bs_bs_banner
Pediatrics International (2015) 57, 567–571
doi: 10.1111/ped.12624
Original Article
Proton beam therapy for pediatric ependymoma Masashi Mizumoto,1 Yoshiko Oshiro,1,4 Daichi Takizawa,1 Takashi Fukushima,2 Hiroko Fukushima,2 Tetsuya Yamamoto,3 Ai Muroi,3 Toshiyuki Okumura,1 Koji Tsuboi1 and Hideyuki Sakurai1 Departments of 1Radiation Oncology, 2Pediatrics and 3Neurosurgery, Tsukuba University and 4Department of Radiation Oncology, Tsukuba Medical Center Hospital, Tsukuba, Japan Abstract
Background: The aim of this study was to evaluate the efficacy of proton beam therapy for pediatric patients with ependymoma. Methods: Proton beam therapy was conducted for six patients (three boys and three girls; age, 2–6 years; median, 5 years) with ependymoma. The tumors were WHO grades 2 and 3 in two and four patients, respectively. All patients underwent surgery (subtotal and gross total resection in three patients each) and proton beam therapy at doses of 50.4–61.2 GyE (median, 56.7 GyE). The mean doses to normal brain tissue in proton beam therapy and photon radiotherapy were simulated using the same treatment planning computed tomography images. Results: All patients completed the planned irradiation. The follow-up period was 13–44 months (median, 24.5 months) from completion of proton beam therapy and all patients were alive at the end of this period. Local recurrence in the treatment field occurred in one patient at 4 months after proton beam therapy at 50.4 GyE. Alopecia and mild dermatitis occurred in all patients, but there was no severe toxicity. One patient had a once-off seizure after proton beam therapy and alopecia persisted in another patient for 31 months, but no patients had difficulty with daily life. The simulation showed that proton beam therapy reduces the dose to normal brain tissue by approximately half compared with photon radiotherapy. Conclusions: Proton beam therapy for pediatric ependymoma is safe, does not have specific toxicities, and can reduce irradiation of normal brain tissue.
Key words brain, ependymoma, pediatric, proton beam therapy, radiotherapy.
Intracranial ependymoma accounts for approximately 10% of all intracranial tumors in children1 and has a 5 year survival rate of 50–80%.2–6 Surgery followed by postoperative radiotherapy using doses 54–59.4 Gy is a common treatment strategy for intracranial ependymoma in children.3,5,6 Postoperative radiotherapy may contribute to improved survival, but late toxicity of the brain may impair intellectual development and compromise quality of life. Merchant et al. showed that intelligence quotient (IQ) is significantly associated with age and the fractional dose volume received over specific intervals (e.g. V0–20, V20–40, V40–65 Gy), and that radiation dosimetry can be used to predict IQ after conformal radiotherapy in patients with ependymoma.7–9 Another report showed that IQ after radiotherapy is significantly associated with the mean dose to normal brain tissue.10 Recent technological advances in radiotherapy have made it possible to largely avoid irradiation of normal brain tissue while maintaining delivery of an adequate dose to the target volume. Proton beam therapy is particularly likely to have an important role in the treatment of pediatric intracranial tumors because of its physical advantage of dose concentration. We have previously Correspondence: Masashi Mizumoto, MD, Proton Medical Research Center, University of Tsukuba, Tennoudai, Tsukuba, Ibaraki 305-8575, Japan. Email: [email protected] Received 16 May 2014; revised 12 December 2014; accepted 8 January 2015.
© 2015 Japan Pediatric Society
described the treatment outcomes of proton beam therapy for various tumors.11–17 In this report, we evaluate the use of proton beam therapy for pediatric intracranial ependymoma and estimate the mean dose to normal brain tissue compared with conformal radiotherapy.
Methods Patients
The subjects were six patients with ependymoma who were treated with proton beam therapy from January 2009 to December 2012. The patients were three boys and three girls, and ranged in age from 2 to 6 years old (median, 5 years). The tumors were grade 2 and grade 3 in two and four patients, respectively, using the WHO classification, and had supratentorial and infratentorial locations in three patients each. All patients underwent surgery and chemotherapy, with subtotal resection and gross total resection conducted in three patients each. The duration from surgery to proton beam therapy was 20–87 days (median, 50 days). The doses of proton beam therapy ranged from 50.4 to 61.2 GyE (median, 56.7 GyE). Proton beam therapy
All patients received proton beam therapy after surgery. Treatment planning for proton beam therapy involved use of computed
Comparison with conformal radiotherapy
Time from surgery (days) 48 52 49 87 20 57
Total dose (GyE) 50.4 61.2 54.0 50.4 59.4 61.2
CTV1 (cm3)
To evaluate the merits of proton beam therapy compared with conformal radiotherapy, we prepared a treatment plan for conformal radiotherapy using the same treatment planning CT images, with the goal of evaluating the mean dose to normal brain tissue at the same dose for the clinical target volume. To evaluate late brain toxicity, the change in IQ was evaluated using the predictive model proposed by Merchant et al.,8 in which the decrease in IQ is proportional to the mean dose received by all normal brain tissue: IQ = 93.11 + (0.028 × age − 0.0095 × mean dose to normal brain tissue) × time.
