V5 and High Sensitivity Cardiac Troponin T for Early Detection of Cardiac Toxicity During Left Breast Cancer Irradiation.

BACKGROUND/AIM: The high sensitivity cardiac troponin T (Hs-cTnT) is a myocardial damage biomarker that could have a predictive value in patients who undergo radiotherapy for left sided breast cancer. The aim of this study was to evaluate the early effect of left whole breast radiotherapy (WB-RT) on serum Hs-cTnT levels and its correlation with pre-existing factors. PATIENTS AND METHODS: The study was conducted from December 2017 to May 2018. Forty-five patients with early stage left-sided breast cancer who received adjuvant breast hypofractionated RT without prior chemotherapy were included. Serum levels of Hs-cTnT were obtained before, weekly during RT, and within one week after the end of treatment. Considering the physiological variations of serum levels, an increase in Hs-cTnT (∆Hs-cTnT) of more than 30% from the baseline value was chosen as a threshold. The main cardiovascular risk factors were recorded. Dose volume histograms (DVHs) were used to provide a quantitative analysis for the whole heart, left ventricle, and left anterior descending artery (LAD). RESULTS: Twelve of 45 patients (26.6%) showed a ∆Hs-cTnT ≥30%. The maximum Hs-cTnT level was recorded in the last week of treatment. ∆Hs-cTnT was strongly associated with heart V5 (p=0.05) and hypertension (p=0.05). Multivariate analysis confirmed the importance of the heart V5 and correlated with ∆Hs-cTnT. CONCLUSION: The increase in Hs-cTnT serum levels during adjuvant WB-RT suggested a correlation with the cardiac radiation dose in chemotherapy-naive breast cancer patients. A longer follow-up is needed to correlate Hs-cTnT values with cardiac events.

Whole breast external beam radiotherapy in elderly patients affected by left-sided early breast cancer: a dosimetric comparison between two simple free-breathing techniques.

BACKGROUND: Elderly breast cancer patients are frequently affected by significant comorbidities that make sophisticated radiotherapy treatments particularly challenging. AIMS: We dosimetrically analyzed two different simple free-breathing external beam radiotherapy (EBRT) techniques for the hypofractionated treatment of the left breast in elderly patients with a low compliance, to compare target coverage, and heart and left anterior descending coronary artery (LADCA) sparing. METHODS: We developed radiation plans for 24 elderly patients using 3D conformal (3DCRT) field-in-field tangential technique and intensity-modulated (IMRT) tangential beam technique. Dose-Volume-Histograms (DVHs) were used to provide a quantitative comparison between plans. RESULTS: The median breast volume was 645 cm3. IMRT and 3DCRT plans comparison demonstrated no significant differences in terms of organ sparing for the heart. Regarding LADCA, mean dose (10.3 ± 9.5 Gy vs 11.9 ± 9.6 Gy, p = 0.0003), maximum dose (26.1 ± 16.1 Gy vs 29.1 ± 16.1 Gy, p = 0.004) and V17 Gy (21.5% ± 26.9% vs 25.0% ± 27.2%, p = 0.002) significantly decreased using IMRT compared with 3DCRT. IMRT plans showed a better target coverage compared with 3DCRT (0.91 ± 0.05 vs 0.93 ± 0.04, p = 0.05). DISCUSSION: Comparing the two different EBRT techniques, we demonstrated few, although substantial, dosimetric differences in terms of doses to the organs at risk characterized by a statistically significant dose reduction of LADCA in the IMRT plans. CONCLUSIONS: Elderly patients with a low compliance to treatment might benefit from 3DCRT with field-in-field tangential arrangement or from a simple IMRT approach. IMRT should be preferred.

Oligometastatic cancer in elderly patients: the "blitzkrieg" radiotherapy approach : SBRT in oligometastatic elderly patients.

