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Proton beam therapy for olfactory neuroblastoma
Radiotherapy and Oncology xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Radiotherapy and Oncology journal homepage: www.thegreenjournal.com
Original article
Proton beam therapy for olfactory neuroblastoma Naoki Nakamura a,⇑, Sadamoto Zenda a, Makoto Tahara b, Susumu Okano b, Ryuichi Hayashi c, Hidehiro Hojo a, Kenji Hotta a, Satoe Kito a, Atsushi Motegi a, Satoko Arahira a,d, Hidenobu Tachibana a, Tetsuo Akimoto a a d
Division of Radiation Oncology and Particle Therapy; b Division of Head and Neck Surgery; c Division of Head and Neck Oncology, National Cancer Center Hospital East; and Department of Radiation Oncology, Kanto Rosai Hospital, Kawasaki, Japan
a r t i c l e
i n f o
Article history: Received 11 July 2016 Received in revised form 27 November 2016 Accepted 19 December 2016 Available online xxxx Keywords: Olfactory neuroblastoma Proton beam therapy Nasal cavity Craniofacial surgery Reirradiation
a b s t r a c t Purpose: To clarify the efficacy and feasibility of proton beam therapy (PBT) for olfactory neuroblastoma (ONB). Methods and materials: We retrospectively reviewed 42 consecutive patients who received PBT with curative intent for ONB at National Cancer Center Hospital East from November 1999 to March 2012. Results: Five patients (12%) had Kadish A disease, nine (21%) had Kadish B, and twenty-eight (67%) had Kadish C. All patients except one received a total dose of 65 Gy (relative biological effectiveness: RBE) in 26 fractions. Twenty-four patients (57%) received induction and/or concurrent chemotherapy. The median follow-up for all eligible patients was 69 months (7–186). The 5-year overall survival (OS) and progression-free survival (PFS) rates were 100% and 80% for Kadish A, 86 and 65% for Kadish B, and 76% and 39% for Kadish C, respectively. The sites of the first progression were local in six patients (30%), regional in eight (40%), distant in two (10%), local and regional in two (10%), and local and distant in two (10%). Late adverse events of grade 3–4 were seen in six patients (ipsilateral visual impairment, 3; bilateral visual impairment, 1; liquorrhea, 1; cataract, 1). Conclusion: PBT was a safe and effective modality for ONB. Ó 2016 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology xxx (2017) xxx–xxx
Olfactory neuroblastoma (ONB) is a rare malignant neoplasm of the nasal cavity, believed to arise from the olfactory epithelium [1]. Because of its rarity, a standard treatment strategy has not been established. Radiotherapeutic management for ONB is challenging because of its proximity to organs at risk (OAR), such as the anterior visual pathway or brain stem [2–8]. Proton beam therapy (PBT) can provide a better dose distribution compared with conventional X-ray treatment because of its physical characteristics [9]. Therefore, PBT may facilitate curative high-dose irradiation of the tumor, without increasing normal tissue toxicity [10,11]. In our institution, we recommended the treatment modality according to the stage classification based on Kadish et al. [12]. For patients with Kadish A, which is limited to the nasal cavity, single modality treatment by surgery or PBT is recommended. For those with Kadish B, which extends to the paranasal sinus, concurrent therapy of PBT and chemotherapy is recommended. For those with Kadish C, which extends beyond the paranasal sinus, induction chemotherapy followed by concurrent therapy of PBT and chemotherapy is ⇑ Corresponding author at: Divison of Radiation Oncology and Particle Therapy, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba 2778577, Japan. E-mail address: [email protected] (N. Nakamura).
recommended. There are multiple reasons why we recommend induction chemotherapy for Kadish C: (1) to reduce the intracranial irradiated volume and risk of radiation brain injury, (2) expecting the reduction of distant metastases, and (3) to quickly start treatment. For those with Kadish D, which is accompanied by cervical lymph node or distant metastases, curative treatment is not usually recommended. We previously reported clinical outcomes following PBT for ONB in our institution in 2007 [13]. To further examine the efficacy and feasibility of PBT for ONB, we provide an update of our experience.
Methods and materials Patient identification We identified 42 consecutive patients who received PBT with curative intent for ONB at National Cancer Center Hospital East from November 1999 to March 2012. With the approval of our Institutional Review Board, we performed a retrospective chart review of patient characteristics, treatments, and clinical outcomes.
http://dx.doi.org/10.1016/j.radonc.2016.12.020 0167-8140/Ó 2016 Elsevier Ireland Ltd. All rights reserved.
Please cite this article in press as: Nakamura N et al. Proton beam therapy for olfactory neuroblastoma. Radiother Oncol (2017), http://dx.doi.org/10.1016/j. radonc.2016.12.020
2
PBT for olfactory neuroblastoma
Treatments All patients received passive PBT. The clinical target volume (CTV) typically included the gross tumor volume and adjacent sinus. The planning target volume (PTV) was set by isotropically expanding the CTV by 2 mm. To avoid late toxicity, we determined the dose constraints for OAR as follows: <64 Gy (relative biological effectiveness: RBE) for the surface of the brainstem, <53 Gy (RBE) for the center of the brainstem, <60 Gy (RBE) for the optic nerves and optic chiasm, and <13 Gy (RBE) for the optic lenses. The dose was prescribed at the isocenter. A dose distribution and dose–volume histogram for typical treatment planning is shown in Figs. 1 and 2.
