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Intensity-modulated radiation therapy in the treatment of children
Medical Dosimetry, Vol. 27, No. 2, pp. 115–120, 2002 Copyright © 2002 American Association of Medical Dosimetrists Printed in the USA. All rights reserved 0958-3947/02/$–see front matter
PII: S0958-3947(02)00093-6
INTENSITY-MODULATED RADIATION THERAPY IN THE TREATMENT OF CHILDREN ARNOLD C. PAULINO, M.D. and MARK SKWARCHUK, PH.D. Departments of Radiation Oncology and Pediatrics, The University of Iowa College of Medicine, University of Iowa Health Care and the Children’s Hospital of Iowa, Iowa City, IA ( Accepted 26 February 2002)
Abstract—Intensity-modulated radiation therapy (IMRT) is a relatively new method of conformal radiotherapy delivery that is rapidly being incorporated in clinical practice. Of all patients treated with conformal techniques, children are the most likely to benefit as normal, developing structures can be minimized in the radiation field. The advantages of IMRT, including increased conformality and possible dose escalation, are discussed in this review. Possible disadvantages of IMRT in children are also discussed, such as lack of dose homogeneity in the target volume, increased dose to nontarget tissues, reliability of treatment setup, increased anesthesia time in younger children, and prolonged treatment planning. The issue of increased risk of second malignancy in this very young population is important, as many of these children will be long-term survivors with current multimodality therapy. © 2002 American Association of Medical Dosimetrists. Key Words: Intensity modulated radiation therapy; Pediatric oncology; Children; Late effects.
INTRODUCTION
control, the intensity profile changed every 10° of arc, producing intensity profiles with 10 non-zero steps. Serial tomotherapy delivery was facilitated by moving the couch between arcs at either 1.66-cm or 3.375-cm intervals in either 1-cm or 2-cm MIMiC modes, respectively, using the Mini-CRANE indexing device (Nomos Corp.).
Intensity-modulated radiation therapy (IMRT) is a relatively new method of treatment delivery that has been increasing in popularity over the past few years. This method of treatment can achieve an extremely conformal distribution of radiation to the target volume while sparing critical, surrounding normal tissue. Because of its ability to highly conform to the target, the potential for dose escalation exists, which may translate to better local control without increasing complication rates. Most studies that have been reported, however, have dealt with IMRT in the adult population with prostate, central nervous system, and head-and-neck cancers.1– 4 Children are particularly vulnerable to the late effects of RT and may be the population most likely to benefit from conformal techniques. This article will review the potential advantages and disadvantages of IMRT in the treatment of children. The Corvus inverse treatment planning system was used to generate intensity-modulated plans (version 3.0, Nomos Corp., Sewickley, PA).5 The IMRT plan was delivered using the multileaf intensity modulating collimator (MIMiC, Nomos Corp.) as a series of multiple 220° arcs. The MIMiC device was mounted on the blocking tray of a 10-MV linear accelerator (Cl-18/R, Varian Corp., Palo Alto, CA). IMRT plans were delivered through either a 1 ⫻ 20-cm or 2 ⫻ 20-cm slit of the collimator oriented along the axial plane of the patient. In synchrony with the gantry rotation and under computer
ADVANTAGES Increased conformality One of the advantages of using IMRT is the ability to achieve conformal isodose distributions, which is achieved by varying beam intensity across each field by using a multileaf modulator. This ability to spare normal, critical structures is of paramount importance in children, where the normal tissues are not fully developed and are particularly susceptible to radiation injury. Below are 2 cases where IMRT has been shown to improve dose distribution to the target volume and spare surrounding normal organs. Case 1. Patient no. 1 is a 7-year-old male who initially presented with a 3-month history of morning emesis and occipital headaches. Magnetic resonance imaging (MRI) of the brain revealed a 4-cm midline mass in the posterior fossa compressing the fourth ventricle and brainstem (Fig. 1). The patient underwent a posterior fossa craniotomy and resection of the mass. Pathology was consistent with medulloblastoma. The rest of his workup including MRI of the spine, and cerebrospinal fluid (CSF) cytology was negative for neuraxis dissemination. Postoperative MRI revealed no residual tumor in the posterior fossa. He was treated with weekly vincristine and craniospinal irradiation (CSI) to a dose of 23.4
Reprint requests to: Arnold C. Paulino, M.D., Associate Professor of Radiation Oncology and Pediatrics, Emory Clinic, Department of Radiation Oncology, 1365 Clifton Road NE, Room A 1300, Atlanta, GA 30322. E-mail: [email protected] 115
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Fig. 1. MRI sagittal scan of a child with medulloblastoma. Note the tumor in the cerebellum.
Gy in 13 fractions. Upon completion of CSI, a posterior fossa boost consisting of 32.4 Gy in 18 fractions was planned using serial tomotherapy and prescribed to the 82% isodose line. Figure 2 shows the isodose distributions to the clinical target volume (entire posterior fossa) and the surrounding normal tissue. Table 1 outlines the doses to the normal surrounding organs. The patient received further chemotherapy consisting of vincristine, cisplatin, and cyclophosphamide.
Fig. 2. Transverse slice of an IMRT plan for patient with medulloblastoma. This plan is for the posterior fossa boost after craniospinal irradiation. CTV is outlined in red, cochlea outlined in purple. Color legend for isodose lines: 120% light green, 110% sky blue, 100% dark blue, 90% green, 70% yellow, 50% orange, 30% red, 10% red violet.
Fig. 3. Transverse slice of an IMRT plan for patient with parameningeal rhabdomyosarcoma. Notice the multiple critical structures in close proximity to the tumor such as the orbit, optic nerve. and brain. See color legend in Fig. 2.
In this particular case, IMRT was able to spare some dose to the cochlea, which is important because both radiotherapy and cisplatin chemotherapy are known to cause high-frequency hearing loss. Sensorineural hearing loss from RT is most likely secondary to damage to the
Fig. 4. Transverse slice of an IMRT plan for a child with orbital rhabdomyosarcoma. Note the areas in the clinical target volume (CTV), which are receiving higher than the prescribed fraction size. In this particular case, the optic nerve is in the CTV and portions of this structure are getting 10% more than the prescribed dose. See color legend in Fig. 2.
