.4 95%CI[1.1 – 1.9] (p=0.02) and OR/1Gy=1.2 95%CI[1.1 – 1.3] (p=0.01) even after adjustment on cardiac risk factors including age, hypertension, BMI and hypercholesterolemia. LV doses was the best predictor of “decreased GLS”, in particular the volume of LV receiving at least 10 Gy (OR/1%=1.07 [1.02 – 1.12] (p=0.007)). Patients with ≥15% of the LV receiving at least 10 Gy had 4 times more risk to have “decreased GLS” (OR=3.9 [1.6 – 9.9], p=0.0027).Conclusion: This study is the first to establish a dose-response relationship between RT-induced cardiac doses and decreased GLS 6 months after RT, illustrating the importance to reduce cardiac exposure in order to limit the risk of LV dysfunction. Longer follow-up until 2 years post RT will allow refining these results on the detection of sub-clinical LV dysfunction in patients treated for breast cancer

Cardiac radiation exposure associated with breast cancer radiotherapy: dose distribution to the heart substructures and coronary arteries (BACCARAT study)

International audienceBackground: Radiotherapy (RT) is a major component of breast cancer treatment and advanced RT techniques allowed reducing irradiation of healthy tissue. However, the heart often remains partially exposed. Detailed individual heart dosimetry information is required to better understand radiation-induced cardiac damage. Purpose: To analyze the distribution of individually-determined radiation dose to the heart and its substructures, in particular coronary arteries, after RT in breast cancer patients from the BACCARAT cohort. Methods: BACCARAT is a monocentric prospective cohort study that included unilateral breast cancer patients treated with RT between 2015 and 2017 and followed for 2 years with repeated cardiac imaging examinations, including coronary computed tomography angiography. Using the 3D dose matrix generated during RT treatment planning and the added coronary contours, dose distributions were generated for the following cardiac structures: whole heart, left ventricle (LV), left main coronary artery (LM), left anterior descending artery (LAD), left circumflex artery (LCX) and right coronary artery (RCA). A descriptive analysis of the physical doses in Gray (Gy) was performed.Results: Dose distributions were generated for 59 patients (50 left-sided breast cancer, 9 right-sided) who all received a treatment of 50 Gy to the breast. The mean heart dose was 2.98 Gy for left sided patients and 0.42 Gy for right sided and mean LV doses were respectively 6.23 Gy and 0.09 Gy. For left-sided patients, mean dose to LM (D_LM)=1.29 Gy, D_LAD=16.32 Gy, D_LCX=1.59 Gy and D_RCA=0.67Gy, whereas corresponding doses for right-sided patients were D_LM=0.35 Gy, D_LAD=0.11 Gy, D_LCX=0.14 Gy and D_RCA=1.10 Gy. For left sided patients, the most exposed part of the LAD could receive doses > 45 Gy.Conclusion: Our study illustrates the wide range of doses experienced by the heart substructures and thus the poor significance of the mean heart dose as a radiation damage indicator. Keywords: Radiotherapy; Breast Cancer; Radiation Dosimetry; Cardiotoxicit