Results Patient characteristics The median follow-up for all eligible patients was 69 months (7–186). Patient characteristics are shown in Table 1. For induction chemotherapy, a regimen comprising three agents (cisplatin, S-1, and docetaxel) [15,16] was used for twelve patients. A nonplatinum-based regimen with irinotecan and docetaxel was used for six patients [17]. Other regimens used were cisplatin and etoposide for one patient, cisplatin, etoposide, and adriamycin for one patient, cisplatin, docetaxel, and adriamycin for one patient, and cisplatin, etoposide, Adriamycin, and vincristine for one patient. For concurrent chemotherapy, a single cisplatin regimen was used except for one patient who received a regimen with irinotecan and docetaxel.
Endpoints and statistical analysis As clinical outcomes, overall survival (OS), progression-free survival (PFS), the site of the first progression, and adverse effects were evaluated. The response to induction chemotherapy was assessed using the Response Evaluation Criteria in Solid Tumors (RECIST). Adverse effects were evaluated by the chart review and graded based on the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. Non-hematological adverse effects of grade 3 or higher were collected. Adverse effects that occurred within 3 months from the start of PBT were regarded as acute adverse effects, while those that occurred after 3 months were regarded as late adverse effects. We used EZR [14] version 1.27 for statistical analysis. Time analysis was calculated from the day when induction chemotherapy began for patients who received induction chemotherapy, and from the day when PBT began for the others. Fisher’s exact test was used to determine the significance of intergroup differences in discontinuous variables, and the independent t-test was used for continuous variables. Survival probabilities were estimated using the Kaplan–Meyer method, and comparisons of survival according to clinical parameters were performed using the log-rank test. Differences were deemed significant when two-tailed p-values were less than 0.05.
Survival The 5-year OS and PFS rates were 100% and 80% for Kadish A, 86% and 65% for Kadish B, and 76% and 39% for Kadish C, respectively (Fig. 2). OS and PFS according to the age are shown in Figs. 3 and 4. Patients who were younger than 50 years showed significantly better OS than those who were 50 years or older (p = 0.01) (Supplementary Fig. 1). However, PFS was not significantly different between the two groups (p = 0.34) (Supplementary Fig. 2). Patient characteristics according to age are summarized in Supplementary Table 1. Among 28 Kadish C patients, eight did not receive chemotherapy because of comorbidities, old age, or patient’s refusal. Among twenty patients who received induction chemotherapy, nine patients received concurrent chemotherapy, while eleven patients did not receive it because of a poor response to induction chemotherapy, severe adverse effects, or patient’s refusal. The response to induction chemotherapy was a complete response in one patient (5%), partial response in five (25%), stable disease in eleven (55%), and progressive disease in three patients (15%). OS and PFS according to the usage of chemotherapy in Kadish C
PTV
CTV
GTV
62 60 50 40 20
Gy Gy Gy Gy Gy
(RBE) (RBE) (RBE) (RBE) (RBE)
Fig. 1. Dose distribution for typical treatment planning. Abbreviations: GTV = gross tumor volume; CTV = clinical target volume; PTV = planning target volume; RBE = relative biological effectiveness.
Please cite this article in press as: Nakamura N et al. Proton beam therapy for olfactory neuroblastoma. Radiother Oncol (2017), http://dx.doi.org/10.1016/j. radonc.2016.12.020
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N. Nakamura et al. / Radiotherapy and Oncology xxx (2017) xxx–xxx
Fig. 2. Dose–volume histogram for the treatment planning indicated in Fig. 1. Abbreviations: GTV = gross tumor volume; CTV = clinical target volume; PTV = planning target volume; RBE = relative biological effectiveness.
Table 1 Patient characteristics. Factor
Number of patients
Median age (range)
51 years (20–87)
Sex
Female Male
25 (60%) 17 (40%)
Stage by Kadish et al. [12]
A B C
5 (12%) 9 (21%) 28 (67%)
Chemotherapy
None Induction Concurrent Induction and concurrent
18 (43%) 13 (31%) 2 (5%) 9 (21%)
Median CTV dimension (range)
118 ml (31–288)
Median PTV dimension (range)
152 ml (45–333)
Dose fractionation
41 (98%) 1 (2%)
65 Gy (RBE) in 26 70 Gy (RBE) in 35
CTV: clinical target volume, PTV: planning target volume, RBE: relative biological effectiveness.
patients are shown in Supplementary Figs. 3 and 4. No significant differences were seen in OS (p = 0.44) or PFS (p = 0.63). Recurrent sites and salvage treatments Until the last follow-up, disease progression was noted in 20 patients (48%). The sites of the first progression are shown in Fig. 5. Salvage treatments are summarized in Table 2. Of the ten patients who had local recurrence, all five patients who were younger than 50 years received aggressive local salvage treatment (craniofacial surgery or reirradiation), while none of the five patients who were 50 years or older received aggressive local salvage treatment. Adverse effects As acute adverse effects, grade 3 mucositis was seen in four patients (10%) and grade 3 dermatitis was seen in one patient (2%). No grade 4–5 acute adverse effects were noted.
Overall survival
100%
Kadish A
80%
Kadish B
60%
Kadish C
40% 20%
0
Number at risk 5 Kadish A 9 Kadish B 28 Kadish C
Kadish A vs. B: p = 0.40 Kadish A vs. C: p = 0.15 Kadish B vs. C: p = 0.35
2 5 8 21
4 Years 6
8
10
5 5 15
4 4 5
4 3 2
5 4 11
Fig. 3. Overall survival according to the stage based on Kadish et al. [12].
