Treatment Of Deep-seated Tumors Research Articles

Hyperthermia phased arrays pre-treatment evaluation

Purpose: In the hyperthermia treatment of deep-seated tumours by a phased array of radiofrequency (RF) antennas, heatability will be investigated in terms of power-to-tumour and other figures-of-merit of hyperthermia treatments to be optimised. The assumption is that each source is individually constrained to not exceed a maximal nominal power. The nominal power may differ from a source to another as a physical limit or an operative modality.Method: Under such constraint, new procedures for the maximisation of (i) power-to-tumour, (ii) heating efficiency and, in general, (iii) power ratios as tumour-heating selectivity are proposed. (iv) The problem whether a tumour is equally heatable after turning off some antennas is addressed as array thinning.Case study: An array of eight dipoles arranged on two lines around a head/neck is introduced to perform a numerical analysis. The achievable power-to-tumour according to the new optimizations and other performance indices adopted from the literature is tested against values of power that can be found to be sufficient for heating tumours to clinical temperatures. New solutions to data rendering in hyperthermia heating are proposed.

Conformal image‐guided microbeam radiation therapy at the ESRF biomedical beamline ID17

Upcoming veterinary trials in microbeam radiation therapy (MRT) demand for more advanced irradiation techniques than in preclinical research with small animals. The treatment of deep-seated tumors in cats and dogs with MRT requires sophisticated irradiation geometries from multiple ports, which impose further efforts to spare the normal tissue surrounding the target. This work presents the development and benchmarking of a precise patient alignment protocol for MRT at the biomedical beamline ID17 of the European Synchrotron Radiation Facility (ESRF). The positioning of the patient prior to irradiation is verified by taking x-ray projection images from different angles. Using four external fiducial markers of 1.7 mm diameter and computed tomography-based treatment planning, a target alignment error of less than 2 mm can be achieved with an angular deviation of less than 2(∘). Minor improvements on the protocol and the use of smaller markers indicate that even a precision better than 1 mm is technically feasible. Detailed investigations concerning the imaging dose lead to the conclusion that doses for skull radiographs lie in the same range as dose reference levels for human head radiographs. A currently used online dose monitor for MRT has been proven to give reliable results for the imaging beam. The ESRF biomedical beamline ID17 is technically ready to apply conformal image-guided MRT from multiple ports to large animals during future veterinary trials.

Scintillating Nanoparticles as Energy Mediators for Enhanced Photodynamic Therapy.

Achieving effective treatment of deep-seated tumors is a major challenge for traditional photodynamic therapy (PDT) due to difficulties in delivering light into the subsurface. Thanks to their great tissue penetration, X-rays hold the potential to become an ideal excitation source for activating photosensitizers (PS) that accumulate in deep tumor tissue. Recently, a wide variety of nanoparticles have been developed for this purpose. The nanoparticles are designed as carriers for loading various kinds of PSs and can facilitate the activation process by transferring energy harvested from X-ray irradiation to the loaded PS. In this review, we focus on recent developments of nanoscintillators with high energy transfer efficiency, their rational designs, as well as potential applications in next-generation PDT. Treatment of deep-seated tumors by using radioisotopes as an internal light source will also be discussed.

Electrochemotherapy -an effective method for the treatment of tumors with a combination of chemotherapeutic agent and electric field

Electrochemotherapy is a local treatment for skin tumors and also deep seated tumors and metastases. Electrochemotherapy is based on enhanced cytotoxic effectiveness of bleomycin or cisplatin by electroporation, which increases drug delivery into cells in tumors. Electrochemotherapy is an ablative technique of high effectiveness with over 80% objective responses of electrochemotherapy treated tumors. Its advantage is the simplicity of the procedure that can be utilized in treatment of different tumor histiotypes. Currently it is predominantly used in palliative intent when the other treatment options have been exhausted. For the translation of electrochemotherapy into the clinics also the technological development that is now focusing into the treatment of deep-seated tumors was important. In Slovenia we are at the forefront in the treatment of liver tumors and head and neck tumors, while the others are developing electrochemotherapy for treatment of bone and brain metastases as well as endoluminal tumors.

