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BNCT for advanced or recurrent head and neck cancer Teruhito Aihara a,b,n, Norimasa Morita b, Nobuhiko Kamitani c, Hiroaki Kumada a, Koji Ono d, Junichi Hiratsuka c, Tamotsu Harada b a

Proton Medical Research Centre, University of Tsukuba, Tsukuba, Japan Departments of Otolaryngology Head and Neck Surgery, Japan c Radiation Oncology, Kawasaki Medical School, Kurashiki, Japan d Radiation Oncology Research Laboratory, Research Reactor Institute, Kyoto University, Osaka, Japan b

H I G H L I G H T S

    

This study is clinical trials of BNCT for head and neck cancers. BNCT was performed in 20 advanced/recurrent head and neck cancer patients. The effective rate [(CR þPR)/total cases] was 90%. BNCT is effective the patients with radio resistance head and neck cancer. BNCT is a potential curative therapy for patients with head and neck cancer.

art ic l e i nf o

Keywords: Head and neck cancer Recurrent SCC Locally advanced non-SCC BNCT

a b s t r a c t The therapeutic effect of surgery and/or combination of conventional chemoradiotherapy is limited in the patients with recurrent squamous cell carcinoma (SCC) and locally advanced non-squamous cell carcinoma without malignant melanoma (non-SCC) of the head and neck. Currently, clinical trials of BNCT for head and neck cancers are being conducted in some institutes to verify its the effectiveness. BNCT was performed in 10 patients with recurrent SCC, 7 patients with recurrent non-SCC and 3 patients with newly diagnosed non-SCC in our university between October 2003 and September 2007. Eleven patients showed complete remission and 7 patients showed partial remission of irradiated site. The effective rate [(CRþPR)/total cases] was 90%. No severe acute or chronic normal-tissue reactions were observed in any patients. BNCT is effective and safe in the patients with recurrent SCC and locally advanced non-SCC. & 2014 Elsevier Ltd. All rights reserved.

1. Introduction Head and neck cancers (HNCs) account for approximately 10% of all cancers, and about 90% of them are squamous cell carcinoma (SCC). Surgery represents the mainstay of treatment for resectable primary site. However, the main drawback of surgery, especially for advanced T-stage (primary tumor) cancer, is deterioration of patients' quality of life (QOL) because the head and neck have many important physiological and cosmetic functions. On the other hand, the patients with unresectable cancer are candidates for radiation therapy or chemoradiotherapy. Although these therapies are effective for SCC, it is difficult to perform re-radiation therapy for SCCs that recur after these therapies, because of intolerable of surrounding normal-tissue

against re-radiation therapy. In addition, these SCCs might show radio resistance. T3–T4 advanced non-SCCs, such as adenocarcinoma, mucoepidermoid carcinoma and adenoid cystic carcinoma, also show radio- and chemoresistant. BNCT is high linear energy transfer (LET) radiation and tumor-selective radiation without serious damage of surrounding normal-tissue. BNCT might be effective and safe in the patients with inoperable, locally advanced HNCs even if that recur at previously irradiated sites. This paper is intended to present our preliminary experience of treating patients with HNC (recurrent SCC, locally advanced non-SCC) at the Kyoto University Reactor (KUR) and Japan Research Reactor 4 (JRR4) of the Japan Atomic Energy Agency.

2. Material and method n

Corresponding author at: Proton Medical Research Centre, University of Tsukuba, Tennodai 1-1-1, Tsukuba, Ibaraki, 305-8575, Japan. Tel.: þ81 29 853 7100; fax: þ81 29 853 7102. E-mail address: [email protected] (T. Aihara).

2.1.

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F-BPA-PET study

The accumulations of BPA (para-boronophenylalanine) in the tumor and surrounding normal-tissue were imaged and quantified

http://dx.doi.org/10.1016/j.apradiso.2014.04.007 0969-8043/& 2014 Elsevier Ltd. All rights reserved.

