Results of the IROCA international clinical audit in prostate cancer radiotherapy at six comprehensive cancer centres.

To assess adherence to standard clinical practice for the diagnosis and treatment of patients undergoing prostate cancer (PCa) radiotherapy in four European countries using clinical audits as part of the international IROCA project. Multi-institutional, retrospective cohort study of 240 randomly-selected patients treated for PCa (n = 40/centre) in the year 2015 at six European hospitals. Clinical indicators applicable to general and PCa-specific radiotherapy processes were evaluated. All data were obtained directly from medical records. The audits were performed in the year 2017. Adherence to clinical protocols and practices was satisfactory, but with substantial inter-centre variability in numerous variables, as follows: staging MRI (range 27.5-87.5% of cases); presentation to multidisciplinary tumour board (2.5-100%); time elapsed between initial visit to the radiation oncology department and treatment initiation (42-102.5 days); number of treatment interruptions ≥ 1 day (7.5-97.5%). The most common deviation from standard clinical practice was inconsistent data registration, mainly failure to report data related to diagnosis, treatment, and/or adverse events. This clinical audit detected substantial inter-centre variability in adherence to standard clinical practice, most notably inconsistent record keeping. These findings confirm the value of performing clinical audits to detect deviations from standard clinical practices and procedures.

Consensus statement from the Spanish Brachytherapy Group (GEB) on accelerated partial breast irradiation using multicatheter interstitial brachytherapy.

AIM: To establish consensus guidelines for a safe clinical practice of accelerated partial breast irradiation (APBI) interstitial multicatheter brachytherapy (BT). BACKGROUND: APBI with interstitial multicatheter BT has proved to be effective in the treatment of early stage breast cancer. This paradigm shift in the approach to early breast cancer conservative treatment, along with the existing controversies on the clinical practice of APBI, prompted the Spanish Brachytherapy Group (GEB) of the Spanish Societies of Radiation Oncology (SEOR) and Medical Physics (SEFM) to address BT APBI in a consensus meeting. MATERIALS AND METHODS: Prior to the meeting, a survey with 27 questions on indication, inclusion criteria, BT modality, implant technique, image guidance and simulation, CTV and OAR definition, dose prescription and fractionation, dose calculation, implant quality metrics and OAR dose constrains was distributed. Items not reaching a level of agreement of 70% were discussed and voted during the meeting. RESULTS: 26 Institutions completed the survey, 60% of them perform APBI procedures. The analysis of the survey showed consensus reached on approximately half the questions. An expert panel discussed the remaining items; thereafter, a voting established the definite consensus. CONCLUSIONS: This document summarizes the consensus guidelines agreed during the meeting of the Spanish Brachytherapy Group SEOR-SEFM. Institutions with BT facilities available should offer interstitial BT APBI as a treatment option to patients fulfilling the inclusion criteria. Institutions willing to implement interstitial BT APBI are encouraged to follow the consensus guidelines established herein.

Tumor Volumes in Choroidal Melanoma: Agreement Between Three-Dimensional Ultrasound and Two Mathematical Models.

PURPOSE: To determine the degree of agreement between 2 mathematical models and 3-dimensional ultrasonography (3DUS) in estimating choroidal melanoma tumor volumes. DESIGN: Reliability analysis. METHODS: Tumor measurements estimated by 2 mathematical models (designated Formula 1 and Formula 2) were compared to those obtained by 3DUS in 45 consecutive patients with primary choroidal melanoma to determine the percentage agreement between the models and 3DUS. RESULTS: Both formulas tended to overestimate the tumor volume. Overall, the mean volume differences between 3DUS and Formula 1 and between 3DUS and Formula 2, respectively, were 51.7 mm(3) (95% confidence interval [CI], 187.6 to 84.3) and 23.8 mm(3) (95% CI, 122.5 to 74.8). Excluding mushroom-shaped tumors, the mean volume differences were 52.0 mm(3) (95% CI, 194.9 to 91.0) and 23.0 mm(3) (95% CI, 127.0 to 81.0), respectively. In mushroom-shaped tumors, mean volume differences were 49.9 mm(3) (95% CI, 135.7 to 35.9) and 29.3 mm(3) (95% CI, 87.6 to 29.0), respectively. CONCLUSIONS: The agreement between these mathematical models and the measured 3DUS volume was high. The data obtained in this study show that both formulas provide a simple, fast, and accurate method of estimating tumor volumes in the clinical setting, suggesting that these models could be used as a reliable and inexpensive alternative to time-consuming procedures such as 3DUS or magnetic resonance imaging. The accurate tumor volume values provided by these formulas may help to provide more reliable estimates of tumor regression or regrowth following globe-preserving treatment of choroidal melanomas, and may be a valuable prognostic indicator.

Impact of prostate catheter displacement in inverse planning--simulated annealing and geometric optimization.

