Radiation induced lung damage - Chapter 3 Radiation dose-effect relations and local recovery in perfusion for patients with non-small-cell lung cancer

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Radiation induced lung damage

Seppenwoolde, Y.

Publication date

2002

Link to publication

Citation for published version (APA):

Seppenwoolde, Y. (2002). Radiation induced lung damage.

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Chapterr 3

Radiationn dose-effect relations and

locall recovery in perfusion for patients

withh non-small-cell lung cancer

Yvettee Seppenwookte, Sara H. Mutter, Jacqueline C M . Theuws, Paul Baas, Joséé SA. Belderbos, Uesbeth J. Boersma, Joos V. Lebesque

Radiationn dose-effect relations and local recovery in

perfusionn for patients with non-small cell lung cancer

Too determine local dose-effect relations for king perfusion and density changes due to irradiationn for patients with noo-smal cell lung cancer (NSCLC) and to quantity the effect off reperfusion, registered Single Photon Emission Computed Tomography (SPECT) lung perfusionn scans and CT-scans were made, before and alter radiotherapy lor 25 NSCLC-patientss and a reference group of 81 patients with healthy lungs. Average dose-effect relationsrelations for perfusion and CT-density changes were calculated and compared with the dose-effectt relation of the reference group. On the basis of these dose-effect relations, tf» post-RTT perfusion was predicted for each patient and compared to the measured post-RT perfusion.. WeH-perfused rung regions of the NSCLC-patients showed the same dose-effectt relation as the reference patients. By comparing predicted and measured post-treatmentt perfusion scans, regions of reperfusion could be determined for 18 of 25 NSCLC-patientss but for none of the reference patients. Well-perfused lung tissue of patiëntee with NSCLC behaves like healthy lung tissue with respect to radiation. The dose-effectt relation for perfusion and CT-density was extended for doses up to 80 Gy. Radiation damagee in poorly perfused lung regions was less than predicted as a consequence of locall reperfusion.

Introduction n

Whenn optimizing treatment plans for lung cancer patients, lung tissue is one of the dose-limitingg structures, besides the spinal cord, the esophagus and the heart Although the mean lungg dose can be used to predict Normal Tissue Complication Probabilities (NTCP's) (Kwa 1998a),, it might be better to include functional information of lung tissue to design the plan that minimizess the complication risk (Marks 1993, 199$). Single Photon Emission Computed Tomographyy ( S P E C T ) lung ventiiation/perfusion scans provide information in three dimensionss about local functionality of lung tissue.

Thee effect of inhomogeneous dose distributions on lung perfusion for patients with healthy lungss (malignant lymphoma and breast cancer patiënte) can be predicted using an average dose-effectt relation for the whole group (Theuws 1998a). in that patient group it was assumed thatt all observed damage was due to irradiation. However, for patients with intra-thoracic tumorr or for patients with pre-existent lung disease, prediction of post-radiotherapy <RT) lung functionn can be inadequate because not all changes will be caused by the irradiation, i.e. tumorr progression can also induce lung damage.

Patientss with non-small cell lung cancer (NSCLC) can have inhomogeneous perfusion already beforee RT due to several causes. Patients with chronic obstructive pulmonary disease (COPD) aree more likely to have a tower CT-density throughout the lungs, and their lung perfusion is inhomogeneous.. Some patients suffer from bullous disease and have lung regions where locallyy the density is very tow. These bullous regions are neither well ventilated nor perfused. Furthermore,, the perfusion can be obstructed by atelectasis, infiltrates and, most importantly, tumor. .

Iff reduced perfusion is caused by compression of an artery due to a (large) tumor, tumor regressionn can induce re-opening of these btood vessels which may cause a part of the lung, distall from the tumor, to re-perfuse. Therefore, in the high dose regions two opposite effects

ChapterChapter 3

cann be induced by the treatment: on one hand the radiation causes damage resulting in a decreasee in perfusion and an increase of tissue density; on the other hand, tumor-regression mayy cause a 'recovery* in perfusion. When mis local recovery takes place in a lung region mat iss also damaged by the irradiation, the observed damage will be less than expected on the bastss of the applied radiation dose.

inn this paper we investigated whether the local dose-effect relation for NSCLC-patients is the samee as for breast cancer and malignant lymphoma patients, we determined the dose-effect relationn for higher doses and found a way to visualize and quantify local recovery effects.