AIMS: To retrospectively evaluate the outcome of stereotactic body radiation therapy (SBRT) in the treatment of elderly patients affected by isolated body metastasis from different primitive tumors. METHODS: 70 patients with isolated body metastasis were treated. Median age at diagnosis was 75 years (IQR 69-80). The most common SBRT fractionation scheme was 5 × 7 Gy (total dose 35 Gy). The primary endpoints were Local Control (LC) and Toxicity. Secondary endpoints were Overall Survival (OS) and Disease-Specific Survival (DSS). Response to radiotherapy was assessed according to RECIST criteria v1.1. Toxicity was registered according to Common Terminology Criteria for Adverse Events (CTCAE) v 4.0. We performed survival analysis with the Kaplan-Meier method. The correlation between time actuarial incidence and clinical parameters was studied. RESULTS: Median follow-up was 26.5 months. 44 patients (62.8%) were alive at the time of analysis, while 22 (31.4%) died because of the disease. Local control at 2 and 3 years was 87%. The 2-year OS and DSS were 84 and 71%, respectively, while the 3-year values were 57 and 62%. PFS at 2 and 3 years was 41 and 25%, respectively. On univariate analysis, KPS ≥ 90 is statistically correlated with improved OS and DSS (p < 0.05). Acute toxicity of grade ≥ 2 occurred in 4 (5.7%) patients, while late toxicity ≥ 2 was recorded in 6 (8.6%) patients. CONCLUSIONS: Ablative Radiotherapy represents a safe, effective, and minimally invasive treatment modality for elderly oligometastatic patients who are judged unfit for systemic therapy.

Volumetric image-guided conformal radiotherapy for localized prostate cancer: Analysis of dosimetric and clinical factors affecting acute and late toxicity.

AIM: To identify factors influencing toxicity in patients affected by localized prostate cancer treated with conformal image-guided radiotherapy. BACKGROUND: Image guidance in combination with conformal techniques is the standard of care in localized prostate cancer, but factors affecting toxicity are still under investigation. MATERIALS AND METHODS: 294 patients were analyzed. Median age at diagnosis was 71 year. 76 Gy (38 × 2 Gy) were delivered to the target volume. We used the χ2 test to analyse associations between toxicity and dosimetric and clinical parameters. Multivariate analysis was performed using binary logistic regression. Kaplan-Meier method was used for survival analysis. RESULTS: Median follow-up was 62.9 months. Acute grade ≥2 gastro-intestinal toxicity (GI) was 12.1%. Acute genito-urinary (GU) toxicity of grade ≥2 was 33.9%. Actuarial 4 and 5 years late grade ≥2 GI was 3% and 4%, respectively. Four and 5-year late grade ≥2 GU toxicity was 6% and 10%. At multivariate analysis for acute toxicity rectal V70 was correlated with GI toxicity (p = 0.01, HR 2.73 CI 1.19-6.26), and smoking habit with GU toxicity (p < 0.01, HR 2.50 CI 1.51-4.14). For late toxicity, rectal V70 was correlated with gastro-intestinal toxicity (p = 0.04, HR 4.76 CI 1.07-21.13), and pre-radiotherapy urinary symptoms with genito-urinary toxicity (p = 0.01, HR 2.84 CI 1.29-6.22). DISCUSSION: Conformal image-guided radiotherapy shows low rates of toxicity. Smoking should be avoided during radiotherapy. Besides the evaluation of high doses received by the organs at risk, individual factors, such as co-morbidities and lifestyle choices, have an impact on normal-tissue complication risk.

Oligometastatic cancer: stereotactic ablative radiotherapy for patients affected by isolated body metastasis.