ELEKTROKEMOTERAPIJA – UČINKOVITA METODA ZDRAVLJENJA TUMORJEV S KOMBINACIJO KEMOTERAPEVTIKA IN ELEKTRIČNEGA POLJA

Electrochemotherapy is a local treatment for skin tumors and also deep seated tumors and metastases. Electrochemotherapy is based on enhanced cytotoxic effectiveness of bleomycin or cisplatin by electroporation, which increases drug delivery into cells in tumors. Electrochemotherapy is an ablative technique of high effectiveness with over 80% objective responses of electrochemotherapy treated tumors. Its advantage is the simplicity of the procedure that can be utilized in treatment of different tumor histiotypes. Currently it is predominantly used in palliative intent when the other treatment options have been exhausted. For the translation of electrochemotherapy into the clinics also the technological development that is now focusing into the treatment of deep-seated tumors was important. In Slovenia we are at the forefront in the treatment of liver tumors and head and neck tumors, while the others are developing electrochemotherapy for treatment of bone and brain metastases as well as endoluminal tumors.

Mesoporous-silica-coated upconversion nanoparticles loaded with vitamin B12 for near-infrared-light mediated photodynamic therapy

Near-infrared (NIR)-to-visible upconversion nanotechnology has potential to be used for photodynamic therapy (PDT) because the use of NIR-irradiation provides deep tissue penetration and avoids photodamge to nomal cells, thus overcoming a major hurdle in the treatment of deep-seated tumors. In this study, a novel nano-platform of mesoporous-silica-coated NaYF4:Yb/Er upconverting nanoparticles with a large surface area of 770m2/g and an average pore size of 2nm, was fabricated and used for NIR-mediated PDT. Vitamin B12 (VB12), a nontoxic, easy-to-obtain and biocompatible photosensitizer, was incorporated into the mesoporous silica and used as PDT drug. There is a good overlap (545nm) between the fluorescence emission of NaYF4:Yb/Er nanoparticles and the UV–visible absorption of VB12. Under NIR-irradiation, the visible fluorescent emission from the upconverting nanoparticles will be absorbed by the VB12 coated on their surfaces. Then, the VB12 molecules under excited-state interact with surrounding ground-state molecular oxygen, generating reactive oxygen species, leading to oxidative damage of cancer cells.

Dosimetric evaluation of new approaches in GRID therapy using nonconventional radiation sources.

Spatial fractionation of the dose has proven to be a promising approach to increase the tolerance of healthy tissue, which is the main limitation of radiotherapy. A good example of that is GRID therapy, which has been successfully used in the management of large tumors with low toxicity. The aim of this work is to explore new avenues using nonconventional sources: GRID therapy by using kilovoltage (synchrotron) x-rays, the use of very high-energy electrons, and proton GRID therapy. They share in common the use of the smallest possible grid sizes in order to exploit the dose-volume effects. Monte Carlo simulations (penelope/peneasy and geant4/GATE codes) were used as a method to study dose distributions resulting from irradiations in different configurations of the three proposed techniques. As figure of merit, percentage (peak and valley) depth dose curves, penumbras, and central peak-to-valley dose ratios (PVDR) were evaluated. As shown in previous biological experiments, high PVDR values are requested for healthy tissue sparing. A superior tumor control may benefit from a lower PVDR. High PVDR values were obtained in the healthy tissue for the three cases studied. When low energy photons are used, the treatment of deep-seated tumors can still be performed with submillimetric grid sizes. Superior PVDR values were reached with the other two approaches in the first centimeters along the beam path. The use of protons has the advantage of delivering a uniform dose distribution in the tumor, while healthy tissue benefits from the spatial fractionation of the dose. In the three evaluated techniques, there is a net reduction in penumbra with respect to radiosurgery. The high PVDR values in the healthy tissue and the use of small grid sizes in the three presented approaches might constitute a promising alternative to treat tumors with such spatially fractionated radiotherapy techniques. The dosimetric results presented here support the interest of performing radiobiology experiments in order to evaluate these new avenues.

