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Intensity-Modulated Arc Therapy for Pediatric Posterior Fossa Tumors
Int. J. Radiation Oncology Biol. Phys., Vol. 82, No. 2, pp. e299–e304, 2012 Copyright Ó 2012 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/$ - see front matter
doi:10.1016/j.ijrobp.2010.11.024
PHYSICS CONTRIBUTION
INTENSITY-MODULATED ARC THERAPY FOR PEDIATRIC POSTERIOR FOSSA TUMORS CHRIS BELTRAN, PH.D., JONATHAN GRAY, M.S., AND THOMAS E. MERCHANT, D.O., PH.D. Department of Radiological Sciences, St. Jude Children’s Research Hospital, Memphis, TN Purpose: To compare intensity-modulated arc therapy (IMAT) to noncoplanar intensity-modulated radiation therapy (IMRT) in the treatment of pediatric posterior fossa tumors. Methods and Materials: Nine pediatric patients with posterior fossa tumors, mean age 9 years (range, 6–15 years), treated using IMRT were chosen for this comparative planning study because of their tumor location. Each patient’s treatment was replanned to receive 54 Gy to the planning target volume (PTV) using five different methods: eight-field noncoplanar IMRT, single coplanar IMAT, double coplanar IMAT, single noncoplanar IMAT, and double noncoplanar IMAT. For each method, the dose to 95% of the PTV was held constant, and the doses to surrounding critical structures were minimized. The different plans were compared based on conformity, total linear accelerator dose monitor units, and dose to surrounding normal tissues, including the entire body, whole brain, temporal lobes, brainstem, and cochleae. Results: The doses to the target and critical structures for the various IMAT methods were not statistically different in comparison with the noncoplanar IMRT plan, with the following exceptions: the cochlear doses were higher and whole brain dose was lower for coplanar IMAT plans; the cochleae and temporal lobe doses were lower and conformity increased for noncoplanar IMAT plans. The advantage of the noncoplanar IMAT plan was enhanced by doubling the treatment arc. Conclusion: Noncoplanar IMAT results in superior treatment plans when compared to noncoplanar IMRT for the treatment of posterior fossa tumors. IMAT should be considered alongside IMRT when treatment of this site is indicated. Ó 2012 Elsevier Inc. Intensity-modulated arc therapy, Intensity-modulated radiation therapy, Brain tumor, Pediatric.
INTRODUCTION
the goal of delivering the total prescribed dose to the targeted volume and avoiding or selectively reducing dose to normal tissues. The advent of three-dimensional conformal RT (3DCRT) for children with brain tumors over a decade ago showed the advantage of conformal treatment methods, which evolved to show that noncoplanar beam arrangements were superior to coplanar beam arrangements in forward treatment planning (7, 8) and later that intensity-modulated RT (IMRT) was superior to earlier 3DCRT methods (9, 10). Intensity-modulated arc therapy (IMAT) (11) has recently gained popularity because of its ability to rapidly deliver highly conformal treatments with potentially better conformity and normal tissue sparing than IMRT. Dosimetric comparisons between IMAT and IMRT have been published for a variety of sites (12–26). These studies show that IMAT improves target coverage and reduces normal tissue doses with a decrease in treatment time. Along with the dosimetric advantages that IMAT may deliver to pediatric
The indications for radiation therapy (RT) in children with brain tumors has increased during the past decade because of the promise of newer delivery methods that spare normal tissues and reduce side effects (1). Normal tissue dose reduction has been a primary goal of clinical trials for children because of their susceptibility to a wide variety of associated side effects (2–6). There are several ways to reduce normal tissue irradiation, including the way target volumes are defined and highly conformal methods of irradiation. The former includes the definition of the gross tumor volume (GTV), which is the volume at highest risk for tumor recurrence, the disease-specific clinical target volume (CTV) margins chosen to encompass subclinical microscopic disease, and the margins chosen to account for variability in patient positioning, which are dependent on sophisticated methods of immobilization and verification. The latter includes high-conformity RT methods used with Reprint requests to: Chris Beltran, Ph.D., Division of Radiation Oncology, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, MS #220, Memphis, TN 38120, USA. Tel: (902) 595-2389; Fax: (901) 595-3981; E-mail: [email protected] Presented in part at the American Association of Physicist in Medicine conference held in Anaheim, CA July 18-22, 2010.
Supported by the American Lebanese Syrian Associated Charities. Conflict of interest: none Received April 13, 2010, and in revised form Nov 16, 2010. Accepted for publication Nov 24, 2010. e299
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patients, the possibility of reduced treatment time has a unique benefit for pediatric patients. Reducing the amount of time while patients are under general anesthesia would be beneficial for young children and increase compliance for those who are older and do not require anesthesia. Concerns about IMAT for children have focused on two questions: can IMAT deliver more conformal treatment than noncoplanar IMRT, and is there an increase in the volume of normal tissue that receives both low and intermediate doses? To address these concerns, we designed a treatment planning study to investigate the potential benefits of coplanar and noncoplanar IMAT compared to noncoplanar IMRT for pediatric patients with posterior fossa tumors. The posterior fossa was the focus of our investigation because it is the most commonly irradiated site in children with brain tumors (1). METHODS AND MATERIALS Nine children with posterior fossa tumors (medulloblastoma) and a median age of 9.6 years (range, 6.1–15.1 years) were included in this study. Five new plans were created for each patient: stepand-shoot noncoplanar IMRT (NC-IMRT), single coplanar IMAT (IMAT), double coplanar IMAT (double IMAT), single noncoplanar IMAT (NC-IMAT), and double noncoplanar IMAT (double NC-IMAT). The planning target volume (PTV) was the volume created by expanding the CTV with a geometric margin of 0.3 centimeters. The CTV was an anatomically confined expansion of GTV using a margin of 1.0 centimeters, and the GTV was the postoperative residual tumor bed. The goal of treatment planning was to irradiate the PTV with a total dose of 54 Gy and minimize dose to normal tissues, including cochleae, brainstem, spinal cord, hypothalamus, and supratentorial brain. Although the treatment of medulloblastoma generally involves craniospinal irradiation, in addition to treatment of the primary site, there is a trend toward omitting craniospinal irradiation for young children. In addition, the primary site of irradiation for medulloblastoma matches treatment of other posterior fossa tumors (ependymoma, low-grade glioma) in terms of dose, target location, target volume, target margins, and normal tissue dose constraints; therefore, this patient population can act as a reasonable surrogate for other types of tumors. Planning for all the arc treatments include the creation of an avoidance structure in the face to reduce dose to this area. All treatment plans were created by one physicist with the Pinnacle treatment planning system version 9.0 (Phillips Medical Systems, Fitchburg, WI). The IMRT plans consisted of eight fields with the gantry (G) and treatment table (T) optimized for each patient; the general setup is given in Table 1. IMAT started at G = 180, rotated clockwise, and ended at G = 180. Double IMAT started at G = 180, rotated clockwise 360 until it reached G = 180, then rotated counterclockwise back to G = 180. The NC-IMAT consisted of an IMAT followed by a table rotation to T = 270 and an arc from G = 180 to 40.
