Quality assurance and safety of hippocampal avoidance prophylactic cranial irradiation in the multicenter randomized phase III trial (NCT01780675).

Objective: NCT01780675, a multicenter randomized phase III trial of prophylactic cranial irradiation (PCI) versus PCI with hippocampal sparing in small cell lung cancer (SCLC) investigated neurocognitive decline and safety. As part of quality assurance, we evaluated if hippocampal avoidance (HA)-PCI was performed according to the NCT01780675 trial protocol instructions, and performed a safety analysis to study the incidence and location of brain metastases for patients treated with HA-PCI. Methods: This retrospective analysis evaluated the quality of the irradiation given in the randomized controlled trial (RCT) comparing SCLC patients receiving PCI with or without hippocampal avoidance, using intensity modulated radiotherapy (IMRT) or volumetric modulated arc therapy (VMAT). The dose distribution for each patient receiving HA-PCI was retrieved and analyzed to evaluate if the treatment dose constraints were met. A questionnaire was sent out to all participating sites, and data on radiotherapy technique, pre-treatment dummy runs, phantom measurements and treatment electronic portal imaging device (EPID) dosimetry were collected and analyzed. As part of the safety analysis, the follow-up magnetic resonance imaging (MRI) or computerized tomography (CT) scans on which cranial disease progression was first diagnosed were collected and matched to the radiotherapy planning dose distribution. The matched scans were reviewed to analyze the location of the brain metastases in relation to the prescribed dose. Results: A total of 168 patients were randomized in the NCT01780675 trial in 10 centers in the Netherlands and Belgium from April 2013 until March 2018. Eighty two patients receiving HA-PCI without evidence of brain metastases were analyzed. All patients were treated with 25 Gy in 10 fractions. Dummy runs and phantom measurements were performed in all institutions prior to enrolling patients into the study. The radiotherapy (RT) plans showed a median mean bilateral hippocampal dose of 8.0 Gy, range 5.4-11.4 (constraint ≤ 8.5 Gy). In six patients (7.3%) there was a protocol violation of the mean dose in one or both hippocampi. In four of these six patients (4.9%) the mean dose to both hippocampi exceeded the constraint, in 1 patient (1.2%) only the left and in 1 patient (1.2%) only the right hippocampal mean dose was violated (average median dose left and right 8.9 Gy). All patients met the trial dose constraint of V 115% PTV ≤ 1%; however the D max PTV constraint of ≤ 28.75 Gy was violated in 22.0% of the patients. The safety analysis showed that 14 patients (17.1%) developed cranial progression. No solitary brain metastases in the underdosed region were found. Two out of 11 patients with multiple brain metastasis developed metastasis in the underdosed region(s). Conclusions: The radiotherapy quality within the HA-PCI trial is performed according to the protocol guidelines. The dose constraints to the hippocampi are met in the vast majority of cases. In all patients, the volume of the brain for which a higher dose was accepted, is according to the trial. However, within this volume there are small areas with higher doses than advised.

The association of internal mammary and medial supraclavicular lymph node radiation technique with clinical outcomes: Results from the EORTC 22922/10925 randomised trial.

