- Email: [email protected]
Dose as a function of liver volume and planning target volume in helical tomotherapy, intensity-modulated radiation therapy–based stereotactic body radiation therapy for hepatic metastasis
Int. J. Radiation Oncology Biol. Phys., Vol. 66, No. 2, pp. 620 – 625, 2006 Copyright © 2006 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/06/$–see front matter
doi:10.1016/j.ijrobp.2006.05.034
PHYSICS CONTRIBUTION
DOSE AS A FUNCTION OF LIVER VOLUME AND PLANNING TARGET VOLUME IN HELICAL TOMOTHERAPY, INTENSITY-MODULATED RADIATION THERAPY– BASED STEREOTACTIC BODY RADIATION THERAPY FOR HEPATIC METASTASIS
JAMES
JOSEPH M. BAISDEN, M.D., PH.D.,* ANDREW G. REISH, B.S.E.,† KE SHENG, PH.D.,* M. LARNER, M.D.,* BRIAN D. KAVANAGH, M.D., M.P.H.,‡ AND PAUL W. READ, M.D., PH.D.*
*Department of Radiation Oncology, University of Virginia Health System, Charlottesville, VA; †Medical School, University of Virginia, Charlottesville, VA; and ‡Department of Radiation Oncology, University of Colorado, Aurora, CO Purpose: Stereotactic body radiation therapy (SBRT) has been shown to be an effective, well-tolerated treatment for local control of tumors metastatic to the liver. Multi-institutional Phase II trials are examining 60 Gy in 3 fractions delivered by linac-based, 3D-conformal IMRT. HiArt Helical TomoTherapy is a treatment unit that delivers co-planar helical IMRT that is capable of image-guided SBRT. We hypothesized that the maximum tolerable dose (MTD) delivered to a lesion by Helical TomoTherapy-based SBRT could be predicted based on the planning target volume (PTV) and liver volume. Methods and Materials: To test this, we performed inverse treatment planning and analyzed the dosimetry for multiple hypothetical liver gross tumor volumes (GTV) with conventional PTV expansions. Inverse planning was carried out to find the maximum tolerated SBRT dose up to 60 Gy to be delivered in 3 fractions based on the dose constraint that 700 cc of normal liver would receive less than 15 Gy. Results: Regression analysis indicated a linear relationship between the MTD, the PTV and the liver volume, supporting our hypothesis. A predictive equation was generated, which was found to have an accuracy of ⴞ3 Gy. In addition, dose constraints based on proximity to other normal tissues were tested. Inverse planning for PTVs located at varying distances from the heart, small bowel, and spinal cord revealed a predictable decrease in the MTD as the PTV increased in size or approached normal organs. Conclusions: These data provide a framework for predicting the likely MTD for patients considered for Helical TomoTherapy liver SBRT. © 2006 Elsevier Inc. Tomotherapy, Stereotactic body radiation therapy, Hepatic metastasis, Intensity-modulated radiation therapy, radiosurgery.
INTRODUCTION Liver metastasis represents a significant clinical area in need of improved treatment. The prevalence of liver metastasis is very high, particularly among patients with colorectal, lung, and breast cancer. It has been shown that up to 50% of patients with Stage II and III colorectal cancer will develop liver metastases within 5 years of diagnosis (1). This is approximately 50,000 patients per year, with half of these presenting with liver as the only site of known metastatic disease (2). The 5-year survival rate for patients with liver metastasis treated with only systemic therapies remains less than 5% (3, 4). Surgical resection for selected patients with liver metastasis provides survival benefit, resulting in a
5-year survival of up to 30% (5–7); however, operative/ perioperative mortality is reportedly as high as 6% (8). Radiotherapy has also been explored for liver metastasis. Traditional treatment of 30 Gy in 10 to 12 fractions results in palliative benefit but no substantial survival benefit. Dose escalation with fractionated regimens have shown some benefit (9), and protocols are currently accruing patients to hypofractionated regimens with 30 to 50 Gy in 10 fractions. SBRT has been used to deliver high doses, from 30 to 60 Gy in 3 to 5 fractions via linear accelerator-based therapies. The results from this approach have been promising, showing 1to 2-year local control rates from 65% to 95% (10 –12). Various techniques have been used for hepatic SBRT. Three-dimensional conformal radiation therapy (3D-CRT)
Reprint requests to: Paul W. Read, M.D., Ph.D., Box 800383, Charlottesville, VA 22908. Tel: (434) 924-5191; Fax: (434) 9823262; E-mail: [email protected] Data presented at the Forty Seventh Annual Meeting of the American Society for Therapeutic Radiology and Oncology (ASTRO), October 16 –19, 2005, Denver, CO.
Paul W. Read, M.D., Ph.D., serves on the scientific steering committee and protocol development committee for Tomotherapy. He has received several small honoraria for travel expenses in this role but has received no other compensation. Received Feb 7, 2006, and in revised form April 20, 2006. Accepted for publication May 9, 2006. 620
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with linear accelerators has dominated the published experiences. These reports indicate the treatments are well tolerated and often allow retreatment of the same patient for out-of-field recurrence (11, 12). Side effects reported include mild radiation-induced liver disease (RILD), characterized by transient transaminase elevation with or without fever and rare hemorrhagic gastritis. More recently, a Phase I dose escalation study established the safety of delivering 60 Gy in 3 fractions (13). The goals of the current dosimetric study were to determine if Helical TomoTherapy is a suitable tool for hepatic SBRT and examine the relationship between target dose and normal tissue dose. We therefore examined the effect of the PTV and liver volume on MTD using hypothetical cases planned for treatment with tomotherapy. We hypothesized that the MTD to be delivered in 3 fractions would follow a linear function dependent on both PTV and liver volume. We also wanted to determine whether a simple patient eligibility formula for liver SBRT could be derived to screen potential candidates, especially patients with smaller total liver volumes after partial liver resection for previous metastases, based on easily measurable uninvolved liver and tumor volumes from diagnostic CT or MRI scans. In addition, the effect of PTV location relative to the heart, small bowel, and spinal cord on MTD was explored.
