Contouring of emerging organs-at-risk (OARS) of the female pelvis and interobserver variability: A study by the Italian association of radiotherapy and clinical oncology (AIRO).

Purpose: To provide straightforward instructions for daily practice in delineating emerging organs-at-risk (OARs) of the female pelvis and to discuss the interobserver variability in a two-step multicenter study. Methods and materials: A contouring atlas with anatomical boundaries for each emerging OAR was realized by radiation oncologists and radiologists who are experts in pelvic imaging, as per their knowledge and clinical practice. These contours were identified as quality benchmarks for the analysis subsequently carried out. Radiation oncologists not involved in setting the custom-built contouring atlas and interested in the treatment of gynecological cancer were invited to participate in this 2-step trial. In the first step all participants were supplied with a selected clinical case of locally advanced cervical cancer and had to identify emerging OARs (Levator ani muscle; Puborectalis muscle; Internal anal sphincter; External anal sphincter; Bladder base and trigone; Bladder neck; Iliac Bone Marrow; Lower Pelvis Bone Marrow; Lumbosacral Bone Marrow) based on their own personal knowledge of pelvic anatomy and experience. The suggested OARs and the contouring process were then presented at a subsequent webinar meeting with a contouring laboratory. Finally, in the second step, after the webinar meeting, each participant who had joined the study but was not involved in setting the benchmark received the custom-built contouring atlas with anatomical boundaries and was requested to delineate again the OARs using the tool provided. The Dice Similarity Coefficient (DSC) and the Jaccard Similarity Coefficient (JSC) were used to evaluate the spatial overlap accuracy of the different volume delineations and compared with the benchmark; the Hausdorff distance (HD) and the mean distance to agreement (MDA) to explore the distance between contours. All the results were reported as sample mean and standard deviation (SD). Results: Fifteen radiation oncologists from different Institutions joined the study. The participants had a high agreement degree for pelvic bones sub-structures delineation according to DICE (IBM: 0.9 ± 0.02; LPBM: 0.91 ± 0.01). A moderate degree according to DICE was showed for ovaries (Right: 0.61 ± 0.16, Left: 0.72 ± 0.05), vagina (0.575 ± 0.13), bladder sub-structures (0.515 ± 0.08) and EAS (0.605 ± 0.05), whereas a low degree for the other sub-structures of the anal-rectal sphincter complex (LAM: 0.345 ± 0.07, PRM: 0.41 ± 0.10, and IAS: 0.4 ± 0.07). Conclusion: This study found a moderate to low level of agreement in the delineation of the female pelvis emerging OARs, with a high degree of variability among observers. The development of delineation tools should be encouraged to improve the routine contouring of these OARs and increase the quality and consistency of radiotherapy planning.

Reproducibility of rectal tumor volume delineation using diffusion-weighted MRI: Agreement on volumes between observers.

PURPOSE: To retrospectively evaluate the inter-observer agreement between a radiologist and a radiation oncologist and volume differences, in T2 and diffusion-weighted (DWI) MRI of gross tumor volume (GTV) delineation, in rectal cancer patients. MATERIALS AND METHODS: Two observers, a radiologist and a radiation oncologist, delineated GTVs of 50 patients on T2-weighted MRI (T2GTV) and echo planar DWI (DWIGTV). Observers agreement was assessed using DICE index, Bland-Altman analysis and intra-class correlation coefficient (ICC). Student's t-test was used for GTV comparison. RESULTS: Median T2GTV and DWIGTV were 17.09±14.12 cm3 (1.92-62.03) and 12.79±12.31 cm3 (1.23-62.25) for radiologist, and 16.82±13.66 cm3 (1.78-65.9) and 13.72±12.77 cm3 (1.29-69.75) for radiation oncologist. T2GTV were significantly larger compared to DWIGTV (P<0.001 and P<0.001, for both observers). Mean DICE index for T2GTV and DWIGTV were 0.80±0.07 and 0.77±0.06. The mean difference between the two observers were 0.26cm3 (95% CI: -5.36 to 5.88) and -1.13cm3 (95% CI: -5.70 to 3.44) for T2 and DWI volumes. The ICC for T2 volumes was 0.989 (95% CI: 0.981-0.994) (P<0.001) and 0.992 (95% CI: 0.986-0.996) (P<0.001) for DWI volumes. CONCLUSION: DWI resulted in smaller volumes delineation compared to T2-weighted MRI. Substantial and almost perfect agreements were reported for DWIGTV and T2GTV between radiologist and radiation oncologist. Due to the fact that DWI could be considered a simple technique for volume delineation for radiation oncologist, DWI could be used to improve quality in radiation planning for an accurate boost volume delineation when a dose escalation is investigated.

Hippocampal sparing in stereotactic radiotherapy for brain metastases: To contour or not contour the hippocampus?

