Comparison of breast sequential and simultaneous integrated boost using the biologically effective dose volume histogram (BEDVH)

Purpose: A method is presented to radiobiologically compare sequential (SEQ) and simultaneously integrated boost (SIB) breast radiotherapy. Methods: The method is based on identically prescribed biologically effective dose (iso-BED) which was achieved by different prescribed doses due to different fractionation schemes. It is performed by converting the calculated three-dimensional dose distribution to the corresponding BED distribution taking into consideration the different number of fractions for generic α/β ratios. A cumulative BED volume histogram (BEDVH) is then derived from the BED distribution and is compared for the two delivery schemes. Ten breast cancer patients (4 right-sided and 6 left-sided) were investigated. Two tangential intensity modulated whole breast beams with two other oblique (with different gantry angles) beams for the boost volume were used. The boost and the breast target volumes with either α/β = 10 or 3 Gy, and ipsi-lateral and contra-lateral lungs, heart, and contra-lateral breast as organs at risk (OARs) with α/β = 3 Gy were compared. Results: Based on the BEDVH comparisons, the use of SIB reduced the biological breast mean dose by about 3%, the ipsi-lateral lung and heart by about 10%, and contra-lateral breast and lung by about 7%. Conclusion: BED based comparisons should always be used in comparing plans that have different fraction sizes. SIB schemes are dosimetrically more advantageous than SEQ in breast target volume and OARs for equal prescribed BEDs for breast and boost

A fast radiotherapy paradigm for anal cancer with volumetric modulated arc therapy (VMAT)

Background/Purpose: Radiotherapy (RT) volumes for anal cancer are large and of moderate complexity when organs at risk ( OAR) such as testis, small bowel and bladder are at least partially to be shielded. Volumetric intensity modulated arc therapy (VMAT) might provide OAR-shielding comparable to step-and-shoot intensity modulated radiotherapy (IMRT) for this tumor entity with better treatment efficiency. Materials and methods: Based on treatment planning CTs of 8 patients, we compared dose distributions, comformality index (CI), homogeneity index ( HI), number of monitor units (MU) and treatment time (TTT) for plans generated for VMAT, 3D-CRT and step-and-shoot-IMRT (optimized based on Pencil Beam (PB) or Monte Carlo ( MC) dose calculation) for typical anal cancer planning target volumes (PTV) including inguinal lymph nodes as usually treated during the first phase (0-36 Gy) of a shrinking field regimen. Results: With values of 1.33 +/- 0.21/1.26 +/- 0.05/1.3 +/- 0.02 and 1.39 +/- 0.09, the CI's for IMRT (PB-Corvus/PB-Hyperion/MC-Hyperion) and VMAT are better than for 3D-CRT with 2.00 +/- 0.16. The HI's for the prescribed dose (HI36) for 3D-CRT were 1.06 +/- 0.01 and 1.11 +/- 0.02 for VMAT, respectively and 1.15 +/- 0.02/1.10 +/- 0.02/1.11 +/- 0.08 for IMRT (PB-Corvus/PB-Hyperion/MCHyperion). Mean TTT and MU's for 3D-CRT is 220s/225 +/- 11MU and for IMRT (PB-Corvus/PBHyperion/MC-Hyperion) is 575s/1260 +/- 172MU, 570s/477 +/- 84MU and 610s748 +/- 193MU while TTT and MU for two-arc-VMAT is 290s/268 +/- 19MU. Conclusion: VMAT provides treatment plans with high conformity and homogeneity equivalent to step-and-shoot-IMRT for this mono-concave treatment volume. Short treatment delivery time and low primary MU are the most important advantages

INTRAGO: intraoperative radiotherapy in glioblastoma multiforme – a Phase I/II dose escalation study

Background: Glioblastoma multiforme (GBM) is the most frequent primary malignant brain tumor in adults. Despite multimodal therapies, almost all GBM recur within a narrow margin around the initial resected lesion. Thus, novel therapeutic intensification strategies must target both, the population of dispersed tumor cells around the cavity and the postoperative microenvironment. Intraoperative radiotherapy (IORT) is a pragmatic and effective approach to sterilize the margins from persistent tumor cells, abrogate post-injury proliferative stimuli and to bridge the therapeutic gap between surgery and radiochemotherapy. Therefore, we have set up INTRAGO, a phase I/II dose-escalation study to evaluate the safety and tolerability of IORT added to standard therapy in newly diagnosed GBM. In contrast to previous approaches, the study involves the application of isotropic low-energy (kV) x-rays delivered by spherical applicators, providing optimal irradiation properties to the resection cavity. Methods/Design: INTRAGO includes patients aged 50 years or older with a Karnofsky performance status of at least 50% and a histologically confirmed (frozen sections) supratentorial GBM. Safety and tolerability (i.e., the maximum tolerated dose, MTD) will be assessed using a classical 3 + 3 dose-escalation design. Dose-limiting toxicities (DLT) are wound healing deficits or infections requiring surgical intervention, IORT-related cerebral bleeding or ischemia, symptomatic brain necrosis requiring surgical intervention and early termination of external beam radiotherapy (before the envisaged dose of 60 Gy) due to radiotoxicity. Secondary end points are progression-free and overall survival. Trial registration: The study is registered with clinicaltrials.gov, number: NCT02104882 (Registration Date: 03/26/2014)

Combined kyphoplasty and intraoperative radiotherapy (Kypho-IORT) versus external beam radiotherapy (EBRT) for painful vertebral metastases - a randomized phase III study

