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Intensity modulated radiotherapy (IMRT) in the treatment of children and Adolescents - a single institution's experience and a review of the literature

Intensity modulated radiotherapy (IMRT) in the treatment of children and Adolescents - a single... Background: While IMRT is widely used in treating complex oncological cases in adults, it is not commonly used in pediatric radiation oncology for a variety of reasons. This report evaluates our 9 year experience using stereotactic-guided, inverse planned intensity-modulated radiotherapy (IMRT) in children and adolescents in the context of the current literature. Methods: Between 1999 and 2008 thirty-one children and adolescents with a mean age of 14.2 years (1.5 - 20.5) were treated with IMRT in our department. This heterogeneous group of patients consisted of 20 different tumor entities, with Ewing's sarcoma being the largest (5 patients), followed by juvenile nasopharyngeal fibroma, esthesioneuroblastoma and rhabdomyosarcoma (3 patients each). In addition a review of the available literature reporting on technology, quality, toxicity, outcome and concerns of IMRT was performed. Results: With IMRT individualized dose distributions and excellent sparing of organs at risk were obtained in the most challenging cases. This was achieved at the cost of an increased volume of normal tissue receiving low radiation doses. Local control was achieved in 21 patients. 5 patients died due to progressive distant metastases. No severe acute or chronic toxicity was observed. Conclusion: IMRT in the treatment of children and adolescents is feasible and was applied safely within the last 9 years at our institution. Several reports in literature show the excellent possibilities of IMRT in selective sparing of organs at risk and achieving local control. In selected cases the quality of IMRT plans increases the therapeutic ratio and outweighs the risk of potentially increased rates of secondary malignancies by the augmented low dose exposure. Page 1 of 10 (page number not for citation purposes) Radiation Oncology 2009, 4:37 http://www.ro-journal.com/content/4/1/37 From 1999 through 2008, at the German Cancer Research Background In more than a decade of clinical Intensity Modulated Center, 31 children and adolescents with a mean age of Radiation Therapy (IMRT) this method of high precision 14.2 years (range 1.5 - 20.5 years) were treated using radiotherapy has proven remarkable advances in target IMRT. 17 patients were female, 14 were male. 21 patients conformity, dose escalation in the target volume and spar- were less than 18 years old. In total, the treated group con- ing of neighbouring organs at risk [1-14]. These qualities sisted of twenty different tumor histologies, with Ewing's permit the irradiation of patients with complex shaped sarcoma being the largest group (n = 5), followed by juve- tumors at problematic locations which could not be nile nasopharyngeal angiofibroma, esthesioneuroblast- treated successfully with conventional radiation methods. oma and rhabdomyosarcoma with three patients each. Within IMRT again different technical solutions are being Table 1 shows more detailed information about the used. They all have the principle in common that radia- patients' characteristics. Treatment location was head and tion beams with different intensities are used depending neck in 50% of the treated sites (n = 17), other treatment on how much tumor or organ at risk is located within dif- locations were abdominopelvic (n = 5), intracranial (n = ferent areas of the beam. This way dose distributions can 3), thoracic wall (n = 5) and spine (n = 4). 28 patients be adapted to irregular tumor geometries close to organs were treated with curative intent despite most patients at risk. It is a rather difficult task to produce irregular having advanced or even metastatic (cases #2, #4, #23, intensity maps with a linear accelerator that is designed to #30) disease. Eighteen patients underwent IMRT as part of produce beams of homogeneous intensity. A very com- multimodality therapy, e.g. as part of a protocol. Eleven mon approach is segmental MLC-IMRT (step-and-shoot- patients received adjuvant radiotherapy and two patients IMRT) [1]. The irregular fields are created as a summation radiotherapy only (cases #29, #7). One boy with alveolar of many small fields resulting in a pulsed dose applica- rhabdomyosarcoma of the nasal cavity was treated twice tion. Another way to modulate intensity is the dynamic due to local relapse (case #23). One adolescent with a movement of collimator leaves during beam application desmoplastic small cell tumor was treated three times at which is called dynamic MLC-IMRT or sliding window different sites (case #12). technique [15]. A third common technique is helical tomotherapy that uses a rotational beam delivery in a hel- Three patients had previously received standard external ical fashion together with a binary collimator [16]. With beam radiation (cases #2, #10, #14), including a girl with all these devices excellent treatment options can be metastatic Ewing's sarcoma, after definitive treatment opened for the most challenging cases in radiation oncol- with multiagent chemotherapy and radiotherapy of the ogy. Examples are parotid gland sparing in head-and-neck pelvis. This girl received IMRT for tumor recurrence tumors or spinal cord sparing for tumors of the vertebral involving the cervical spine. The second patient, a 19-year column. old male with aggressive fibromatosis of the thoracic wall started radiation treatment two years ago, but declined The history of IMRT for children is markedly different to further treatment after an administered total dose of 28.8 the history of IMRT for adult patients. While IMRT for Gy at that time. He received IMRT to the previously treated adults is a widely used as a standard of care for many indi- site. The third patient, a 16-year old boy underwent radi- cations meanwhile, for several reasons IMRT was used otherapy of the neurocranium (total dose 5.4 Gy) six years with great caution in the paediatric population. Among ago as part of multimodality treatment of an acute lym- these are increased fraction time, necessity for exact phoblastic leukaemia. About four years later he presented immobilization with tailor-made steep dose gradients with an anaplastic astrocytoma and therefore received present and the fear of increased secondary malignancy external beam radiation to the right hemisphere (total induction by changes in low dose spillage or integral dose dose 54 Gy). IMRT was delivered sixteen months later for [17-21]. recurrent astrocytoma. This study describes experience and outcome of IMRT for One girl with malignant optical nerve glioma was treated children and adolescents in our institution. In addition a with an iodine seed implantation four years prior to IMRT review of the available literature reporting on technology, (case #15). quality, toxicity, outcome and concerns of IMRT is given. Administered doses varied according to whether IMRT Methods was definitive, postoperative, delivered to a previously When radiotherapy is required for children within a mul- treated tumor site, or part of a treatment protocol (e.g. timodal study protocol, in our institution first planning Ewing's sarcoma) and depended on the proximity of crit- with conventional techniques is performed. If problems ical organs. with target coverage or sparing of close organs at risk occur, IMRT is evaluated for potential benefits in this Follow up examinations including MRI scans were per- regard. formed six weeks after completing radiotherapy and after Page 2 of 10 (page number not for citation purposes) Radiation Oncology 2009, 4:37 http://www.ro-journal.com/content/4/1/37 Table 1: Patient characteristics Case Diagnosis Location Age # fields median Dose number of Previous RT [years, months] [Gy] fractions 1 Ewing's sarcoma orbita 14, 7 9 54 30 2 Ewing's sarcoma spine (cervical) 15, 0 7 45 25 RT pelvis 45 Gy 3 Ewing's sarcoma infratemporal fossa 15, 4 7 54 30 4 Ewing's sarcoma pelvis 16, 10 8 54 30 5 Ewing's sarcoma scapula 19, 9 9 45 25 6 Myoepithelial Parotis parotid gland 19, 1 7 66 33 Ca 7 Giant cell tumor os sacrum 20, 6 7 66 33 8 Meningeoma intracranial 12, 4 7 57.6 32 9 Desmoid Tumor spine (cervical) 17, 7 7 54 30 10 Aggressive thoracic wall 19, 8 5 45 25 RT thoracic wall 28.8 fibromatosis Gy 11 Angiofibromatous spine (cervical) 19, 1 7 56 28 tumor 12 Desmoplastic small abdomen 17, 3 7 56 28 cell tumor abdomen 18, 1 7 45 25 thoracic wall 19, 3 7 50.4 28 13 Adenoid cystic parotid gland 17, 0 7 66 33 carcinoma 14 Astrocytoma WHO intracranial 16, 0 8 30.6 17 RT neurocranium 5.4 III Gy + TBI 12Gy, RT right hemisphere 54 Gy 15 Malignant opticus optic nerve 4, 5 7 50 25 previous iodine seed glioma implantation 16 Lymphoepithelial nasopharynx 17, 11 9 66 30 Carcinoma 17 Melanoma orbita 7, 6 8 60 30 18 Juvenile nasopharynx 10, 11 7 50.4 28 nasopharyngeal fibroma 19 Juvenile nasopharynx 15, 11 7 50.4 28 nasopharyngeal fibroma Page 3 of 10 (page number not for citation purposes) Radiation Oncology 2009, 4:37 http://www.ro-journal.com/content/4/1/37 Table 1: Patient characteristics (Continued) 20 Juvenile nasopharynx 18, 5 7 50.4 28 nasopharyngeal fibroma 21 Rhabdomyosarcoma thoracic wall 5, 0 7 21.6 12 22 Rhabdomyosarcoma abdomen 18, 2 7 45 25 23 Rhabdomyosarcoma neck 4, 9 7 45 25 neck (re-Rt) 7, 4 7 36 20 24 Esthesioneuroblasto 15, 10 10 60 30 ma 25 Esthesioneuroblasto 17, 10 7 54 30 ma 26 Esthesioneuroblasto 18, 6 7 63 32 ma 27 PNET thoracic wall 1, 6 7 41.4 23 28 PNET thoracic wall/spine 19, 5 7 54 30 29 Chondrosarcoma scull 16, 3 7 64 32 30 Neuroblastoma adrenal gland 3, 4 8 39.6 22 31 Hypopharynx-ca neck 4, 9 5 60 30 that in intervals of three to six months for the first two of 2.75 mm at isocenter was used. This collimator is years. Further follow-up visits usually took place annually. attached to an accessory holder of the Siemens accelerator. Radiotherapy During treatment all patients were evaluated at least on a Inverse treatment planning for stereotactic-guided IMRT weekly basis to assess acute toxicity. was realized by the KonRad treatment planning system, developed at our institute [8,22]. The KonRad system is Results connected to the 3D treatment planning system VIR- Median follow up time was 34 (1 - 68) months; mean administered dose was 51.6 Gy (21.6 - 66), including the TUOS, which allows calculation and visualization of the dose distribution. 