Frederic Bludau

Intraoperative radiotherapy during kyphoplasty for vertebral metastases (Kypho-IORT): First clinical results

AIMS AND BACKGROUND Kyphoplasty is an effective procedure providing structural stability and pain alleviation in vertebral metastases. To prevent early regrowth, patients typically receive postoperative fractionated radiotherapy, which is associated with long treatment duration. Therefore, we established a new approach to deliver intraoperative radiotherapy during kyphoplasty to shorten the treatment time and reach structural stability and sterilization of the metastases (Kypho-IORT). METHODS AND STUDY DESIGN For Kypho-IORT, a 50 kV X-ray source with a specially designed applicator was used. A radiation dose of 8 Gy in 5 mm distance was delivered. After radiation the device was removed and the kyphoplasty was completed according to the standard procedure. Since August 2009, 18 patients with instable or painful spinal metastases received Kypho-IORT. The median age was 63 years (range, 43-73). RESULTS Kypho-IORT was successfully performed in 18 of 21 vertebral lesions (86%). No severe complications occurred during or early after IORT. The median pain score using a visual analogue scale decreased from 5/10 before the procedure to 2.5/10 at day 1 (P <0.001) and to 0/10 six weeks after the procedure (P = 0.001). Imaging studies were available for 15 of 18 patients. Stable disease within the irradiated vertebral body was seen in 14 patients (93%) and local progressive disease in one patient (7%). No re-irradiation due to local progressive disease or pain recurrence was necessary within the median follow-up of 4.5 months. CONCLUSIONS Kypho-IORT is well tolerated without severe side effects and provides fast improvement of pain. Although stable disease was seen in 93% of the patients, a longer follow-up is necessary to assess the effectiveness. A dose escalation study to establish the maximally tolerated dose has been initiated.

Kyphoplasty and intra-operative radiotheray, combination of kyphoplasty and intra-operative radiation for spinal metastases: technical feasibility of a novel approach

PurposeTo evaluate whether this new method is clinically applicable after theoretical and cadaver testing.MethodsThe incidence of spinal metastases requiring therapy is increasing, due to enhanced life expectancy. Due to results from studies with epidural compression a combined surgical and radiation therapy is often chosen. Minimal invasive cement augmentation is an increasingly used technique, due to fast pain relief and immediate stabilisation. On the other hand, stereotactic radiosurgery is considered to provide a more durable response and better local disease control than conventional radiotherapy with the application of higher doses. Therefore the combination of cement stabilisation and simultaneous intra-operative radiation with immediate stabilisation and high-dose radiation could be an interesting therapeutic option. The results of a clinical feasibility study are presented.Results17 patients could be treated with the new method. In two patients (10%) intra-operative radiation could not be applied. No surgical interventions for complications were required.ConclusionsSummarizing Kypho-IORT is technically feasible with an intra-operative risk profile comparable to sole kyphoplasty and a shorter treatment time and hospitalisation for the patients compared to conventional multifraction radiation. Radiation could not be applied in 10% of cases due to technical difficulties. The results of this feasibility study permit further evaluation of this new technique by a dose escalation study which is currently in preparation.

Radiation protection for an intraoperative x-ray source compared to C-arm fluoroscopy

BACKGROUND Intraoperative radiotherapy (IORT) using the INTRABEAM(®) system promises a flexible use regarding radiation protection compared to other approaches such as electron treatment or HDR brachytherapy with (192)Ir or (60)Co. In this study we compared dose rate measurements of breast- and Kypho-IORT with C-arm fluoroscopy which is needed to estimate radiation protection areas. MATERIALS AND METHODS C-arm fluoroscopy, breast- and Kypho-IORTs were performed using phantoms (silicon breast or bucket of water). Dose rates were measured at the phantoms surface, at 30 cm, 100 cm and 200 cm distance. Those measurements were confirmed during 10 Kypho-IORT and 10 breast-IORT patient treatments. RESULTS The measured dose rates were in the same magnitude for all three paradigms and ranges from 20 μSv/h during a simulated breast-IORT at two meter distance up to 64 mSv/h directly at the surface of a simulated Kypho-IORT. Those measurements result in a circle of controlled area (yearly doses >6 mSv) for each paradigm of about 4 m±2 m. DISCUSSION/CONCLUSIONS All three paradigms show comparable dose rates which implies that the radiation protection is straight forward and confirms the flexible use of the INTRABEAM(®) system.

