Maurizio Portaluri

Radiation-induced cardiac damage in early left breast cancer patients: Risk factors, biological mechanisms, radiobiology, and dosimetric constraints

Today there is general awareness of the potential damage to the heart in left-sided (more than in right-sided) breast cancer radiotherapy (RT). Historical changes in tumor and heart doses are presented here along with the impact of different RT techniques and volumes. Individual and pharmacological risk factors are also examined with respect to radiation damage. The biological mechanisms of harm are only partially understood, such as the radiobiology of heart damage due to the presence of various radiosensitive structures and their topographic heterogeneity. Furthermore, individual variability may expose patients to higher or lower risks of late cardiac damage or death. Damage mechanisms and radiobiological characteristics in heart irradiation are presented in relation to dosimetric and biological parameters.

N-TERMINAL PRO-B-TYPE NATRIURETIC PEPTIDE PLASMA LEVELS AS A POTENTIAL BIOMARKER FOR CARDIAC DAMAGE AFTER RADIOTHERAPY IN PATIENTS WITH LEFT-SIDED BREAST CANCER

PURPOSE Adjuvant radiotherapy (RT) after breast-conserving surgery has been associated with increased cardiovascular mortality. Cardiac biomarkers may aid in identifying patients with radiation-mediated cardiac dysfunction. We evaluated the correlation between N-terminal pro-B–type natriuretic peptide (NT-proBNP) and troponin (TnI) and the dose of radiation to the heart in patients with left-sided breast cancer. METHODS AND MATERIALS NT-proBNP and TnI plasma concentrations were measured in 30 left-sided breast cancer patients (median age, 55.0 years) 5 to 22 months after RT (Group I) and in 30 left-sided breast cancer patients (median age, 57.0 years) before RT as control group (Group II). Dosimetric and geometric parameters of heart and left ventricle were determined in all patients of Group I. Seventeen patients underwent complete two-dimensional echocardiography. RESULTS NT-proBNP levels were significantly higher (p = 0.03) in Group I (median, 90.0 pg/ml; range, 16.7–333.1 pg/ml) than in Group II (median, 63.2 pg/ml; range, 11.0–172.5 pg/ml). TnI levels remained below the cutoff threshold of 0.07 ng/ml in both groups. In patients with NT-proBNP values above the upper limit of 125 pg/ml, there were significant correlations between plasma levels and V(3 Gy)(%) (p = 0.001), the ratios (p = 0.01), the ratios D(15 cm)(3)/D(50%) (Gy) (p = 0.008) for the heart and correlations between plasma levels and V(2 Gy) (%) (p = 0.002), the ratios (p = 0.03), and the ratios (p = 0.05) for the ventricle. CONCLUSIONS Patients with left-sided breast cancer show higher values of NT-pro BNP after RT when compared with non–RT-treated matched patients, increasing in correlation with high doses in small volumes of heart and ventricle. The findings of this study show that the most important parameters are not the mean doses but instead the small percentage of organ volumes (heart or ventricle) receiving high dose levels, supporting the notion that the heart behaves as a serial organ.

Effects of external irradiation of the neck region on intima media thickness of the common carotid artery