BACKGROUND: To evaluate the outcome of patients affected by a single isolated body metastasis treated with stereotactic body radiotherapy (SBRT). MATERIAL AND METHODS: Seven-eight patients were treated with SBRT for isolated body metastasis. The most frequent primary tumor was prostate cancer (28.2%), followed by colorectal cancer (23.1%) and lung cancer (20.5%). Median age at diagnosis of oligometastatic disease was 70 years (range 47-88). Median Karnofsky Performance Status (KPS) was 90 (range 70-100). The most common SBRT fractionation scheme was 5 × 7 Gy (total dose 35 Gy). Response to radiotherapy was determined according to RECIST criteria v1.1. Toxicity was registered according to Common Terminology Criteria for Adverse Events (CTCAE) v4.0. The survival analysis was performed with the Kaplan-Meier method. The correlation between time actuarial incidence and clinical parameters was studied, and the Kaplan-Meier method of log-rank test was applied. RESULTS: With a median follow-up of 22.68 months, local control was achieved in 89.7% of the cases. The two-year overall survival (OS) and progression-free survival (PFS) were 68% and 42%, respectively. On univariate analysis, KPS ≥80 is predictive for improved OS (p = .001) and PFS (p = .001). Acute toxicity of grade ≥2 occurred in eight (10.2%) patients and late grade ≥2 toxicity in five (6.4%) patients. CONCLUSIONS: Ablative radiotherapy in 'early oligometastatic state' is a safe, effective and minimally invasive treatment modality. A good performance status (KPS ≥80) seems to influence the clinical outcome.

Volumetric image-guided highly conformal radiotherapy of the prostate bed: Toxicity analysis.

AIM: To evaluate toxicity of high conformal image-guided radiotherapy of the prostate bed. BACKGROUND: Radiotherapy of the prostate bed has a pivotal role in the post-operative and salvage settings, but few clinical data are available on the use of daily image guidance in combination with highly conformal techniques, and data on long-term results are lacking. MATERIALS AND METHODS: We analyzed 118 patients irradiated on the prostate bed using conformal plans processed with a micro-multileaf collimator, and daily checking treatment set-up with a cone-beam CT system. Correlation between toxicity and clinical-dosimetric parameters was assessed by the Cox regression model and log-rank test. Survival analyses were performed with the Kaplan-Meier method. RESULTS: Median follow-up was 54.08 months. Late grade ≥2 gastro-intestinal (GI) and genito-urinary (GU) toxicity were 3.4% and 4.2%, respectively. Actuarial 4-year late grade ≥2 GI and GU toxicities were 4% and 6%, respectively. Four-year relapse-free survival was 87%. At log-rank test, acute grade ≥2 GI toxicity is associated with the use of antihypertensives (p = 0.03), and there is a trend toward significance between the use of anticoagulants and late grade ≥2 GI toxicity (p = 0.07). At Cox analysis, acute grade ≥2 GU toxicity is correlated with the percentage of bladder volume receiving more than 65 Gy (p = 0.02, HR 1.87 CI 1.25-2.8), and the maximal dose to the rectum is correlated to the development of late grade ≥2 GI toxicity (p = 0.03, HR 2.75 CI 1.10-6.9). CONCLUSIONS: Conformal volumetric image-guided radiotherapy of the prostate bed leads to low toxicity rates.

Stereotactic body radiotherapy in oligometastatic prostate cancer patients with isolated lymph nodes involvement: a two-institution experience.

OBJECTIVE: Stereotactic body radiotherapy (SBRT) is emerging as a treatment option in oligometastatic cancer patients. This retrospective study aimed to analyze local control, biochemical progression-free survival (b-PFS), and toxicity in patients affected by isolated prostate cancer lymph node metastases. Finally, we evaluated androgen deprivation therapy-free survival (ADT-FS). METHODS: Forty patients with 47 isolated lymph nodes of recurrent prostate cancer were treated with SBRT. Mostly, two different fractionation schemes were used: 5 × 7 Gy in 23 (48.9 %) lesions and 5 × 8 Gy in 13 (27.7 %) lesions. Response to treatment was assessed with periodical PSA evaluation. Toxicity was registered according to RTOG/EORTC criteria. RESULTS: With a mean follow-up of 30.18 months, local control was achieved in 98 % of the cases, with a median b-PFS of 24 months. We obtained a 2-year b-PFS of 44 % with 40 % of the patients ADT-free at last follow-up (mean value 26.18 months; range 3.96-59.46), whereas 12.5 % had a mean ADT-FS of 13.58 months (range 2.06-37.13). Late toxicity was observed in one (2.5 %) patient who manifested a grade 3 gastrointestinal toxicity 11.76 months after the end of SBRT. CONCLUSION: Our study demonstrates that SBRT is safe, effective, and minimally invasive in the eradication of limited nodal metastases, yielding an important delay in prescribing ADT.

