A clinician’s perspective on boron neutron capture therapy: promising advances, ongoing trials, and future outlook

Figures & data

Figure 1. Mechanisms of BNCT in cancer.

Patients were injected intravenously with a boron delivery agent before and sometimes during treatment (A). Cancer cells selectively absorb the boron-delivery agent with little uptake by normal tissues (B). The boron nucleus absorbs neutrons and undergoes nuclear fission, yielding an alpha particle and a ⁷Li. The range of the particle is 4-7 μm, equal to the diameter of a cell (C). Tumor cells were eliminated following BNCT therapy without causing considerable damage to normal tissue cells (D).

Figure 2. Global AB-BNCT projects: operational status of completed and under-construction facilities.

The figure illustrates the operational status of accelerator-based boron neutron capture therapy (AB-BNCT) projects worldwide that have been completed or are currently under construction. The data used to create this figure was obtained from the official website of the International Society for Neutron Capture Therapy (ISNCT) and is current as of the end of 2022.

Figure 3. Classification and structures of boron delivery agents for BNCT.

This figure illustrates the development of boron delivery agents for BNCT across three generations. The first-generation compounds, such as boric acid, borax, nanoparticles, and pentaborates, had low tumor selectivity and accumulation. The second generation introduced the clinically successful BPA and BSH, which exhibited improved tumor targeting and lower toxicity than the first generation. The third generation enhances tumor specificity and boron delivery by conjugating BPA and BSH with tumor-targeting moieties. These include amino acids, peptides, antibodies, porphyrins, liposomes, and oligonucleotides.

Table 1. Globally registered clinical trials of Reactor-based BNCT^¶.

Country or Region	Investigator	Types of Cancer	ID	Phase	Boron carrier	Sample#	Recruitment status
Japan	Nara Medical University	Head and neck SCC (recurrent)	jRCTs051180160	II	NA	7	Completed
Japan	Osaka Medical College	Skin angiosarcoma (recurrent)	jRCTs051180217	II	NA	2	Terminated*
Japan	University of Tsukuba	Brain tumor (recurrent)	UMIN000003692	I/II	L-BPA	2	Completed
Japan	Osaka Medical College	Breast cancer (recurrent)	UMIN000029403	I/II	L-BPA	1	Terminated*
Japan	Osaka Medical College	Glioblastoma (newly diagnosed)	UMIN000002385	II	BSH + L-BPA	32	Completed
Japan	University of Tsukbua	Glioma (high-grade)	C000000298	II	NA	20	Completed
Japan	University of Tsukuba	Glioma (newly diagnosed)	UMIN000003984	NA	L-BPA	20	Recruiting
Japan	Osaka Medical College	Glioma (recurrent)	UMIN000029144	II	NA	4	Terminated*
Japan	Osaka Medical College	Glioma (recurrent)	UMIN000013419	I/II	NA	50	Not yet recruiting
Japan	Osaka Medical College	Head and neck cancer	UMIN000011221	I/II	NA	10	Recruiting
Japan	Kawasaki Medical School	Melanoma	UMIN000005124	NA	NA	4	Completed
Japan	Osaka Medical College	Melanoma (choroidal)	UMIN000029402	I/II	NA	3	Not yet recruiting
Japan	NA	Pleural mesothelioma	UMIN000005478	I/II	L-BPA	20	Recruiting
Japan	Kawasaki Medical School	Skin malignant tumors	UMIN000027541	I/II	L-BPA	3	Completed
Japan	Kawasaki Medical School	Head and neck cancer(recurrent)	jRCTs061180067	I/II	L-BPA	21	Terminated*
Japan	Kawasaki Medical School	Skin malignancies (advanced or recurrent)	jRCTs061180066	I/II	L-BPA	3	Terminated*
Finland	Helsinki University Central Hospital	Head and neck cancer	NCT00114790	I/II	L-BPA	30	Completed
Finland	Helsinki University Central Hospital	Central nervous system tumors	NCT00115440	I/II	L-BPA	22	Completed
Finland	Helsinki University Central Hospital	Central nervous system tumors	NCT00115453	I/II	L-BPA	50	Completed
Finland	Helsinki University Central Hospital	Head and neck cancer	NCT00927147	I/II	L-BPA	17	Completed
Germany	EORTC^&	Colorectal cancer, head and neck cancer	NCT00062348	I	L-BPA or BSH	NA	Unknown
Germany	EORTC^&	Melanoma	NCT00085059	II	L-BPA	NA	Unknown
Global	EORTC^&	Central nervous system tumors	NCT00004015	I	BSH	NA	Unknown
Taiwan	Taipei Veterans General Hospital	Head and neck cancer	NCT01173172	I/II	L-BPA	17	Completed
Taiwan	Taipei Veterans General Hospital	Head and neck cancer	NCT02004795	I/II	L-BPA	NA	Unknown
UK	Cancer Research UK	Central nervous system tumors	NCT01233492	I	L-BPA	NA	Completed
US	Beth Israel Deaconess Medical Center	Melanoma	NCT00002781	I	L-BPA	NA	Unknown
US	Beth Israel Deaconess Medical Center	Central nervous system tumors	NCT00039572	I/II	L-BPA	NA	Completed
US	Beth Israel Deaconess Medical Center	Melanoma	NCT00059800	II	NA	NA	Completed
China	The Third Xiangya Hospital of Central South University	Melanoma	NCT02759536	I/II	L-BPA	NA	Recruiting

