Long term safety and visibility of a novel liquid fiducial marker for use in image guided radiotherapy of non-small cell lung cancer.

Safety and clinical feasibility of injecting a novel liquid fiducial marker for use in image guided radiotherapy in 15 patients with non-small cell lung cancer are reported. No major safety or toxicity issues were encountered. Markers present at start of radiotherapy remained visible in cone beam computed tomography and fluoroscopy images throughout the treatment course and on computed tomography images during follow-up (0-38 months). Marker volume reduction was seen until 9 months after treatment, after which no further marker breakdown was found. No post-treatment migration or marker related complications were found.

The prognostic value of FET PET at radiotherapy planning in newly diagnosed glioblastoma.

BACKGROUND: Glioblastoma patients show a great variability in progression free survival (PFS) and overall survival (OS). To gain additional pretherapeutic information, we explored the potential of O-(2-18F-fluoroethyl)-L-tyrosine (FET) PET as an independent prognostic biomarker. METHODS: We retrospectively analyzed 146 consecutively treated, newly diagnosed glioblastoma patients. All patients were treated with temozolomide and radiation therapy (RT). CT/MR and FET PET scans were obtained postoperatively for RT planning. We used Cox proportional hazards models with OS and PFS as endpoints, to test the prognostic value of FET PET biological tumor volume (BTV). RESULTS: Median follow-up time was 14 months, and median OS and PFS were 16.5 and 6.5 months, respectively. In the multivariate analysis, increasing BTV (HR = 1.17, P < 0.001), poor performance status (HR = 2.35, P < 0.001), O(6)-methylguanine-DNA methyltransferase protein status (HR = 1.61, P = 0.024) and higher age (HR = 1.32, P = 0.013) were independent prognostic factors of poor OS. For poor PFS, only increasing BTV (HR = 1.18; P = 0.002) was prognostic. A prognostic index for OS was created based on the identified prognostic factors. CONCLUSION: Large BTV on FET PET is an independent prognostic factor of poor OS and PFS in glioblastoma patients. With the introduction of FET PET, we obtain a prognostic index that can help in glioblastoma treatment planning.

Fast intra-fractional image-guidance with 6D positioning correction reduces delivery uncertainty for stereotactic radiosurgery and radiotherapy.

The purpose of this study is to analyze intra-fractional positioning uncertainty for stereotactic radiotherapy and radiosurgery of cranial tumors. Specifically, we wish to determine the use of intra-fractional image guided patient positioning verification is necessary during delivery of "frameless" stereotactic radiotherapy and radiosurgery (SRT/SRS) and non-coplanar radiation beams, and if positioning uncertainty is associated with overall treatment time. Orthogonal radiographic treatment verification data was extracted for 288 patients and 1344 fractions, and were analyzed with respect to 3D translational and angular corrections once during treatment delivery of SRT/SRS. We find that positioning corrections greater than 2 mm are required for approximately 6% of beams, and that the magnitude of the translational corrections was significantly associated with the delay time between beams (p=0.003). Further, we find that the maximum angular and translational deviations were associated (p<0.001). We conclude that a subgroup of SRT/SRS patients may have considerable positioning error unless this is monitored and corrected during treatment, and that keeping the imaging and delivery times below approximately 5 min is beneficial towards clinically relevant geographical errors. In case longer time-delays than 5 min occurs, the treatment staff should consider acquiring a new set of radiographs in order to verify the patient's position, assuming this technically feasible to be performed quickly.

Stereotactic radiosurgery versus decompressive surgery followed by postoperative radiotherapy for metastatic spinal cord compression (STEREOCORD): Study protocol of a randomized non-inferiority trial.

Current treatment standard for patients with metastatic spinal cord compression (MSCC) is decompressive surgery followed by radiotherapy. Stereotactic radiosurgery (SRS) could be considered a treatment option for MSCC for patients with minor neurologic deficits. If SRS is safely and effectively delivered with equivalent functional outcome, the patients would avoid the risks associated with an invasive procedure. This paper presents the design of a non-inferiority clinical trial evaluating the safety, tolerability and feasibility of SRS vs. current standard treatment for patients with MSCC. Patients fulfilling inclusion criteria will be randomized 1:1 to each arm. The primary endpoint is ability to walk six weeks after treatment. Secondary endpoints are levels of pain, bladder control, quality of life, response rate, toxicity and number of treatment days. 65 patients in each arm are required for the power of 89% to detect a clinically relevant inferior outcome.

