Akos Gulyban

Toxicity at three years with and without irradiation of the internal mammary and medial supraclavicular lymph node chain in stage I to III breast cancer (EORTC trial 22922/10925)

Abstract Introduction. The EORTC 22922/10925 trial investigated the potential survival benefit and toxicity of elective irradiation of the internal mammary and medial supraclavicular (IM-MS) nodes Accrual completed in January 2004 and first results are expected in 2012. We present the toxicity reported until year 3 after treatment. Patients and methods. At each visit, toxicity was reported but severity was not graded routinely. Toxicity rates and performance status (PS) changes at three years were compared by χ2 tests and logistic regression models in all the 3 866 of 4 004 patients eligible to the trial who received the allocated treatment. Results. Only lung (fibrosis; dyspnoea; pneumonitis; any lung toxicities) (4.3% vs. 1.3%; p < 0.0001) but not cardiac toxicity (0.3% vs. 0.4%; p = 0.55) significantly increased with IM-MS treatment. No significant worsening of the PS was observed (p = 0.79), suggesting that treatment-related toxicity does not impair patients daily activities. Conclusions. IM-MS irradiation seems well tolerated and does not significantly impair WHO PS at three years. A follow-up period of at least 10 years is needed to determine whether cardiac toxicity is increased after radiotherapy.

EORTC Radiation Oncology Group quality assurance platform: Establishment of a digital central review facility

OBJECTIVE Quality assurance (QA) in clinical trials is essential to ensure treatment is safely and effectively delivered. As QA requirements have increased in complexity in parallel with evolution of radiation therapy (RT) delivery, a need to facilitate digital data exchange emerged. Our objective is to present the platform developed for the integration and standardization of QART activities across all EORTC trials involving RT. METHODS The following essential requirements were identified: secure and easy access without on-site software installation; integration within the existing EORTC clinical remote data capture system; and the ability to both customize the platform to specific studies and adapt to future needs. After retrospective testing within several clinical trials, the platform was introduced in phases to participating sites and QART study reviewers. RESULTS The resulting QA platform, integrating RT analysis software installed at EORTC Headquarters, permits timely, secure, and fully digital central DICOM-RT based data review. Participating sites submit data through a standard secure upload webpage. Supplemental information is submitted in parallel through web-based forms. An internal quality check by the QART office verifies data consistency, formatting, and anonymization. QART reviewers have remote access through a terminal server. Reviewers evaluate submissions for protocol compliance through an online evaluation matrix. Comments are collected by the coordinating centre and institutions are informed of the results. CONCLUSIONS This web-based central review platform facilitates rapid, extensive, and prospective QART review. This reduces the risk that trial outcomes are compromised through inadequate radiotherapy and facilitates correlation of results with clinical outcomes.

Quality assurance in the EORTC 22033–26033/CE5 phase III randomized trial for low grade glioma: The digital individual case review

INTRODUCTION The phase III EORTC 22033-26033/NCIC CE5 intergroup trial compares 50.4 Gy radiotherapy with up-front temozolomide in previously untreated low-grade glioma. We describe the digital EORTC individual case review (ICR) performed to evaluate protocol radiotherapy (RT) compliance. METHODS Fifty-eight institutions were asked to submit 1-2 randomly selected cases. Digital ICR datasets were uploaded to the EORTC server and accessed by three central reviewers. Twenty-seven parameters were analysed including volume delineation, treatment planning, organ at risk (OAR) dosimetry and verification. Consensus reviews were collated and summary statistics calculated. RESULTS Fifty-seven of seventy-two requested datasets from forty-eight institutions were technically usable. 31/57 received a major deviation for at least one section. Relocation accuracy was according to protocol in 45. Just over 30% had acceptable target volumes. OAR contours were missing in an average of 25% of cases. Up to one-third of those present were incorrectly drawn while dosimetry was largely protocol compliant. Beam energy was acceptable in 97% and 48 patients had per protocol beam arrangements. CONCLUSIONS Digital RT plan submission and review within the EORTC 22033-26033 ICR provide a solid foundation for future quality assurance procedures. Strict evaluation resulted in overall grades of minor and major deviation for 37% and 32%, respectively.

