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.

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.

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.

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.

Bolus arrival time estimation in dynamic contrast-enhanced magnetic resonance imaging of small animals based on spline models.

Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is used to quantify perfusion and vascular permeability. In most cases a bolus arrival time (BAT) delay exists between the arterial input function (AIF) and the contrast agent arrival in the tissue of interest which needs to be estimated. Existing methods for BAT estimation are tailored to tissue concentration curves, which have a fast upslope to the peak as frequently observed in patient data. However, they may give poor results for curves that do not have this characteristic shape such as tissue concentration curves of small animals. In this paper, we propose a method for BAT estimation of signals that do not have a fast upslope to their peak. The model is based on splines which are able to adapt to a large variety of concentration curves. Furthermore, the method estimates BATs on a continuous time scale. All relevant model parameters are automatically determined by generalized cross validation. We use simulated concentration curves of small animal and patient settings to assess the accuracy and robustness of our approach. The proposed method outperforms a state-of-the-art method for small animal data and it gives competitive results for patient data. Finally, it is tested on in vivo acquired rat data where accuracy of BAT estimation was also improved upon the state-of-the-art method. The results indicate that the proposed method is suitable for accurate BAT estimation of DCE-MRI data, especially for small animals.

Photoacoustic imaging to assess pixel-based sO2 distributions in experimental prostate tumors.

A protocol for photoacoustic imaging (PAI) has been developed to assess pixel-based oxygen saturation (sO2) distributions of experimental tumor models. The protocol was applied to evaluate the dependence of PAI results on measurement settings, reproducibility of PAI, and for the characterization of the oxygenation status of experimental prostate tumor sublines (Dunning R3327-H, -HI, -AT1) implanted subcutaneously in male Copenhagen rats. The three-dimensional (3-D) PA data employing two wavelengths were used to estimate sO2 distributions. If the PA signal was sufficiently strong, the distributions were independent from signal gain, threshold, and positioning of animals. Reproducibility of sO2 distributions with respect to shape and median values was demonstrated over several days. The three tumor sublines were characterized by the shapes of their sO2 distributions and their temporal response after external changes of the oxygen supply (100% O2 or air breathing and clamping of tumor-supplying artery). The established protocol showed to be suitable for detecting temporal changes in tumor oxygenation as well as differences in oxygenation between tumor sublines. PA results were in accordance with histology for hypoxia, perfusion, and vasculature. The presented protocol for the assessment of pixel-based sO2 distributions provides more detailed information as compared to conventional region-of-interest-based analysis of PAI, especially with respect to the detection of temporal changes and tumor heterogeneity.