As late adverse effects, bilateral grade 4 visual impairment was observed in one patient (2%). Ipsilateral grade 3 and 4 visual impairment was seen in one (2%) and two patients (5%), respectively. Among four patients who experienced ipsilateral or bilateral grade 3 or 4 visual impairment, three had Kadish C disease, while one had Kadish A disease. Grade 3 ipsilateral cataract was noted in one patient (2%). Grade 4 liquorrhea was observed in one patient (2%), who had Kadish C disease widely destroying the skull base. No grade 3 or higher brain necrosis was found. Discussion To our knowledge, this is the largest report of PBT for ONB [13,18–20]. The optimal treatment for patients with ONB has not been established in randomized clinical trials due to its rarity. Radiotherapy (RT) alone has been reported to lead to unsatisfactory outcomes [2–6]. Benfari et al. reported 55 ONB patients trea-
Please cite this article in press as: Nakamura N et al. Proton beam therapy for olfactory neuroblastoma. Radiother Oncol (2017), http://dx.doi.org/10.1016/j. radonc.2016.12.020
4
PBT for olfactory neuroblastoma
Progression-free survival
100% Kadish A
80%
Kadish B 60% Kadish C
40% 20%
Kadish A vs. B: p = 0.29 Kadish A vs. C: p = 0.14 Kadish B vs. C: p = 0.56
0
2
Number at risk 5 Kadish A 9 Kadish B 28 Kadish C
4 Years 6
4 7 17
4 3 10
4 1 5
8
10
3 1 2
3 0 0
Fig. 4. Progression free survival according to the stage based on Kadish et al. [12].
Local 6 (1/1/4) 2 (0/0/2)
2 (0/1/1)
Regional
Distant 2 (0/0/2)
8 (0/2/6)
Fig. 5. Sites of the first progression. Numbers indicate total numbers (numbers among Kadish A/B/C).
ted with RT alone. The mean follow-up period was 56 months (range: 2–216) [2]. The mean radiotherapy dose was 55.1 Gy (range: 23.0–80.0). Local control was achieved in 6/6 (100%) Kadish A patients. However, local control for Kadish B and C patients was achieved in 7/12 (58%) and 7/37 (19%), respectively. Therefore, the
mainstay of the treatment is surgery. Multiple observational studies found that craniofacial surgery improved the ability to achieve en bloc resection and improved progression-free and overall survival compared with a transfacial approach [1,21–23]. Furthermore, observational studies indicated that combining surgery and RT resulted in prolonged survival compared with surgery or RT alone, except in selected patients with Kadish A [22,24–30]. A recent international collaborative study involving 17 centers reported the outcomes following craniofacial resection with or without RT for 149 patients [31]. The 5-year OS was 97% for Kadish A/B and 73% for Kadish C, being similar to our results. More favorable OS was noted in the younger subgroup in spite of a similar stage distribution. PFS was not significantly better in the younger subgroup. A marked difference was noted in the salvage treatment for local recurrence between the younger and older groups. It is possible that the difference in local salvage treatment after recurrence may result in the improved OS. Our results support aggressive salvage treatment including craniofacial surgery or reirradiation for local recurrence. Our results also suggest that many patients do not need to receive invasive surgery if they initially receive PBT. We failed to show the survival benefit of chemotherapy even in Kadish C patients. The small number of patients in this study may make it difficult to prove the existing survival advantage. Chemotherapy may decrease the chances of systemic failure by acting on systemic micro metastases like head and neck squamous cell carcinoma [32]. A retrospective study by Porter et al. identified twelve Kadish C patients with full surgical resection. Six of these patients received adjuvant chemotherapy, and six did not. The median time to relapse for patients who received and did not receive adjuvant chemotherapy was 35 and 10.5 months, respectively [33]. Furthermore, our institution recommends induction chemotherapy mainly because it can reduce the intracranial irradiated volume and risk of radiation brain injury. In our cohort, no grade 3 or more advanced brain necrosis was seen. In addition to the excellent dose distribution of PBT, induction chemotherapy might contribute to a decrease in adverse effects. Finally, chemotherapy can be administered earlier than PBT, which may lead to early symptom relief. Among the six grade 3–4 late adverse effects, three were ipsilateral optic problems. It may be acceptable to compromise the ipsilateral visual ability in order to increase the treatment intensity. Although one patient experienced bilateral grade 4 visual impairment, the low rates of acute and late severe adverse effects in our cohort suggest that our treatment strategy including PBT for ONB is feasible. This study is inevitably limited by its single institutional and retrospective nature. Nevertheless, the outcomes of our study offer some guidance to clinicians in an area where little evidence is available.