METHODS AND MATERIALS PTV and normal organ contouring An existing CT simulation scan with 3-mm slice thickness was used in the creation of target and normal organ contours. All contouring was performed using AcQsim software (Philips Medical System North America, Bothell, WA). PTV structures were created from hypothetical GTV structures (cylinders of diameters 1 to 6 cm in whole-centimeter increments with similar heights). Cylindrical PTV volumes were used, as most liver metastases are spherical and respiratory motion is the main determinant of the PTV expansion. Because respiratory motion has been shown by multiple investigators to be greater in the craniocaudad dimension than in the anterioposterior and mediolateral dimensions, an asymmetric expansion was used for the PTV, resulting in a cylindrically shaped volume. These structures were used to test the dependence of MTD on PTV and liver volume and were therefore placed in the right liver to minimize the effect of normal organ proximity. PTVs were based on a 5-mm radial expansion and a 10-mm craniocaudal expansion. Livers of volumes ranging from 750 cc to 2000 cc were created and used with the previously mentioned PTV structures. For dosimetric analysis, liver volume included the PTV. Similar PTV structures were also contoured at varying distances from normal organs that included the heart, spinal cord, stomach, and small bowel. To examine the effect of PTV proximity to the heart, PTV structures were placed with the superior most limit of the structure on the CT slices either adjacent, or 2 to 4 slices away from the heart. Based on a CT slice thickness of 3 mm, this corresponded to GTV to heart distances of 12 mm, 15 mm, 18 mm and 21 mm. GTV sizes from 1 to 3 cm only were tested for proximity to the heart, as larger GTV structures in the left lobe of the liver were unable to be accommodated because of proximity to multiple normal structures. For proximity to the stomach and small
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bowel, PTV structures were placed 1 mm, 3 mm, 7 mm, and 11 mm from the small bowel in the radial plane. This corresponds to distances between the GTV and the bowel of 6 mm, 8 mm, 12 mm, and 16 mm. Similarly, PTV structures were placed within 15 mm of the spinal cord, corresponding to a distance between the GTV and the spinal cord of 20 mm. All contouring was performed using AcQsim software with some adjustment of structures using the HI-Art Helical TomoTherapy inverse planning software.
Helical tomotherapy– based inverse planning All planning was performed using the HI-Art Helical TomoTherapy inverse planning software. Plans were run with the goal of delivering the MTD between 30 and 60 Gy while meeting the normal tissue constraints, as per the Colorado Multiple Institutional Review Board (COMIRB) Phase I protocol (13). For the liver, this constraint was 700 cc of normal liver to receive less than 15 Gy. For the heart, stomach, and small bowel, this was 30 Gy maximum point dose. For the spinal cord, this was 18 Gy maximum point dose. Doses were increased or decreased by multiples of 3 Gy until the MTD was achieved. The PTV doses were prescribed to cover 95% of the PTV with no greater than a 140% maximum point dose. For all plans, a 2.5-cm jaw width was used.
Statistical analysis Dosimetric data were analyzed using SYSTAT 11 software (Systat Software Inc., Point Richmond, CA). Multiple regression analysis was performed yielding a linear model based on the PTV and liver volume. Data points of 60 Gy MTD were excluded if they were believed not to represent the true MTD but rather the upper MTD limit considered for this study. Coefficients obtained were analyzed for statistical significance by F-test and significance of F-test. The R2 and adjusted R2 tests were performed to confirm linear fit of model and to give an estimate of the standard error of the model.
RESULTS To explore the relationship between PTV, liver volume, and MTD, 6 hypothetical lesions were evaluated. Table 1 provides the raw dosimetric data from the inverse planning of PTVs from 8 cc to 299 cc in livers of 750 cc to 1625 cc. The uninvolved liver volumes ranged from 742 cc to 1451 cc (mean, 1073 cc; median, 1060 cc). Liver volumes between 1625 cc and 2000 cc were also evaluated and MTD was not constrained by these larger liver volumes, even with the maximum PTV for a 6-cm lesion. These are therefore excluded from this dataset. These data are plotted in Fig. 1, which illustrates the MTD is a linear function of PTV and liver volume. A representative plan from this study is shown in Fig. 2 and illustrates the ability of Helical TomoTherapy to spare normal tissue, such as the spinal cord. This plan used a PTV of 299 cc and a liver of 1625 cc. Considering dose inhomogeneity, all plans resulted in the prescribed dose covering 95% of the PTV and maximum doses varied between 108% and 129%. The average maximum dose was 119% and all hot spots were within the PTV. Minimum PTV doses range from 67% to 89%, with an average of 80%. To model mathematically the data in Table 1, a regression
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Table 1. Maximum tolerable dose (MTD) as determined for each planning target volume (PTV) of listed volume for each listed liver volume Liver volume (cc) 750 GTV (cm)
PTV (cc)
1 2 3 4 5 6
8 25 61 109 190 299
875
1000
1125
1250
1375
1500
1625
60 60 60 60 57 39
60 60 60 60 60 48
60 60 60 60 60 60
MTD (Gy) 33
48 45 30
60 54 42 36
60 60 57 48 36
60 60 60 54 42 30
Structures were created and inverse plans run as per materials and methods. Gross tumor volume (GTV) size corresponding to each PTV expansion is included for reference. Data in bold-face type were included in the regression analysis.