Background: The spine is the most frequent location of bone metastases. Local treatment aims at palliation of pain and, given the increased likelihood of long-term cancer survival, at local control. Kyphoplasty and intraoperative radiotherapy (Kypho-IORT) provided instantaneous pain relief in 70% of patients at the first day after the intervention and resulted in local control rates of > 93% at 1 year in a recently conducted phase I/II trial. To assess its clinical value, we designed a phase III trial which tests Kypho-IORT against the most widespread standard-of-care, external beam radiotherapy (EBRT), in patients with painful vertebral metastases. Methods: This phase III study includes patients ≥50 years of age with up to 4 vertebral metastases and a pain score of at least 3/10 points on the visual/numeric analogy scale (VAS). Patients randomized into the experimental arm (A) will undergo Kypho-IORT (Kyphoplasty plus IORT with 8 Gy prescribed to 13 mm depth). Patients randomized into the control arm (B) will receive EBRT with either 30 Gy in 10 fractions or 8 Gy as a single dose. The primary end point is pain reduction defined as at least − 3 points on the VAS compared to baseline at day 1. Assuming that 40% of patients in the Kypho-IORT arm and 5% of patients in the control arm will achieve this reduction and 20% will drop out, a total of 54 patients will have to be included to reach a power of 0.817 with a two-sided alpha of 0.05. Secondary endpoints are evaluation of the percentage of patients with a pain reduction of at least 3 points at 2 and 6 weeks, local tumor control, frequency of re-intervention, secondary fractures/sintering, complication rates, skin toxicity/wound healing, progression-free survival (PFS), overall survival (OS) and quality of life. Discussion: This trial will generate level 1 evidence on the clinical value of a one-stop procedure which may provide instantaneous pain relief, long-term control and shortened intervals to further adjuvant (systemic) therapies in patients with spinal metastases. Trial registration Registered with ClinicalTrials.gov, number: NCT02773966. Registration date: 05/16/2016

Novel radiotherapy techniques for involved-field and involved-node treatment of mediastinal Hodgkin lymphoma: when should they be considered and which questions remain open?

PURPOSE Hodgkin lymphoma (HL) is a highly curable disease. Reducing late complications and second malignancies has become increasingly important. Radiotherapy target paradigms are currently changing and radiotherapy techniques are evolving rapidly. DESIGN This overview reports to what extent target volume reduction in involved-node (IN) and advanced radiotherapy techniques, such as intensity-modulated radiotherapy (IMRT) and proton therapy-compared with involved-field (IF) and 3D radiotherapy (3D-RT)- can reduce high doses to organs at risk (OAR) and examines the issues that still remain open. RESULTS Although no comparison of all available techniques on identical patient datasets exists, clear patterns emerge. Advanced dose-calculation algorithms (e.g., convolution-superposition/Monte Carlo) should be used in mediastinal HL. INRT consistently reduces treated volumes when compared with IFRT with the exact amount depending on the INRT definition. The number of patients that might significantly benefit from highly conformal techniques such as IMRT over 3D-RT regarding high-dose exposure to organs at risk (OAR) is smaller with INRT. The impact of larger volumes treated with low doses in advanced techniques is unclear. The type of IMRT used (static/rotational) is of minor importance. All advanced photon techniques result in similar potential benefits and disadvantages, therefore only the degree-of-modulation should be chosen based on individual treatment goals. Treatment in deep inspiration breath hold is being evaluated. Protons theoretically provide both excellent high-dose conformality and reduced integral dose. CONCLUSION Further reduction of treated volumes most effectively reduces OAR dose, most likely without disadvantages if the excellent control rates achieved currently are maintained. For both IFRT and INRT, the benefits of advanced radiotherapy techniques depend on the individual patient/target geometry. Their use should therefore be decided case by case with comparative treatment planning

TARGIT-E(lderly)—Prospective phase II study of intraoperative radiotherapy (IORT) in elderly patients with small breast cancer

<p>Abstract</p> <p>Background</p> <p>Patients ≥ 70 years with small, low-risk breast cancer who are operated but not irradiated how local relapse rates around 4% after 4 years. With adjuvant whole breast radiotherapy (WBRT) the local relapse rate drops to 1% after 4 years under Tamoxifen. It has been demonstrated that the efficacy of radiotherapy of the tumor bed only in a selected group can be non-inferior to WBRT.</p> <p>Methods/Design</p> <p>This prospective, multicentric single arm phase II study is based on the protocol of the international TARGIT-A study. The TARGIT-E study should confirm the efficacy of a single dose of intraoperative radiotherapy (IORT) in a well selected group of elderly patients with small breast cancer and absence of risk factors. Patients will receive IORT (20 Gy with Intrabeam system/Carl Zeiss) during breast conserving surgery. In presence of risk factors postoperative WBRT will be added to complete the radiotherapeutic treatment according to international guidelines. Endpoints are the local relapse rate (within 2 cm of the tumor bed), ipsilateral in breast relapse, cancer-specific and overall survival and contralateral breast cancer as well as documentation of quality of life and cosmetic outcome.</p> <p>The expected local relapse rates are 0.5/1/1.5% after 2.5/5/7.5 years, respectively. Discontinuation of the trial is scheduled if rates of local relapse rates rise to 3/4/6% after 2.5/5/7.5 years. Power calculations result in 540 patients with a calculated dropout rate of 20% and loss to follow-up of 20%, an alpha of 0.01 and a beta 0.05. There will be a pre- and a post-pathology stratum (n = 270 each).</p> <p>Discussion</p> <p>It is a pragmatic trial in which each participating centre has the option to modify entry criteria and criteria for WBRT according to this core protocol after consultation with the steering committee and local ethics committee (e.g. size, free margins). Only centers with access to the Intrabeam system (Carl Zeiss) can recruit patients into the trial.</p> <p>Its aim is to confirm the efficacy and toxicity of IORT in a well selected collective of elderly patients with breast cancer.</p> <p>Trail registration</p> <p>NCT01299987</p