PURPOSE: The aim of our study was to evaluate hippocampal irradiation in patients treated with fractionated stereotactic brain radiotherapy. PATIENTS AND METHODS: Retrospective hippocampal dosimetric analysis performed on 22 patients with one to four brain metastases treated with fractionated stereotactic radiotherapy using volumetric intensity-modulated arc therapy. Original plans did not include hippocampus as avoidance structure in optimization criteria; hippocampus was retrospectively delineated on magnetic resonance coregistered with planning CT and using as reference the RTOG 0933 atlas. Hippocampus was defined both as a single and as pair organ. Constraints analysed were: Dmax<16Gy, D40%<7.3Gy, D100%=Dmin<9Gy. Assuming a α/ß ratio of 2Gy, biologically equivalent dose in 2Gy fractions was calculated. Hippocampal-sparing plans were developed in cases where hippocampal constraints were not respected in the original plan. RESULTS: Among constraints analysed Dmax and D40% have been exceeded in ten out of 22 cases. The constraints were not respected in patients with more than one metastatic lesion and in three patients with only one lesion. Considering all exceeded constraints values in non-hippocampal sparing plans, the 50% of them was respected after replanning. No significant differences were found among conformity and homogeneity index between non-hippocampal sparing and hippocampal sparing plans. CONCLUSION: Volumetric intensity-modulated arc therapy hippocampal sparing plans significantly decreases dose to hippocampus assuring an equal target coverage and organs at risk avoiding.

Stereotactic radiosurgery (SRS) with volumetric modulated arc therapy (VMAT): interim results of a multi-arm phase I trial (DESTROY-2).

AIMS: To present the interim results of a phase I trial on stereotactic radiosurgery (SRS) delivered using volumetric modulated arc therapy (VMAT) in patients with primary or metastatic tumours in different extracranial sites. MATERIALS AND METHODS: Patients were enrolled in different arms according to tumour site and clinical stage, and sequentially assigned to a given dose level. Acute toxicity, tumour response and early local control were investigated and reported. RESULTS: One hundred lesions in 65 consecutive patients (male/female: 30/35, median age: 66 years; range: 40-89) were treated. Of these 100 lesions, 21 were primary or metastatic lung tumours, 24 were liver metastases, 30 were bone metastases, 24 were nodal metastases and one was a primary vulvar melanoma. The prescribed dose ranged from 12 (BED(2Gy,α/ß:10) = 26.4 Gy) to 28 Gy (BED(2Gy,α/ß:10) = 106.4 Gy) to the planning target volume. Twenty-one patients (32.3%) experienced grade 1-2 acute toxicity, which was grade 2 in only two cases. The overall response rate based on computed tomography/magnetic resonance imaging was 52% (95% confidence interval 40.1-63.2%) and based on positron emission tomography scan was 90% (95% confidence interval 76.2-96.4%). As of November 2013, the median duration of follow-up was 11 months (range = 1-38). Recurrence/progression within the SRS-VMAT treated field was observed in nine patients (total lesions = 18): the inside SRS-VMAT field local control expressed on a per lesion basis was 87.8% at 12 months and 71.9% at 24 months. CONCLUSIONS: The maximum tolerable dose has not yet been reached in any study arm. SRS-VMAT resulted in positive early clinical results in terms of tumour response, local control rate and acute toxicity.

Planning comparison between standard and conformal 3D techniques in post-operative radiotherapy of gastric cancer: a systematic review.

The objective of this study was to establish the impact of three-dimensional conformal radiotherapy (3D-CRT) technique in post-operative radiotherapy of gastric cancer. A bibliographical research was performed using the PubMed. On the database, Search was carried out using Medical Subject Heading (MeSH) database; the algorithm for search was ''Radiotherapy" (MeSH) AND ''Stomach Neoplasms" (MeSH). Only planning comparative studies on conformal techniques vs standard techniques in post-operative radiotherapy of gastric cancer were included in the review process. We identified 185 papers, five of them fulfilling the inclusion criteria. A great inhomogeneity was observed regarding the analysed dosimetric end points. Three of the five studies reported a benefit in favour of 3D-CRT for target irradiation despite a minimal advantage in most cases. The liver was better spared from irradiation by the traditional technique in all studies. No univocal result was obtained for the right kidney: the traditional technique performed better in two studies, 3D-CRT yielded better results in two others, whereas in the fifth study, each technique was either better or worse according to the different considered end point. 3D-CRT, however, allowed for better sparing of the left kidney in four studies. There is no absolute reason to prefer 3D-CRT with multiple beams in every patient. It may be preferable to choose the technique based on individual patient characteristics. Because there is no proof of superiority for 3D-CRT, there is no absolute reason to exclude patients who are treated in centres equipped with only the two-dimensional technique from the potential benefit of post-operative chemoradiation.

