Functional imaging of normal tissues with nuclear medicine: Applications in radiotherapy

Functional Imaging of Normal Tissues With Nuclear Medicine: Apphcations in Radiotherapy Michael T. Munley, Lawrence B. Marks, Patricia H. Hardenbergh, and Gunilla C. Bentel Functional imaging techniques are gaining significant interest from radiation oncologists. Many now claim the need for physical and physiological information during both treatment planning and in the study of normal tissue injury. Toward this goal, the nuclear medicine functional imaging modalities, single-photon

emission computed tomography and positron-emission computed tomography, have been used. This article reviews the studies performed in radiotherapy that used these modalities, and attempts to stimulate further interest in this topic. Copyright 9 2001 by W.B. Saunders Company

T therapy

he use of 3-dimensional conformal radio(3D-CRT) has increased greatly over the last several years. Limited 10 years ago to larger academic centers, commercial 3D-CRT treatment planning systems are now readily available and affordable. Current 3D-CRT treatment planning is primarily x-ray computed tomography (CT)-based. Such systems allow radiation oncology personnel to compute and view the entire 3D dose distribution within the patient. This technology also permits 3D definition of the target and normal tissue structures. The calculation and interpretation of the CT-defined dosevolume histogram (DVH) using 3D planning systems is an important tool to compare competing treatment strategies. However, functional information given by imaging modalities such as magnetic resonance imaging (MRI), positron-emission computed tomography (PET), and singlephoton emission computed tomography (SPECT) may yield additional data useful for both target delineation and normal tissue response. This article focuses on the use of nuclear medicine functional imaging data to study the consequence of incidental normal tissue irradiation, and to a lesser extent, its use in 3D-CRT treatment planning. Although interest has grown considerably in the last several years, few studies report the di-

rect use of functional imaging data in radiation oncology. These studies examined how the functional data influenced the treatment plan and how to use such data to formulate predictive normal tissue injury models. Results of studies of radiation-induced normal lung, heart, and brain injury using functional imaging modaiities have been reported. SPECT images have been analyzed to assess their effect on treatment planning for patients with lung cancer, 1,2 and to examine and quantify normal lung injury. 3-l~The effect of PET data on target delineation during treatmerit planning has also been studied.l,11,12 Preliminary studies of radiation-induced damage to the heart13-19 and brain 2~ using nuclear medicine data have been reported. Functional MRI techniques are under extensive development for diagnostic purposes, and should lead to valuable normal tissue response d/ira for radiation oncology. Although the number of functional imaging studies reported in the radiation oncology literature is limited, there is now significant interest in the RT community to explore the full potential of these functional imaging tools. With the advent of intensity-modulated RT and other advanced anatomy-based treatment methods, the next areas of interest in treatment planning and optimization will most likely be in biological imaging and modeling.

From the Department of Radiation Oncology, Duke University Medical Center, Durham, NC. Address reprint requests to Michael 72 Munley, t~hD, Department of Radiation Oncology, Box 3085, Duke University Medical Center, Durham, NC 27710. E-maib [email protected] Copyright 9 2001 by W.B. Saunders Company 1053-4296/01/1101-0004510. 00/0 doi:l O.l O53/srao.2001.18101

General Methods Qualitative Approach

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The qualitative use of functional images to assess normal tissue damage can be performed simply by visually comparing hard copies of functional images before and after RT. Such a technique is

Seminars in Radiation Oncology, Vol 11, No 1 (January), 2001." pp 28-36

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useful in determining if a functional change has occurred and the approximate location with respect to the radiation fields. Data such as these can confirm existing radiation-induced damage, help to understand the incidence and possibly the severity of injury for a given treatment approach, or may lead to early predictors of symptomatic injury (if post-RT scans are taken before the onset of symptoms). However, an accurate visual interpretation of the entire 3D distribution is difficult, and subtle functional changes may not be appreciated.