BACKGROUND AND PURPOSE: The multicentre EORTC 22922/10925 trial (ClinicalTrials.gov, NCT00002851) was conducted between 1996 and 2004. The trial evaluated the effect of irradiation of the internal mammary and medial supraclavicular lymph node chains (IM-MS) vs no further radiation therapy (RT) on survival and cause of death in breast cancer stage I-III patients. At 15.7 years of median follow-up, a significant reduction of breast cancer specific mortality (BCSM) and any recurrence, not translating in improved overall survival (OS), and low absolute rates of side effects were found. The aim of the current analysis was to evaluate the association of RT techniques of IM-MS lymph node irradiation with long-term outcomes. PATIENTS AND METHODS: Three RT techniques were used for IM-MS: a standard technique using a fixed set-up combining photon/electron beams to the IM and tangential fields to the breast or chest wall vs a standard-modified technique with minor adaptation for beam settings vs a more individualised technique based on individual localisation of the IM. Techniques used were fixed per institution over the duration of the trial. We performed an exploratory and descriptive analysis of the outcomes after 15 years follow-up for the three RT techniques. RESULTS: Between July 1996 and January 2004, 46 radiation oncology departments from 13 countries accrued 4004 patients. Median follow-up was 15.7 years. The number of patients treated by each technique was 2440 (61%) by standard vs 635 (16%) by standard-modified vs 929 (23%) patients by individualised technique. The absolute improvements of oncological outcomes in terms of disease-free survival (DFS), OS and BCSM with IM-MS RT compared to no IM-MS RT were 6.8%, 4.9% and -5.8% for the individualised technique, vs 1.6%, 2.9% and -4.3% for modified standard and -1.4%, 1.1% and -3% for standard technique, respectively. The increase in 15-year rates of side effects due to IM-MS RT, both scored longitudinally and cross-sectionally, were similar among the techniques. CONCLUSION: Even though a straightforward comparison by technique is not possible because of variations in baseline characteristics between institutions, our findings suggest that the use of more individualised RT techniques is associated with higher rates of oncological improvements without increased risks for late side effects.

A Delphi study and International Consensus Recommendations: The use of bolus in the setting of postmastectomy radiation therapy for early breast cancer.

Bolus serves as a tissue equivalent material that shifts the 95-100% isodose line towards the skin and subcutaneous tissue. The need for bolus for all breast cancer patients planned for postmastectomy radiation therapy (PMRT) has been questioned. The work was initiated by the faculty of the European SocieTy for Radiotherapy & Oncology (ESTRO) breast cancer courses and represents a multidisciplinary international breast cancer expert collaboration to optimize PMRT. Due to the lack of randomised trials evaluating the benefits of bolus, we designed a stepwise project to evaluate the existing evidence about the use of bolus in the setting of PMRT to achieve an international consensus for the indications of bolus in PMRT, based on the Delphi method.

Tricks and tips for target volume definition and delineation in breast cancer: Lessons learned from ESTRO breast courses.

Delineation of target and 'organ at risk' volumes is a critical part of modern radiation therapy planning, the next essential step after deciding the indication, patient discussion and image acquisition. Adoption of volume-based treatment planning for non-metastatic breast cancer has increased greatly along with the use of improved planning techniques, essential for modern therapy. However, identifying the volumes on a planning CT is no easy task. The current paper is written by ESTRO's breast course faculty, providing tricks and tips for target volume definition and delineation for optimal postoperative breast cancer irradiation.

The use of bolus in postmastectomy radiation therapy for breast cancer: A systematic review.

PURPOSE: Post mastectomy radiation therapy (PMRT) reduces locoregional recurrence (LRR) and breast cancer mortality for selected patients. Bolus overcomes the skin-sparing effect of external-beam radiotherapy, ensuring adequate dose to superficial regions at risk of local recurrence (LR). This systematic review summarizes the current evidence regarding the impact of bolus on LR and acute toxicity in the setting of PMRT. RESULTS: 27 studies were included. The use of bolus led to higher rates of acute grade 3 radiation dermatitis (pooled rates of 9.6% with bolus vs. 1.2% without). Pooled crude LR rates from thirteen studies (n = 3756) were similar with (3.5%) and without (3.6%) bolus. CONCLUSIONS: Bolus may be indicated in cases with a high risk of LR in the skin, but seems not to be necessary for all patients. Further work is needed to define the role of bolus in PMRT.

Selection criteria for early breast cancer patients in the DBCG proton trial - The randomised phase III trial strategy.