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The double NC-IMAT consisted of a double IMAT followed by a table rotation to T = 270 and an arc from G = 180 to 40 then back again to G = 180. The key settings in Pinnacle for dynamic arc therapy were 4 gantry spacing with maximum delivery time of 90 seconds per arc; axial arcs traversed 360 , whereas the sagittal arcs traversed only 220 because of gantry/couch collision constraints. For each planning method of every patient, the initial optimization criteria were identical and were modified during optimization to maximize target coverage and minimize dose to normal structures. The dose of each arc plan was renormalized to ensure that the dose to 95% of the PTV (D95) would be equal to the D95 of the IMRT plan for each patient. The plans were then compared based on the volume of the scanned body (top of the head to the sternal notch) receiving a dose of 5% and 50% of the prescription (V5 and V50), the dose to 5% (D5) of serial-type structures—spinal cord (cord) and brainstem—and the mean dose (D50) to paralleltype structures: right and left cochleae, whole brain (brain), and the temporal lobes. Also of interest was the conformity index (CI) of the 98% dose volume to the PTV and the number of linear accelerator monitor units (MU). The CI was calculated based on the method described by Van’t Reit et al. (27). This method calculates the CI using the target volume covered by the reference isodose (TVRI), target volume (TV), and volume of the reference isodose (VRI), CI ¼ ðTVRI TVRI Þ=ðTV VRI Þ. A paired Student’s t-test was used to determine statistical significance between the IMAT plans and the IMRT plans for the above-mentioned items. A p value of <0.05 was considered to indicate statistical significance.
RESULTS The average PTV was 84 21 cc (range, 61–114). Five of the targets were centrally located within the posterior fossa; two had a predominant bias to the left; and two to the right. Comparing IMAT and double IMAT to NC-IMRT, the body V5 (p < 0.01) and brain D50 (p < 0.01) were reduced, the body V50 (p < 0.01) and cochlear D50 (right, p < 0.04; left, p < 0.01) were increased, and the CI (p = 0.01) and MU (p < 0.01) were decreased. Comparing NC-IMAT to NCIMRT, the body V5 was increased (p = 0.01), and the right cochlear D50 (p < 0.01) and left and right temporal lobes D50 (p = 0.01) were decreased. Comparing double NCIMAT to NC-IMRT, the body V50, right and left cochlear D50 (p = 0.05) and right (p < 0.01) and left (p = 0.05) temporal lobe D50 were decreased, whereas the body V5 (p < 0.01), number of MU (p < 0.01), and CI were increased (p = 0.05). Table 2 contains the CI, MU, and mean, standard deviation, and p values for all structures of interests. Figure 1 shows the PTV and the IMRT, double IMAT, and double NC-IMAT isodose distributions for a representative patient. Apparent is the difference in the low (10%) and medium (50%) dose distributions for each plan. Figure 2 includes the dose–volume histogram of selected structures for the
Table 1. General beam setup, gantry (G), and treatment table (T) angles for the eight-field noncoplanar intensity-modulated radiation therapy plans Field 1
Field 2
Field 3
Field 4
Field 5
Field 6
Field 7
Field 8
G
T
G
T
G
T
G
T
G
T
G
T
G
T
G
T
335
90
320
15
50
90
320
330
55
345
55
35
110
40
250
320
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Table 2. Mean, standard deviation (SD), and p values for structures of interest, conformity index (CI), and monitor units (MU) for each planning method
Body Body V5% (cc) V50% (cc) NC-IMRT Mean 2437 StDev 228 IMAT Mean 1650 SD 252 p <0.01 Double IMAT Mean 1655 SD 273 p <0.01 NC-IMAT Mean 2733 SD 452 p 0.01 Double NC-IMAT Mean 2761 SD 404 p <0.01
Brainstem D5 (Gy)
Left Right cochlea cochlea Whole Optic Right Left CI D50 D50 brain chiasm T-lobe T-lobe 98% (Gy) (Gy) D50 (Gy) D5 (Gy) D50 (Gy) D50 (Gy) Isodose
Number of MU
304 40
53.72 3.65
18.79 9.64
20.30 8.82
11.22 1.92
9.51 4.07
12.20 5.03
13.62 5.23
0.68 0.03
352.1 48.9
409 68 <0.01
53.61 4.75 0.77
23.83 10.30 <0.01
26.09 8.89 <0.01
2.24 0.93 <0.01
8.24 3.97 0.21
11.36 6.52 0.51
12.59 6.99 0.72
0.65 0.03 0.01
278.2 34.1 <0.01
388 69 <0.01
53.64 5.43 0.90
21.61 10.23 0.04
23.90 9.42 0.01
2.29 1.08 <0.01
7.11 3.65 0.02
11.37 6.32 0.53
12.53 6.65 0.70
0.69 0.03 0.57
343.2 41.6 0.68
285 57 0.07
53.83 4.14 0.62
14.93 8.47 0.01
16.65 9.07 0.06
10.37 2.16 0.24
6.73 2.95 0.01
8.59 5.31 0.01
10.97 5.62 0.11
0.70 0.03 0.20
371.6 42.1 0.37
264 52 <0.01
53.71 4.81 0.97
13.32 7.51 <0.01
14.67 8.19 0.01
10.68 2.49 0.49
6.48 2.71 0.01
8.01 5.09 0.01
10.01 4.90 0.05
0.71 0.02 0.05
521.6 64.3 <0.01
The p value is based on the various intensity-modulated arc therapy (IMAT) planning method vs. the noncoplanar intensity modulated radiation therapy (NC-IMRT) plans. The p values in bold type indicate an improvement of the arc plan over NC-IMRT; italics indicate degradation.