Positron Emission Tomography Based Elucidation of the Enhanced Permeability and Retention Effect in Dogs with Cancer Using Copper-64 Liposomes.

Since the first report of the enhanced permeability and retention (EPR) effect, the research in nanocarrier based antitumor drugs has been intense. The field has been devoted to treatment of cancer by exploiting EPR-based accumulation of nanocarriers in solid tumors, which for many years was considered to be a ubiquitous phenomenon. However, the understanding of differences in the EPR-effect between tumor types, heterogeneities within each patient group, and dependency on tumor development stage in humans is sparse. It is therefore important to enhance our understanding of the EPR-effect in large animals and humans with spontaneously developed cancer. In the present paper, we describe a novel loading method of copper-64 into PEGylated liposomes and use these liposomes to evaluate the EPR-effect in 11 canine cancer patients with spontaneous solid tumors by PET/CT imaging. We thereby provide the first high-resolution analysis of EPR-based tumor accumulation in large animals. We find that the EPR-effect is strong in some tumor types but cannot be considered a general feature of solid malignant tumors since we observed a high degree of accumulation heterogeneity between tumors. Six of seven included carcinomas displayed high uptake levels of liposomes, whereas one of four sarcomas displayed signs of liposome retention. We conclude that nanocarrier-radiotracers could be important in identifying cancer patients that will benefit from nanocarrier-based therapeutics in clinical practice.

Injectable Colloidal Gold for Use in Intrafractional 2D Image-Guided Radiation Therapy.

In the western world, approximately 50% of all cancer patients receive radiotherapy alone or in combination with surgery or chemotherapy. Image-guided radiotherapy (IGRT) has in recent years been introduced to enhance precision of the delivery of radiation dose to tumor tissue. Fiducial markers are often inserted inside the tumor to improve IGRT precision and to enable monitoring of the tumor position during radiation therapy. In the present article, a liquid fiducial tissue marker is presented, which can be injected into tumor tissue using thin and flexible needles. The liquid fiducial has high radio-opacity, which allows for marker-based image guidance in 2D and 3D X-ray imaging during radiation therapy. This is achieved by surface-engineering gold nanoparticles to be highly compatible with a carbohydrate-based gelation matrix. The new fiducial marker is investigated in mice where they are highly biocompatible and stable after implantation. To investigate the clinical potential, a study is conducted in a canine cancer patient with spontaneous developed solid tumor in which the marker is successfully injected and used to align and image-guide radiation treatment of the canine patient. It is concluded that the new fiducial marker has highly interesting properties that warrant investigations in cancer patients.

Improvement in toxicity in high risk prostate cancer patients treated with image-guided intensity-modulated radiotherapy compared to 3D conformal radiotherapy without daily image guidance.

BACKGROUND: Image-guided radiotherapy (IGRT) facilitates the delivery of a very precise radiation dose. In this study we compare the toxicity and biochemical progression-free survival between patients treated with daily image-guided intensity-modulated radiotherapy (IG-IMRT) and 3D conformal radiotherapy (3DCRT) without daily image guidance for high risk prostate cancer (PCa). METHODS: A total of 503 high risk PCa patients treated with radiotherapy (RT) and endocrine treatment between 2000 and 2010 were retrospectively reviewed. 115 patients were treated with 3DCRT, and 388 patients were treated with IG-IMRT. 3DCRT patients were treated to 76 Gy and without daily image guidance and with 1-2 cm PTV margins. IG-IMRT patients were treated to 78 Gy based on daily image guidance of fiducial markers, and the PTV margins were 5-7 mm. Furthermore, the dose-volume constraints to both the rectum and bladder were changed with the introduction of IG-IMRT. RESULTS: The 2-year actuarial likelihood of developing grade > = 2 GI toxicity following RT was 57.3% in 3DCRT patients and 5.8% in IG-IMRT patients (p < 0.001). For GU toxicity the numbers were 41.8% and 29.7%, respectively (p = 0.011). On multivariate analysis, 3DCRT was associated with a significantly increased risk of developing grade > = 2 GI toxicity compared to IG-IMRT (p < 0.001, HR = 11.59 [CI: 6.67-20.14]). 3DCRT was also associated with an increased risk of developing GU toxicity compared to IG-IMRT.The 3-year actuarial biochemical progression-free survival probability was 86.0% for 3DCRT and 90.3% for IG-IMRT (p = 0.386). On multivariate analysis there was no difference in biochemical progression-free survival between 3DCRT and IG-IMRT. CONCLUSION: The difference in toxicity can be attributed to the combination of the IMRT technique with reduced dose to organs-at-risk, daily image guidance and margin reduction.