BACKGROUND AND PURPOSE: Adjuvant radiotherapy of internal mammary nodes (IMN) improves survival in high-risk early breast cancer patients but inevitably leads to more dose to heart and lung. Target coverage is often compromised to meet heart/lung dose constraints. We estimate heart and lung dose when target coverage is not compromised in consecutive patients. These estimates are used to guide the choice of selection criteria for the randomised Danish Breast Cancer Group (DBCG) Proton Trial. MATERIALS AND METHODS: 179 breast cancer patients already treated with loco-regional IMN radiotherapy from 18 European departments were included. If the clinically delivered treatment plan did not comply with defined target coverage requirements, the plan was modified retrospectively until sufficient coverage was reached. The choice of selection criteria was based on the estimated number of eligible patients for different heart and lung dose thresholds in combination with proton therapy capacity limitations and dose-response relationships for heart and lung. RESULTS: Median mean heart dose was 3.0 Gy (range, 1.1-8.2 Gy) for left-sided and 1.4 Gy (0.4-11.5 Gy) for right-sided treatment plans. Median V17Gy/V20Gy (hypofractionated/normofractionated plans) for ipsilateral lung was 31% (9-57%). The DBCG Radiotherapy Committee chose mean heart dose ≥ 4 Gy and/or lung V17Gy/V20Gy ≥ 37% as thresholds for inclusion in the randomised trial. Using these thresholds, we estimate that 22% of patients requiring loco-regional IMN radiotherapy will be eligible for the trial. CONCLUSION: The patient selection criteria for the DBCG Proton Trial are mean heart dose ≥ 4 Gy and/or lung V17Gy/V20Gy ≥ 37%.

ESTRO ACROP consensus guideline for target volume delineation in the setting of postmastectomy radiation therapy after implant-based immediate reconstruction for early stage breast cancer.

Immediate breast reconstruction (IBR) rates after mastectomy are increasing. Postmastectomy radiation therapy (PMRT) contouring guidelines for target volumes in the setting of IBR are lacking. Therefore, many patients who have had IBR receive PMRT to target volumes similar to conventional simulator-based whole breast irradiation. The aim of this paper is to describe delineation guidelines for PMRT after implant-based IBR based on a thorough understanding of the surgical procedures, disease stage, patterns of recurrence and radiation techniques. They are based on a consensus endorsed by a global multidisciplinary group of breast cancer experts.

Should breathing adapted radiotherapy also be applied for right-sided breast irradiation?

BACKGROUND: Voluntary moderate deep inspiration breath-hold (vmDIBH) is widely used for left sided breast cancer patients. The purpose of this study was to investigate the usefulness of vmDIBH in local and locoregional radiation therapy (RT) of right-sided breast cancer. MATERIALS AND METHODS: For fourteen right-sided breast cancer patients, 3D-conformal (3D-CRT) RT plans (i.e., forward IMRT) were calculated on free-breathing (FB) 3D-CRT(FB) and vmDIBHCT-scans, for local- as well as locoregional breast treatment, with and without internal mammary nodes (IMN). Dose volume parameters were compared. RESULTS: For local breast treatment, no relevant reduction in mean lung dose (MLD) was found. For locoregional breast treatment without IMN, the average MLD reduced from 6.5 to 5.4 Gy (p < 0.005) for the total lung and from 11.2 to 9.7 Gy (p < 0.005) for the ipsilateral lung. For locoregional breast treatment with IMN, the average MLD reduced from 10.8 to 9.1 Gy (p < 0.005) for the total lung and from 18.7 to 16.2 Gy (p < 0.005) for the ipsilateral lung, whilea small reduction in mean heart dose of 0.4 Gy (p = 0.07) was also found. CONCLUSIONS: Breathing adapted radiation therapy in left-sided breast cancer patients is becoming widely introduced. As a result of the slight reduction in lung dose found for locoregional right-sided breast cancer treatment in this study, a slightly lower risk of pneumonitis and secondary lung cancer (in ever smoking patients) can be expected.In addition, for some patients the heart dose will also be reduced by more than 0.5 up to 2.6 Gy. We therefore suggest to also apply breath-hold for locoregional irradiation of right-sided breast cancer patients.

ESTRO consensus guideline on target volume delineation for elective radiation therapy of early stage breast cancer.

