Normal Liver Tissue Density Dose Response in Patients Treated With Stereotactic Body Radiation Therapy for Liver Metastases

doi:10.1016/j.ijrobp.2012.04.041

International Journal of Radiation OncologyBiologyPhysics

Volume 84, Issue 3, 1 November 2012, Pages e441-e446

Preliminary results were presented at the Joint American Association of Physicists in Medicine (AAPM)/Canadian Organization of Medical Physicists (COMP) meeting, Vancouver, Canada, July 31-August 4 2011, and at the 10th Annual Meeting of the International Conference on Machine Learning and Applications (ICMLA) of Institute for Electrical and Electronics Engineers (IEEE), Honolulu, HI, December 18-21, 2011.

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Purpose

To evaluate the temporal dose response of normal liver tissue for patients with liver metastases treated with stereotactic body radiation therapy (SBRT).

Methods and Materials

Ninety-nine noncontrast follow-up computed tomography (CT) scans of 34 patients who received SBRT between 2004 and 2011 were retrospectively analyzed at a median of 8 months post-SBRT (range, 0.7-36 months). SBRT-induced normal liver tissue density changes in follow-up CT scans were evaluated at 2, 6, 10, 15, and 27 months. The dose distributions from planning CTs were mapped to follow-up CTs to relate the mean Hounsfield unit change (ΔHU) to dose received over the range 0-55 Gy in 3-5 fractions. An absolute density change of 7 HU was considered a significant radiographic change in normal liver tissue.

Results

Increasing radiation dose was linearly correlated with lower post-SBRT liver tissue density (slope, −0.65 ΔHU/5 Gy). The threshold for significant change (−7 ΔHU) was observed in the range of 30-35 Gy. This effect did not vary significantly over the time intervals evaluated.

Conclusions

SBRT induces a dose-dependent and relatively time-independent hypodense radiation reaction within normal liver tissue that is characterized by a decrease of >7 HU in liver density for doses >30-35 Gy.

Introduction

Stereotactic body radiation therapy (SBRT) is a form of external beam radiation treatment that uses advanced planning, delivery, and localization techniques to achieve steep dose falloff from target to surrounding healthy tissue. Constraining high-dose distribution enables delivery of 40-60 Gy in 5 or fewer fractions and limits potential toxicity to normal liver tissue 1, 2. Clinical studies have reported local control of up to 95% at 2 years 2, 3. Although occurrences of severe toxicity are rare (4), radiation-induced density changes, which could relate to local liver injuries, are often observed on follow-up CT scans 5, 6. The reaction manifests as a hypodense region surrounding the target volume and is aligned with lower-than-prescription isodose lines 5, 6. The reaction is different from that seen in other organs, for example, the lung (7), so a specific understanding of the processes occurring following SBRT to the liver is needed.

Multiphasic CT scans have been used to explain the damage to the liver. Herfarth et al (5) analyzed single-fraction stereotactic RT in 36 patients treated for liver malignancies and identified 3 focal reaction types based on density behaviors seen in the precontrast, portal-venous, and late phases. Notably, a shift from hypodensity to hyperdensity in the portal venous phase implied acute effects manifesting as chronic effects. In the acute phase, congestion of the sinusoids with erythrocytes reduces blood flow, giving way to a hypodense appearance. Edema and fatty infiltration similarly give way to a hypodense appearance in noncontrast CT scans. In the chronic phase, vascular obstruction (progressive fibrin deposition in the central veins and afferent sinusoids) causes a sustained, hyperdense appearance in the portal venous phase. Importantly, these microscopic changes and their macroscopic impact on liver density values have been histologically proven 8, 9.

Irradiated regions depicted in noncontrast CTs tend to reveal only a trend toward various degrees of hypodensity (although it has been suggested that chronic injury can cause decreased fatty replacement resulting in hyperdensity (9). Nonetheless, noncontrast scans are necessary to quantify actual density changes. Sixty-one of the 95 noncontrast scans presented by Herfarth et al (5) demonstrated a mean change in Hounsfield units (ΔHU) of −15 ΔHU (range, −10 to −30 ΔHU) between irradiated and nonirradiated regions. In a separate study, Ahmadi et al (10) showed that 27 of the 40 noncontrast scans obtained after proton therapy showed an area of lower density, averaging 41.2 ± 5.4 HU, significantly lower than the surrounding nonirradiated tissue, averaging 49.2 ± 6.1 HU (10).

