Eirik Malinen

Strategies for biologic image-guided dose escalation: a review.

There is increasing interest in how to incorporate functional and molecular information obtained by noninvasive, three-dimensional tumor imaging into radiotherapy. The key issues are to identify radioresistant regions that can be targeted for dose escalation, and to develop radiation dose prescription and delivery strategies providing optimal treatment for the individual patient. In the present work, we review the proposed strategies for biologic image-guided dose escalation with intensity-modulated radiation therapy. Biologic imaging modalities and the derived images are discussed, as are methods for target volume delineation. Different dose escalation strategies and techniques for treatment delivery and treatment plan evaluation are also addressed. Furthermore, we consider the need for response monitoring during treatment. We conclude with a summary of the current status of biologic image-based dose escalation and of areas where further work is needed for this strategy to become incorporated into clinical practice.

Hypoxia-Induced Gene Expression in Chemoradioresistant Cervical Cancer Revealed by Dynamic Contrast-Enhanced MRI

Knowledge of the molecular background of functional magnetic resonance (MR) images is required to fully exploit their potential in cancer management. We explored the prognostic impact of dynamic contrast-enhanced MR imaging (DCE-MRI) parameters in cervical cancer combined with global gene expression data to reveal their underlying molecular phenotype and construct a representative gene signature for the relevant parameter. On the basis of 78 patients with cervical cancer subjected to curative chemoradiotherapy, we identified the prognostic DCE-MRI parameter A(Brix) by pharmacokinetic analysis of pretreatment images based on the Brix model, in which tumors with low A(Brix) appeared to be most aggressive. Gene set analysis of 46 tumors with pairwise DCE-MRI and gene expression data showed a significant correlation between A(Brix) and the hypoxia gene sets, whereas gene sets related to other tumor phenotypes were not significant. Hypoxia gene sets specific for cervical cancer created in cell culture experiments, including both targets of the hypoxia inducible factor (HIF1α) and the unfolded protein response, were the most significant. In the remaining 32 tumors, low A(Brix) was associated with upregulation of HIF1α protein expression, as assessed by immunohistochemistry, consistent with increased hypoxia. On the basis of the hypoxia gene sets, a signature of 31 genes that were upregulated in tumors with low A(Brix) was constructed. This DCE-MRI hypoxia gene signature showed prognostic impact in an independent validation cohort of 109 patients. Our findings reveal the molecular basis of an aggressive hypoxic phenotype and suggest the use of DCE-MRI to noninvasively identify patients with hypoxia-related chemoradioresistance.

Optimization of tumour control probability in hypoxic tumours by radiation dose redistribution: a modelling study.

Tumour hypoxia is a known cause of clinical resistance to radiation therapy. The purpose of this work was to model the effects on tumour control probability (TCP) of selectively boosting the dose to hypoxic regions in a tumour, while keeping the mean tumour dose constant. A tumour model with a continuous oxygen distribution, incorporating pO(2) histograms published for head and neck patients, was developed. Temporal and spatial variations in the oxygen distribution, non-uniform cell density and cell proliferation during treatment were included in the tumour modelling. Non-uniform dose prescriptions were made based on a segmentation of the tumours into four compartments. The main findings were: (1) Dose redistribution considerably improved TCP for all tumours. (2) The effect on TCP depended on the degree of reoxygenation during treatment, with a maximum relative increase in TCP for tumours with poor or no reoxygenation. (3) Acute hypoxia reduced TCP moderately, while underdosing chronic hypoxic cells gave large reductions in TCP. (4) Restricted dose redistribution still gave a substantial increase in TCP as compared to uniform dose boosts. In conclusion, redistributing dose according to tumour oxygenation status might increase TCP when the tumour response to radiotherapy is limited by chronic hypoxia. This could potentially improve treatment outcome in a subpopulation of patients who respond poorly to conventional radiotherapy.

Adapting radiotherapy to hypoxic tumours

In the current work, the concepts of biologically adapted radiotherapy of hypoxic tumours in a framework encompassing functional tumour imaging, tumour control predictions, inverse treatment planning and intensity modulated radiotherapy (IMRT) were presented. Dynamic contrast enhanced magnetic resonance imaging (DCEMRI) of a spontaneous sarcoma in the nasal region of a dog was employed. The tracer concentration in the tumour was assumed related to the oxygen tension and compared to Eppendorf histograph measurements. Based on the pO(2)-related images derived from the MR analysis, the tumour was divided into four compartments by a segmentation procedure. DICOM structure sets for IMRT planning could be derived thereof. In order to display the possible advantages of non-uniform tumour doses, dose redistribution among the four tumour compartments was introduced. The dose redistribution was constrained by keeping the average dose to the tumour equal to a conventional target dose. The compartmental doses yielding optimum tumour control probability (TCP) were used as input in an inverse planning system, where the planning basis was the pO(2)-related tumour images from the MR analysis. Uniform (conventional) and non-uniform IMRT plans were scored both physically and biologically. The consequences of random and systematic errors in the compartmental images were evaluated. The normalized frequency distributions of the tracer concentration and the pO(2) Eppendorf measurements were not significantly different. 28% of the tumour had, according to the MR analysis, pO(2) values of less than 5 mm Hg. The optimum TCP following a non-uniform dose prescription was about four times higher than that following a uniform dose prescription. The non-uniform IMRT dose distribution resulting from the inverse planning gave a three times higher TCP than that of the uniform distribution. The TCP and the dose-based plan quality depended on IMRT parameters defined in the inverse planning procedure (fields and step-and-shoot intensity levels). Simulated random and systematic errors in the pO(2)-related images reduced the TCP for the non-uniform dose prescription. In conclusion, improved tumour control of hypoxic tumours by dose redistribution may be expected following hypoxia imaging, tumour control predictions, inverse treatment planning and IMRT.