NC-IMRT and double NC-IMAT plans for the chosen representative patient. Figure 3 is a bar graph comparing the critical structure doses for each planning method. There were 4 patients who had NC-IMRT plans wherein both right and left cochleae received more than 25 Gy; the average for these patients was 27.9 Gy. The average dose was increased for the IMAT (32.7 Gy p = 0.01) and double IMAT (31.0 Gy p = 0.05) plans. The dose decreased to 22.5 Gy (p = 0.03) for the NC-IMAT and to 20.0 Gy (p < 0.01) for the double NC-IMAT plan. Figure 4 depicts the change in cochlear doses for each of these patients based on planning method. The size of the target did influence the dose to some normal structures for all plan types. Specifically for the NC-
IMRT and double NC-IMAT, there was a positive and statistically significant (p < 0.05) correlation for the Pearson coefficient of determination between the size of the target and dose to body V50, cochlear D50, and brain D50. Comparing the dose differences between NC-IMRT and double NCIMAT, only the body V50 had a statistically significant correlation between target size and dose difference. DISCUSSION The results of this study confirm the advantages of noncoplanar methods to reduce the intermediate- and high-dose volumes of normal tissue irradiation with the cost of
Fig. 1. The isodose distributions (95%, 50%, and 10% of the prescribed dose) and planning target volume (PTV) for a representative patient for the noncoplanar intensity-modulated radiation therapy (NC-IMRT), double-intensity modulated arc therapy (double IMAT), and double noncoplanar IMAT (double NC-IMAT) plans in three different views.
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Fig. 2. Planning target volume (PTV), right temporal lobe, right cochlea, and body dose–volume histograms calculated from a representative patient for noncoplanar intensity-modulated radiation therapy (NC-IMRT, dotted line) and double noncoplanar intensity-modulated arc therapy (double NC-IMAT, solid line).
increasing the volume that receives the lowest doses and the required linear accelerator MU and treatment times. Although there is some debate surrounding the relative merits of highly conformal therapy when normal tissue irradiation is increased, conformity should be a priority in the treatment of pediatric brain tumor patients with RT for the most severe and highly consequential effects in these patients, namely, necrosis, vasculopathy, and secondary malignancies, which arise predominately in the high-dose volume (28, 29). In addition, the insidious and more commonly observed effects on cognition, endocrine function, and hearing are attributed to the volume that receives the highest doses
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as suggested by central nervous system dose effects models in pediatric patients (3, 5, 30, 31). This position does not suggest that normal tissue irradiation is without consequences, nor does it diminish the impact of low-dose normal tissue irradiation to reduce the tolerance of functional elements within normal tissues of the same organ that receive the highest doses. The doses prescribed for the treatment of pediatric patients with brain tumors tend to be in the conservative range in terms of dose, expected response, and potential for severe complications. In addition, the same pediatric central nervous system dose effects models noted above indicate that low-dose irradiation has a statistically significant effect but one that is an order of magnitude smaller than when similar volumes receive higher doses. We found that for smaller targets, the dose to the normal structures was lower. This may explain the large standard deviations in normal tissue doses shown in Table 2, inasmuch as the largest target was nearly twice the size of the smallest. In general, it seemed that when critical structures were far from the PTV, target coverage compromise was not required to achieve normal tissue sparing such that double NC-IMAT and NC-IMRT yielded similar benefits. However, double NC-IMAT did allow better sparing of critical structures in close proximity to the PTV because of its ability to distribute dose that resulted in no noticeable beam pathway. Based on these findings, NC-IMAT has merit and should be considered alongside IMRT for pediatric patients with posterior fossa tumors. Wagner et al. (23) recommended using 3DCRT for pediatric patients over IMRT or IMAT. This recommendation was derived from their calculations that the body V5 was 8% larger for IMRT than for 3DCRT (2953 vs. 2721 cc).However, based on their data, the mean dose
Fig. 3. Bar graph displaying the mean and standard deviation for critical structures by dose, volume, conformity index, and monitor units using different planning methods. IMRT = intensity-modulated radiation therapy; IMAT = intensitymodulated arc therapy; D50 = dose (cGy) to 50% of the volume; V5% and V50% = volume (cc) receiving 5% or 50% of the prescribed dose; MU = linear accelerator monitor units.
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Fig. 4. Bar graph displaying the change in cochlear doses based on planning method for the 4 patients who received high noncoplanar IMRT cochlear doses. IMRT = intensity-modulated radiation therapy; IMAT = intensity-modulated arc therapy; R1 = Patient 1 right cochlea, L1 = Patient 1 left cochlea (R1 and L2, Patient 2; etc.).
to the body was the same for the two methods, and the target coverage for 3DCRT was noticeably worse, with a D95 of 54.0 Gy for 3DCRT vs. 56.7 Gy for IMRT (the prescribed dose was 60 Gy). If the 3DCRT D95 were increased to match the IMRT D95, the body D50 of the 3DCRT plan would actually be greater than the body D50 of the IMRT plan. Hence, the minimal difference in V5, when compared to the target coverage compromise, may not justify a recommendation of 3DCRT over IMRT for pediatric brain tumor patients. Comparing the various arc planning methods, we found that multiple arcs were better than single arcs and that noncoplanar arcs improved conformity and decreased dose to normal tissues. These findings paralleled, respectively, those of Guckenberger et al. (16) and Krayenbuehl et al. (17), who studied adult tumors at different body sites. Based on these findings, a direct comparison between NC-IMRT and double NC-IMAT favors the former because of the lower V5 (10%) and required MU. Directly countering this are lower body V50, brain, temporal lobe, and cochlear D50 values for
the double NC-IMAT and increased conformity. NC-IMAT may have an advantage when treatment time is considered. Based on a study by Oliver et al. (18), the estimated treatment time is 1.5 minutes for IMAT and 3 minutes for double IMAT. Taking this into account and including the treatment table rotation, the treatment time for the double NC-IMAT would be 8 minutes. An efficiently delivered eight-field NC-IMRT takes approximately 10 minutes.