PURPOSE: The aim of this study was to compare inverse planning-simulated annealing (IPSA) with geometric optimization (GO) in high-dose-rate (HDR) prostate brachytherapy, to assess variations in dosimetric indices associated to catheter displacement. METHODS AND MATERIALS: We retrospectively studied the dosimetric effect of catheter displacement in 20 patients treated with HDR prostate brachytherapy with salvage intention. The catheter loadings, with optimized dwell positions, from the first fraction were transferred to the catheter positions in the second fraction. RESULTS: Median catheter displacement was 8.7 ± 3.3 mm (range, 2.7 ± 1.1 mm-14.7 ± 1.7 mm). D90% median variations for IPSA and GO were -10% with a maximum of -59%, and -29% with a maximum of -63%, respectively. V100% median variation was -11% with a maximum of -37% for IPSA, and -20% with a maximum of -37% for GO. V150/V100 implant median variations were 15% and 9% for IPSA and GO with maximum values of 65% and 47%, respectively (p < 0.05). No significant differences were observed for V200/V100 indices, nor were any significant differences found for organs at risk. Correlation between mean catheter displacement and dosimetric indices was found only in the planning target volume D90% and V100%; linear regression slopes were -2.0% per mm and -2.6% per mm for IPSA vs. -2.4% per mm and -3.5% per mm for GO. CONCLUSIONS: IPSA does not present any additional risk compared with GO in HDR prostate brachytherapy when catheter uncertainties are taken into account. Moreover, IPSA optimization preserves planning target volume coverage better than GO, suggesting that it may be superior when catheter displacement is considered.

Development of a preclinical therapeutic model of human brain metastasis with chemoradiotherapy.

Currently, survival of breast cancer patients with brain metastasis ranges from 2 to 16 months. In experimental brain metastasis studies, only 10% of lesions with the highest permeability exhibited cytotoxic responses to paclitaxel or doxorubicin. Therefore, radiation is the most frequently used treatment, and sensitizing agents, which synergize with radiation, can improve the efficacy of the therapy. In this study we used 435-Br1 cells containing the fluorescent protein (eGFP) gene and the photinus luciferase (PLuc) gene to develop a new brain metastatic cell model in mice through five in vivo/in vitro rounds. BR-eGFP-CMV/Luc-V5 brain metastatic cells induce parenchymal brain metastasis within 60.8 ± 13.8 days of intracarotid injection in all mice. We used this model to standardize a preclinical chemoradiotherapy protocol comprising three 5.5 Gy fractions delivered on consecutive days (overall dose of 16.5 Gy) which improved survival with regard to controls (60.29 ± 8.65 vs. 47.20 ± 11.14). Moreover, the combination of radiotherapy with temozolomide, 60 mg/Kg/day orally for five consecutive days doubled survival time of the mice 121.56 ± 52.53 days (Kaplan-Meier Curve, p < 0.001). This new preclinical chemoradiotherapy protocol proved useful for the study of radiation response/resistance in brain metastasis, either alone or in combination with new sensitizing agents.

Development and characterization of an isogenic cell line with a radioresistant phenotype.

INTRODUCTION: Radiation resistance is a major cause of death in cancer patients. Cancer cells react during radiotherapy by re-programming specific cell functions that may confer resistance to radiation. The understanding of this complex process is hindered due to the lack of appropriate study models. We describe an experimental development of a radioresistant isogenic cancer cell line, and its molecular characterization. MATERIALS AND METHODS: A431-cultured cells were irradiated for 7 month until 85 Gy. Then, a selected single cell was left to grow as stable A431-R cell line. Clonogenic assay was used to determine cell survival, the α and ß parameters of the LQ model, and the mean inactivation dose. The DNA repair ability of cells was evaluated by pulsed-field electrophoresis method. Differential effect of fractionated radiation was ultimately tested in xenografts. Furthermore, we used a wound healing assay, Western blot for EGFR, AKT and ERK1/2 and ELISA test for vascular endothelial growth factor (VEGF) secretion. Finally we explored CD44 marker and cell cycle distribution. RESULTS: The established A431-R cell line showed radiation resistance in clonogenic assays, repair of radiation-induced DNA fragmentation and xenografted tumours. The radiation resistance was associated with in vitro higher cell growth and migration, increased levels of former oncoproteins, and secretion of VEGF. CONCLUSIONS: In this model, the emergence of radiation resistance was associated with the acquisition of biological traits that support more aggressive behaviour of cancer cells. We have generated a model that will be useful for mechanistic studies and development of rational treatments against radiation resistance in cancer.

Development and refinement of a technique using a medical radiation therapy facility to irradiate immunodeficient mice bearing xenografted human tumours.

The need for using immunodeficient mice for xenoimplantation of tumours is increasing in translational research in radiation oncology. However, adverse effects of radiation and infectious diseases may ruin the experimental work, in particular when appropriate facilities are not available. In this report, we describe a procedure to deliver fractionated radiotherapy to xenoimplanted tumours in immunodeficient mice using a medical linear accelerator, a method that was devised as an alternative to the lack of facilities devoted to radiation research. The mice were irradiated under anaesthesia and aseptic conditions. Thirty Gray in 10 days using a 6 MV photon beam were delivered only to the right thigh of the mice where tumours were implanted. The mice were evaluated twice a week up to planned euthanasia. The follow-up of mice was completed without premature interruption due to toxicities or infectious diseases, an observation which demonstrates the feasibility of the method.