Feasibility and Safety of Intraoperative Electrochemotherapy in Locally Advanced Pancreatic Tumor: A Preliminary Experience

Electrochemotherapy is an effective treatment for various cutaneous tumors and could be translated into treatment of deep-seated tumors. With this aim, a prospective clinical phase I/II study was conducted to evaluate the feasibility and safety of intraoperative Electrochemotherapy (ECT) in locally advanced pancreatic adenocarcinoma: the preliminary results are reported in this study. The secondary endpoint was to assess treatment response in terms of morphological and functional criteria based on Magnetic Resonance Imaging. Eleven consecutive patients were enrolled in a clinical phase I/II study approved by the Ethics Committee of the National Cancer Institute G. Pascale Foundation - IRCCS of Naples. Electrochemotherapy with bleomycin was performed during open surgery. All patients underwent MR and CT scan, before and after ECT treatment, using morphological and functional imaging. RECIST criteria were used to evaluate ECT response on CT and MR images. Functional parameters were also used to evaluate ECT response on MR images. No acute (intraoperative) and/or postoperative serious adverse events related to electrochemotherapy were observed; no clinically significant electrocardiographic, hemodynamic, or serum biologic changes were noted. No clinically relevant elevation of amylase or lipase levels was observed and no bleeding or damage to surrounding viscera occurred. Electrochemotherapy of locally advanced pancreatic adenocarcinoma proved to be a feasible and safe treatment modality. Dynamic and diffusion MR imaging is more suitable to assess ECT treatment response than CT imaging and morphological MR alone, after one month of treatment.

Exploring Boron Neutron Capture Therapy for non-small cell lung cancer

Boron Neutron Capture Therapy (BNCT) is a radiotherapy that combines biological targeting and high LET radiation. It consists in the enrichment of tumour with 10B and in the successive irradiation of the target with low energy neutrons producing charged particles that mainly cause non-repairable damages to the cells.The feasibility to treat Non Small Cells Lung Cancer (NSCLC) with BNCT was explored. This paper proposes a new approach to determine treatment plans, introducing the possibility to choose the irradiation start and duration to maximize the tumour dose. A Tumour Control Probability (TCP) suited for lung BNCT as well as other high dose radiotherapy schemes was also introduced.Treatment plans were evaluated in localized and disseminated lung tumours. Semi-ideal and real energy spectra beams were employed to assess the best energy range and the performance of non-tailored neutron sources for lung tumour treatments.The optimal neutron energy is within [500 eV−3 keV], lower than the 10 keV suggested for the treatment of deep-seated tumours in the brain. TCPs higher than 0.6 and up to 0.95 are obtained for all cases.Conclusions drawn from [Suzuki et al., Int Canc Conf J 1 (4) (2012) 235–238] supporting the feasibility of BNCT for shallow lung tumours are confirmed, however discussions favouring the treatment of deeper lesions and disseminated disease are also opened. Since BNCT gives the possibility to deliver a safe and potentially effective treatment for NSCLC, it can be considered a suitable alternative for patients with few or no treatment options.

Intraoperative electrochemotherapy of colorectal liver metastases

Electrochemotherapy is effective in treatment of various cutaneous tumors and could be translated into treatment of deep-seated tumors. With this aim a prospective pilot study was conducted to evaluate feasibility, safety, and efficacy of intraoperative electrochemotherapy in the treatment of colorectal liver metastases. Electrochemotherapy with bleomycin was performed during open surgery, by insertion of long needle electrodes into and around the tumor according to the individualized pretreatment plan. A 29 metastases in 16 patients were treated in 16 electrochemotherapy sessions. No immediate (intraoperative) and/or postoperative serious adverse events related to electrochemotherapy were observed. Radiological evaluation of all the treated metastases showed 85% complete responses and 15% partial responses. In a group of seven patients that underwent a second operation at 6-12 weeks after the first one, during which electrochemotherapy was performed, the histology of resected metastases treated by electrochemotherapy showed less viable tissue (P = 0.001) compared to non-treated ones. Electrochemotherapy of colorectal liver metastases proved to be feasible, safe, and efficient treatment modality, providing its specific place in difficult to treat metastases, located in the vicinity of major hepatic vessels, not amenable to surgery or radiofrequency ablation.