Table 2 Sites of the first progression and salvage treatments. Patients =50 years
Site
Salvage therapy
All patients
Patients <50 years
Local
Craniofacial surgery Chemotherapy Supportive care Reirradiation and neck dissection Supportive care Reirradiation and lung metastasectomy Supportive care Neck dissection Supportive care
3 1 2 1 1 1 1 8 2
3
5 1
1 3 1
20
11
9
Local and regional Local and distant Regional Distant Total
1 2 1 1 1
Please cite this article in press as: Nakamura N et al. Proton beam therapy for olfactory neuroblastoma. Radiother Oncol (2017), http://dx.doi.org/10.1016/j. radonc.2016.12.020
N. Nakamura et al. / Radiotherapy and Oncology xxx (2017) xxx–xxx
In conclusion, PBT was a safe and effective modality for ONB. In cases with local recurrence after PBT, aggressive salvage treatment including craniofacial surgery or reirradiation might be considered. Conflict of interest Dr. Tahara reports grants and personal fees from Ono Pharmaceutical, personal fees from Bristol-Myers Squibb, during the conduct of the study; personal fees from Merck Serono, grants and personal fees from Eisai, personal fees from Otsuka, grants and personal fees from Bayer, grants and personal fees from MSD, grants and personal fees from Astra Zeneca, grants and personal fees from Pfizer, grants from NanoCarrier, grants from Novartis, outside the submitted work. No other authors declare any conflict of interest. Acknowledgements This study was supported in part by Grants-in-Aid for Scientific Research (16K10412) from the Ministry of Education, Science and Culture of Japan, by Health Science Research Grants from the Ministry of Health and Welfare, and by the National Cancer Center Research and Development Fund (25-A-10 & 28-A-14). Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.radonc.2016.12. 020. References [1] Levine PA, McLean WC, Cantrell RW. Esthesioneuroblastoma: the University of Virginia experience 1960–1985. Laryngoscope 1986;96:742–6. [2] Benfari G, Fusconi M, Ciofalo A, et al. Radiotherapy alone for local tumour control in esthesioneuroblastoma. Acta Otorhinolaryngol Ital 2008;28:292–7. [3] Chao KS, Kaplan C, Simpson JR, et al. Esthesioneuroblastoma: the impact of treatment modality. Head Neck 2001;23:749–57. [4] Gruber G, Laedrach K, Baumert B, Caversaccio M, Raveh J, Greiner R. Esthesioneuroblastoma: irradiation alone and surgery alone are not enough. Int J Radiat Oncol Biol Phys 2002;54:486–91. [5] Kaur G, Kane AJ, Sughrue ME, et al. The prognostic implications of Hyam’s subtype for patients with Kadish stage C esthesioneuroblastoma. J Clin Neurosci 2013;20:275–80. [6] Slevin NJ, Irwin CJ, Banerjee SS, Gupta NK, Farrington WT. Olfactory neural tumours–the role of external beam radiotherapy. J Laryngol Otol 1996;110:1012–6. [7] McLean JN, Nunley SR, Klass C, Moore C, Muller S, Johnstone PA. Combined modality therapy of esthesioneuroblastoma. Otolaryngol Head Neck Surg 2007;136:998–1002. [8] Zenda S, Kawashima M, Arahira S, et al. Late toxicity of proton beam therapy for patients with the nasal cavity, para-nasal sinuses, or involving the skull base malignancy: importance of long-term follow-up. Int J Clin Oncol 2015;20:447–54. [9] Mock U, Georg D, Bogner J, Auberger T, Potter R. Treatment planning comparison of conventional, 3D conformal, and intensity-modulated photon (IMRT) and proton therapy for paranasal sinus carcinoma. Int J Radiat Oncol Biol Phys 2004;58:147–54.
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[10] Patel SH, Wang Z, Wong WW, et al. Charged particle therapy versus photon therapy for paranasal sinus and nasal cavity malignant diseases: a systematic review and meta-analysis. Lancet Oncol 2014;15:1027–38. [11] Zenda S, Kohno R, Kawashima M, et al. Proton beam therapy for unresectable malignancies of the nasal cavity and paranasal sinuses. Int J Radiat Oncol Biol Phys 2011;81:1473–8. [12] Kadish S, Goodman M, Wang CC. Olfactory neuroblastoma. A clinical analysis of 17 cases. Cancer 1976;37:1571–6. [13] Nishimura H, Ogino T, Kawashima M, et al. Proton-beam therapy for olfactory neuroblastoma. Int J Radiat Oncol Biol Phys 2007;68:758–62. [14] Kanda Y. Investigation of the freely available easy-to-use software ’EZR’ for medical statistics. Bone Marrow Transplant 2013;48:452–8. [15] Tahara M, Araki K, Okano S, et al. Phase I trial of combination chemotherapy with docetaxel, cisplatin and S-1 (TPS) in patients with locally advanced or recurrent/metastatic head and neck cancer. Ann Oncol 2011;22:175–80. [16] Okano S, Tahara M, Zenda S, et al. Induction chemotherapy with docetaxel, cisplatin and S-1 followed by proton beam therapy concurrent with cisplatin in patients with T4b nasal and sinonasal malignancies. Jpn J Clin Oncol 2012;42:691–6. [17] Kiyota N, Tahara M, Fujii S, et al. Nonplatinum-based chemotherapy with irinotecan plus docetaxel for advanced or metastatic olfactory neuroblastoma: a retrospective analysis of 12 cases. Cancer 2008;112:885–91. [18] Fitzek MM, Thornton AF, Varvares M, et al. Neuroendocrine tumors of the sinonasal tract. Results of a prospective study incorporating chemotherapy, surgery, and combined proton-photon radiotherapy. Cancer 2002;94:2623–34. [19] Bhattacharyya N, Thornton AF, Joseph MP, Goodman ML, Amrein PC. Successful treatment of esthesioneuroblastoma and neuroendocrine carcinoma with combined chemotherapy and proton radiation. Results in 9 cases. Arch Otolaryngol Head Neck Surg 1997;123:34–40. [20] Lucas Jr JT, Ladra MM, MacDonald SM, et al. Proton therapy for pediatric and adolescent esthesioneuroblastoma. Pediatr Blood Cancer 2015;62:1523–8. [21] Dulguerov P, Calcaterra T. Esthesioneuroblastoma: the UCLA experience 1970– 1990. Laryngoscope 1992;102:843–9. [22] Dulguerov P, Allal AS, Calcaterra TC. Esthesioneuroblastoma: a meta-analysis and