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Anders Brahme - One of the best experts on this subject based on the ideXlab platform.
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recent advances in light ion radiation therapy
International Journal of Radiation Oncology Biology Physics, 2004Co-Authors: Anders BrahmeAbstract:Abstract Background The fast development of energy- and intensity-modulated radiation therapy during the last two decades using photon and electron beams has when implemented resulted in a considerable improvement of radiation therapy, particularly if combined with radiobiologically based treatment optimization techniques. This has made intensity-modulated electron and photon beams as powerful as today's uniform dose proton therapy. To be able to cure also the most advanced hypoxic and radiation-resistant tumors of complex local spread, intensity-modulated light ion beams are really the ultimate tool and in clinical practice 2 to 3 times less expensive per patient treated than proton therapy. This development and the recent development of advanced tumor diagnostics based on PET-CT imaging of the tumor cell density open the field for new powerful radiobiologically based treatment optimization methods. The ultimate step is to use the unique radiobiologic and dose distributional advantages of light ion beams for truly optimized bioeffect planning where the integral three-dimensional dose delivery and tumor cell survival can be monitored by PET-CT imaging and corrected by biologically based adaptive therapy optimization methods. Purpose The main purpose of the present paper is to discuss the principal areas of development of therapy optimization, by considering the therapy chain from tumor diagnostics and the use of three-dimensional Predictive Assay to biologically based treatment optimization with special focus on the rapid clinical development of advanced light ion therapy. Methods Besides the "classical" approaches using low ionization density hydrogen ions (protons, but also possibly deuterons and tritium nuclei) and high ionization density carbon ions, two new approaches will be discussed. In the first one, lithium or beryllium or boron ions, which induce the least detrimental biologic effect to normal tissues for a given biologic effect in a small volume of the tumor, will be key particles. In the second approach, referred patients will be given a high-dose, high-precision "boost" treatment with carbon or oxygen ions during 1 week preceding the final treatment with conventional radiation in the referring hospital. The rationale behind these approaches is to minimize the high ionization density dose to the normal-tissue stroma outside but sometimes also inside the tumor bed and to ensure a more uniform and optimal biologic effectiveness in the tumor, also on the microscopic scale. The present discussion indicates that BIologically Optimized Predictive Assay based light ion Radiation Therapy (Bio-Art) is really the ultimate way to perform high-precision radiation therapy using checkpoints of the integral dose delivery and the tumor response and, based on this information, perform compensating corrections of the dose delivery. By using biologically optimized scanned high-energy photon or ion beams, it is possible to measure in vivo the three-dimensional dose delivery using the same PET-CT camera that was used for diagnosing the tumor spread. This method thus opens up the door for truly three-dimensional biologically optimized adaptive radiation therapy, where the measured dose delivery to the true target tissues can be used to fine-adjust the incoming beams, so that possible errors in the integral therapy process are eliminated toward the end of the treatment. Interestingly enough, practically all major error sources—such as organ motion, treatment planning errors, patient setup errors, and dose delivery problems due to gantry, multileaf, or scanning beam errors—can be corrected for in this way. Results and conclusions Radiobiologically optimized dose delivery using intensity and radiation quality modulation based on high-resolution PET-CT or Magnetic Resonance Spectroscopic Imaging (MRSI)-based tumor and normal-tissue imaging is probably the ultimate development of radiation therapy, taking the unique physical and biologic advantages of light ions fully into account in truly patient-individualized curative treatment schedules. Using recently available biologically based treatment optimization algorithms, it is possible to improve the treatment outcome for advanced tumors by as much as 10–40%. The adaptive radiotherapy process based both on three-dimensional tumor cell survival and dose delivery monitoring has the potential of percent accuracy in tumor response and dose delivery monitoring, using two-dimensional, narrow high-energy photon beam scanning and three-dimensional 11 C Bragg peak scanning for radiation quality and intensity-modulated dose delivery. There is no doubt that the future of radiation therapy is very promising, and gradually more and more patients may not even need advanced surgery. Instead, they could be cured by biologically optimized electron, photon, or light ion therapy, where the densely ionizing Bragg peak is placed solely in the gross tumor, and a lower ionization density is used in microscopically invasive tumor volumes.