Salvage Stereotactic Body Radiotherapy for Patients With Prostate Cancer With Isolated Lymph Node Metastasis: A Single-Center Experience.

OBJECTIVE: The study objective was to evaluate the efficacy of salvage stereotactic body radiation therapy (SBRT) as a treatment modality in patients with oligometastatic prostate cancer. METHODS: A total of 16 patients with 18 isolated lymph nodes with recurrent prostate cancer were treated between 2008 and 2013. All patients underwent [(11)C] choline-positron emission tomography/computed tomography before SBRT. Two patients were treated in different sessions for metachronous metastases. Ten patients received androgen deprivation therapy concomitant to SBRT (total dose range, 12-35 Gy, delivered in 1-5 daily fractions). RESULTS: The mean and median follow-up periods were 29.35 and 29.38 months, respectively (range, 6.3-68.8 months). Local disease control and a decrease in serum prostate-specific antigen were obtained in 15 of 16 patients (94%); only 1 patient had an in-field progression. In the 6 patients without androgen deprivation therapy at the time of SBRT, the mean time of deferment of palliative androgen deprivation therapy was 23.7 months (range, 2.5-51 months). At last follow-up, 8 patients had active prostate cancer disease; biochemical progression was observed after a mean time of 7.9 months from the completion of SBRT. One patient died of disease. Overall survival was 94%. The 2-year biochemical relapse-free survival was 44%. Late toxicity (gastrointestinal) was observed in 1 patient who had a G3 toxicity. CONCLUSIONS: SBRT seems to be safe, effective, and minimally invasive in the eradication of limited nodal recurrence from oligometastatic prostate cancer. SBRT is well tolerated by patients with low toxicity and yielded a local control of the disease.

Acute and late toxicity after three-dimensional conformal image-guided radiotherapy for localized prostate cancer.

We evaluated the clinical impact of a high definition micro-multileaf collimator and a linac-integrated cone-beam computed tomography in 142 patients treated with conformal radiotherapy for localized prostate cancer to a total dose of 76 Gy. Details on treatment toxicity and tumour control were collected. The 3 years biochemical relapse-free survival was 90%. Acute and late gastrointestinal toxicities were low (3-year actuarial late toxicity of 11.2%). Acute genitourinary toxicity was relatively high, the 3-year actuarial genitourinary late toxicity was 12%. Conformal image-guided radiotherapy for localized prostate cancer leads to low rates of late toxicity with a high rate of tumor control.

Dosimetric effect of Elekta Beam modulator micromultileaf in three-dimensional conformal radiotherapy and intensity-modulated radiotherapy for prostate cancer.

The purpose of this study is to analyze the dosimetric effect of Elekta Beam Modulator in 3-dimensional conformal radiation therapy (3DCRT) and in intensity-modulated radiation therapy (IMRT) for localized prostate cancer. We compared treatment plans developed with 2 different Elekta multileaf collimators (MLC): Beam Modulator micro-MLC (mMLC) (4-mm leaf width at the isocenter) and standard MLC (10-mm leaf width at the isocenter). The comparison was performed for 15 patients with localized prostate cancer in 3DCRT and IMRT delivery; a total of 60 treatment plans were processed. The dose-volume histograms were used to provide the quantitative comparison between plans. In particular, we analyzed differences between rectum and bladder sparing in terms of a set of appropriate Vx (percentage of organ at risk [OAR] volume receiving the x dose) and differences between target conformity and coverage in terms of coverage factor and conformation number. Our analysis demonstrates that in 3DCRT there is an advantage in the use of Elekta Beam Modulator mMLC in terms of organ sparing; in particular, a significant decrease in rectal V60 and V50 (p = 0.001) and in bladder V70 and V65 (p = 0.007 and 0.002, respectively) was found. Moreover, a better target dose conformity was obtained (p = 0.002). IMRT plans comparison demonstrated no significant differences between the use of the 4 or 10-mm MLCs. Our analysis shows that in 3DCRT the use of the Elekta Beam Modulator mMLC gives a gain in target conformity and in OARs dose sparing whereas in IMRT plans there is no advantage.