3D planning based on contrast patients that received concomitant chemotherapy. The enhanced MRI and CT imaging was performed, using two patients previously treated with standard external individually manufactured rigid scotch masks for head beam radiation on the IMRT treatment site, were treated immobilization. Thoracic and abdominopelvic targets up to a total dose of 45 Gy and 30.6 Gy respectively (cases were positioned with a vacuum bag and a scotch cast mask #10, #14). fixation. Definition of the planning target volume was performed on the basis of image fusion techniques. In Intravenous sedation with propofol during radiotherapy most patients IMRT was administered using a simultane- session was necessary in 6 children (cases #15, #21, #23, ous integrated boost concept. #27, #30, #31). These children were all younger than 6 years at the time of treatment This was tolerated well with- A Siemens linear accelerator (Medical Solutions Siemens, out severe side-effects and with fast recovery after treat- Erlangen, Germany) with 6 MV photons was used for ment. No general anaesthesia with intubation was treatment. It is equipped with an integrated motorized necessary. multileaf collimator, which allows a sequential step-and- shoot technique. In three patients (cases #17, #26, #27) a side effects miniature-multileaf collimator (ModuLeaf MLC, MRC- Reported acute side effects of radiotherapy were low grade Systems GmbH, Heidelberg, Germany) with a leaf width skin erythema (CTC grade I-II), mucositis (CTC grade I- Page 4 of 10 (page number not for citation purposes) Radiation Oncology 2009, 4:37 http://www.ro-journal.com/content/4/1/37 II), local alopecia, mild nausea, mild diarrhoea, loss of growth of the thoracic wall is a possible explanation for taste and epistaxis (case #19). Pancytopenia occurred in this. four patients (cases #1, #2, #4, #28) who received con- comitant chemotherapy. In two of them pancytopenia Figure 2 shows the IMRT plan for a 14 year old girl (case (CTC grade III) resulted in treatment interruption for two # 1) with a Ewing's sarcoma of the left orbit, infiltrating days. No other severe acute side effects were observed. the dura mater and the left ethmoid sinus. The patient received multiagent chemotherapy (7 cycles VIDE (vinc- One patient developed thoracic scoliosis two years follow- ristine, ifosfamide, doxorubicin, etoposide) followed by 6 ing spine irradiation (case #27, figure 1). One adolescent, cycles VAC (vincristine, adriamycin, cyclophosphamide)) who was also treated with chemotherapy, claims of hypo- and tumor resection (R1) prior to IMRT treatment. IMRT aesthesia in his right forearm, two years after upper tho- was delivered in order to spare the lacrimal gland, optic racic wall irradiation (case #28). One girl developed slight nerve and eyeball. At present, there are no signs of tumor enophthalmia after irradiation for a Ewing's sarcoma of recurrence with an actuarial follow up of four and a half the orbit, visual acuity though is not impaired (case #1). years. Visual acuity is 1.0 on both eyes, though the patient No other late toxicity was observed so far among survi- developed slight enophthalmia on the treated site. vors. local control and survival Figure 1 displays the treatment plan for a 18 months old Local failure occurred in 10 of 31 patients (table 2), time boy (case #27) with primitive neuroectodermal tumor to local failure was 4 - 53 months. In the event of local (PNET) of the right thoracic wall. He received chemother- tumor progression patients received chemotherapy or sur- apy according to the Euro Ewing 99 protocol followed by gical tumor resection, one patient with carcinoma of the tumor resection with positive pathological margins. Post- hypopharynx was reirradiated using IMRT (case #31). No operative IMRT was delivered in order to decrease the local relapse occurred among patients with juvenile dose to the nearby spinal cord and lungs with a median nasopharyngeal fibroma and esthesioneuroblastoma. So prescribed dose of 30.6 Gy to the PTV and 41.4 Gy to the far, 5 patients died due to distant metastases (cases #30, boost. During the radiation course regular CT-scans with #31, #21, #5, #4). an in-room CT-Scanner were performed to confirm cor- rect patient position. Thirty-eight months after finishing Discussion treatment he underwent surgery for straightening of tho- We present a very heterogeneous group of children and racic scoliosis. This occurred inspite of inclusion of the adolescents with 20 different tumor entities. All of these complete vertebral body in the PTV. An asymmetric 31 patients have a very complex oncological constellation IMRT-Plan for treatment of a 1 Figure 1 .5 year old boy with a primitive neuroectodermal tumor (PNET) of the right thoracic wall IMRT-Plan for treatment of a 1.5 year old boy with a primitive neuroectodermal tumor (PNET) of the right thoracic wall. A: A prescribed dose of 30.6 Gy to the PTV. B: 41.4 Gy prescribed to the boost. IMRT-Plan in colour wash shows the 90% isodose region (dotted line). Page 5 of 10 (page number not for citation purposes) Radiation Oncology 2009, 4:37 http://www.ro-journal.com/content/4/1/37 IMRT-plan for Figure 2 treatment of a 14 year old girl with Ewing sarcoma of the left orbit with a median prescribed dose of 54 Gy IMRT-plan for treatment of a 14 year old girl with Ewing sarcoma of the left orbit with a median prescribed dose of 54 Gy. A: Axial view of the dose distribution in colour wash shows the 90% isodose region (dotted line). B: Coronal view of the dose distribution with sparing of the eye. in common that made the application of a sufficient radi- secondary malignancies. We tried to increase chances of ation dose extremely difficult with conventional radio- cure the patients accepting possible risks in a matter of therapy techniques. Here the possible benefits of IMRT decades in case of success. IMRT was feasible even if like the sparing of organs at risk and the possibility of dose anaesthesia was necessary and resulted in good local con- escalation were considered to be more important for the trol rates for this group of children who represents a selec- treatment success than the potentially increased risk of tion of extraordinary and difficult cases. Table 2: Local failure after IMRT Case Diagnosis Time to local failure [months] Dose Treatment following failure [Gy] 2 Ewing sarcoma 7 45 chemotherapy 4 Ewing sarcoma 9 54 chemotherapy 6 myoepithelial Parotis-carcinoma 7 66 surgery 8 Meningeoma 53 57.6 surgery 9 Desmoid tumor 14 54 surgery 11 Angiofibromatous tumor 7 56 surgery 15 Optic nerve glioma 36 50 surgery 21 Rhabdomyosarcoma 8 21.6 chemotherapy 23 Rhabdomyosarcoma 29 45 chemotherapy 31 Hypopharynx-Carcinoma 4 60 Re-irradiation (IMRT) Page 6 of 10 (page number not for citation purposes) Radiation Oncology 2009, 4:37 http://www.ro-journal.com/content/4/1/37 IMRT could be applied with only few low grade acute tox- [27]. In a retrospective planning evaluation they illustrate icities and hardly any long term side effects so far. It is the possibilities of helical tomotherapy (as one solution important to note that the follow up is still quite short to of IMRT) to cover a target volume of this size avoiding the assess secondary malignancies. This radiotherapy tech- problems of field junctions and the resulting dangers of nique allows reirradiations in difficult localisation that under or overdosage inherent in conventional techniques. could not be performed safely before. After treating the whole craniospinal axis the primary tumor region is supposed to be irradiated with an extra In contrast to the big amount of publications in treating boost to the posterior fossa. Huang et al. describe reduced adult patients with IMRT, there is only few data in litera- ototoxicity when sparing the inner ear by IMRT compared ture about the use of IMRT in the paediatric population. to conventional radiotherapy, where the cochlear region Good experiences with the treatment of twenty-two chil- receives the full therapeutic dose [28]. Thirteen percent of dren with IMRT have been reported by Bhatnagar et al. the IMRT Group had grade 3 or 4 hearing loss, compared [23]. They described substantial sparing of surrounding to 64% of the conventional-RT group. The sparing of the critical structures in cranial, abdominopelvic or spinal hearing apparatus is of special importance since several lesions, altogether a selection of very difficult oncological modern combined chemotherapy regimens contain oto- situations. Conventional treatment technologies would toxic agents like cisplatinum. Jain et al. showed that this have resulted in a markedly higher dose to organs at risk improvement of ototoxicity was not achieved at the cost or would have required compromises regarding