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biologically optimized 3 dimensional in vivo Predictive Assay based radiation therapy using positron emission tomography computerized tomography imaging
Acta Oncologica, 2003Co-Authors: Anders BrahmeAbstract:PET-CT is probably the ultimate tool for accurate tumor imaging and 3-dimensional in vivo Predictive Assay of radiation sensitivity. By imaging the tumor twice during the early course of therapy, it should be possible to quantify both the tumor responsiveness to therapy and the rate of loss of functional tumor cells using the presently derived equations. This new information is ideal for use together with biologically based therapy optimization and makes it possible accurately to quantitate the dose-response relation, at least for the bulk of the tumor cells. Since the tumor responsiveness is available after about one and a half weeks of therapy, the information is also ideal for use with adaptive therapy where all forms of deviations from the original treatment plan can be accurately corrected for since they generally influence the still functional, but mainly doomed tumor cell compartment. Thus, uncertainties such as: 1) the geometric misalignment of the therapeutic beam with the tumor, 2) deviations of the delivered dose distribution from the planned delivery whether due to 3) an erroneous treatment planning algorithm or 4) treatment equipment uncertainties and 5) deviations in the anticipated responsiveness of the tumor of the patient based on historical response data, can all be taken into account. Fortunately, when a larger tumor cell compartment than expected is seen an increased dose during the remainder of the treatment should always be delivered independently on whichever combination of the above deviations was the true reason. With high-energy photon and hadron therapy it is even possible to image the integral dose delivery in vivo during or after a treatment using PET-CT imaging. The high-energy photons above about 20 MeV produce positron emitters through photonuclear reactions in tissue which are proportional to the photon fluence and thus approximately also to the absorbed dose. Light ion beams, the ultimate radiation modality with regard to physical and biological selectivity, instead produce PET emitters through direct nuclear interactions in tissue, but can also be used as radioactive beams consisting of intrinsic PET emitters such as 8B, 11C, 13N and 15O. These radioactive beams allow more accurate imaging of the Bragg peak distribution and thus indirectly the absorbed dose. The most universal feedback for adaptive radiation therapy would then be to use the measured image of mean dose delivery during the early part of the treatment while revising the treatment plan based on the initially planned dose distribution and the radiation responsiveness of the tumor as seen after the first week or two of therapy. By this so-called BIO-ART approach (Biologically Optimized 3D in vivo Predictive Assay-based Radiation Therapy) radiation therapy optimization may become an almost exact science, where the patient's true individual radiation response, considering hypoxia and general radiation resistance as well as possible dose delivery and planning errors, is taken into account.
Jens Overgaard - One of the best experts on this subject based on the ideXlab platform.
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Radiation-induced gene expression in human subcutaneous fibroblasts is Predictive of radiation-induced fibrosis
Radiotherapy and Oncology, 2008Co-Authors: Olaug K. Rødningen, Jan Alsner, Anne Lise Børresen-dale, Trevor Hastie, Jens OvergaardAbstract:Abstract Background and purpose Breast cancer patients show a large variation in normal tissue reactions after ionizing radiation (IR) therapy. One of the most common long-term adverse effects of ionizing radiotherapy is radiation-induced fibrosis (RIF), and several attempts have been made over the last years to develop Predictive Assays for RIF. Our aim was to identify basal and radiation-induced transcriptional profiles in fibroblasts from breast cancer patients that might be related to the individual risk of RIF in these patients. Materials and methods Fibroblast cell lines from 31 individuals with variable risk of RIF (grouped into five classes from low to high risk) were irradiated with two different schemes: 1 × 3.5 Gy with RNA isolated 2 and 24 h after irradiation, and a fractionated scheme with 3 × 3.5 Gy in intervals of 24 h with RNA isolated 2 h after the last dose. RNA was also isolated from non-treated fibroblasts. Transcriptional differences in basal and radiation-induced gene expression profiles were investigated using 15K cDNA microarrays, and results analyzed by both SAM and PAM. Results Sixty differentially expressed genes were identified by applying SAM on 10 patients with the highest risk of RIF and the four patients with the lowest risk of RIF after the fractionated scheme. The genes were associated with known functions in processes like apoptosis, extracellular matrix remodelling/cell adhesion, proliferation and ROS scavenging. A minimum set of 18 genes were identified that could differentiate high risk from low risk-patients after the fractionated scheme. Conclusions The classifier of 18 genes may provide basis for a Predictive Assay for normal tissue reactions after radiotherapy, and provide new insight into the molecular mechanisms of RIF.
Christian Nicolaj Andreassen - One of the best experts on this subject based on the ideXlab platform.