Results
© 2015 Japan Pediatric Society
Fourth ventricle Fourth ventricle Cerebellar-pontine angle Left frontal lobe Left parietal lobe Left occipital lobe II III III II III III M M M F F F 6 5 6 2 3 4
Sex Age (years)
Assuming that 2 Gy is delivered to the clinical target volume, the mean normal brain dose of proton beam therapy was 0.11–0.69 GyE (median, 0.23 GyE) and that of conformal radiotherapy was 0.25–0.97 Gy (median, 0.41 Gy). Thus, use of proton beam therapy reduced the mean normal brain dose by 28–64%
Patient ID no.
Comparison of proton beam therapy with photon radiotherapy
Table 1 Patient background
As of May 2013, all patients were alive and the median follow-up period was 24.5 months (range, 13–44 months). The median treatment period was 50 days (range, 43–59 days). One patient (patient 1) had local recurrence at 4 months after proton beam therapy and the other five patients had no recurrence at 13–35 months (median, 20 months). In the recurrent case, the tumor was adjacent to the brainstem and thus a minimum treatment margin of 5 mm and irradiation dose of 50.4 GyE were selected. The clinical courses of the six patients are listed in Table 1.
Tumor (grade)
Local control and overall survival
1 2 3 4 5 6
Location
Surgery
Acute treatment-related toxicities were generally mild, with three and one patients developing acute dermatitis of grades 1 and 2, respectively, and all patients having alopecia. Regarding late toxicity, one patient had a one-time seizure after proton beam therapy, and alopecia was prolonged in another patient for 35 months. Radiation necrosis, white matter changes, volume loss, cystic changes and vascular problems were not found at the last follow up, and no patients had difficulties with daily life.
Total resection Subtotal resection Total resection Total resection Subtotal resection Subtotal resection
Toxicity
†Assuming that 2 Gy is delivered to the CTV. ‡(Mean dose to normal brain tissue using conformal radiotherapy – mean dose to normal brain tissue using proton beam therapy)/mean dose to normal brain tissue using conformal radiotherapy. CRT, conformal radiotherapy; CTV, clinical target volume; PBT, proton beam therapy.
Overall survival (months) 44 26 20 13 35 23
Mean dose to brain (CRT)† 0.25 0.31 0.45 0.36 0.63 0.97
Mean dose to brain (PBT)† 0.11 0.17 0.29 0.13 0.31 0.69
Reduction ratio‡ (%)
tomography (CT) at 3 mm intervals around the treatment location. Proton beams of 250 MeV were generated by a booster synchrotron at the Proton Medical Research Center. The treatment planning system provided dose distributions and settings for the collimator configuration, bolus, and range-shifter thickness. The relative biological effectiveness of the proton beam therapy was assumed to be 1.1.18,19 The clinical target volume was defined as the area of contrast enhancement on magnetic resonance imaging and the tumor bed plus an adequate margin. The margin for the clinical target volume was initially 8–10 mm, and was reduced to 5 mm after 45–54 GyE. The dose of proton beam therapy was 50.4 GyE in 28 fractions to 61.2 GyE in 34 fractions. The optic chiasm was avoided from 40 GyE and the brainstem was avoided from 50 GyE.
59 43 36 64 51 28
M Mizumoto et al.
11.4 16.4 83.2 10.4 47.0 134.7
568
PBT for pediatric ependymoma
a
b
c
d
569
Fig. 1 Treatment planning for (a,c) proton beam therapy and (b,d) conformal radiotherapy in patients (a,b) 4 and (c,d) 6.
(median, 47%) compared with conformal radiotherapy (Table 1). Using the predictive model,8 IQ at 10 years after proton beam therapy was calculated to deteriorate from 0 to 17.7 points (median, 5.4 points), while that after radiotherapy deteriorates from 0 to 27.3 points (median, 10.7 points). The treatment plan for proton beam therapy and conformal radiotherapy using the same treatment planning CT for patient 4 (Table 1) is shown in Figure 1(a,b). This patient had left frontal lobe ependymoma and received postoperative proton beam therapy (Fig. 1a). The conformal radiotherapy plan (Fig. 1b) included selection of the optimal angle to avoid normal brain tissue as much as possible. In this case, the tumor was small (10.4 cm3) and was located near the surface of skull, which allowed proton beam therapy to be used with avoidance of a large part of the normal brain volume (non-irradiated area in Fig. 1a). Confor-
mal radiotherapy could cover the tumor similarly to proton beam therapy, but the normal brain beyond the tumor was included in the 40–50% isodose line (Fig. 1b). In this case, use of proton beam therapy reduced the mean normal brain dose by 64%. The treatment plan for proton beam therapy and conformal radiotherapy using the same treatment planning CT for patient 6 (Table 1) is shown in Figure 1(c,d). This patient had left occipital lobe ependymoma that reached the ventricle from the surface of the brain. Postoperative proton beam therapy was performed (Fig. 1c). The conformal radiotherapy plan (Fig. 1d) included selection of the optimal angle to avoid normal brain tissue as much as possible. In this case, the tumor was large (134.7 cm3) and the normal brain outside the irradiated area was avoided in proton beam therapy (non-irradiated area in Fig. 1c). In contrast, the 50% isodose line covered the normal brain beyond the tumor © 2015 Japan Pediatric Society
570
M Mizumoto et al.
in conformal radiotherapy (Fig. 1d) and only a small volume of normal brain tissue was included in the non-irradiated area. In this case, use of proton beam therapy reduced the mean normal brain dose by 28%. For patients 4 and 6, the dose at the surface near the tumor with proton beam therapy was almost the same as the dose in the clinical target volume (area within red isodose lines in Fig. 1a,c).