BackgroundSeveral studies have shown that common carotid intima-media thickness (IMT) is increased after radiotherapy (RT) to the head and neck. However, further studies are needed to define the exact mechanism of radiation-induced injury in large vessels, investigate the relationship between radiation dose and large vessel injury and evaluate the rate of progress of atherosclerosis in irradiated vessels.ObjectivesTo investigate whether external irradiation to the carotid area has any effect on IMT of the common carotid artery in a group of patients who received RT vs control group matched for age, gender and race.MethodsWe studied 19 patients (10 male; 47.8 ± 17.4 years) during a 5-month period (January 2009-July 2009); they had completed RT with a mean of 2.9 years before (range: 1 month-6 years) The mean radiation dose to the neck in the irradiated patients was 41.2 ± 15.6 Gy (range: 25-70 Gy). Common carotid IMT was measured with echo-color Doppler. Nineteen healthy adult patients (10 male; 47.8 ± 17.6) were recruited as a control group.ResultsIMT was not significantly higher in patients when compared to the control group (0.59 ± 0.16 vs 0.56 ± 0.16 mm, p = 0.4). There was no significant difference between the two groups in relation to the absence (p = 0.7) or presence (p = 0.6) of vascular risk factors. Although the difference did not reach statistical significance (p = 0.1), the irradiated young patients (age ≤ 52 years) had IMT measurements higher (0.54 ± 0.08 mm) than the non-irradiated young patients (0.49 ± 0.14 mm). The mean carotid IMT increased with increasing doses of radiation to the neck (p = 0.04).ConclusionThis study shows that increased IMT of the common carotid artery after RT is radiation-dose-related. Therefore it is important to monitor IMT, which can be used as an imaging biomarker for early diagnosis of cerebrovascular disease in patients who have had radiotherapy for treatment of cancer of the head and neck and who are at increased risk for accelerated atherosclerosis in carotid arteries.

Epithelioid hemangioendothelioma: an overview and update on a rare vascular tumor.

Epithelioid hemangioendothelioma is a rare vascular tumor, described for the first time in 1975 by Dail and Liebow as an aggressive bronchoalveolar cell carcinoma. The etiology is still a dilemma. Studies about suggestive hypothesis are ongoing. Most of the times it affects lung, liver and bones, although this kind of tumor may involve the head and neck area, breast, lymph nodes, mediastinum, brain and meninges, the spine, skin, abdomen and many other sites. Because of its heterogeneous presentation, as it represents less than 1% of all the vascular tumors, it is often misdiagnosed and not suitably treated, leading to a poor prognosis in some cases. Over 50-76% of the patients are asymptomatic. A small number of them complains respiratory symptoms. Bone metastases might cause pathological fractures or spine compression, if they arise in vertebrae. Imaging is necessary to determine morphological data, the involvement of surrounding tissues, and potentially the cleavage plan. It is important to recognize the expression of vascular markers (Fli-1 and CD31 are endothelial-specific markers), and the microscopic evidence of vascular differentiation to make a correct diagnosis, as many pulmonary diseases show multiple nodular lesions. Because of its rarity, there is no standard for treatment. We focused on radiotherapy as a good therapeutic option: despite the poor prognosis, evidence is in favor of radiotherapy which offers local pain control with good tolerance and better quality of life at least at a one-year follow-up in most of cases. Further studies are needed to establish the standard radiation dose to be used for locoregional control of such a complex and extremely rare disease.

Geometric and dosimetric approach to determine probability of late cardiac mortality in left tangential breast irradiation: comparison between wedged beams and field-in-field technique.

PURPOSE To evaluate the probability of late cardiac mortality resulting from left breast irradiation planned with tangential fields and to compare this probability between the wedged beam and field-in-field (FIF) techniques and to investigate whether some geometric/dosimetric indicators can be determined to estimate the cardiac mortality probability before treatment begins. METHODS AND MATERIALS For 30 patients, differential dose-volume histograms were calculated for the wedged beam and FIF plans, and the corresponding cardiac mortality probabilities were determined using the relative seriality model. As a comparative index of the dose distribution uniformity, the planning target volume (PTV) percentages involved in 97-103% of prescribed dose were determined for the two techniques. Three geometric parameters were measured for each patient: the maximal length, indicates how much the heart contours were displaced toward the PTV, the angle subtended at the center of the computed tomography slice by the PTV contour, and the thorax width/thickness ratio. RESULTS Evaluating the differential dose-volume histograms showed that the gain in uniformity between the two techniques was about 1.5. With the FIF technique, the mean dose sparing for the heart, the left anterior descending coronary artery, and the lung was 15% (2.5 Gy vs. 2.2 Gy), 21% (11.3 Gy vs. 9.0 Gy), and 42% (8.0 Gy vs. 4.6 Gy) respectively, compared with the wedged beam technique. Also, the cardiac mortality probability decreased by 40% (from 0.9% to 0.5%). Three geometric parameters, the maximal length, angle subtended at the center of the computed tomography slice by the PTV contour, and thorax width/thickness ratio, were the determining factors (p = .06 for FIF, and p = .10 for wedged beam) for evaluating the cardiac mortality probability. CONCLUSION The FIF technique seemed to yield a lower cardiac mortality probability than the conventional wedged beam technique. However, although our study demonstrated that FIF technique improved the dose coverage of the PTV, the restricted number of patients enrolled and the short follow-up did not allow us to evaluate and compare the breast cancer survival rates of the patients.