EPR dosimetric properties of formates.

As a part of a program to develop an electron paramagnetic resonance (EPR) dosimeter suited for clinical use (doses in the cGy range), polycrystalline samples of lithium formate monohydrate (HCO2Li.H2O), magnesium formate dihydrate (C2H2O4Mg.2H2O), and calcium formate (C2H2O4Ca) have been examined. L-Alanine was included for comparison and reference. Samples were irradiated with 60Co gamma-rays and 60-220 kV X-rays. The dosimeter response was assessed using the peak-to-peak amplitude of the first-derivative EPR spectrum. Dose-response curves for the 60Co gamma-irradiated samples were constructed, and the dependences of the response on the photon energy, microwave power, and modulation amplitude were studied. Stability of the irradiation products upon storage (signal fading) was also investigated. Lithium formate monohydrate is by far the best candidate of the tested formates, suitable for measuring doses down to approximately 0.1 Gy. Lithium formate monohydrate is more sensitive than alanine by a factor of 5.6-6.8 in the tested photon energy range, it exhibits no zero-dose signal and shows a linear dose response in the dose range from 0.2 to 1000 Gy. Its EPR signal was found unchanged in shape and intensity 1 week after irradiation to 10 Gy. Various less favorable properties rendered the other formates generally unsuitable, although calcium formate exhibits some interesting EPR dosimetric properties.

Dosimetric impact of interobserver variability in MRI-based delineation for cervical cancer brachytherapy

PURPOSE AND BACKGROUND To study the dosimetric impact of interobserver delineation variability (IODV) in MRI-based cervical cancer brachytherapy. MATERIALS AND METHODS MR images of six patients were distributed to 10 experienced observers worldwide. They were asked to delineate the target volumes and the organs at risk (OARs) for each patient. Two types of reference contours were created (Expert Consensus - EC and Simultaneous Truth and Performance Level Estimation - STAPLE). Optimised plans based on both EC- and STAPLE-contours were prepared. These plans were transferred to each of the observer contour sets and the resulting DVH parameters (D(90) and D(2cc)) were calculated. For each patient the standard deviation (SD) for the 10 observers was calculated. RESULTS A mean relative SD of 8-10% was found for GTV and High Risk CTV (HR-CTV) D(90) analysing one single fraction. For rectum and bladder the mean relative SD for D(2cc) was 5-8% while sigmoid was at 11%. For the whole treatment the IODV in HR-CTV caused an uncertainty of ±5 Gy(α/β=10) (1SD). The corresponding figure for OARs was ±2-3 Gy(α/β=3). The results were not sensitive as to which structure set was used for the optimisation. CONCLUSIONS For the target volumes the dosimetric impact of IODV was smallest for the GTV and HR-CTV, while IODV had an even smaller impact on the bladder and rectum.

Alanine Radicals, Part 3: Properties of the Components Contributing to the EPR Spectrum of X-Irradiated Alanine Dosimeters

Abstract Malinen, E., Heydari, M. Z., Sagstuen, E. and Hole, E. O. Alanine Radicals, Part 3: Properties of the Components Contributing to the EPR Spectrum of X-Irradiated Alanine Dosimeters. Radiat. Res. 159, 23–32 (2003). The amino acid l-α-alanine has attracted considerable interest for use in radiation dosimetry and has been formally accepted as a secondary standard for high-dose and transfer dosimetry. Recent results have shown that the alanine EPR spectrum consists of contributions from three different radicals. A set of benchmark spectra describing the essential spectral features of these three radical components was used for reconstructions of the experimental spectra. In the present work, these basis spectra have been used to investigate the differential effects of variations in radiation doses and microwave power, as well as the dependence upon temperature annealing and UV illumination. The results presented here, based solely on relatively low-energy (60–80 keV) X rays, indicate that the three components behave very similarly with respect to radiation dose at room temperature. However, with respect to the thermal annealing/fading behavior and microwave power saturation properties, the three species behave significantly differently. It is concluded that even if it is now realized that three different radicals contribute to the composite EPR alanine spectrum, this has a minor impact on the established protocols for present-day applications (high-dose) of EPR/alanine dosimetry. However, some care should be exercised when e.g. constructing calibration curves, since fading and power saturation behavior may vary over the dose range in question. New results from UV-illumination experiments suggest a possible procedure for experimental spectral separation of the EPR signals due to the three radicals.