Methodss and Materials

Thee 25 patients in this study were irradiated for non-small cell lung cancer. All patients had a follow-upp of three months to assess changes in lung perfusion and tissue density. Six patients weree classified as stage I NSCLC, two patients as stage II, seven as stage IIIA and ten as stagee NIB. All patients were irradiated with conformal AP-PA fields and a boost up to 70 Gy in fractionss of 2 Gy, except for two patients who got 51 Gy in fractions of 3 Gy. All patients were scannedd and treated in supine position with the arms raised above their head in a forearm supportt No further immobilization was used but all possible effort was made to reproduce the treatmentt position during the different scans. Eighty-one malignant lymphoma and breast cancerr patients from a previous study (Theuws 1998b) were used to provide a reference set forr evaluating the current results. These patients had healthy lungs and good pulmonary functionn test results. The presence of intra pulmonary tumor in the lymphoma group did not affectt the dose-effect relation.

Thee local hospital ethics committee approved the study, and before the patients were included, writtenn informed consent was obtained.

Dosee calculation

CT-basedd dose calculations were performed as described previously (Boersma 1994), using aa 3D treatment planning system (U-MPIan, University of Michigan) with tissue inhomogeneity correction.. For inhomogeneous dose distributions, the dose per fraction largely differs for differentt regions of the lungs. To take this dose per fraction effect into account, the physical dosee distribution was converted into the normalized total dose (NTD) distribution, using the linearr quadratic model with an ct/p* ratio of 3.0 Gy (Van Dyk 1989, Newcomb 1993). The NTD iss defined as the total biological equivalent dose given in fractions of 2 Gy (Maciejewski 1986). Alll radiation doses in the data presented in this paper (local dose, mean dose, etc.) are biologicall equivalent doses.

Dataa acquisition

Beforee radiotherapy, and three to four months after radiotherapy, a SPECT lung perfusion scan andd a GT thorax scan were obtained. For SPECT, a dual-head gamma camera (ADAC Genesyss or ADAC Vertex) was used equipped with medium-energy general-purpose collimators.. After administration of about 4 mCi of 99mTc-macroaggregated albumin to the patientt in supine position, SPECT lung perfusion scans were made (scan time: approximately 155 minutes). For three patients ventilation was measured simultaneously using the dual-isotopee acquisition mode and 81fnKr. The SPECT scans were reconstructed using filtered back projectionn with software provided by the manufacturer (ADAC). The number of voxels was

RadiationRadiation dose-effect relations and heal recovery

64x64x644 and the voxel size was approximately 6x6x6 mm3. The resolution of the reconstructedd SPECT images was 20-25 mm (full width at half maximum), as was measured withh a line source filled with " T c . The CT scan was made within one week of the accompanyingg SPECT scans, with the patient in the same position (scanner Siemens, Somatomm Pius). Both CT and SPECT acquisition were performed under normal breathing conditionss (no "breath-artd-hold" procedure) and included the entire lung volume. Five external skinn positions were marked with 57Co point sources during SPECT scanning, and with crossed radio-opaquee catheters during CT scanning.

Lungg contour matching

Too obtain lung contours, the CT images were segmented by binary thresholding. The threshold valuee was chosen at a density of 0.7 g/rhi. The Gross Tumor Volume (GTV) delineated by the radiationn oncologist was excluded. For correlation of the CT and SPECT scans, chamfer-matchingg (Kwa 1998b) was applied on the lung contours. To obtain lung contours from SPECT, thee lung perfusion scans were segmented by binary thresholding as well, using an initial thresholdd of 200 counts that was adjusted during matching with the lung contours in the CT-scann until the best fitting threshold was obtained. Because the patients were CT-scanned white continuouslyy breathing, contours in the slices near the diaphragm were quite different from scann to scan. These contours were manually omitted from the post-treatment scan before matching.. After correlating the SPECT lung perfusion scans with the CT images, a first order Chang-likee (Chang 1978) attenuation correction (Damen 1994a) was applied on the SPECT perfusionn scans, based on CT-densrty in homogeneities. The quality of the chamfer match was visuallyy evaluated and in case the lung contours did not correlate well, the five skin markers weree used to align the SPECT-scans with the accompanying CT-scan (in only 3 of the 50 SPECT-CTT matches we used the skin markers). These five skin positions were identified visuallyy in the SPECT and CT-scans, and the root-mean-square distance between the correspondingg markers was minimized by allowing translations and rotations.