^¶ This table is compiled based on data from the International Clinical Trials Registry Platform (https://trialsearch.who.int/). The data retrieval date is April 25, 2024.

^& : This is a trial sponsor.

^# If the trial is completed or terminated, the number of patients represents the actual number of participants recruited; otherwise, NA.

BNCT: Boron neutron capture therapy; EORTC: European Organization for Research and Treatment of Cancer; L-BPA: L-p-boronophenylalanine; BSH: Borocaptate sodium; EORTC: European Organization for Research and Treatment of Cancer; NA: Not applicable.

Table 2. Globally registered clinical trials of AB-BNCT.

Country	Investigator	Types of Cancer	ID	Phase	Neutron Source	Boron carrier	Sample^#	Date of registration	Recruitment status
Japan	Osaka Medical and Pharmaceutical University	Glioma (recurrent)	jRCT2051210053	I	BNCT30	SPM-011	9	2021/7/16	Completed
Japan	Southern Tohoku BNCT Research Center	Head and neck SCC (recurrent)	UMIN000044118	II	BNCT30	SPM-011	120	2021/5/10	Not yet recruiting
Japan	Osaka Medical and Pharmaceutical University	Meningioma (recurrent)	jRCT2051190044	II	BNCT30	SPM-011	18	2019/9/4	Not Recruiting
Japan	Osaka Medical College	Malignant glioma(recurrent)	jRCT2080224670, JapicCTI-194742	II	BNCT30	SPM-011	27	2021/7/19	Completed
Japan	Southern Tohoku BNCT Research Center	Head and neck cancer (recurrent)	jRCT2080224571, JapicCTI-194640	II	BNCT30	SPM-011	21	2019/2/22	Completed
Japan	National Cancer Center Hospital	Skin angiosarcoma (unresectable)	jRCT2031220410, NCT05601232	II	CICS-1	SPM-011	10	2022/10/26	Recruiting
Japan	National Cancer Center Hospital	Melanoma or angiosarcoma	JapicCTI-195062	I	CICS-1	SPM-011	10	2019/12/3	Completed
Japan	National Cancer Center Hospital	Malignant melanoma and angiosarcoma	jRCT1080224974, JapicCTI-195062	I	CICS-1	SPM-011	10	2019/12/3	Completed
Japan	Edogawa Hospital	Breast cancer (recurrent)	jRCTs031220371	I	CICS-2	SPM-011	5	2022/10/7	Recruiting
Japan	University of Tsukuba	Glioblastoma (newly diagnosed)	jRCT2032230554	I	iBNCT001	SPM-011	18	2024/1/10	Recruiting
China	Xiamen Honghai Hospital	Head and neck cancer, primary brain tumor(recurrent)	ChiCTR2300078618	I	NeuPex	NBB-001	16	2023/12/14	Recruiting
Korea	Gachon University Gil Medical Center	Gliomas(recurrent)	NCT05737212	I/II	DM-BNCT	DMX-102	39	2022/12/6	Recruiting

^¶ This table is compiled based on data from the International Clinical Trials Registry Platform(https://trialsearch.who.int/). The data retrieval date is April 25, 2024.

^# If the trial is completed or terminated, the number of patients represents the actual number of participants recruited; otherwise, NA.

BNCT: Boron neutron capture therapy; NA: Not applicable.

Table 3. BNCT clinical trial of head and neck squamous cell carcinoma.