IMRT in children ● A. C. PAULINO
Table 1. Clinical target volume and normal tissue doses using IMRT in the treatment of the posterior fossa in medulloblastoma
Structure
Mean Dose (Gy)
Minimum Dose (Gy)
Maximum Dose (Gy)
Clinical target volume Left cochlea Right cochlea Pituitary gland
33.64 8.69 9.38 6.47
16.4 4.15 7.11 4.74
37.73 12.05 12.84 9.48
Clinical target volume prescribed dose: 32.4 Gy in 18 fractions, prescribed to 82% isodose line. 4.68% of CTV below the prescribed dose, 1-cm MIMiC mode, approximate treatment time: 20 minutes.
organ of Corti, affecting primarily higher frequencies (⬎2 kHz), with a latency period of 6 to 12 months after treatment.6 Sensorineural hearing loss occurs in one third of patients receiving doses of 60 to 70 Gy to the cochlea for nasopharyngeal carcinoma.7 Using parallel-opposed lateral fields for the posterior fossa boost in medulloblastoma, the cochlea receives the full dose given to the posterior fossa, which, in this particular case, amounts to 55.8 Gy. We have previously compared parallel-opposed lateral fields (2-dimensional radiotherapy) and 3-dimensional techniques to treat the posterior fossa and found that 3-dimensional treatment planning limits the mean dose to the cochlea to approximately 45% of the dose given by conventional techniques.8 IMRT, as seen in this patient, limited the mean cochlear dose further to 25% to 30% of the dose to the posterior fossa. Preliminary evidence from the Methodist Hospital in Houston shows a reduction of ototoxicity despite a higher cisplatin dose in children with medulloblastoma.9 IMRT also delivered a mean dose of 6.47 Gy to the pituitary gland, which is comparable to the other methods of 3-dimensional treatment delivery.8 Case 2. Patient no. 2 is a 17-year-old male who initially presented with a 1-month history of increasing back pain and epistaxis. He subsequently developed weakness and paresthesia of bilateral lower extremity. An MRI scan of the thoracic spine revealed an extradural mass at the T9-10 vertebral body level with compression of the spinal cord. Further workup included an MRI of the head and neck, which showed a large mass in the nasopharynx with extension to the left maxillary, ethmoid, and frontal sinuses. Biopsy of the nasopharyngeal mass was consistent with embryonal rhabdomyosarcoma. Bone marrow biopsy was significant for the presence of metastatic tumor. He was then classified as having Stage IV, Group 4 disease. The patient received 40.4 Gy in 19 fractions to the T7 to T12 spine, with shrinkage of the mass and reversal of neurologic symptoms. He then received 4 cycles of vincristine, actinomycin-D, and cyclophosphamide chemotherapy, with a complete response in both the nasopharynx and spine.
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Table 2. Clinical target volume and normal tissue doses using IMRT in the treatment of nasopharyngeal rhabdomyosarcoma
Structure
Mean Dose (Gy)
Minimum Dose (Gy)
Maximum Dose (Gy)
Clinical target volume Optic chiasm Right optic nerve Left optic nerve Right orbit Left orbit Right parotid gland Left parotid gland Brain
57.85 26.29 26.70 34.08 19.74 26.52 4.74 6.25 4.17
30.58 15.79 22.51 25.54 4.37 6.38 1.01 1.01 0.00
67.20 41.33 32.26 39.65 36.29 52.08 17.81 21.17 65.86
Clinical target volume prescribed dose: 50.4 Gy in 28 fractions, prescribed to 75% isodose line. 1.98% of clinical target volume was below prescribed dose, 1-cm MIMiC mode, approximate treatment time: 25 minutes.
Repeat bone marrow biopsy was negative for tumor. The boy was referred to us for treatment to the nasopharynx. In this particular case, IMRT was employed to spare the normal ocular apparatus and brain and minimize the late toxicity secondary to RT. Figure 3 shows a representative slice of the highly conformal isodose distributions with serial tomotherapy. The minimum, maximum, and mean doses to various surrounding critical organs are shown in Table 2. The prescribed dose of 50.4 Gy was delivered to the 75% isodose line, with 1.98% of the clinical target volume receiving less than 50.4 Gy, mainly adjacent to the optic structures. The doses to the optic nerves, optic chiasm, spinal cord, and brain were within tolerance dose levels. In addition, both parotid glands received mean doses of 4.74 and 6.25 Gy, respectively, both below the dose necessary to induce xerostomia. Although the patient achieved local control, he eventually succumbed to his disease 6 months after completion of IMRT, secondary to relapse in the bone marrow and bilateral testicles. Dose escalation Another advantage of IMRT is the potential for dose escalation. Because of increased conformality and avoidance of surrounding normal tissue, doses to the target can be increased without increased toxicity to the neighboring structures. The following case is presented to illustrate this point. Case 3. Patient no. 3 is a 24-month-old female with a 2-week history of headaches, projectile vomiting, and gait instability. An MRI scan of the brain revealed a posterior fossa tumor involving the inferior vermis. An MRI of the spinal cord showed no evidence of leptomeningeal dissemination. She underwent a subtotal resection of the tumor, which was read by the neuropathologist as an anaplastic ependymoma. Postoperative MRI of the brain revealed residual tumor. CSF cytology showed no