Dose-effectt relations

Thee dose-effect relations for local changes in perfusion and lung density (which is quantified byy changes in air-filled fraction1) for each individual patient were determined by calculating the reductionn in function compared to the pre-RT function for each dose interval (Boersma 1993). Beforee the dose-effect relation of an individual patient could be determined, voxels with an inaccuratelyy measured effect should be excluded. In all data sets, voxels positioned near the diaphragmm were excluded because of the poor image correlation due to breaming movements. Voxelss with a high dose gradient (more than 10 Gy/cm), located at field and block edgess were alsoo excluded from the analysis because small spatial inaccuracy in matching of the data sets couidd cause a considerable uncertainty in dose in these voxels. To avoid further mismatch errors,, the peripheral king region (one voxel thickness) was excluded from the analysis as well.. On average 40% of the lung volume was excluded for the NSCLC-patients. To limit the effectt of this large excluded volume, a threshold for the minimum number of voxels in a dose-intervall could be estimated from variance analysis. For each patient a minimum of 30 voxels perr dose interval was needed to assure that the intra-patient variance was less than 20% of thee total variance.

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B»fotawinBrelaöorck=(1^)=^-0O^T/w w inn HouwSeld unite.

ChapterChapter 3

Normalization n

Whenn comparing multiple SPECT scans, internal normalization is required because the perfusionn pattern through the lungs is altered after treatment and the amount of injected activityy that reaches the lung capillaries is not known exactly. In general, normalization is appliedd on the average number of SPECT counts in the parts of the lungs receiving less than aa certain low dose (in our study 8 Gy), assuming that such a low radiation dose has no significantt influence on perfusion resistance in that region. Due to the parallel structure of lung tissue,tissue, damage in high dose regions leads to compensation effects in the rest of the lungs and normalizationn on the average number of counts in the tow dose area yields the correct representationn of the damage in other dose bins. However, due to possible local recovery of perfusionn capacity in the normalization area, damage in the higher dose bins may be overestimated.. Therefore, normalization was applied on welt-perfused low dose regions of the lung,, assuming not only that lung injury is not present at this tow dose level but also that well-perfusedd areas are less influenced by tumor-regression. Formulas used tor the normalization proceduree can be found in Appendix II (Equations 6-9). The difference between the two normalizationn methods was tested for the reference patient group. For changes in CT-densrty, normalizationn on well-perfused low dose regions was applied to correct for changes in breathingg level; although in the low-dose regions the tissue-density will not increase due to treatment,, it is possible mat the patient at the follow-up time breathes at a different level. Lung tissuee density changes with the amount of inhaled air. For the construction of an average dose-effectt relation, tile normalized effect in each dose interval was averaged over all patients or patientt subgroups. This averaging was performed logarithmically (geometric mean, because thee effect is a ratio of a pre- and post-RT value) and giving equal weights to each patient Dose-effectt (DE) relations were calculated for thé entire patient group and for patient subgroups: :

DEmm is the average dose-effect relation for all patients (n=25);

DEhomm is the average dose-effect relation for patients with homogeneous perfusion ; throughoutt the lungs (without decreased perfusion adjacent to the tumor before irradiation,, n=6);

DEtnhomm is the average dose-effect relation for patients having reduced perfusion likely due too obstruction of vessels by the tumor (n=19);

DEwpp is the average dose-effect relation for well-perfused (>60% of the maximum pre-RT perfusion)) areas of alt patiënte (n=25) and

DEppp is the average dose-effect relation for poorly perfused (<30% of the maximum pre-RTT perfusion) areas of all patients (n=25).

