A role for dynamic contrast-enhanced magnetic resonance imaging in predicting tumour radiation response.

BACKGROUND: Dynamic contrast-enhanced (DCE) MRI may provide prognostic insights into tumour radiation response. This study examined quantitative DCE MRI parameters in rat tumours, as potential biomarkers of tumour growth delay following single high-dose irradiation. METHODS: Dunning R3327-AT1 prostate tumours were evaluated by DCE MRI following intravenous injection of Gd-DTPA. The next day tumours were irradiated (single dose of 30 Gy), while animals breathed air (n=4) or oxygen (n=4); two animals were non-irradiated controls. Growth was followed and tumour volume-quadrupling time (T4) was compared with pre-irradiation DCE assessments. RESULTS: Irradiation caused significant tumour growth delay (T4 ranged from 28 to 48 days for air-breathing rats, and 40 to 75 days for oxygen-breathing rats) compared with the controls (T4=7 to 9 days). A strong correlation was observed between T4 and extravascular-extracellular volume fraction (ve) irrespective of the gas inhaled during irradiation. There was also a correlation between T4 and volume transfer constant (K(trans)) for the air-breathing group alone. CONCLUSIONS: The data provide rationale for expanded studies of other tumour sites, types and progressively patients, and are potentially significant, as many patients undergo contrast-enhanced MRI as part of treatment planning.

Dynamic oxygen challenge evaluated by NMR T1 and T2*--insights into tumor oxygenation.

There is intense interest in developing non-invasive prognostic biomarkers of tumor response to therapy, particularly with regard to hypoxia. It has been suggested that oxygen sensitive MRI, notably blood oxygen level-dependent (BOLD) and tissue oxygen level-dependent (TOLD) contrast, may provide relevant measurements. This study examined the feasibility of interleaved T2*- and T1-weighted oxygen sensitive MRI, as well as R2* and R1 maps, of rat tumors to assess the relative sensitivity to changes in oxygenation. Investigations used cohorts of Dunning prostate R3327-AT1 and R3327-HI tumors, which are reported to exhibit distinct size-dependent levels of hypoxia and response to hyperoxic gas breathing. Proton MRI R1 and R2* maps were obtained for tumors of anesthetized rats (isoflurane/air) at 4.7 T. Then, interleaved gradient echo T2*- and T1-weighted images were acquired during air breathing and a 10 min challenge with carbogen (95% O2 -5% CO2). Signals were stable during air breathing, and each type of tumor showed a distinct signal response to carbogen. T2* (BOLD) response preceded T1 (TOLD) responses, as expected. Smaller HI tumors (reported to be well oxygenated) showed the largest BOLD and TOLD responses. Larger AT1 tumors (reported to be hypoxic and resist modulation by gas breathing) showed the smallest response. There was a strong correlation between BOLD and TOLD signal responses, but ΔR2* and ΔR1 were only correlated for the HI tumors. The magnitude of BOLD and TOLD signal responses to carbogen breathing reflected expected hypoxic fractions and oxygen dynamics, suggesting potential value of this test as a prognostic biomarker of tumor hypoxia.

A noninvasive tumor oxygenation imaging strategy using magnetic resonance imaging of endogenous blood and tissue water.

PURPOSE: To present a novel imaging strategy for noninvasive measurement of tumor oxygenation using MR imaging of endogenous blood and tissue water. THEORY AND METHODS: The proposed approach for oxygen partial pressure (pO2) estimation is based on intravoxel incoherent motion diffusion MRI and the dependence of the blood R2 relaxation rate on the inter-echo spacing measured using a multiple spin-echo Carr-Purcell-Meiboom-Gill sequence and weak-field diffusion model. The accuracy of the approach was validated by comparison with (19)F MRI oximetry. RESULTS: The results in eight rats at 4.7 T showed that tumors have longer T1 (1980 ± 186 ms) and T2 (59 ± 9 ms) relaxation times, heterogeneous blood volume fraction (0.23 ± 0.1), oxygen saturation level (Y) (0.53 ± 0.12), and pO2 (36 ± 15 mmHg) distributions compared with normal muscle (T1 1480 ± 86 ms, T2 29 ± 2 ms, blood volume fraction 0.22 ± 0.03, Y 0.49 ± 0.06, and pO2 39 ± 5 mmHg). pO2 estimates based on the novel (1)H approach were essentially identical with (19)F observations. CONCLUSION: The study indicates that noninvasive measurement of tumor pO2 using (1)H MRI derived multiparametric maps is feasible and could become a valuable tool to evaluate tumor hypoxia.