Please cite this article as: Aihara, T., et al., BNCT for advanced or recurrent head and neck cancer. Appl. Radiat. Isotopes (2014), http://dx. doi.org/10.1016/j.apradiso.2014.04.007i

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irradiation. After final setting of the patients, thermo-luminescence dosimeters (TLDs) are attached to the skin surface involved in the irradiation field and gold wires are placed in the collimator for dosimetry. We placed a gelatin sheet, 5-mm thickness, on the skin of the radiation field to enhance the irradiation dose at the tumor surface. Neutron flux (n/cm2/s) is measured using gold wires 15 min after the start of irradiation. The neutron irradiation time is decided using the JCDS based on the neutron flux measured at 15 min after the start of irradiation and the estimated blood boron concentration curves. 2.4. Radiation doses by BNCT

Fig. 1. Kawasaki Medical School (KMS) group data of 18F-BPA-PET. Eleven patients with recurrent SCC and 8 patients with non-SCC were registered in 18F-BPA-PET study from October 2003 to September 2007. There was no difference in the T/N ratio between SCC and non-SCC group. Ten of 11 patients with SCC and 10 of 13 patients with non-SCC showed T/N ratio of 2.5 and over, and underwent BNCT.

by an 18F-BPA-PET (fluorine-18-labeled BPA positron emission tomography) study before BNCT in all patients. Imahori et al. (1998) The tumor/blood, normal-tissue/blood, and tumor/normal-tissue (T/N) ratios of 18F-BPA intensity was estimated 40 min after 18 FBPA i.v. administration. T/N ratios of SCC and non-SCC patients are shown in Fig. 1. 2.2. Indications for BNCT (1) A newly diagnosed T3/T4 advanced and recurrent HNCs. (2) The maximum depth of tumor is within 5 cm in depth from the skin surface to achieve a curative dose of the target by using an epithermal neutron beam. (3) T/N ratio is more than 2.5. T/N ratio is calculated by the results of 18 F-BPA-PET. (4) Consent to perform BNCT is obtained from the patient and their family. (5) Approval for BNCT is given by our Medical Ethics Committee.

2.3. Treatment procedures The patient undergo CT scan for treatment planning just prior to BNCT using a computer workstation equipped with the Japan Atomic Energy Research Institute Computational Dosimetry System: JCDS (JRR4) (Kumada et al., 2001) and SERA (KUR) (Nigg et al., 1999) dose planning software. The total dose of BPA (L-enantiomer, 4 95% 10B enriched) is 500 mg/kg body weight (B.W.). Two hours before neutron irradiation, intravenous administration of 200 mg/kg B.W./h of BPA is started. To monitor the boron concentration in the blood, venous blood samples were obtained every 1 h from starting BPA administration to finishing neutron irradiation. The boron concentrations in the blood are measured by prompt γ-ray analysis and/or inductively coupled plasmaatomic emission spectrometry (ICP-AES). The blood boron concentration curves are plotted against time. The tumor and normal-tissue boron concentrations are estimated by the results of 18F-BPA-PET. Patients are positioned on the treatment table in the irradiation room of the reactor and attached the collimator to shield normal tissue, and then tumor site is irradiated with epithermal neutron with the BPA flow rate of 100 mg/kg B.W./h (Ono et al., 2006). All patients are placed in a sitting or supine position during

BNCT for the HNC is performed using epithermal neutron beam of the reactor with single fraction at a reactor power of 3.5 MW (JRR4) and 5 MW (KUR), in our group (2 fractions in Finland group (Kankaanranta et al., 2007)). The control dose to the tumor is planned to be more than 20 Gy-Eq (weighted dose) and the maximum dose to tumor-surrounding normal tissue is set not to exceed 15 Gy-Eq. These values were calculated by JCDS on the basis of the mean blood boron level during neutron irradiation and directly measuring the neutron flux at the tumor site using gold wires. These treatment doses are achieved by the indications of BNCT (2) and (3).