CONCLUSION Double NC-IMAT has the potential to improve the treatment of posterior fossa tumors in pediatric patients when compared to noncoplanar IMRT. For certain patients, this option may provide significant dose reduction to normal tissues with increased conformity of the high-dose volume. This method has merit and should be considered alongside IMRT for pediatric patients with posterior fossa tumors.
REFERENCES 1. Merchant TE, Pollack IF, Loeffler JS. Brain tumors across the age spectrum: Biology, therapy, and late effects. Semin Radiat Oncol 2010;20:58–66. 2. Brenner DJ, Hall EJ. Computed tomography: An increasing source of radiation exposure. N Engl J Med 2007;357:2277– 2284. 3. Hua C, Bass JK, Khan R, et al. Hearing loss after radiotherapy for pediatric brain tumors: Effect of cochlear dose. Int J Radiat Oncol Biol Phys 2008;72:892–899. 4. Krasin MJ, Xiong X, Wu S, et al. The effects of external beam irradiation on the growth of flat bones in children: Modeling
a dose-volume effect. Int J Radiat Oncol Biol Phys 2005;62: 1458–1463. 5. Merchant TE, Kiehna EN, Li C, et al. Radiation dosimetry predicts IQ after conformal radiation therapy in pediatric patients with localized ependymoma. Int J Radiat Oncol Biol Phys 2005;63:1546–1554. 6. Merchant TE, Kiehna EN, Miles MA, et al. Acute effects of irradiation on cognition: Changes in attention on a computerized continuous performance test during radiotherapy in pediatric patients with localized primary brain tumors. Int J Radiat Oncol Biol Phys 2002;53:1271–1278.
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7. Pugachev A, Li JG, Boyer AL, et al. Role of beam orientation optimization in intensity-modulated radiation therapy. Int J Radiat Oncol Biol Phys 2001;50:551–560. 8. Llacer J, Li S, Agazaryan N, et al. Non-coplanar automatic beam orientation selection in cranial IMRT: A practical methodology. Phys Med Biol 2009;54:1337–1368. 9. Hermanto U, Frija EK, Lii MJ, et al. Intensity-modulated radiotherapy (IMRT) and conventional three-dimensional conformal radiotherapy for high-grade gliomas: Does IMRT increase the integral dose to normal brain? Int J Radiat Oncol BiolPhys 2007;67:1135–1144. 10. Beltran C, Naik M, Merchant TE. Dosimetric effect of setup motion and target volume margin reduction in pediatric ependymoma. Radiother Oncol 2010;96:216–222. 11. Yu CX. Intensity-modulated arc therapy with dynamic multileaf collimation: An alternative to tomotherapy. Phys Med Biol 1995;40:1435–1449. 12. Bignardi M, Cozzi L, Fogliata A, et al. Critical appraisal of volumetric modulated arc therapy in stereotactic body radiation therapy for metastases to abdominal lymph nodes. Int J Radiat Oncol Biol Phys 2009;75:1570–1577. 13. Cozzi L, Dinshaw KA, Shrivastava SK, et al. A treatment planning study comparing volumetric arc modulation with RapidArc and fixed field IMRT for cervix uteri radiotherapy. Radiother Oncol 2008;89:180–191. 14. Duthoy W, De Gersem W, Vergote K, et al. Clinical implementation of intensity-modulated arc therapy (IMAT) for rectal cancer. Int J Radiat Oncol Biol Phys 2004;60:794–806. 15. Fogliata A, Clivio A, Nicolini G, et al. Intensity modulation with photons for benign intracranial tumours: A planning comparison of volumetric single arc, helical arc and fixed gantry techniques. Radiother Oncol 2008;89:254–262. 16. Guckenberger M, Richter A, Krieger T, et al. Is a single arc sufficient in volumetric-modulated arc therapy (VMAT) for complex-shaped target volumes? Radiother Oncol 2009;93: 259–265. 17. Krayenbuehl J, Davis JB, Ciernik IF. Dynamic intensitymodulated non-coplanar arc radiotherapy (INCA) for head and neck cancer. Radiother Oncol 2006;81:151–157. 18. Oliver M, Ansbacher W, Beckham WA. Comparing planning time, delivery time and plan quality for IMRT, RapidArc and tomotherapy. J Appl Clin Med Phys 2009;10:3068. 19. Palma D, Vollans E, James K, et al. Volumetric modulated arc therapy for delivery of prostate radiotherapy: Comparison with intensity-modulated radiotherapy and three-dimensional conformal radiotherapy. Int J Radiat Oncol Biol Phys 2008;72: 996–1001.