the possi- of increased neuropsychological changes [29]. ble target dose. Another challenging situation in that IMRT might sub- Penagaricano et al. summarized their experience of 5 chil- stantially improve the treatment is retinoblastoma. Krasin dren treated with IMRT with a high degree of conformality et al. presented a planning study comparing different con- [24]. The dose distribution could be adapted to arc shaped ventional photon, electron and IMRT techniques in the volumes in contrast to conventional therapy where treatment of intraocular retinoblastoma [30]. The best treated volumes are usually box shaped and encompass sparing of the bony orbit was achieved with IMRT yielding big areas of treated normal tissue. Similar conclusions are a promising potential of avoiding asymmetrical bone drawn by Paulino et al. in their synopsis of this method growth after successful radiotherapy. The mean volume of for children [24,25]. They summarize that IMRT is a valu- bony orbit treated with IMRT above 20 Gy (as a threshold able alternative to conventional treatment techniques for of bone growth disturbance) was 60% in contrast to 90% paediatric cancer patients. The improved dose distribu- in conventional technique. Schroeder et al. report on 22 tions coupled with the ease of delivery of the IMRT fields children with localized intracranial ependymoma treated make this technique very attractive, especially in view of with IMRT. They were able to achieve a three year local the potential to increase local control and possibly control of 68% while enabling minimal rates of toxicity improve on survival. A third survey of a heterogeneous (no visual or hearing impairment, no necrosis, no myeli- group of children treated with IMRT is given by Teh et al. tis) [31]. within a general article about decreased treatment related morbidity with IMRT [26]. Experiences with 185 patients The irradiation of head-and-neck tumors is quite rare in treated with IMRT in general are presented, among these children. Nevertheless long term toxicity is a huge concern forty children suffering from different tumors. Similar to and often impairs the quality of life. Special focus here is the conclusions by the authors described before they con- xerostomia caused by a fibrotic atrophy of the parotid clude that IMRT offers new options in escalating dose and glands. Consecutive dental damage, dysphagia, problems achieving better local control while simultaneously reduc- of speach and taste are feared. In a study by Wolden et al. ing toxicity. twenty-eight patients with head-and-neck rhabdomyosar- coma were treated with IMRT. The age ranged from 1-29 Besides these compilations of composed cohorts a larger years, the thee year local control was 95% with minimal number of articles provides data on special indications side effects [9]. In a similar approach by the groups of and more predefined collectives. They specially deal with Atlanta (20 children) and Houston (19 children) head- intracranial or head-and-neck tumors since the sensitive and-neck rhabdomyosarcomas could be treated with a 3 structures like eyes, brain stem, parotid glands or inner year local control of 100% and a four year local control of ears represent an extraordinary challenge in the radiother- 92.9% respectively [32,33]. Combs et al. presented a apeutic management. Starting with the biggest of all cen- cohort of 19 children with rhabdomyosarcoma treated tral nervous treatments the irradiation of the entire with stereotactic radiotherapy (n = 14) or IMRT (n = 5) craniospinal axis as required in medulloblastoma or ger- [34]. The three and five-year local control rate was 89%, minoma can be done with improved conformity and spar- no toxicity > CTC grade 2 were observed. An Indian anal- ing of sensitive structures as shown by Penagaricano et al. ysis of IMRT for nasopharyngeal cancer (19 children) Page 7 of 10 (page number not for citation purposes) Radiation Oncology 2009, 4:37 http://www.ro-journal.com/content/4/1/37 showed reduced toxicity in terms of xerostomia, skin reac- risk is especially increased in patients of very young age, tion and mucous membrane reaction compared to con- Hodgkin's disease, treatment with alkylating agents, radi- ventional radiotherapy (17 children) [35]. Acute ation therapy and female gender [47,48]. xerostomia grade 2 occurred in 31.6% in IMRT vs. 88.2% in conventional radiotherapy. Grade 2 dysphagia was also Secondary cancer induction is dose dependent and tissue significantly reduced with 42.0% vs. 94.1%. IMRT was irradiated with doses below 6 Gy is known to be especially also able to provide superior target coverage and as a con- endangered to develop secondary cancer [49]. The calcu- sequence of the reduced toxicity an improved compliance. lated risk of secondary malignancies after treatment with IMRT was estimated to be doubled [17,19]. It is important Juvenile angiofibroma can be cured by radiotherapy in to note that these numbers are only estimations and cal- unresectable or relapsing cases. They are difficult to treat culations with no fundament of clinical data due to the for because of the same surrounding risk structures as dis- lack of enough follow-up time. In addition integral dose cussed above. Especially with respect to the benign nature is often discussed to be potentially higher in IMRT com- of these tumors a well balanced toxicity profile is vital as pared to conventional radiotherapy. This is not necessar- described by Kuppersmith et al. and can be achieved by ily true since the high dose region to normal tissue is the means of IMRT [36]. markedly reduced with the improved conformity [50]. As stated above the characteristic new feature of dose expo- Another potential indication is the radiosurgical treat- sure in IMRT is a shift towards low dose spread out. Espe- ment of arteriovenous malformations (avm). Lesions that cially in the tissues with a high incidence of secondary are unresectable and not accessible for interventional neu- cancers the ability of IMRT to produce conformal avoid- roradiology can be obliterated by high dose single course ance of these structures might limit the risk of these late radiotherapy. Fuss et al. presented the possibilities of effects. Techniques like helical tomotherapy have the IMRT in seven children with avm of complex shape, that potential of selectively sparing the thyroid gland and could hardly be treated with conventional methods [37]. breast tissue in craniospinal irradiation. Two avm obliterated completely, three partially, while no treatment related side effects occurred. The number of children treated with IMRT and the hard evidence for the benefit of this technology is limited [13]. In the discussions about precautions of IMRT in children However, waiting for this evidence would last for many the advantages are achieved at the cost of raised low dose years. Many of the uncertainties cannot be answered by outside the target. With a higher number of monitor units simply transferring the standards of evidence based med- required the total body dose can increase significantly icine in medical oncology one by one to radiation oncol- [38]. However, in a study by Koshy et al. no increased ogy. Randomizing children or adults in two different extra target dose to thyroid, breast, and testis was seen in radiotherapy regimens knowing that one will definitely children treated with IMRT compared with a control inactivate the parotid glands, one kidney or affect bone group of children treated with conventional radiotherapy growth is simply unethical. Withholding children the pos- for cranial and abdominopelvic tumors [39]. sibility to reduce doses to organs at risk in difficult cases is hard to justify. As long as proton treatment with its great The methods that allow the intensity modulation of the potential of decreased integral dose is not widely availa- radiation beams increase the volume of tissue receiving ble, IMRT provides an excellent tool in difficult situations. low dose compared to conventional radiotherapy [40]. Patient selection is absolutely crucial with regard to the The effects in adult patients are the same, however, there worries about potentially increased chances of secondary are 3 reasons for special consideration in the treatment of malignancies. Reserved for complex cases with close prox- children: higher sensitivity to radiation induced cancer, imity of organs at risk IMRT represents a powerful and ver- relation of scattered dose to the small body volume and satile treatment option when used with the necessary genetic susceptibility due to germline mutations [18,41- caution [25,51]. 45]. While high dose to neighbouring structures can be selectively decreased by the means of IMRT, low dose is Conclusion distributed in the rest of the body. Consequences of this Intensity modulated radiotherapy is a feasible method of special treatment technique can only be estimated until radiotherapy for paediatric malignancies. It was applied now. safely in 31 patients within the last eight years in difficult oncologic situations. Conventional radiotherapy would Data of the childhood cancer survivor study (CCSS) have been associated with limited dose to the target or showed 5 year survival rates of 79% for all different tumor high normal tissue complication probability. In all the entities [46]. With such a high number of long term survi- presented patients it was decided that the benefit of vors secondary neoplasms become highly relevant. The increased tumor control probabilities and improved spar- Page 8 of 10 (page number not for citation purposes) Radiation Oncology 2009, 4:37 http://www.ro-journal.com/content/4/1/37 sity-modulated radiation therapy (IMRT) and inverse treat- ing of organs at risk had a higher clinical impact than the ment planning for advanced pleural mesothelioma. calculated increased risk of late side-effects. Strahlenther Onkol 2003, 179:535-541. 