None of these studies provided extensive dose response modeling of normal liver tissue in SBRT patients by using CT density changes within the reaction volume and surrounding tissue. Consequently, we have undertaken an image-based, computational approach using ΔHU in order to quantify SBRT-induced liver density changes as a function of dose and time from treatment.

Section snippets

Patients

Thirty-four patients treated between 2004 and 2011 with SBRT for liver metastases were retrospectively evaluated. Patients were selected based upon the availability of planning CTs and follow-up CTs without contrast and the requirements that treated lesions were locally controlled and in-field recurrences were not detected in follow-up imaging. A total of 99 follow-up noncontrast CTs were analyzed. Between 1 and 8 post-treatment CT scans (median, 2) were obtained for each patient, including 9

Significant change in liver density

We calculated an RMS of ∼3.5 HU for normal, nonirradiated liver tissue. Therefore, we defined 7 HU as the threshold beyond which constitutes a radiographic change in liver CT density. A power calculation (α = 5%; β = 20%) for when to decide whether a change in 7 HU was considered significant revealed that n=5 was the minimum number of scans, when σ = 5.7 HU (15).

Normal liver tissue dose response

Figure 2 shows a typical patient's planning CT and 4 registered follow-up CT scans at 4, 5, 7, and 8 months. Also shown in these scans

Discussion

Several studies of the effects of conventional RT, 3D conformal RT, and SBRT to the normal liver have reported the appearance of a radiologically hypodense region in follow-up noncontrast CT scans 5, 6, 17, 18, 19. Of the 95 follow-up noncontrast scans analyzed in the study by Herfarth et al (5), 61 scans showed hypodense radiation reactions, 32 showed no difference, and 2 showed hyperdense reactions. Of the 21 noncontrast CT scans reviewed by Chiou et al (19), all scans revealed either a

Conclusions

SBRT induces a dose-dependent and relatively time-independent hypodense radiation reaction within normal liver tissue. A 7-HU (or greater) hypodense change in liver density, likely to be associated with hepatic injury, occurs with doses above 30-35 Gy. This change is linearly related to dose.

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Cited by (19)

