Predicting Radiotherapy Impact on Late Bladder Toxicity in Prostate Cancer Patients: An Observational Study.

BACKGROUND AND PURPOSE: The aim of our study was to elaborate a suitable model on bladder late toxicity in prostate cancer (PC) patients treated by radiotherapy with volumetric technique. MATERIALS AND METHODS: PC patients treated between September 2010 and April 2017 were included in the analysis. An observational study was performed collecting late toxicity data of any grade, according to RTOG and CTCAE 4.03 scales, cumulative dose volumes histograms were exported for each patient. Vdose, the value of dose to a specific volume of organ at risk (OAR), impact was analyzed through the Mann-Whitney rank-sum test. Logistic regression was used as the final model. The model performance was estimated by taking 1000 samples with replacement from the original dataset and calculating the AUC average. In addition, the calibration plot (Hosmer-Lemeshow goodness-of-fit test) was used to evaluate the performance of internal validation. RStudio Software version 3.3.1 and an in house developed software package "Moddicom" were used. RESULTS: Data from 175 patients were collected. The median follow-up was 39 months (min-max 3.00-113.00). We performed Mann-Whitney rank-sum test with continuity correction in the subset of patients with late bladder toxicity grade ≥ 2: a statistically significant p-value with a Vdose of 51.43 Gy by applying a logistic regression model (coefficient 4.3, p value 0.025) for the prediction of the development of late G ≥ 2 GU toxicity was observed. The performance for the model's internal validation was evaluated, with an AUC equal to 0.626. Accuracy was estimated through the elaboration of a calibration plot. CONCLUSIONS: Our preliminary results could help to optimize treatment planning procedures and customize treatments.

Review and meta-analysis of incidence and clinical predictors of anthracycline cardiotoxicity.

The management of individual patients requiring anthracyclines remains challenging because uncertainty persists on predictors of cardiotoxicity. We aimed to perform a systematic review and meta-analysis on incidence and predictors of anthracycline chemotherapy in patients with cancer. Databases were searched for pertinent studies. Meta-analytic pooling with random-effects methods was performed for incidence estimates, while relying on descriptive statistics for prevalence and strength of association of predictors. From 16,054 retrieved citations, 18 studies reporting on 49,017 patients with cancer were included, with 22,815 treated with anthracyclines. After a median follow-up of 9 years, clinically overt cardiotoxicity occurred in 6% (95% confidence interval 3% to 9%), whereas subclinical cardiotoxicity developed in 18% (95% confidence interval 12% to 24%). Appraisal of independent risk factors of cardiotoxicity showed that cumulative anthracycline dose was most consistently reported as an accurate and robust predictor of cardiotoxicity, with an acceptable prognostic role also for chest radiotherapy, African-American ethnicity, very young or very old age, diabetes, hypertension, very high or very low body weight, or severe co-morbidities. In conclusion, despite ongoing refinements in chemotherapy regimens, anthracyclines still pose a significant risk of cardiotoxicity, especially in those requiring a high cumulative dose or chest radiotherapy.

Temporal changes in standard and tissue Doppler imaging echocardiographic parameters after anthracycline chemotherapy in women with breast cancer.

Anthracyclines are established cardiotoxic agents; however, the exact extent and time course of such cardiotoxicity has not been appraised in detail. We aimed to exploit serial measurements of standard and tissue Doppler imaging (TDI) echocardiographic parameters collected in a prospective clinical trial to clarify the outlook of cardiac function during and long after anthracycline chemotherapy. Women enrolled in a randomized trial focusing on liposomal doxorubicin-based chemotherapy for breast cancer and providing ≥4 separate echocardiographic assessments were included. Repeat-measure nonparametric analyses were used to appraise changes over time in the standard and tissue Doppler imaging echocardiographic parameters. A total of 39 patients with serial imaging evaluations were enrolled. Significant temporal changes were found for the left ventricular ejection fraction and diastolic parameters, despite different temporal trends. Specifically, the left ventricular ejection fraction exhibited a V-shaped trend, decreasing initially from 63% to 61% but then recovering to 64% (p <0.001), with a similar trend in the TDI E/Em ratio (p = 0.011). In contrast, persistent impairments typical of an L-shaped trend were found for the E wave (p = 0.006), TDI lateral Em wave (p = 0.001), and TDI septal Em wave (p = 0.001). In conclusion, subclinical temporal changes in the standard and TDI echocardiographic parameters after anthracycline chemotherapy showed a distinctive pattern of transient impairment followed by full recovery of the left ventricular ejection fraction versus a persistent impairment of the diastolic parameters, which must be taken into account in the everyday treatment of such patients.

Comparative cardiac toxicity of anthracyclines in vitro and in vivo in the mouse.