7. Schulz-Ertner D, Didinger B, Nikoghosyan A, Jakel O, Zuna I, Wan- nenmacher M, Debus J: Optimization of radiation therapy for As long as the risk of secondary cancer induction can only locally advanced adenoid cystic carcinomas with infiltration be estimated IMRT for children should only be used with of the skull base using photon intensity-modulated radiation therapy (IMRT) and a carbon ion boost. Strahlenther Onkol caution. Longer follow up time is needed to quantify this 2003, 179:345-351. long term complication. Conventional radiotherapy 8. Munter MW, Debus J, Hof H, Nill S, Haring P, Bortfeld T, Wannen- remains the standard of care in radiation oncology for macher M: Inverse treatment planning and stereotactic inten- sity-modulated radiation therapy (IMRT) of the tumor and children and can be delivered with acceptable toxicity in lymph node levels for nasopharyngeal carcinomas. Descrip- the majority of children. tion of treatment technique, plan comparison, and case study. Strahlenther Onkol 2002, 178:517-523. 9. Wolden SL, Wexler LH, Kraus DH, Laquaglia MP, Lis E, Meyers PA: Nevertheless, reserved to special cases with close proxim- Intensity-modulated radiotherapy for head-and-neck rhab- ity of sensitive structures, it can provide great benefit for domyosarcoma. Int J Radiat Oncol Biol Phys 2005, 61:1432-1438. 10. Studer G, Lutolf UM, Davis JB, Glanzmann C: IMRT in Hypopha- paediatric patients and should not be withheld because of ryngeal Tumors. Strahlenther Onkol 2006, 182:331-335. estimations based on a radiobiological model. It widens 11. Cavey ML, Bayouth JE, Colman M, Endres EJ, Sanguineti G: IMRT to the therapeutic window and reduces long term toxicity for escalate the dose to the prostate while treating the pelvic nodes. Strahlenther Onkol 2005, 181:431-441. an increased number of long term cancer survivors. 12. Guckenberger M, Flentje M: Intensity-Modulated Radiotherapy (IMRT) of Localized Prostate Cancer: A Review and Future Perspectives. Strahlenther Onkol 2007, 183:57-62. Declaration of competing interests 13. Veldeman L, Madani I, Hulstaert F, De Meerleer G, Mareel M, De The authors declare that they have no competing interests. Neve W: Evidence behind use of intensity-modulated radio- therapy: a systematic review of comparative clinical studies. Lancet Oncol 2008, 9:367-375. Authors' contributions 14. Sterzing F, Schubert K, Sroka-Perez G, Kalz J, Debus J, Herfarth K: FS is responsible for data acquisition, literature research Helical Tomotherapy: Experiences of the First 150 Patients and writing of the manuscript. ES is responsible for data in Heidelberg. Strahlenther Onkol 2008, 184:8-14. 15. Boyer A, Xing L, Luxton G, Chen Y, Ma C: IMRT by dynamic MLC. acquisition, statistical analysis and writing of the manu- In The Use of Computers in Radiation therapy, XIIIth International Confer- script. SN is responsible for the physical aspects of IMRT ence, Heidelberg, Germany, May 22-25 2000 Edited by: Schlegel W, Bortfeld T. Berlin: Springer; 2000:160-163. planning and treatment of the children. HB is responsible 16. Mackie TR, Balog J, Ruchala K, Shepard D, Aldridge S, Fitchard E, for the anaesthesia management of the children. PH is Reckwerdt P, Olivera G, McNutt T, Mehta M: Tomotherapy. Semin responsible for the clinical treatment of the children as Radiat Oncol 1999, 9:108-117. 17. Hall EJ, Wuu CS: Radiation-induced second cancers: the head of the division of radiation oncology in the German impact of 3D-CRT and IMRT. Int J Radiat Oncol Biol Phys 2003, Cancer Research Center. JD is responsible for the clinical 56:83-88. treatment of the children as of the department of radia- 18. Hall EJ: Intensity-modulated radiation therapy, protons, and the risk of second cancers. Int J Radiat Oncol Biol Phys 2006, 65:1-7. tion oncology in the University of Heidelberg. MM is 19. Kry SF, Salehpour M, Followill DS, Stovall M, Kuban DA, White RA, responsible for the medical aspects of treatment planning Rosen II: The calculated risk of fatal secondary malignancies from intensity-modulated radiation therapy. Int J Radiat Oncol and application, idea for this paper, literature research Biol Phys 2005, 62:1195-1203. and proof reading. All authors read and approved the final 20. Schneider U, Lomax A, Pemler P, Besserer J, Ross D, Lombriser N, manuscript. Kaser-Hotz B: The impact of IMRT and proton radiotherapy on secondary cancer incidence. Strahlenther Onkol 2006, 182:647-652. Acknowledgements 21. Mazonakis M, Zacharopoulou F, Kachris S, Varveris C, Damilakis J, The work was supported by the German Research foundation (DFG) and Gourtsoyiannis N: Scattered dose to gonads and associated risks from radiotherapy for common pediatric malignancies: the University of Heidelberg, Germany, through a young investigator a phantom study. 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Br J Radiol 2000, 73:459-469. apy in the treatment of children. Med Dosim 2002, 27:115-120. 4. Pirzkall A, Carol M, Lohr F, Hoss A, Wannenmacher M, Debus J: 26. Teh BS, Mai WY, Grant WH 3rd, Chiu JK, Lu HH, Carpenter LS, Woo Comparison of intensity-modulated radiotherapy with con- SY, Butler EB: Intensity modulated radiotherapy (IMRT) ventional conformal radiotherapy for complex-shaped decreases treatment-related morbidity and potentially tumors. Int J Radiat Oncol Biol Phys 2000, 48:1371-1380. enhances tumor control. Cancer Invest 2002, 20:437-451. 5. Zhen W, Thompson RB, Enke CA: Intensity-modulated radiation 27. Penagaricano JA, Yan Y, Corry P, Moros E, Ratanatharathorn V: Ret- therapy (IMRT): the radiation oncologist's perspective. Med rospective evaluation of pediatric cranio-spinal axis irradia- Dosim 2002, 27:155-159. tion plans with the Hi-ART tomotherapy system. Technol 6. Munter MW, Nill S, Thilmann C, Hof H, Hoss A, Haring P, Partridge Cancer Res Treat 2007, 6:355-360. M, Manegold C, Wannenmacher M, Debus J: Stereotactic inten- Page 9 of 10 (page number not for citation purposes) Radiation Oncology 2009, 4:37 http://www.ro-journal.com/content/4/1/37 28. Huang E, Teh BS, Strother DR, Davis QG, Chiu JK, Lu HH, Carpenter hood cancer: a summary from the Childhood Cancer Survi- LS, Mai WY, Chintagumpala MM, South M, Grant WH 3rd, Butler EB, vor Study. J Clin Oncol 2009, 27:2328-2338. Woo SY: Intensity-modulated radiation therapy for pediatric 48. Nguyen F, Rubino C, Guerin S, Diallo I, Samand A, Hawkins M, Ober- medulloblastoma: early report on the reduction of ototoxic- lin O, Lefkopoulos D, De Vathaire F: Risk of a second malignant ity. Int J Radiat Oncol Biol Phys 2002, 52:599-605. neoplasm after cancer in childhood treated with radiother- 29. Jain N, Krull KR, Brouwers P, Chintagumpala MM, Woo SY: Neu- apy: correlation with the integral dose restricted to the irra- ropsychological outcome following intensity-modulated diated fields. Int J Radiat Oncol Biol Phys 2008, 70:908-915. radiation therapy for pediatric medulloblastoma. Pediatr Blood 49. Dorr W, Herrmann T: Second primary tumors after radiother- Cancer 2008, 51:275-279. apy for malignancies. Strahlenther Onkol 2002, 178:357-362. 30. Krasin MJ, Crawford BT, Zhu Y, Evans ES, Sontag MR, Kun LE, Mer- 50. Parker W, Filion E, Roberge D, Freeman CR: Intensity-modulated chant TE: Intensity-modulated radiation therapy for children radiotherapy for craniospinal irradiation: target volume con- with intraocular retinoblastoma: potential sparing of the siderations, dose constraints, and competing risks. Int J Radiat bony orbit. Clin Oncol (R Coll Radiol) 2004, 16:215-222. Oncol Biol Phys 2007, 69:251-257. 31. Schroeder TM, Chintagumpala M, Okcu MF, Chiu JK, Teh BS, Woo 51. Rembielak A, Woo TC: Intensity-modulated radiation therapy SY, Paulino AC: Intensity-modulated radiation therapy in for the treatment of pediatric cancer patients. 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Paulino AC, Fowler BZ: Secondary neoplasms after radiother- "BioMed Central will be the most significant development for apy for a childhood solid tumor. Pediatr Hematol Oncol 2005, disseminating the results of biomedical researc h in our lifetime." 22:89-101. Sir Paul Nurse, Cancer Research UK 45. Lin HM, Teitell MA: Second malignancy after treatment of pediatric Hodgkin disease. J Pediatr Hematol Oncol 2005, Your research papers will be: 27:28-36. available free of charge to the entire biomedical community 46. Robison LL: Treatment-associated subsequent neoplasms among long-term survivors of childhood cancer: the experi- peer reviewed and published immediately upon acceptance ence of the Childhood Cancer Survivor Study. Pediatr Radiol cited in PubMed and archived on PubMed Central 2009, 39(Suppl 1):S32-37. 47. Armstrong GT, Liu Q, Yasui Y, Neglia JP, Leisenring W, Robison LL, yours — you keep the copyright Mertens AC: Late mortality among 5-year survivors of child- BioMedcentral Submit your manuscript here: http://www.biomedcentral.com/info/publishing_adv.asp Page 10 of 10 (page number not for citation purposes) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Radiation Oncology Springer Journals

Intensity modulated radiotherapy (IMRT) in the treatment of children and Adolescents - a single institution's experience and a review of the literature

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Springer Journals
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Copyright © 2009 by Sterzing et al; licensee BioMed Central Ltd.