Evaluating dose constraints for radiation induced liver damage following magnetic resonance image guided Stereotactic Body radiotherapy
2021, Physics and Imaging in Radiation Oncology
Citation Excerpt :
Thus, it appears that our approach of correlating the liver damage region using dice coefficient can help in determining appropriate time for obtaining follow up scans. In the studies that quantified radiation changes using either Hounsfield Unit differences on follow-up CT scans or intensity changes on follow up MRI scans, imaging changes were associated with lower isodose lines in the range of 25 Gy–42 Gy [14]. Takeda et al. [15] analyzed follow up CT scans and proposed using 30 Gy in 5 fractions as a threshold dose.
This study reports dose corresponding to visible radiation induced liver damage following Stereotactic Body Radiation Therapy (SBRT) for liver metastasis, and the optimal time for follow up scans using post radiation imaging. Diagnostic magnetic resonance scans of nine patients treated with liver SBRT using a 0.35 T MRI-guided radiotherapy system were analyzed. The dice coefficients between the region of visible liver damage and the delivered dose were calculated. A median dose of 35 Gy correlated most closely with the visible radiation induced liver damage. We compared scans over two to nine months and observed maximal dice coefficients at two to five months post radiation. We have presented a new method for developing treatment planning guidelines for liver SBRT.
In-vivo treatment accuracy analysis of active motion-compensated liver SBRT through registration of plan dose to post-therapeutic MRI-morphologic alterations
2019, Radiotherapy and Oncology
In-vivo-accuracy analysis (IVA) of dose-delivery with active motion-management (gating/tracking) was performed based on registration of post-radiotherapeutic MRI-morphologic-alterations (MMA) to the corresponding dose-distributions of gantry-based/robotic SBRT-plans.
Forty targets in two patient cohorts were evaluated: (1) gantry-based SBRT (deep-inspiratory breath-hold-gating; GS) and (2) robotic SBRT (online fiducial-tracking; RS). The planning-CT was deformably registered to the first post-treatment contrast-enhanced T1-weighted MRI. An isodose-structure cropped to the liver (ISL) and corresponding to the contoured MMA was created. Structure and statistical analysis regarding volumes, surface-distance, conformity metrics and center-of-mass-differences (CoMD) was performed.
Liver volume-reduction was −43.1 ± 148.2 cc post-RS and −55.8 ± 174.3 cc post-GS. The mean surface-distance between MMA and ISL was 2.3 ± 0.8 mm (RS) and 2.8 ± 1.1 mm (GS). ISL and MMA volumes diverged by 5.1 ± 23.3 cc (RS) and 16.5 ± 34.1 cc (GS); the median conformity index of both structures was 0.83 (RS) and 0.80 (GS). The average relative directional errors were ≤0.7 mm (RS) and ≤0.3 mm (GS); the median absolute 3D-CoMD was 3.8 mm (RS) and 4.2 mm (GS) without statistically significant differences between the two techniques. Factors influencing the IVA included GTV and PTV (p = 0.041 and p = 0.020). Four local relapses occurred without correlation to IVA.
For the first time a method for IVA was presented, which can serve as a benchmarking-tool for other treatment techniques. Both techniques have shown median deviations <5 mm of planned dose and MMA. However, IVA also revealed treatments with errors ≥5 mm, suggesting a necessity for patient-specific safety-margins. Nevertheless, the treatment accuracy of well-performed active motion-compensated liver SBRT seems not to be a driving factor for local treatment failure.
Regional Radiation Dose-Response Modeling of Functional Liver in Hepatocellular Carcinoma Patients With Longitudinal Sulfur Colloid SPECT/CT: A Proof of Concept
2018, International Journal of Radiation Oncology Biology Physics
Citation Excerpt :
Future precision medicine clinical trials could selectively assign patients to functional image-guided RT regimens based on their predicted liver sensitivity to radiation. Normal liver dose-response studies have traditionally focused on radiobiological modeling with serial CT imaging (31) or qualitative changes in longitudinal planar scintigraphy (32), which revealed dose thresholds for significant radiographic or scintigraphic changes at 30 to 35 Gy under variable fractionation schemes. These trends were averaged over patient populations, which provided improved statistical power but did not account for interpatient and intrapatient variability in liver sensitivity to radiation.
Hepatotoxicity risk in patients with hepatocellular carcinoma (HCC) is modulated by radiation dose delivered to normal liver tissue, but reported dose-response data are limited. Our prior work established baseline [^99mTc]sulfur colloid (SC) single-photon emission computed tomography (SPECT)/computed tomography (CT) liver function imaging biomarkers that predict clinical outcomes. We conducted a proof-of-concept investigation with longitudinal SC SPECT/CT to characterize patient-specific radiation dose-response relationships as surrogates for liver radiosensitivity.