Correlations of noninvasive BOLD and TOLD MRI with pO2 and relevance to tumor radiation response.

PURPOSE: To examine the potential use of blood oxygenation level dependent (BOLD) and tissue oxygenation level dependent (TOLD) contrast MRI to assess tumor oxygenation and predict radiation response. METHODS: BOLD and TOLD MRI were performed on Dunning R3327-AT1 rat prostate tumors during hyperoxic gas breathing challenge at 4.7 T. Animals were divided into two groups. In Group 1 (n = 9), subsequent (19) F MRI based on spin lattice relaxation of hexafluorobenzene reporter molecule provided quantitative oximetry for comparison. For Group 2 rats (n = 13) growth delay following a single dose of 30 Gy was compared with preirradiation BOLD and TOLD assessments. RESULTS: Oxygen (100%O2 ) and carbogen (95%O2 /5%CO2 ) challenge elicited similar BOLD, TOLD and pO2 responses. Strong correlations were observed between BOLD or R2* response and quantitative (19) F pO2 measurements. TOLD response showed a general trend with weaker correlation. Irradiation caused a significant tumor growth delay and tumors with larger changes in TOLD and R1 values upon oxygen breathing exhibited significantly increased tumor growth delay. CONCLUSION: These results provide further insight into the relationships between oxygen sensitive (BOLD/TOLD) MRI and tumor pO2 . Moreover, a larger increase in R1 response to hyperoxic gas challenge coincided with greater tumor growth delay following irradiation.

Effects of Photon versus Carbon-Ion Irradiation in the Rat Cervical Spinal Cord - a Serial T2 and Diffusion-weighted Magnetic Resonance Imaging Study.

Carbon-ion irradiation is increasingly used at the skull base and spine near the radiation-sensitive spinal cord. To better characterize the in vivo radiation response of the cervical spinal cord, radiogenic changes in the high-dose area were measured in rats using magnetic resonance imaging (MRI) diffusion measurements in comparison to conventional photon irradiations. In this longitudinal MRI study, we examined the gray matter (GM) of the cervical spinal cord in 16 female Sprague-Dawley rats after high-dose photon (n = 8) or carbon-ion (12C) irradiation (n = 8) and in 6 sham-exposed rats until myelopathy occurred. The differences in the diffusion pattern of the GM of the cervical spinal cord were examined until the endpoint of the study, occurrence of paresis grade II of both forelimbs was reached. In both radiation techniques, the same order of the occurrence of MR-morphological pathologies was observed - from edema formation to a blood spinal cord barrier (BSCB) disruption to paresis grade II of both forelimbs. However, carbon-ion irradiation showed a significant increase of the mean apparent diffusion coefficient (ADC; P = 0.031) with development of a BSCB disruption in the GM. Animals with paresis grade II as a late radiation response had a highly significant increase in mean ADC (P = 0.0001) after carbon-ion irradiation. At this time, a tendency was observed for higher mean ADC values in the GM after 12C irradiation as compared to photon irradiation (P = 0.059). These findings demonstrated that carbon-ion irradiation leads to greater structural damage to the GM of the rat cervical spinal cord than photon irradiation due to its higher linear energy transfer (LET) value.