review. Lancet Oncol 2001;2:683–90. [23] Nichols AC, Chan AW, Curry WT, Barker FG, Deschler DG, Lin DT. Esthesioneuroblastoma: the massachusetts eye and ear infirmary and massachusetts general hospital experience with craniofacial resection, proton beam radiation, and chemotherapy. Skull Base 2008;18:327–37. [24] Ward PD, Heth JA, Thompson BG, Marentette LJ. Esthesioneuroblastoma: results and outcomes of a single institution’s experience. Skull Base 2009;19:133–40. [25] Diaz Jr EM, Johnigan 3rd RH, Pero C, et al. Olfactory neuroblastoma: the 22year experience at one comprehensive cancer center. Head Neck 2005;27:138–49. [26] Bachar G, Goldstein DP, Shah M, et al. Esthesioneuroblastoma: the Princess Margaret Hospital experience. Head Neck 2008;30:1607–14. [27] Theilgaard SA, Buchwald C, Ingeholm P, Kornum Larsen S, Eriksen JG, Sand Hansen H. Esthesioneuroblastoma: a Danish demographic study of 40 patients registered between 1978 and 2000. Acta Otolaryngol 2003;123:433–9. [28] Foote RL, Morita A, Ebersold MJ, et al. Esthesioneuroblastoma: the role of adjuvant radiation therapy. Int J Radiat Oncol Biol Phys 1993;27:835–42. [29] Ozsahin M, Gruber G, Olszyk O, et al. Outcome and prognostic factors in olfactory neuroblastoma: a rare cancer network study. Int J Radiat Oncol Biol Phys 2010;78:992–7. [30] Tajudeen BA, Arshi A, Suh JD, St John M, Wang MB. Importance of tumor grade in esthesioneuroblastoma survival: a population-based analysis. JAMA Otolaryngol Head Neck Surg 2014;140:1124–9. [31] Patel SG, Singh B, Stambuk HE, et al. Craniofacial surgery for esthesioneuroblastoma: report of an international collaborative study. J Neurol Surg B Skull Base 2012;73:208–20. [32] Pignon JP, le Maitre A, Maillard E, Bourhis J, Group M-NC. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomised trials and 17,346 patients. Radiother Oncol 2009;92:4–14. [33] Porter AB, Bernold DM, Giannini C, et al. Retrospective review of adjuvant chemotherapy for esthesioneuroblastoma. J Neurooncol 2008;90:201–4.
Please cite this article in press as: Nakamura N et al. Proton beam therapy for olfactory neuroblastoma. Radiother Oncol (2017), http://dx.doi.org/10.1016/j. radonc.2016.12.020
Contents lists available at ScienceDirect
Radiotherapy and Oncology journal homepage: www.thegreenjournal.com
Original article
Proton beam therapy for olfactory neuroblastoma Naoki Nakamura a,⇑, Sadamoto Zenda a, Makoto Tahara b, Susumu Okano b, Ryuichi Hayashi c, Hidehiro Hojo a, Kenji Hotta a, Satoe Kito a, Atsushi Motegi a, Satoko Arahira a,d, Hidenobu Tachibana a, Tetsuo Akimoto a a d
Division of Radiation Oncology and Particle Therapy; b Division of Head and Neck Surgery; c Division of Head and Neck Oncology, National Cancer Center Hospital East; and Department of Radiation Oncology, Kanto Rosai Hospital, Kawasaki, Japan
a r t i c l e
i n f o
Article history: Received 11 July 2016 Received in revised form 27 November 2016 Accepted 19 December 2016 Available online xxxx Keywords: Olfactory neuroblastoma Proton beam therapy Nasal cavity Craniofacial surgery Reirradiation
a b s t r a c t Purpose: To clarify the efficacy and feasibility of proton beam therapy (PBT) for olfactory neuroblastoma (ONB). Methods and materials: We retrospectively reviewed 42 consecutive patients who received PBT with curative intent for ONB at National Cancer Center Hospital East from November 1999 to March 2012. Results: Five patients (12%) had Kadish A disease, nine (21%) had Kadish B, and twenty-eight (67%) had Kadish C. All patients except one received a total dose of 65 Gy (relative biological effectiveness: RBE) in 26 fractions. Twenty-four patients (57%) received induction and/or concurrent chemotherapy. The median follow-up for all eligible patients was 69 months (7–186). The 5-year overall survival (OS) and progression-free survival (PFS) rates were 100% and 80% for Kadish A, 86 and 65% for Kadish B, and 76% and 39% for Kadish C, respectively. The sites of the first progression were local in six patients (30%), regional in eight (40%), distant in two (10%), local and regional in two (10%), and local and distant in two (10%). Late adverse events of grade 3–4 were seen in six patients (ipsilateral visual impairment, 3; bilateral visual impairment, 1; liquorrhea, 1; cataract, 1). Conclusion: PBT was a safe and effective modality for ONB. Ó 2016 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology xxx (2017) xxx–xxx
Olfactory neuroblastoma (ONB) is a rare malignant neoplasm of the nasal cavity, believed to arise from the olfactory epithelium [1]. Because of its rarity, a standard treatment strategy has not been established. Radiotherapeutic management for ONB is challenging because of its proximity to organs at risk (OAR), such as the anterior visual pathway or brain stem [2–8]. Proton beam therapy (PBT) can provide a better dose distribution compared with conventional X-ray treatment because of its physical characteristics [9]. Therefore, PBT may facilitate curative high-dose irradiation of the tumor, without increasing normal tissue toxicity [10,11]. In our institution, we recommended the treatment modality according to the stage classification based on Kadish et al. [12]. For patients with Kadish A, which is limited to the nasal cavity, single modality treatment by surgery or PBT is recommended. For those with Kadish B, which extends to the paranasal sinus, concurrent therapy of PBT and chemotherapy is recommended. For those with Kadish C, which extends beyond the paranasal sinus, induction chemotherapy followed by concurrent therapy of PBT and chemotherapy is ⇑ Corresponding author at: Divison of Radiation Oncology and Particle Therapy, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba 2778577, Japan. E-mail address: [email protected] (N. Nakamura).