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20. Popescu CC, Olivotto IA, Beckham WA, et al. Volumetric modulated arc therapy improves dosimetry and reduces treatment time compared to conventional intensity-modulated radiotherapy for locoregional radiotherapy of left-sided breast cancer and internal mammary nodes. Int J Radiat Oncol Biol Phys 2010;76:287–295. 21. Shaffer R, Nichol AM, Vollans E, et al. A comparison of volumetric modulated arc therapy and conventional intensitymodulated radiotherapy for frontal and temporal high-grade gliomas. Int J Radiat Oncol Biol Phys 2010;76:1177–1184. 22. Verbakel WFAR, Cuijpers JP, Hoffmans D, et al. Volumetric intensity-modulated arc therapy vs. conventional imrt in head-and-neck cancer: A comparative planning and dosimetric study. Int J Radiat Oncol Biol Phys 2009;74:252–259. 23. Wagner D, Christiansen H, Wolff H, et al. Radiotherapy of malignant gliomas: Comparison of volumetric single arc technique (RapidArc), dynamic intensity-modulated technique and 3D conformal technique. Radiother Oncol 2009;93:593–596. 24. Wiggenraad RGJ, Petoukhova AL, Versluis L, et al. Stereotactic radiotherapy of intracranial tumors: A comparison of intensity-modulated radiotherapy and dynamic conformal arc. Int J Radiat Oncol Biol Phys 2009;74:1018–1026. 25. Wolff D, Stieler F, Welzel G, et al. Volumetric modulated arc therapy (VMAT) vs. serial tomotherapy, step-and-shoot IMRT and 3D-conformal RT for treatment of prostate cancer. Radiother Oncol 2009;93:226–233. 26. Wong E, D’Souza DP, Chen JZ, et al. Intensity-modulated arc therapy for treatment of high-risk endometrial malignancies. Int J Radiat Oncol Biol Phys 2005;61:830–841. 27. van’t Riet A, Mak AC, Moerland MA, et al. A conformation number to quantify the degree of conformality in brachytherapy and external beam irradiation: Application to the prostate. Int J Radiat Oncol Biol Phys 1997;37:731–736. 28. Merchant TE, Kun LE, Wu S, et al. Phase II trial of conformal radiation therapy for pediatric low-grade glioma. J Clin Oncol 2009;27:3598–3604. 29. Merchant TE, Li C, Xiong X, et al. Conformal radiotherapy after surgery for paediatric ependymoma: A prospective study. Lancet Oncol 2009;10:258–266. 30. Merchant TE, Conklin HM, Wu S, et al. Late effects of conformal radiation therapy for pediatric patients with low-grade glioma: Prospective evaluation of cognitive, endocrine, and hearing deficits. J Clin Oncol 2009;27:3691–3697. 31. Merchant TE, Goloubeva O, Pritchard DL, et al. Radiation dose-volume effects on growth hormone secretion. Int J Radiat Oncol Biol Phys 2002;52:1264–1270.
doi:10.1016/j.ijrobp.2010.11.024
PHYSICS CONTRIBUTION
INTENSITY-MODULATED ARC THERAPY FOR PEDIATRIC POSTERIOR FOSSA TUMORS CHRIS BELTRAN, PH.D., JONATHAN GRAY, M.S., AND THOMAS E. MERCHANT, D.O., PH.D. Department of Radiological Sciences, St. Jude Children’s Research Hospital, Memphis, TN Purpose: To compare intensity-modulated arc therapy (IMAT) to noncoplanar intensity-modulated radiation therapy (IMRT) in the treatment of pediatric posterior fossa tumors. Methods and Materials: Nine pediatric patients with posterior fossa tumors, mean age 9 years (range, 6–15 years), treated using IMRT were chosen for this comparative planning study because of their tumor location. Each patient’s treatment was replanned to receive 54 Gy to the planning target volume (PTV) using five different methods: eight-field noncoplanar IMRT, single coplanar IMAT, double coplanar IMAT, single noncoplanar IMAT, and double noncoplanar IMAT. For each method, the dose to 95% of the PTV was held constant, and the doses to surrounding critical structures were minimized. The different plans were compared based on conformity, total linear accelerator dose monitor units, and dose to surrounding normal tissues, including the entire body, whole brain, temporal lobes, brainstem, and cochleae. Results: The doses to the target and critical structures for the various IMAT methods were not statistically different in comparison with the noncoplanar IMRT plan, with the following exceptions: the cochlear doses were higher and whole brain dose was lower for coplanar IMAT plans; the cochleae and temporal lobe doses were lower and conformity increased for noncoplanar IMAT plans. The advantage of the noncoplanar IMAT plan was enhanced by doubling the treatment arc. Conclusion: Noncoplanar IMAT results in superior treatment plans when compared to noncoplanar IMRT for the treatment of posterior fossa tumors. IMAT should be considered alongside IMRT when treatment of this site is indicated. Ó 2012 Elsevier Inc. Intensity-modulated arc therapy, Intensity-modulated radiation therapy, Brain tumor, Pediatric.
INTRODUCTION
the goal of delivering the total prescribed dose to the targeted volume and avoiding or selectively reducing dose to normal tissues. The advent of three-dimensional conformal RT (3DCRT) for children with brain tumors over a decade ago showed the advantage of conformal treatment methods, which evolved to show that noncoplanar beam arrangements were superior to coplanar beam arrangements in forward treatment planning (7, 8) and later that intensity-modulated RT (IMRT) was superior to earlier 3DCRT methods (9, 10). Intensity-modulated arc therapy (IMAT) (11) has recently gained popularity because of its ability to rapidly deliver highly conformal treatments with potentially better conformity and normal tissue sparing than IMRT. Dosimetric comparisons between IMAT and IMRT have been published for a variety of sites (12–26). These studies show that IMAT improves target coverage and reduces normal tissue doses with a decrease in treatment time. Along with the dosimetric advantages that IMAT may deliver to pediatric
The indications for radiation therapy (RT) in children with brain tumors has increased during the past decade because of the promise of newer delivery methods that spare normal tissues and reduce side effects (1). Normal tissue dose reduction has been a primary goal of clinical trials for children because of their susceptibility to a wide variety of associated side effects (2–6). There are several ways to reduce normal tissue irradiation, including the way target volumes are defined and highly conformal methods of irradiation. The former includes the definition of the gross tumor volume (GTV), which is the volume at highest risk for tumor recurrence, the disease-specific clinical target volume (CTV) margins chosen to encompass subclinical microscopic disease, and the margins chosen to account for variability in patient positioning, which are dependent on sophisticated methods of immobilization and verification. The latter includes high-conformity RT methods used with Reprint requests to: Chris Beltran, Ph.D., Division of Radiation Oncology, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, MS #220, Memphis, TN 38120, USA. Tel: (902) 595-2389; Fax: (901) 595-3981; E-mail: [email protected] Presented in part at the American Association of Physicist in Medicine conference held in Anaheim, CA July 18-22, 2010.