Discussion Postoperative radiotherapy 50–60 Gy is standard treatment for pediatric ependymoma and results in a 5 year survival rate of 50–80%.2–6 In this report, all patients were alive at a median of 24.5 months after radiotherapy and five of six patients were well controlled. Local recurrence in one case was probably caused by an insufficient irradiation dose. This occurred because the tumor was adhered to the brainstem, and thus we selected a minimum treatment margin on the brainstem side, which led to the dose not completely covering the tumor. The small number of patients and short follow-up period prevent further evaluation of the treatment efficacy of proton beam therapy. Acute toxicities were generally mild, but alopecia was prolonged in one patient for 35 months. This may be because proton beams do not have a build-up effect and doses at the skin surface are higher than those in photon radiotherapy when the target is located near the surface (Fig. 1). Also, proton beam therapy was mainly delivered from two directions, so the skin near the tumor bed may receive the same dose as the tumor (Fig. 1a,c). Thus, prolonged alopecia may occur at increased frequency with proton beam therapy compared with photon radiotherapy. Proton beam therapy has some advantages in terms of late toxicity due to reduction of the dose to vital organs.20–22 Macdonald et al. found that preliminary disease control in childhood ependymoma was favorable with proton beam therapy, and that proton beam therapy spared normal tissue compared to intensity moderated radiotherapy.23 Miralbell et al. reported a reduced incidence of radiation-induced secondary cancer after use of proton beams in pediatric patients with rhabdomyosarcoma and medulloblastoma.24 In the present simulation (Fig. 1), the nonirradiated area of normal brain tissue was larger with proton beam therapy compared with that for photon radiotherapy, which suggests that proton beam therapy may reduce the risk of secondary cancer in treatment of ependymoma. Merchant et al. compared proton beam therapy and photon radiotherapy for common pediatric brain tumors and developed a model for predicting IQ after radiotherapy (noted herein), in which the decrease of IQ after radiotherapy is proportional to the mean dose to normal brain tissue.10 In the present patients, this dose was reduced by 28–64% (median, 47%) using proton beam therapy compared with photon radiotherapy. Thus, if the decrease of IQ after radiotherapy is proportional to the mean dose to normal brain tissue, proton beam therapy may reduce the reduction in IQ by approximately half compared with photon radiotherapy. We note, however, that the Merchant et al. model was calculated based on radiotherapy for medulloblastoma, including whole brain radiation, and thus the relationship between IQ reduction and the mean dose to normal brain tissue is unclear in © 2015 Japan Pediatric Society
treatment of ependymoma. Merchant et al. also showed that radiation dosimetry can be used to predict IQ after photon radiotherapy in 88 patients with localized pediatric ependymoma who received conformal radiotherapy (54–59.4 Gy) with a 1 cm margin on the postoperative tumor bed.8 A negative effect on IQ occurred when the dose to normal brain tissue was 0–20 Gy or 40–65 Gy, but a positive effect was observed when this dose was 20–40 Gy. These results may indicate that IQ after radiotherapy is not simply proportional to the mean dose to normal brain tissue and that maximization of the effects of proton beam therapy requires a further study on the influence of irradiation on normal brain tissue. A disadvantage of proton beam therapy is the high cost of the treatment facility. In Japan, 2 500 000–3 000 000 JPY is needed per treatment, and parents may struggle with the heavy burden of this medical expense. For this reason, it is important to select patients in whom proton beam therapy will be particularly advantageous to justify the cost of the treatment. The risk of late toxicity caused by radiotherapy is likely to increase over time and is higher for young patients. Therefore, younger patients with a good prognosis are priorities for proton beam therapy. Conclusion
Proton beam therapy was performed for six pediatric patients with ependymoma. Proton beam therapy may reduce the dose to normal brain tissue by approximately half compared with conformal radiotherapy.
Acknowledgments This work was supported in part by Grant-in-Aid for Scientific Research (B) (24390286), Challenging Exploratory Research (24659556), Young Scientists (B) (25861064), Scientific Research (C) (24591832) from the Ministry of Education, Science, Sports and Culture of Japan. None of the authors have any actual or potential conflicts of interest regarding the work in this study.
