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A Dosimetric Comparison of Proton and Intensity-Modulated Photon Radiotherapy for Pediatric Parameningeal Rhabdomyosarcomas
Int. J. Radiation Oncology Biol. Phys., Vol. 74, No. 1, pp. 179–186, 2009 Copyright Ó 2009 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/09/$–see front matter
doi:10.1016/j.ijrobp.2008.06.1942
CLINICAL INVESTIGATION
Sarcoma
A DOSIMETRIC COMPARISON OF PROTON AND INTENSITY-MODULATED PHOTON RADIOTHERAPY FOR PEDIATRIC PARAMENINGEAL RHABDOMYOSARCOMAS KEVIN R. KOZAK, M.D., PH.D., JUDITH ADAMS, C.M.D., STEPHANIE J. KREJCAREK, M.D., NANCY J. TARBELL, M.D., AND TORUNN I. YOCK, M.D. Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA Purpose: We compared tumor and normal tissue dosimetry of proton radiation therapy with intensity-modulated radiation therapy (IMRT) for pediatric parameningeal rhabdomyosarcomas (PRMS). Methods and Materials: To quantify dosimetric differences between contemporary proton and photon treatment for pediatric PRMS, proton beam plans were compared with IMRT plans. Ten patients treated with proton radiation therapy at Massachusetts General Hospital had IMRT plans generated. To facilitate dosimetric comparisons, clinical target volumes and normal tissue volumes were held constant. Plans were optimized for target volume coverage and normal tissue sparing. Results: Proton and IMRT plans provided acceptable and comparable target volume coverage, with at least 99% of the CTV receiving 95% of the prescribed dose in all cases. Improved dose conformality provided by proton therapy resulted in significant sparing of all examined normal tissues except for ipsilateral cochlea and mastoid; ipsilateral parotid gland sparing was of borderline statistical significance (p = 0.05). More profound sparing of contralateral structures by protons resulted in greater dose asymmetry between ipsilateral and contralateral retina, optic nerves, cochlea, and mastoids; dose asymmetry between ipsilateral and contralateral parotids was of borderline statistical significance (p = 0.05). Conclusions: For pediatric PRMS, superior normal tissue sparing is achieved with proton radiation therapy compared with IMRT. Because of enhanced conformality, proton plans also demonstrate greater normal tissue dose distribution asymmetry. Longitudinal studies assessing the impact of proton radiotherapy and IMRT on normal tissue function and growth symmetry are necessary to define the clinical consequences of these differences. Ó 2009 Elsevier Inc. Comparison, Intensity-modulated radiation therapy, Parameningeal rhabdomyosarcoma, Pediatric, Protons.
from intensified locoregional therapy. On the other hand, the anatomic constraints that commonly prevent complete surgical resection of parameningeal lesions also present serious limitations to radiation oncologists. The proximity of multiple critical normal structures, including those involved in vision, hearing, cognition, and development, can limit the ability to deliver radiation and can increase treatment toxicity. For example, among 213 long-term survivors of nonorbital, head and neck, soft-tissue sarcoma treated on International Rhabdomyosarcoma Studies II and III, more than three quarters experienced at least one late toxicity of treatment (9). Thus, while considering more aggressive locoregional treatment in select patients, it is also essential that strategies be developed to safely permit this intensification. Further complicating this balance is the expected longevity of cured patients. Although late radiation toxicity often develops within the first 10 years of treatment, several serious complications have been documented more than a decade
INTRODUCTION Soft tissue sarcomas are a heterogenous group of malignancies that comprise approximately 8% of all childhood cancers. Rhabdomyosarcoma is the most common malignancy in this diverse group (1, 2). Rhabdomyosarcomas arise in an array of locations; however the most common sites are within the head and neck and include parameningeal lesions (1,2). Pediatric parameningeal rhabdomyosarcoma (PRMS) presents an enormous challenge to radiation oncologists. Despite steady progress, local failure remains a substantial cause of morbidity and mortality, with 5-year locoregional recurrence rates approaching 20% (3, 4). In addition, locoregional failure portends a dismal prognosis: long-term survival with salvage therapies is less than 20% (4). Several studies have implicated higher radiation doses in improved locoregional control (4–8). Consequently there is a pressing need to prospectively identify select patients who may benefit Reprint requests to: Torunn I. Yock, M.D., Department of Radiation Oncology, Massachusetts General Hospital, 100 Blossom Street, Boston, MA 02114. Tel: (617) 726-6050; Fax: (617) 7263603; E-mail: [email protected]
Conflict of interest: none Received April 8, 2008, and in revised form June 8, 2008. Accepted for publication June 12, 2008. 179
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Table 1. Beam arrangements Patient no.
Parameningeal Site
IMRT beam arrangement
Proton beam arrangement
1 2 3 4 5 6 7 8 9 10
Infratemporal fossa Infratemporal fossa Nasopharynx Infratemporal fossa Paranasal sinus Infratemporal fossa Middle ear Paranasal sinus Infratemporal fossa Infratemporal fossa
IAO:IPOx2:CAO:CPO IAO:IPO:CAOx2:CPO IAO:IPOx2:AP:CAO:CPOx2 IAO:IPOx2:ILat:CAO IAO:IPOx2:AP:CAO:CPOx2 IAOx2:IPOx2:CAO IAOx2:IPOx2:CAO IAO:IPO:AP:CAO:CPO IAO:IPOx2:ILat:CAO:CPO IAO:IPOx3:CAO:CPO
IAO:IPO:ILat IAOx2:IPO:ILat IPO:ILat:AP:PA:CPO:CLat IAOx2:IPOx3:ILat:CLat ILat:CLat:CAOx2 IAO:IPOx2:ILat IAO:IPO IAO:ILat:CAO:CLat IAO:IPO:ILat:Sup IAOx2:IPOx2:CAO:Sup
Abbreviations: AP = anterior–posterior; CAO = contralateral anterior oblique; CLat = contralateral lateral; CPO = contralateral posterior oblique; IAO = ipsilateral anterior oblique; ILat = ipsilateral lateral; IPO = ipsilateral posterior oblique; PA = posterior–anterior; Sup = superior.
after treatment (10,11). Finally, as PRMSs generally affect prepubescent children, growth and maturation are still essential, and radiation therapy has been implicated in disturbances in these processes (9–12). With the aim of delivering effective radiation doses to tumor volumes while minimizing radiation doses to adjacent, critical normal structures, we have treated pediatric PRMS patients with proton beam radiotherapy since 1996. To quantify the impact of proton beam therapy on doses to normal structures, we compared proton treatment plans to contemporary, intensity-modulated radiation therapy (IMRT) plans. METHODS AND MATERIALS
#30.6 Gy, optic nerves and chiasm #46.8 Gy, lens #14.4 Gy, and lacrimal gland #41.4 Gy. In addition, brainstem maximum doses were required to be <54 Gy, and mean retina doses were maintained at <40 Gy. To avoid bias in comparisons with treated proton plans, which were known to provide clinically acceptable target volume coverage, IMRT target volume coverage was assigned the highest planning priority. Analyzed proton plans were those used for treatment. In 9 cases, the prescribed GTV dose was 50.4 Gy in 28 fractions. In the remaining case, the prescribed GTV dose was 52.2 Gy in 29 fractions. The median CTV prescription dose was 47.7 Gy (range, 36–52.2 Gy). Proton beam arrangements are shown in Table 1. Plans were approved for analysis by a pediatric radiation oncologist. For simplicity, doses are expressed as Gy. Proton doses were corrected with the accepted relative biologic effectiveness value of 1.1.
Study population At the time of study initiation, 17 PRMS patients had been treated with definitive proton radiotherapy at Massachusetts General Hospital. Of these, 10 had proton treatment plans generated with the XiO planning system (CMS, Inc., St. Louis, MO) permitting the development of a matched IMRT plan. The remaining 7 patients were treated before 2001 and planned on Rx, a Massachusetts General Hospital developed proton planning system that did not permit comparison IMRT plans to be generated. The 10 patients planned on CMS systems formed the final study population. Primary sites represented included the infratemporal fossa (6 patients), paranasal sinuses (2 patients), nasopharynx (1 patient), and middle ear (1 patient). All patients were treated between May 2001 and August 2005.