Subject
Medicine & Public Health; Oncology; Radiotherapy
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1748-717X
DOI
10.1186/1748-717X-4-37
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19775449
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Abstract

Background: While IMRT is widely used in treating complex oncological cases in adults, it is not commonly used in pediatric radiation oncology for a variety of reasons. This report evaluates our 9 year experience using stereotactic-guided, inverse planned intensity-modulated radiotherapy (IMRT) in children and adolescents in the context of the current literature. Methods: Between 1999 and 2008 thirty-one children and adolescents with a mean age of 14.2 years (1.5 - 20.5) were treated with IMRT in our department. This heterogeneous group of patients consisted of 20 different tumor entities, with Ewing's sarcoma being the largest (5 patients), followed by juvenile nasopharyngeal fibroma, esthesioneuroblastoma and rhabdomyosarcoma (3 patients each). In addition a review of the available literature reporting on technology, quality, toxicity, outcome and concerns of IMRT was performed. Results: With IMRT individualized dose distributions and excellent sparing of organs at risk were obtained in the most challenging cases. This was achieved at the cost of an increased volume of normal tissue receiving low radiation doses. Local control was achieved in 21 patients. 5 patients died due to progressive distant metastases. No severe acute or chronic toxicity was observed. Conclusion: IMRT in the treatment of children and adolescents is feasible and was applied safely within the last 9 years at our institution. Several reports in literature show the excellent possibilities of IMRT in selective sparing of organs at risk and achieving local control. In selected cases the quality of IMRT plans increases the therapeutic ratio and outweighs the risk of potentially increased rates of secondary malignancies by the augmented low dose exposure. Page 1 of 10 (page number not for citation purposes) Radiation Oncology 2009, 4:37 http://www.ro-journal.com/content/4/1/37 From 1999 through 2008, at the German Cancer Research Background In more than a decade of clinical Intensity Modulated Center, 31 children and adolescents with a mean age of Radiation Therapy (IMRT) this method of high precision 14.2 years (range 1.5 - 20.5 years) were treated using radiotherapy has proven remarkable advances in target IMRT. 17 patients were female, 14 were male. 21 patients conformity, dose escalation in the target volume and spar- were less than 18 years old. In total, the treated group con- ing of neighbouring organs at risk [1-14]. These qualities sisted of twenty different tumor histologies, with Ewing's permit the irradiation of patients with complex shaped sarcoma being the largest group (n = 5), followed by juve- tumors at problematic locations which could not be nile nasopharyngeal angiofibroma, esthesioneuroblast- treated successfully with conventional radiation methods. oma and rhabdomyosarcoma with three patients each. Within IMRT again different technical solutions are being Table 1 shows more detailed information about the used. They all have the principle in common that radia- patients' characteristics. Treatment location was head and tion beams with different intensities are used depending neck in 50% of the treated sites (n = 17), other treatment on how much tumor or organ at risk is located within dif- locations were abdominopelvic (n = 5), intracranial (n = ferent areas of the beam. This way dose distributions can 3), thoracic wall (n = 5) and spine (n = 4). 28 patients be adapted to irregular tumor geometries close to organs were treated with curative intent despite most patients at risk. It is a rather difficult task to produce irregular having advanced or even metastatic (cases #2, #4, #23, intensity maps with a linear accelerator that is designed to #30) disease. Eighteen patients underwent IMRT as part of produce beams of homogeneous intensity. A very com- multimodality therapy, e.g. as part of a protocol. Eleven mon approach is segmental MLC-IMRT (step-and-shoot- patients received adjuvant radiotherapy and two patients IMRT) [1]. The irregular fields are created as a summation radiotherapy only (cases #29, #7). One boy with alveolar of many small fields resulting in a pulsed dose applica- rhabdomyosarcoma of the nasal cavity was treated twice tion. Another way to modulate intensity is the dynamic due to local relapse (case #23). One adolescent with a movement of collimator leaves during beam application desmoplastic small cell tumor was treated three times at which is called dynamic MLC-IMRT or sliding window different sites (case #12). technique [15]. A third common technique is helical tomotherapy that uses a rotational beam delivery in a hel- Three patients had previously received standard external ical fashion together with a binary collimator [16]. With beam radiation (cases #2, #10, #14), including a girl with all these devices excellent treatment options can be metastatic Ewing's sarcoma, after definitive treatment opened for the most challenging cases in radiation oncol- with multiagent chemotherapy and radiotherapy of the ogy. Examples are parotid gland sparing in head-and-neck pelvis. This girl received IMRT for tumor recurrence tumors or spinal cord sparing for tumors of the vertebral involving the cervical spine. The second patient, a 19-year column. old male with aggressive fibromatosis of the thoracic wall started radiation treatment two years ago, but declined The history of IMRT for children is markedly different to further treatment after an administered total dose of 28.8 the history of IMRT for adult patients. While IMRT for Gy at that time. He received IMRT to the previously treated adults is a widely used as a standard of care for many indi- site. The third patient, a 16-year old boy underwent radi- cations meanwhile, for several reasons IMRT was used otherapy of the neurocranium (total dose 5.4 Gy) six years with great caution in the paediatric population. Among ago as part of multimodality treatment of an acute lym- these are increased fraction time, necessity for exact phoblastic leukaemia. About four years later he presented immobilization with tailor-made steep dose gradients with an anaplastic astrocytoma and therefore received present and the fear of increased secondary malignancy external beam radiation to the right hemisphere (total induction by changes in low dose spillage or integral dose dose 54 Gy). IMRT was delivered sixteen months later for [17-21]. recurrent astrocytoma. This study describes experience and outcome of IMRT for One girl with malignant optical nerve glioma was treated children and adolescents in our institution. In addition a with an iodine seed implantation four years prior to IMRT review of the available literature reporting on technology, (case #15). quality, toxicity, outcome and concerns of IMRT is given. Administered doses varied according to whether IMRT Methods was definitive, postoperative, delivered to a previously When radiotherapy is required for children within a mul- treated tumor site, or part of a treatment protocol (e.g. timodal study protocol, in our institution first planning Ewing's sarcoma) and depended on the proximity of crit- with conventional techniques is performed. If problems ical organs. with target coverage or sparing of close organs at risk occur, IMRT is evaluated for potential benefits in this Follow up examinations including MRI scans were per- regard. formed six weeks after completing radiotherapy and after Page 2 of 10 (page number not for citation purposes) Radiation Oncology 2009, 4:37 http://www.ro-journal.com/content/4/1/37 Table 1: Patient characteristics Case Diagnosis Location Age # fields median Dose number of Previous RT [years, months] [Gy] fractions 1 Ewing's sarcoma orbita 14, 7 9 54 30 2 Ewing's sarcoma spine (cervical) 15, 0 7 45 25 RT pelvis 45 Gy 3 Ewing's sarcoma infratemporal fossa 15, 4 7 54 30 4 Ewing's sarcoma pelvis 16, 10 8 54 30 5 Ewing's sarcoma scapula 19, 9 9 45 25 6 Myoepithelial Parotis parotid gland 19, 1 7 66 33 Ca 7 Giant cell tumor os sacrum 20, 6 7 66 33 8 Meningeoma intracranial 12, 4 7 57.6 32 9 Desmoid Tumor spine (cervical) 17, 7 7 54 30 10 Aggressive thoracic wall 19, 8 5 45 25 RT thoracic wall 28.8 fibromatosis Gy 11 Angiofibromatous spine (cervical) 19, 1 7 56 28 tumor 12 Desmoplastic small abdomen 17, 3 7 56 28 cell tumor abdomen 18, 1 7 45 25 thoracic wall 19, 3 7 50.4 28 13 Adenoid cystic