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malignant cells. She then started induction chemotherapy followed by maintenance chemotherapy consisting of vincristine, ifosphamide, carboplatin, and etoposide. Repeat imaging showed disappearance of residual tumor. She presented to us for postoperative RT upon turning 3 years of age. IMRT was employed to treat the tumor bed. Based on a previous report from the Pediatric Oncology Group showing an improvement in outcome for subtotally resected tumors using hyperfractionated RT, a dose of 69.6 Gy given 1.2-Gy BID was planned.10 The entire posterior fossa was not treated in this case based on a previous report from our institution that showed that most local failures for infratentorial ependymomas occur in the tumor bed and not the nontumor bed posterior fossa.11 POTENTIAL PROBLEMS Although IMRT has been increasingly used in the treatment of adults with head-and-neck, prostate, and central nervous tumors, limited experience is available in children. The treatment of a child presents a challenge for the radiation oncologist using this modality. In this section, we will review the potential problems using IMRT in the treatment of children. They include dose inhomogeneity, increased dose to nontarget tissues, reliability of treatment setup, increased anesthesia time in younger children, and prolonged treatment planning. Lack of dose homogeneity Although IMRT is excellent in sparing surrounding critical structures, the dose in the planning target volume may be less predictable and can be relatively nonhomogenous. This is especially true with the use of CORVUS planned IMRT. In one study, the dose was prescribed to 65% to 97.5% isodose line.12 “Hot spots” were present in the target volume and may be detrimental if a critical structure is in the target volume. Therefore, one of the disadvantages of IMRT is this lack of dose homogeneity in the target volume. This is best illustrated in the following case, where one of the critical structures is in the clinical target volume. Case 4. Patient no. 4 is a 3-year-old girl with a 1-week history of swelling and deviation of the right eye. Her workup included a CT scan of the orbit that showed a right orbital mass without erosion into the bone. MRI did not reveal any intracranial extension. A biopsy of the mass showed embryonal rhabdomyosarcoma. CSF cytology, bone scan, CT of the chest, and bone marrow biopsy were all negative for tumor dissemination. Based on the above studies, her disease was classified as Intergroup Rhabdomyosarcoma Study Stage 1, Group III disease. She received 3 weeks of chemotherapy and presented to our department for radiotherapy to the right orbit. Prescription dose was 4500 cGy in 25 fractions. The first 3600 cGy was to be delivered using the original tumor volume prior to any chemotherapy, while the remaining
Volume 27, Number 2, 2002
900 cGy was to be given only to the remaining tumor after 3 weeks of chemotherapy. A representative slice of the IMRT plan is shown in Fig. 4. Because the right optic nerve was included in the clinical target volume due to potential spread of tumor, an inhomogeneous dose was given to this critical structure. A dose 20% higher than the prescription dose was present in the clinical target volume. The tolerance dose of the optic nerve may be lower than 5000 cGy with the use of a larger fraction size and chemotherapy.13,14 Another situation where an inhomogeneous dose can cause potential late toxicity is in the treatment of regions next to growing bone and soft tissue. In the management of malignancies, such as Wilms’ tumor and neuroblastoma, care is given to deliver a homogenous dose of radiation to the vertebral bodies to avoid scoliosis or kyphosis. Musculoskeletal effects are most prominent at doses ⬎ 2400 cGy.15 A situation where this problem may arise is in the treatment of Ewing’s sarcoma of the spine. In such a case, the vertebral body will receive an inhomogeneous dose of radiation. Including the entire vertebral body in the clinical target volume will invariably deliver potential “hot spots” to spinal cord, which is not desirable. Increased dose to nontarget tissues The whole body dose for patients treated with IMRT for the head-and-neck region have ranged from 300 to 543 mSv.16 This is due to the increased amount of leakage radiation, because workload values for MIMicdelivered and MLC-based IMRT vary from 8 to 12 times and 2 to 5 times larger than conventional therapy.4,17,18 In 2 studies, the average MUs setting/patient/day were 1426 and 1561.16 Increased whole body dose is particularly important in the consideration of treatment of pediatric patients. Most children have a 1% to 2% risk of second malignancy 15 years after conventional treatment. Exceptions include children with retinoblastoma and Ewing’s sarcoma, which have higher second cancer rates.19 Long-term follow-up of children treated with IMRT will be required to determine if an increase in secondary malignancy occurs. Treatment setup Because IMRT provides highly conformal isodose distribution to the target volume, immobilization is paramount to assure adequate dose delivery. In our institution, IMRT is employed in children with head-and-neck and brain primary sites. We have used a thermoplastic mask to ensure day-to-day positioning. Positional inaccuracy with a thermoplastic mask usually ranges from 2 to 3 mm and is taken into account when designing the planning target volume.20 This type of immobilization is noninvasive, and construction is easily implemented by therapists. Other types of immobilization for the head include the Talon system and the stereotactic frame, both of which are invasive and need expertise.21
IMRT in children ● A. C. PAULINO
The thorax and abdomen are more difficult to immobilize because of respiration. The pelvis is easier to immobilize than the thorax and abdomen. Thermoplastic molds and alpha cradle system can be used to immobilize the pelvis as in the treatment of prostate cancer. Prolonged anesthesia time Young children may need anesthesia so they can be treated with radiotherapy. In one study, anesthesia was employed in 96%, 93%, 80%, and 51% of children ages ⬍ 1, 1–2, 2–3, and 3– 4-years old, respectively.22 It is not surprising that very young children who are separated from their primary caretaker will be scared of an unfamiliar, large machine. Because of the increased treatment time to deliver the desired dose configuration and the noise associated with a beam modulator, some young patients will require anesthesia with IMRT and not with conventional radiotherapy. In our department, treatment times using Mimic-based IMRT in adults range from 20 to 30 minutes depending on the number of arcs utilized. Ancillary support including anesthesia will also require time and, in combination with IMRT treatment delivery, will occupy at least 1 hour of linear accelerator room time. In comparison to 2-dimensional methods of treatment delivery, IMRT in the treatment of very young children will require more anesthesia time. Prolonged treatment planning Before arriving