Supported by the American Lebanese Syrian Associated Charities. Conflict of interest: none Received April 13, 2010, and in revised form Nov 16, 2010. Accepted for publication Nov 24, 2010. e299
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patients, the possibility of reduced treatment time has a unique benefit for pediatric patients. Reducing the amount of time while patients are under general anesthesia would be beneficial for young children and increase compliance for those who are older and do not require anesthesia. Concerns about IMAT for children have focused on two questions: can IMAT deliver more conformal treatment than noncoplanar IMRT, and is there an increase in the volume of normal tissue that receives both low and intermediate doses? To address these concerns, we designed a treatment planning study to investigate the potential benefits of coplanar and noncoplanar IMAT compared to noncoplanar IMRT for pediatric patients with posterior fossa tumors. The posterior fossa was the focus of our investigation because it is the most commonly irradiated site in children with brain tumors (1). METHODS AND MATERIALS Nine children with posterior fossa tumors (medulloblastoma) and a median age of 9.6 years (range, 6.1–15.1 years) were included in this study. Five new plans were created for each patient: stepand-shoot noncoplanar IMRT (NC-IMRT), single coplanar IMAT (IMAT), double coplanar IMAT (double IMAT), single noncoplanar IMAT (NC-IMAT), and double noncoplanar IMAT (double NC-IMAT). The planning target volume (PTV) was the volume created by expanding the CTV with a geometric margin of 0.3 centimeters. The CTV was an anatomically confined expansion of GTV using a margin of 1.0 centimeters, and the GTV was the postoperative residual tumor bed. The goal of treatment planning was to irradiate the PTV with a total dose of 54 Gy and minimize dose to normal tissues, including cochleae, brainstem, spinal cord, hypothalamus, and supratentorial brain. Although the treatment of medulloblastoma generally involves craniospinal irradiation, in addition to treatment of the primary site, there is a trend toward omitting craniospinal irradiation for young children. In addition, the primary site of irradiation for medulloblastoma matches treatment of other posterior fossa tumors (ependymoma, low-grade glioma) in terms of dose, target location, target volume, target margins, and normal tissue dose constraints; therefore, this patient population can act as a reasonable surrogate for other types of tumors. Planning for all the arc treatments include the creation of an avoidance structure in the face to reduce dose to this area. All treatment plans were created by one physicist with the Pinnacle treatment planning system version 9.0 (Phillips Medical Systems, Fitchburg, WI). The IMRT plans consisted of eight fields with the gantry (G) and treatment table (T) optimized for each patient; the general setup is given in Table 1. IMAT started at G = 180, rotated clockwise, and ended at G = 180. Double IMAT started at G = 180, rotated clockwise 360 until it reached G = 180, then rotated counterclockwise back to G = 180. The NC-IMAT consisted of an IMAT followed by a table rotation to T = 270 and an arc from G = 180 to 40.
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The double NC-IMAT consisted of a double IMAT followed by a table rotation to T = 270 and an arc from G = 180 to 40 then back again to G = 180. The key settings in Pinnacle for dynamic arc therapy were 4 gantry spacing with maximum delivery time of 90 seconds per arc; axial arcs traversed 360 , whereas the sagittal arcs traversed only 220 because of gantry/couch collision constraints. For each planning method of every patient, the initial optimization criteria were identical and were modified during optimization to maximize target coverage and minimize dose to normal structures. The dose of each arc plan was renormalized to ensure that the dose to 95% of the PTV (D95) would be equal to the D95 of the IMRT plan for each patient. The plans were then compared based on the volume of the scanned body (top of the head to the sternal notch) receiving a dose of 5% and 50% of the prescription (V5 and V50), the dose to 5% (D5) of serial-type structures—spinal cord (cord) and brainstem—and the mean dose (D50) to paralleltype structures: right and left cochleae, whole brain (brain), and the temporal lobes. Also of interest was the conformity index (CI) of the 98% dose volume to the PTV and the number of linear accelerator monitor units (MU). The CI was calculated based on the method described by Van’t Reit et al. (27). This method calculates the CI using the target volume covered by the reference isodose (TVRI), target volume (TV), and volume of the reference isodose (VRI), CI ¼ ðTVRI TVRI Þ=ðTV VRI Þ. A paired Student’s t-test was used to determine statistical significance between the IMAT plans and the IMRT plans for the above-mentioned items. A p value of <0.05 was considered to indicate statistical significance.