3-DD evaluation of local recovery

Too separate the effect of the irradiation and the opposite effect of local recovery, we constructedd a prediction of the post-RT SPECT lung perfusion scan, based on the pre-RT perfusion,, the 3-D dose distribution and the dose-effect relation for healthy lung tissue (see Figuree 1 and Equation II-23). The average dose response curve for patients with malignant lymphomaa and breast cancer (Theuws 1998a) could be combined with the dose-response for thee welt-perfused lung regions of the NSCLC-pattents, yielding DE^patavvprwdc By applying thiss extended average dose-effect relation to the pre-RT perfusion scans, the post-RT function off the lung could be predicted, based on the individual dose distribution and the individual functioningg of the lung before radiotherapy. The scans constructed in this manner could be comparedd with the measured post-RT perfusion SPECT-scans, resulting in a local recovery image;; for each voxel the ratio between the measured and the predicted post-RT perfusion

RadiationRadiation dose-effect relations and local recovery

wass calculated. This method gave us the possibility to differentiate (in three dimensions) betweenn regions of the lung which react as predicted on the radiation dose distribution and regionss which react stronger or less strong than predicted.

3DD dose distribution Perfusionn pre-RT Averagee dose-effect relation Predictedd post-RT _{perfusion n}

FigureFigure 1. Construction of predicted post-RT perfusion, based on the individual 3D-dose distribution, the average dose-effecteffect relation of the reference patients and the well-perfused regions of the patients with NSCLC (0E«/:p8f4APnscfc) and

friee individual perfusion pre-RT for each patient. For each voxel, the reduction in perfusion based on the local dose in

thatthat voxel is calculated, using DE^^oiNPna*- The

resulting perfusion is represented in the predicted post-RT perfusion image. image.

Quantificationn of local recovery effects

Too evaluate whether NSCLC-patients show a clinically relevant functional increase in average perfusionn throughout their lungs due to local recovery (reperfusion), the average measured andd average predicted function loss (see Appendix II, Equations 21 and 30) over the lungs was calculatedd for each patient. The amount of reperfusion is given by the difference between the averagee measured and predicted function loss (Equation II-33).

Results s

Thee influence of the new normalization method on the dose-effect relation was tested for malignantt lymphoma and breast cancer patients. For the dose-effect relation normalized on well-perfusedd low dose regions, a difference of less than 1 % was present. The change in fit-parameterss was not statistically significant; consequently, the dose-effect relation can be fitted withh the same sigmoidal curve as before (Dso = (54.7 1.2) Gy and k = 2.2 0.2 (Theuws 1998a)). .

8 0 ,, , 80

FigureFigure 2. Doseeffect relations for perfusion (A) and the air-filled fraction (B) for 25 NSCLC-patients. The solid fine (extrapolation(extrapolation 'is dashed) represents the dose-effect relation (logistic fit) for the reference patients

(DEMPJ-ChapterChapter 3

Dose-effectt relations

Normalizedd dose-effect relations for perfusion and air-filled fraction were calculated for differentt patient subgroups and different regions in the lung. The changes in perfusion as a functionn of dose (Figure 2A) for all NSCLC-patients was less than the changes for patients with healthyy lungs (Theuws 1998a), especially above 50 Gy. However, for the air-filled fraction (Figuree 2B), no deviation from the previously derived dose-effect relation for healthy lung tissuee could be seen. When we divided the group into patients with (DEinhom, n=19) and without (DEhom,, n=6) reduced perfusion adjacent to the tumor (Figure 3A), the dose response curve forr the group with homogeneous perfusion before radiotherapy shows more damage in lung perfusionn than the dose response curve for the group with reduced perfusion adjacent to the tumor.. Because only 6 of the 25 patients did not show hypo-perfusion adjacent to the tumor andd thus the data at some dose levels was limited, the data were pooled within 8 Gy dose levelss instead of 4 Gy. Average dose-effect relations for different regions of the lung ( D E ^ and DEpp)) are shown in Figure 3B.

400 60 NTD(Gy) )

FigureFigure 3. A. The average dose-effect relation for the NSCLC-patient subgroup with homogeneous perfusion before RT, DEhomDEhom (triangles, n=6) and the average dose-effect relation for the patient subgroup showing hypo-perfusion adjacent toto the tumor before RT, DEinhom (open circles, n=19). The solid line (extrapolation is dashed) represents the dose-effect

relationrelation (logistic Tit) for the reference patients (DEmtpai. B. The average dose-effect relation for well-perfused lung

regions,regions, DEwp (triangles) and the average dose-effect relation for poorly perfused lung regions, DE„, (open circles). The

solidsolid line (extrapolation is dashed) represents the dose-effect relation (logistic fit) for the reference patients (DEmtpJ.