at the final IMRT plan, most physicists and oncologists will have reviewed multiple plans. Contouring of the target volume and critical structures takes time, like other 3-dimensional methods of treatment delivery. We usually reserve 5 working days for treatment planning because of this high level of complexity. Some children may not start with an IMRT plan because of such time constraints. Such is the case of patients with parameningeal rhabdomyosarcoma and intracranial extension who need to start RT at day 0 of chemotherapy.23 For children with Wilms’ tumor undergoing nephrectomy, final pathologic stage may not be available after a week after surgery. Children with Stage II to IV anaplastic histology and III–IV favorable histology have to start RT prior to postoperative day 10, as earlier studies show a better local control with such strategy.24 CONCLUSIONS In summary, IMRT has advantages and disadvantages in the treatment of children. In our institution, most of the children treated with this modality have tumors in the brain or head-and-neck region, as these sites are in close proximity to normal critical structures and immobilization is less problematic. IMRT is not used in tumors where a critical structure (i.e., optic nerve/chiasm, spinal cord) is part of the clinical target volume because of the possibility of giving a dose higher than the prescription
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dose to these organs. Treatment with IMRT also depends on the age of the child. If the patient has undergone puberty, bone asymmetry is of less concern. Long-term follow-up of children treated with IMRT is needed to determine whether there is a higher risk of second malignancy with this modality. REFERENCES 1. Grant III, W.; Cain, R.B. Intensity modulated conformal therapy for intracranial lesions. Med. Phys. 23:237– 41; 1998. 2. Hunt, M.A.; Zelefsky, M.J.; Wolden, S.; et al. Treatment planning and delivery of intensity-modulated radiation therapy for primary nasopharynx cancer. Int. J. Radiat. Oncol. Biol. Phys. 49:623–32; 2001. 3. Ling, C.C.; Burman, C.; Chui, C.S.; et al. Conformal radiation treatment of prostate cancer using intensity-modulated photon beams produced with dynamic multileaf collimation. Int. J. Radiat. Oncol. Biol. Phys. 35:721–30; 1996. 4. Intensity Modulated Radiation Therapy Collaborative Working Group. Intensity-modulated radiotherapy: current status and issues of interest. Int. J. Radiat. Oncol. Biol. Phys. 51:880 –914; 2001. 5. Curran, B. Where goest the peacock? Med. Dosim. 26:3–9; 2001. 6. Grau, C.; Overgaard, J. Postirradiation sensorineural hearing loss: A common but ignored late radiation complication. Int. J. Radiat. Oncol. Biol. Phys. 36:515–7; 1996. 7. Kwong, D.L.W.; Wei, W.I.; Sham, J.S.T.; et al. Sensorineural hearing loss in patients treated for nasopharyngeal carcinoma: A prospective study of the effect of radiation and cisplatin treatment. Int. J. Radiat. Oncol. Biol. Phys. 36:281–9; 1996. 8. Paulino, A.C.; Narayana, A.; Mohideen, N.M.; et al. Posterior fossa boost in medulloblastoma: An analysis of dose to surrounding structures using 3-dimensional (conformal) radiotherapy. Int. J. Radiat. Oncol. Biol. Phys. 46:281– 6; 2000. 9. Woo, S.Y.; Huang, E.; Teh B.S.; et al. Reduction of ototoxicity in pediatric patients with medulloblastoma using intensity modulated radiation therapy (IMRT) (Abstr.). Int. J. Radiat. Oncol. Biol. Phys. 51S:121; 2001. 10. Kovnar E.; Curran W.; Tomita T.; et al. Hyperfractionated irradiation for childhood ependymoma: Improved control in subtotally resected tumors (Abstr.) Childs Nerv. Syst. 14:569; 1998. 11. Paulino, A.C. The local field in infratentorial ependymoma: Does the entire posterior fossa need to be treated? Int. J. Radiat. Oncol. Biol. Phys. 49:757– 61; 2001. 12. Al Ghazi, M.; Kwon, R.; Kuo, J.; et al. The University of California Irvine experience with tomotherapy using the peacock system. Med. Dosim. 26:17–27; 2001. 13. Emami, B.; Lyman, J.; Brown, A.; et al. Tolerance of normal tissue to therapeutic irradiation. Int. J. Radiat. Oncol. Biol. Phys. 21: 109 –22; 1991. 14. Parsons, J.T.; Bova, F.J.; Fitzgerald, C.R.; et al. Radiation optic neuropathy after megavoltage external-beam irradiation: Analysis of time-dose factors. Int. J. Radiat. Oncol. Biol. Phys. 30:755– 63; 1994. 15. Paulino, A.C.; Wen, B-C.; Brown, C.K.; et al. Late effects in children treated with radiation therapy for Wilms’ tumor. Int. J. Radiat. Oncol. Biol. Phys. 46:1239 – 46; 2000. 16. Grant III, W. Experience with intensity modulated beam delivery. In: Palta, J.; Mackie, T.R., editors. Teletherapy: Present and Future. College Park, MD: Advanced Medical Publishing; 1996: 793– 804. 17. Followill, D.; Geis, P.; Boyer, A. Estimates of whole-body dose equivalent produced by beam intensity modulated conformal therapy. Int. J. Radiat. Oncol. Biol. Phys. 38:667–72; 1997. 18. Mutic, S.; Low, D.A.; Klein, E.E.; et al. Room shielding for intensity-modulated radiation therapy treatment facilities. Int. J. Radiat. Oncol. Biol. Phys. 50:239 – 46; 2001. 19. Halperin, E.C.; Constine, L.S.; Tarbell, N.J.; et al. Secondary tumors. In: Halperin, E.C., Constine, L.S., Tarbell, N.J., Kun, L.E., editors. Pediatric Radiation Oncology. 3rd ed. Philadelphia: Lippincott Williams & Wilkins; 1999: 538 – 62. 20. Saw, C.B.; Yakoob, R.; Enke, C.; et al. Immobilization devices for intensity-modulated radiation therapy (IMRT). Med. Dosim. 26: 71– 8; 2001.
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21. Carol, M.P. A system for planning and rotational delivery of intensity-modulated fields. Int. J. Imag. Syst. Tech. 6:56 – 61; 1995. 22. Fortney, J.T.; Halperin, E.C.; Hertz, C.M.; et al. One hundred forty one consecutive cases of anesthesia for pediatric external beam radiation therapy. Int. J. Radiat. Oncol. Biol. Phys. 44:587–91; 1998.
Volume 27, Number 2, 2002 23. Christ, W.M.; Anderson, J.R.; Meza, J.L.; et al. Intergroup Rhabdomyosarcoma Study-IV: Results for patients with nonmetastatic disease. J. Clin. Oncol. 19:3091–102; 2001. 24. Thomas, P.R.M.; Tefft, M.; Farewell, V.; et al. Abdominal relapses in irradiated Second National Wilms’ Tumor Study patients. J. Clin. Oncol. 2:1098 –101; 1984.