analysis was performed. This yielded the following equation: MTD ⫽ 0.082 (Liver volume) ⫺ 0.16 (PTV) ⫺ 26.7. Both uninvolved liver volume and PTV are in units of cc. Results of the regression analysis of these data indicate this model is an excellent predictive tool. F-tests for all 3 coefficients were statistically significant (p ⬍ 0.0001). Both R2 and adjusted R2 (values of 0.92 and 0.90, respectively) indicate a relatively good fit for the model with a standard error of the estimate to be ⫾3 Gy (data not shown). Figure 3 includes this predictive model in both equation and graphical form. To explore the relationship between PTV proximity to craniocaudal structures and the MTD, dose constraints based on proximity to the heart were also tested. The data are presented in Table 2, which shows that the MTD is constrained as the PTV approaches the heart. GTV sizes ⬎3 cm were found to be the upper limit of size for left hepatic lobe lesions. Radial proximity to normal organs with a maximum point dose of 30 Gy (stomach and small bowel) also constrains the MTD, as shown in Table 3. Again, the MTD is predictably decreased with increasing proximity of the PTV to the normal organ. The MTD is also decreased as the PTV is increased. Data shown in Table 3 were gathered using small
bowel proximity; data gathered using the stomach were found to be in agreement (data not shown). DISCUSSION The integration of the limits on dose found in this study is the crucial step in determining the likely deliverable dose to a liver lesion with Helical TomoTherapy-based SBRT given the dosimetric constraints used. Although it was not tested, the results likely apply to other forms of coplanar IMRT or 3D conformal RT– based SBRT for liver metastasis, as the basic constraints of liver volume, PTV, and prescribed dose are the same. The many degrees of freedom for tomotherapy with beamlets allowed from any angle result in highly conformal coplanar plans. Noncoplanar beam arrangements may have a dosimetric advantage in certain instances although this was not tested in this study. The predictive equation presented provides an initial dose based on the optimal placement of the GTV in reference to constraining normal tissues. Although the predictive value for this linear function is high as indicated by the standard error, the data set had the worst fit at both ends of the PTVs tested. Thus, the dose found using the equation may be a less reliable prediction for extremes of PTV. In addition, the
Fig. 1. Plot of data in Table 1. Each point represents a single data point. The right panel shows the same data as the left, rotated 90° about the vertical axis. PTV ⫽ planning target volume.
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Fig. 2. Representative dosimetry from 1 plan included in the data set. For this 6-cm gross tumor volume (GTV) (planning target volume (PTV) ⫽ 299 cc) in a 1625 cc liver, 60 Gy was found to be the maximum tolerable dose.
dose may be limited by the non–liver-related normal tissue constraints as shown in Tables 2 and 3. Dose constraints caused by proximity to the heart are limited by 2 factors: (1) the craniocaudal expansion of the PTV, and (2) the craniocaudal penumbra from the photon beam. The PTV expansion for this study was 10 mm in the craniocaudad dimension and 5 mm in the radial. This was a generic expansion used for calculation purposes only. Evaluation of tumor motion secondary to respiration with
4D-CT imaging, real-time fluoroscopy, or dynamic MRI in conjunction with abdominal compression allows for patientspecific PTV expansions (14 –18). This could have a large effect on the PTV placement, thereby influencing the prescribed dose. Helical TomoTherapy may reduce the PTV component because of patient setup uncertainty by providing daily image-guided radiotherapy (IGRT) compared with systems without IGRT. This, in conjunction with adequate immobilization and abdominal compression to minimize intrafraction patient respiratory motion (BodyFix vacuum immobilization, for example; Medical Intelligence Corp., Schwabmünchen, Germany) may allow minimal PTV expansions. In reference to the penumbra, the use of smaller jaw size (primary collimator widths) may significantly decrease the penumbra in the direction of the heart while maintaining adequate PTV coverage, although smaller jaw Table 2. Dose constraints based on 30-Gy maximum point dose to the heart Craniocaudal distance from heart 12 mm GTV size 1 cm 2 cm 3 cm
Fig. 3. Predictive equation from the regression analysis of the data in Table 1 and plot of this equation. PTV ⫽ planning target volume.
15 mm
18 mm
21 mm
MTD (Gy) 36 Gy 36 Gy 30 Gy
60 Gy 54 Gy 33 Gy
60 Gy 60 Gy 39 Gy
60 Gy 60 Gy 54 Gy
Abbreviations: GTV ⫽ gross tumor volume; MTD ⫽ maximum tolerable dose. Structures were created and plans were run as described in Methods and Materials section.
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Table 3. Dose constraints based on 30-Gy maximum point dose to the small bowel Radial distance from small bowel 6 mm
8 mm
GTV 3 4 5 6
cm cm cm cm
12 mm
16 mm
MTD (Gy) 60 45 39 39
60 54 45 42
60 57 51 48
60 60 60 60
Abbreviations as in Table 2. Structures were created and plans were run as described in Methods and Materials section.