Forr the well-perfused lung regions we find a steeper dose-effect relation than for the poorly perfusedd areas; these last regions show a more chaotic dose response and in the lower dose binss some recovery could be observed. For the reference group (lymphoma and breast cancer patients),, there is no difference in dose-effect for the well and poorly perfused lung regions (dataa not shown). For the air-filled fraction no significant differences in dose response could bee observed between the patient subgroups and the different regions of the lungs. For perfusion,, the DEwp of the NSCLC-patients and the average dose-effect relation (DEref.pat) of thee reference patients do not differ significantly for doses below 55 Gy (D50 = (62 11) Gy and kk = 1.7 0.5 for DEwp<55Gy). To obtain a dose-effect relation, valid up to 80 Gy, we extended thee data of the reference group with the data of the well-perfused parts of the lungs of the patientss with NSCLC. This dose effect relation (DEref.pat&WpnsC|C), could be described with a logisticc fit with a D50 of (63 3) Gy and a steepness parameter k of 1.7 0.2 (Figure 4).

RadiationRadiation dose-effect relations and local recovery

Reperfusion n

Thee average dose-effect relation, for 'healthy' lungs (including the well-perfused parts of the lungss of patients with NSCLC), could be used to assess reperfusion effects in the NSCLC-patientt group. By applying this dose-effect relation to the pre-RT SPECT lung perfusion scan, aa predicted post-RT perfusion scan was produced. Comparison of the predicted scan with the measuredd post-RT perfusion scan, resulted in a 3D image of lung regions where reperfusion occurred.. Many of our patients showed coherent regions where the radiation damage was less thann predicted or where recovery of perfusion was seen. These regions where mostly situated adjacentt to, or distal from the tumor. For two patients, the measured reduction in perfusion was equall to the predicted reduction. Only one patient showed more reduction in perfusion than expected. . 80 0 60 0 Ull 4 0 O O 20 0 00 _ 00 20 40 60 80 Dosee (Gy)

FigureFigure 4. The average dose effect relation (solid line), fitted for the reference patients (open squares), and the

well-perfusedperfused lung regions of the NSCLC-patients (solid circles). This dose effect relation (DErefpatiwpnsatJ could be describeddescribed with a logistic fit with a D^ of 63 Gy and a steepness parameter k of 1.7. This dose-effect relation implies thatthat exposure ofnomnal lung tissue to, for example, 20 Gy nonvalized total dose would result in approximately 13% reductionreduction on local perfusion, whereas exposure of 50 Gy would result in 40% decrease in perfusion. Inn Figure 5 examples of different degrees of reperfusion are displayed for three different patientss (I: a patient whose entire right lung reperfused, II: an example of reperfusion in combinationn with radiation damage; the measured damage in perfusion is not as large as the predictedd damage based on the irradiation dose. Ill: the images of a patient who did not respondd to irradiation at all). The damage was thus much lower than expected and the shape off the region with less damage than expected perfectly fitted the shape of the high dose region.. No unexpected changes in CT-density could be observed. Figures 5A, B and C show thee pre-RT, measured post-RT and predicted post-RT perfusion SPECT scans, respectively. Figuree 5D shows the corresponding post/predicted image. In Figure 5E purple/green overlay plotss of the CT-scans before (green) and after RT (purple) are shown. The principle of this methodd is that when there are no changes in CT-density, this overlay plot shows the normal CTT gray-scale. In the reperfused right lungs, no changes in density in the lungs could be observedd which could explain the reperfusion for patients I and II; on the contrary, the radiation damagee in the right lungs (purple) would rather predict a reduction in perfusion after treatment.

££ Breast cancer and lymphoma patients Lung patients, well perfused

ChapterChapter 3

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3 3

RadiatbnRadiatbn dose-effect relations and local recovery

Quantifyingg the amount of reperfusion

Althoughh the 3D post/predicted images gave a good impression of where reperfusion occurred,, a quantitative analysis was required to evaluate how much reperfusion each patient experienced.. Therefore, the difference between the measured and predicted function loss (reperfusion,, Appendix II, Equation 33) was plotted as a function of the pre-RT perfusion deficiencyy (Appendix II, Equation 14) throughout the lungs for the NSCLC-patients and the referencee group (Figure 6).