Irradiation with Carbon Ions Effectively Counteracts Hypoxia-related Radioresistance in a Rat Prostate Carcinoma.

PURPOSE: Hypoxia in tumors is associated with increased malignancy and resistance to conventional photon radiation therapy. This study investigated the potential of particle therapy to counteract radioresistance in syngeneic rat prostate carcinoma. METHODS AND MATERIALS: Subcutaneously transplanted R3327-HI tumors were irradiated with photons or carbon ions under acute hypoxic conditions, induced by clamping the tumor-supplying artery 10 min before and during irradiation. Dose-response curves were determined for the endpoint "local tumor control within 300 days" and compared with previously published data acquired under oxic conditions. Doses at 50% tumor control probability (TCD50) were used to quantify hypoxia-induced radioresistance relative to that under oxic conditions and also to quantify the increased effectiveness of carbon ions under oxic and hypoxic conditions relative to photons. RESULTS: Compared with those under oxic conditions, TCD50 values under hypoxic conditions increased by a factor of 1.53 ± 0.08 for photons and by a factor of 1.28 ± 0.06 for carbon ions (oxygen enhancement ratio). Compared with those for photons, TCD50 values for carbon ions decreased by a factor of 2.08 ± 0.13 under oxic conditions and by a factor of 2.49 ± 0.08 under hypoxic conditions (relative biological effectiveness). While the slope of the photon dose-response curves increased when changing from oxic to hypoxic conditions, the slopes were steeper and remained unchanged for carbon ions. CONCLUSIONS: The reduced oxygen enhancement ratio of carbon ions indicated that the required dose increase in hypoxic tumors was 17% lower for carbon ions than for photons. Additionally, carbon ions reduced the effect of intertumor heterogeneity on the radiation response. Therefore, carbon ions may confer a significant advantage for the treatment of hypoxic tumors that are highly resistant to conventional photon radiation therapy.

Relative biological effectiveness of oxygen ion beams in the rat spinal cord: Dependence on linear energy transfer and dose and comparison with model predictions.

Background and purpose: Ion beams exhibit an increased relative biological effectiveness (RBE) with respect to photons. This study determined the RBE of oxygen ion beams as a function of linear energy transfer (LET) and dose in the rat spinal cord. Materials and methods: The spinal cord of rats was irradiated at four different positions of a 6 cm spread-out Bragg-peak (LET: 26, 66, 98 and 141 keV/µm) using increasing levels of single and split oxygen ion doses. Dose-response curves were established for the endpoint paresis grade II and based on ED50 (dose at 50 % effect probability), the RBE was determined and compared to model predictions. Results: When LET increased from 26 to 98 keV/µm, ED50 decreased from 17.2 ± 0.3 Gy to 13.5 ± 0.4 Gy for single and from 21.7 ± 0.4 Gy to 15.5 ± 0.5 Gy for split doses, however, at 141 keV/µm, ED50 rose again to 15.8 ± 0.4 Gy and 17.2 ± 0.4 Gy, respectively. As a result, the RBE increased from 1.43 ± 0.05 to 1.82 ± 0.08 (single dose) and from 1.58 ± 0.04 to 2.21 ± 0.08 (split dose), respectively, before declining again to 1.56 ± 0.06 for single and 1.99 ± 0.06 for split doses at the highest LET. Deviations from RBE-predictions were model-dependent. Conclusion: This study established first RBE data for the late reacting central nervous system after single and split doses of oxygen ions. The data was used to validate the RBE-dependence on LET and dose of three RBE-models. This study extends the existing data base for protons, helium and carbon ions and provides important information for future patient treatments with oxygen ions.

Flow cytometric characterization of tumor subpopulations in three sublines of the Dunning R3327 rat prostate tumor model.