SC SPECT/CT images of 15 patients with HCC with variable Child-Pugh (CP) status (8 CP-A, 7 CP-B/C) were acquired in treatment position before and 1 month (nominal) after stereotactic body radiation therapy (n = 6) or proton therapy (n = 9). Localized rigid registrations between pre/posttreatment CT to planning CT scans were performed, and transformations were applied to pre/posttreatment SC SPECT images. Radiation therapy doses were converted to EQD2 and Gy RBE (relative biological effectiveness) and binned in 5 GyEQD2 increments within tumor-subtracted livers. Mean dose and percent change (%ΔSC) between pre- and posttreatment SPECT uptake, normalized to regions receiving <5 GyEQD2, were calculated in each binned dose region. Dose-response data were parameterized by sigmoid functions (double exponential) consisting of maximum reduction (%ΔSC_max), dose midpoint (D_mid), and dose-response slope (α_mid) parameters.
Individual patient sigmoid dose-response curves had high goodness-of-fit (median R² = 0.96, range 0.76-0.99). Large interpatient variability was observed, with median (range) in %ΔSC_max of 44% (20%-75%), D_mid of 13 Gy (4-27 GyEQD2), and α_mid of 0.11 GyEQD2⁻¹ (0.04-0.29 GyEQD2⁻¹), respectively. Eight of 15 patients had %ΔSC_max of 20% to 45%, whereas 7 of 15 had %ΔSC_max of 60% to 75%, with subgroups made up of variable baseline liver function status and radiation treatment modality. Fatal hepatotoxicity occurred in patients (2 of 15) with low total liver funcation (<0.12) and low D_mid (<7 GyEQD2).
Longitudinal SC SPECT/CT imaging revealed patient-specific variations in dose-response and may identify patients with poor baseline liver function and increased sensitivity to radiation therapy. Validation of this regional liver dose-response modeling concept as a surrogate for patient-specific radiosensitivity has potential to guide HCC therapy regimen selection and planning constraints.
Early Prediction of Acute Xerostomia During Radiation Therapy for Head and Neck Cancer Based on Texture Analysis of Daily CT
2018, International Journal of Radiation Oncology Biology Physics
Citation Excerpt :
Recently, it has been reported based on an analysis of the daily computed tomographies (CTs) collected during RT for HNC that the mean CT number (MCTN), measured in Hounsfield Units (HU), in tumors and certain organs at risk can change during a course of RT (11). Similar MCTN changes have also been observed in lung, liver, or pancreas tumors and certain organs at risk during or after RT (12-17). It is highly desirable to identify metrics to predict radiation-induced acute xerostomia during the early phase of RT delivery for HNC so that treatment management can be altered if necessary.
To investigate radiation-induced changes of computed tomography (CT) textures in parotid glands (PG) to predict acute xerostomia during radiotherapy (RT) for head and neck cancer (HNC).
Daily or fraction kilovoltage CTs acquired using diagnostic CT scanners (eg, in-room CTs) during intensity-modulated RT for 59 HNC patients at 3 institutions were analyzed. The PG contours were generated on selected daily/fraction CTs. A series of histogram-based texture features, including the mean CT number (MCTN) in Hounsfield units, volume, standard deviation, skewness, kurtosis, and entropy for PGs were calculated for each fraction. Correlations between the changes of the texture features, radiation dose, and observed acute xerostomia were analyzed. A classifier model and the incurred CT-based xerostomia score (CTXS) were introduced to predict xerostomia based on combined changes of MCTN and volume of PGs. The t test and Spearman and Pearson correlation tests were used in the analyses.
Substantial changes in various CT texture features of PGs were observed during RT delivery. The changes of PG MCTN or volume are not strongly correlated with the observed xerostomia grades if they are considered separately. The CTXS showed a significant correlation to the observed xerostomia grades (r = 0.71, P < .00001). The CTXS-based classifier can predict the xerostomia severity with a success rate ranging from 79% to 98%. The xerostomia severity at the end of treatment can be predicted based on the CTXS determined at the fifth week with a precision and sensitivity of 100%.
Significant changes in the CT histogram features of the parotid glands were observed during RT of HNC. A practical method of using the changes of MCTN and volume of PGs is proposed to predict radiation-induced acute xerostomia, which may be used to help design adaptive treatment.
Changes in liver volume observed following sorafenib and liver radiation therapy
2016, International Journal of Radiation Oncology Biology Physics
The purpose of this study was to quantify unexpected liver volume reductions in patients treated with sorafenib prior to and during liver radiation therapy (RT).