PII: S0958-3947(02)00093-6
INTENSITY-MODULATED RADIATION THERAPY IN THE TREATMENT OF CHILDREN ARNOLD C. PAULINO, M.D. and MARK SKWARCHUK, PH.D. Departments of Radiation Oncology and Pediatrics, The University of Iowa College of Medicine, University of Iowa Health Care and the Children’s Hospital of Iowa, Iowa City, IA ( Accepted 26 February 2002)
Abstract—Intensity-modulated radiation therapy (IMRT) is a relatively new method of conformal radiotherapy delivery that is rapidly being incorporated in clinical practice. Of all patients treated with conformal techniques, children are the most likely to benefit as normal, developing structures can be minimized in the radiation field. The advantages of IMRT, including increased conformality and possible dose escalation, are discussed in this review. Possible disadvantages of IMRT in children are also discussed, such as lack of dose homogeneity in the target volume, increased dose to nontarget tissues, reliability of treatment setup, increased anesthesia time in younger children, and prolonged treatment planning. The issue of increased risk of second malignancy in this very young population is important, as many of these children will be long-term survivors with current multimodality therapy. © 2002 American Association of Medical Dosimetrists. Key Words: Intensity modulated radiation therapy; Pediatric oncology; Children; Late effects.
INTRODUCTION
control, the intensity profile changed every 10° of arc, producing intensity profiles with 10 non-zero steps. Serial tomotherapy delivery was facilitated by moving the couch between arcs at either 1.66-cm or 3.375-cm intervals in either 1-cm or 2-cm MIMiC modes, respectively, using the Mini-CRANE indexing device (Nomos Corp.).
Intensity-modulated radiation therapy (IMRT) is a relatively new method of treatment delivery that has been increasing in popularity over the past few years. This method of treatment can achieve an extremely conformal distribution of radiation to the target volume while sparing critical, surrounding normal tissue. Because of its ability to highly conform to the target, the potential for dose escalation exists, which may translate to better local control without increasing complication rates. Most studies that have been reported, however, have dealt with IMRT in the adult population with prostate, central nervous system, and head-and-neck cancers.1– 4 Children are particularly vulnerable to the late effects of RT and may be the population most likely to benefit from conformal techniques. This article will review the potential advantages and disadvantages of IMRT in the treatment of children. The Corvus inverse treatment planning system was used to generate intensity-modulated plans (version 3.0, Nomos Corp., Sewickley, PA).5 The IMRT plan was delivered using the multileaf intensity modulating collimator (MIMiC, Nomos Corp.) as a series of multiple 220° arcs. The MIMiC device was mounted on the blocking tray of a 10-MV linear accelerator (Cl-18/R, Varian Corp., Palo Alto, CA). IMRT plans were delivered through either a 1 ⫻ 20-cm or 2 ⫻ 20-cm slit of the collimator oriented along the axial plane of the patient. In synchrony with the gantry rotation and under computer
ADVANTAGES Increased conformality One of the advantages of using IMRT is the ability to achieve conformal isodose distributions, which is achieved by varying beam intensity across each field by using a multileaf modulator. This ability to spare normal, critical structures is of paramount importance in children, where the normal tissues are not fully developed and are particularly susceptible to radiation injury. Below are 2 cases where IMRT has been shown to improve dose distribution to the target volume and spare surrounding normal organs. Case 1. Patient no. 1 is a 7-year-old male who initially presented with a 3-month history of morning emesis and occipital headaches. Magnetic resonance imaging (MRI) of the brain revealed a 4-cm midline mass in the posterior fossa compressing the fourth ventricle and brainstem (Fig. 1). The patient underwent a posterior fossa craniotomy and resection of the mass. Pathology was consistent with medulloblastoma. The rest of his workup including MRI of the spine, and cerebrospinal fluid (CSF) cytology was negative for neuraxis dissemination. Postoperative MRI revealed no residual tumor in the posterior fossa. He was treated with weekly vincristine and craniospinal irradiation (CSI) to a dose of 23.4
Reprint requests to: Arnold C. Paulino, M.D., Associate Professor of Radiation Oncology and Pediatrics, Emory Clinic, Department of Radiation Oncology, 1365 Clifton Road NE, Room A 1300, Atlanta, GA 30322. E-mail: [email protected] 115
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Fig. 1. MRI sagittal scan of a child with medulloblastoma. Note the tumor in the cerebellum.
Gy in 13 fractions. Upon completion of CSI, a posterior fossa boost consisting of 32.4 Gy in 18 fractions was planned using serial tomotherapy and prescribed to the 82% isodose line. Figure 2 shows the isodose distributions to the clinical target volume (entire posterior fossa) and the surrounding normal tissue. Table 1 outlines the doses to the normal surrounding organs. The patient received further chemotherapy consisting of vincristine, cisplatin, and cyclophosphamide.
Fig. 2. Transverse slice of an IMRT plan for patient with medulloblastoma. This plan is for the posterior fossa boost after craniospinal irradiation. CTV is outlined in red, cochlea outlined in purple. Color legend for isodose lines: 120% light green, 110% sky blue, 100% dark blue, 90% green, 70% yellow, 50% orange, 30% red, 10% red violet.
Fig. 3. Transverse slice of an IMRT plan for patient with parameningeal rhabdomyosarcoma. Notice the multiple critical structures in close proximity to the tumor such as the orbit, optic nerve. and brain. See color legend in Fig. 2.
In this particular case, IMRT was able to spare some dose to the cochlea, which is important because both radiotherapy and cisplatin chemotherapy are known to cause high-frequency hearing loss. Sensorineural hearing loss from RT is most likely secondary to damage to the
Fig. 4. Transverse slice of an IMRT plan for a child with orbital rhabdomyosarcoma. Note the areas in the clinical target volume (CTV), which are receiving higher than the prescribed fraction size. In this particular case, the optic nerve is in the CTV and portions of this structure are getting 10% more than the prescribed dose. See color legend in Fig. 2.