Thee differences in measured and predicted average effects were small for the reference group andd the average difference (-0.6%) did not differ significantly from zero (p = 0.34). For the NSCLC-patients,, however, the average difference between the predicted and measured functionn loss was 7.2% (p < 0.0005). Also a weak con-elation with the perfusion deficiency couldd be observed (r = -0.4, p=0.001, for all patients). The same analysis for the air-filled fraction,, yielded no significant difference in measured function loss between the reference groupp and the NSCLC-patients (0.3%, p = 0.56). The difference between the measured and predictedpredicted air-filled fraction was about zero (-0.14%, p = 0.5) on average for all patients.

30 0 20 0 ^^ 10 o o w w & & -10 0 -20 0 -100 0 10 20 30 40 Perfusionn deficiency (%)

FigureFigure 6. Reperfusion as a function of the perfusion deficiency for malignant lymphoma (open squares), breast cancer

(open(open triangles) and NSCLC-patients (solid circles). The solid line represents the fit through the data.

Correlationn between air-filled fraction and perfusion

Noo correlation between the differences in measured and predicted reduction in perfusion and air-filledd fraction could be observed, large reperfusion effects did not correspond to unexpectedd CT-density changes. This means that for most patients, the CT-density in regions wheree hypo-perfusion was present was not increased before RT and did not decrease during treatment. .

Ventilation n

Forr only three patients, we were able to measure SPECT ventilation scans as well. For those patients,, reventilation occurred in the same regions as reperfusion.

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ChapterChapter 3

Discussion n

Inn a previous study, our group derived dose-effect relations for lung perfusion and air-filled fractionn (Ttieuws 1998a) for patients with heafthy lung tissue. These dose-effect relations were determinedd in the dose range 0 to 55 Gy. Because lung cancer patients were irradiated with dosess up to 80 Gy (NTD) we aimed to extend the dose-effect relation to higher doses. Lung cancerr patients often suffer from pre-existent disease like chronic obstructive pulmonary disease,, and atelectasis, or are heavy smokers. These factors could have influenced the dose-effectt and therefore the dose-response curves had to be validated for the specific patient groupp they are used for. Also the presence of a tumor could have influenced the dose-effect itt can obstruct blood flow and cause a part of the lungs to be hypo-perfused. Due to irradiation thee tumor often reduced in volume and the hypo-perfused lung could regain its perfusion. We saww an absolute recovery in perfusion after treatment in 15 of the 25 analyzed patiënte. When wee corrected for the dose-effect, 18 of the patients showed coherent regions with local recoveryy in perfusion. The well-perfused parts of the lungs for NSCLC-patients showed a consistentt dose-effect relation that corresponded to the previously derived dose-effect relation forr healthy lung tissue of the reference patient group. These findings suggest that notwithstandingg pre-existing lung disease the relatively healthy (-well perfused) lung regions off NSCLC-patients react similarly to radiation as lung tissue of malignant lymphoma and breastt cancer patiënte.

Reperfusionn is observed by several other groups: Fazio et al. (1979) and Goldman et at. (1969)) saw improvement in regional perfusion after radiotherapy, measured with planar perfusionn scans. Later Marks et al. (1995) observed reperfusion in his patient group and decidedd to exclude patients from analysis who had reduction of perfusion adjacent to the tumor andd likely would show reperfusion after treatment

Thee majority of our NSCLC-patients (n=19) showed reduced perfusion adjacent to the tumor beforee treatment. These regions with hypo-perfusion were situated centrally in the lung, adjacentt to, or more distal from the tumor and were mainly hot accompanied by increased tissuetissue density. For the reference patients, small lung regions with reduced perfusion were situatedd in the apices and lung edges only. No differences in radiosensitivity were found for the referencee group for the well and poorly perfused lung regions. That reperfusion is not always presentt in all poorly perfused lung regions of NSCLC-patients is reflected in the larger standardd deviation (inter-patient variance) for the dose-effect relation for the poorly perfused lungg regions.

Reperfusionn can also be caused by disappearance of atelectasis due to irradiation (Majid 1986,, Reddy 1990, Ofiara 1997). However, in our patient group, the average dose-effect relationss for the air-tilled fraction did not reveal different dose responses for well and poorly perfusedd lung regions. This means that the recovery in perfusion is not accompanied by recoveryy in tissue density. However, one patient had a small area of reperfusion in tile contra-laterall lung that appeared to be induced by disappearing lung infiltrates. As expected, neither reperfusionn nor reventilation was seen in bullous regions.