parotid gland 17, 0 7 66 33 carcinoma 14 Astrocytoma WHO intracranial 16, 0 8 30.6 17 RT neurocranium 5.4 III Gy + TBI 12Gy, RT right hemisphere 54 Gy 15 Malignant opticus optic nerve 4, 5 7 50 25 previous iodine seed glioma implantation 16 Lymphoepithelial nasopharynx 17, 11 9 66 30 Carcinoma 17 Melanoma orbita 7, 6 8 60 30 18 Juvenile nasopharynx 10, 11 7 50.4 28 nasopharyngeal fibroma 19 Juvenile nasopharynx 15, 11 7 50.4 28 nasopharyngeal fibroma Page 3 of 10 (page number not for citation purposes) Radiation Oncology 2009, 4:37 http://www.ro-journal.com/content/4/1/37 Table 1: Patient characteristics (Continued) 20 Juvenile nasopharynx 18, 5 7 50.4 28 nasopharyngeal fibroma 21 Rhabdomyosarcoma thoracic wall 5, 0 7 21.6 12 22 Rhabdomyosarcoma abdomen 18, 2 7 45 25 23 Rhabdomyosarcoma neck 4, 9 7 45 25 neck (re-Rt) 7, 4 7 36 20 24 Esthesioneuroblasto 15, 10 10 60 30 ma 25 Esthesioneuroblasto 17, 10 7 54 30 ma 26 Esthesioneuroblasto 18, 6 7 63 32 ma 27 PNET thoracic wall 1, 6 7 41.4 23 28 PNET thoracic wall/spine 19, 5 7 54 30 29 Chondrosarcoma scull 16, 3 7 64 32 30 Neuroblastoma adrenal gland 3, 4 8 39.6 22 31 Hypopharynx-ca neck 4, 9 5 60 30 that in intervals of three to six months for the first two of 2.75 mm at isocenter was used. This collimator is years. Further follow-up visits usually took place annually. attached to an accessory holder of the Siemens accelerator. Radiotherapy During treatment all patients were evaluated at least on a Inverse treatment planning for stereotactic-guided IMRT weekly basis to assess acute toxicity. was realized by the KonRad treatment planning system, developed at our institute [8,22]. The KonRad system is Results connected to the 3D treatment planning system VIR- Median follow up time was 34 (1 - 68) months; mean administered dose was 51.6 Gy (21.6 - 66), including the TUOS, which allows calculation and visualization of the dose distribution. 3D planning based on contrast patients that received concomitant chemotherapy. The enhanced MRI and CT imaging was performed, using two patients previously treated with standard external individually manufactured rigid scotch masks for head beam radiation on the IMRT treatment site, were treated immobilization. Thoracic and abdominopelvic targets up to a total dose of 45 Gy and 30.6 Gy respectively (cases were positioned with a vacuum bag and a scotch cast mask #10, #14). fixation. Definition of the planning target volume was performed on the basis of image fusion techniques. In Intravenous sedation with propofol during radiotherapy most patients IMRT was administered using a simultane- session was necessary in 6 children (cases #15, #21, #23, ous integrated boost concept. #27, #30, #31). These children were all younger than 6 years at the time of treatment This was tolerated well with- A Siemens linear accelerator (Medical Solutions Siemens, out severe side-effects and with fast recovery after treat- Erlangen, Germany) with 6 MV photons was used for ment. No general anaesthesia with intubation was treatment. It is equipped with an integrated motorized necessary. multileaf collimator, which allows a sequential step-and- shoot technique. In three patients (cases #17, #26, #27) a side effects miniature-multileaf collimator (ModuLeaf MLC, MRC- Reported acute side effects of radiotherapy were low grade Systems GmbH, Heidelberg, Germany) with a leaf width skin erythema (CTC grade I-II), mucositis (CTC grade I- Page 4 of 10 (page number not for citation purposes) Radiation Oncology 2009, 4:37 http://www.ro-journal.com/content/4/1/37 II), local alopecia, mild nausea, mild diarrhoea, loss of growth of the thoracic wall is a possible explanation for taste and epistaxis (case #19). Pancytopenia occurred in this. four patients (cases #1, #2, #4, #28) who received con- comitant chemotherapy. In two of them pancytopenia Figure 2 shows the IMRT plan for a 14 year old girl (case (CTC grade III) resulted in treatment interruption for two # 1) with a Ewing's sarcoma of the left orbit, infiltrating days. No other severe acute side effects were observed. the dura mater and the left ethmoid sinus. The patient received multiagent chemotherapy (7 cycles VIDE (vinc- One patient developed thoracic scoliosis two years follow- ristine, ifosfamide, doxorubicin, etoposide) followed by 6 ing spine irradiation (case #27, figure 1). One adolescent, cycles VAC (vincristine, adriamycin, cyclophosphamide)) who was also treated with chemotherapy, claims of hypo- and tumor resection (R1) prior to IMRT treatment. IMRT aesthesia in his right forearm, two years after upper tho- was delivered in order to spare the lacrimal gland, optic racic wall irradiation (case #28). One girl developed slight nerve and eyeball. At present, there are no signs of tumor enophthalmia after irradiation for a Ewing's sarcoma of recurrence with an actuarial follow up of four and a half the orbit, visual acuity though is not impaired (case #1). years. Visual acuity is 1.0 on both eyes, though the patient No other late toxicity was observed so far among survi- developed slight enophthalmia on the treated site. vors. local control and survival Figure 1 displays the treatment plan for a 18 months old Local failure occurred in 10 of 31 patients (table 2), time boy (case #27) with primitive neuroectodermal tumor to local failure was 4 - 53 months. In the event of local (PNET) of the right thoracic wall. He received chemother- tumor progression patients received chemotherapy or sur- apy according to the Euro Ewing 99 protocol followed by gical tumor resection, one patient with carcinoma of the tumor resection with positive pathological margins. Post- hypopharynx was reirradiated using IMRT (case #31). No operative IMRT was delivered in order to decrease the local relapse occurred among patients with juvenile dose to the nearby spinal cord and lungs with a median nasopharyngeal fibroma and esthesioneuroblastoma. So prescribed dose of 30.6 Gy to the PTV and 41.4 Gy to the far, 5 patients died due to distant metastases (cases #30, boost. During the radiation course regular CT-scans with #31, #21, #5, #4). an in-room CT-Scanner were performed to confirm cor- rect patient position. Thirty-eight months after finishing Discussion treatment he underwent surgery for straightening of tho- We present a very heterogeneous group of children and racic scoliosis. This occurred inspite of inclusion of the adolescents with 20 different tumor entities. All of these complete vertebral body in the PTV. An asymmetric 31 patients have a very complex oncological constellation IMRT-Plan for treatment of a 1 Figure 1 .5 year old boy with a primitive neuroectodermal tumor (PNET) of the right thoracic wall IMRT-Plan for treatment of a 1.5 year old boy with a primitive neuroectodermal tumor (PNET) of the right thoracic wall. A: A prescribed dose of 30.6 Gy to the PTV. B: 41.4 Gy prescribed to the boost. IMRT-Plan in colour wash shows the 90% isodose region (dotted line). Page 5 of 10 (page number not for citation purposes) Radiation Oncology 2009, 4:37 http://www.ro-journal.com/content/4/1/37 IMRT-plan for Figure 2 treatment of a 14 year old girl with Ewing sarcoma of the left orbit with a median prescribed dose of 54 Gy IMRT-plan for treatment of a 14 year old girl with Ewing sarcoma of the left orbit with a median prescribed dose of 54 Gy. A: Axial view of the dose distribution in colour wash shows the 90% isodose region (dotted line). B: Coronal view of the dose distribution with sparing of the eye. in common that made the application of a sufficient radi- secondary malignancies. We tried to increase chances of ation dose extremely difficult with conventional radio- cure the patients accepting possible risks in a matter of therapy techniques. Here the possible benefits of IMRT decades in case of success. IMRT was feasible even if like the sparing of organs at risk and the possibility of dose anaesthesia was necessary and resulted in good local con- escalation were considered to be more important for the trol rates for this group of children who represents a selec- treatment success than the potentially increased risk of tion of extraordinary and difficult cases. Table 2: Local failure after IMRT Case Diagnosis Time to local failure [months] Dose Treatment following failure [Gy] 2 Ewing sarcoma 7 45 chemotherapy 4 Ewing sarcoma 9 54 chemotherapy 6 myoepithelial Parotis-carcinoma 7 66 surgery 8 Meningeoma 53 57.6 surgery 9 Desmoid tumor 14 54 surgery 11 Angiofibromatous tumor 7 56 surgery 15 Optic nerve glioma 36 50 surgery 21 Rhabdomyosarcoma 8 21.6 chemotherapy 23 Rhabdomyosarcoma 