recommended. There are multiple reasons why we recommend induction chemotherapy for Kadish C: (1) to reduce the intracranial irradiated volume and risk of radiation brain injury, (2) expecting the reduction of distant metastases, and (3) to quickly start treatment. For those with Kadish D, which is accompanied by cervical lymph node or distant metastases, curative treatment is not usually recommended. We previously reported clinical outcomes following PBT for ONB in our institution in 2007 [13]. To further examine the efficacy and feasibility of PBT for ONB, we provide an update of our experience.
Methods and materials Patient identification We identified 42 consecutive patients who received PBT with curative intent for ONB at National Cancer Center Hospital East from November 1999 to March 2012. With the approval of our Institutional Review Board, we performed a retrospective chart review of patient characteristics, treatments, and clinical outcomes.
http://dx.doi.org/10.1016/j.radonc.2016.12.020 0167-8140/Ó 2016 Elsevier Ireland Ltd. All rights reserved.
Please cite this article in press as: Nakamura N et al. Proton beam therapy for olfactory neuroblastoma. Radiother Oncol (2017), http://dx.doi.org/10.1016/j. radonc.2016.12.020
2
PBT for olfactory neuroblastoma
Treatments All patients received passive PBT. The clinical target volume (CTV) typically included the gross tumor volume and adjacent sinus. The planning target volume (PTV) was set by isotropically expanding the CTV by 2 mm. To avoid late toxicity, we determined the dose constraints for OAR as follows: <64 Gy (relative biological effectiveness: RBE) for the surface of the brainstem, <53 Gy (RBE) for the center of the brainstem, <60 Gy (RBE) for the optic nerves and optic chiasm, and <13 Gy (RBE) for the optic lenses. The dose was prescribed at the isocenter. A dose distribution and dose–volume histogram for typical treatment planning is shown in Figs. 1 and 2.
Results Patient characteristics The median follow-up for all eligible patients was 69 months (7–186). Patient characteristics are shown in Table 1. For induction chemotherapy, a regimen comprising three agents (cisplatin, S-1, and docetaxel) [15,16] was used for twelve patients. A nonplatinum-based regimen with irinotecan and docetaxel was used for six patients [17]. Other regimens used were cisplatin and etoposide for one patient, cisplatin, etoposide, and adriamycin for one patient, cisplatin, docetaxel, and adriamycin for one patient, and cisplatin, etoposide, Adriamycin, and vincristine for one patient. For concurrent chemotherapy, a single cisplatin regimen was used except for one patient who received a regimen with irinotecan and docetaxel.
Endpoints and statistical analysis As clinical outcomes, overall survival (OS), progression-free survival (PFS), the site of the first progression, and adverse effects were evaluated. The response to induction chemotherapy was assessed using the Response Evaluation Criteria in Solid Tumors (RECIST). Adverse effects were evaluated by the chart review and graded based on the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. Non-hematological adverse effects of grade 3 or higher were collected. Adverse effects that occurred within 3 months from the start of PBT were regarded as acute adverse effects, while those that occurred after 3 months were regarded as late adverse effects. We used EZR [14] version 1.27 for statistical analysis. Time analysis was calculated from the day when induction chemotherapy began for patients who received induction chemotherapy, and from the day when PBT began for the others. Fisher’s exact test was used to determine the significance of intergroup differences in discontinuous variables, and the independent t-test was used for continuous variables. Survival probabilities were estimated using the Kaplan–Meyer method, and comparisons of survival according to clinical parameters were performed using the log-rank test. Differences were deemed significant when two-tailed p-values were less than 0.05.
Survival The 5-year OS and PFS rates were 100% and 80% for Kadish A, 86% and 65% for Kadish B, and 76% and 39% for Kadish C, respectively (Fig. 2). OS and PFS according to the age are shown in Figs. 3 and 4. Patients who were younger than 50 years showed significantly better OS than those who were 50 years or older (p = 0.01) (Supplementary Fig. 1). However, PFS was not significantly different between the two groups (p = 0.34) (Supplementary Fig. 2). Patient characteristics according to age are summarized in Supplementary Table 1. Among 28 Kadish C patients, eight did not receive chemotherapy because of comorbidities, old age, or patient’s refusal. Among twenty patients who received induction chemotherapy, nine patients received concurrent chemotherapy, while eleven patients did not receive it because of a poor response to induction chemotherapy, severe adverse effects, or patient’s refusal. The response to induction chemotherapy was a complete response in one patient (5%), partial response in five (25%), stable disease in eleven (55%), and progressive disease in three patients (15%). OS and PFS according to the usage of chemotherapy in Kadish C
PTV
CTV
GTV
62 60 50 40 20
Gy Gy Gy Gy Gy
(RBE) (RBE) (RBE) (RBE) (RBE)
Fig. 1. Dose distribution for typical treatment planning. Abbreviations: GTV = gross tumor volume; CTV = clinical target volume; PTV = planning target volume; RBE = relative biological effectiveness.