sizes result in substantially increased treatment time. Additional constraints in relation to proximity to the spinal cord were tested. The proximity between the cord and the GTV were found to have no constraining effect on the tolerated dose, even for lesions up to 6 cm in diameter (data not shown). Normal tissue constraints as presented were tested as separate limitations. The interaction of these constraints is most pertinent in the left lobe of the liver, where proximity to stomach, small bowel, and heart can be simultaneous limiting factors. In this scenario, the utility of the plans as presented may be limited in predicting a tolerable dose. The dose constraints used in this study were taken from a current multi-institutional Phase II SBRT protocol that is accruing patients nationally (Personal Communication with B. Kavanagh, University of Colorado, 2005). This protocol prescribes 60 Gy in 3 fractions. Helical tomotherapy SBRT for liver lesions based on the results of this publication should take this into consideration and should prescribe the MTD based on PTV and liver volume in 3 equal fractions. The dose constraints for normal organs in this trial were extrapolated from the critical volume model (19) as well as the known constraints on partial liver resection (20). The constraint of 700 cc of normal liver to receive less than 15 Gy may be overly conservative for individuals with normal liver function, as no significant instances of RILD have been seen with this constraint (13). Another model used to predict liver tolerance, the NTCP model, has shown that the mean liver dose is the most significant predictor of RILD, with a threshold dose of 31 Gy. This has been supported by several reports of clinical experience (21, 22). All plans in this study also met this constraint, with mean liver doses ranging from 5.3 Gy to 27.7 Gy. Use of SBRT with helical tomotherapy for liver metastases is likely to be increasingly common in the future. The predictive equation reported in this work is intended to add value to treatment planning by providing a likely MTD based on patient-specific normal liver and tumor volumes. There are two main limitations to this model that must be addressed. First, the application of this equation is based on dose constraints that may prove to be overly conservative.
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Reports from the Phase I study by Schefter, et al. indicated that treatment with up to 60 Gy in 3 fractions using 3D-CRT was uniformly well tolerated (13). This study included some patients who would have fallen into the liver volume range included in the present study (uninvolved liver range, 875– 2806 cc; median, 1783 cc). However, given the small number of patients treated, it seems unlikely that many (if any) patients were treated to a dose that would test the limitations of the predictive equation presented here. Indeed, the authors conclude that none of the patients treated were likely to experience RILD, based on mean liver dose. The second factor limiting the usefulness of this model is the lack of precise measurements of normal liver and target volumes before treatment planning. The uninvolved liver and tumor volumes can be measured from diagnostic MRI and CT images resulting in a rapid screen for potential candidates, especially those with small liver volumes after partial liver resection, which is not uncommon in this patient population. Before the simulation, normal liver volume can be predicted by several formulas. Liver volume can be predicted by body surface area (BSA) (23, 24). The model developed based on adults in the western hemisphere is as follows: total liver volume (TLV) ⫽ 1267.28 ⫻ BSA ⫺ 794.41. Vauthey et al. also presented a predictive equation based solely on patient weight, with similar predictive utility to the BSA-based equation. This equation is TLV ⫽ 18.51 ⫻ weight (kg) ⫹ 191.8. Normal liver volume can be measured or predicted from diagnostic CT images as well. PTV prediction may be difficult because of the irregular shape of many tumors as well as the required PTV expansion. This may be easily accomplished for spherical tumors using simple geometric formulas. This study was performed using cylindrical GTV structures with appropriate PTV expansions and therefore may represent a larger than average PTV for the maximum GTV diameter, as listed in Table 1. However the asymmetric expansion of a spherical GTV because of the greatest motion in the craniocaudad direction secondary to respiratory motion will result in a more cylindrical than spherical PTV. These exercises in estimating PTV, liver volumes and subsequently dose may be useful in assessing the feasibility of liver SBRT before treatment simulation but will not substitute for careful CT planning with measurement of respiratory motion. CONCLUSION The HiArt Helical TomoTherapy system (TomoTherapy Inc., Middleton, WI) is capable of performing SBRT for liver lesions that meet the specified target and normal organ constraints as described above. This study provides broad initial screening eligibility criteria for patients with hepatic lesions who may potentially be suitable for tomotherapy or other linac-based SBRT with coplanar beams. These guidelines provide a likely acceptable SBRT dose to start with for planning purposes based on: GTV volume, total liver volume, radial proximity to stomach, small bowel and spinal cord; and craniocaudal proximity to the heart.
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REFERENCES 1. Scheele J, Stang R, Altendorf-Hofmann A, et al. Resection of colorectal liver metastases. World J Surg 1995;19: 59 –71. 2. Blumgart LH, Fong Y. Surgical options in the treatment of hepatic metastasis from colorectal cancer. Curr Probl Surg 1995;32:333– 421. 3. Doci R, Gennari L, Bignami P, et al. One hundred patients with hepatic metastases from colorectal cancer treated by resection: analysis of prognostic determinants. Br J Surg 1991;78:797– 801. 4. Wagner JS, Adson MA, Van Heerden JA, et al. The natural history of hepatic metastases from colorectal cancer. A comparison with resective treatment. Ann Surg 1984;199:502– 508. 5. Gayowski T, Wagener MM, Marino IR, et al. Quality of life and functional status of liver transplant recipients with recurrent viral hepatitis C. Transplant Proc 1999;31:1386 –1387. 6. Rosen CB, Nagorney DM, Taswell HF, et al. Perioperative blood transfusion and determinants of survival after liver resection for metastatic colorectal carcinoma. Ann Surg 1992; 216:493–504; discussion 504 – 495. 7. Fong Y, Cohen AM, Fortner JG, et al. Liver resection for colorectal metastases. J Clin Oncol 1997;15:938 –946. 8. Doci R, Gennari L, Bignami P, et al. Morbidity and mortality after hepatic resection of metastases from colorectal cancer. Br J Surg 1995;82:377–381. 9. Dawson LA, McGinn CJ, Normolle D, et al. Escalated focal liver radiation and concurrent hepatic artery fluorodeoxyuridine for unresectable intrahepatic malignancies. J Clin Oncol 2000;18:2210 –2218. 10. Blomgren H, Lax I, Naslund I, et al. Stereotactic high dose fraction radiation therapy of extracranial tumors using an accelerator. Clinical experience of the first thirty-one patients. Acta Oncol 1995;34:861– 870. 11. Wulf J, Hadinger U, Oppitz U, et al. Stereotactic radiotherapy of targets in the lung and liver. Strahlenther Onkol 2001;177: 645– 655. 12. Herfarth KK, Debus J, Lohr F, et al. Stereotactic single-dose radiation therapy of liver tumors: results of a phase I/II trial. J Clin Oncol 2001;19:164 –170.