3. Results Ten patients with recurrent SCC, 7 patients with recurrent nonSCC (adenoid cystic carcinoma, 2 cases; adenocarcinoma, 1; papillary adenocarcinoma, 2; mucoepidermoid carcinoma, 1; and undifferentiated cancer, 1) and 3 with newly diagnosed T4 advanced non-SCC (adenoid cystic carcinoma, 2 cases; and acinic cell carcinoma, 1) underwent BNCT between October 2003 and September 2007. The median follow up time was 15.9 months (range, 3–56 months). Local response of these 20 patients after BNCT was as follows: 11 showed complete remission (CR) clinically. Fig. 2 represents the images of CT and 18F-BPA-PET before, and that of CT 5 months after treatment in recurrent SCC case which showed CR with BNCT. Seven patients showed partial remission (PR), and 2 did no change. The effective rate [(CRþ PR)/total cases] was 90% (Aihara et al., 2006). No severe acute or chronic normal-tissue reactions (more than grade II of the RTOG/EORTC score) were experienced in any patients. Seventeen patients died 3–44 months (median 18.8 months) after BNCT and the main cause of death was distant metastasis. In all patients, 1- and 2-year overall survival rates were 47.1% and 31.4%, respectively, and the 1- and 2-year disease free survival rates were 22.0% and 0%. However, the 1- and 2-year loco-regional progression-free survival rates were 55.9% and 22.4%, respectively (Fig. 3). All 3 patients with newly diagnosed T4 advanced non-SCC showed complete response of the primary site within 3 months after BNCT. The 1-year loco-regional progression-free survival rate was 100% and overall survival rate was 66.7% at 18 months in these 3 patients.

4. Discussion The treatment of locally advanced and recurrent SCC were very difficult. The reported tumor effective rate and the median survival of 69 patients with advanced/recurrent head and neck SCC who received palliative chemotherapy and/or radiation therapy were approximately 30% and 6–10 months, respectively (Worden et al., 2006). The 2-year loco-regional progression-free survival and

Please cite this article as: Aihara, T., et al., BNCT for advanced or recurrent head and neck cancer. Appl. Radiat. Isotopes (2014), http://dx. doi.org/10.1016/j.apradiso.2014.04.007i

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Fig. 2. Recurrent Oropharynx SCC. The tumor recurred after full-dose conventional radiotherapy combined with chemotherapy. (A) CT shows the recurrent tumor at oral floor space as indicated by the circle. (B) 18F-BPA-PET study reveals that T/N ratio is 5.0. (C) The tumor completely disappeared five months after BNCT. Unfortunately, this patient died of local recurrence 2 years after BNCT.

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1 - year 47.1%, 2 - year 31.4%

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1 - year 55.9%, 2- year 22.4%

Fig. 3. Kaplan–Meier survival curve. Two-year loco-regional progression-free survival and overall survival rates are 22.4% and 31.4%, respectively.

overall survival rates in 105 patients with recurrent HNC who underwent re-radiotherapy were 42% and 37%, respectively [82]. On the other hand, the treatment of non-SCC in the head and neck without malignant melanoma presents the extreme difficulty, too. The postoperative radiation therapy improved local control from 75% to 83% among 100 patients with non-SCC, such as mucoepidermoid, adenoid cystic, acinic cell and adenocarcinoma, of the major salivary glands (Fu et al., 1977). Operation with postoperative radiotherapy improved the 10-year estimates of loco-regional control to 63% in 70 patients with resectable T3-4 non-SCC of the major salivary glands (Chen et al., 2007). It was proved that BNCT was very effective for treatment of HNC as for in this results. Specially, response rate were higher than a mentioned above report of the recurrence and advanced HNC. However, the high response rate was not related for the

enhancement of the survival rate. Because, many our patients were thought to already have micro-metastasis at the time of BNCT. It was guessed by their main cause of death having been distant metastasis. We regard BNCT as a suitable therapy for these advanced or recurrent HNC. There are several advantages in applying BNCT to HNCs as follows. First, the head and neck have many important physiological and cosmetic functions. Surgery can be a great influence on his/her QOL in the patients with advanced or recurrent HNCs. Therefore, organ preservation is one of the most important things. Second, there are many patients with SCC that recur after intensive treatment including surgery and chemoradiotherapy, and locally advanced non-SCC that cannot be controlled by conventional cancer therapy. Third, as HNCs exist superficially and are near the skin surface, it is possible to