Simulation, treatment planning, and treatment Computed tomographic simulation provided images at 2.5-mm intervals through the cranium and neck. The gross tumor volume (GTV), including the primary tumor and any pathologically involved or enlarged regional lymph nodes, was contoured by a pediatric radiation oncologist. The clinical treatment volume (CTV) was generated manually to cover areas of suspected microscopic involvement. Normal tissues were contoured by either a radiation oncologist or a neuroanatomist, and all volumes were approved by a pediatric radiation oncologist. Target and normal tissue volumes were held constant for both proton and IMRT planning. The XiO planning system (CMS, Inc., St. Louis, MO) was used for both proton and IMRT planning. IMRT plans employed a minimum of five, 6 MV photon fields. IMRT beam arrangements are shown in Table 1. Normal tissue constraints were derived from Children’s Oncology Group guidance and included whole brain
RESULTS Patient age ranged from 2 to 12 years (median, 3 years), and there was a male predominance (8 male and 2 female patients). Intracranial extension was radiographically evident in 8 cases. Tumor histology was embryonal in 7 cases and alveolar in 3 cases. Five patients had T2bN0M0 lesions and 3 had T2aN0M0 lesions; the remaining 2 patients had metastatic disease limited to the lungs (T2bN0M1 and T2bN1M1). Surgical intervention consisted of biopsy only in all cases. Thus the 8 patients with nonmetastatic disease were Intergroup Rhabdomyosarcoma Study (IRS) Group III and the 2 patients with metastatic disease were classified as IRS Group IV. At the time, all patients were considered intermediate risk per IRS V protocol because of age and histology. All patients received multiagent chemotherapy. Target volume dosimetry is shown in Table 2. Both treatment techniques provide clinically acceptable target volume coverage. In all but 1 case, the GTV was entirely covered by $95% of the prescribed dose. In the single exception, the proton plan provided a GTV V95 of 99%. Similarly, in all but 2 cases, the CTV was entirely covered by 95% of the prescribed dose. In the 2 exceptions, IMRT plans provided CTV V95s of 99%. Dose homogeneity, reflected by global dose maxima, was similar for IMRT and proton plans. In all but 2 cases, dose maxima were <120% of the prescribed dose. In the two exceptions, small volume dose maxima of
Proton vs. photon IMRT for parameningeal rhabdomyosarcomas d K. R. KOZAK et al.
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Table 2. Target volume dosimetry (n = 10) Proton beam therapy
CTV V100 (%) V95 (%) V90 (%) GTV V100 (%) V95 (%) V90 (%) Dmax (%)
IMRT
Mean SE
Median (range)
Mean SE
Median (range)
94 3 100 100
98 (75–100) 100 (100) 100 (100)
94 3 100 1 100
98 (78–100) 100 (99–100) 100 (100)
93 3 100 1 100 113 3
94 (75–100) 100 (99–100) 100 (100) 108 (104–136)
95 3 100 100 112 1
98 (73–100) 100 (100) 100 (100) 111 (108–117)
Abbreviations: CTV = clinical target volume; Dmax (%) dose maximum (expressed as percent of prescribed dose); GTV = gross tumor volume; NS = not significant (p > 0.1); SE = standard error; VX (%) volume (in percent total volume), receiving X% of the prescribed dose. All values were nonsignificant (p > 0.1, two-tailed Wilcoxon signed-rank test).
>120% of the prescribed dose were observed in proton plans that required field patching. In both cases, the volume receiving >120% of the prescribed dose was less than 1 cc. Representative axial, coronal and sagittal images of proton and IMRT plans for a patient with a right infratemporal fossa lesion are shown in Fig. 1. Mean normal tissue doses are shown in Table 3. Proton plans provided superior dose sparing for all examined organs although the differences did not achieve statistical significance for ipsilateral cochlea and mastoid and was of borderline significance for ipsilateral parotid. Average dose–volume histograms for each organ are shown in Figs. 2 to 7.
The differences in mean dose between ipsilateral and contralateral, paired organs are shown in Table 4. For all organs evaluated except the lenses, proton plans provided greater dose asymmetry. However these differences did not reach statistical significance for globes, temporal lobes, or lacrimal glands and were of borderline significance for parotid glands. DISCUSSION Clinically acceptable proton and IMRT plans could be generated for all patients (Table 2). The entire CTV and GTV universally received 90% of the prescription dose. In
Fig. 1. Representative dosimetry for a three-field, proton treatment plan and a five-field intensity-modulated radiation therapy (IMRT) plan, with axial, coronal and sagittal views. The right infratemporal fossa clinical target volume (CTV) (thin purple) and 105% (maroon), 100% (thick red), 80% (orange), 60% (yellow), 40% (light green), and 20% (light blue) isodose lines are depicted. In the top panel, the GTV is also depicted (thin red).
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Table 3. Normal tissue dosimetry
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mean organ doses in cGy (n = 10)
Proton beam therapy
IMRT
Anatomic site
Mean SE
Median (range)
Mean SE
Median (range)
p
Contralateral globe Ipsilateral globe Contralateral lens Ipsilateral lens Contralateral retina Ipsilateral retina Contralateral optic nerve Ipsilateral optic nerve Optic chiasm Whole brain Brainstem Contralateral temporal lobe Ipsilateral temporal lobe Pituitary Hypothalamus Contralateral parotid Ipsilateral parotid Contralateral lacrimal Ipsilateral lacrimal Contralateral cochlea Ipsilateral cochlea Contralateral mastoid Ipsilateral mastoid
310 130 850 230 90 80 170 100 460 190 1360 300 1390 460 3020 450 1770 470 330 60 690 150 200 90 1320 250 2890 580 1200 450 230 130 3090 740 130 80 630 210 430 270 3680 620 110 100 2920 710
30 (0–1100) 730 (0–2690) 0 (0–810) 50 (0–1000) 80 (0–1470) 1360 (0–3560) 1120 (0–4200) 3070 (0–5110) 1230 (0–4570) 270 (110–720) 810 (0–1170) 30 (0–740) 1400 (30–2700) 3270 (10–5350) 380 (0–3720) 80 (0–1310) 4390 (0–5460) 0 (0–820) 380 (0–1690) 20 (0–2630) 4990 (0–5200) 0 (0–1000) 4210 (0–5170)
1330 190 1640 230 580 70 680 80 1800 280 2080 300 3060 330 3730 320 3330 380 810 130 2640 280 1560 150 2250 260 4340 240 2240 470 2430 320 3750 600 1250 260 1650 310 2920 340 4060 520 1930 240 3460 550
1190 (630–2540) 1570 (540–2860) 610 (240–950) 730 (240–1000) 1400 (800–3320) 1850 (720–3930) 2960 (1750–4740) 3990 (1990–5060) 3690 (1130–4990) 740 (310–1610) 2990 (1050–3730) 1400 (1000–2280) 2260 (1230–3800) 4320 (3020–5360) 2480 (170–4170) 2790 (30–3300) 4780 (30–5440) 1000 (450–2690) 1570 (580–3320) 3160 (190–3860) 4710 (210–5710) 2120 (20–2670) 4450 (20–5100)
<0.01 <0.01 <0.01 <0.01 <0.01 <0.01 <0.01 0.01 <0.01 <0.01 <0.01 <0.01 0.01 <0.01 0.01 <0.01 0.05 <0.01 0.01 <0.01 NS <0.01 NS
Abbreviations: IMRT = intensity-modulated radiation therapy; NS = not significant (p > 0.1, two-tailed, Wilcoxon signed-rank test); SE = standard error. Values have been rounded to nearest 10 cGy. For ipsilateral parotid, n = 9 because of an inability to define the gland radiographically as a result of tumor infiltration.
