Christian Neumaier

Kypho-IORT - a novel approach of intraoperative radiotherapy during kyphoplasty for vertebral metastases

BackgroundInstable and painful vertebral metastases in patients with progressive visceral metastases present a common therapeutic dilemma. We developed a novel approach to deliver intraoperative radiotherapy (IORT) during kyphoplasty and report the first treated case.Methods/Results60 year old patient with metastasizing breast cancer under chemotherapy presented with a newly diagnosed painful metastasis in the 12th thoracic vertebra. Under general anaesthesia, a bipedicular approach into the vertebra was chosen with insertion of specially designed metallic sleeves to guide the electron drift tube of the miniature X-ray generator (INTRABEAM, Carl Zeiss Surgical, Oberkochen, Germany). This was inserted with a novel sheet designed for this approach protecting the drift tube. A radiation dose of 8 Gy in 5 mm distance (50 kV X-rays) was delivered. The kyphoplasty balloons (KyphX, Kyphon Inc, Sunnyvale) were inflated after IORT and polymethylmethacrylate cement was injected. The whole procedure lasted less than 90 minutes.ConclusionIn conclusion, this novel, minimally invasive procedure can be performed in standard operating rooms and may become a valuable option for patients with vertebral metastases providing immediate stability and local control. A phase I/II study is under way to establish the optimal dose prescription.

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

BackgroundPatients ≥ 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.Methods/DesignThis 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.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).DiscussionIt 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.Its aim is to confirm the efficacy and toxicity of IORT in a well selected collective of elderly patients with breast cancer.Trail registrationNCT01299987

Clinical outcome of hypofractionated breath-hold image-guided SABR of primary lung tumors and lung metastases.

BackgroundStereotactic Ablative RadioTherapy (SABR) of lung tumors/metastases has been shown to be an effective treatment modality with low toxicity. Outcome and toxicity were retrospectively evaluated in a unique single-institution cohort treated with intensity-modulated image-guided breath-hold SABR (igSABR) without external immobilization. The dose–response relationship is analyzed based on Biologically Equivalent Dose (BED).Patients and methods50 lesions in 43 patients with primary NSCLC (n = 27) or lung-metastases of various primaries (n = 16) were consecutively treated with igSABR with Active-Breathing-Coordinator (ABC®) and repeat-breath-hold cone-beam-CT. After an initial dose-finding/-escalation period, 5x12 Gy for peripheral lesions and single doses of 5 Gy to varying dose levels for central lesions were applied. Overall-survival (OS), progression-free-survival (PFS), progression pattern, local control (LC) and toxicity were analyzed.ResultsThe median BED2 was 83 Gy. 12 lesions were treated with a BED2 of <80 Gy, and 38 lesions with a BED2 of >80 Gy. Median follow-up was 15 months. Actuarial 1- and 2-year OS were 67% and 43%; respectively. Cause of death was non-disease-related in 27%. Actuarial 1- and 2-year PFS was 42% and 28%. Progression site was predominantly distant. Actuarial 1- and 2 year LC was 90% and 85%. LC showed a trend for a correlation to BED2 (p = 0.1167). Pneumonitis requiring conservative treatment occurred in 23%.ConclusionIntensity-modulated breath-hold igSABR results in high LC-rates and low toxicity in this unfavorable patient cohort with inoperable lung tumors or metastases. A BED2 of <80 Gy was associated with reduced local control.

Accelerated Partial Breast Irradiation in Clinical Practice.

Accelerated partial breast irradiation (APBI) has been under clinical investigation for more than 15 years. There are several technical approaches that are clinically established, e.g. brachytherapy, intraoperative radiotherapy (IORT), or external-beam radiotherapy. The understanding of the underlying biology, optimal technical procedures, patient selection criteria, and imaging changes during follow-up has increased enormously. After completion of several phase III trials using brachytherapy or IORT, APBI is currently increasingly used either in phase IV studies, registries, or in selected patients outside of clinical studies. Consensus statements about suitable patients are available from several international and national societies like ASTRO, ESTRO, and DEGRO. One may expect that 15-25% of patients undergoing breast-conserving surgery may qualify for APBI, i.e. patients with small invasive ductal breast cancer without clinical lymph node involvement.

TGF-β1 Is Present at High Levels in Wound Fluid from Breast Cancer Patients Immediately Post-Surgery, and Is Not Increased by Intraoperative Radiation Therapy (IORT).

In patients with low-risk breast cancer, intraoperative radiotherapy (IORT) during breast-conserving surgery is a novel and convenient treatment option for delivering a single high dose of irradiation directly to the tumour bed. However, edema and fibrosis can develop after surgery and radiotherapy, which can subsequently impair quality of life. TGF- β is a strong inducer of the extracellular matrix component hyaluronan (HA). TGF-β expression and HA metabolism can be modulated by irradiation experimentally, and are involved in edema and fibrosis. We therefore hypothesized that IORT may regulate these factors.Wound fluid (WF) draining from breast lumpectomy sites was collected and levels of TGF-β1 and HA were determined by ELISA. Proliferation and marker expression was analyzed in primary lymphatic endothelial cells (LECs) treated with recombinant TGF-β or WF. Our results show that IORT does not change TGF-β1 or HA levels in wound fluid draining from breast lumpectomy sites, and does not lead to accumulation of sHA oligosaccharides. Nevertheless, concentrations of TGF-β1 were high in WF from patients regardless of IORT, at concentrations well above those associated with fibrosis and the suppression of LEC identity. Consistently, we found that TGF-β in WF is active and inhibits LEC proliferation. Furthermore, all three TGF-β isoforms inhibited LEC proliferation and suppressed LEC marker expression at pathophysiologically relevant concentrations. Given that TGF-β contributes to edema and plays a role in the regulation of LEC identity, we suggest that inhibition of TGF-β directly after surgery might prevent the development of side effects such as edema and fibrosis.

Comparison of the proliferative and clonogenic growth capacity of wound fluid from breast cancer patients treated with and without intraoperative radiotherapy

The physiological wound healing process after breast-conserving surgery is believed to contribute to a microenvironment promoting motility and invasive activity of residual malignant cells. In intraoperative radiotherapy (IORT), a high single dose of radiation is applied to the tumor bed directly after surgical removal of the tumor and this has been reported to abrogate the stimulatory effects of wound fluid (WF). In the present study, we tested whether IORT alters the influence of WF on the proliferative and clonogenic growth of human MCF7 breast cancer cells. Breast cancer patients were recruited from our IORT studies. WF from 12 patients who underwent IORT, and 18 control patients without IORT, were collected for 24 h. Proliferation was tested in a short-term (MTT) assay and the colony formation assay. A non-significant trend for reduced proliferation was seen in the MTT assay when WF from IORT-treated patients was added at 1% (P=0.07) but not at 3% (P=0.16). No significant effect of IORT-treated WF on the clonogenic growth capacity of MCF7 cells (P=0.79) was found. Our short-term proliferation results with the ER/PgR + -Her2/neu − cell line MCF7 complement previously published data with ER/PgR − -Her2/neu − and ER/PgR − -Her2/neu + breast cancer cell lines showing no significant effect of IORT on short-term proliferation. In addition, for the first time, a lack of an effect of IORT on the clonogenic growth capacity of WF was shown. It should be noted that the present results do not exclude potential other effects of IORT on the cytokine composition and functional activity of WF.

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.