IMRT in children ● A. C. PAULINO
Table 1. Clinical target volume and normal tissue doses using IMRT in the treatment of the posterior fossa in medulloblastoma
Structure
Mean Dose (Gy)
Minimum Dose (Gy)
Maximum Dose (Gy)
Clinical target volume Left cochlea Right cochlea Pituitary gland
33.64 8.69 9.38 6.47
16.4 4.15 7.11 4.74
37.73 12.05 12.84 9.48
Clinical target volume prescribed dose: 32.4 Gy in 18 fractions, prescribed to 82% isodose line. 4.68% of CTV below the prescribed dose, 1-cm MIMiC mode, approximate treatment time: 20 minutes.
organ of Corti, affecting primarily higher frequencies (⬎2 kHz), with a latency period of 6 to 12 months after treatment.6 Sensorineural hearing loss occurs in one third of patients receiving doses of 60 to 70 Gy to the cochlea for nasopharyngeal carcinoma.7 Using parallel-opposed lateral fields for the posterior fossa boost in medulloblastoma, the cochlea receives the full dose given to the posterior fossa, which, in this particular case, amounts to 55.8 Gy. We have previously compared parallel-opposed lateral fields (2-dimensional radiotherapy) and 3-dimensional techniques to treat the posterior fossa and found that 3-dimensional treatment planning limits the mean dose to the cochlea to approximately 45% of the dose given by conventional techniques.8 IMRT, as seen in this patient, limited the mean cochlear dose further to 25% to 30% of the dose to the posterior fossa. Preliminary evidence from the Methodist Hospital in Houston shows a reduction of ototoxicity despite a higher cisplatin dose in children with medulloblastoma.9 IMRT also delivered a mean dose of 6.47 Gy to the pituitary gland, which is comparable to the other methods of 3-dimensional treatment delivery.8 Case 2. Patient no. 2 is a 17-year-old male who initially presented with a 1-month history of increasing back pain and epistaxis. He subsequently developed weakness and paresthesia of bilateral lower extremity. An MRI scan of the thoracic spine revealed an extradural mass at the T9-10 vertebral body level with compression of the spinal cord. Further workup included an MRI of the head and neck, which showed a large mass in the nasopharynx with extension to the left maxillary, ethmoid, and frontal sinuses. Biopsy of the nasopharyngeal mass was consistent with embryonal rhabdomyosarcoma. Bone marrow biopsy was significant for the presence of metastatic tumor. He was then classified as having Stage IV, Group 4 disease. The patient received 40.4 Gy in 19 fractions to the T7 to T12 spine, with shrinkage of the mass and reversal of neurologic symptoms. He then received 4 cycles of vincristine, actinomycin-D, and cyclophosphamide chemotherapy, with a complete response in both the nasopharynx and spine.
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Table 2. Clinical target volume and normal tissue doses using IMRT in the treatment of nasopharyngeal rhabdomyosarcoma
Structure
Mean Dose (Gy)
Minimum Dose (Gy)
Maximum Dose (Gy)
Clinical target volume Optic chiasm Right optic nerve Left optic nerve Right orbit Left orbit Right parotid gland Left parotid gland Brain
57.85 26.29 26.70 34.08 19.74 26.52 4.74 6.25 4.17
30.58 15.79 22.51 25.54 4.37 6.38 1.01 1.01 0.00
67.20 41.33 32.26 39.65 36.29 52.08 17.81 21.17 65.86
Clinical target volume prescribed dose: 50.4 Gy in 28 fractions, prescribed to 75% isodose line. 1.98% of clinical target volume was below prescribed dose, 1-cm MIMiC mode, approximate treatment time: 25 minutes.
Repeat bone marrow biopsy was negative for tumor. The boy was referred to us for treatment to the nasopharynx. In this particular case, IMRT was employed to spare the normal ocular apparatus and brain and minimize the late toxicity secondary to RT. Figure 3 shows a representative slice of the highly conformal isodose distributions with serial tomotherapy. The minimum, maximum, and mean doses to various surrounding critical organs are shown in Table 2. The prescribed dose of 50.4 Gy was delivered to the 75% isodose line, with 1.98% of the clinical target volume receiving less than 50.4 Gy, mainly adjacent to the optic structures. The doses to the optic nerves, optic chiasm, spinal cord, and brain were within tolerance dose levels. In addition, both parotid glands received mean doses of 4.74 and 6.25 Gy, respectively, both below the dose necessary to induce xerostomia. Although the patient achieved local control, he eventually succumbed to his disease 6 months after completion of IMRT, secondary to relapse in the bone marrow and bilateral testicles. Dose escalation Another advantage of IMRT is the potential for dose escalation. Because of increased conformality and avoidance of surrounding normal tissue, doses to the target can be increased without increased toxicity to the neighboring structures. The following case is presented to illustrate this point. Case 3. Patient no. 3 is a 24-month-old female with a 2-week history of headaches, projectile vomiting, and gait instability. An MRI scan of the brain revealed a posterior fossa tumor involving the inferior vermis. An MRI of the spinal cord showed no evidence of leptomeningeal dissemination. She underwent a subtotal resection of the tumor, which was read by the neuropathologist as an anaplastic ependymoma. Postoperative MRI of the brain revealed residual tumor. CSF cytology showed no