29 45 chemotherapy 31 Hypopharynx-Carcinoma 4 60 Re-irradiation (IMRT) Page 6 of 10 (page number not for citation purposes) Radiation Oncology 2009, 4:37 http://www.ro-journal.com/content/4/1/37 IMRT could be applied with only few low grade acute tox- [27]. In a retrospective planning evaluation they illustrate icities and hardly any long term side effects so far. It is the possibilities of helical tomotherapy (as one solution important to note that the follow up is still quite short to of IMRT) to cover a target volume of this size avoiding the assess secondary malignancies. This radiotherapy tech- problems of field junctions and the resulting dangers of nique allows reirradiations in difficult localisation that under or overdosage inherent in conventional techniques. could not be performed safely before. After treating the whole craniospinal axis the primary tumor region is supposed to be irradiated with an extra In contrast to the big amount of publications in treating boost to the posterior fossa. Huang et al. describe reduced adult patients with IMRT, there is only few data in litera- ototoxicity when sparing the inner ear by IMRT compared ture about the use of IMRT in the paediatric population. to conventional radiotherapy, where the cochlear region Good experiences with the treatment of twenty-two chil- receives the full therapeutic dose [28]. Thirteen percent of dren with IMRT have been reported by Bhatnagar et al. the IMRT Group had grade 3 or 4 hearing loss, compared [23]. They described substantial sparing of surrounding to 64% of the conventional-RT group. The sparing of the critical structures in cranial, abdominopelvic or spinal hearing apparatus is of special importance since several lesions, altogether a selection of very difficult oncological modern combined chemotherapy regimens contain oto- situations. Conventional treatment technologies would toxic agents like cisplatinum. Jain et al. showed that this have resulted in a markedly higher dose to organs at risk improvement of ototoxicity was not achieved at the cost or would have required compromises regarding the possi- of increased neuropsychological changes [29]. ble target dose. Another challenging situation in that IMRT might sub- Penagaricano et al. summarized their experience of 5 chil- stantially improve the treatment is retinoblastoma. Krasin dren treated with IMRT with a high degree of conformality et al. presented a planning study comparing different con- [24]. The dose distribution could be adapted to arc shaped ventional photon, electron and IMRT techniques in the volumes in contrast to conventional therapy where treatment of intraocular retinoblastoma [30]. The best treated volumes are usually box shaped and encompass sparing of the bony orbit was achieved with IMRT yielding big areas of treated normal tissue. Similar conclusions are a promising potential of avoiding asymmetrical bone drawn by Paulino et al. in their synopsis of this method growth after successful radiotherapy. The mean volume of for children [24,25]. They summarize that IMRT is a valu- bony orbit treated with IMRT above 20 Gy (as a threshold able alternative to conventional treatment techniques for of bone growth disturbance) was 60% in contrast to 90% paediatric cancer patients. The improved dose distribu- in conventional technique. Schroeder et al. report on 22 tions coupled with the ease of delivery of the IMRT fields children with localized intracranial ependymoma treated make this technique very attractive, especially in view of with IMRT. They were able to achieve a three year local the potential to increase local control and possibly control of 68% while enabling minimal rates of toxicity improve on survival. A third survey of a heterogeneous (no visual or hearing impairment, no necrosis, no myeli- group of children treated with IMRT is given by Teh et al. tis) [31]. within a general article about decreased treatment related morbidity with IMRT [26]. Experiences with 185 patients The irradiation of head-and-neck tumors is quite rare in treated with IMRT in general are presented, among these children. Nevertheless long term toxicity is a huge concern forty children suffering from different tumors. Similar to and often impairs the quality of life. Special focus here is the conclusions by the authors described before they con- xerostomia caused by a fibrotic atrophy of the parotid clude that IMRT offers new options in escalating dose and glands. Consecutive dental damage, dysphagia, problems achieving better local control while simultaneously reduc- of speach and taste are feared. In a study by Wolden et al. ing toxicity. twenty-eight patients with head-and-neck rhabdomyosar- coma were treated with IMRT. The age ranged from 1-29 Besides these compilations of composed cohorts a larger years, the thee year local control was 95% with minimal number of articles provides data on special indications side effects [9]. In a similar approach by the groups of and more predefined collectives. They specially deal with Atlanta (20 children) and Houston (19 children) head- intracranial or head-and-neck tumors since the sensitive and-neck rhabdomyosarcomas could be treated with a 3 structures like eyes, brain stem, parotid glands or inner year local control of 100% and a four year local control of ears represent an extraordinary challenge in the radiother- 92.9% respectively [32,33]. Combs et al. presented a apeutic management. Starting with the biggest of all cen- cohort of 19 children with rhabdomyosarcoma treated tral nervous treatments the irradiation of the entire with stereotactic radiotherapy (n = 14) or IMRT (n = 5) craniospinal axis as required in medulloblastoma or ger- [34]. The three and five-year local control rate was 89%, minoma can be done with improved conformity and spar- no toxicity > CTC grade 2 were observed. An Indian anal- ing of sensitive structures as shown by Penagaricano et al. ysis of IMRT for nasopharyngeal cancer (19 children) Page 7 of 10 (page number not for citation purposes) Radiation Oncology 2009, 4:37 http://www.ro-journal.com/content/4/1/37 showed reduced toxicity in terms of xerostomia, skin reac- risk is especially increased in patients of very young age, tion and mucous membrane reaction compared to con- Hodgkin's disease, treatment with alkylating agents, radi- ventional radiotherapy (17 children) [35]. Acute ation therapy and female gender [47,48]. xerostomia grade 2 occurred in 31.6% in IMRT vs. 88.2% in conventional radiotherapy. Grade 2 dysphagia was also Secondary cancer induction is dose dependent and tissue significantly reduced with 42.0% vs. 94.1%. IMRT was irradiated with doses below 6 Gy is known to be especially also able to provide superior target coverage and as a con- endangered to develop secondary cancer [49]. The calcu- sequence of the reduced toxicity an improved compliance. lated risk of secondary malignancies after treatment with IMRT was estimated to be doubled [17,19]. It is important Juvenile angiofibroma can be cured by radiotherapy in to note that these numbers are only estimations and cal- unresectable or relapsing cases. They are difficult to treat culations with no fundament of clinical data due to the for because of the same surrounding risk structures as dis- lack of enough follow-up time. In addition integral dose cussed above. Especially with respect to the benign nature is often discussed to be potentially higher in IMRT com- of these tumors a well balanced toxicity profile is vital as pared to conventional radiotherapy. This is not necessar- described by Kuppersmith et al. and can be achieved by ily true since the high dose region to normal tissue is the means of IMRT [36]. markedly reduced with the improved conformity [50]. As stated above the characteristic new feature of dose expo- Another potential indication is the radiosurgical treat- sure in IMRT is a shift towards low dose spread out. Espe- ment of arteriovenous malformations (avm). Lesions that cially in the tissues with a high incidence of secondary are unresectable and not accessible for interventional neu- cancers the ability of IMRT to produce conformal avoid- roradiology can be obliterated by high dose single course ance of these structures might limit the risk of these late radiotherapy. Fuss et al. presented the possibilities of effects. Techniques like helical tomotherapy have the IMRT in seven children with avm of complex shape, that potential of selectively sparing the thyroid gland and could hardly be treated with conventional methods [37]. breast tissue in craniospinal irradiation. Two