13. Schefter TE, Kavanagh BD, Timmerman RD, et al. A phase I trial of stereotactic body radiation therapy (SBRT) for liver metastases. Int J Radiat Oncol Biol Phys 2005;62:1371–1378. 14. Underberg RW, Lagerwaard FJ, Slotman BJ, et al. Benefit of respiration-gated stereotactic radiotherapy for stage I lung cancer: an analysis of 4DCT datasets. Int J Radiat Oncol Biol Phys 2005;62:554 –560. 15. Liu HH, Koch N, Starkschall G, et al. Evaluation of internal lung motion for respiratory-gated radiotherapy using MRI: part II—margin reduction of internal target volume. Int J Radiat Oncol Biol Phys 2004;60:1473–1483. 16. Plathow C, Ley S, Fink C, et al. Analysis of intrathoracic tumor mobility during whole breathing cycle by dynamic MRI. Int J Radiat Oncol Biol Phys 2004;59:952–959. 17. Seppenwoolde Y, Shirato H, Kitamura K, et al. Precise and real-time measurement of 3D tumor motion in lung due to breathing and heartbeat, measured during radiotherapy. Int J Radiat Oncol Biol Phys 2002;53:822– 834. 18. Vedam SS, Keall PJ, Docef A, et al. Predicting respiratory motion for four-dimensional radiotherapy. Med Phys 2004;31: 2274 –2283. 19. Yaes RJ, Kalend A. Local stem cell depletion model for radiation myelitis. Int J Radiat Oncol Biol Phys 1988;14: 1247–1259. 20. Penna C, Nordlinger B. Surgery of liver metastases from colorectal cancer: new promises. Br Med Bull 2002;64:127– 140. 21. McGinn CJ, Ten Haken RK, Ensminger WD, et al. Treatment of intrahepatic cancers with radiation doses based on a normal tissue complication probability model. J Clin Oncol 1998;16: 2246 –2252. 22. Emami B, Lyman J, Brown A, et al. Tolerance of normal tissue to therapeutic irradiation. Int J Radiat Oncol Biol Phys 1991;21:109 –122. 23. Vauthey JN, Abdalla EK, Doherty DA, et al. Body surface area and body weight predict total liver volume in Western adults. Liver Transpl 2002;8:233–240. 24. Urata K, Kawasaki S, Matsunami H, et al. Calculation of child and adult standard liver volume for liver transplantation. Hepatology 1995;21:1317–1321.
doi:10.1016/j.ijrobp.2006.05.034
PHYSICS CONTRIBUTION
DOSE AS A FUNCTION OF LIVER VOLUME AND PLANNING TARGET VOLUME IN HELICAL TOMOTHERAPY, INTENSITY-MODULATED RADIATION THERAPY– BASED STEREOTACTIC BODY RADIATION THERAPY FOR HEPATIC METASTASIS
JAMES
JOSEPH M. BAISDEN, M.D., PH.D.,* ANDREW G. REISH, B.S.E.,† KE SHENG, PH.D.,* M. LARNER, M.D.,* BRIAN D. KAVANAGH, M.D., M.P.H.,‡ AND PAUL W. READ, M.D., PH.D.*
*Department of Radiation Oncology, University of Virginia Health System, Charlottesville, VA; †Medical School, University of Virginia, Charlottesville, VA; and ‡Department of Radiation Oncology, University of Colorado, Aurora, CO Purpose: Stereotactic body radiation therapy (SBRT) has been shown to be an effective, well-tolerated treatment for local control of tumors metastatic to the liver. Multi-institutional Phase II trials are examining 60 Gy in 3 fractions delivered by linac-based, 3D-conformal IMRT. HiArt Helical TomoTherapy is a treatment unit that delivers co-planar helical IMRT that is capable of image-guided SBRT. We hypothesized that the maximum tolerable dose (MTD) delivered to a lesion by Helical TomoTherapy-based SBRT could be predicted based on the planning target volume (PTV) and liver volume. Methods and Materials: To test this, we performed inverse treatment planning and analyzed the dosimetry for multiple hypothetical liver gross tumor volumes (GTV) with conventional PTV expansions. Inverse planning was carried out to find the maximum tolerated SBRT dose up to 60 Gy to be delivered in 3 fractions based on the dose constraint that 700 cc of normal liver would receive less than 15 Gy. Results: Regression analysis indicated a linear relationship between the MTD, the PTV and the liver volume, supporting our hypothesis. A predictive equation was generated, which was found to have an accuracy of ⴞ3 Gy. In addition, dose constraints based on proximity to other normal tissues were tested. Inverse planning for PTVs located at varying distances from the heart, small bowel, and spinal cord revealed a predictable decrease in the MTD as the PTV increased in size or approached normal organs. Conclusions: These data provide a framework for predicting the likely MTD for patients considered for Helical TomoTherapy liver SBRT. © 2006 Elsevier Inc. Tomotherapy, Stereotactic body radiation therapy, Hepatic metastasis, Intensity-modulated radiation therapy, radiosurgery.