Preliminary studies for a CBCT imaging protocol for offline organ motion analysis: registration software validation and CTDI measurements.

Cone-beam X-ray volumetric imaging in the treatment room, allows online correction of set-up errors and offline assessment of residual set-up errors and organ motion. In this study the registration algorithm of the X-ray volume imaging software (XVI, Elekta, Crawley, United Kingdom), which manages a commercial cone-beam computed tomography (CBCT)-based positioning system, has been tested using a homemade and an anthropomorphic phantom to: (1) assess its performance in detecting known translational and rotational set-up errors and (2) transfer the transformation matrix of its registrations into a commercial treatment planning system (TPS) for offline organ motion analysis. Furthermore, CBCT dose index has been measured for a particular site (prostate: 120 kV, 1028.8 mAs, approximately 640 frames) using a standard Perspex cylindrical body phantom (diameter 32 cm, length 15 cm) and a 10-cm-long pencil ionization chamber. We have found that known displacements were correctly calculated by the registration software to within 1.3 mm and 0.4°. For the anthropomorphic phantom, only translational displacements have been considered. Both studies have shown errors within the intrinsic uncertainty of our system for translational displacements (estimated as 0.87 mm) and rotational displacements (estimated as 0.22°). The resulting table translations proposed by the system to correct the displacements were also checked with portal images and found to place the isocenter of the plan on the linac isocenter within an error of 1 mm, which is the dimension of the spherical lead marker inserted at the center of the homemade phantom. The registration matrix translated into the TPS image fusion module correctly reproduced the alignment between planning CT scans and CBCT scans. Finally, measurements on the CBCT dose index indicate that CBCT acquisition delivers less dose than conventional CT scans and electronic portal imaging device portals. The registration software was found to be accurate, and its registration matrix can be easily translated into the TPS and a low dose is delivered to the patient during image acquisition. These results can help in designing imaging protocols for offline evaluations.

Aggregation of gramicidin A in phospholipid Langmuir-Blodgett monolayers.

The aggregation of Gramicidin A (gA) in dipalmitoylphosphatidylcoline (DPPC) monolayers is investigated by both thermodynamic and structural methods. Compression isotherm analysis and atomic force microscopy (AFM) observations are performed. Our experimental results indicate that gA aggregation does occur in DPPC monolayers even at very low gA concentration (about 8 x 10(-4) mol%). At the low gA concentration limit, the aggregation process seems to be mainly horizontal (i.e., side-by-side, into the monolayer plane), following a fractal pattern growth producing the formation of typical, flat (0.5 nm height) "doughnut" structures, with a diameter of approximately 150 nm. These structures appear to be composed of smaller subunits (about 70 nm diameter) showing the same doughnut structure. At a molar fraction of approximately 3.8 mol%, the big doughnuts start to disaggregate and only small doughnuts appear. Above a gA concentration of approximately 4.4 mol%, all doughnuts (large and small) disappear, and the morphology assumes the appearance of a patchwork of two distinct phases: one that, being very flat, can be associated with a gA-free or gA-poor DPPC phase, and a second one, characterized by a more corrugated surface, associated with a gA-rich DPPC phase. At gA concentration of approximately 5 mol%, a percolation transition in the gA-rich DPPC phase occurs. Thermodynamic data indicate that the maximum of miscibility between gA and DPPC molecules occurs at approximately 28 mol%, suggesting that gA could aggregate in hexamers that are, on average, bound to 16 DPPC molecules. At the same concentration, AFM images show a network of small gA aggregation units of a size compatible with gA hexamers.