Quantitative Analysis The quantitative evaluation of functional imaging data in terms of normal issue injury after RT requires several steps and sophisticated tools. The general outline follows: 1. Acquire pre-RT planning CT and functional imaging data in the treatment position. 2. Perform treatment planning and dose calculation. 3. Treat patient as prescribed by physician. 4. After completion of RT, review and edit, as needed, the treatment plan to reflect that which was actually treated (ie, account for field changes during treatment and calculate for actual monitor units used for each field). 5. Calculate treated 3D dose distribution. 6. Register functional imaging data to planning CT, and thus, the dose distribution. (The registration can be performed at any time assuming the appropriate image sets are available.) 7. Acquire post-RT follow-up functional imaging data. 8. Register post-RT functional imaging scans to planning CT. 9. Evaluate functional changes between pre-RT data and post-RT data with respect to dose and/or changes in organ function tests, symptoms, etc. Fortunately, mosf 3D-CRT systems now provide the tools to perform the majority of the preceding steps. While many radiation oncology facilities now have the capability to perform such studies, skill and expertise are required to accurately delineate structures of interest, formulate a treatment plan, accurately calculate the 3D dose distribution, and register image sets from different modalides.

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The result of having a quantitative measure of normal tissue injury may lead to models that use both physical (anatomy and dose) and physiological (pre-RT functional imaging) information. These data may help to optimize treatment planning and to predict the likelihood of changes in organ function and/or symptomatic injury resulting from a course of RT. The following describes some of the recent and ongoing studies that use a functional imaging approach to understand and predict normal tissue injury. These studies may potentially lead to improvements in RT treatment planning and eventually show clinical benefit.

Lung Assessment of Regional Function SPECT has been the functional imaging modality of choice to examine the normal lung response to radiation. Studies have been reported by researchers at Duke and the Netherlands Cancer Institute using SPECT to correlate regional dose with regional normal lung injury. 3-1~ These groups have used technetium 99m macroaggregated albumin lung perfusion imaging techniques as a surrogate for lung function. The Netherlands studies also considered SPECT ventilation. Patients included in the studies are those who receive incidental irradiation of a portion of their lungs as a consequence of thoracic irradiation in treatment of a primary cancer. The experience of the group at Duke with SPECT scans led to the development of the dosefunction histogram (DFH). 24,25 The group at the University of Chicago has also reported on the DFH. 26 The DFH is similar to the conventional DVH, but the DFH displays the percent SPECT perfusion counts (assumed to be proportional to function) versus dose, at dose levels ranging from zero to the maximum lung dose. The potential advantage of DFHs over DVHs is that the former recognizes the functional heterogeneities that exist in patients with lung cancer (eg, generally due to emphysema). Nevertheless, these DFHs still lack spatial information. Furthermore, SPECT perfusion scans image function at a given point in time and do not assess potential function. If there is poor blood flow in a region of the lung caused by compression of central blood vessels by a central lung tumor, then these regions of lung might reperfuse after therapy. 27

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Figure 1. (A) Pretreatment and (B) post-RT SPECT lung perfusion images with the is9

distribution

superimposed. In the Duke and Netherlands studies, regional lung dose was calculated to reflect tissue density heterogeneity and the SPECT perfusion images were registered to the planning CT (and therefore the dose map). The pre-RT and post-RT DFHs were calculated and a corresponding dose response curve (DRC) was derived. The DRC displays the percent reduction in perfusion as a function of dose. Similar results have been reported by the Duke and Netherlands groups. Figure 1 shows transverse SPECT images for a patient before and after RT. Notice the significant reduction in perfusion in the treatment region after RT. The population DRCs of the Duke and Netherlands groups are superimposed in Fig 2. These are population DRCs derived by taking the weighted average of individual DRCs. The Netherlands data shown are from patients with lung 8O

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cancer, whereas the Duke data shown also include patients with other malignancies (eg, lymphoma and breast cancer). Both DRCs appear to plateau in the >60 Gy range at ~60% reduction in perfusion. This implies that 60% is the maximal measurable reduction in regional perfusion detectable with this technique. This m i g h t be related to inaccuracies in the SPECT reconstruction technique used and additional studies are underway to improve SPECT quantification. 2a Alternatively, persistent perfusion within the highdose region may be due to movement of the lung following irradiation. If the lung in the high-dose region scars and retracts, the adjacent still-perfused lung may move into the high-dose space. This is a shortcoming of this approach. R e l a t i n g R e g i o n a l I n j u r y to C h a n g e s i n Global Function