INTRODUCTION Liver metastasis represents a significant clinical area in need of improved treatment. The prevalence of liver metastasis is very high, particularly among patients with colorectal, lung, and breast cancer. It has been shown that up to 50% of patients with Stage II and III colorectal cancer will develop liver metastases within 5 years of diagnosis (1). This is approximately 50,000 patients per year, with half of these presenting with liver as the only site of known metastatic disease (2). The 5-year survival rate for patients with liver metastasis treated with only systemic therapies remains less than 5% (3, 4). Surgical resection for selected patients with liver metastasis provides survival benefit, resulting in a
5-year survival of up to 30% (5–7); however, operative/ perioperative mortality is reportedly as high as 6% (8). Radiotherapy has also been explored for liver metastasis. Traditional treatment of 30 Gy in 10 to 12 fractions results in palliative benefit but no substantial survival benefit. Dose escalation with fractionated regimens have shown some benefit (9), and protocols are currently accruing patients to hypofractionated regimens with 30 to 50 Gy in 10 fractions. SBRT has been used to deliver high doses, from 30 to 60 Gy in 3 to 5 fractions via linear accelerator-based therapies. The results from this approach have been promising, showing 1to 2-year local control rates from 65% to 95% (10 –12). Various techniques have been used for hepatic SBRT. Three-dimensional conformal radiation therapy (3D-CRT)
Reprint requests to: Paul W. Read, M.D., Ph.D., Box 800383, Charlottesville, VA 22908. Tel: (434) 924-5191; Fax: (434) 9823262; E-mail: [email protected] Data presented at the Forty Seventh Annual Meeting of the American Society for Therapeutic Radiology and Oncology (ASTRO), October 16 –19, 2005, Denver, CO.
Paul W. Read, M.D., Ph.D., serves on the scientific steering committee and protocol development committee for Tomotherapy. He has received several small honoraria for travel expenses in this role but has received no other compensation. Received Feb 7, 2006, and in revised form April 20, 2006. Accepted for publication May 9, 2006. 620
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with linear accelerators has dominated the published experiences. These reports indicate the treatments are well tolerated and often allow retreatment of the same patient for out-of-field recurrence (11, 12). Side effects reported include mild radiation-induced liver disease (RILD), characterized by transient transaminase elevation with or without fever and rare hemorrhagic gastritis. More recently, a Phase I dose escalation study established the safety of delivering 60 Gy in 3 fractions (13). The goals of the current dosimetric study were to determine if Helical TomoTherapy is a suitable tool for hepatic SBRT and examine the relationship between target dose and normal tissue dose. We therefore examined the effect of the PTV and liver volume on MTD using hypothetical cases planned for treatment with tomotherapy. We hypothesized that the MTD to be delivered in 3 fractions would follow a linear function dependent on both PTV and liver volume. We also wanted to determine whether a simple patient eligibility formula for liver SBRT could be derived to screen potential candidates, especially patients with smaller total liver volumes after partial liver resection for previous metastases, based on easily measurable uninvolved liver and tumor volumes from diagnostic CT or MRI scans. In addition, the effect of PTV location relative to the heart, small bowel, and spinal cord on MTD was explored.
METHODS AND MATERIALS PTV and normal organ contouring An existing CT simulation scan with 3-mm slice thickness was used in the creation of target and normal organ contours. All contouring was performed using AcQsim software (Philips Medical System North America, Bothell, WA). PTV structures were created from hypothetical GTV structures (cylinders of diameters 1 to 6 cm in whole-centimeter increments with similar heights). Cylindrical PTV volumes were used, as most liver metastases are spherical and respiratory motion is the main determinant of the PTV expansion. Because respiratory motion has been shown by multiple investigators to be greater in the craniocaudad dimension than in the anterioposterior and mediolateral dimensions, an asymmetric expansion was used for the PTV, resulting in a cylindrically shaped volume. These structures were used to test the dependence of MTD on PTV and liver volume and were therefore placed in the right liver to minimize the effect of normal organ proximity. PTVs were based on a 5-mm radial expansion and a 10-mm craniocaudal expansion. Livers of volumes ranging from 750 cc to 2000 cc were created and used with the previously mentioned PTV structures. For dosimetric analysis, liver volume included the PTV. Similar PTV structures were also contoured at varying distances from normal organs that included the heart, spinal cord, stomach, and small bowel. To examine the effect of PTV proximity to the heart, PTV structures were placed with the superior most limit of the structure on the CT slices either adjacent, or 2 to 4 slices away from the heart. Based on a CT slice thickness of 3 mm, this corresponded to GTV to heart distances of 12 mm, 15 mm, 18 mm and 21 mm. GTV sizes from 1 to 3 cm only were tested for proximity to the heart, as larger GTV structures in the left lobe of the liver were unable to be accommodated because of proximity to multiple normal structures. For proximity to the stomach and small
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bowel, PTV structures were placed 1 mm, 3 mm, 7 mm, and 11 mm from the small bowel in the radial plane. This corresponds to distances between the GTV and the bowel of 6 mm, 8 mm, 12 mm, and 16 mm. Similarly, PTV structures were placed within 15 mm of the spinal cord, corresponding to a distance between the GTV and the spinal cord of 20 mm. All contouring was performed using AcQsim software with some adjustment of structures using the HI-Art Helical TomoTherapy inverse planning software.
Helical tomotherapy– based inverse planning All planning was performed using the HI-Art Helical TomoTherapy inverse planning software. Plans were run with the goal of delivering the MTD between 30 and 60 Gy while meeting the normal tissue constraints, as per the Colorado Multiple Institutional Review Board (COMIRB) Phase I protocol (13). For the liver, this constraint was 700 cc of normal liver to receive less than 15 Gy. For the heart, stomach, and small bowel, this was 30 Gy maximum point dose. For the spinal cord, this was 18 Gy maximum point dose. Doses were increased or decreased by multiples of 3 Gy until the MTD was achieved. The PTV doses were prescribed to cover 95% of the PTV with no greater than a 140% maximum point dose. For all plans, a 2.5-cm jaw width was used.
Statistical analysis Dosimetric data were analyzed using SYSTAT 11 software (Systat Software Inc., Point Richmond, CA). Multiple regression analysis was performed yielding a linear model based on the PTV and liver volume. Data points of 60 Gy MTD were excluded if they were believed not to represent the true MTD but rather the upper MTD limit considered for this study. Coefficients obtained were analyzed for statistical significance by F-test and significance of F-test. The R2 and adjusted R2 tests were performed to confirm linear fit of model and to give an estimate of the standard error of the model.