BACKGROUND AND PURPOSE: Delineation of clinical target volumes (CTVs) is a weak link in radiation therapy (RT), and large inter-observer variation is seen in breast cancer patients. Several guidelines have been proposed, but most result in larger CTVs than based on conventional simulator-based RT. The aim was to develop a delineation guideline obtained by consensus between a broad European group of radiation oncologists. MATERIAL AND METHODS: During ESTRO teaching courses on breast cancer, teachers sought consensus on delineation of CTV through dialogue based on cases. One teacher delineated CTV on CT scans of 2 patients, followed by discussion and adaptation of the delineation. The consensus established between teachers was sent to other teams working in the same field, both locally and on a national level, for their input. This was followed by developing a broad consensus based on discussions. RESULTS: Borders of the CTV encompassing a 5mm margin around the large veins, running through the regional lymph node levels were agreed, and for the breast/thoracic wall other vessels were pointed out to guide delineation, with comments on margins for patients with advanced breast cancer. CONCLUSION: The ESTRO consensus on CTV for elective RT of breast cancer, endorsed by a broad base of the radiation oncology community, is presented to improve consistency.

Volumetric modulated arc therapy and breath-hold in image-guided locoregional left-sided breast irradiation.

PURPOSE: To investigate the effects of using volumetric modulated arc therapy (VMAT) and/or voluntary moderate deep inspiration breath-hold (vmDIBH) in the radiation therapy (RT) of left-sided breast cancer including the regional lymph nodes. MATERIALS AND METHODS: For 13 patients, four treatment combinations were compared; 3D-conformal RT (i.e., forward IMRT) in free-breathing 3D-CRT(FB), 3D-CRT(vmDIBH), 2 partial arcs VMAT(FB), and VMAT(vmDIBH). Prescribed dose was 42.56 Gy in 16 fractions. For 10 additional patients, 3D-CRT and VMAT in vmDIBH only were also compared. RESULTS: Dose conformity, PTV coverage, ipsilateral and total lung doses were significantly better for VMAT plans compared to 3D-CRT. Mean heart dose (D(mean,heart)) reduction in 3D-CRT(vmDIBH) was between 0.9 and 8.6 Gy, depending on initial D(mean,heart) (in 3D-CRT(FB) plans). VMAT(vmDIBH) reduced the D(mean,heart) further when D(mean,heart) was still >3.2 Gy in 3D-CRT(vmDIBH). Mean contralateral breast dose was higher for VMAT plans (2.7 Gy) compared to 3DCRT plans (0.7 Gy). CONCLUSIONS: VMAT and 3D-CRT(vmDIBH) significantly reduced heart dose for patients treated with locoregional RT of left-sided breast cancer. When Dmean,heart exceeded 3.2 Gy in 3D-CRT(vmDIBH) plans, VMAT(vmDIBH) resulted in a cumulative heart dose reduction. VMAT also provided better target coverage and reduced ipsilateral lung dose, at the expense of a small increase in the dose to the contralateral breast.

Accelerated partial breast irradiation (APBI): are breath-hold and volumetric radiation therapy techniques useful?

BACKGROUND: In a selective group of patients accelerated partial breast irradiation (APBI) might be applied after conservative breast surgery to reduce the amount of irradiated healthy tissue. The role of volumetric modulated arc therapy (VMAT) and voluntary moderately deep inspiration breath-hold (vmDIBH) techniques in further reducing irradiated healthy--especially heart--tissue is investigated. MATERIAL AND METHODS: For 37 partial breast planning target volumes (PTVs), three-dimensional conformal radiotherapy (3D-CRT) (3-5 coplanar or non-coplanar 6 and/or 10 MV beams) and VMAT (two partial 6 MV arcs) plans were made on CTs acquired in free-breathing (FB) and/or in vmDIBH. Dose-volume parameters for the PTV, heart, lungs, and breasts were compared. RESULTS: Better dose conformity was achieved with VMAT compared to 3D-CRT (conformity index 1.24±0.09 vs. 1.49±0.20). Non-PTV ipsilateral breast receiving ≥50% of the prescribed dose was on average reduced by 28% in VMAT plans compared to 3D-CRT plans. Mean heart dose (MHD) reduced from 2.0 (0.1-5.1) Gy in 3D-CRT(FB) to 0.6 (0.1-1.6) Gy in VMAT(vmDIBH). VMAT is beneficial for MHD reduction if MHD with 3D-CRT exceeds 0.5Gy. Cardiac dose reduction as a result of VMAT increases with increasing initial MHD, and adding vmDIBH reduces the cardiac dose further. Mean dose to the ipsilateral lung decreased from 3.7 (0.7-8.7) to 1.8 (0.5-4.0) Gy with VMAT(vmDIBH) compared to 3D-CRT(FB). VMAT resulted in a slight increase in the contralateral breast dose (DMean) always remaining <1.9 Gy). CONCLUSIONS: For APBI patients, VMAT improves PTV dose conformity and delivers lower doses to the ipsilateral breast and lung compared to 3D-CRT. This goes at the cost of a slight but acceptable increase of the contralateral breast dose. VMAT reduces cardiac dose if MHD exceeds 0.5 Gy for 3D-CRT. Adding vmDIBH results in a further reduction of heart and ipsilateral lung dose.