addition, no less than 99% of these target volumes received 95% of the prescription dose. Importantly, no significant differences in target volume coverage were observed between IMRT and proton plans, suggesting that comparisons of normal tissue dosimetry will not be subject to bias. With both proton and IMRT plans, target volume coverage was achieved with reasonable dose homogeneity; maximal doses exceeded 120% of the prescribed dose in only 2 cases, and the average maximal dose exceeded the prescribed dose by approximately 10%. This target volume coverage and dose homogeneity were achieved despite a diversity in tumor location, suggesting that both radiation techniques are suitable for PRMS treatment. Proton beam therapy plans provided significant reductions in radiation doses to all optic structures examined (Table 3). Visual and orbital toxicities are a significant burden on PRMS survivors. For example, 45 of 213 (21%) long-term, relapse-free survivors with localized, nonorbital, soft-tissue sarcoma of the head and neck treated on IRS II and III developed eye problems (9). Similarly, Paulino et al. described visual/orbital toxicities in 3 of 11 (27%) 5-year survivors of nonorbital, head-and-neck rhabdomyosarcoma (11). Only long-term clinical follow-up will clarify whether optic structure sparing with protons will translate into reduced morbidity. However, dose–response relationships previously identified for these structures provide a framework for predicting the clinical impact of proton radiotherapy.
Cataracts are a common cause of treatment-related, visual impairment in this population, occurring in approximately 10% of long-term survivors (9). Classically, the threshold lens dose during fractionated radiotherapy for clinically significant cataracts has been taken to be 5 Gy (13). Henk et al. estimated lens doses in 40 patients with orbital tumors treated with fractionated radiotherapy and noted no lens changes in patients receiving #5 Gy to the germinative zone of the lens after an average follow-up of approximately 6 years
Fig. 2. Average dose–volume histograms for contralateral globe (blue), ipsilateral globe (red), contralateral lens (black), and ipsilateral lens (green) for proton (straight lines) and intensity-modulated radiation therapy (IMRT) (dashed lines) plans.
Proton vs. photon IMRT for parameningeal rhabdomyosarcomas d K. R. KOZAK et al.
Fig. 3. Average dose–volume histograms for neuro-optic structures including contralateral retina (blue), ipsilateral retina (red), contralateral optic nerve (black), and ipsilateral optic nerve (green) for proton (straight lines) and intensity-modulated radiation therapy (IMRT) (dashed lines) plans.
(13). Furthermore these investigators estimated that a lens dose of 15 Gy resulted in a 50% probability of visual impairment. These dose thresholds may be overly liberal when applied to a pediatric population and when considering longer follow-up. Hall et al. examined 484 patients treated with ionizing radiation for facial hemangiomas (14). Treatment was delivered to patients <18 months of age and the minimum follow-up was 34 years. They found an increased risk of opacities at lens doses of <0.5 Gy and calculated a 35–50% increase in the risk of opacity development per unit of Gray. Whatever form the dose–response curve takes, it is clear that lens sparing by proton plans is striking. Mean ipsilateral and contralateral lens doses with IMRT plans exceeded 5 Gy in 80% and 60% of cases, respectively. In contrast, ipsilateral or contralateral lens dose exceeded 5 Gy in only 1 case with proton planning (Table 3, Fig. 2 and data not shown). These data suggest that proton beam therapy may reduce the risk of cataract development. Late visual toxicities related to radiation damage of neurooptic structures, including the retina, optic nerves, and optic
Fig. 4. Average dose–volume histograms for whole brain (blue), brainstem (red), contralateral temporal lobe (black), and ipsilateral temporal lobe (green) for proton (straight lines) and (intensity-modulated radiation therapy) IMRT (dashed lines) plans.
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Fig. 5. Average dose–volume histograms for pituitary (blue) and hypothalamus (red) for proton (straight lines) and intensity-modulated radiation therapy (IMRT) (dashed lines) plans.
chiasm, as well as uncommon eye injuries including dry eye syndrome, conjunctivitis, and extraocular abnormalities, are known consequences of conventional PRMS treatment (9, 11). Although proton use resulted in significant sparing of optic/orbital structures, this may not prove to be clinically significant. The incidence of these toxicities following treatment of head-and-neck soft-tissue sarcomas with conventional radiation techniques is low (9, 11). Compared with conventional techniques, IMRT offers the ability to spare relevant normal tissues and, in our series, IMRT doses to optic/ orbital structures would be predicted to result in exceptionally low rates of late visual toxicity (15–18). Despite this predictable low risk of visual toxicity with IMRT, the dose sparing provided by protons suggests that this modality may serve as a useful platform to investigate dose escalation. Although modest radiation dose intensification was investigated in IRS IV with no impact on local control or survival, locoregional failure remains an important component of total failure, and the rationale for dose escalation persists (3). Hearing loss represents another significant morbidity of PRMS treatment. Among 213 long-term survivors treated
Fig. 6. Average dose–volume histograms for contralateral parotid gland (blue), ipsilateral parotid gland (red), contralateral lacrimal gland (black) and ipsilateral lacrimal gland (green) for proton (straight lines) and intensity-modulated radiation therapy (IMRT) (dashed lines) plans.
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Fig. 7. Average dose–volume histograms for contralateral cochlea (blue), ipsilateral cochlea (red), contralateral mastoid (black) and ipsilateral mastoid (green) for proton (straight lines) and intensitymodulated radiation therapy (IMRT) (dashed lines) plans.
on Intergroup Rhabdomyosarcoma Studies II and III, 36 (17%) experienced decreased hearing (9). Neuro-otologic morbidity in this population is multifactorial but is attributable in part to cochlea irradiation. The precise dose–response relationship between cochlea dose and hearing loss remains to be defined. Based on an evaluation of 72 children with primary brain tumors, Merchant et al. suggested cochlear doses be kept to <32 Gy to minimize the risk of hearing loss (19). However the application of these findings to PRMS patients is not straightforward, given the multiple, significant differences in both patient and treatment factors. Huang et al. found that IMRT reduced both cochlear doses and ototoxicity compared with conventional radiotherapy among 26 children treated for medulloblastoma (20). Despite the reductions offered by IMRT, ototoxicity was still observed in 60% of patients. Again, these results must be interpreted cautiously because of the role of ototoxic chemotherapy in medulloblastoma management. In adults, cochlea dose has routinely been correlated with sensorineural hearing loss; however dose thresholds have varied widely between 30 and 60 Gy (21–24). Proton beam therapy resulted in mean contralateral
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cochlear doses of less than 27 Gy in all patients. In contrast, IMRT plans resulted in mean contralateral cochlear doses exceeding 32 Gy in half of the patients (Table 3). Because of anatomic constraints, ipsilateral cochlea doses were high for both proton and IMRT plans and differences did not achieve statistical significance. Nonetheless, mean ipsilateral cochlear doses exceeded 32 Gy in six proton beam therapy plans and eight IMRT plans. Although only long-term follow-up will unambiguously define the neuro-otologic safety of proton beam therapy, these data suggest that proton beam use may reduce the risk of hearing loss in children with PRMS. Neurocognitive toxic effects of PRMS treatment span an array of clinical manifestations including reduced school performance, behavioral problems, and frank central nervous system dysfunction. Raney et al. found learning disabilities in 35 of 71 (49%) evaluable, long-term survivors of headand neck-sarcoma (9). Such complicated sequelae cannot be attributed to single factors such as radiation dose to central nervous system structures. Nonetheless, substantial evidence suggests that radiation doses to the total brain and temporal lobes contribute to neurocognitive toxicity. Merchant et al. examined the impact of radiation doses to a number of brain regions on IQ decline after treatment in an array of pediatric populations (25–27). In general, mean radiation doses to the whole brain, supratentorial brain, and temporal lobes correlated with IQ decline. Brain volume receiving >45 Gy may be particularly important in predicting neurocognitive decline, but modeling suggests that even low doses may be detrimental (25–27). In this series, proton planning dramatically reduced radiation doses to the whole brain and temporal lobes (Table 3). Furthermore dose sparing was observed in both low- and high-dose volumes (Fig. 4). These data suggest protons may reduce the risk of neurocognitive decline in PRMS survivors. Dental problems are common in survivors of PRMSs. Raney et al. identified poor dentition in 29% of survivors treated on Intergroup Rhabdomyosarcoma Studies II and III (9). Although direct irradiation of teeth and jaw likely contributes to dental problems and was not evaluated here,
Table 4. Differential mean organ dose in cGy (n = 10) Proton beam therapy
Globe Lens Retina Optic Nerve Temporal Lobe Parotid Lacrimal Cochlea Mastoid
IMRT
Mean SE
Median (range)
Mean SE
Median (range)
p
550 180 80 30 900 250 1630 410 1120 240 2870 780 500 210 3240 690 2810 740
480 ( 220–1580) 30 ( 10–260) 850 ( 110–2090) 1690 ( 260–3670) 1300 (0–1960) 4330 (0–5200) 190 ( 370–1500) 4340 (0–5160) 4170 ( 120–5170)
310 110 100 40 280 200 670 260 690 200 1410 330 400 200 1140 300 1530 460
260 ( 100–850) 100 ( 100–240) 310 ( 1060–1260) 570 ( 610–2020) 540 ( 50–1810) 1810 ( 80–2520) 180 ( 440–1580) 1070 (20–2880) 1990 ( 180–3500)
NS NS 0.03 <0.01 0.1 0.05 NS <0.01 <0.01
Abbreviations: IMRT = intensity-modulated radiation therapy; NS = not significant (p > 0.1, two-tailed Wilcoxon signed-rank test); SE = standard error. Values are obtained by subtracting mean contralateral organ dose from mean ipsilateral organ dose; values are rounded to nearest 10 cGy. For parotid, n = 9 because of an inability to define the ipsilateral gland radiographically in 1 case.