Phase I/II trial of combined kyphoplasty and intraoperative radiotherapy in spinal metastases

BACKGROUND CONTEXT Spinal metastases occur in 30%-50% of patients with systemic cancer. The primary goals of palliation are pain control and prevention of local recurrence. PURPOSE This study aimed to test the safety and efficacy of a combined modality approach consisting of kyphoplasty and intraoperative radiotherapy (Kypho-IORT). STUDY DESIGN/SETTING Kyphoplasty and intraoperative radiotherapy was a prospective, single-center phase I/II trial. Patients were enrolled in a classical 3+3 scheme within the initial phase I, where Kypho-IORT was applied using a needle-shaped 50 kV X-ray source at three radiation dose levels (8 Gy in 8-mm, 8 Gy in 11-mm, and 8 Gy in 13-mm depth). Thereafter, cohort expansion was performed as phase II of the trial. The trial is registered with clinicaltrials.gov, number NCT01280032. PATIENT SAMPLE Patients aged 50 years and older with a Karnofsky Performance Status of at least 60% and with one to three painful vertebral metastases confined to the vertebral body were eligible to participate. OUTCOME MEASURES The primary end point was safety as per the occurrence of dose-limiting toxicities. The secondary end points were pain reduction, local progression-free survival (L-PFS), and overall survival (OS). METHODS Pain was measured using the visual analog scale (VAS) and local control was assessed in serial computed tomography or magnetic resonance imaging scans. RESULTS None of the nine patients enrolled in the phase I showed dose-limiting toxicities at any level and thus, 52 patients were subsequently enrolled into a phase II, where Kypho-IORT was performed at various dose levels. The median pain score significantly dropped from 5 preoperatively to 2 at the first postoperative day (p<.001). Of 43 patients who reported a pre-interventional pain level of 3 or more, 30 (69.8%) reported a reduction of ≥3 points on the first postoperative day. A persistent pain reduction beyond the first postoperative day of ≥3 points was seen in 34 (79.1%) patients. The 3, 6, and 12 month L-PFS was excellent with 97.5%, 93.8%, and 93.8%. The 3, 6, and 12 months OS was 76.9%, 64.0%, and 48.4%. CONCLUSION Kyphoplasty and intraoperative radiotherapy is safe and immediately provided sustained pain relief with excellent local control rates in patients with painful vertebral metastases.

Intraoperative radiotherapy during kyphoplasty (Kypo-IORT): a novel treatment approach for patients with symptomatic spinal metastases

Palliation like pain reduction, stabilization and local control are main treatment goals for patients with spinal metastases. To shorten treatment and reduce hospitalization time, various novel therapy approaches like stereotactic body radiotherapy (SBRT) with single high-doses or minimally invasive surgical techniques (e.g., kyphoplasty) combined with other physical method are increasingly used. Intraoperative radiotherapy combined with kyphoplasty (Kypo-IORT) is an X-ray based approach using the Intrabeam ® system. It is a technically feasible therapy method with immediate pain relief and excellent local tumor control. In our recently closed dose escalation study a dose of 8 Gy in 13 mm depth from isocenter of the radiation source was determined as the maximally tolerated dose and will be tested in a phase III study.

Other Applications of INTRABEAM

Intraoperative radiotherapy (IORT) permits the delivery of a high radiation dose directly to the residual tumour or tumour bed while sparing nearby normal tissues. In most cases, IORT with the INTRABEAM® system is employed as a part of multimodal treatment, with the aim of providing an additional benefit in terms of prevention of local recurrence. IORT is used to treat many tumours, the most common being:

Avulsion fracture of the lesser trochanter in adolescents

INTRODUCTION Avulsion fractures of the lesser trochanter in adolescents are rare. They are a result of a sudden and forceful contraction of the iliopsoas muscle. Functional results in the medium term after non-operative treatment are unknown. Therefore we aimed to report these in the present study. MATERIALS AND METHODS A retrospective two-center study was performed in a case series treated between 2011 and 2017. All adolescents with an acute avulsion fracture of the lesser trochanter were included. Age, gender, mechanism of injury, fracture side, amount of displacement, and therapy were analyzed. In the follow-up, the Harris Hip Score (HHS), the sports level, the power of flexion in the hip, and signs of an ischio-femoral impingement (IFI) were investigated. RESULTS An avulsion fracture of the lesser trochanter was diagnosed in 4 boys and 1 girl. The mean age of the patients was 13.8 years (range: 13-15 years). We observed 2 type II and 3 type III fractures. The patients received similar non-operative treatment. Follow-up was performed at a mean of 4.9 years (range: 3.5-6.2 years) after injury. All patients returned to competitive sports. The Harris Hip Score (HHS) was 100 out of 100 points. History and provocation test concerning an IFI were negative in all patients. CONCLUSION Our study shows excellent results with non-operative treatment in acute avulsion fractures of the lesser trochanter in a case series of five adolescents. All patients returned to competitive sports. In our opinion, acute avulsion fractures of the lesser trochanter should be treated non-operatively.

Circulating Tumour Cell Release after Cement Augmentation of Vertebral Metastases

Cement augmentation via percutaneous vertebroplasty or kyphoplasty for treatment of spinal metastasis is a well-established treatment option. We assessed whether elevated intrametastatic pressure during cement augmentation results in an increased dissemination of tumour cells into the vascular circulation. We prospectively collected blood from patients with osteolytic spinal column metastases and analysed the prevalence of circulating tumour cells (CTCs) at three time-points: preoperatively, 20 minutes after cement augmentation, and 3–5 days postoperatively. Enrolling 21 patients, including 13 breast- (61.9%), 5 lung- (23.8%), and one (4.8%) colorectal-, renal-, and prostate-carcinoma patient each, we demonstrate a significant 1.8-fold increase of EpCAM+/K+ CTCs in samples taken 20 minutes post-cement augmentation (P < 0.0001). Despite increased mechanical CTC dissemination due to cement augmentation, follow-up blood draws demonstrated that no long-term increase of CTCs was present. Array-CGH analysis revealed a specific profile of the CTC collected 20 minutes after cement augmentation. This is the first study to report that peripheral CTCs are temporarily increased due to vertebral cement augmentation procedures. Our findings provide a rationale for the development of new prophylactic strategies to reduce the increased release of CTC after cement augmentation of osteolytic spinal metastases.

Precision IORT – Image guided intraoperative radiation therapy (igIORT) using online treatment planning including tissue heterogeneity correction☆

BACKGROUND To the present date, IORT has been eye and hand guided without treatment planning and tissue heterogeneity correction. This limits the precision of the application and the precise documentation of the location and the deposited dose in the tissue. Here we present a set-up where we use image guidance by intraoperative cone beam computed tomography (CBCT) for precise online Monte Carlo treatment planning including tissue heterogeneity correction. MATERIALS AND METHODS An IORT was performed during balloon kyphoplasty using a dedicated Needle Applicator. An intraoperative CBCT was registered with a pre-op CT. Treatment planning was performed in Radiance using a hybrid Monte Carlo algorithm simulating dose in homogeneous (MCwater) and heterogeneous medium (MChet). Dose distributions on CBCT and pre-op CT were compared with each other. Spinal cord and the metastasis doses were evaluated. RESULTS The MCwater calculations showed a spherical dose distribution as expected. The minimum target dose for the MChet simulations on pre-op CT was increased by 40% while the maximum spinal cord dose was decreased by 35%. Due to the artefacts on the CBCT the comparison between MChet simulations on CBCT and pre-op CT showed differences up to 50% in dose. CONCLUSIONS igIORT and online treatment planning improves the accuracy of IORT. However, the current set-up is limited by CT artefacts. Fusing an intraoperative CBCT with a pre-op CT allows the combination of an accurate dose calculation with the knowledge of the correct source/applicator position. This method can be also used for pre-operative treatment planning followed by image guided surgery.