Serum levels of angiogenic cytokines decrease after radiotherapy in non-Hodgkin lymphomas

PurposeSerum levels of angiogenic cytokines decrease after radiotherapy in patients with cancer, and this may be relevant for treatment response and progression-free survival. Herein, we set out to determine whether circulating fibroblast growth factor-2 (FGF-2), vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF) and platelet-derived growth factor-β (PDGF-β) decrease after radiotherapy in patients with non-Hodgkin lymphomas (NHLs) and if so, whether their decrease correlates with age, tumour histotype and stage, and radiation dose.Material and methodsThe serum levels of FGF-2, VEGF, HGF and PDGF-β were evaluated before and after radiotherapy by an enzyme-linked immunosorbent assay (ELISA). These levels were correlated both reciprocally and with age, histotype, stage and radiation dose.ResultsAfter radiotherapy, FGF-2, VEGF and PDGF-β, but not HGF, significantly decreased in relation to the radiation dose and response. No correlation was established between cytokine levels, except for VEGF and PDGF-β, which decreased in parallel. Haemoglobin levels did not decrease after radiotherapy, while FGF-2, VEGF, HGF and PDGF-β levels did not correlate with age, NHL stage and histotype.ConclusionsSoluble FGF-2, VEGF and PDGF-β levels decline after radiotherapy in NHLs, and may have predictive significance for response to treatment and recurrence.

Patient positioning in the proton radiotherapy era.

The main hindrance to the diffusion of proton therapy facilities is the high cost for gantry installations. An alternative technical option is provided by fixed-beam treatment rooms, where the patient is rotated and translated in space with a robotic arm solution to enable beam incidence from various angles. The technological efforts based on robotic applications made up to now for patient positioning in proton beam facilities are described here, highlighting their limitations and perspectives.

Collection and Evaluation of Incidents in a Radiotherapy Department

Purpose:To report on the use of an internal system for incident reporting.Patients and Methods:From October 2001 until June 2009, data on incidents were collected in the radiotherapy department (RT) by means of an incident reporting worksheet. The risk analysis was based on the US Navy method of mishap cause investigation, the Human Factors Analysis and Classification System (HFACS).Results:37 incidents over 5,635 treatments were collected. Of the incidents, 20 involved deviation of the dose to the patient; only 6 showed clinical evidence of overdosage, while 2 of them showed permanent evidence of overdosage. There were 24 incidents that were classified as near misses (NM). Incorrect data input and use of an incorrect treatment field were the most common causes of the registered incidents. Reactive risk analysis showed how skill-based errors were associated with attention failure at the unsafe act level. Dose prescription and dose calculation are the most critical phases of the entire process. Most of the errors were discovered in set-up/treatment and during treatment visit/follow-up phases. The highest number of correction procedures was necessary in the phases of dose prescription and dose calculation.Conclusion:Collecting and analyzing internal incidents improves the operative procedures used in the department.Ziel:Bericht über den Gebrauch eines internen Systems zur Ereignismeldung.Patienten und Methodik:Von Oktober 2001 bis Juni 2009 wurden Daten über Ereignisse in der Strahlentherapieabteilung (RT) anhand eines “Arbeitsblattes Ereignisbericht” gesammelt. Die Risikoanalyse basierte auf der US Navy Methode der “mishap cause investigation, the Human Factors Analysis and Classification System (HFACS)”.Ergebnisse:37 Ereignisse bei 5635 Behandlungen wurden erfasst. Davon waren 20 Abweichungen von Dosierungen, die den Patienten verabreicht wurden, nur 6 wiesen klinische Anzeichen von Überdosierung auf; zwei von diesen zeigten permanente Anzeichen von Überdosierung (Tabellen 1 und 2). 24 waren “Near misses” (NM). Eine nicht korrekte Dateneingabe und Verwendung eines falschen Behandlungsfeldes waren die häufigsten Gründe der registrierten Ereignisse. Eine reaktive Risikoanalyse zeigte, wie auf Fähigkeit beruhende Fehler mit Aufmerksamkeitsfehlern auf dem „unsafe act level” assoziiert werden (Abbildung 1). Dosisverschreibung und Dosisberechnung sind die kritischste Phasen des gesamten Prozesses (Abbildung 2). Die meisten Fehler wurden bei Verordnung/Behandlung und Kontrolluntersuchungen/Verlaufskontrollen festgestellt (Abbildung 3). Die meisten Korrekturen waren in der Dosisverschreibungsphase und der Dosiskalkulationsphase nötig (Abbildung 4).Schlussfolgerung:Das Erfassen und Analysieren von internen Ereignissen verbessert die angewandten operativen Prozeduren in der Abteilung.