BACKGROUND: Subsets of tumor cells were characterized by mapping DNA ploidy patterns in correlation with established cell surface markers in three non-treated sublines of the Dunning R3327 prostate tumor system representing different progressional stages. METHODS: Flow cytometry was used to analyze DNA-index, cell cycle distribution as well as multiparametric aquisition of single and combined cell surface markers in single cell suspensions of frozen tumor tissues. RESULTS: The three Dunning prostate tumor sublines clearly differ in their ploidy status. In addition each tumor subline displays a characteristic cell surface marker profile, which is correlated with the cell cycle phase and the amount of genomic alterations. CONCLUSIONS: In a feasibility study we have shown that cross-reacting antibodies to human cell surface markers stain discrete tumor subpopulations in three sublines of the Dunning tumor model. Although it remains presently uncertain, which cell surface markers are most suitable for cell sorting to display cancer initiating (CIC) properties following subcutaneous or orthotopic grafting, the model may be useful for mechanistic investigations of putative stem-like tumor subpopulations and their significance in response to radio- or chemotherapy.

Relative biological effectiveness of single and split helium ion doses in the rat spinal cord increases strongly with linear energy transfer.

BACKGROUND AND PURPOSE: Determination of the relative biological effectiveness (RBE) of helium ions as a function of linear energy transfer (LET) for single and split doses using the rat cervical spinal cord as model system for late-responding normal tissue. MATERIAL AND METHODS: The rat cervical spinal cord was irradiated at four different positions within a 6 cm spread-out Bragg-peak (SOBP) (LET 2.9, 9.4, 14.4 and 20.7 keV/µm) using increasing levels of single or split doses of helium ions. Dose-response curves were determined and based on TD50-values (dose at 50% effect probability using paresis II as endpoint), RBE-values were derived for the endpoint of radiation-induced myelopathy. RESULTS: With increasing LET, RBE-values increased from 1.13 ± 0.04 to 1.42 ± 0.05 (single dose) and 1.12 ± 0.03 to 1.50 ± 0.04 (split doses) as TD50-values decreased from 21.7 ± 0.3 Gy to 17.3 ± 0.3 Gy (single dose) and 30.6 ± 0.3 Gy to 22.9 ± 0.3 Gy (split doses), respectively. RBE-models (LEM I and IV, mMKM) deviated differently for single and split doses but described the RBE variation in the high-LET region sufficiently accurate. CONCLUSION: This study established the LET-dependence of the RBE for late effects in the central nervous system after single and split doses of helium ions. The results extend the existing database for protons and carbon ions and allow systematic testing of RBE-models. While the RBE-values of helium were generally lower than for carbon ions, the increase at the distal edge of the Bragg-peak was larger than for protons, making detailed RBE-modeling necessary.

The RBE in ion beam radiotherapy: In vivo studies and clinical application.

Ion beams used for radiotherapy exhibit an increased relative biological effectiveness (RBE), which depends on several physical treatment parameters as well as on biological factors of the irradiated tissues. While the RBE is an experimentally well-defined quantity, translation to patients is complex and requires radiobiological studies, dedicated models to calculate the RBE in treatment planning as well as strategies for dose prescription. Preclinical in vivo studies and analysis of clinical outcome are important to validate and refine RBE-models. This review describes the concept of the experimental and clinical RBE and explains the fundamental dependencies of the RBE based on in vitro experiments. The available preclinical in vivo studies on normal tissue and tumor RBE for ions heavier than protons are reviewed in the context of the historical and present development of ion beam radiotherapy. In addition, the role of in vivo RBE-values in the development and benchmarking of RBE-models as well as the transition of these models to clinical application are described. Finally, limitations in the translation of experimental RBE-values into clinical application and the direction of future research are discussed.

Effectiveness of fractionated carbon ion treatments in three rat prostate tumors differing in growth rate, differentiation and hypoxia.