Mammography before post-operative radiotherapy in conservatively managed breast cancer patients: is it useful?

OBJECTIVE: The aim of this study was to evaluate the role of bilateral mammography undertaken before adjuvant radiotherapy in patients with conservatively managed invasive carcinoma of the breast. METHODS: Patients with invasive breast cancer referred to the Radiotherapy Unit of the Università Cattolica del Sacro Cuore, in Campobasso, Italy, between March 2002 and September 2006 were retrospectively reviewed. Patients were referred to our facility from other local and regional hospitals where they received breast-conserving surgery and adjuvant chemotherapy. They presented to our department for post-operative whole-breast radiotherapy. All patients underwent physical examination and bilateral mammography prior to adjuvant irradiation. RESULTS: 201 patients met the selection criteria as delineated. Of these 201 patients who underwent pre-radiotherapy mammography, 3 had suspicious findings on mammography. In two of those cases, the histopathological examination confirmed the presence of residual disease within the residual mammary gland. In one case, the pre-radiotherapy mammogram allowed for the detection of disease persistence which was not otherwise appreciated on physical exam. In the other case, the diagnostic imaging confirmed only the findings of the physical exam. In both cases of residual disease, the tumour was found elsewhere in the breast and not at the primary site. In one patient, the radiological re-assessment led to a false-positive result. No cases of contralateral synchronous breast cancer were observed. The overall adjunctive cost of this strategy including a routine mammography besides the clinical visit was €7012 for all patients. CONCLUSIONS: No clear recommendation exists regarding post-operative mammography before adjuvant radiotherapy. In our experience, this strategy allowed for the detection of gross disease persistence after surgery which was not appreciated at clinical examination in 1 case out of 201. In this patient, adjuvant radiotherapy up to a total dose of 50 Gy would have been inadequate. Given the low cost of mammography, further investigation about its role in pre-radiotherapy evaluation is warranted.

Volumetric modulated arc therapy with simultaneous integrated boost for locally advanced rectal cancer.

AIMS: To report the feasibility of volumetric modulated arc therapy (VMAT) for neoadjuvant radiotherapy in locally advanced rectal cancer in a dose-escalation protocol and simultaneous integrated boost (SIB) approach. Moreover, the VMAT technique was compared with three-dimensional conformal radiotherapy (3D-CRT) and fixed-field intensity modulated radiotherapy (IMRT), in terms of target coverage and irradiation of organs at risk. MATERIALS AND METHODS: Eight patients with locally advanced rectal cancer were treated with the SIB-VMAT technique. The VMAT plans were compared with 3D-CRT and IMRT techniques in terms of several clinically dosimetric parameters. The number of monitor units and the delivery time were analysed to score the treatment efficiency. All plans were verified in a dedicated solid water phantom using a two-dimensional array of ionisation chambers. RESULTS: All techniques meet the prescription goal for planning target volume coverage, with VMAT showing the highest level of conformality. VMAT is associated with 40, 53 and 58% reduction in the percentage of volume of small bowel irradiated to 30, 40 and 50Gy, compared with 3D-CRT. No significant differences were found with respect to SIB-IMRT. VMAT plans showed a significant reduction of monitor units by nearly 20% with respect to IMRT and reduced treatment time from 14 to 5min for a single fraction. CONCLUSIONS: SIB-VMAT plans can be planned and carried out with high quality and efficiency for rectal cancer, providing similar sparing of organs at risk to SIB-IMRT and resulting in the most efficient treatment option. SIB-VMAT is currently our standard approach for radiotherapy of locally advanced rectal cancer.

Regulation of CREB activation by p38 mitogen activated protein kinase during human primary erythroblast differentiation.

Among the molecular events underlying erythroid differentiation, we analyzed the signalling pathway leading to cAMP response element binding (CREB) nuclear transcription factor activation. Normal donor blood light density cells differentiated to pro-erythroblasts during the proliferative phase (10 days) of the human erythroblast massive amplification (HEMA) culture, and to orthochromatic erythroblasts, during the differentiation phase (4 additional days) of the culture. Since erythropoietin was present all over the culture, also pro-erythroblasts left in proliferative medium for 14 days continued their maturation without reaching the final steps of differentiation. p38 mitogen activated protein kinase (p38 MAPK) and CREB maximal activation occurred upon 4 days of differentiation induction, whereas a lower activation was detectable in the cells maintained in parallel in proliferative medium (14 days). Interestingly, when SB203580, a specific p38 MAPK inhibitor, was added to the culture the percentage of differentiated cells decreased along with p38 MAPK and CREB phosphorylation. All in all, our results evidence a role for p38 MAPK in activating CREB metabolic pathway in the events leading to erythroid differentiation.