RESULTS To explore the relationship between PTV, liver volume, and MTD, 6 hypothetical lesions were evaluated. Table 1 provides the raw dosimetric data from the inverse planning of PTVs from 8 cc to 299 cc in livers of 750 cc to 1625 cc. The uninvolved liver volumes ranged from 742 cc to 1451 cc (mean, 1073 cc; median, 1060 cc). Liver volumes between 1625 cc and 2000 cc were also evaluated and MTD was not constrained by these larger liver volumes, even with the maximum PTV for a 6-cm lesion. These are therefore excluded from this dataset. These data are plotted in Fig. 1, which illustrates the MTD is a linear function of PTV and liver volume. A representative plan from this study is shown in Fig. 2 and illustrates the ability of Helical TomoTherapy to spare normal tissue, such as the spinal cord. This plan used a PTV of 299 cc and a liver of 1625 cc. Considering dose inhomogeneity, all plans resulted in the prescribed dose covering 95% of the PTV and maximum doses varied between 108% and 129%. The average maximum dose was 119% and all hot spots were within the PTV. Minimum PTV doses range from 67% to 89%, with an average of 80%. To model mathematically the data in Table 1, a regression
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Table 1. Maximum tolerable dose (MTD) as determined for each planning target volume (PTV) of listed volume for each listed liver volume Liver volume (cc) 750 GTV (cm)
PTV (cc)
1 2 3 4 5 6
8 25 61 109 190 299
875
1000
1125
1250
1375
1500
1625
60 60 60 60 57 39
60 60 60 60 60 48
60 60 60 60 60 60
MTD (Gy) 33
48 45 30
60 54 42 36
60 60 57 48 36
60 60 60 54 42 30
Structures were created and inverse plans run as per materials and methods. Gross tumor volume (GTV) size corresponding to each PTV expansion is included for reference. Data in bold-face type were included in the regression analysis.
analysis was performed. This yielded the following equation: MTD ⫽ 0.082 (Liver volume) ⫺ 0.16 (PTV) ⫺ 26.7. Both uninvolved liver volume and PTV are in units of cc. Results of the regression analysis of these data indicate this model is an excellent predictive tool. F-tests for all 3 coefficients were statistically significant (p ⬍ 0.0001). Both R2 and adjusted R2 (values of 0.92 and 0.90, respectively) indicate a relatively good fit for the model with a standard error of the estimate to be ⫾3 Gy (data not shown). Figure 3 includes this predictive model in both equation and graphical form. To explore the relationship between PTV proximity to craniocaudal structures and the MTD, dose constraints based on proximity to the heart were also tested. The data are presented in Table 2, which shows that the MTD is constrained as the PTV approaches the heart. GTV sizes ⬎3 cm were found to be the upper limit of size for left hepatic lobe lesions. Radial proximity to normal organs with a maximum point dose of 30 Gy (stomach and small bowel) also constrains the MTD, as shown in Table 3. Again, the MTD is predictably decreased with increasing proximity of the PTV to the normal organ. The MTD is also decreased as the PTV is increased. Data shown in Table 3 were gathered using small
bowel proximity; data gathered using the stomach were found to be in agreement (data not shown). DISCUSSION The integration of the limits on dose found in this study is the crucial step in determining the likely deliverable dose to a liver lesion with Helical TomoTherapy-based SBRT given the dosimetric constraints used. Although it was not tested, the results likely apply to other forms of coplanar IMRT or 3D conformal RT– based SBRT for liver metastasis, as the basic constraints of liver volume, PTV, and prescribed dose are the same. The many degrees of freedom for tomotherapy with beamlets allowed from any angle result in highly conformal coplanar plans. Noncoplanar beam arrangements may have a dosimetric advantage in certain instances although this was not tested in this study. The predictive equation presented provides an initial dose based on the optimal placement of the GTV in reference to constraining normal tissues. Although the predictive value for this linear function is high as indicated by the standard error, the data set had the worst fit at both ends of the PTVs tested. Thus, the dose found using the equation may be a less reliable prediction for extremes of PTV. In addition, the
Fig. 1. Plot of data in Table 1. Each point represents a single data point. The right panel shows the same data as the left, rotated 90° about the vertical axis. PTV ⫽ planning target volume.
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Fig. 2. Representative dosimetry from 1 plan included in the data set. For this 6-cm gross tumor volume (GTV) (planning target volume (PTV) ⫽ 299 cc) in a 1625 cc liver, 60 Gy was found to be the maximum tolerable dose.
dose may be limited by the non–liver-related normal tissue constraints as shown in Tables 2 and 3. Dose constraints caused by proximity to the heart are limited by 2 factors: (1) the craniocaudal expansion of the PTV, and (2) the craniocaudal penumbra from the photon beam. The PTV expansion for this study was 10 mm in the craniocaudad dimension and 5 mm in the radial. This was a generic expansion used for calculation purposes only. Evaluation of tumor motion secondary to respiration with
4D-CT imaging, real-time fluoroscopy, or dynamic MRI in conjunction with abdominal compression allows for patientspecific PTV expansions (14 –18). This could have a large effect on the PTV placement, thereby influencing the prescribed dose. Helical TomoTherapy may reduce the PTV component because of patient setup uncertainty by providing daily image-guided radiotherapy (IGRT) compared with systems without IGRT. This, in conjunction with adequate immobilization and abdominal compression to minimize intrafraction patient respiratory motion (BodyFix vacuum immobilization, for example; Medical Intelligence Corp., Schwabmünchen, Germany) may allow minimal PTV expansions. In reference to the penumbra, the use of smaller jaw size (primary collimator widths) may significantly decrease the penumbra in the direction of the heart while maintaining adequate PTV coverage, although smaller jaw Table 2. Dose constraints based on 30-Gy maximum point dose to the heart Craniocaudal distance from heart 12 mm GTV size 1 cm 2 cm 3 cm
Fig. 3. Predictive equation from the regression analysis of the data in Table 1 and plot of this equation. PTV ⫽ planning target volume.