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Fig. 2. Dose–volume histogram for the treatment planning indicated in Fig. 1. Abbreviations: GTV = gross tumor volume; CTV = clinical target volume; PTV = planning target volume; RBE = relative biological effectiveness.
Table 1 Patient characteristics. Factor
Number of patients
Median age (range)
51 years (20–87)
Sex
Female Male
25 (60%) 17 (40%)
Stage by Kadish et al. [12]
A B C
5 (12%) 9 (21%) 28 (67%)
Chemotherapy
None Induction Concurrent Induction and concurrent
18 (43%) 13 (31%) 2 (5%) 9 (21%)
Median CTV dimension (range)
118 ml (31–288)
Median PTV dimension (range)
152 ml (45–333)
Dose fractionation
41 (98%) 1 (2%)
65 Gy (RBE) in 26 70 Gy (RBE) in 35
CTV: clinical target volume, PTV: planning target volume, RBE: relative biological effectiveness.
patients are shown in Supplementary Figs. 3 and 4. No significant differences were seen in OS (p = 0.44) or PFS (p = 0.63). Recurrent sites and salvage treatments Until the last follow-up, disease progression was noted in 20 patients (48%). The sites of the first progression are shown in Fig. 5. Salvage treatments are summarized in Table 2. Of the ten patients who had local recurrence, all five patients who were younger than 50 years received aggressive local salvage treatment (craniofacial surgery or reirradiation), while none of the five patients who were 50 years or older received aggressive local salvage treatment. Adverse effects As acute adverse effects, grade 3 mucositis was seen in four patients (10%) and grade 3 dermatitis was seen in one patient (2%). No grade 4–5 acute adverse effects were noted.
Overall survival
100%
Kadish A
80%
Kadish B
60%
Kadish C
40% 20%
0
Number at risk 5 Kadish A 9 Kadish B 28 Kadish C
Kadish A vs. B: p = 0.40 Kadish A vs. C: p = 0.15 Kadish B vs. C: p = 0.35
2 5 8 21
4 Years 6
8
10
5 5 15
4 4 5
4 3 2
5 4 11
Fig. 3. Overall survival according to the stage based on Kadish et al. [12].
As late adverse effects, bilateral grade 4 visual impairment was observed in one patient (2%). Ipsilateral grade 3 and 4 visual impairment was seen in one (2%) and two patients (5%), respectively. Among four patients who experienced ipsilateral or bilateral grade 3 or 4 visual impairment, three had Kadish C disease, while one had Kadish A disease. Grade 3 ipsilateral cataract was noted in one patient (2%). Grade 4 liquorrhea was observed in one patient (2%), who had Kadish C disease widely destroying the skull base. No grade 3 or higher brain necrosis was found. Discussion To our knowledge, this is the largest report of PBT for ONB [13,18–20]. The optimal treatment for patients with ONB has not been established in randomized clinical trials due to its rarity. Radiotherapy (RT) alone has been reported to lead to unsatisfactory outcomes [2–6]. Benfari et al. reported 55 ONB patients trea-
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PBT for olfactory neuroblastoma
Progression-free survival
100% Kadish A
80%
Kadish B 60% Kadish C
40% 20%
Kadish A vs. B: p = 0.29 Kadish A vs. C: p = 0.14 Kadish B vs. C: p = 0.56
0
2
Number at risk 5 Kadish A 9 Kadish B 28 Kadish C
4 Years 6
4 7 17
4 3 10
4 1 5
8
10
3 1 2
3 0 0
Fig. 4. Progression free survival according to the stage based on Kadish et al. [12].
Local 6 (1/1/4) 2 (0/0/2)
2 (0/1/1)
Regional
Distant 2 (0/0/2)
8 (0/2/6)
Fig. 5. Sites of the first progression. Numbers indicate total numbers (numbers among Kadish A/B/C).