Research sponsor	Year of Study	Neutron source	Type(s) of cancer/number of patients	Boron carrier	Main outcomes
Kyoto University	2001-2007	Reactor	rHN 49 urHN 13	BSH and L-BPA	CR 28%, PR 29%; 2yOS 24.2%
Osaka University	2001-2007	Reactor	rHN 26	L-BPA or L-BPA + BSH	CR 46%, PR 38%; Average OS 13.6 m
University of Tsukuba	2003-2007	Reactor	rSCC 10 r-nonSCC 7 urHN 3	L-BPA	CR 55%, PR 35%; 2yPFS 22.4%, 2yOS 31.4%
Helsinki University Central Hospital	2003-2008	Reactor	urHN30	L-BPA	CR 45%, PR 31%; 2yPFS 20%, 2yOS 30%
	2003-2012	Reactor	rSCC 79	L-BPA	CR 36%, PR 25%; 2yPFS 38%, 2yOS: 21%
Taipei Veterans General Hospital	2010-2013	Reactor	rHN 17*	L-BPA	2yLC 20%, 2 y OS 47%
Southern Tohoku BNCT Research Center	2016-2018	Accelerator	rHN 22	SPM-011	CR 23.8%, PR 47.6%; 2yOS 85.3%

* Report on the first stage.

BNCT: Boron neutron capture therapy; L-BPA: p-boronophenylalanine; BSH: Na2B12H11SH; CR: complete response; PR: partial response; LC: local control; PFS: progression-free survival; OS: overall survival; 2 y: years; rHN: recurrent head and neck carcinoma; urHN: unresectable recurrent head and neck carcinoma; rSCC: recurrent squamous cell carcinoma; r-nonSCC: recurrent non-squamous cell carcinoma.

Table 4. Clinical outcomes of RB-BNCT in the treatment of newly diagnosed and recurrent GBM.

Research sponsor	Year of Study	Type(s) of cancer	Sample Size	Boron carrier/administration	mOS (month)
Brookhaven National Laboratory	1994–1999	nGBM	53	BPA 250∼330mg/kg in 2 h	12.8
Beth Israel Deaconess Medical Center	1996–1999	nGBM	20	BPA 250∼350 mg/kg in 1.5 h	11.1
	2002–2003	nGBM	6	BPA 14 g/m2 in 1.5 h	NA
Essen University Hospital	1997–2002	nGBM	26	BSA 100 mg/kg in 1.7 h	10.4–13.2
Helsinki University Central Hospital	1999–2001	nGBM	30	BPA 290–500 mg/kg in 2 h	11.0–21.9
	2001–2008	rGBM	20	BPA 290–450 mg/kg in 2 h	7 (post-BNCT)
Charles University College Hospital	2000–2002	nGBM	5	BSH 100 mg/kg in 1 h	NA
Nyköping Hospital (Sweden)	2001–2003	nGBM	29	BPA 900 mg/kg in 6 h	17.7
	2001–2005	rGBM	12	BPA 900 mg/kg in 6 h	8.7 (post-BNCT)
University of Tsukuba	1999–2002	nGBM	5	BSH 100 mg/kg in 1–1.5 h (IO-BNCT)	23.2
	1998–2007	nGBM	7	BSH 5 g in 1 h (IO-BNCT)	23.3
	1998–2007	nGBM	8	BSH 5 g in 1 h + BPA 250 mg/kg in 1 h (BNCT + XRT)	27.1
Tokushima University	1998–2000	nGBM	6	BSH 64.9–178.6 mg/kg (IO-BNCT)	15.5
	2001–2004	nGBM	11	BSH 64.9–178.6 mg/kg (IO-BNCT)	19.5
	2005–2008	nGBM	6	BSH 100 mg/kg and BPA 250 mg/kg in 1 h (BNCT + XRT)	26.2
Osaka Medical College	2002–2003	nGBM	10	BSH 5 g + BPA 250 mg/kg in 1 h	14.5
	2003–2006	nGBM	11	BSH 5 g in 1 h + BPA 700 mg/kg in 3 h (BNCT + XRT)	23.5
	2002–2007	rGBM	19	BSH 5 g + BPA 250 mg/kg in 1 h or BSH 5 g + BPA 700 mg/kg in 3 h	10.8
	2010–2013	nGBM	32	BSH 5 g in 1 h + BPA 500 mg/kg in 3 h (BNCT + XRT + TMZ)	21.1
	2013–2018	rGBM	10	BPA 500 mg/kg in 3 h (BNCT + Bev)	12
Taipei Veterans General Hospital	2017–2019	rGBM	15#	BPA 450 mg /kg	7.34*

Note: This table is adapted from the review by Miyatake SI et al.

n: newly diagnosed; r: recurrent; GBM: glioblastoma; IO-BNCT: Intraoperative BNCT; XRT: X-ray radiotherapy; mOS: median overall survival; TMZ: temozolomide; Bev: Bevacizumab.

All newly diagnosed GMB patients in the table underwent reductive surgery.

^# 34 patients with malignant brain tumors, including 15 patients with GBM, relapsed after standard treatment and were in critical condition.

* 7.34 months is the average rather than the median.

Data availability statement

These data are made available upon request.