Proton vs. photon IMRT for parameningeal rhabdomyosarcomas d K. R. KOZAK et al.
xerostomia is a major contributor to poor dentition after headand-neck radiation. Significant effort has been dedicated to defining relationships between parotid doses and xerostomia. The bulk of available data suggests that when mean parotid dose exceeds 24–30 Gy, salivary output declines to near zero shortly after radiation therapy and remains persistently depressed (28–31). The clinical consequences of parotid irradiation are understandably more pronounced when both glands receive significant radiation doses. Because of unmodifiable anatomic constraints among the patients evaluated here, both proton and IMRT plans deliver radiation doses predicted to significantly reduce ipsilateral parotid gland function. However, when the contralateral parotid gland is considered, a striking contrast is seen between proton and IMRT plans. For proton beam therapy, the mean dose to contralateral parotid never exceeded 13.1 Gy. In contrast, in 70% of IMRT plans, the mean contralateral parotid dose exceeded 26 Gy (Table 3). These data suggest that, in PRMS patients, proton beam therapy may result in lower rates of xerostomia and fewer dental problems compared with IMRT. Hypothalamic–pituitary irradiation increases the risk of endocrinopathies and, potentially, statural growth delay (32–35). These toxicities are well documented in survivors of head-and-neck rhabdomyosarcoma. Diminished height velocity was observed in 61% of orbital rhabdomyosarcoma patients treated in IRS I (12). Similarly, 48% of long term survivors treated in IRS II and III showed poor statural growth (9). Growth hormone deficiency, abnormal pubertal progression, hypothyroidism and other endocrinopathies are also observed (9, 11, 12). Although dose–response relationships are not unambiguously defined for hypothalamic–pituitary axis irradiation, toxicities are dose dependent. The observation that proton beam therapy reduces average pituitary doses by one third and hypothalamic doses by nearly half suggests protons may reduce the incidence of statural growth delay and late endocrinopathies (Table 3 and Fig. 5).
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Long-term cosmetic outcome of PRMS survivors is impacted by multiple factors including radiation to bone and soft tissue which can contribute to hypoplasia and facial asymmetry (36). Among 76 evaluable survivors treated on IRS II and III, only 2 patients were noted to have no facial/nuchal hypoplasia or asymmetry (9). Although not well studied, it is possible that greater radiation dose asymmetry will increase the risk and/or severity of late facial asymmetry. Because of enhanced conformality, proton beam therapy increases dose asymmetry between paired tissues (e.g., mastoid). For several tissues, including cochlea, mastoid (and thus portions of the temporal bone), and parotid (and thus mandibular rami), the average difference in mean radiation dose to ipsilateral and contralateral sides in proton plans exceeds 25 Gy. Use of IMRT typically reduces this dose asymmetry by approximately 50% (Table 4). Thus proton beam therapy may increase the risk of late facial/nuchal asymmetry. However the decreased risk of second malignancy because of the irradiation of less normal tissue may be worth any slight increase in facial/ nuchal asymmentry (37).
CONCLUSION In conclusion, proton beam therapy for PRMS reduces radiation doses to several critical structures. Based on historical dose–response relationships, proton beam therapy may reduce the risk of cataracts, hearing loss, neurocognitive decline, xerostomia/poor dentition, growth delay, and endocrinopathies compared with IMRT. However, proton use may increase the risk of late facial asymmetry. Although recent clinical results from Timmerman et al. suggest that proton therapy for PRMS is feasible and is tolerated (38), long-term follow-up of PRMS survivors treated with protons will be required to confirm these potential clinical sequelae.
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12. Heyn R, Ragab A, Raney RB, et al. Late effects of therapy in orbital rhabdomyosarcoma in children: A report from the Intergroup Rhabdomyosarcoma Study. Cancer 1986;57:1738–1743. 13. Henk JM, Whitelocke RAF, Warrington AP, et al. Radiation dose to the lens and cataract formation. Int J Radiat Oncol Biol Phys 1993;25:815–820. 14. Hall P, Granath F, Lundell M, et al. Lenticular opacities in individuals exposed to ionizing radiation in infancy. Radiat Res 1999;152:190–195. 15. Jiang GL, Tucker SL, Guttenberger R, et al. Radiation-induced injury to the visual pathway. Radiother Oncol 1994;30:17–25. 16. Parsons JT, Bova FJ, Fitzgerald CR, et al. Radiation optic neuropathy after megavoltage external-beam irradiation: Analysis of time-dose factors. Int J Radiat Oncol Biol Phys 1994;30: 755–763. 17. Parsons JT, Fitzgerald CR, Hood CI, et al. The effects of irradiation on the eye and optic nerve. Int J Radiat Oncol Biol Phys 1983;9:609–622. 18. Parsons JT, Bova FJ, Fitzgerald CR, et al. Severe dry-eye syndrome following external beam irradiation. Int J Radiat Oncol Biol Phys 1994;30:775–780. 19. Merchant TE, Gould CJ, Xiong X, et al. Early neuro-otologic effects of three-dimensional irradiation in children with primary brain tumors. Int J Radiat Oncol Biol Phys 2004;58:1194–1207. 20. Huang E, Teh BS, Strother DR, et al. Intensity-modulated radiation therapy for pediatric medulloblastoma: Early report on the reduction of ototoxicity. Int J Radiat Oncol Biol Phys 2002;52: 599–605. 21. Bhandare N, Antonelli PJ, Morris CG, et al. Ototoxicity after radiotherapy for head and neck tumors. Int J Radiat Oncol Biol Phys 2007;67:469–479. 22. Honore HB, Bentzen SM, Moller K, et al. Sensori-neural hearing loss after radiotherapy for nasopharyngeal carcinoma: individualized risk estimation. Radiother Oncol 2002;65:9–16. 23. Pan CC, Eisbruch A, Lee JS, et al. Prospective study of inner ear radiation dose and hearing loss in head-and-neck cancer patients. Int J Radiat Oncol Biol Phys 2005;61:1393–1402. 24. Grau C, Moller K, Overgaard M, et al. Sensori-neural hearing loss in patients treated with irradiation for nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 1991;21:723–728. 25. 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. 26. Merchant TE, Kiehna EN, Li C, et al. Modeling radiation dosimetry to predict cognitive outcomes in pediatric patients