Theree are many uncertainties in measuring dose dependent changes in both CT and SPECT: setupp errors, breathing artifacts, image fusion mismatches, SPECT artifacts (scatter and blurring)) and uncertainties in the dose calculation. By applying several filters before analysts, wee tiled to reduce the effects of the measurement uncertainties, but of course some practical

RadiationRadiation dose^ffect relations and local recovery

limitationss of the technique still remain. In future studies we will estimate the effect of measurementt errors on the dose-effect relations and reperfusion effects.

3DD post/predicted images

Thee comparison between the measured and the predicted post-RT perfusion was valuable to visualizee the location and extension of reperfusion. Coherent regions where less damage than predictedd was observed were mostly situated nearby the tumor. The reperfusion extended to otherr regions in many cases and appeared to be independent. In only two cases, dose-dependentt 'reperfusion' was observed and review of the individual dose-effect relations showedd a very gradual dose-effect relation (less than 10% effect in all dose bins), indicating reducedd radiosensitivity. One of these patients suffered from diffuse emphysema (Figure 5-III), resultingg in a higher air-filled fraction. An explanation for this observation coutd have been that thee lower tissue density of this patient would have resulted in further loss of electronic equilibriumm of the photon beams, causing broadening of the penumbra (Young 1983, Ekstrand 1990).. However, after adjusting the dose-gradient fitter for this case, still no radiation damage wass observed.

Quantification n

Thee volume of the lung where the post-RT perfusion was more than twice as good as predicted (thee red areas in Figure 5D), measured in the reference group, was mainly due to mismatch-errorss on the lung edges and remained far below 1% of the lung volume, the functional influencee of the reperfusion in the NSCLC-group can be up to 23% for an exceptional case, andd the deviation of 7.2% from predicted is statistically significant for the whole patient-group. However,, the question is whether or not reperfusion effects are traceable in diffusion capacity (Tucoc)) or in the results of spirometric tests (VA, VC, FEV,). For the functionality of the lungs,

besidess ventilation and perfusion, membrane function is essential. If the membrane function is stilll present in the irradiated and reperfused regions, our data would predict 7% less reduction inn overall lung function in this patient group than predicted based on the dose-distribution. In severall studies was found that for patients with lung cancer the radiation damage in FEVi and TL,cocc was less than predicted (Abratt 1990). In these studies the prediction of post-RT overall

lungg function was based on the irradiated functional lung volume, determined with planar perfusionn images. Some of these patients showed recovery (Choi 1994) in lung function (Currann 1992).

Thee impact of 30 reperfusion effects on overall lung function parameters is the subject of furtherr studies in our institution, as are the long-term effects of radiation damage (18 months follow-up)) for NSCLC-patients.

Optimization n

Forr treatment optimization it is still useful to consider functional information of lung tissue. The weakk correlation between the inhomogeneity in perfusion and reperfusion indicates that if the perfusionn is inhomogeneous betore RT, the chance of reperfusion is higher. However, due to thee limited number of patients in this study, the correlation is not sufficiently strong to be a reliablee prediction. Because the overall effect of reperfusion is 7% at most (if membrane functionn is retained), optimization of treatment plans by sparing the well-perfused regions will probablyy result in the best possible lung function after treatment. Placing beams through bullouss lung regions can also be considered as advantageous because bullous regions will neverr regain their original lung function.

Inn conclusion we can say that well-perfused lung tissue of patients with NSCLC behaves like healthyy lung tissue with respect to radiation. Thus the dose-effect relation obtained for patients

ChapterChapter 3

withh malignant lymphoma and breast cancer was extended for doses up to 80 Gy and can be describedd by a logistic function with a D» of 63 Gy and a k of 1.67. Comparison of predicted andd measured post-RT perfusion scans gives useful information about the localization of reperfusion.. Prediction of radiation damage with the dose-effect relation for healthy lung tissue givess a worst-case prediction. Damage in local lung perfusion may be less than predicted due too reperfusion, especially for patients with large regions of hypo-perfuston before radiotherapy. Therefore,, the gain of designing treatment plans with beams through hypo-perfused lung regionss might be higher than expected due to reperfusion, but ft is dependent on the membranee function.