ENLIGHT and LEIR biomedical facility

Particle therapy (including protons and carbon ions) allows a highly conformal treatment of deep-seated tumours with good accuracy and minimal dose to surrounding tissues, compared to conventional radiotherapy using X-rays. Following impressive results from early phase trials, over the last decades particle therapy in Europe has made considerable progress in terms of new institutes dedicated to charged particle therapy in several countries. Particle therapy is a multidisciplinary subject that involves physicists, biologists, radio-oncologists, engineers and computer scientists. The European Network for Light Ion Hadron Therapy (ENLIGHT) was created in response to the growing needs of the European community to coordinate such efforts.A number of treatment centres are already operational and treating patients across Europe, including two dual ion (protons and carbon ions) centres in Heidelberg (the pioneer in Europe) and Pavia. However, much more research needs to be carried out and beamtime is limited. Hence there is a strong interest from the biomedical research community to have a facility with greater access to relevant beamtime. Such a facility would facilitate research in radiobiology and the development of more accurate techniques of dosimetry and imaging. The Low Energy Ion Ring (LEIR) accelerator at CERN presents such an opportunity, and relies partly on CERN's existing infrastructure.The ENLIGHT network, European Commission projects under the ENLIGHT umbrella and the future biomedical facility are discussed.

Comparison of simulations with PHITS and HIBRAC with experimental data in the context of particle therapy monitoring

Therapeutic irradiation with protons and ions is advantageous over radiotherapy with photons due to its favorable dose deposition. Additionally, ion beams provide a higher relative biological effectiveness than photons. For this reason, an improved treatment of deep-seated tumors is achieved and normal tissue is spared. However, small deviations from the treatment plan can have a large impact on the dose distribution. Therefore, a monitoring is required to assure the quality of the treatment. Particle therapy positron emission tomography (PT-PET) is the only clinically proven method which provides a non-invasive monitoring of dose delivery. It makes use of the β+-activity produced by nuclear fragmentation during irradiation. In order to evaluate these PT-PET measurements, simulations of the β+-activity are necessary. Therefore, it is essential to know the yields of the β+-emitting nuclides at every position of the beam path as exact as possible. We evaluated the three-dimensional Monte-Carlo simulation tool PHITS (version 2.30) [ 1] and the 1D deterministic simulation tool HIBRAC [ 2] with respect to the production of β+-emitting nuclides. The yields of the most important β+-emitting nuclides for carbon, lithium, helium and proton beams have been calculated. The results were then compared with experimental data obtained at GSI Helmholtzzentrum für Schwerionenforschung Darmstadt, Germany. GEANT4 simulations provide an additional benchmark [ 3]. For PHITS, the impact of different nuclear reaction models, total cross-section models and evaporation models on the β+-emitter production has been studied. In general, PHITS underestimates the yields of positron-emitters and cannot compete with GEANT4 so far. The β+-emitters calculated with an extended HIBRAC code were in good agreement with the experimental data for carbon and proton beams and comparable to the GEANT4 results, see [ 4] and Fig. 1. Considering the simulation results and its speed compared with three-dimensional Monte-Carlo tools, HIBRAC is a good candidate for the implementation in clinical routine PT-PET. Fig 1.Depth-dependent yields of the production of 11C and 15O during proton irradiation of a PMMA target with 140 MeV [ 4].