Please cite this article as: Aihara, T., et al., BNCT for advanced or recurrent head and neck cancer. Appl. Radiat. Isotopes (2014), http://dx. doi.org/10.1016/j.apradiso.2014.04.007i

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administer curative doses to the target by using an epithermal neutron beam. The results of our clinical studies showed efficacy of BNCT for HNC. In this report demonstrate that BNCT is a potential curative therapy for patients with HNC. The treatment does not appear to cause serious adverse effects, and may be used as treatment for either primary or recurrent disease. Although these excellent clinical results will have a major impact on future strategies for treatment of HNC. A longer duration of follow-up and a larger prospective study of accelerator-based neutron sources are needed to verify these initial results.

5. Conclusion BNCT for recurrent SCC and locally advanced non-SCC in the head and neck is a promising modality that might be indicated in the following situations. 1. The maximum depth of tumor is within 5 cm in depth from the skin surface. 2. T/N ratio is more than 2.5 which is calculated by the results of 18 F-BPA-PET. BNCT increases the chance for local control in these patients. However, main cause of death in the patients is distant metastasis and overall survival rate is not significantly improved by BNCT compared to conventional cancer treatments. A combination of BNCT with chemotherapies should be considered in high-risk patients to improve overall survival.

Acknowledgments This work was supported by JSPS Grant-in-Aid for Scientific Research (C) No. 24592611. References Aihara, T., et al., 2006. Using BPA alone for boron neutron capture therapy of recurrent head and neck malignancies. In: Nakagawa, Y., Kobayashi, T., Fukuda, H. (Eds.), Advances in Neutron Capture Therapy 2006. International Society for Neutron Capture Therapy, Kagawa, Japan, ISBN: 4-9903242-0-X, pp. 5–6. Chen, A.M., et al., 2007. Local-regional recurrence after surgery without postoperative irradiation for carcinomas of the major salivary glands. Int. J. Radiat. Oncol. Biol. Phys. 67, 982–987. Fu, K.K., et al., 1977. Carcinoma of the major and minor salivary glands. Cancer 40, 2882–2890. Imahori, Y., et al., 1998. Positron emission tomography-based boron neutron capture therapy using boronophenylalanine for high-grade gliomas: Part II. Clin. Cancer Res. 4, 1833–1841. Kankaanranta, L., et al., 2007. Boron neutron capture therapy in the treatment of locally recurred head and neck cancer. Int. J. Radiat. Oncol. Biol. Phys. 69, 475–482. Kumada H., et al., 2001. Development of computational dosimetry system and measurement of dose distribution in water head phantom for BNCT in JAERI. In: Proceeding of the 2000 Workshop on Utilization of Research Reactors. JAERIConf 2001. pp. 357–362. Nigg, D.W., Wemple, C.A., Wessol, D.E., Wheeler, F.J., 1999. SERA an advanced treatment planning system for neutron therapy and BNCT. Trans. ANS 80, 66–68. Ono, K., et al., 2006. Neutron irradiation under continuous BPA injection for solving the problem of heterogenous distribution of BPA. In: Nakagawa, Y., Kobayashi, T., Fukuda, H. (Eds.), Advances in Neutron Capture Therapy 2006. International Society for Neutron Capture Therapy, Kagawa, Japan, ISBN: 4-9903242-0-X, pp. 27–30. Worden, F.P., et al., 2006. A phase II evaluation of a 3-hour infusion of paclitaxel, cisplatin, and 5-fluorouracil in patients with advanced or recurrent squamous cell carcinoma of the head and neck. Cancer 107, 319–327.

Please cite this article as: Aihara, T., et al., BNCT for advanced or recurrent head and neck cancer. Appl. Radiat. Isotopes (2014), http://dx. doi.org/10.1016/j.apradiso.2014.04.007i

BNCT for advanced or recurrent head and neck cancer.

The therapeutic effect of surgery and/or combination of conventional chemoradiotherapy is limited in the patients with recurrent squamous cell carcino...
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