References 1 CBTRUS. Statistical report: Primary brain tumors in the United States, 2004–2006. Central Brain Tumor Registry of the United States, Hinsdale, IL, 2010. 2 Merchant TE, Mulhern RK, Krasin MJ et al. Preliminary results from a phase II trial of conformal radiation therapy and evaluation of radiation-related CNS effects for pediatric patients with localized ependymoma. J. Clin. Oncol. 2004; 22: 3156–62. 3 Landau E, Boop FA, Conklin HM, Wu S, Xiong X, Merchant TE. Supratentorial ependymoma: Disease control, complications, and functional outcomes after irradiation. Int. J. Radiat. Oncol. Biol. Phys. 2013; 85: e193–199. 4 Conter C, Carrie C, Bernier V et al. Intracranial ependymomas in children: Society of Pediatric Oncology experience with postoperative hyperfractionated local radiotherapy. Int. J. Radiat. Oncol. Biol. Phys. 2009; 74: 1536–42. 5 Merchant TE, Li C, Xiong X, Kun LE, Boop FA, Sanford RA. Conformal radiotherapy after surgery for paediatric ependymoma: A prospective study. Lancet Oncol. 2009; 10: 258–66. 6 Koshy M, Rich S, Merchant TE, Mahmood U, Regine WF, Kwok Y. Post-operative radiation improves survival in children younger than 3 years with intracranial ependymoma. J. Neurooncol. 2011; 105: 583–90.
PBT for pediatric ependymoma 7 Conklin HM, Li C, Xiong X, Ogg RJ, Merchant TE. Predicting change in academic abilities after conformal radiation therapy for localized ependymoma. J. Clin. Oncol. 2008; 26: 3965–70. 8 Merchant TE, Kiehna EN, Li C, Xiong X, Mulhern RK. Radiation dosimetry predicts IQ after conformal radiation therapy in pediatric patients with localized ependymoma. Int. J. Radiat. Oncol. Biol. Phys. 2005; 63: 1546–54. 9 Netson KL, Conklin HM, Wu S, Xiong X, Merchant TE. A 5-year investigation of children’s adaptive functioning following conformal radiation therapy for localized ependymoma. Int. J. Radiat. Oncol. Biol. Phys. 2012; 84: 217–23. 10 Merchant TE, Hua CH, Shukla H, Ying X, Nill S, Oelfke U. Proton versus photon radiotherapy for common pediatric brain tumors: Comparison of models of dose characteristics and their relationship to cognitive function. Pediatr. Blood Cancer 2008; 51: 110– 17. 11 Oshiro Y, Mizumoto M, Okumura T et al. Clinical results of proton beam therapy for advanced neuroblastoma. Radiat. Oncol. 2013; 8: 142. 12 Mizumoto M, Tsuboi K, Igaki H et al. Phase I/II trial of hyperfractionated concomitant boost proton radiotherapy for supratentorial glioblastoma multiforme. Int. J. Radiat. Oncol. Biol. Phys. 2010; 77: 98–105. 13 Oshiro Y, Mizumoto M, Okumura T et al. Results of proton beam therapy without concurrent chemotherapy for patients with unresectable stage III non-small cell lung cancer. J. Thorac. Oncol. 2012; 7: 370–75. 14 Mizumoto M, Okumura T, Hashimoto T et al. Proton beam therapy for hepatocellular carcinoma: A comparison of three treatment protocols. Int. J. Radiat. Oncol. Biol. Phys. 2011; 81: 1039–45.
571
15 Mizumoto M, Sugahara S, Okumura T et al. Hyperfractionated concomitant boost proton beam therapy for esophageal carcinoma. Int. J. Radiat. Oncol. Biol. Phys. 2011; 81: e601–606. 16 Mizumoto M, Sugahara S, Nakayama H et al. Clinical results of proton-beam therapy for locoregionally advanced esophageal cancer. Strahlenther. Onkol. 2010; 186: 482–8. 17 Mizumoto M, Okumura T, Ishikawa E et al. Reirradiation for recurrent malignant brain tumor with radiotherapy or proton beam therapy. Strahlenther. Onkol. 2013; 189: 656–63. 18 Gerweck LE, Kozin SV. Relative biological effectiveness of proton beams in clinical therapy. Radiother. Oncol. 1999; 50: 135–42. 19 Paganetti H, Niemierko A, Ancukiewicz M et al. Relative biological effectiveness (RBE) values for proton beam therapy. Int. J. Radiat. Oncol. Biol. Phys. 2002; 53: 407–21. 20 Oshiro Y, Okumura T, Mizumoto M et al. Proton beam therapy for unresectable hepatoblastoma in children: Survival in one case. Acta Oncol. 2013; 52: 600–3. 21 Kanemoto A, Oshiro Y, Sugahara S et al. Proton beam therapy for inoperable recurrence of bronchial high-grade mucoepidermoid carcinoma. Jpn J. Clin. Oncol. 2012; 42: 552–5. 22 Mizumoto M, Hashii H, Senarita M et al. Proton beam therapy for malignancy in Bloom syndrome. Strahlenther. Onkol. 2013; 189: 335–8. 23 MacDonald SM, Safai S, Trofimov A et al. Proton radiotherapy for childhood ependymoma: Initial clinical outcomes and dose comparisons. Int. J. Radiat. Oncol. Biol. Phys. 2008; 71: 979–86. 24 Miralbell R, Lomax A, Cella L, Schneider U. Potential reduction of the incidence of radiation-induced second cancers by using proton beams in the treatment of pediatric tumors. Int. J. Radiat. Oncol. Biol. Phys. 2002; 54: 824–9.