Clinical efficacy and toxicity of radio-chemotherapy and magnetic resonance imaging-guided brachytherapy for locally advanced cervical cancer patients: A mono-institutional experience

ABSTRACT Background. To evaluate efficacy and toxicity of radio-chemotherapy (RCT) and MR-guided pulsed-dose-rate (PDR) adaptive brachytherapy (IGABT) for locally advanced cervical cancer (LACC). Material and methods. Between 2007 and 2014 85 patients with FIGO stage 1B1 N+ or ≥ 1B2 cervical cancer were treated with RCT+ IGABT. The treatment consisted of a pelvic± paraaortic external beam radiotherapy (EBRT) (45–50.4 Gy ± 10 Gy boost to primary tumor and/or to pathologic lymph nodes) with concurrent cisplatin followed by 25–35 Gy of PDR IGABT in 30–50 pulses. The ratio of 3D-CFRT/IMRT was 61/24 patients. Dose-volume parameters of high-risk clinical target volume (HR-CTV), intermediate-risk clinical target volume (IR-CTV) and D2cm3 organs at risk (OARs) were reported. Local control (LC), cancer-specific survival (CCS) and overall survival (OS) were analyzed actuarially and morbidity crude rates were scored using CTCAEv4.0. Results. Mean follow-up was 36 months (range 6–94). The mean D90 and D98 for HR-CTV was 84.4 ± 9 Gy and 77 ± 8.1 Gy, while for IR-CTV was 69.1 ± 4.3 Gy and 64.8 ± 4.3 Gy, respectively. The mean D2cm3 for OARs was the following: bladder: 77.3 ± 10.5 Gy, rectum: 65 ± 6.8 Gy, sigmoid: 63 ± 7.9 Gy and intestine: 64.0 ± 9.1 Gy. Three year LC, CSS and OS were: 94%, 85% and 81%. The three-year regional- and distant control rates were 95% and 74%. Node negative patients had significantly higher three-year CSS (100 vs. 72%, p = 0.016) and OS (92 vs. 72%, p = 0.001) compared to node positive ones. Three-year actuarial late Grade ≥ 3 morbidity was the following: GI: 8%, GU: 5%, Vaginal: 8%. The frequency of Grade ≥ 3 hematological toxicities including anemia/leukopenia/neutropenia/thrombocytopenia were 8.6%/34.7%/24.3%/24.3%, respectively. Conclusion. This large mono-institutional experience builds up further evidences that IGABT in conjunction with RCT should be the standard of care for patients suffering LACC.

Adaptive radiotherapy for locally advanced non-small cell lung cancer, can we predict when and for whom?

ABSTRACT Background. Adaptive radiotherapy (ART) could be a tool to reduce toxicity and to facilitate dose escalation in stage III NSCLC. Our aim was to identify the most appropriate time and potential benefit of ART. Material and methods. We analyzed volume reduction and dosimetric consequences of 41 patients who were treated with concurrent (cCRT) (n = 21) or sequential (sCRT) chemoradiotherapy to a median dose of 70 Gy, 2 Gy/F. At every treatment fraction a cone-beam CT (CBCT) was performed. The gross tumor volume (GTV-T) was adapted (exclusion of lymph nodes) to create the GTV-T-F1. Every fifth fraction (F5–F30), the GTV-T-F1 was adapted on the CBCT to create a GTV-T-Fx. Dose volume histograms were recalculated for every GTV-T-Fx, enabling to create lookup tables to predict the theoretical dosimetric advantage on common lung dose constraints. Results. The average GTV reduction was 42.1% (range 4.0–69.3%); 50.1% and 33.7% for the cCRT and sCRT patients, respectively. A linear relationship between GTV-T-F1 volume and absolute volume decrease was found for both groups. The mean V5, V20, V30 and mean lung dose increased by 0.8, 3.1, 5.2 and 3.4%, respectively. A larger increase (p < 0.05) was observed for peripheral tumors and cCRT. Lookup tables were generated. Conclusion. ART offers the most beneficial dosimetric effects when performed around fraction 15, especially for patients with a large initial GTV-T treated by cCRT.