RESULTS The average PTV was 84 21 cc (range, 61–114). Five of the targets were centrally located within the posterior fossa; two had a predominant bias to the left; and two to the right. Comparing IMAT and double IMAT to NC-IMRT, the body V5 (p < 0.01) and brain D50 (p < 0.01) were reduced, the body V50 (p < 0.01) and cochlear D50 (right, p < 0.04; left, p < 0.01) were increased, and the CI (p = 0.01) and MU (p < 0.01) were decreased. Comparing NC-IMAT to NCIMRT, the body V5 was increased (p = 0.01), and the right cochlear D50 (p < 0.01) and left and right temporal lobes D50 (p = 0.01) were decreased. Comparing double NCIMAT to NC-IMRT, the body V50, right and left cochlear D50 (p = 0.05) and right (p < 0.01) and left (p = 0.05) temporal lobe D50 were decreased, whereas the body V5 (p < 0.01), number of MU (p < 0.01), and CI were increased (p = 0.05). Table 2 contains the CI, MU, and mean, standard deviation, and p values for all structures of interests. Figure 1 shows the PTV and the IMRT, double IMAT, and double NC-IMAT isodose distributions for a representative patient. Apparent is the difference in the low (10%) and medium (50%) dose distributions for each plan. Figure 2 includes the dose–volume histogram of selected structures for the
Table 1. General beam setup, gantry (G), and treatment table (T) angles for the eight-field noncoplanar intensity-modulated radiation therapy plans Field 1
Field 2
Field 3
Field 4
Field 5
Field 6
Field 7
Field 8
G
T
G
T
G
T
G
T
G
T
G
T
G
T
G
T
335
90
320
15
50
90
320
330
55
345
55
35
110
40
250
320
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Table 2. Mean, standard deviation (SD), and p values for structures of interest, conformity index (CI), and monitor units (MU) for each planning method
Body Body V5% (cc) V50% (cc) NC-IMRT Mean 2437 StDev 228 IMAT Mean 1650 SD 252 p <0.01 Double IMAT Mean 1655 SD 273 p <0.01 NC-IMAT Mean 2733 SD 452 p 0.01 Double NC-IMAT Mean 2761 SD 404 p <0.01
Brainstem D5 (Gy)
Left Right cochlea cochlea Whole Optic Right Left CI D50 D50 brain chiasm T-lobe T-lobe 98% (Gy) (Gy) D50 (Gy) D5 (Gy) D50 (Gy) D50 (Gy) Isodose
Number of MU
304 40
53.72 3.65
18.79 9.64
20.30 8.82
11.22 1.92
9.51 4.07
12.20 5.03
13.62 5.23
0.68 0.03
352.1 48.9
409 68 <0.01
53.61 4.75 0.77
23.83 10.30 <0.01
26.09 8.89 <0.01
2.24 0.93 <0.01
8.24 3.97 0.21
11.36 6.52 0.51
12.59 6.99 0.72
0.65 0.03 0.01
278.2 34.1 <0.01
388 69 <0.01
53.64 5.43 0.90
21.61 10.23 0.04
23.90 9.42 0.01
2.29 1.08 <0.01
7.11 3.65 0.02
11.37 6.32 0.53
12.53 6.65 0.70
0.69 0.03 0.57
343.2 41.6 0.68
285 57 0.07
53.83 4.14 0.62
14.93 8.47 0.01
16.65 9.07 0.06
10.37 2.16 0.24
6.73 2.95 0.01
8.59 5.31 0.01
10.97 5.62 0.11
0.70 0.03 0.20
371.6 42.1 0.37
264 52 <0.01
53.71 4.81 0.97
13.32 7.51 <0.01
14.67 8.19 0.01
10.68 2.49 0.49
6.48 2.71 0.01
8.01 5.09 0.01
10.01 4.90 0.05
0.71 0.02 0.05
521.6 64.3 <0.01
The p value is based on the various intensity-modulated arc therapy (IMAT) planning method vs. the noncoplanar intensity modulated radiation therapy (NC-IMRT) plans. The p values in bold type indicate an improvement of the arc plan over NC-IMRT; italics indicate degradation.
NC-IMRT and double NC-IMAT plans for the chosen representative patient. Figure 3 is a bar graph comparing the critical structure doses for each planning method. There were 4 patients who had NC-IMRT plans wherein both right and left cochleae received more than 25 Gy; the average for these patients was 27.9 Gy. The average dose was increased for the IMAT (32.7 Gy p = 0.01) and double IMAT (31.0 Gy p = 0.05) plans. The dose decreased to 22.5 Gy (p = 0.03) for the NC-IMAT and to 20.0 Gy (p < 0.01) for the double NC-IMAT plan. Figure 4 depicts the change in cochlear doses for each of these patients based on planning method. The size of the target did influence the dose to some normal structures for all plan types. Specifically for the NC-
IMRT and double NC-IMAT, there was a positive and statistically significant (p < 0.05) correlation for the Pearson coefficient of determination between the size of the target and dose to body V50, cochlear D50, and brain D50. Comparing the dose differences between NC-IMRT and double NCIMAT, only the body V50 had a statistically significant correlation between target size and dose difference. DISCUSSION The results of this study confirm the advantages of noncoplanar methods to reduce the intermediate- and high-dose volumes of normal tissue irradiation with the cost of
Fig. 1. The isodose distributions (95%, 50%, and 10% of the prescribed dose) and planning target volume (PTV) for a representative patient for the noncoplanar intensity-modulated radiation therapy (NC-IMRT), double-intensity modulated arc therapy (double IMAT), and double noncoplanar IMAT (double NC-IMAT) plans in three different views.
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Fig. 2. Planning target volume (PTV), right temporal lobe, right cochlea, and body dose–volume histograms calculated from a representative patient for noncoplanar intensity-modulated radiation therapy (NC-IMRT, dotted line) and double noncoplanar intensity-modulated arc therapy (double NC-IMAT, solid line).
increasing the volume that receives the lowest doses and the required linear accelerator MU and treatment times. Although there is some debate surrounding the relative merits of highly conformal therapy when normal tissue irradiation is increased, conformity should be a priority in the treatment of pediatric brain tumor patients with RT for the most severe and highly consequential effects in these patients, namely, necrosis, vasculopathy, and secondary malignancies, which arise predominately in the high-dose volume (28, 29). In addition, the insidious and more commonly observed effects on cognition, endocrine function, and hearing are attributed to the volume that receives the highest doses
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as suggested by central nervous system dose effects models in pediatric patients (3, 5, 30, 31). This position does not suggest that normal tissue irradiation is without consequences, nor does it diminish the impact of low-dose normal tissue irradiation to reduce the tolerance of functional elements within normal tissues of the same organ that receive the highest doses. The doses prescribed for the treatment of pediatric patients with brain tumors tend to be in the conservative range in terms of dose, expected response, and potential for severe complications. In addition, the same pediatric central nervous system dose effects models noted above indicate that low-dose irradiation has a statistically significant effect but one that is an order of magnitude smaller than when similar volumes receive higher doses. We found that for smaller targets, the dose to the normal structures was lower. This may explain the large standard deviations in normal tissue doses shown in Table 2, inasmuch as the largest target was nearly twice the size of the smallest. In general, it seemed that when critical structures were far from the PTV, target coverage compromise was not required to achieve normal tissue sparing such that double NC-IMAT and NC-IMRT yielded similar benefits. However, double NC-IMAT did allow better sparing of critical structures in close proximity to the PTV because of its ability to distribute dose that resulted in no noticeable beam pathway. Based on these findings, NC-IMAT has merit and should be considered alongside IMRT for pediatric patients with posterior fossa tumors. Wagner et al. (23) recommended using 3DCRT for pediatric patients over IMRT or IMAT. This recommendation was derived from their calculations that the body V5 was 8% larger for IMRT than for 3DCRT (2953 vs. 2721 cc).However, based on their data, the mean dose
Fig. 3. Bar graph displaying the mean and standard deviation for critical structures by dose, volume, conformity index, and monitor units using different planning methods. IMRT = intensity-modulated radiation therapy; IMAT = intensitymodulated arc therapy; D50 = dose (cGy) to 50% of the volume; V5% and V50% = volume (cc) receiving 5% or 50% of the prescribed dose; MU = linear accelerator monitor units.