© 2015 Japan Pediatric Society
Pediatrics International (2015) 57, 567–571
doi: 10.1111/ped.12624
Original Article
Proton beam therapy for pediatric ependymoma Masashi Mizumoto,1 Yoshiko Oshiro,1,4 Daichi Takizawa,1 Takashi Fukushima,2 Hiroko Fukushima,2 Tetsuya Yamamoto,3 Ai Muroi,3 Toshiyuki Okumura,1 Koji Tsuboi1 and Hideyuki Sakurai1 Departments of 1Radiation Oncology, 2Pediatrics and 3Neurosurgery, Tsukuba University and 4Department of Radiation Oncology, Tsukuba Medical Center Hospital, Tsukuba, Japan Abstract
Background: The aim of this study was to evaluate the efficacy of proton beam therapy for pediatric patients with ependymoma. Methods: Proton beam therapy was conducted for six patients (three boys and three girls; age, 2–6 years; median, 5 years) with ependymoma. The tumors were WHO grades 2 and 3 in two and four patients, respectively. All patients underwent surgery (subtotal and gross total resection in three patients each) and proton beam therapy at doses of 50.4–61.2 GyE (median, 56.7 GyE). The mean doses to normal brain tissue in proton beam therapy and photon radiotherapy were simulated using the same treatment planning computed tomography images. Results: All patients completed the planned irradiation. The follow-up period was 13–44 months (median, 24.5 months) from completion of proton beam therapy and all patients were alive at the end of this period. Local recurrence in the treatment field occurred in one patient at 4 months after proton beam therapy at 50.4 GyE. Alopecia and mild dermatitis occurred in all patients, but there was no severe toxicity. One patient had a once-off seizure after proton beam therapy and alopecia persisted in another patient for 31 months, but no patients had difficulty with daily life. The simulation showed that proton beam therapy reduces the dose to normal brain tissue by approximately half compared with photon radiotherapy. Conclusions: Proton beam therapy for pediatric ependymoma is safe, does not have specific toxicities, and can reduce irradiation of normal brain tissue.
Key words brain, ependymoma, pediatric, proton beam therapy, radiotherapy.
Intracranial ependymoma accounts for approximately 10% of all intracranial tumors in children1 and has a 5 year survival rate of 50–80%.2–6 Surgery followed by postoperative radiotherapy using doses 54–59.4 Gy is a common treatment strategy for intracranial ependymoma in children.3,5,6 Postoperative radiotherapy may contribute to improved survival, but late toxicity of the brain may impair intellectual development and compromise quality of life. Merchant et al. showed that intelligence quotient (IQ) is significantly associated with age and the fractional dose volume received over specific intervals (e.g. V0–20, V20–40, V40–65 Gy), and that radiation dosimetry can be used to predict IQ after conformal radiotherapy in patients with ependymoma.7–9 Another report showed that IQ after radiotherapy is significantly associated with the mean dose to normal brain tissue.10 Recent technological advances in radiotherapy have made it possible to largely avoid irradiation of normal brain tissue while maintaining delivery of an adequate dose to the target volume. Proton beam therapy is particularly likely to have an important role in the treatment of pediatric intracranial tumors because of its physical advantage of dose concentration. We have previously Correspondence: Masashi Mizumoto, MD, Proton Medical Research Center, University of Tsukuba, Tennoudai, Tsukuba, Ibaraki 305-8575, Japan. Email: [email protected] Received 16 May 2014; revised 12 December 2014; accepted 8 January 2015.
© 2015 Japan Pediatric Society
described the treatment outcomes of proton beam therapy for various tumors.11–17 In this report, we evaluate the use of proton beam therapy for pediatric intracranial ependymoma and estimate the mean dose to normal brain tissue compared with conformal radiotherapy.
Methods Patients
The subjects were six patients with ependymoma who were treated with proton beam therapy from January 2009 to December 2012. The patients were three boys and three girls, and ranged in age from 2 to 6 years old (median, 5 years). The tumors were grade 2 and grade 3 in two and four patients, respectively, using the WHO classification, and had supratentorial and infratentorial locations in three patients each. All patients underwent surgery and chemotherapy, with subtotal resection and gross total resection conducted in three patients each. The duration from surgery to proton beam therapy was 20–87 days (median, 50 days). The doses of proton beam therapy ranged from 50.4 to 61.2 GyE (median, 56.7 GyE). Proton beam therapy
All patients received proton beam therapy after surgery. Treatment planning for proton beam therapy involved use of computed
Comparison with conformal radiotherapy
Time from surgery (days) 48 52 49 87 20 57
Total dose (GyE) 50.4 61.2 54.0 50.4 59.4 61.2
CTV1 (cm3)
To evaluate the merits of proton beam therapy compared with conformal radiotherapy, we prepared a treatment plan for conformal radiotherapy using the same treatment planning CT images, with the goal of evaluating the mean dose to normal brain tissue at the same dose for the clinical target volume. To evaluate late brain toxicity, the change in IQ was evaluated using the predictive model proposed by Merchant et al.,8 in which the decrease in IQ is proportional to the mean dose received by all normal brain tissue: IQ = 93.11 + (0.028 × age − 0.0095 × mean dose to normal brain tissue) × time.