For parallel organs such as the lung, regional injury should be related to regional dose, and changes in whole-organ function are likely related to the sum of regional injuries. To test this hypothesis, studies that relate the regional radiation dose to changes in regional lung function were first performed to obtain the DRC. 3,7,9 Once the DRC for regional injury is well defined, one should be able to "multiply" a differential DFH by the population's DRC, and determine the sum of regional change to predict changes in whole<)rgan function. 4 Figure 3 illustrates this approach schematically. This model might overestimate the degree of lung injury because nonirradiated regions of the lung might, at least in part, compensate for the radiation damage within the irradiated field. Such studies are on-

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Percent Perfusion'

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going by both the Duke and Netherlands research teams. The goal of both groups is to determine a predictive model of normal lung injury by simultaneously using demographic, physical, and biological data. Preliminary data from these groups showed statistically significant relationships between predicted regional perfusion changes and changes in pulmonary function tests; however, the correlation coefficients are low. 1~ Abratt et al 3~ and Choi et al a2,33 have also reported on the use of perfusion data to predict changes in pulmonary function tests.

Treatment Planning SPECT lung perfusion images can also be used to identify functional regions of the lung during t r e a t m e n t planning. The goal here is to design radiation beams that purposely exclude the regions of the lung with greater relative function. In practice, this really is only practical in patients where the target volume is small (such that there is a great flexibility in beam orientation) and the pre-RT pulmonary function is extremely poor (since there is a desire to minimize/incidental pulmonary irradiation). In a Duke analysis of 104 patients who had SPECT scans performed as part of their t r e a t m e n t / p l a n n i n g process', 11% of the patients had their beams altered based on the SPECT information.1 All of the patients who had their t r e a t m e n t plan influenced by their pre-RT SPECT had poor pre-RT pulmonary function. An additional 39 patients had SPECT-defined functional heterogeneities within the lungs, but these data were not used during t r e a t m e n t planning because the pre-RT and predicted post-RT pulmonary function tests were considered accept-

able. Therefore, the potential exists to reduce dose to functional lung volume in a larger number of patients by using SPECT perfusion scans during t r e a t m e n t planning. In general, hypoperfusion located apart from the tumor will enable the t r e a t m e n t planner to construct beams that avoid highly functioning lung regions more often than hypoperfusion adjacent to the tumor. For target identification, 3 studies report the use of [18F]-fluorodeoxyglucose (FDG) PET scans to delineate areas of metabolic hyperactivity. After a retrospective study, KJffer et a111 reported that the RT volume would have changed because of PET data in 4 of 15 patients (27%). These changes were due to evidence of abnormal PET activity not seen on CT. In an analysis of 35 patients who had PET scans obtained as part of the t r e a t m e n t planning process, a Duke trial 1 reported that the PET data led to modification of the treatment b e a m in 34% of the cases (12 of 35 patients). The target volume was frequently enlarged to include equivocal-sized lymph nodes that were hyperactive on PET. The union of the CT and PET abnormalities were typically used as the target volume. Meanwhile, Nestle et al I2 showed a change in target size using PET information as opposed to the planning CT in 12 of 34 cases (35%). These changes were primarily a reduction (n = 10) in the area of the beam aperture. The Kiffer and Duke studies appear to have taken a conservative approach to the simultaneous use of C T and PET, and i m p l e m e n t e d the union of the CT- and PET-defined targets. Nestle et al quantitatively compared the areas of the CT-only and PET-only defined target portals and

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showed that the PET-defined targets were usually smaller than CT-defined targets. The Nestle study concluded that the smaller PET-defined portal was possibly related to tumor-associated atelectasis seen on CT. The Duke study also noted atelectasis as a possible explanation for the difference in the CT and PET target volumes, but chose to use the union. Therefore, the data of the three studies are not necessarily contradictory. However, none of these studies has shown an improvement in outcome and further studies are needed to examine the clinical benefit.