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Fig. 4. Bar graph displaying the change in cochlear doses based on planning method for the 4 patients who received high noncoplanar IMRT cochlear doses. IMRT = intensity-modulated radiation therapy; IMAT = intensity-modulated arc therapy; R1 = Patient 1 right cochlea, L1 = Patient 1 left cochlea (R1 and L2, Patient 2; etc.).
to the body was the same for the two methods, and the target coverage for 3DCRT was noticeably worse, with a D95 of 54.0 Gy for 3DCRT vs. 56.7 Gy for IMRT (the prescribed dose was 60 Gy). If the 3DCRT D95 were increased to match the IMRT D95, the body D50 of the 3DCRT plan would actually be greater than the body D50 of the IMRT plan. Hence, the minimal difference in V5, when compared to the target coverage compromise, may not justify a recommendation of 3DCRT over IMRT for pediatric brain tumor patients. Comparing the various arc planning methods, we found that multiple arcs were better than single arcs and that noncoplanar arcs improved conformity and decreased dose to normal tissues. These findings paralleled, respectively, those of Guckenberger et al. (16) and Krayenbuehl et al. (17), who studied adult tumors at different body sites. Based on these findings, a direct comparison between NC-IMRT and double NC-IMAT favors the former because of the lower V5 (10%) and required MU. Directly countering this are lower body V50, brain, temporal lobe, and cochlear D50 values for
the double NC-IMAT and increased conformity. NC-IMAT may have an advantage when treatment time is considered. Based on a study by Oliver et al. (18), the estimated treatment time is 1.5 minutes for IMAT and 3 minutes for double IMAT. Taking this into account and including the treatment table rotation, the treatment time for the double NC-IMAT would be 8 minutes. An efficiently delivered eight-field NC-IMRT takes approximately 10 minutes.
CONCLUSION Double NC-IMAT has the potential to improve the treatment of posterior fossa tumors in pediatric patients when compared to noncoplanar IMRT. For certain patients, this option may provide significant dose reduction to normal tissues with increased conformity of the high-dose volume. This method has merit and should be considered alongside IMRT for pediatric patients with posterior fossa tumors.
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20. Popescu CC, Olivotto IA, Beckham WA, et al. Volumetric modulated arc therapy improves dosimetry and reduces treatment time compared to conventional intensity-modulated radiotherapy for locoregional radiotherapy of left-sided breast cancer and internal mammary nodes. Int J Radiat Oncol Biol Phys 2010;76:287–295. 21. Shaffer R, Nichol AM, Vollans E, et al. A comparison of volumetric modulated arc therapy and conventional intensitymodulated radiotherapy for frontal and temporal high-grade gliomas. Int J Radiat Oncol Biol Phys 2010;76:1177–1184. 22. Verbakel WFAR, Cuijpers JP, Hoffmans D, et al. Volumetric intensity-modulated arc therapy vs. conventional imrt in head-and-neck cancer: A comparative planning and dosimetric study. Int J Radiat Oncol Biol Phys 2009;74:252–259. 23. Wagner D, Christiansen H, Wolff H, et al. Radiotherapy of malignant gliomas: Comparison of volumetric single arc technique (RapidArc), dynamic intensity-modulated technique and 3D conformal technique. Radiother Oncol 2009;93:593–596. 24. Wiggenraad RGJ, Petoukhova AL, Versluis L, et al. Stereotactic radiotherapy of intracranial tumors: A comparison of intensity-modulated radiotherapy and dynamic conformal arc. Int J Radiat Oncol Biol Phys 2009;74:1018–1026. 25. Wolff D, Stieler F, Welzel G, et al. Volumetric modulated arc therapy (VMAT) vs. serial tomotherapy, step-and-shoot IMRT and 3D-conformal RT for treatment of prostate cancer. Radiother Oncol 2009;93:226–233. 26. Wong E, D’Souza DP, Chen JZ, et al. Intensity-modulated arc therapy for treatment of high-risk endometrial malignancies. Int J Radiat Oncol Biol Phys 2005;61:830–841. 27. van’t Riet A, Mak AC, Moerland MA, et al. A conformation number to quantify the degree of conformality in brachytherapy and external beam irradiation: Application to the prostate. Int J Radiat Oncol Biol Phys 1997;37:731–736. 28. Merchant TE, Kun LE, Wu S, et al. Phase II trial of conformal radiation therapy for pediatric low-grade glioma. J Clin Oncol 2009;27:3598–3604. 29. Merchant TE, Li C, Xiong X, et al. Conformal radiotherapy after surgery for paediatric ependymoma: A prospective study. Lancet Oncol 2009;10:258–266. 30. Merchant TE, Conklin HM, Wu S, et al. Late effects of conformal radiation therapy for pediatric patients with low-grade glioma: Prospective evaluation of cognitive, endocrine, and hearing deficits. J Clin Oncol 2009;27:3691–3697. 31. Merchant TE, Goloubeva O, Pritchard DL, et al. Radiation dose-volume effects on growth hormone secretion. Int J Radiat Oncol Biol Phys 2002;52:1264–1270.