Quality assurance for the EORTC 22071¿26071 study: dummy run prospective analysis.

PurposeThe phase III 22071–26071 trial was designed to evaluate the addition of panitumumab to adjuvant chemotherapy plus intensity modulated radiotherapy (IMRT) in locally advanced resected squamous cell head and neck cancer. We report the results of the dummy run (DR) performed to detect deviations from protocol guidelines.Methods and MaterialsDR datasets consisting of target volumes, organs at risk (OAR) and treatment plans were digitally uploaded, then compared with reference contours and protocol guidelines by six central reviewers. Summary statistics and analyses of potential correlations between delineations and plan characteristics were performed.ResultsOf 23 datasets, 20 (87.0%) GTVs were evaluated as acceptable/borderline, along with 13 (56.5%) CTVs and 10 (43.5%) PTVs. All PTV dose requirements were met by 73.9% of cases. Dose constraints were met for 65.2-100% of mandatory OARs. Statistically significant correlations were observed between the subjective acceptability of contours and the ability to meet dose constraints for all OARs (p ≤ 0.01) except for the parotids and spinal cord. Ipsilateral parotid doses correlated significantly with CTV and PTV volumes (p ≤ 0.05).ConclusionsThe observed wide variations in treatment planning, despite strict guidelines, confirms the complexity of development and quality assurance of IMRT-based multicentre studies for head and neck cancer.

Does an integrated boost increase acute toxicity in prone hypofractionated breast irradiation? A randomized controlled trial

BACKGROUND AND PURPOSE The safety of a simultaneous integrated boost (SIB) in combination with prone hypofractionated whole-breast irradiation (WBI) was investigated. MATERIALS AND METHODS 167 patients were randomized between WBI with a sequential boost (SeB) or SIB. All patients were treated in prone position to 40.05Gy in 15 fractions to the whole breast. In the control arm, a SeB of 10Gy in 4 fractions (negative surgical margins) or 14.88Gy in 6 fractions (transsection) was prescribed. In the experimental arm a SIB of 46.8 or 49.95Gy (negative and positive surgical margins, respectively) was prescribed. RESULTS Patient age was the only significantly different parameter between treatment arms with patients in the SIB arm being slightly older. In both arms, 6/83 patients developed moist desquamation. Grade 2/3 dermatitis was significantly more frequent in the SeB arm (38/83vs 24/83 patients, p=0.037). In the SIB and SeB arm, respectively, 36 patients (43%) and 51 patients (61%) developed pruritus (p=0.015). The incidence of oedema was lower in the SIB arm (59vs 68 patients), but not statistically significant (p=0.071). CONCLUSIONS The primary endpoint, moist desquamation, was not significantly different between treatment arms.

Clinical outcomes of 130 patients with primary and secondary lung tumors treated with Cyberknife robotic stereotactic body radiotherapy