In Vivo Targeted Deep-Tissue Photodynamic Therapy Based on Near-Infrared Light Triggered Upconversion Nanoconstruct

Two major challenges of current photodynamic therapy (PDT) are the limited tissue penetration of excitation light and poor tumor-selectivity of the photosensitizer (PS). To address these issues, we developed a multifunctional nanoconstruct consisting of upconversion nanoparticles (UCNPs) that transform near-infrared (NIR) light to visible light and a photosensitizer zinc(II) phthalocyanine (ZnPc). Folate-modified amphiphilic chitosan (FASOC) was coated on the surface of UCNPs to anchor the ZnPc close to the UCNPs, thereby facilitating resonance energy transfer from UCNPs to ZnPc. Confocal microscopy and NIR small animal imaging demonstrated the enhanced tumor-selectivity of the nanoconstructs to cancer cells that overexpressed folate receptor. Reactive oxygen species (ROS) generation in cancer cells under a 1-cm tissue was higher upon excitation of UCNPs with the 980 nm light than that with 660 nm irradiation. In vivo PDT treatments for deep-seated tumors demonstrated that NIR light-triggered PDT based on the nanoconstructs possessed remarkable therapeutic efficacy with tumor inhibition ratio up to 50% compared with conventional visible light-activated PDT with a noticeable reduced tumor inhibition ratio of 18%. These results indicate that the multifunctional nanoconstruct is a promising PDT agent for deep-seated tumor treatment and demonstrate a new paradigm for enhancing PDT efficacy.

Cost-effective Radiation Therapy With Kilovoltage Photon Beams: A Monte Carlo Study

Due to their maximum dose deposition on the skin, kilovoltage (kV) photon beams have been considered unfeasible for treatment of deep-seated tumors. The purpose of this work was to design and optimize a cost-effective kV x-ray source for treatments of deep targets by means of Monte Carlo (MC) simulations with the objective of matching kV treatment plans to ones generated with commonly used megavoltage beams.

Ex Vivo and In Silico Feasibility Study of Monitoring Electric Field Distribution in Tissue during Electroporation Based Treatments

Magnetic resonance electrical impedance tomography (MREIT) was recently proposed for determining electric field distribution during electroporation in which cell membrane permeability is temporary increased by application of an external high electric field. The method was already successfully applied for reconstruction of electric field distribution in agar phantoms. Before the next step towards in vivo experiments is taken, monitoring of electric field distribution during electroporation of ex vivo tissue ex vivo and feasibility for its use in electroporation based treatments needed to be evaluated. Sequences of high voltage pulses were applied to chicken liver tissue in order to expose it to electric field which was measured by means of MREIT. MREIT was also evaluated for its use in electroporation based treatments by calculating electric field distribution for two regions, the tumor and the tumor-liver region, in a numerical model based on data obtained from clinical study on electrochemotherapy treatment of deep-seated tumors. Electric field distribution inside tissue was successfully measured ex vivo using MREIT and significant changes of tissue electrical conductivity were observed in the region of the highest electric field. A good agreement was obtained between the electric field distribution obtained by MREIT and the actual electric field distribution in evaluated regions of a numerical model, suggesting that implementation of MREIT could thus enable efficient detection of areas with insufficient electric field coverage during electroporation based treatments, thus assuring the effectiveness of the treatment.

Electrochemotherapy: Progress and Prospects

Treatment of recurrent or unresectable cutaneous and subcutaneaous tumors continues to be a major therapeutic challenge. Electrochemotherapy (ECT) is a palliative treatment of cutaneous and subcutaneous tumor nodules for which standard treatments (e.g. radiotherapy, chemotherapy, and surgery) have failed or proved to be insufficient. ECT combines the electropulsation of tumor cells (by local application of electric pulses) and the administration of antineoplastic drugs such as cisplatin or bleomycin (either intravenous or intratumoral). The permeability of the cancer cells to these poorly permeant anti-tumor drugs is transiently increased up to a hundred-fold. ECT is thus an efficient loco-regional therapy for palliative treatment of unresectable recurrent tumor nodules with overall objective response rates of approximatively 80-90% and has satisfactory cosmetic results. The next challenge for ECT is the treatment of deep-seated tumors and metastases. The joint therapy of ECT and electrotransfer of immune-stimulating genes or electro-photodynamic therapy could be a promising strategy for cancer eradication.

Carbon Ion Radiotherapy at the Gunma University Heavy Ion Medical Center: New Facility Set-up.