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malignant cells. She then started induction chemotherapy followed by maintenance chemotherapy consisting of vincristine, ifosphamide, carboplatin, and etoposide. Repeat imaging showed disappearance of residual tumor. She presented to us for postoperative RT upon turning 3 years of age. IMRT was employed to treat the tumor bed. Based on a previous report from the Pediatric Oncology Group showing an improvement in outcome for subtotally resected tumors using hyperfractionated RT, a dose of 69.6 Gy given 1.2-Gy BID was planned.10 The entire posterior fossa was not treated in this case based on a previous report from our institution that showed that most local failures for infratentorial ependymomas occur in the tumor bed and not the nontumor bed posterior fossa.11 POTENTIAL PROBLEMS Although IMRT has been increasingly used in the treatment of adults with head-and-neck, prostate, and central nervous tumors, limited experience is available in children. The treatment of a child presents a challenge for the radiation oncologist using this modality. In this section, we will review the potential problems using IMRT in the treatment of children. They include dose inhomogeneity, increased dose to nontarget tissues, reliability of treatment setup, increased anesthesia time in younger children, and prolonged treatment planning. Lack of dose homogeneity Although IMRT is excellent in sparing surrounding critical structures, the dose in the planning target volume may be less predictable and can be relatively nonhomogenous. This is especially true with the use of CORVUS planned IMRT. In one study, the dose was prescribed to 65% to 97.5% isodose line.12 “Hot spots” were present in the target volume and may be detrimental if a critical structure is in the target volume. Therefore, one of the disadvantages of IMRT is this lack of dose homogeneity in the target volume. This is best illustrated in the following case, where one of the critical structures is in the clinical target volume. Case 4. Patient no. 4 is a 3-year-old girl with a 1-week history of swelling and deviation of the right eye. Her workup included a CT scan of the orbit that showed a right orbital mass without erosion into the bone. MRI did not reveal any intracranial extension. A biopsy of the mass showed embryonal rhabdomyosarcoma. CSF cytology, bone scan, CT of the chest, and bone marrow biopsy were all negative for tumor dissemination. Based on the above studies, her disease was classified as Intergroup Rhabdomyosarcoma Study Stage 1, Group III disease. She received 3 weeks of chemotherapy and presented to our department for radiotherapy to the right orbit. Prescription dose was 4500 cGy in 25 fractions. The first 3600 cGy was to be delivered using the original tumor volume prior to any chemotherapy, while the remaining
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900 cGy was to be given only to the remaining tumor after 3 weeks of chemotherapy. A representative slice of the IMRT plan is shown in Fig. 4. Because the right optic nerve was included in the clinical target volume due to potential spread of tumor, an inhomogeneous dose was given to this critical structure. A dose 20% higher than the prescription dose was present in the clinical target volume. The tolerance dose of the optic nerve may be lower than 5000 cGy with the use of a larger fraction size and chemotherapy.13,14 Another situation where an inhomogeneous dose can cause potential late toxicity is in the treatment of regions next to growing bone and soft tissue. In the management of malignancies, such as Wilms’ tumor and neuroblastoma, care is given to deliver a homogenous dose of radiation to the vertebral bodies to avoid scoliosis or kyphosis. Musculoskeletal effects are most prominent at doses ⬎ 2400 cGy.15 A situation where this problem may arise is in the treatment of Ewing’s sarcoma of the spine. In such a case, the vertebral body will receive an inhomogeneous dose of radiation. Including the entire vertebral body in the clinical target volume will invariably deliver potential “hot spots” to spinal cord, which is not desirable. Increased dose to nontarget tissues The whole body dose for patients treated with IMRT for the head-and-neck region have ranged from 300 to 543 mSv.16 This is due to the increased amount of leakage radiation, because workload values for MIMicdelivered and MLC-based IMRT vary from 8 to 12 times and 2 to 5 times larger than conventional therapy.4,17,18 In 2 studies, the average MUs setting/patient/day were 1426 and 1561.16 Increased whole body dose is particularly important in the consideration of treatment of pediatric patients. Most children have a 1% to 2% risk of second malignancy 15 years after conventional treatment. Exceptions include children with retinoblastoma and Ewing’s sarcoma, which have higher second cancer rates.19 Long-term follow-up of children treated with IMRT will be required to determine if an increase in secondary malignancy occurs. Treatment setup Because IMRT provides highly conformal isodose distribution to the target volume, immobilization is paramount to assure adequate dose delivery. In our institution, IMRT is employed in children with head-and-neck and brain primary sites. We have used a thermoplastic mask to ensure day-to-day positioning. Positional inaccuracy with a thermoplastic mask usually ranges from 2 to 3 mm and is taken into account when designing the planning target volume.20 This type of immobilization is noninvasive, and construction is easily implemented by therapists. Other types of immobilization for the head include the Talon system and the stereotactic frame, both of which are invasive and need expertise.21
IMRT in children ● A. C. PAULINO
The thorax and abdomen are more difficult to immobilize because of respiration. The pelvis is easier to immobilize than the thorax and abdomen. Thermoplastic molds and alpha cradle system can be used to immobilize the pelvis as in the treatment of prostate cancer. Prolonged anesthesia time Young children may need anesthesia so they can be treated with radiotherapy. In one study, anesthesia was employed in 96%, 93%, 80%, and 51% of children ages ⬍ 1, 1–2, 2–3, and 3– 4-years old, respectively.22 It is not surprising that very young children who are separated from their primary caretaker will be scared of an unfamiliar, large machine. Because of the increased treatment time to deliver the desired dose configuration and the noise associated with a beam modulator, some young patients will require anesthesia with IMRT and not with conventional radiotherapy. In our department, treatment times using Mimic-based IMRT in adults range from 20 to 30 minutes depending on the number of arcs utilized. Ancillary support including anesthesia will also require time and, in combination with IMRT treatment delivery, will occupy at least 1 hour of linear accelerator room time. In comparison to 2-dimensional methods of treatment delivery, IMRT in the treatment of very young children will require more anesthesia time. Prolonged treatment planning Before