avm obliterated completely, three partially, while no treatment related side effects occurred. The number of children treated with IMRT and the hard evidence for the benefit of this technology is limited [13]. In the discussions about precautions of IMRT in children However, waiting for this evidence would last for many the advantages are achieved at the cost of raised low dose years. Many of the uncertainties cannot be answered by outside the target. With a higher number of monitor units simply transferring the standards of evidence based med- required the total body dose can increase significantly icine in medical oncology one by one to radiation oncol- [38]. However, in a study by Koshy et al. no increased ogy. Randomizing children or adults in two different extra target dose to thyroid, breast, and testis was seen in radiotherapy regimens knowing that one will definitely children treated with IMRT compared with a control inactivate the parotid glands, one kidney or affect bone group of children treated with conventional radiotherapy growth is simply unethical. Withholding children the pos- for cranial and abdominopelvic tumors [39]. sibility to reduce doses to organs at risk in difficult cases is hard to justify. As long as proton treatment with its great The methods that allow the intensity modulation of the potential of decreased integral dose is not widely availa- radiation beams increase the volume of tissue receiving ble, IMRT provides an excellent tool in difficult situations. low dose compared to conventional radiotherapy [40]. Patient selection is absolutely crucial with regard to the The effects in adult patients are the same, however, there worries about potentially increased chances of secondary are 3 reasons for special consideration in the treatment of malignancies. Reserved for complex cases with close prox- children: higher sensitivity to radiation induced cancer, imity of organs at risk IMRT represents a powerful and ver- relation of scattered dose to the small body volume and satile treatment option when used with the necessary genetic susceptibility due to germline mutations [18,41- caution [25,51]. 45]. While high dose to neighbouring structures can be selectively decreased by the means of IMRT, low dose is Conclusion distributed in the rest of the body. Consequences of this Intensity modulated radiotherapy is a feasible method of special treatment technique can only be estimated until radiotherapy for paediatric malignancies. It was applied now. safely in 31 patients within the last eight years in difficult oncologic situations. Conventional radiotherapy would Data of the childhood cancer survivor study (CCSS) have been associated with limited dose to the target or showed 5 year survival rates of 79% for all different tumor high normal tissue complication probability. In all the entities [46]. With such a high number of long term survi- presented patients it was decided that the benefit of vors secondary neoplasms become highly relevant. The increased tumor control probabilities and improved spar- Page 8 of 10 (page number not for citation purposes) Radiation Oncology 2009, 4:37 http://www.ro-journal.com/content/4/1/37 sity-modulated radiation therapy (IMRT) and inverse treat- ing of organs at risk had a higher clinical impact than the ment planning for advanced pleural mesothelioma. calculated increased risk of late side-effects. Strahlenther Onkol 2003, 179:535-541. 7. Schulz-Ertner D, Didinger B, Nikoghosyan A, Jakel O, Zuna I, Wan- nenmacher M, Debus J: Optimization of radiation therapy for As long as the risk of secondary cancer induction can only locally advanced adenoid cystic carcinomas with infiltration be estimated IMRT for children should only be used with of the skull base using photon intensity-modulated radiation therapy (IMRT) and a carbon ion boost. Strahlenther Onkol caution. Longer follow up time is needed to quantify this 2003, 179:345-351. long term complication. Conventional radiotherapy 8. Munter MW, Debus J, Hof H, Nill S, Haring P, Bortfeld T, Wannen- remains the standard of care in radiation oncology for macher M: Inverse treatment planning and stereotactic inten- sity-modulated radiation therapy (IMRT) of the tumor and children and can be delivered with acceptable toxicity in lymph node levels for nasopharyngeal carcinomas. Descrip- the majority of children. tion of treatment technique, plan comparison, and case study. Strahlenther Onkol 2002, 178:517-523. 9. Wolden SL, Wexler LH, Kraus DH, Laquaglia MP, Lis E, Meyers PA: Nevertheless, reserved to special cases with close proxim- Intensity-modulated radiotherapy for head-and-neck rhab- ity of sensitive structures, it can provide great benefit for domyosarcoma. Int J Radiat Oncol Biol Phys 2005, 61:1432-1438. 10. Studer G, Lutolf UM, Davis JB, Glanzmann C: IMRT in Hypopha- paediatric patients and should not be withheld because of ryngeal Tumors. Strahlenther Onkol 2006, 182:331-335. estimations based on a radiobiological model. It widens 11. Cavey ML, Bayouth JE, Colman M, Endres EJ, Sanguineti G: IMRT to the therapeutic window and reduces long term toxicity for escalate the dose to the prostate while treating the pelvic nodes. Strahlenther Onkol 2005, 181:431-441. an increased number of long term cancer survivors. 12. Guckenberger M, Flentje M: Intensity-Modulated Radiotherapy (IMRT) of Localized Prostate Cancer: A Review and Future Perspectives. Strahlenther Onkol 2007, 183:57-62. Declaration of competing interests 13. Veldeman L, Madani I, Hulstaert F, De Meerleer G, Mareel M, De The authors declare that they have no competing interests. Neve W: Evidence behind use of intensity-modulated radio- therapy: a systematic review of comparative clinical studies. Lancet Oncol 2008, 9:367-375. Authors' contributions 14. Sterzing F, Schubert K, Sroka-Perez G, Kalz J, Debus J, Herfarth K: FS is responsible for data acquisition, literature research Helical Tomotherapy: Experiences of the First 150 Patients and writing of the manuscript. ES is responsible for data in Heidelberg. Strahlenther Onkol 2008, 184:8-14. 15. Boyer A, Xing L, Luxton G, Chen Y, Ma C: IMRT by dynamic MLC. acquisition, statistical analysis and writing of the manu- In The Use of Computers in Radiation therapy, XIIIth International Confer- script. SN is responsible for the physical aspects of IMRT ence, Heidelberg, Germany, May 22-25 2000 Edited by: Schlegel W, Bortfeld T. Berlin: Springer; 2000:160-163. planning and treatment of the children. HB is responsible 16. Mackie TR, Balog J, Ruchala K, Shepard D, Aldridge S, Fitchard E, for the anaesthesia management of the children. PH is Reckwerdt P, Olivera G, McNutt T, Mehta M: Tomotherapy. Semin responsible for the clinical treatment of the children as Radiat Oncol 1999, 9:108-117. 17. Hall EJ, Wuu CS: Radiation-induced second cancers: the head of the division of radiation oncology in the German impact of 3D-CRT and IMRT. Int J Radiat Oncol Biol Phys 2003, Cancer Research Center. JD is responsible for the clinical 56:83-88. treatment of the children as of the department of radia- 18. Hall EJ: Intensity-modulated radiation therapy, protons, and the risk of second cancers. Int J Radiat Oncol Biol Phys 2006, 65:1-7. tion oncology in the University of Heidelberg. MM is 19. 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Paulino AC, Fowler BZ: Secondary neoplasms after radiother- "BioMed Central will be the most significant development for apy for a childhood solid tumor. Pediatr Hematol Oncol 2005, disseminating the results of biomedical researc h in our lifetime." 22:89-101. Sir Paul Nurse, Cancer Research UK 45. Lin HM, Teitell MA: Second malignancy after treatment of pediatric Hodgkin disease. J Pediatr Hematol Oncol 2005, Your research papers will be: 27:28-36. available free of charge to the entire biomedical community 46. Robison LL: Treatment-associated subsequent neoplasms among long-term survivors of childhood cancer: the experi- peer reviewed and published immediately upon acceptance ence of the Childhood Cancer Survivor Study. Pediatr Radiol cited in PubMed and archived on PubMed Central 2009, 39(Suppl 1):S32-37. 47. Armstrong GT, Liu Q, Yasui Y, Neglia JP, Leisenring W, Robison LL, yours — you keep the copyright Mertens AC: Late mortality among 5-year survivors of child- BioMedcentral Submit your manuscript here: http://www.biomedcentral.com/info/publishing_adv.asp Page 10 of 10 (page number not for citation purposes)

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Published: Sep 23, 2009

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