Abstract Background Authors report clinical outcomes of patients treated with robotic stereotactic body radiotherapy (SBRT) for primary, recurrent and metastatic lung lesions. Patients and methods 130 patients with 160 lesions were treated with Cyberknife SBRT, including T1-3 primary lung cancers (54%), recurrent tumors (22%) and pulmonary metastases (24%). The mean biologically equivalent dose (BED10Gy) was 151 Gy (72–180 Gy). Median prescribed dose for peripheral and central lesions was 3×20 Gy and 3×15 Gy, respectively. Local control (LC), overall survival (OS), and cause-specific survival (CSS) rates, early and late toxicities are reported. Statistical analysis was performed to identify factors influencing local tumor control. Results Median follow-up time was 21 months. In univariate analysis, higher dose was associated with better LC and a cut-off value was detected at BED10Gy ≤ 112.5 Gy, resulting in 1-, 2-, and 3-year actuarial LC rates of 93%, vs 73%, 80% vs 61%, and 63% vs 54%, for the high and low dose groups, respectively (p = 0.0061, HR = 0.384). In multivariate analysis, metastatic origin, histological confirmation and larger Planning Target Volume (PTV) were associated with higher risk of local failure. Actuarial OS and CSS rates at 1, 2, and 3 years were 85%, 74% and 62%, and 93%, 89% and 80%, respectively. Acute and late toxicities ≥ Gr 3 were observed in 3 (2%) and 6 patients (5%), respectively. Conclusions Our favorable LC and survival rates after robotic SBRT, with low rates of severe toxicities, are coherent with the literature data in this mixed, non-selected study population.

Stereotactic Robotic Body Radiotherapy for Patients With Unresectable Hepatic Oligorecurrence

Micro‐Abstract We present our retrospective study of 42 patients treated for hepatic oligorecurrence with stereotactic body radiotherapy using the CyberKnife system (Accuray Inc). Besides reporting on acute and late toxicities, the influence of patient and lesion characteristics on local control, liver and distant progression‐free survival, and overall survival were also investigated. Background The purpose of this study was to analyze local control (LC), liver progression‐free survival (PFS), and distant PFS (DFS), overall survival (OS), and toxicity in a cohort of patients treated with stereotactic body radiotherapy (SBRT) with fiducial tracking for oligorecurrent liver lesions; and to evaluate the potential influence of lesion size, systemic treatment, physical and biologically effective dose (BED), treatment calculation algorithms and other parameters on the obtained results. Patients and Methods Unoperable patients with sufficient liver function had [18F]‐fluorodeoxyglucose‐positron emission tomography‐computed tomography and liver magnetic resonance imaging to confirm the oligorecurrent nature of the disease and to further delineate the gross tumor volume (GTV). An intended dose of 45 Gy in 3 fractions was prescribed on the 80% isodose and adapted if risk‐related. Treatment was executed with the CyberKnife system (Accuray Inc) platform using fiducials tracking. Initial plans were recalculated using the Monte Carlo algorithm. Patient and treatment data were processed using the Kaplan–Meier method and log rank test for survival analysis. Results Between 2010 and 2015, 42 patients (55 lesions) were irradiated. The mean GTV and planning target volume (PTV) were 30.5 cc and 96.8 cc, respectively. Treatments were delivered 3 times per week in a median of 3 fractions to a PTV median dose of 54.6 Gy. The mean GTV and PTV D98% were 51.6 Gy and 51.2 Gy, respectively. Heterogeneity corrections did not influence dose parameters. After a median follow‐up of 18.9 months, the 1‐ and 2‐year LC/liver PFS/DFS/OS were 81.3%/55%/62.4%/86.9%, and 76.3%/42.3%/52%/78.3%, respectively. Performance status and histology had a significant effect on LC, whereas age (older than 65 years) marginally influenced liver PFS. Clinical target volume physical dose V45 Gy > 95%, generalized equivalent uniform dose (a = −30) > 45 Gy and a BED (&agr;/&bgr; = 10) V105 Gy > 96% showed statistically significant effect on the LC. Acute Grade 3 gastrointestinal (GI) and late Grade 2 GI and fatigue toxicity were found in 5% and 11% patients, respectively. Conclusion Favorable survival and toxicity results support the potential paradigm shift in which the use of SBRT in oligorecurrent liver disease could benefit patients with unresectable or resectable liver metastases.

Adaptive radiotherapy for locally advanced non-small cell lung cancer: dosimetric gain and treatment outcome prediction

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