A Vinyl Chloride-exposed Worker with an Adrenal Gland Angiosarcoma : A Case Report

Adrenal epithelioidangiosarcoma (AEA) is a rare neoplasm that accounts for less than 1% of sarcomas. Due to its rarity, it can easily be misdiagnosed, both by the clinician and the pathologist. Data on the patient’s occupational history was collected and analyzed. The bibliographic data was found on the PUBMED bibliographic search site after entering the word “extrahepaticangiosarcoma”. We report a case of adrenal epithelioidangiosarcoma (AEA) in a 68 yr-old Caucasian male factory worker exposed to Vinyl Chloride (VC) for 15 yr. He underwent surgery, chemotherapy and radiotherapy. Hepatic angiosarcoma is a known consequence of VC exposure, but occupational causality of extra-hepatic angiosarcoma is controversial. Extra-hepatic angiosarcomas have been reported in VC workers, but never AEA. Cancerogenic effects of VC involve all endothelial areas of the body and extra-hepatic endothelial tumors may also be caused by this substance. This is the first published report of AEA diagnosed in a worker exposed to VC.

Fractionations in radiotherapy of brain metastases.

Aims and background The aim of this study was to evaluate different fractionations for radiotherapy of brain metastases. Methods One hundred and twenty-five patients treated with whole brain cobalt therapy (WBRT) were examined to evaluate the effect on survival and quality of life of three different dose fractionations (2 Gy × 25, 3 Gy × 10 and 4 Gy × 5). Fractionation was evaluated in relation to mean survival, single or multiple lesions, presence of extracranial metastases, primary tumor control and neurological status before and after treatment. Kaplan-Meier analysis of survival and univariate and multivariate analysis of these factors were performed. Twenty-six (21%) patients were treated with 2 Gy × 25, 48 patients (38%) with 3 Gy × 10 and 42 patients (33%) with 4 Gy × 5. The other 9 patients were treated with unusual fractionations. Results In 66% of patients an improvement in neurological status after radiotherapy was recorded. Patients with controlled primary tumors had a better mean survival, 8.6 months, if they had no extracranial metastases. The six-month survival was 21% in the 4 Gy × 5 group, 36% in the 3 Gy × 10 group, and 21% in the 2 Gy × 25 group; the results for one-year actuarial survival were highly similar in the three fractionation groups (5%, 11% and 6%, respectively). Conclusions The use of 5 × 4 Gy fractionation may be appropriate in lung cancer patients, where no significant difference in 6- and 12-month survival was observed with respect to the other fractionation groups despite the most unfavorable prognosis of these patients and the lower biological effectiveness of this fractionation with respect to the other schedules.