Results
© 2015 Japan Pediatric Society
Fourth ventricle Fourth ventricle Cerebellar-pontine angle Left frontal lobe Left parietal lobe Left occipital lobe II III III II III III M M M F F F 6 5 6 2 3 4
Sex Age (years)
Assuming that 2 Gy is delivered to the clinical target volume, the mean normal brain dose of proton beam therapy was 0.11–0.69 GyE (median, 0.23 GyE) and that of conformal radiotherapy was 0.25–0.97 Gy (median, 0.41 Gy). Thus, use of proton beam therapy reduced the mean normal brain dose by 28–64%
Patient ID no.
Comparison of proton beam therapy with photon radiotherapy
Table 1 Patient background
As of May 2013, all patients were alive and the median follow-up period was 24.5 months (range, 13–44 months). The median treatment period was 50 days (range, 43–59 days). One patient (patient 1) had local recurrence at 4 months after proton beam therapy and the other five patients had no recurrence at 13–35 months (median, 20 months). In the recurrent case, the tumor was adjacent to the brainstem and thus a minimum treatment margin of 5 mm and irradiation dose of 50.4 GyE were selected. The clinical courses of the six patients are listed in Table 1.
Tumor (grade)
Local control and overall survival
1 2 3 4 5 6
Location
Surgery
Acute treatment-related toxicities were generally mild, with three and one patients developing acute dermatitis of grades 1 and 2, respectively, and all patients having alopecia. Regarding late toxicity, one patient had a one-time seizure after proton beam therapy, and alopecia was prolonged in another patient for 35 months. Radiation necrosis, white matter changes, volume loss, cystic changes and vascular problems were not found at the last follow up, and no patients had difficulties with daily life.
Total resection Subtotal resection Total resection Total resection Subtotal resection Subtotal resection
Toxicity
†Assuming that 2 Gy is delivered to the CTV. ‡(Mean dose to normal brain tissue using conformal radiotherapy – mean dose to normal brain tissue using proton beam therapy)/mean dose to normal brain tissue using conformal radiotherapy. CRT, conformal radiotherapy; CTV, clinical target volume; PBT, proton beam therapy.
Overall survival (months) 44 26 20 13 35 23
Mean dose to brain (CRT)† 0.25 0.31 0.45 0.36 0.63 0.97
Mean dose to brain (PBT)† 0.11 0.17 0.29 0.13 0.31 0.69
Reduction ratio‡ (%)
tomography (CT) at 3 mm intervals around the treatment location. Proton beams of 250 MeV were generated by a booster synchrotron at the Proton Medical Research Center. The treatment planning system provided dose distributions and settings for the collimator configuration, bolus, and range-shifter thickness. The relative biological effectiveness of the proton beam therapy was assumed to be 1.1.18,19 The clinical target volume was defined as the area of contrast enhancement on magnetic resonance imaging and the tumor bed plus an adequate margin. The margin for the clinical target volume was initially 8–10 mm, and was reduced to 5 mm after 45–54 GyE. The dose of proton beam therapy was 50.4 GyE in 28 fractions to 61.2 GyE in 34 fractions. The optic chiasm was avoided from 40 GyE and the brainstem was avoided from 50 GyE.
59 43 36 64 51 28
M Mizumoto et al.
11.4 16.4 83.2 10.4 47.0 134.7
568
PBT for pediatric ependymoma
a
b
c
d
569
Fig. 1 Treatment planning for (a,c) proton beam therapy and (b,d) conformal radiotherapy in patients (a,b) 4 and (c,d) 6.
(median, 47%) compared with conformal radiotherapy (Table 1). Using the predictive model,8 IQ at 10 years after proton beam therapy was calculated to deteriorate from 0 to 17.7 points (median, 5.4 points), while that after radiotherapy deteriorates from 0 to 27.3 points (median, 10.7 points). The treatment plan for proton beam therapy and conformal radiotherapy using the same treatment planning CT for patient 4 (Table 1) is shown in Figure 1(a,b). This patient had left frontal lobe ependymoma and received postoperative proton beam therapy (Fig. 1a). The conformal radiotherapy plan (Fig. 1b) included selection of the optimal angle to avoid normal brain tissue as much as possible. In this case, the tumor was small (10.4 cm3) and was located near the surface of skull, which allowed proton beam therapy to be used with avoidance of a large part of the normal brain volume (non-irradiated area in Fig. 1a). Confor-
mal radiotherapy could cover the tumor similarly to proton beam therapy, but the normal brain beyond the tumor was included in the 40–50% isodose line (Fig. 1b). In this case, use of proton beam therapy reduced the mean normal brain dose by 64%. The treatment plan for proton beam therapy and conformal radiotherapy using the same treatment planning CT for patient 6 (Table 1) is shown in Figure 1(c,d). This patient had left occipital lobe ependymoma that reached the ventricle from the surface of the brain. Postoperative proton beam therapy was performed (Fig. 1c). The conformal radiotherapy plan (Fig. 1d) included selection of the optimal angle to avoid normal brain tissue as much as possible. In this case, the tumor was large (134.7 cm3) and the normal brain outside the irradiated area was avoided in proton beam therapy (non-irradiated area in Fig. 1c). In contrast, the 50% isodose line covered the normal brain beyond the tumor © 2015 Japan Pediatric Society
570
M Mizumoto et al.
in conformal radiotherapy (Fig. 1d) and only a small volume of normal brain tissue was included in the non-irradiated area. In this case, use of proton beam therapy reduced the mean normal brain dose by 28%. For patients 4 and 6, the dose at the surface near the tumor with proton beam therapy was almost the same as the dose in the clinical target volume (area within red isodose lines in Fig. 1a,c).