Dose escalation to high-risk sub-volumes based on non-invasive imaging of hypoxia and glycolytic activity in canine solid tumors: a feasibility study.

INTRODUCTION: Glycolytic activity and hypoxia are associated with poor prognosis and radiation resistance. Including both the tumor uptake of 2-deoxy-2-[18 F]-fluorodeoxyglucose (FDG) and the proposed hypoxia tracer copper(II)diacetyl-bis(N4)-methylsemithio-carbazone (Cu-ATSM) in targeted therapy planning may therefore lead to improved tumor control. In this study we analyzed the overlap between sub-volumes of FDG and hypoxia assessed by the uptake of 64Cu-ATSM in canine solid tumors, and evaluated the possibilities for dose redistribution within the gross tumor volume (GTV). MATERIALS AND METHODS: Positron emission tomography/computed tomography (PET/CT) scans of five spontaneous canine solid tumors were included. FDG-PET/CT was obtained at day 1, 64Cu-ATSM at day 2 and 3 (3 and 24 h pi.). GTV was delineated and CT images were co-registered. Sub-volumes for 3 h and 24 h 64Cu-ATSM (Cu3 and Cu24) were defined by a threshold based method. FDG sub-volumes were delineated at 40% (FDG40) and 50% (FDG50) of SUVmax. The size of sub-volumes, intersection and biological target volume (BTV) were measured in a treatment planning software. By varying the average dose prescription to the tumor from 66 to 85 Gy, the possible dose boost (DB) was calculated for the three scenarios that the optimal target for the boost was one, the union or the intersection of the FDG and 64Cu-ATSM sub-volumes. RESULTS: The potential boost volumes represented a fairly large fraction of the total GTV: Cu3 49.8% (26.8-72.5%), Cu24 28.1% (2.4-54.3%), FDG40 45.2% (10.1-75.2%), and FDG50 32.5% (2.6-68.1%). A BTV including the union (∪) of Cu3 and FDG would involve boosting to a larger fraction of the GTV, in the case of Cu3∪FDG40 63.5% (51.8-83.8) and Cu3∪FDG50 48.1% (43.7-80.8). The union allowed only a very limited DB whereas the intersection allowed a substantial dose escalation. CONCLUSIONS: FDG and 64Cu-ATSM sub-volumes were only partly overlapping, suggesting that the tracers offer complementing information on tumor physiology. Targeting the combined PET positive volume (BTV) for dose escalation within the GTV results in a limited DB. This suggests a more refined dose redistribution based on a weighted combination of the PET tracers in order to obtain an improved tumor control.

Three-dimensional MRI-linac intra-fraction guidance using multiple orthogonal cine-MRI planes.

The introduction of integrated MRI-radiation therapy systems will offer live intra-fraction imaging. We propose a feasible low-latency multi-plane MRI-linac guidance strategy. In this work we demonstrate how interleaved acquired, orthogonal cine-MRI planes can be used for low-latency tracking of the 3D trajectory of a soft-tissue target structure. The proposed strategy relies on acquiring a pre-treatment 3D breath-hold scan, extracting a 3D target template and performing template matching between this 3D template and pairs of orthogonal 2D cine-MRI planes intersecting the target motion path. For a 60 s free-breathing series of orthogonal cine-MRI planes, we demonstrate that the method was capable of accurately tracking the respiration related 3D motion of the left kidney. Quantitative evaluation of the method using a dataset designed for this purpose revealed a translational error of 1.15 mm for a translation of 39.9 mm. We have demonstrated how interleaved acquired, orthogonal cine-MRI planes can be used for online tracking of soft-tissue target volumes.