arriving at the final IMRT plan, most physicists and oncologists will have reviewed multiple plans. Contouring of the target volume and critical structures takes time, like other 3-dimensional methods of treatment delivery. We usually reserve 5 working days for treatment planning because of this high level of complexity. Some children may not start with an IMRT plan because of such time constraints. Such is the case of patients with parameningeal rhabdomyosarcoma and intracranial extension who need to start RT at day 0 of chemotherapy.23 For children with Wilms’ tumor undergoing nephrectomy, final pathologic stage may not be available after a week after surgery. Children with Stage II to IV anaplastic histology and III–IV favorable histology have to start RT prior to postoperative day 10, as earlier studies show a better local control with such strategy.24 CONCLUSIONS In summary, IMRT has advantages and disadvantages in the treatment of children. In our institution, most of the children treated with this modality have tumors in the brain or head-and-neck region, as these sites are in close proximity to normal critical structures and immobilization is less problematic. IMRT is not used in tumors where a critical structure (i.e., optic nerve/chiasm, spinal cord) is part of the clinical target volume because of the possibility of giving a dose higher than the prescription
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dose to these organs. Treatment with IMRT also depends on the age of the child. If the patient has undergone puberty, bone asymmetry is of less concern. Long-term follow-up of children treated with IMRT is needed to determine whether there is a higher risk of second malignancy with this modality. REFERENCES 1. Grant III, W.; Cain, R.B. Intensity modulated conformal therapy for intracranial lesions. Med. Phys. 23:237– 41; 1998. 2. Hunt, M.A.; Zelefsky, M.J.; Wolden, S.; et al. Treatment planning and delivery of intensity-modulated radiation therapy for primary nasopharynx cancer. Int. J. Radiat. Oncol. Biol. Phys. 49:623–32; 2001. 3. Ling, C.C.; Burman, C.; Chui, C.S.; et al. Conformal radiation treatment of prostate cancer using intensity-modulated photon beams produced with dynamic multileaf collimation. Int. J. Radiat. Oncol. Biol. Phys. 35:721–30; 1996. 4. Intensity Modulated Radiation Therapy Collaborative Working Group. Intensity-modulated radiotherapy: current status and issues of interest. Int. J. Radiat. Oncol. Biol. Phys. 51:880 –914; 2001. 5. Curran, B. Where goest the peacock? Med. Dosim. 26:3–9; 2001. 6. Grau, C.; Overgaard, J. Postirradiation sensorineural hearing loss: A common but ignored late radiation complication. Int. J. Radiat. Oncol. Biol. Phys. 36:515–7; 1996. 7. Kwong, D.L.W.; Wei, W.I.; Sham, J.S.T.; et al. Sensorineural hearing loss in patients treated for nasopharyngeal carcinoma: A prospective study of the effect of radiation and cisplatin treatment. Int. J. Radiat. Oncol. Biol. Phys. 36:281–9; 1996. 8. Paulino, A.C.; Narayana, A.; Mohideen, N.M.; et al. Posterior fossa boost in medulloblastoma: An analysis of dose to surrounding structures using 3-dimensional (conformal) radiotherapy. Int. J. Radiat. Oncol. Biol. Phys. 46:281– 6; 2000. 9. Woo, S.Y.; Huang, E.; Teh B.S.; et al. Reduction of ototoxicity in pediatric patients with medulloblastoma using intensity modulated radiation therapy (IMRT) (Abstr.). Int. J. Radiat. Oncol. Biol. Phys. 51S:121; 2001. 10. Kovnar E.; Curran W.; Tomita T.; et al. Hyperfractionated irradiation for childhood ependymoma: Improved control in subtotally resected tumors (Abstr.) Childs Nerv. Syst. 14:569; 1998. 11. Paulino, A.C. The local field in infratentorial ependymoma: Does the entire posterior fossa need to be treated? Int. J. Radiat. Oncol. Biol. Phys. 49:757– 61; 2001. 12. Al Ghazi, M.; Kwon, R.; Kuo, J.; et al. The University of California Irvine experience with tomotherapy using the peacock system. Med. Dosim. 26:17–27; 2001. 13. Emami, B.; Lyman, J.; Brown, A.; et al. Tolerance of normal tissue to therapeutic irradiation. Int. J. Radiat. Oncol. Biol. Phys. 21: 109 –22; 1991. 14. Parsons, J.T.; Bova, F.J.; Fitzgerald, C.R.; et al. Radiation optic neuropathy after megavoltage external-beam irradiation: Analysis of time-dose factors. Int. J. Radiat. Oncol. Biol. Phys. 30:755– 63; 1994. 15. Paulino, A.C.; Wen, B-C.; Brown, C.K.; et al. Late effects in children treated with radiation therapy for Wilms’ tumor. Int. J. Radiat. Oncol. Biol. Phys. 46:1239 – 46; 2000. 16. Grant III, W. Experience with intensity modulated beam delivery. In: Palta, J.; Mackie, T.R., editors. Teletherapy: Present and Future. College Park, MD: Advanced Medical Publishing; 1996: 793– 804. 17. Followill, D.; Geis, P.; Boyer, A. Estimates of whole-body dose equivalent produced by beam intensity modulated conformal therapy. Int. J. Radiat. Oncol. Biol. Phys. 38:667–72; 1997. 18. Mutic, S.; Low, D.A.; Klein, E.E.; et al. Room shielding for intensity-modulated radiation therapy treatment facilities. Int. J. Radiat. Oncol. Biol. Phys. 50:239 – 46; 2001. 19. Halperin, E.C.; Constine, L.S.; Tarbell, N.J.; et al. Secondary tumors. In: Halperin, E.C., Constine, L.S., Tarbell, N.J., Kun, L.E., editors. Pediatric Radiation Oncology. 3rd ed. Philadelphia: Lippincott Williams & Wilkins; 1999: 538 – 62. 20. Saw, C.B.; Yakoob, R.; Enke, C.; et al. Immobilization devices for intensity-modulated radiation therapy (IMRT). Med. Dosim. 26: 71– 8; 2001.
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21. Carol, M.P. A system for planning and rotational delivery of intensity-modulated fields. Int. J. Imag. Syst. Tech. 6:56 – 61; 1995. 22. Fortney, J.T.; Halperin, E.C.; Hertz, C.M.; et al. One hundred forty one consecutive cases of anesthesia for pediatric external beam radiation therapy. Int. J. Radiat. Oncol. Biol. Phys. 44:587–91; 1998.
Volume 27, Number 2, 2002 23. Christ, W.M.; Anderson, J.R.; Meza, J.L.; et al. Intergroup Rhabdomyosarcoma Study-IV: Results for patients with nonmetastatic disease. J. Clin. Oncol. 19:3091–102; 2001. 24. Thomas, P.R.M.; Tefft, M.; Farewell, V.; et al. Abdominal relapses in irradiated Second National Wilms’ Tumor Study patients. J. Clin. Oncol. 2:1098 –101; 1984.