Discussion Postoperative radiotherapy 50–60 Gy is standard treatment for pediatric ependymoma and results in a 5 year survival rate of 50–80%.2–6 In this report, all patients were alive at a median of 24.5 months after radiotherapy and five of six patients were well controlled. Local recurrence in one case was probably caused by an insufficient irradiation dose. This occurred because the tumor was adhered to the brainstem, and thus we selected a minimum treatment margin on the brainstem side, which led to the dose not completely covering the tumor. The small number of patients and short follow-up period prevent further evaluation of the treatment efficacy of proton beam therapy. Acute toxicities were generally mild, but alopecia was prolonged in one patient for 35 months. This may be because proton beams do not have a build-up effect and doses at the skin surface are higher than those in photon radiotherapy when the target is located near the surface (Fig. 1). Also, proton beam therapy was mainly delivered from two directions, so the skin near the tumor bed may receive the same dose as the tumor (Fig. 1a,c). Thus, prolonged alopecia may occur at increased frequency with proton beam therapy compared with photon radiotherapy. Proton beam therapy has some advantages in terms of late toxicity due to reduction of the dose to vital organs.20–22 Macdonald et al. found that preliminary disease control in childhood ependymoma was favorable with proton beam therapy, and that proton beam therapy spared normal tissue compared to intensity moderated radiotherapy.23 Miralbell et al. reported a reduced incidence of radiation-induced secondary cancer after use of proton beams in pediatric patients with rhabdomyosarcoma and medulloblastoma.24 In the present simulation (Fig. 1), the nonirradiated area of normal brain tissue was larger with proton beam therapy compared with that for photon radiotherapy, which suggests that proton beam therapy may reduce the risk of secondary cancer in treatment of ependymoma. Merchant et al. compared proton beam therapy and photon radiotherapy for common pediatric brain tumors and developed a model for predicting IQ after radiotherapy (noted herein), in which the decrease of IQ after radiotherapy is proportional to the mean dose to normal brain tissue.10 In the present patients, this dose was reduced by 28–64% (median, 47%) using proton beam therapy compared with photon radiotherapy. Thus, if the decrease of IQ after radiotherapy is proportional to the mean dose to normal brain tissue, proton beam therapy may reduce the reduction in IQ by approximately half compared with photon radiotherapy. We note, however, that the Merchant et al. model was calculated based on radiotherapy for medulloblastoma, including whole brain radiation, and thus the relationship between IQ reduction and the mean dose to normal brain tissue is unclear in © 2015 Japan Pediatric Society
treatment of ependymoma. Merchant et al. also showed that radiation dosimetry can be used to predict IQ after photon radiotherapy in 88 patients with localized pediatric ependymoma who received conformal radiotherapy (54–59.4 Gy) with a 1 cm margin on the postoperative tumor bed.8 A negative effect on IQ occurred when the dose to normal brain tissue was 0–20 Gy or 40–65 Gy, but a positive effect was observed when this dose was 20–40 Gy. These results may indicate that IQ after radiotherapy is not simply proportional to the mean dose to normal brain tissue and that maximization of the effects of proton beam therapy requires a further study on the influence of irradiation on normal brain tissue. A disadvantage of proton beam therapy is the high cost of the treatment facility. In Japan, 2 500 000–3 000 000 JPY is needed per treatment, and parents may struggle with the heavy burden of this medical expense. For this reason, it is important to select patients in whom proton beam therapy will be particularly advantageous to justify the cost of the treatment. The risk of late toxicity caused by radiotherapy is likely to increase over time and is higher for young patients. Therefore, younger patients with a good prognosis are priorities for proton beam therapy. Conclusion
Proton beam therapy was performed for six pediatric patients with ependymoma. Proton beam therapy may reduce the dose to normal brain tissue by approximately half compared with conformal radiotherapy.
Acknowledgments This work was supported in part by Grant-in-Aid for Scientific Research (B) (24390286), Challenging Exploratory Research (24659556), Young Scientists (B) (25861064), Scientific Research (C) (24591832) from the Ministry of Education, Science, Sports and Culture of Japan. None of the authors have any actual or potential conflicts of interest regarding the work in this study.