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with CNS embryonal tumors including medulloblastoma. Int J Radiat Oncol Biol Phys 2006;65:210–221. Merchant TE, Kiehna EN, Kun LE, et al. Phase II trial of conformal radiation therapy for pediatric patients with craniopharyngioma and correlation of surgical factors and radiation dosimetry with change in cognitive function. J Neurosurg 2006;104:94–102. Eisbruch A, Ten Haken RK, Kim HM, et al. Dose, volume, and function relationships in parotid salivary glands following conformal and intensity-modulated irradiation of head and neck cancer. Int J Radiat Oncol Biol Phys 1999;45:577–587. Eisbruch A, Ship JA, Kim HM, et al. Partial irradiation of the parotid gland. Semin Radiat Oncol 2001;11:234–239. Eisbruch A, Kim HM, Terrell JE, et al. Xerostomia and its predictors following parotid-sparing irradiation of head-and-neck cancer. Int J Radiat Oncol Biol Phys 2001;50:695–704. Li Y, Taylor JMG, Ten Haken RK, et al. The impact of dose on parotid salivary recovery in head and neck cancer patients treated with radiation therapy. Int J Radiat Oncol Biol Phys 2007;67:660–669. Sklar CA. Growth and neuroendocrine dysfunction following therapy for childhood cancer. Pediatr Clin North Am 1997; 44:489–504. Rappaport R, Brauner R. Growth and endocrine disorders secondary to cranial irradiation. Pediatr Res 1989;25:561–567. Cicognani A, Cacciari E, Carla G, et al. Magnetic resonance imaging of the pituitary area in children treated for acute lymphoblastic leukemia with low-dose (18 Gy) cranial irradiation. Relationships to growth and growth hormone secretion. Am J Dis Child 1992;146:1343–1348. Avizonis VN, Fuller DB, Thomson JW, et al. Late effects following central nervous system radiation in a pediatric population. Neuropediatrics 1992;23:228–234. Jaffe N, Toth BB, Hoar RE, et al. Dental and maxillofacial abnormalities in long-term survivors of childhood cancer: Effects of treatment with chemotherapy and radiation to head and neck. Pediatrics 1984;73:816–823. Miralbell R, Lomax A, Cella L, et al. Potential reduction of the incidence of radiation-induced second cancers by using proton beams in the treatment of pediatric tumors. Int J Radiat Oncol Biol Phys 2002;54:824–829. Timmermann B, Schuck A, Niggli F, et al. Spot-scanning proton therapy for malignant soft tissue tumors in childhood: First experiences at the Paul Scherrer Institute. Int J Radiat Oncol Biol Phys 2007;67:497–504.
doi:10.1016/j.ijrobp.2008.06.1942
CLINICAL INVESTIGATION
Sarcoma
A DOSIMETRIC COMPARISON OF PROTON AND INTENSITY-MODULATED PHOTON RADIOTHERAPY FOR PEDIATRIC PARAMENINGEAL RHABDOMYOSARCOMAS KEVIN R. KOZAK, M.D., PH.D., JUDITH ADAMS, C.M.D., STEPHANIE J. KREJCAREK, M.D., NANCY J. TARBELL, M.D., AND TORUNN I. YOCK, M.D. Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA Purpose: We compared tumor and normal tissue dosimetry of proton radiation therapy with intensity-modulated radiation therapy (IMRT) for pediatric parameningeal rhabdomyosarcomas (PRMS). Methods and Materials: To quantify dosimetric differences between contemporary proton and photon treatment for pediatric PRMS, proton beam plans were compared with IMRT plans. Ten patients treated with proton radiation therapy at Massachusetts General Hospital had IMRT plans generated. To facilitate dosimetric comparisons, clinical target volumes and normal tissue volumes were held constant. Plans were optimized for target volume coverage and normal tissue sparing. Results: Proton and IMRT plans provided acceptable and comparable target volume coverage, with at least 99% of the CTV receiving 95% of the prescribed dose in all cases. Improved dose conformality provided by proton therapy resulted in significant sparing of all examined normal tissues except for ipsilateral cochlea and mastoid; ipsilateral parotid gland sparing was of borderline statistical significance (p = 0.05). More profound sparing of contralateral structures by protons resulted in greater dose asymmetry between ipsilateral and contralateral retina, optic nerves, cochlea, and mastoids; dose asymmetry between ipsilateral and contralateral parotids was of borderline statistical significance (p = 0.05). Conclusions: For pediatric PRMS, superior normal tissue sparing is achieved with proton radiation therapy compared with IMRT. Because of enhanced conformality, proton plans also demonstrate greater normal tissue dose distribution asymmetry. Longitudinal studies assessing the impact of proton radiotherapy and IMRT on normal tissue function and growth symmetry are necessary to define the clinical consequences of these differences. Ó 2009 Elsevier Inc. Comparison, Intensity-modulated radiation therapy, Parameningeal rhabdomyosarcoma, Pediatric, Protons.
from intensified locoregional therapy. On the other hand, the anatomic constraints that commonly prevent complete surgical resection of parameningeal lesions also present serious limitations to radiation oncologists. The proximity of multiple critical normal structures, including those involved in vision, hearing, cognition, and development, can limit the ability to deliver radiation and can increase treatment toxicity. For example, among 213 long-term survivors of nonorbital, head and neck, soft-tissue sarcoma treated on International Rhabdomyosarcoma Studies II and III, more than three quarters experienced at least one late toxicity of treatment (9). Thus, while considering more aggressive locoregional treatment in select patients, it is also essential that strategies be developed to safely permit this intensification. Further complicating this balance is the expected longevity of cured patients. Although late radiation toxicity often develops within the first 10 years of treatment, several serious complications have been documented more than a decade
INTRODUCTION Soft tissue sarcomas are a heterogenous group of malignancies that comprise approximately 8% of all childhood cancers. Rhabdomyosarcoma is the most common malignancy in this diverse group (1, 2). Rhabdomyosarcomas arise in an array of locations; however the most common sites are within the head and neck and include parameningeal lesions (1,2). Pediatric parameningeal rhabdomyosarcoma (PRMS) presents an enormous challenge to radiation oncologists. Despite steady progress, local failure remains a substantial cause of morbidity and mortality, with 5-year locoregional recurrence rates approaching 20% (3, 4). In addition, locoregional failure portends a dismal prognosis: long-term survival with salvage therapies is less than 20% (4). Several studies have implicated higher radiation doses in improved locoregional control (4–8). Consequently there is a pressing need to prospectively identify select patients who may benefit Reprint requests to: Torunn I. Yock, M.D., Department of Radiation Oncology, Massachusetts General Hospital, 100 Blossom Street, Boston, MA 02114. Tel: (617) 726-6050; Fax: (617) 7263603; E-mail: [email protected]
Conflict of interest: none Received April 8, 2008, and in revised form June 8, 2008. Accepted for publication June 12, 2008. 179
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Table 1. Beam arrangements Patient no.