Heart Perfusion Studies Several studies report examining radiation-induced cardiac toxicity using functional imaging. Five studies used thallium 201 myocardial perfusion scintigraphy to examine the incidence of cardiac perfusion defects after irradiation for the t r e a t m e n t of Hodgkin's disease. Constine et al t3 noted 2 perfusion abnormalities out of 50 asymptomatic patients. Similarly, Morgan et a114 studied 25 patients and Savage et a115 studied 12 patients following RT for Hodgkin's disease. Neither group noted a perfusi0n defect on t h a l l i u m scintigraphy scans. Maunoury et a116 compared 31 previously irradiated asymptomatic patients with a group of 35 control subjects with a low likelihood of coronary artery disease; 84% of the evaluable irradiated patients had a visible defect. In 68% of the irradiated patients, the 2~ activity in bulls-eye sectorial images of the short axis were lower than the m e a n minus 2 standard deviations of the controls. The investigators suggest that the observed abnormalities were attributable to disease of the small coronary vessels and/or myocardial fibrosis. A related study by Pierga et aP 7 also reported on the incidence of visible cardiac abnormalities (85%) after irradiation of Hodgkin's disease. Pre-RT perfusion scans and 3D dosimetry were not used in these studies. Gyenes et al la used 99mTc sestamibi perfusion scintigraphy to detect radiation-induced myocardial damage. This was a prospective analysis of patients with left-sided breast cancer in which 3D-CRT tools were used to correlate dose and cardiac injury. H a l f of the patients (6 of 12) showed new regions of hypoperfusion after RT in areas of the left ventricle that corresponded well with the RT t r e a t m e n t fields. The hypoperfusion

was observed 13 months after RT and is believed to be indicative of microvascular damage. Recently, researchers at Duke 19 reported on the incidence of cardiac perfusion abnormalities and a dose response for the left ventricle based on a prospective study of 20 patients treated for left-sided breast cancer. These patients underwent SPECT 99mTc sestamibi perfusion scans before and after RT (6 month follow-up). The 3D dose distribution was calculated from a CT-based t r e a t m e n t plan, and the SPECT image sets were registered to the appropriate planning CTs. H a l f of these patients also underwent doxorubicin chem o t h e r a p y before RT. There was a 60% incidence of visually detectable perfusion defects in the post-RT SPECT scans corresponding to regions of the left ventricle in the tangential t r e a t m e n t beams. Figure 4 shows a patient's cardiac SPECT perfusion scans before and after RT. A post-RT reduction in perfusion is clearly evident in the region of the left ventricle corresponding to the t r e a t m e n t fields. For patients with any volume of left ventricle in the t r e a t m e n t field, the rates of detection of visible abnormalities were 100% and 50% for patients treated with chemotherapy and those treated without chemotherapy, respectively. This study is in agreement with the previous work by Gyenes et al, 18 and suggests that microvascular damage after RT is common. A DRC was acquired by a similar strategy as described for the lung trials. The population DRC from this study is shown in Fig 5. It is hypothesized that the DRC may.be used to predict cardiac injury before RT. Future work is needed to correlate predicted change in cardiac perfusion to changes in left ventricular ejection fraction and/or symptomatic injury.

Discussion These cardiac studies were preliminary reports that examined the incidence of subclinical myocardial damage using nuclear medicine imaging data. The 2~~ studies gave conflicting results with an incidence of an observed perfusion defect ranging from 0% to 85%. Cardiac injury in the form of microvascular damage Was noted in ->50% of the patients entered in the 99mTc sestamibi SPECT studies. This shows the potential of SPECT as a sensitive modality for detection of perfusion damage. However, no correlation with long-term symptomatic injury has been reported. The Maunoury 16 and Pierga 17 studies had no

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Figure 4. Examples of a patient's (A) pretreatment and (B) post-RT cardiac SPECT perfusion scans.

symptomatic patients 7 years after RT. The Gyenes and Duke studies had short follow-up intervals. Local perfusion injury may improve with longer follow-up as has been suggested to occur in the lung. 34 Future studies are required to further explore the usefulness of SPECT in determining the seOerity of radiation-induced cardiac injury and its relation to myocardial infarction or congestive heart failure, which may occur years after irradiation.

PET

Brain SPECT Normal brain response to irradiation has been reported on using SPECT and PET imaging techniques. A Japanese study by Araki et al 2~ looked

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at the change in mean cerebral blood flow of the nontumor-bearing regions of the brain using xenon 133 SPECT. The m e a n cerebral blood flow of 40 15atients treated with RT and chemotherapy was cothpared with that of 40 normal volunteers. Flow m e a s u r e m e n t s made during therapy showed an increase in m e a n blood flow in some patients; however, a significant reduction in flow was seen in the patient population starting 3 months after the initiation of RT.

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Figure 5. Left ventricle DRC from a preliminary prospective study at Duke of patients with left-sided breast cancer (n = 20).