Dosimetric accuracy and clinical quality of Acuros XB and AAA dose calculation algorithm for stereotactic and conventional lung volumetric modulated arc therapy plans.

INTRODUCTION: The main aim of the current study was to assess the dosimetric accuracy and clinical quality of volumetric modulated arc therapy (VMAT) plans for stereotactic (stage I) and conventional (stage III) lung cancer treatments planned with Eclipse version 10.0 Anisotropic Analytical Algorithm (AAA) and Acuros XB (AXB) algorithm. METHODS: The dosimetric impact of using AAA instead of AXB, and grid size 2.5 mm instead of 1.0 mm for VMAT treatment plans was evaluated. The clinical plan quality of AXB VMAT was assessed using 45 stage I and 73 stage III patients, and was compared with published results, planned with VMAT and hybrid-VMAT techniques. RESULTS: The dosimetric impact on near-minimum PTV dose (D98%) using AAA instead of AXB was large (underdose up to 12.3%) for stage I and very small (underdose up to 0.8%) for stage III lung treatments. There were no significant differences for dose volume histogram (DVH) values between grid sizes. The calculation time was significantly higher for AXB grid size 1.0 than 2.5 mm (p < 0.01). The clinical quality of the VMAT plans was at least comparable with clinical qualities given in literature of lung treatment plans with VMAT and hybrid-VMAT techniques. The average mean lung dose (MLD), lung V(20Gy) and V(5Gy) in this study were respectively 3.6 Gy, 4.1% and 15.7% for 45 stage I patients and 12.4 Gy, 19.3% and 46.6% for 73 stage III lung patients. The average contra-lateral lung dose V(5Gy-cont) was 35.6% for stage III patients. CONCLUSIONS: For stereotactic and conventional lung treatments, VMAT calculated with AXB grid size 2.5 mm resulted in accurate dose calculations. No hybrid technique was needed to obtain the dose constraints. AXB is recommended instead of AAA for avoiding serious overestimation of the minimum target doses compared to the actual delivered dose.

Patient positioning based on a radioactive tracer implanted in patients with localized prostate cancer: a performance and safety evaluation.

PURPOSE: To evaluate the performance and safety of a radiation therapy positioning system (RealEye) based on tracking a radioactive marker (Tracer) implanted in patients with localized prostate cancer. METHODS AND MATERIALS: We performed a single-arm multi-institutional trial in 20 patients. The iridium-192 ((192)Ir)-containing Tracer was implanted in the patient together with 4 standard gold seed fiducials. Patient prostate-related symptoms were evaluated with the International Prostate Symptom Score (IPSS) questionnaire. Computed tomography (CT) was performed for treatment planning, during treatment, and after treatment to evaluate the migration stability of the Tracer. At 5 treatment sessions, cone beam CT was performed to test the positioning accuracy of the RealEye. RESULTS: The Tracer was successfully implanted in all patients. No device or procedure-related adverse events occurred. Changes in IPSS scores were limited. The difference between the mean change in Tracer-fiducial distance and the mean change in fiducial-fiducial distance was -0.39 mm (95% confidence interval [CI] upper boundary, -0.22 mm). The adjusted mean difference between Tracer position according to RealEye and the Tracer position on the CBCT for all patients was 1.34 mm (95% CI upper boundary, 1.41 mm). CONCLUSIONS: Implantation of the Tracer is feasible and safe. Migration stability of the Tracer is good. Prostate patients can be positioned and monitored accurately by using RealEye.