15 mm
18 mm
21 mm
MTD (Gy) 36 Gy 36 Gy 30 Gy
60 Gy 54 Gy 33 Gy
60 Gy 60 Gy 39 Gy
60 Gy 60 Gy 54 Gy
Abbreviations: GTV ⫽ gross tumor volume; MTD ⫽ maximum tolerable dose. Structures were created and plans were run as described in Methods and Materials section.
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Table 3. Dose constraints based on 30-Gy maximum point dose to the small bowel Radial distance from small bowel 6 mm
8 mm
GTV 3 4 5 6
cm cm cm cm
12 mm
16 mm
MTD (Gy) 60 45 39 39
60 54 45 42
60 57 51 48
60 60 60 60
Abbreviations as in Table 2. Structures were created and plans were run as described in Methods and Materials section.
sizes result in substantially increased treatment time. Additional constraints in relation to proximity to the spinal cord were tested. The proximity between the cord and the GTV were found to have no constraining effect on the tolerated dose, even for lesions up to 6 cm in diameter (data not shown). Normal tissue constraints as presented were tested as separate limitations. The interaction of these constraints is most pertinent in the left lobe of the liver, where proximity to stomach, small bowel, and heart can be simultaneous limiting factors. In this scenario, the utility of the plans as presented may be limited in predicting a tolerable dose. The dose constraints used in this study were taken from a current multi-institutional Phase II SBRT protocol that is accruing patients nationally (Personal Communication with B. Kavanagh, University of Colorado, 2005). This protocol prescribes 60 Gy in 3 fractions. Helical tomotherapy SBRT for liver lesions based on the results of this publication should take this into consideration and should prescribe the MTD based on PTV and liver volume in 3 equal fractions. The dose constraints for normal organs in this trial were extrapolated from the critical volume model (19) as well as the known constraints on partial liver resection (20). The constraint of 700 cc of normal liver to receive less than 15 Gy may be overly conservative for individuals with normal liver function, as no significant instances of RILD have been seen with this constraint (13). Another model used to predict liver tolerance, the NTCP model, has shown that the mean liver dose is the most significant predictor of RILD, with a threshold dose of 31 Gy. This has been supported by several reports of clinical experience (21, 22). All plans in this study also met this constraint, with mean liver doses ranging from 5.3 Gy to 27.7 Gy. Use of SBRT with helical tomotherapy for liver metastases is likely to be increasingly common in the future. The predictive equation reported in this work is intended to add value to treatment planning by providing a likely MTD based on patient-specific normal liver and tumor volumes. There are two main limitations to this model that must be addressed. First, the application of this equation is based on dose constraints that may prove to be overly conservative.
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Reports from the Phase I study by Schefter, et al. indicated that treatment with up to 60 Gy in 3 fractions using 3D-CRT was uniformly well tolerated (13). This study included some patients who would have fallen into the liver volume range included in the present study (uninvolved liver range, 875– 2806 cc; median, 1783 cc). However, given the small number of patients treated, it seems unlikely that many (if any) patients were treated to a dose that would test the limitations of the predictive equation presented here. Indeed, the authors conclude that none of the patients treated were likely to experience RILD, based on mean liver dose. The second factor limiting the usefulness of this model is the lack of precise measurements of normal liver and target volumes before treatment planning. The uninvolved liver and tumor volumes can be measured from diagnostic MRI and CT images resulting in a rapid screen for potential candidates, especially those with small liver volumes after partial liver resection, which is not uncommon in this patient population. Before the simulation, normal liver volume can be predicted by several formulas. Liver volume can be predicted by body surface area (BSA) (23, 24). The model developed based on adults in the western hemisphere is as follows: total liver volume (TLV) ⫽ 1267.28 ⫻ BSA ⫺ 794.41. Vauthey et al. also presented a predictive equation based solely on patient weight, with similar predictive utility to the BSA-based equation. This equation is TLV ⫽ 18.51 ⫻ weight (kg) ⫹ 191.8. Normal liver volume can be measured or predicted from diagnostic CT images as well. PTV prediction may be difficult because of the irregular shape of many tumors as well as the required PTV expansion. This may be easily accomplished for spherical tumors using simple geometric formulas. This study was performed using cylindrical GTV structures with appropriate PTV expansions and therefore may represent a larger than average PTV for the maximum GTV diameter, as listed in Table 1. However the asymmetric expansion of a spherical GTV because of the greatest motion in the craniocaudad direction secondary to respiratory motion will result in a more cylindrical than spherical PTV. These exercises in estimating PTV, liver volumes and subsequently dose may be useful in assessing the feasibility of liver SBRT before treatment simulation but will not substitute for careful CT planning with measurement of respiratory motion. CONCLUSION The HiArt Helical TomoTherapy system (TomoTherapy Inc., Middleton, WI) is capable of performing SBRT for liver lesions that meet the specified target and normal organ constraints as described above. This study provides broad initial screening eligibility criteria for patients with hepatic lesions who may potentially be suitable for tomotherapy or other linac-based SBRT with coplanar beams. These guidelines provide a likely acceptable SBRT dose to start with for planning purposes based on: GTV volume, total liver volume, radial proximity to stomach, small bowel and spinal cord; and craniocaudal proximity to the heart.
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