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searching for genetic determinants of normal tissue radiosensitivity are we on the right track
Radiotherapy and Oncology, 2010Co-Authors: Christian Nicolaj AndreassenAbstract:The ability to predict individual normal tissue complication risk prior to radiotherapy has been referred to as ‘the Holy Grail of radiobiology’ [1]. This saying implies that a reliable and clinically useful Predictive Assay for normal tissue radiosensitivity has been something long sought but never found. In the 1990s, efforts were made to develop Predictive Assays based on in vitro irradiation of various cell types. Though some studies have reported significant associations between normal tissue outcome after radiotherapy and certain cellular and sub-cellular damage endpoints, a Predictive Assay applicable for clinical use has never been established [2,3]. Around the turn of the millennium, increasing interest was taken in the hypothesis that the risk of adverse radiotherapy effects is influenced by genetic factors and that individual normal tissue radiosensitivity could be predicted by means of genetic analysis [4]. Initially, a number of relatively small studies addressed truncating mutations in genes such as ATM, BRCA1 and BRCA2 but did not provide any strong indications that heterozygous carriers of these sequence alterations constitute a radiosensitive sub-population. Later on, there was a growing consensus that normal tissue complication risk should be regarded as a so-called polygenic or complex trait dependent on the combined influence of several different sequence alterations. Furthermore, it was hypothesized that single nucleotide polymorphisms (SNPs), the most abundant type of sequence variation in the human genome, could make up a proportion of the genetic background [5]. Under these assumptions, 66 studies have been carried out in order to investigate possible associations between genetic variants and various types of adverse reactions after radiotherapy. Fifty-eight studies published until May 2009 have recently been reviewed [6]. Since then, another 8 studies have been published [7–14]. Forty-seven of these studies had a particular focus on SNPs (see Appendix). In the current issue of Radiotherapy and Oncology, Barnett and co-workers present a study of almost 800 breast cancer patients given adjuvant radiotherapy after lumpectomy [7]. This study investigates the impact of two TGFB1 SNPs (position 509 C/T and codon 10 Leu/Pro) upon risk of late toxicity in the breast. TGFb-1 is a versatile cytokine that has been convincingly linked to the development of radiation-induced fibrosis [15]. A few relatively small studies have previously indicated that SNPs in TGFB1 may affect
Peter Vaupel - One of the best experts on this subject based on the ideXlab platform.
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intratumoral po2 histography as Predictive Assay in advanced cancer of the uterine cervix
Advances in Experimental Medicine and Biology, 1994Co-Authors: Michael Hockel, Claudia Knoop, Karlheinz Schlenger, Birgit Vorndran, P G Knapstein, Peter VaupelAbstract:Experimental evidence suggests that the hypoxic fraction in a solid tumor may increase its malignant potential and reduce its sensitivity towards nonsurgical treatment modalities such as standard irradiation and certain anticancer agents1–5. However, the clinical importance of tumor hypoxia remains uncertain since valid methods for the routine measurement of intratumoral O2-tensions in patients have so far been lacking.
Richard Potter - One of the best experts on this subject based on the ideXlab platform.
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intratumoral po2 measurements as Predictive Assay in the treatment of carcinoma of the uterine cervix
Radiotherapy and Oncology, 1999Co-Authors: T H Knocke, Hajodirk Weitmann, H J Feldmann, Edgar Selzer, Richard PotterAbstract:Abstract Background : Several studies have shown that pretreatment oxygenation status of cervical tumors measured with a polarographic oxygen electrode could be a Predictive factor for radiation response and survival. The purpose of this study was to evaluate the impact of intratumoral pO 2 levels and hypoxic fractions on local control and disease free survival employing a standardized measuring procedure under routine conditions. Materials and methods : Between April 1994 and December 1997 pO 2 measurements were performed prior to radiotherapy with an Eppendorf histograph in 51 evaluable patients with primary cervical carcinoma. All patients were treated with curative intent by combined external beam therapy (median total dose 49.6 Gy) and 3–6 applications of high dose rate- (7 Gy/fr. at point ‘A') or pulse dose rate brachytherapy (20–25 h pulses, 1 Gy/pulse at point ‘A'). Oxygenation data are given as median pO 2 of pooled readings and percentage of readings below 5 mm Hg (HF 5). Results : Median pO 2 values ranged from 0 to 60 mm Hg (median 10). HF5 ranged from 0 to 95% (median 22%). Median follow-up was 26 months (range 9–54 months). Actuarial overall and disease-free survival rates (OS/DFS) at 3 years were 53%/50%. Comparing patients with median pO 2 ≤10 mm Hg ( n =26) to patients with higher median pO 2 levels ( n =25) calculated DFS was 34 and 69%, respectively ( P P =0.053). Comparing patients with HF5 below and above the median calculated DFS was 36 and 66%, respectively ( P 2 20% had the worst prognosis (3-year DFS: 28%). Besides oxygenation status, stage and initial hemoglobin concentration were statistically significant for treatment outcome. Conclusions : This study confirms earlier data that the presence of hypoxia is associated with poor local control and survival in patients with carcinoma of the uterine cervix. Polarographic pO 2 measurements are feasible under routine conditions and can be regarded as a reproducible Predictive Assay.