Pharmacokinetic parameters derived from dynamic contrast enhanced MRI of cervical cancers predict chemoradiotherapy outcome

PURPOSE To assess the prognostic value of pharmacokinetic parameters derived from pre-chemoradiotherapy dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) of cervical cancer patients. MATERIALS AND METHODS Seventy-eight patients with locally advanced cervical cancer underwent DCE-MRI with Gd-DTPA before chemoradiotherapy. The pharmacokinetic Brix and Tofts models were fitted to contrast enhancement curves in all tumor voxels, providing histograms of several pharmacokinetic parameters (Brix: A(Brix), k(ep), k(el), Tofts: K(trans), ν(e)). A percentile screening approach including log-rank survival tests was undertaken to identify the clinically most relevant part of the intratumoral parameter distribution. Clinical endpoints were progression-free survival (PFS) and locoregional control (LRC). Multivariate analysis including FIGO stage and tumor volume was used to assess the prognostic significance of the imaging parameters. RESULTS A(Brix), k(el), and K(trans) were significantly (P<0.05) positively associated with both clinical LRC and PFS, while ν(e) was significantly positively correlated with PFS only. k(ep) showed no association with any endpoint. A(Brix) was positively correlated with K(trans) and ν(e), and showed the strongest association with endpoint in the log-rank testing. k(el) and K(trans) were independent prognostic factors in multivariate analysis with LRC as endpoint. CONCLUSIONS Parameters estimated by pharmacokinetic analysis of DCE-MR images obtained prior to chemoradiotherapy may be used for identifying patients at risk of treatment failure.

Electron paramagnetic resonance (EPR) dosimetry using lithium formate in radiotherapy: comparison with thermoluminescence (TL) dosimetry using lithium fluoride rods

Solid-state radiation dosimetry by electron paramagnetic resonance (EPR) spectroscopy and thermoluminescence (TL) was utilized for the determination of absorbed doses in the range of 0.5-2.5 Gy. The dosimeter materials used were lithium formate and lithium fluoride (TLD-100 rods) for EPR dosimetry and TL dosimetry, respectively. 60Co gamma-rays and 4, 6, 10 and 15 MV x-rays were employed. The main objectives were to compare the variation in dosimeter reading of the respective dosimetry systems and to determine the photon energy dependence of the two dosimeter materials. The EPR dosimeter sensitivity was constant over the dose range in question, while the TL sensitivity increased by more than 5% from 0.5 to 2.5 Gy, thus displaying a supralinear dose response. The average relative standard deviation in the dosimeter reading per dose was 3.0% and 1.2% for the EPR and TL procedures, respectively. For EPR dosimeters, the relative standard deviation declined significantly from 4.3% to 1.1% over the dose range in question. The dose-to-water energy response for the megavoltage x-ray beams relative to 60Co gamma-rays was in the range of 0.990-0.979 and 0.984-0.962 for lithium formate and lithium fluoride, respectively. The results show that EPR dosimetry with lithium formate provides dose estimates with a precision comparable to that of TL dosimetry (using lithium fluoride) for doses above 2 Gy, and that lithium formate is slightly less dependent on megavoltage photon beam energy than lithium fluoride.

Arm and shoulder morbidity following surgery and radiotherapy for breast cancer

Abstract Purpose. To explore the relationship between radiotherapy (RT) dose levels in the arm/shoulder region and arm/shoulder morbidity in breast cancer patients. Material and methods. This study included 183 breast cancer patients who had received locoregional RT with or without chemotherapy and/or hormone treatment during the period 1998–2002. Individual RT dose level, reflected by dose-volume histograms (DVHs), for the shoulder joint and joining structures were obtained from archived CT-based RT plans. Individual median, mean and maximum arm/shoulder RT dose levels were extracted. Arm/shoulder morbidity was assessed 29–58 months after breast cancer treatment using the following clinical endpoints: arm pain, arm stiffness, swollen arm, use of arm, numbness, shoulder flexion and shoulder abduction difference, fibrosis and breast cancer-related lymphedema. The relationship between arm/shoulder RT dose level and these clinical endpoints was assessed by Spearmans correlation and multivariate logistic regression. Results. Ninety-one percent of the included patients had some degree of arm/shoulder morbidity. Neither mean nor maximum RT dose level was associated with clinical endpoints. However, significant correlations (p < 0.05) were found between DVHs and arm stiffness, arm pain, use of arm and shoulder abduction difference, when arm/shoulder RT dose levels were approximately 15 Gy. Conclusions. Three-dimensional conformal locoregional RT for breast cancer results in long-term arm/shoulder morbidity. To minimize this risk, large shoulder volumes receiving RT doses of approximately 15 Gy should be reduced.