Parameningeal Site
IMRT beam arrangement
Proton beam arrangement
1 2 3 4 5 6 7 8 9 10
Infratemporal fossa Infratemporal fossa Nasopharynx Infratemporal fossa Paranasal sinus Infratemporal fossa Middle ear Paranasal sinus Infratemporal fossa Infratemporal fossa
IAO:IPOx2:CAO:CPO IAO:IPO:CAOx2:CPO IAO:IPOx2:AP:CAO:CPOx2 IAO:IPOx2:ILat:CAO IAO:IPOx2:AP:CAO:CPOx2 IAOx2:IPOx2:CAO IAOx2:IPOx2:CAO IAO:IPO:AP:CAO:CPO IAO:IPOx2:ILat:CAO:CPO IAO:IPOx3:CAO:CPO
IAO:IPO:ILat IAOx2:IPO:ILat IPO:ILat:AP:PA:CPO:CLat IAOx2:IPOx3:ILat:CLat ILat:CLat:CAOx2 IAO:IPOx2:ILat IAO:IPO IAO:ILat:CAO:CLat IAO:IPO:ILat:Sup IAOx2:IPOx2:CAO:Sup
Abbreviations: AP = anterior–posterior; CAO = contralateral anterior oblique; CLat = contralateral lateral; CPO = contralateral posterior oblique; IAO = ipsilateral anterior oblique; ILat = ipsilateral lateral; IPO = ipsilateral posterior oblique; PA = posterior–anterior; Sup = superior.
after treatment (10,11). Finally, as PRMSs generally affect prepubescent children, growth and maturation are still essential, and radiation therapy has been implicated in disturbances in these processes (9–12). With the aim of delivering effective radiation doses to tumor volumes while minimizing radiation doses to adjacent, critical normal structures, we have treated pediatric PRMS patients with proton beam radiotherapy since 1996. To quantify the impact of proton beam therapy on doses to normal structures, we compared proton treatment plans to contemporary, intensity-modulated radiation therapy (IMRT) plans. METHODS AND MATERIALS
#30.6 Gy, optic nerves and chiasm #46.8 Gy, lens #14.4 Gy, and lacrimal gland #41.4 Gy. In addition, brainstem maximum doses were required to be <54 Gy, and mean retina doses were maintained at <40 Gy. To avoid bias in comparisons with treated proton plans, which were known to provide clinically acceptable target volume coverage, IMRT target volume coverage was assigned the highest planning priority. Analyzed proton plans were those used for treatment. In 9 cases, the prescribed GTV dose was 50.4 Gy in 28 fractions. In the remaining case, the prescribed GTV dose was 52.2 Gy in 29 fractions. The median CTV prescription dose was 47.7 Gy (range, 36–52.2 Gy). Proton beam arrangements are shown in Table 1. Plans were approved for analysis by a pediatric radiation oncologist. For simplicity, doses are expressed as Gy. Proton doses were corrected with the accepted relative biologic effectiveness value of 1.1.
Study population At the time of study initiation, 17 PRMS patients had been treated with definitive proton radiotherapy at Massachusetts General Hospital. Of these, 10 had proton treatment plans generated with the XiO planning system (CMS, Inc., St. Louis, MO) permitting the development of a matched IMRT plan. The remaining 7 patients were treated before 2001 and planned on Rx, a Massachusetts General Hospital developed proton planning system that did not permit comparison IMRT plans to be generated. The 10 patients planned on CMS systems formed the final study population. Primary sites represented included the infratemporal fossa (6 patients), paranasal sinuses (2 patients), nasopharynx (1 patient), and middle ear (1 patient). All patients were treated between May 2001 and August 2005.
Simulation, treatment planning, and treatment Computed tomographic simulation provided images at 2.5-mm intervals through the cranium and neck. The gross tumor volume (GTV), including the primary tumor and any pathologically involved or enlarged regional lymph nodes, was contoured by a pediatric radiation oncologist. The clinical treatment volume (CTV) was generated manually to cover areas of suspected microscopic involvement. Normal tissues were contoured by either a radiation oncologist or a neuroanatomist, and all volumes were approved by a pediatric radiation oncologist. Target and normal tissue volumes were held constant for both proton and IMRT planning. The XiO planning system (CMS, Inc., St. Louis, MO) was used for both proton and IMRT planning. IMRT plans employed a minimum of five, 6 MV photon fields. IMRT beam arrangements are shown in Table 1. Normal tissue constraints were derived from Children’s Oncology Group guidance and included whole brain
RESULTS Patient age ranged from 2 to 12 years (median, 3 years), and there was a male predominance (8 male and 2 female patients). Intracranial extension was radiographically evident in 8 cases. Tumor histology was embryonal in 7 cases and alveolar in 3 cases. Five patients had T2bN0M0 lesions and 3 had T2aN0M0 lesions; the remaining 2 patients had metastatic disease limited to the lungs (T2bN0M1 and T2bN1M1). Surgical intervention consisted of biopsy only in all cases. Thus the 8 patients with nonmetastatic disease were Intergroup Rhabdomyosarcoma Study (IRS) Group III and the 2 patients with metastatic disease were classified as IRS Group IV. At the time, all patients were considered intermediate risk per IRS V protocol because of age and histology. All patients received multiagent chemotherapy. Target volume dosimetry is shown in Table 2. Both treatment techniques provide clinically acceptable target volume coverage. In all but 1 case, the GTV was entirely covered by $95% of the prescribed dose. In the single exception, the proton plan provided a GTV V95 of 99%. Similarly, in all but 2 cases, the CTV was entirely covered by 95% of the prescribed dose. In the 2 exceptions, IMRT plans provided CTV V95s of 99%. Dose homogeneity, reflected by global dose maxima, was similar for IMRT and proton plans. In all but 2 cases, dose maxima were <120% of the prescribed dose. In the two exceptions, small volume dose maxima of
Proton vs. photon IMRT for parameningeal rhabdomyosarcomas d K. R. KOZAK et al.
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Table 2. Target volume dosimetry (n = 10) Proton beam therapy
CTV V100 (%) V95 (%) V90 (%) GTV V100 (%) V95 (%) V90 (%) Dmax (%)
IMRT
Mean SE
Median (range)
Mean SE
Median (range)
94 3 100 100
98 (75–100) 100 (100) 100 (100)
94 3 100 1 100
98 (78–100) 100 (99–100) 100 (100)
93 3 100 1 100 113 3
94 (75–100) 100 (99–100) 100 (100) 108 (104–136)
95 3 100 100 112 1
98 (73–100) 100 (100) 100 (100) 111 (108–117)
Abbreviations: CTV = clinical target volume; Dmax (%) dose maximum (expressed as percent of prescribed dose); GTV = gross tumor volume; NS = not significant (p > 0.1); SE = standard error; VX (%) volume (in percent total volume), receiving X% of the prescribed dose. All values were nonsignificant (p > 0.1, two-tailed Wilcoxon signed-rank test).
>120% of the prescribed dose were observed in proton plans that required field patching. In both cases, the volume receiving >120% of the prescribed dose was less than 1 cc. Representative axial, coronal and sagittal images of proton and IMRT plans for a patient with a right infratemporal fossa lesion are shown in Fig. 1. Mean normal tissue doses are shown in Table 3. Proton plans provided superior dose sparing for all examined organs although the differences did not achieve statistical significance for ipsilateral cochlea and mastoid and was of borderline significance for ipsilateral parotid. Average dose–volume histograms for each organ are shown in Figs. 2 to 7.
The differences in mean dose between ipsilateral and contralateral, paired organs are shown in Table 4. For all organs evaluated except the lenses, proton plans provided greater dose asymmetry. However these differences did not reach statistical significance for globes, temporal lobes, or lacrimal glands and were of borderline significance for parotid glands. DISCUSSION Clinically acceptable proton and IMRT plans could be generated for all patients (Table 2). The entire CTV and GTV universally received 90% of the prescription dose. In
Fig. 1. Representative dosimetry for a three-field, proton treatment plan and a five-field intensity-modulated radiation therapy (IMRT) plan, with axial, coronal and sagittal views. The right infratemporal fossa clinical target volume (CTV) (thin purple) and 105% (maroon), 100% (thick red), 80% (orange), 60% (yellow), 40% (light green), and 20% (light blue) isodose lines are depicted. In the top panel, the GTV is also depicted (thin red).