Interobserver variability in target volume delineation in postoperative radiochemotherapy for gastric cancer. A pilot prospective study.

INTRODUCTION: The aim of this study is to determine the interobserver variability (IV) between radiation oncologists (RO) in target volume delineation for postoperative gastric cancer (GC) radiotherapy planning. MATERIALS AND METHODS: Four physicians were asked to delimitate clinical target volume (CTV) on the same 3D CT images in 9 postoperative radiochemotherapy GC patients. Instructions were given to include tumour bed, remaining stomach, anastomosis, duodenal loop and local lymph nodes. The principal variable was spatial volume discrepancy between the main observer (called "A") and other observers (all called "B"), which were compared using the mathematical formula A⌣B/A⌢B, applied to the 3D CT images using Boolean operators. Analysis of variance with two random effects (observers and patients) was performed. RESULTS: Mean volumes were 1410 cm(3) for OBA, 1231 cm(3) for OB2, 734.6 cm(3) for OB3 and 1350 cm(3) for OB4. Discrepancies were 519.9±431.6 cm(3) for OB2, 652.1±294.36 cm(3) for OB3 and 225.90±237.07 cm(3) for OB4. Standard deviation ascribed to patients as random effect was 898.6 cm(3) and that ascribed to observers was 198.10 cm(3), considered as a statistically significant difference. CONCLUSIONS: A significant IV in target delineation that can be attributed to many factors depends more on patients' characteristics than RO delineating decisions.

(125)I episcleral plaque brachytherapy in the treatment of choroidal melanoma: a single-institution experience in Spain.

PURPOSE: To analyze the results of episcleral plaque brachytherapy from the Catalan Institute of Oncology in Spain. MATERIALS AND METHODS: From September 1996 through December 2004, 120 patients with choroidal melanoma (median age, 59 years) were treated with iodine-125 seeds at our institution. Patients were classified according to the criteria developed by the Collaborative Ocular Melanoma Study (COMS) group, as follows-COMS-I: 3 patients; COMS-II: 87 patients; COMS-III: 24 patients; and indeterminate COMS: 9 patients. Followup ranged from 1 year to 8.4 years. RESULTS: Overall survival at 5 and 8 years was 83.9% and 73.3%, respectively. The 5- and 8-year specific survival rate was 85.7%. Local control was 88.2% and 72.7% at 5 and 8 years, respectively. The most common treatment-related toxicity was cataract formation (31.6% of cases), followed by radiation retinopathy (7.5%) and retinal detachment (4.1%). CONCLUSION: The results of this institutional retrospective study confirm that the use of iodine-125 episcleral plaques to treat choroidal melanoma offers the potential for conserving a functioning eyeball. The toxicity profile is favorable and disease control is similar to other techniques.

Impact of mean rectal dose on late rectal bleeding after conformal radiotherapy for prostate cancer: dose-volume effect.

PURPOSE: To identify the clinical and dosimetric factors predictive of a greater risk of Grade 2 or worse late rectal bleeding in patients with localized prostate cancer treated with three-dimensional conformal radiotherapy in a prospective dose-escalation study. METHODS AND MATERIALS: We performed a retrospective analysis of the clinical records and dose-volume histograms of 107 patients with Stage T1c-T3 prostate cancer treated at our institution with three-dimensional conformal radiotherapy who had a minimal follow-up of 1 year. Of the 107 patients, 21 were treated at dose level 1 (70.0 Gy), 57 at dose level 2 (72.0 Gy), and 29 at dose level 3 (75.6 Gy). The mean International Commission on Radiation Units and Measurements reference dose was 76.5 Gy (range, 69.8-82.6 Gy). RESULTS: The 4-year actuarial incidence of Grade 2 or worse late rectal bleeding was 7.7% +/- 2.5%. The results of the multivariate analysis indicated that the mean rectal dose (rectal D(mean); p = 0.003) and the percentage of rectum receiving >60 Gy (Vr(60); p = 0.002) correlated with Grade 2 or worse rectal bleeding. The receiver operating characteristic curve analysis showed that this logistic regression model using both Vr(60) and rectal D(mean) had good reliability to predict the risk of late rectal bleeding. The area under the curve for Vr(60) and rectal D(mean) was 0.889 and 0.892, respectively. CONCLUSION: The results of the present study provide clear evidence of a dose-volume effect and the importance of intermediate doses (60.0 Gy) on the risk of rectal bleeding at this prescription dose level. On the basis of these results, new constraints have been implemented in our institution to keep the risk of developing Grade 2 rectal bleeding reasonably low (rectal D(mean) 50.0 Gy and Vr(60) 42%).