References 1 CBTRUS. Statistical report: Primary brain tumors in the United States, 2004–2006. Central Brain Tumor Registry of the United States, Hinsdale, IL, 2010. 2 Merchant TE, Mulhern RK, Krasin MJ et al. Preliminary results from a phase II trial of conformal radiation therapy and evaluation of radiation-related CNS effects for pediatric patients with localized ependymoma. J. Clin. Oncol. 2004; 22: 3156–62. 3 Landau E, Boop FA, Conklin HM, Wu S, Xiong X, Merchant TE. Supratentorial ependymoma: Disease control, complications, and functional outcomes after irradiation. Int. J. Radiat. Oncol. Biol. Phys. 2013; 85: e193–199. 4 Conter C, Carrie C, Bernier V et al. Intracranial ependymomas in children: Society of Pediatric Oncology experience with postoperative hyperfractionated local radiotherapy. Int. J. Radiat. Oncol. Biol. Phys. 2009; 74: 1536–42. 5 Merchant TE, Li C, Xiong X, Kun LE, Boop FA, Sanford RA. Conformal radiotherapy after surgery for paediatric ependymoma: A prospective study. Lancet Oncol. 2009; 10: 258–66. 6 Koshy M, Rich S, Merchant TE, Mahmood U, Regine WF, Kwok Y. Post-operative radiation improves survival in children younger than 3 years with intracranial ependymoma. J. Neurooncol. 2011; 105: 583–90.
PBT for pediatric ependymoma 7 Conklin HM, Li C, Xiong X, Ogg RJ, Merchant TE. Predicting change in academic abilities after conformal radiation therapy for localized ependymoma. J. Clin. Oncol. 2008; 26: 3965–70. 8 Merchant TE, Kiehna EN, Li C, Xiong X, Mulhern RK. Radiation dosimetry predicts IQ after conformal radiation therapy in pediatric patients with localized ependymoma. Int. J. Radiat. Oncol. Biol. Phys. 2005; 63: 1546–54. 9 Netson KL, Conklin HM, Wu S, Xiong X, Merchant TE. A 5-year investigation of children’s adaptive functioning following conformal radiation therapy for localized ependymoma. Int. J. Radiat. Oncol. Biol. Phys. 2012; 84: 217–23. 10 Merchant TE, Hua CH, Shukla H, Ying X, Nill S, Oelfke U. Proton versus photon radiotherapy for common pediatric brain tumors: Comparison of models of dose characteristics and their relationship to cognitive function. Pediatr. Blood Cancer 2008; 51: 110– 17. 11 Oshiro Y, Mizumoto M, Okumura T et al. Clinical results of proton beam therapy for advanced neuroblastoma. Radiat. Oncol. 2013; 8: 142. 12 Mizumoto M, Tsuboi K, Igaki H et al. Phase I/II trial of hyperfractionated concomitant boost proton radiotherapy for supratentorial glioblastoma multiforme. Int. J. Radiat. Oncol. Biol. Phys. 2010; 77: 98–105. 13 Oshiro Y, Mizumoto M, Okumura T et al. Results of proton beam therapy without concurrent chemotherapy for patients with unresectable stage III non-small cell lung cancer. J. Thorac. Oncol. 2012; 7: 370–75. 14 Mizumoto M, Okumura T, Hashimoto T et al. Proton beam therapy for hepatocellular carcinoma: A comparison of three treatment protocols. Int. J. Radiat. Oncol. Biol. Phys. 2011; 81: 1039–45.
571
15 Mizumoto M, Sugahara S, Okumura T et al. Hyperfractionated concomitant boost proton beam therapy for esophageal carcinoma. Int. J. Radiat. Oncol. Biol. Phys. 2011; 81: e601–606. 16 Mizumoto M, Sugahara S, Nakayama H et al. Clinical results of proton-beam therapy for locoregionally advanced esophageal cancer. Strahlenther. Onkol. 2010; 186: 482–8. 17 Mizumoto M, Okumura T, Ishikawa E et al. Reirradiation for recurrent malignant brain tumor with radiotherapy or proton beam therapy. Strahlenther. Onkol. 2013; 189: 656–63. 18 Gerweck LE, Kozin SV. Relative biological effectiveness of proton beams in clinical therapy. Radiother. Oncol. 1999; 50: 135–42. 19 Paganetti H, Niemierko A, Ancukiewicz M et al. Relative biological effectiveness (RBE) values for proton beam therapy. Int. J. Radiat. Oncol. Biol. Phys. 2002; 53: 407–21. 20 Oshiro Y, Okumura T, Mizumoto M et al. Proton beam therapy for unresectable hepatoblastoma in children: Survival in one case. Acta Oncol. 2013; 52: 600–3. 21 Kanemoto A, Oshiro Y, Sugahara S et al. Proton beam therapy for inoperable recurrence of bronchial high-grade mucoepidermoid carcinoma. Jpn J. Clin. Oncol. 2012; 42: 552–5. 22 Mizumoto M, Hashii H, Senarita M et al. Proton beam therapy for malignancy in Bloom syndrome. Strahlenther. Onkol. 2013; 189: 335–8. 23 MacDonald SM, Safai S, Trofimov A et al. Proton radiotherapy for childhood ependymoma: Initial clinical outcomes and dose comparisons. Int. J. Radiat. Oncol. Biol. Phys. 2008; 71: 979–86. 24 Miralbell R, Lomax A, Cella L, Schneider U. Potential reduction of the incidence of radiation-induced second cancers by using proton beams in the treatment of pediatric tumors. Int. J. Radiat. Oncol. Biol. Phys. 2002; 54: 824–9.
© 2015 Japan Pediatric Society