Carbon ion radiotherapy (C-ion RT) offers superior dose conformity in the treatment of deep-seated tumors compared with conventional X-ray therapy. In addition, carbon ion beams have a higher relative biological effectiveness compared with protons or X-ray beams. C-ion RT for the first patient at Gunma University Heavy Ion Medical Center (GHMC) was initiated in March of 2010. The major specifications of the facility were determined based on the experience of clinical treatments at the National Institute of Radiological Sciences (NIRS), with the size and cost being reduced to one-third of those at NIRS. The currently indicated sites of cancer treatment at GHMC are lung, prostate, head and neck, liver, rectum, bone and soft tissue. Between March 2010 and July 2011, a total of 177 patients were treated at GHMC although a total of 100 patients was the design specification during the period in considering the optimal machine performance. In the present article, we introduce the facility set-up of GHMC, including the facility design, treatment planning systems, and clinical preparations.

Electrochemotherapy: A New Technological Approach in Treatment of Metastases in the Liver

Electrochemotherapy is now in development for treatment of deep-seated tumors, like in bones and internal organs, such as liver. The technology is available with a newly developed electric pulse generator and long needle electrodes; however the procedures for the treatment are not standardized yet. In order to describe the treatment procedure, including treatment planning, within the ongoing clinical study, a case of successful treatment of a solitary metastasis in the liver of colorectal cancer is presented. The procedure was performed intraoperatively by inserting long needle electrodes, two in the center of the tumor and four around the tumor into the normal tissue. The insertion of electrodes proved to be feasible and was done according to the treatment plan, prepared by numerical modeling. After intravenous bolus injection of bleomycin the tumor was exposed to electric pulses. The delivery of the electric pulses did not interfere with functioning of the heart, since the pulses were synchronized with electrocardiogram in order to be delivered outside the vulnerable period of the ventricles. Also the post treatment period was uneventful without side effects. Re-operation of the treated metastasis demonstrated feasibility of the reoperation, without secondary effects of electrochemotherapy on normal tissue. Good antitumor effectiveness with complete tumor destruction was confirmed with histological analysis. The patient is disease-free 16 months after the procedure. In conclusion, treatment procedure for electrochemotherapy proved to be a feasible technological approach for treatment of liver metastasis. Due to the absence of the side effects and the first complete destruction of the treated tumor, treatment procedure for electrochemotherapy seems to be a safe method for treatment of liver metastases with good treatment effectiveness even in difficult-to-reach locations.

Radiation protection at Hadron therapy facilities

The Italian National Centre for Oncological Hadrontherapy is currently under construction in Pavia. It is designed for the treatment of deep-seated tumours (up to a depth of 27 cm of water equivalent) with proton and C-ion beams as well as for both clinical and radiobiological research. The particles will be accelerated by a 7-MeV u(-1) LINAC injector and a 400-MeV u(-1) synchrotron. In the first phase of the project, three treatment rooms will be in operation, equipped with four fixed beams, three horizontal and one vertical. The accelerators are currently undergoing commissioning. The main radiation protection problems encountered (shielding, activation, etc.) are hereby illustrated and discussed in relation to the constraints set by the Italian national authorities.

Homologous recombination research is heating up and ready for therapy

A report in PNAS suggests that mild hyperthermia can inhibit the process of homologous recombination (HR) and degrade the BRCA2 protein (1). Cellular hyperthermia, up to temperatures of 41 °C to 43 °C, has long been known to be a potent radiosensitizer of proliferating cells, providing the opportunity to enhance the tumoricidal effects of therapeutical radiation, because most nonmalignant cells in an irradiated field are nonproliferating or slowly proliferating (2). The precise mechanism of action has remained obscure, but hyperthermia appears to be toxic, particularly in the S phase of the cell cycle (3, 4). In the 1980s, radiation oncology departments around the world all constructed hyperthermia units, but they were never fully developed for the treatment of deep-seated tumors, because maintaining hyperthermia was a major technical challenge secondary to tumor blood flow being an effective cooling mechanism (5–7). If the technological issues could be overcome, this therapeutical approach would still have substantial merit. An alternative approach is to understand the mechanism of sensitization by heat in detail and then to develop “thermomimetic” drugs to produce the same selective toxicity (8).