PURPOSE: To quantify the fractionation dependence of carbon (12C) ions and photons in three rat prostate carcinomas differing in growth rate, differentiation and hypoxia. MATERIAL AND METHODS: Three sublines (AT1, HI, H) of syngeneic rat prostate tumors (R3327) were treated with six fractions of either 12C-ions or 6 MV photons. Dose-response curves were determined for the endpoint local tumor control within 300 days. The doses at 50% control probability (TCD50) and the relative biological effectiveness (RBE) of 12C-ions were calculated and compared with the values from single and split dose studies. RESULTS: Experimental findings for the three tumor sublines revealed (i) a comparably increased RBE (2.47-2.67), (ii) a much smaller variation of the radiation response for 12C-ions (TCD50: 35.8-43.7 Gy) than for photons (TCD50: 91.3-116.6 Gy), (iii) similarly steep (AT1) or steeper (HI, H) dose-response curves for 12C-ions than for photons, (iv) a larger fractionation effect for photons than for 12C-ions, and (v) a steeper increase of the RBE with decreasing fractional dose for the well-differentiated H- than for the less-differentiated HI- and AT1-tumors, reflected by (vi) the smallest α/ß-value for H-tumors after photon irradiation. CONCLUSION: 12C-ions reduce the radiation response heterogeneity between the three tumor sublines as well as within each subline relative to photon treatments, independently of fractionation. The dose dependence of the RBE varies between tumors of different histology. The results support the use of hypofractionated carbon ion treatments in radioresistant tumors.

DCE-MRI detected vascular permeability changes in the rat spinal cord do not explain shorter latency times for paresis after carbon ions relative to photons.

BACKGROUND AND PURPOSE: Radiation-induced myelopathy, an irreversible complication occurring after a long symptom-free latency time, is preceded by a fixed sequence of magnetic resonance- (MR-) visible morphological alterations. Vascular degradation is assumed the main reason for radiation-induced myelopathy. We used dynamic contrast-enhanced (DCE-) MRI to identify different vascular changes after photon and carbon ion irradiation, which precede or coincide with morphological changes. MATERIALS AND METHODS: The cervical spinal cord of rats was irradiated with iso-effective photon or carbon (12C-)ion doses. Afterwards, animals underwent frequent DCE-MR imaging until they developed symptomatic radiation-induced myelopathy (paresis II). Measurements were performed at certain time points: 1 month, 2 months, 3 months, 4 months, and 6 months after irradiation, and when animals showed morphological (such as edema/syrinx/contrast agent (CA) accumulation) or neurological alterations (such as, paresis I, and paresis II). DCE-MRI data was analyzed using the extended Toft's model. RESULTS: Fit quality improved with gradual disintegration of the blood spinal cord barrier (BSCB) towards paresis II. Vascular permeability increased three months after photon irradiation, and rapidly escalated after animals showed MR-visible morphological changes until paresis II. After 12C-ion irradiation, vascular permeability increased when animals showed morphological alterations and increased further until animals had paresis II. The volume transfer constant and the plasma volume showed no significant changes. CONCLUSION: Only after photon irradiation, DCE-MRI provides a temporal advantage in detecting early physiological signs in radiation-induced myelopathy compared to morphological MRI. As a generally lower level of vascular permeability after 12C-ions led to an earlier development of paresis as compared to photons, we conclude that other mechanisms dominate the development of paresis II.

Longitudinal MRI study after carbon ion and photon irradiation: shorter latency time for myelopathy is not associated with differential morphological changes.