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Table 3. Normal tissue dosimetry
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mean organ doses in cGy (n = 10)
Proton beam therapy
IMRT
Anatomic site
Mean SE
Median (range)
Mean SE
Median (range)
p
Contralateral globe Ipsilateral globe Contralateral lens Ipsilateral lens Contralateral retina Ipsilateral retina Contralateral optic nerve Ipsilateral optic nerve Optic chiasm Whole brain Brainstem Contralateral temporal lobe Ipsilateral temporal lobe Pituitary Hypothalamus Contralateral parotid Ipsilateral parotid Contralateral lacrimal Ipsilateral lacrimal Contralateral cochlea Ipsilateral cochlea Contralateral mastoid Ipsilateral mastoid
310 130 850 230 90 80 170 100 460 190 1360 300 1390 460 3020 450 1770 470 330 60 690 150 200 90 1320 250 2890 580 1200 450 230 130 3090 740 130 80 630 210 430 270 3680 620 110 100 2920 710
30 (0–1100) 730 (0–2690) 0 (0–810) 50 (0–1000) 80 (0–1470) 1360 (0–3560) 1120 (0–4200) 3070 (0–5110) 1230 (0–4570) 270 (110–720) 810 (0–1170) 30 (0–740) 1400 (30–2700) 3270 (10–5350) 380 (0–3720) 80 (0–1310) 4390 (0–5460) 0 (0–820) 380 (0–1690) 20 (0–2630) 4990 (0–5200) 0 (0–1000) 4210 (0–5170)
1330 190 1640 230 580 70 680 80 1800 280 2080 300 3060 330 3730 320 3330 380 810 130 2640 280 1560 150 2250 260 4340 240 2240 470 2430 320 3750 600 1250 260 1650 310 2920 340 4060 520 1930 240 3460 550
1190 (630–2540) 1570 (540–2860) 610 (240–950) 730 (240–1000) 1400 (800–3320) 1850 (720–3930) 2960 (1750–4740) 3990 (1990–5060) 3690 (1130–4990) 740 (310–1610) 2990 (1050–3730) 1400 (1000–2280) 2260 (1230–3800) 4320 (3020–5360) 2480 (170–4170) 2790 (30–3300) 4780 (30–5440) 1000 (450–2690) 1570 (580–3320) 3160 (190–3860) 4710 (210–5710) 2120 (20–2670) 4450 (20–5100)
<0.01 <0.01 <0.01 <0.01 <0.01 <0.01 <0.01 0.01 <0.01 <0.01 <0.01 <0.01 0.01 <0.01 0.01 <0.01 0.05 <0.01 0.01 <0.01 NS <0.01 NS
Abbreviations: IMRT = intensity-modulated radiation therapy; NS = not significant (p > 0.1, two-tailed, Wilcoxon signed-rank test); SE = standard error. Values have been rounded to nearest 10 cGy. For ipsilateral parotid, n = 9 because of an inability to define the gland radiographically as a result of tumor infiltration.
addition, no less than 99% of these target volumes received 95% of the prescription dose. Importantly, no significant differences in target volume coverage were observed between IMRT and proton plans, suggesting that comparisons of normal tissue dosimetry will not be subject to bias. With both proton and IMRT plans, target volume coverage was achieved with reasonable dose homogeneity; maximal doses exceeded 120% of the prescribed dose in only 2 cases, and the average maximal dose exceeded the prescribed dose by approximately 10%. This target volume coverage and dose homogeneity were achieved despite a diversity in tumor location, suggesting that both radiation techniques are suitable for PRMS treatment. Proton beam therapy plans provided significant reductions in radiation doses to all optic structures examined (Table 3). Visual and orbital toxicities are a significant burden on PRMS survivors. For example, 45 of 213 (21%) long-term, relapse-free survivors with localized, nonorbital, soft-tissue sarcoma of the head and neck treated on IRS II and III developed eye problems (9). Similarly, Paulino et al. described visual/orbital toxicities in 3 of 11 (27%) 5-year survivors of nonorbital, head-and-neck rhabdomyosarcoma (11). Only long-term clinical follow-up will clarify whether optic structure sparing with protons will translate into reduced morbidity. However, dose–response relationships previously identified for these structures provide a framework for predicting the clinical impact of proton radiotherapy.
Cataracts are a common cause of treatment-related, visual impairment in this population, occurring in approximately 10% of long-term survivors (9). Classically, the threshold lens dose during fractionated radiotherapy for clinically significant cataracts has been taken to be 5 Gy (13). Henk et al. estimated lens doses in 40 patients with orbital tumors treated with fractionated radiotherapy and noted no lens changes in patients receiving #5 Gy to the germinative zone of the lens after an average follow-up of approximately 6 years
Fig. 2. Average dose–volume histograms for contralateral globe (blue), ipsilateral globe (red), contralateral lens (black), and ipsilateral lens (green) for proton (straight lines) and intensity-modulated radiation therapy (IMRT) (dashed lines) plans.
Proton vs. photon IMRT for parameningeal rhabdomyosarcomas d K. R. KOZAK et al.
Fig. 3. Average dose–volume histograms for neuro-optic structures including contralateral retina (blue), ipsilateral retina (red), contralateral optic nerve (black), and ipsilateral optic nerve (green) for proton (straight lines) and intensity-modulated radiation therapy (IMRT) (dashed lines) plans.
(13). Furthermore these investigators estimated that a lens dose of 15 Gy resulted in a 50% probability of visual impairment. These dose thresholds may be overly liberal when applied to a pediatric population and when considering longer follow-up. Hall et al. examined 484 patients treated with ionizing radiation for facial hemangiomas (14). Treatment was delivered to patients <18 months of age and the minimum follow-up was 34 years. They found an increased risk of opacities at lens doses of <0.5 Gy and calculated a 35–50% increase in the risk of opacity development per unit of Gray. Whatever form the dose–response curve takes, it is clear that lens sparing by proton plans is striking. Mean ipsilateral and contralateral lens doses with IMRT plans exceeded 5 Gy in 80% and 60% of cases, respectively. In contrast, ipsilateral or contralateral lens dose exceeded 5 Gy in only 1 case with proton planning (Table 3, Fig. 2 and data not shown). These data suggest that proton beam therapy may reduce the risk of cataract development. Late visual toxicities related to radiation damage of neurooptic structures, including the retina, optic nerves, and optic
Fig. 4. Average dose–volume histograms for whole brain (blue), brainstem (red), contralateral temporal lobe (black), and ipsilateral temporal lobe (green) for proton (straight lines) and (intensity-modulated radiation therapy) IMRT (dashed lines) plans.
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Fig. 5. Average dose–volume histograms for pituitary (blue) and hypothalamus (red) for proton (straight lines) and intensity-modulated radiation therapy (IMRT) (dashed lines) plans.
chiasm, as well as uncommon eye injuries including dry eye syndrome, conjunctivitis, and extraocular abnormalities, are known consequences of conventional PRMS treatment (9, 11). Although proton use resulted in significant sparing of optic/orbital structures, this may not prove to be clinically significant. The incidence of these toxicities following treatment of head-and-neck soft-tissue sarcomas with conventional radiation techniques is low (9, 11). Compared with conventional techniques, IMRT offers the ability to spare relevant normal tissues and, in our series, IMRT doses to optic/ orbital structures would be predicted to result in exceptionally low rates of late visual toxicity (15–18). Despite this predictable low risk of visual toxicity with IMRT, the dose sparing provided by protons suggests that this modality may serve as a useful platform to investigate dose escalation. Although modest radiation dose intensification was investigated in IRS IV with no impact on local control or survival, locoregional failure remains an important component of total failure, and the rationale for dose escalation persists (3). Hearing loss represents another significant morbidity of PRMS treatment. Among 213 long-term survivors treated
Fig. 6. Average dose–volume histograms for contralateral parotid gland (blue), ipsilateral parotid gland (red), contralateral lacrimal gland (black) and ipsilateral lacrimal gland (green) for proton (straight lines) and intensity-modulated radiation therapy (IMRT) (dashed lines) plans.