Fifteen patients were treated in a phase 1 study of sorafenib for 1 week, followed by concurrent sorafenib-RT (in 6 fractions). Patients had either focal cancer (treated with stereotactic body RT [SBRT]) or diffuse disease (treated with whole-liver RT). Liver volumes were contoured and recorded at planning (day 0) from the exhale CT. After 1 week of sorafenib (day 8), RT image guidance at each fraction was performed using cone beam CT (CBCT). Planning liver contours were propagated and modified on the reconstructed exhale CBCT. This was repeated in 12 patients treated with SBRT alone without sorafenib. Three subsequent patients (2 sorafenib-RT and 1 non-sorafenib) were also assessed with multiphasic helical breath-hold CTs.
Liver volume reductions on CBCT were observed in the 15 sorafenib-RT patients (median decrease of 68 cc, P=.02) between day 0 and 8; greater in the focal (P=.025) versus diffuse (P=.52) cancer stratum. Seven patients (47%) had reductions larger than the 95% intraobserver contouring error. Liver reductions were also observed from multiphasic CTs in the 2 additional sorafenib-RT patients between days 0 and 8 (decreases of 232.5 cc and 331.7 cc, respectively) and not in the non-sorafenib patient (increase of 92 cc). There were no significant changes in liver volume between planning and first RT in 12 patients with focal cancer treated with SBRT alone (median increase, 4.8 cc, P=.86).
Liver volume reductions were observed after 7 days of sorafenib, prior to RT, most marked in patients with focal liver tumors, suggesting an effect of sorafenib on normal liver. Careful assessment of potential liver volume changes immediately prior to SBRT may be necessary in patients in sorafenib or other targeted therapies.
Computed tomography number changes observed during computed tomography-guided radiation therapy for head and neck cancer
2015, International Journal of Radiation Oncology Biology Physics
Citation Excerpt :
Thalacker et al (19) observed that the CTN of white matter was reduced by 5 HU after brain irradiation. Compared with most of these previous studies (5-8, 14-19) reporting CTN changes after RT in selected normal structures according to follow-up CTs after RT, the present study discovers CTN change during the course of RT delivery for HNC for both GTV and OARs. Although CTN changes during and after RT could be measured using various forms of CT (eg, kilovoltage or MV cone-beam CT, MV CT [Tomotherapy CT]), CTN measurement with diagnostic-quality CT (eg, CT-on-rails as used in this work) should be the most accurate.
To investigate CT number (CTN) changes in gross tumor volume (GTV) and organ at risk (OAR) according to daily diagnostic-quality CT acquired during CT-guided intensity modulated radiation therapy for head and neck cancer (HNC) patients.
Computed tomography scans acquired using a CT-on-rails during daily CT-guided intensity modulated radiation therapy for 15 patients with stage II to IVa squamous cell carcinoma of the head and neck were analyzed. The GTV, parotid glands, spinal cord, and nonspecified tissue were generated on each selected daily CT. The changes in CTN distributions and the mean and mode values were collected. Pearson analysis was used to assess the correlation between the CTN change, organ volume reduction, and delivered radiation dose.
Volume and CTN changes for GTV and parotid glands can be observed during radiation therapy delivery for HNC. The mean (±SD) CTNs in GTV and ipsi- and contralateral parotid glands were reduced by 6 ± 10, 8 ± 7, and 11 ± 10 Hounsfield units, respectively, for all patients studied. The mean CTN changes in both spinal cord and nonspecified tissue were almost invisible (<2 Hounsfield units). For 2 patients studied, the absolute mean CTN changes in GTV and parotid glands were strongly correlated with the dose delivered (P<.001 and P<.05, respectively). For the correlation between CTN reductions and delivered isodose bins for parotid glands, the Pearson coefficient varied from −0.98 (P<.001) in regions with low-dose bins to 0.96 (P<.001) in high-dose bins and were patient specific.
The CTN can be reduced in tumor and parotid glands during the course of radiation therapy for HNC. There was a fair correlation between CTN reduction and radiation doses for a subset of patients, whereas the correlation between CTN reductions and volume reductions in GTV and parotid glands were weak. More studies are needed to understand the mechanism for the radiation-induced CTN changes.

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Physics ContributionNormal Liver Tissue Density Dose Response in Patients Treated With Stereotactic Body Radiation Therapy for Liver Metastases

Purpose

Methods and Materials

Results

Conclusions

Introduction

Section snippets

Patients

Significant change in liver density

Normal liver tissue dose response

Discussion

Conclusions

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

J Hepatol

Int J Radiat Oncol Biol Phys

Stereotactic single-dose radiation therapy of liver tumors: results of a phase I/II trial

J Clin Oncol

Multi-institutional phase I/II trial of stereotactic body radiation therapy for liver metastases

J Clin Oncol

Physics Contribution
Normal Liver Tissue Density Dose Response in Patients Treated With Stereotactic Body Radiation Therapy for Liver Metastases