BACKGROUND: Radiation-induced myelopathy is a severe and irreversible complication that occurs after a long symptom-free latency time if the spinal cord was exposed to a significant irradiation dose during tumor treatment. As carbon ions are increasingly investigated for tumor treatment in clinical trials, their effect on normal tissue needs further investigation to assure safety of patient treatments. Magnetic resonance imaging (MRI)-visible morphological alterations could serve as predictive markers for medicinal interventions to avoid severe side effects. Thus, MRI-visible morphological alterations in the rat spinal cord after high dose photon and carbon ion irradiation and their latency times were investigated. METHODS: Rats whose spinal cords were irradiated with iso-effective high photon (n = 8) or carbon ion (n = 8) doses as well as sham-treated control animals (n = 6) underwent frequent MRI measurements until they developed radiation-induced myelopathy (paresis II). MR images were analyzed for morphological alterations and animals were regularly tested for neurological deficits. In addition, histological analysis was performed of animals suffering from paresis II compared to controls. RESULTS: For both beam modalities, first morphological alterations occurred outside the spinal cord (bone marrow conversion, contrast agent accumulation in the musculature ventral and dorsal to the spinal cord) followed by morphological alterations inside the spinal cord (edema, syrinx, contrast agent accumulation) and eventually neurological alterations (paresis I and II). Latency times were significantly shorter after carbon ions as compared to photon irradiation. CONCLUSIONS: Irradiation of the rat spinal cord with photon or carbon ion doses that lead to 100% myelopathy induced a comparable fixed sequence of MRI-visible morphological alterations and neurological distortions. However, at least in the animal model used in this study, the observed MRI-visible morphological alterations in the spinal cord are not suited as predictive markers to identify animals that will develop myelopathy as the time between MRI-visible alterations and the occurrence of myelopathy is too short to intervene with protective or mitigative drugs.

Oxygen-Sensitive MRI: A Predictive Imaging Biomarker for Tumor Radiation Response?

PURPOSE: To develop a noninvasive prognostic imaging biomarker related to hypoxia to predict SABR tumor control. METHODS AND MATERIALS: A total of 145 subcutaneous syngeneic Dunning prostate R3327-AT1 rat tumors were focally irradiated once using cone beam computed tomography guidance on a small animal irradiator at 225 kV. Various doses in the range of 0 to 100 Gy were administered, while rats breathed air or oxygen, and tumor control was assessed up to 200 days. Oxygen-sensitive magnetic resonance imaging (MRI) (T1-weighted, ΔR1, ΔR2*) was applied to 79 of these tumors at 4.7 T to assess response to an oxygen gas breathing challenge on the day before irradiation as a probe of tumor hypoxia. RESULTS: Increasing radiation dose in the range of 0 to 90 Gy enhanced tumor control of air-breathing rats with a TCD50 estimated at 59.6 ± 1.5 Gy. Control was significantly improved at some doses when rats breathed oxygen during irradiation (eg, 40 Gy; P < .05), and overall there was a modest left shift in the control curve: TCD50(oxygen) = 53.1 ± 3.1 Gy (P < .05 vs air). Oxygen-sensitive MRI showed variable response to oxygen gas breathing challenge; the magnitude of T1-weighted signal response (%ΔSI) allowed stratification of tumors in terms of local control at 40 Gy. Tumors showing %ΔSI >0.922 with O2-gas breathing challenge showed significantly better control at 40 Gy during irradiation while breathing oxygen (75% vs 0%, P < .01). In addition, increased radiation dose (50 Gy) substantially overcame resistance, with 50% control for poorly oxygenated tumors. Stratification of dose-response curves based on %ΔSI >0.922 revealed different survival curves, with TCD50 = 36.2 ± 3.2 Gy for tumors responsive to oxygen gas breathing challenge; this was significantly less than the 54.7 ± 2.4 Gy for unresponsive tumors (P < .005), irrespective of the gas inhaled during tumor irradiation. CONCLUSIONS: Oxygen-sensitive MRI allowed stratification of tumors in terms of local control at 40 Gy, indicating its use as a potential predictive imaging biomarker. Increasing dose to 50 Gy overcame radiation resistance attributable to hypoxia in 50% of tumors.

Computer simulation of tumour control probabilities after irradiation for varying intrinsic radio-sensitivity using a single cell based model.