PET has also been used by a few groups to study radiation-induced brain injury. Figure 6 shows an example of an FDG PET image and its corresponding CT image from Duke. Wang et a121 examined the effect of RT on both the tumorand nontumor-bearing regions of the brain using FDG PET. Nine patients had pre-RT and 1-week post-RT PET scans performed to study the change in brain glucose metabolism. Five of these patients showed a decrease in t u m o r metabolism and an increase in normal brain metabolism. The remaining 4 patients did not show a change in metabolism for either the t u m o r or nontumor regions of the brain. In a case report, Mineura et a122 stated that the metabolic rate of glucose in the brain was decreased at 5-month follow-up in a 2-year-old patient with medulloblastoma treated with RT and methotrexate. The FDG activity was markedly depressed in the t e m p o r a l and occipital lobes. After administering steroidal therapy to

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Figure 6. A CT-based treatment plan for a patient with a brain glioma and the corresponding FDG PET image. CT-defined contours, the isodose distribution, and the beam paths are shown on both images.

treat neurologic symptoms, an increase in FDG u p t a k e was seen. A study at Duke 23 was performed to determine the DRC of regional normal brain metabolism using FDG PET imaging and 3D-CRT t r e a t m e n t planning tools. A retrospective study was conducted that examined pre-RT and post-RT (4- to 12-month follow-up) P E T scans for 8 patients (4 children, 4 adults) with brain gliomas. The DRC was determined in a manner similar to the other Duke normal tissue trials. Linear regression analysis was used to relate regional dose to changes in regional metabolic activity. There were no changes in regional metabolic activity at doses up to 50 Gy. Above 50 Gy, a 7% decrease in metabolic activity was seen in 1 patient, 5 patients had 0% to 10% increases, and the remaining 2 patients had 10% to 20% increases. This study concluded that doses of fractionated RT up to 50 Gy do not ,significantly alter the regional FDG activity of normal brain. At higher doses there may be some changes in this small study population; however, both increases and decreases in metabolism were observed.

Discussion The SPECT brain trial gave a result similar to the reductions in perfusion seen after irradiation in the lung and heart studies. These data suggest that SPECT is a sensitive and quantitative

method of determining radiation-induced microvascular injury throughout the body. Perhaps a limiting factor may be the availability of an appropriate SPECT radiopharmaceutical for .a given site. The PET brain studies are inconclusive. A case study reported a decrease in brain glucose metabolism after irradiation. Another study described an increase (5 of 9 patients) in metabolism following RT, whereas a third study (8 patients total) reported observing both dosedependent elevations and reductions in glucose metabolism. The differences in these results may be due to a time-dependent response characterized by an initial metabolic increase from acute inflammation followed by a long-term reduction in glucose metabolism. O t h e r confounding factors may be that different regions of the brain have different metabolic i~esponses to radiation, and that these studies included both children and adults. Given the limited n u m b e r of subjects in these reports, additional studies are clearly needed to answer these questions, and to determine the efficacy of using PET to describe normal brain injury from irradiation.

Other Structures The liver and parotid can be seen on nuclear medicine studies and, therefore, it is possible in theory to determine the incidence of radiation

Nuclear Medicine Imaging in Radiotherapy

injury and dose response for these structures. Techniques similar to those previously described for other normal tissues may be implemented to study these structures. The liver is sometimes incidentally irradiated in the treatment of thoracic, abdominal, and pelvic cancers and its regional function may be proportional to the sulfur colloid uptake in SPECT studies. The parotid gland is often included in head and neck treatment fields. Site-specific challenges will need to be addressed such as the accurate registration of a functional image set of the parotid t ~ the 3D dose distribution because of the small size of the gland.

Conclusion In summary, it is important to consider anatomy and physiology when trying to relate 3D dose distributions to outcome. Several studies, albeit mostly preliminary, have been reported using functional nuclear medicine studies to examine normal tissue response to irradiation. There are several sites in which such modalities have shown their value in obtaining the incidence of normal tissue injury. Quantitative physiologic-based trials to predict changes in pulmonary, cardiac, or neurologic function caused by radiation damage are ongoing. It is hypothesized that changes in whole organ function can be correlated with the summation of regional changes quantified by nuclear medicine image data and sophisticated 3DCRT tools. Incorporation of physiologic and anatomic information into the treatment planning process should further exploit the potential benefits of 3D planning. Studies are needed and are underway to correlate physical and biological data to outcome.

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