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Fig. 7. Average dose–volume histograms for contralateral cochlea (blue), ipsilateral cochlea (red), contralateral mastoid (black) and ipsilateral mastoid (green) for proton (straight lines) and intensitymodulated radiation therapy (IMRT) (dashed lines) plans.
on Intergroup Rhabdomyosarcoma Studies II and III, 36 (17%) experienced decreased hearing (9). Neuro-otologic morbidity in this population is multifactorial but is attributable in part to cochlea irradiation. The precise dose–response relationship between cochlea dose and hearing loss remains to be defined. Based on an evaluation of 72 children with primary brain tumors, Merchant et al. suggested cochlear doses be kept to <32 Gy to minimize the risk of hearing loss (19). However the application of these findings to PRMS patients is not straightforward, given the multiple, significant differences in both patient and treatment factors. Huang et al. found that IMRT reduced both cochlear doses and ototoxicity compared with conventional radiotherapy among 26 children treated for medulloblastoma (20). Despite the reductions offered by IMRT, ototoxicity was still observed in 60% of patients. Again, these results must be interpreted cautiously because of the role of ototoxic chemotherapy in medulloblastoma management. In adults, cochlea dose has routinely been correlated with sensorineural hearing loss; however dose thresholds have varied widely between 30 and 60 Gy (21–24). Proton beam therapy resulted in mean contralateral
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cochlear doses of less than 27 Gy in all patients. In contrast, IMRT plans resulted in mean contralateral cochlear doses exceeding 32 Gy in half of the patients (Table 3). Because of anatomic constraints, ipsilateral cochlea doses were high for both proton and IMRT plans and differences did not achieve statistical significance. Nonetheless, mean ipsilateral cochlear doses exceeded 32 Gy in six proton beam therapy plans and eight IMRT plans. Although only long-term follow-up will unambiguously define the neuro-otologic safety of proton beam therapy, these data suggest that proton beam use may reduce the risk of hearing loss in children with PRMS. Neurocognitive toxic effects of PRMS treatment span an array of clinical manifestations including reduced school performance, behavioral problems, and frank central nervous system dysfunction. Raney et al. found learning disabilities in 35 of 71 (49%) evaluable, long-term survivors of headand neck-sarcoma (9). Such complicated sequelae cannot be attributed to single factors such as radiation dose to central nervous system structures. Nonetheless, substantial evidence suggests that radiation doses to the total brain and temporal lobes contribute to neurocognitive toxicity. Merchant et al. examined the impact of radiation doses to a number of brain regions on IQ decline after treatment in an array of pediatric populations (25–27). In general, mean radiation doses to the whole brain, supratentorial brain, and temporal lobes correlated with IQ decline. Brain volume receiving >45 Gy may be particularly important in predicting neurocognitive decline, but modeling suggests that even low doses may be detrimental (25–27). In this series, proton planning dramatically reduced radiation doses to the whole brain and temporal lobes (Table 3). Furthermore dose sparing was observed in both low- and high-dose volumes (Fig. 4). These data suggest protons may reduce the risk of neurocognitive decline in PRMS survivors. Dental problems are common in survivors of PRMSs. Raney et al. identified poor dentition in 29% of survivors treated on Intergroup Rhabdomyosarcoma Studies II and III (9). Although direct irradiation of teeth and jaw likely contributes to dental problems and was not evaluated here,
Table 4. Differential mean organ dose in cGy (n = 10) Proton beam therapy
Globe Lens Retina Optic Nerve Temporal Lobe Parotid Lacrimal Cochlea Mastoid
IMRT
Mean SE
Median (range)
Mean SE
Median (range)
p
550 180 80 30 900 250 1630 410 1120 240 2870 780 500 210 3240 690 2810 740
480 ( 220–1580) 30 ( 10–260) 850 ( 110–2090) 1690 ( 260–3670) 1300 (0–1960) 4330 (0–5200) 190 ( 370–1500) 4340 (0–5160) 4170 ( 120–5170)
310 110 100 40 280 200 670 260 690 200 1410 330 400 200 1140 300 1530 460
260 ( 100–850) 100 ( 100–240) 310 ( 1060–1260) 570 ( 610–2020) 540 ( 50–1810) 1810 ( 80–2520) 180 ( 440–1580) 1070 (20–2880) 1990 ( 180–3500)
NS NS 0.03 <0.01 0.1 0.05 NS <0.01 <0.01
Abbreviations: IMRT = intensity-modulated radiation therapy; NS = not significant (p > 0.1, two-tailed Wilcoxon signed-rank test); SE = standard error. Values are obtained by subtracting mean contralateral organ dose from mean ipsilateral organ dose; values are rounded to nearest 10 cGy. For parotid, n = 9 because of an inability to define the ipsilateral gland radiographically in 1 case.
Proton vs. photon IMRT for parameningeal rhabdomyosarcomas d K. R. KOZAK et al.
xerostomia is a major contributor to poor dentition after headand-neck radiation. Significant effort has been dedicated to defining relationships between parotid doses and xerostomia. The bulk of available data suggests that when mean parotid dose exceeds 24–30 Gy, salivary output declines to near zero shortly after radiation therapy and remains persistently depressed (28–31). The clinical consequences of parotid irradiation are understandably more pronounced when both glands receive significant radiation doses. Because of unmodifiable anatomic constraints among the patients evaluated here, both proton and IMRT plans deliver radiation doses predicted to significantly reduce ipsilateral parotid gland function. However, when the contralateral parotid gland is considered, a striking contrast is seen between proton and IMRT plans. For proton beam therapy, the mean dose to contralateral parotid never exceeded 13.1 Gy. In contrast, in 70% of IMRT plans, the mean contralateral parotid dose exceeded 26 Gy (Table 3). These data suggest that, in PRMS patients, proton beam therapy may result in lower rates of xerostomia and fewer dental problems compared with IMRT. Hypothalamic–pituitary irradiation increases the risk of endocrinopathies and, potentially, statural growth delay (32–35). These toxicities are well documented in survivors of head-and-neck rhabdomyosarcoma. Diminished height velocity was observed in 61% of orbital rhabdomyosarcoma patients treated in IRS I (12). Similarly, 48% of long term survivors treated in IRS II and III showed poor statural growth (9). Growth hormone deficiency, abnormal pubertal progression, hypothyroidism and other endocrinopathies are also observed (9, 11, 12). Although dose–response relationships are not unambiguously defined for hypothalamic–pituitary axis irradiation, toxicities are dose dependent. The observation that proton beam therapy reduces average pituitary doses by one third and hypothalamic doses by nearly half suggests protons may reduce the incidence of statural growth delay and late endocrinopathies (Table 3 and Fig. 5).
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Long-term cosmetic outcome of PRMS survivors is impacted by multiple factors including radiation to bone and soft tissue which can contribute to hypoplasia and facial asymmetry (36). Among 76 evaluable survivors treated on IRS II and III, only 2 patients were noted to have no facial/nuchal hypoplasia or asymmetry (9). Although not well studied, it is possible that greater radiation dose asymmetry will increase the risk and/or severity of late facial asymmetry. Because of enhanced conformality, proton beam therapy increases dose asymmetry between paired tissues (e.g., mastoid). For several tissues, including cochlea, mastoid (and thus portions of the temporal bone), and parotid (and thus mandibular rami), the average difference in mean radiation dose to ipsilateral and contralateral sides in proton plans exceeds 25 Gy. Use of IMRT typically reduces this dose asymmetry by approximately 50% (Table 4). Thus proton beam therapy may increase the risk of late facial/nuchal asymmetry. However the decreased risk of second malignancy because of the irradiation of less normal tissue may be worth any slight increase in facial/ nuchal asymmentry (37).
CONCLUSION In conclusion, proton beam therapy for PRMS reduces radiation doses to several critical structures. Based on historical dose–response relationships, proton beam therapy may reduce the risk of cataracts, hearing loss, neurocognitive decline, xerostomia/poor dentition, growth delay, and endocrinopathies compared with IMRT. However, proton use may increase the risk of late facial asymmetry. Although recent clinical results from Timmerman et al. suggest that proton therapy for PRMS is feasible and is tolerated (38), long-term follow-up of PRMS survivors treated with protons will be required to confirm these potential clinical sequelae.
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