BACKGROUND: Currently, optimisation of the dose distribution and clinical acceptance are almost entirely based on the physical dose distribution and tumour control probability modelling is far from being routinely used as objective in treatment planning. For future individualised radiotherapeutic strategies, a reliable patient specific simulation model, taking into account customised tumour features, is needed to predict and improve treatment outcome. MATERIALS AND METHODS: To approach these demands, a single cell and Monte-Carlo based model was developed, which enables three-dimensional tumour growth and radiation response simulation. Tumour cells were characterised by cell-associated features such as age, intrinsic radio-sensitivity, proliferation ability, and oxygenation status, while capillary cells were considered as sources of a radial-dependent oxygen profile. Response to radiation was simulated by the linear-quadratic model, taking into account the lower radio-sensitivity of poorly oxygenated tumour cells. RESULTS: The present study shows the influence of the model components and demonstrates the impact of the intra- and inter-tumoural radio-sensitivity heterogeneity on the treatment response. CONCLUSION: The simulation model adequately delineates the importance of the above described selected parameters on tumour control probability, providing an insight into the interplay of different physical and biological parameters, and its relevance for an individual tumour response.

High Doses of Photons and Carbon Ions Comparably Increase Vascular Permeability in R3327-HI Prostate Tumors: A Dynamic Contrast-Enhanced MRI Study.

Carbon- (12C-) ion radiotherapy exhibits enhanced biological effectiveness compared to photon radiotherapy, however, the contribution of its interaction with the vasculature remains debatable. The effect of high-dose 12C-ion and photon irradiation on vascular permeability in moderately differentiated rat prostate tumors was compared using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Syngeneic R3327-HI rat prostate tumors were irradiated with a single dose of either 18 or 37 Gy 12C ions, or 37 or 75 Gy 6-MV photons (sub-curative and curative dose levels, respectively). DCE-MRI was performed one day prior to and 3, 7, 14 and 21 days postirradiation. Voxel-based tumor concentration-time curves were clustered based on their curve shape and treatment response was assessed as the longitudinal changes in the relative abundance per cluster. Radiation-induced vascular damage and increased permeability occurred at day 7 postirradiation for all treatment groups except for the 75 Gy photon-irradiated group, where the onset of vascular damage was delayed until day 14. No differences between irradiation modalities were found. Therefore, early vascular damage cannot explain the higher effectiveness of 12C ions relative to photons in terms of local tumor control for this moderately differentiated prostate tumor and the applied single high doses.

Ramipril reduces incidence and prolongates latency time of radiation-induced rat myelopathy after photon and carbon ion irradiation.

To test the hypothesis that the use of an angiotensin-converting enzyme inhibitor (ACEi) during radiotherapy may be ameliorative for treatment-related normal tissue damage, a pilot study was conducted with the clinically approved (ACE) inhibitor ramipril on the outcome of radiation-induced myelopathy in the rat cervical spinal cord model. Female Sprague Dawley rats were irradiated with single doses of either carbon ions (LET 45 keV/µm) at the center of a 6 cm spread-out Bragg peak (SOBP) or 6 MeV photons. The rats were randomly distributed into 4 experimental arms: (i) photons; (ii) photons + ramipril; (iii) carbon ions and (iv) carbon ions + ramipril. Ramipril administration (2 mg/kg/day) started directly after irradiation and was maintained during the entire follow-up. Complete dose-response curves were generated for the biological endpoint radiation-induced myelopathy (paresis grade II) within an observation time of 300 days. Administration of ramipril reduced the rate of paralysis at high dose levels for photons and for the first time a similar finding for high-LET particles was demonstrated, which indicates that the effect of ramipril is independent from radiation quality. The reduced rate of myelopathy is accompanied by a general prolongation of latency time for photons and for carbon ions. Although the already clinical approved drug ramipril can be considered as a mitigator of radiation-induced normal tissue toxicity in the central nervous system, further examinations of the underlying pathological mechanisms leading to radiation-induced myelopathy are necessary to increase and sustain its mitigative effectiveness.