PURPOSE: The antineoplastic efficacy of anthracyclines is limited by their cardiac toxicity. In this study, we evaluated the toxicity of doxorubicin, non-pegylated liposomal-delivered doxorubicin, and epirubicin in HL-1 adult cardiomyocytes in culture as well as in the mouse in vivo. METHODS: The cardiomyocytes were incubated with the three anthracyclines (1 µM) to assess reactive oxygen generation, DNA damage and apoptotic cell death. CF-1 mice (10/group) received doxorubicin, epirubicin or non-pegylated liposomal-doxorubicin (10 mg/kg) and cardiac function was monitored by Doppler echocardiography to measure left ventricular ejection fraction (LVEF), heart rate (HR) and cardiac output (CO) both prior to and 10 days after drug treatment. RESULTS: In HL-1 cells, non-pegylated liposomal-doxorubicin generated significantly less reactive oxygen species (ROS), as well as less DNA damage and apoptosis activation when compared with doxorubicin and epirubicin. Cultured breast tumor cells showed similar sensitivity to the three anthracyclines. In the healthy mouse, non-pegylated liposomal doxorubicin showed a minimal and non-significant decrease in LVEF with no change in HR or CO, compared to doxorubicin and epirubicin. CONCLUSION: This study provides evidence for reduced cardiac toxicity of non-pegylated-liposomal doxorubicin characterized by attenuation of ROS generation, DNA damage and apoptosis in comparison to epirubicin and doxorubicin.

Appraising cardiotoxicity associated with liposomal doxorubicin by means of tissue Doppler echocardiography end-points: rationale and design of the LITE (Liposomal doxorubicin-Investigational chemotherapy-Tissue Doppler imaging Evaluation) randomized pilot study.

BACKGROUND: Cardiomyopathy following anthracycline chemotherapy may have ominous clinical implications in cancer patients treated with this effective yet potentially toxic therapy. Early detection at subclinical stage is pivotal to minimize the risk of overt cardiotoxicity. Liposomal anthracyclines have the potential for more selective uptake by cancer cells and reduced cardiac toxicity. OBJECTIVE: We designed a single-center randomized clinical trial, the Liposomal doxorubicin-Investigational chemotherapy-Tissue Doppler imaging Evaluation (LITE) pilot study to compare the safety of liposomal doxorubicin vs standard epirubicin in terms of clinical and subclinical cardiotoxicity. METHODS: Whereas diagnostic and prognostic instruments effective at early recognition of cardiomyopathy are lacking, promising data have been reported for tissue Doppler imaging (TDI) echocardiography. The study will enroll 80 patients with breast cancer and indication to anthracycline chemotherapy, randomizing them in a 1:1 ratio to liposomal doxorubicin or standard epirubicin. The primary end-point will be the comparison of changes from baseline to 12-month follow-up of left ventricular TDI systolic function parameters, and the co-primary end-point will be based instead on changes in TDI diastolic function parameters. Among secondary end-points, we will adjudicate changes in standard 2-dimensional echocardiography parameters, including ejection fraction, peak values of biochemical markers of cardiac damage and heart failure, ie cardiac troponin T and BNP, overall survival, functional class, freedom from cancer recurrence, and adverse effects of chemotherapy. CONCLUSIONS: Results of the LITE pilot study should provide important clinical and mechanistic insights on the promising role of liposomal anthracyclines in patients with breast cancer and indication to anthracycline chemotherapy (ClinicalTrials.gov identifier NCT00531973).

Impact of dose and volume on lymphedema.

Lymphedema represents one of the major problem of morbidity in breast cancer therapy. Approximately 15-30% of patients show more or less severe lymphedema of the arm, following cancer therapy. Main pathogenetic mechanisms, risk factors, main grading criteria and scales as LENT-SOMA, CTCv2, CTCAE v3 are presented. A close correlation has been documented between the extent of axillary dissection and the association with radiotherapy in determining an increased risk of lymphedema. Details of surgery and radiotherapy are relevant in the definition of the risk of edema of the arm. Because the axillary area does not correspond to an organ, evaluable parameters as V20 and Dmean available for other organs are not applicable. There is some evidence of a correlation between the irradiation volume and the development of lymphedema. Data of the impact of the dose and its fractionation on the development of lymphedema are contrasting. The monitoring system of late toxicity used by the authors is presented.

Dose fractionation and biological optimization in breast cancer.

Standard radiotherapy in breast cancer is performed at the dose of 1.8-2 Gy daily 5 fractions a week for a total dose between 45 and 60 Gy. However research is addressed to different fractionations. For total time reduction, the interest was focused on conventional brachytherapy which radiobiologically represents "continuous" accelerated hyperfractionation, as well as on conventional external beam radiotherapy with accelerated hyperfractionation. A phase I study was conducted to define and validate a radiotherapy schedule with non conventional fractionation. Nine patients with metastatic breast cancer were enrolled in the study. None of them had undergone breast surgery or lymph node dissection. They were sequentially divided into three different, progressively increasing dose levels administered with double daily fractionation. Each schedule of accelerated fractionation (AF) included the administration of 1.8 Gy in two daily fractions, at least six hours apart for 10, 11 and 12 days and a total dose of 36, 39.6 and 43.2 Gy, respectively. Results of dose escalation, acute toxicity and mathematical calculation of radiobiological equivalence led to consider the dose of 36 Gy in 20 fractions during 10 days the most suitable for cost/benefit ratio within a non conventional fractionation.