ted with RT alone. The mean follow-up period was 56 months (range: 2–216) [2]. The mean radiotherapy dose was 55.1 Gy (range: 23.0–80.0). Local control was achieved in 6/6 (100%) Kadish A patients. However, local control for Kadish B and C patients was achieved in 7/12 (58%) and 7/37 (19%), respectively. Therefore, the
mainstay of the treatment is surgery. Multiple observational studies found that craniofacial surgery improved the ability to achieve en bloc resection and improved progression-free and overall survival compared with a transfacial approach [1,21–23]. Furthermore, observational studies indicated that combining surgery and RT resulted in prolonged survival compared with surgery or RT alone, except in selected patients with Kadish A [22,24–30]. A recent international collaborative study involving 17 centers reported the outcomes following craniofacial resection with or without RT for 149 patients [31]. The 5-year OS was 97% for Kadish A/B and 73% for Kadish C, being similar to our results. More favorable OS was noted in the younger subgroup in spite of a similar stage distribution. PFS was not significantly better in the younger subgroup. A marked difference was noted in the salvage treatment for local recurrence between the younger and older groups. It is possible that the difference in local salvage treatment after recurrence may result in the improved OS. Our results support aggressive salvage treatment including craniofacial surgery or reirradiation for local recurrence. Our results also suggest that many patients do not need to receive invasive surgery if they initially receive PBT. We failed to show the survival benefit of chemotherapy even in Kadish C patients. The small number of patients in this study may make it difficult to prove the existing survival advantage. Chemotherapy may decrease the chances of systemic failure by acting on systemic micro metastases like head and neck squamous cell carcinoma [32]. A retrospective study by Porter et al. identified twelve Kadish C patients with full surgical resection. Six of these patients received adjuvant chemotherapy, and six did not. The median time to relapse for patients who received and did not receive adjuvant chemotherapy was 35 and 10.5 months, respectively [33]. Furthermore, our institution recommends induction chemotherapy mainly because it can reduce the intracranial irradiated volume and risk of radiation brain injury. In our cohort, no grade 3 or more advanced brain necrosis was seen. In addition to the excellent dose distribution of PBT, induction chemotherapy might contribute to a decrease in adverse effects. Finally, chemotherapy can be administered earlier than PBT, which may lead to early symptom relief. Among the six grade 3–4 late adverse effects, three were ipsilateral optic problems. It may be acceptable to compromise the ipsilateral visual ability in order to increase the treatment intensity. Although one patient experienced bilateral grade 4 visual impairment, the low rates of acute and late severe adverse effects in our cohort suggest that our treatment strategy including PBT for ONB is feasible. This study is inevitably limited by its single institutional and retrospective nature. Nevertheless, the outcomes of our study offer some guidance to clinicians in an area where little evidence is available.
Table 2 Sites of the first progression and salvage treatments. Patients =50 years
Site
Salvage therapy
All patients
Patients <50 years
Local
Craniofacial surgery Chemotherapy Supportive care Reirradiation and neck dissection Supportive care Reirradiation and lung metastasectomy Supportive care Neck dissection Supportive care
3 1 2 1 1 1 1 8 2
3
5 1
1 3 1
20
11
9
Local and regional Local and distant Regional Distant Total
1 2 1 1 1
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N. Nakamura et al. / Radiotherapy and Oncology xxx (2017) xxx–xxx
In conclusion, PBT was a safe and effective modality for ONB. In cases with local recurrence after PBT, aggressive salvage treatment including craniofacial surgery or reirradiation might be considered. Conflict of interest Dr. Tahara reports grants and personal fees from Ono Pharmaceutical, personal fees from Bristol-Myers Squibb, during the conduct of the study; personal fees from Merck Serono, grants and personal fees from Eisai, personal fees from Otsuka, grants and personal fees from Bayer, grants and personal fees from MSD, grants and personal fees from Astra Zeneca, grants and personal fees from Pfizer, grants from NanoCarrier, grants from Novartis, outside the submitted work. No other authors declare any conflict of interest. Acknowledgements This study was supported in part by Grants-in-Aid for Scientific Research (16K10412) from the Ministry of Education, Science and Culture of Japan, by Health Science Research Grants from the Ministry of Health and Welfare, and by the National Cancer Center Research and Development Fund (25-A-10 & 28-A-14). Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.radonc.2016.12. 020. References [1] Levine PA, McLean WC, Cantrell RW. Esthesioneuroblastoma: the University of Virginia experience 1960–1985. Laryngoscope 1986;96:742–6. [2] Benfari G, Fusconi M, Ciofalo A, et al. Radiotherapy alone for local tumour control in esthesioneuroblastoma. Acta Otorhinolaryngol Ital 2008;28:292–7. [3] Chao KS, Kaplan C, Simpson JR, et al. Esthesioneuroblastoma: the impact of treatment modality. Head Neck 2001;23:749–57. [4] Gruber G, Laedrach K, Baumert B, Caversaccio M, Raveh J, Greiner R. Esthesioneuroblastoma: irradiation alone and surgery alone are not enough. Int J Radiat Oncol Biol Phys 2002;54:486–91. [5] Kaur G, Kane AJ, Sughrue ME, et al. The prognostic implications of Hyam’s subtype for patients with Kadish stage C esthesioneuroblastoma. J Clin Neurosci 2013;20:275–80. [6] Slevin NJ, Irwin CJ, Banerjee SS, Gupta NK, Farrington WT. Olfactory neural tumours–the role of external beam radiotherapy. J Laryngol Otol 1996;110:1012–6. [7] McLean JN, Nunley SR, Klass C, Moore C, Muller S, Johnstone PA. Combined modality therapy of esthesioneuroblastoma. Otolaryngol Head Neck Surg 2007;136:998–1002. [8] Zenda S, Kawashima M, Arahira S, et al. Late toxicity of proton beam therapy for patients with the nasal cavity, para-nasal sinuses, or involving the skull base malignancy: importance of long-term follow-up. Int J Clin Oncol 2015;20:447–54. [9] Mock U, Georg D, Bogner J, Auberger T, Potter R. Treatment planning comparison of conventional, 3D conformal, and intensity-modulated photon (IMRT) and proton therapy for paranasal sinus carcinoma. Int J Radiat Oncol Biol Phys 2004;58:147–54.
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Please cite this article in press as: Nakamura N et al. Proton beam therapy for olfactory neuroblastoma. Radiother Oncol (2017), http://dx.doi.org/10.1016/j. radonc.2016.12.020