Fractionated carbon ion irradiations of the rat spinal cord: comparison of the relative biological effectiveness with predictions of the local effect model.

BACKGROUND: To determine the relative biological effectiveness (RBE) and α/ß-values after fractionated carbon ion irradiations of the rat spinal cord with varying linear energy transfer (LET) to benchmark RBE-model calculations. MATERIAL AND METHODS: The rat spinal cord was irradiated with 6 fractions of carbon ions at 6 positions within a 6 cm spread-out Bragg-peak (SOBP, LET: 16-99 keV/µm). TD50-values (dose at 50% complication probability) were determined from dose-response curves for the endpoint radiation induced myelopathy (paresis grade II) within 300 days after irradiation. Based on TD50-values of 15 MV photons, RBE-values were calculated and adding previously published data, the LET and fractional dose-dependence of the RBE was used to benchmark the local effect model (LEM I and IV). RESULTS: At six fractions, TD50-values decreased from 39.1 ± 0.4 Gy at 16 keV/µm to 17.5 ± 0.3 Gy at 99 keV/µm and the RBE increased accordingly from 1.46 ± 0.05 to 3.26 ± 0.13. Experimental α/ß-ratios ranged from 6.9 ± 1.1 Gy to 44.3 ± 7.2 Gy and increased strongly with LET. Including all available data, comparison with model-predictions revealed that (i) LEM IV agrees better in the SOBP, while LEM I fits better in the entrance region, (ii) LEM IV describes the slope of the RBE within the SOBP better than LEM I, and (iii) in contrast to the strong LET-dependence, the RBE-deviations depend only weakly on fractionation within the measured range. CONCLUSIONS: This study extends the available RBE data base to significantly lower fractional doses and performes detailed tests of the RBE-models LEM I and IV. In this comparison, LEM IV agrees better with the experimental data in the SOBP than LEM I. While this could support a model replacement in treatment planning, careful dosimetric analysis is required for the individual patient to evaluate potential clinical consequences.

Impact of Single Dose Photons and Carbon Ions on Perfusion and Vascular Permeability: A Dynamic Contrast-Enhanced MRI Pilot Study in the Anaplastic Rat Prostate Tumor R3327-AT1.

We collected initial quantitative information on the effects of high-dose carbon (12C) ions compared to photons on vascular damage in anaplastic rat prostate tumors, with the goal of elucidating differences in response to high-LET radiation, using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Syngeneic R3327-AT1 rat prostate tumors received a single dose of either 16 or 37 Gy 12C ions or 37 or 85 Gy 6 MV photons (iso-absorbed and iso-effective doses, respectively). The animals underwent DCE-MRI prior to, and on days 3, 7, 14 and 21 postirradiation. The extended Tofts model was used for pharmacokinetic analysis. At day 21, tumors were dissected and histologically examined. The results of this work showed the following: 1. 12C ions led to stronger vascular changes compared to photons, independent of dose; 2. Tumor growth was comparable for all radiation doses and modalities until day 21; 3. Nonirradiated, rapidly growing control tumors showed a decrease in all pharmacokinetic parameters (area under the curve, Ktrans, ve, vp) over time; 4. 12C-ion-irradiated tumors showed an earlier increase in area under the curve and Ktrans than photon-irradiated tumors; 5. 12C-ion irradiation resulted in more homogeneous parameter maps and histology compared to photons; and 6. 12C-ion irradiation led to an increased microvascular density and decreased proliferation activity in a largely dose-independent manner compared to photons. Postirradiation changes related to 12C ions and photons were detected using DCE-MRI, and correlated with histological parameters in an anaplastic experimental prostate tumor. In summary, this pilot study demonstrated that exposure to 12C ions increased the perfusion and/or permeability faster and led to larger changes in DCE-MRI parameters resulting in increased vessel density and presumably less hypoxia at the end of the observation period when compared to photons. Within this study no differences were found between curative and sub-curative doses in either modality.