Boron Neutron Capture Therapy (BNCT): Precisely "blast" cancer cells!

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Boron Neutron Capture Therapy (BNCT): Precisely “blast” cancer cells!

Boron neutron capture therapy ( BNCT) is an advanced radiotherapy technology.

This technology kills cancer cells through the 10 B(n, α) 7 Li nuclear reaction that occurs in cancer cells . It is an atomic-level binary targeted therapy, and its clinical implementation requires professional technology and device support.

The core elements of BNCT include suitable neutron sources and neutron capture drugs.

Compared with traditional radiotherapy techniques, BNCT has outstanding advantages in the treatment of locally recurrent tumors (such as central nervous system tumors and head and neck tumors), and can better protect normal organs, especially for tumors that have significantly invaded surrounding organs. Good application prospects.

Boron Neutron Capture Therapy (BNCT): Precisely "blast" cancer cells!

Figure: Schematic diagram of the basic principle of boron neutron capture therapy

First, cancer patients are injected with a special compound containing boron-10 ( 10 B). This compound can be selectively accumulated in cancer cells in vivo, and less distributed in normal tissues. It has strong specificity for cancer cells. sexual affinity.

The compound has very low toxicity to the human body and is ineffective against tumors, but when the local tumor is irradiated with a thermal neutron beam or an epithermal neutron beam that does little damage to the human body, the neutrons will interact with the 10 B enriched in the cancer cells . A 10 B(n, α) 7 Li reaction occurs .

BNCT generates alpha particles and 7 Li recoil nuclei with extremely high linear energy transfer (LET) , with average LETs of 190 keV/μm and 160 keV/μm, respectively.

Theoretically, the energy released by several α particles is enough to destroy any human cell, but in human tissue, these particles only have a very short range (5~9 μm) of one cell size, so 10 B(n, α ) 7 The Li reaction can only kill the tumor cells enriched in 10 B, while the surrounding normal human tissues are less damaged due to the low content of 10 B.

In addition to tumor cells, 10 B may also accumulate in organs such as the liver, kidney, and salivary glands, and the cytotoxicity of 10 B itself is very low.

The range of neutron beam irradiation can be controlled to avoid damage to normal tissues.

Compared with traditional radiotherapy, BNCT has the following characteristics:

(1) Accurate targeting ability reaches the cell level, with little damage to healthy tissues around tumor cells;

(2) The relative biological effect is relatively high, and it can also achieve good curative effect on some tumors that are not sensitive to traditional radiotherapy;

(3) The course of treatment is short, usually several treatments are enough, and the shortest course of treatment is 1 time.

BNCT has not been widely used clinically at present, and some small-sample clinical studies suggest that for some specific patients, BNCT can achieve better curative effect than traditional radiotherapy.

From the perspective of mechanism, the indications of BNCT mainly depend on the characteristics (flux and range) of the neutron beam irradiation system used and the accumulation degree of boron drugs in the tumor.

Drugs used for BNCT should have good targeting, that is, they can accumulate in tumor tissues, have less distribution in normal tissues, and be cleared quickly.

In BNCT treatment, the T/N value of L- 18 F-FBPA PET/CT > 2.5 is regarded as an important index for judging the indications of BNCT, but there are also case reports of complete remission or partial remission with T/N ≤ 2.5.

The current clinical research of BNCT mainly focuses on the treatment of locally recurrent tumors.

Current clinical research results using boron drugs (BPA and BSH) and irradiation systems (reactor and AB-BNCT) show that BNCT has outstanding advantages in central nervous system tumors, head and neck tumors, and skin and mucosal malignant melanoma.

1. Central nervous system tumors

Glioblastoma is the most common malignant tumor of the central nervous system with a high lethality rate, and the median survival time (median survival time, MST) is about 14 months.

BNCT is considered as a new treatment option for newly diagnosed and recurrent glioblastoma.

The results of phase I/II clinical studies conducted by scholars in Europe and the United States show that the survival time of newly diagnosed glioblastoma patients after BNCT treatment is comparable to that of the standard chemotherapy and radiotherapy regimen (Stupp regimen).

A number of clinical studies in Japan have shown that the MST of BNCT combined with X-ray radiotherapy and temozolomide chemotherapy in the treatment of glioblastoma can be extended to 19.5-25.7 months.

The prognosis of recurrent glioma is very poor, and the effect of surgery, radiotherapy and standard chemotherapy is not good.

The MST of BPA-BNCT in the treatment of recurrent glioblastoma in Osaka Medical College, Japan is 10.8 months, the MST of combined BPA-BNCT and BSH-BNCT is 15.6 months, and the MST of combined X-ray radiotherapy can reach 23.5 months.

The Japanese multi-center phase II clinical trial (JG002) included 27 patients with glioma who relapsed after standard treatment and had never used bevacizumab (24 of them were glioblastoma), treated with BPA-BNCT, 1 The annual survival rate and MST were 79.2% and 18.7 months, respectively, and the main side effect was cerebral edema.

Meningioma is the most common central nervous system tumor in adults, and most of them are benign, but high-grade meningioma (WHO grade II or III) is highly aggressive, and the local control rate and overall survival rate are both low.

A retrospective study by Osaka Medical College in Japan from 2005 to 2014 showed that after 2 months of BNCT treatment in 31 patients with recurrent high-grade meningioma, the average volume decreased by 64.5%, and the MST was 24.6 months.

2. Head and Neck Tumors

In the clinical studies of head and neck tumors reported in Japan, Finland and Taiwan, BNCT has shown good curative effect.

Japanese scholar Suzuki et al. used BNCT to treat 62 patients with locally recurrent or unresectable head and neck tumors from 2001 to 2007.

The overall response rate was 58% 6 months after treatment, the MST was 10.1 months, and the average survival period was 18.7 months. moon.

Japanese scholar Kato et al. reported that the overall effective rate of BNCT in treating 26 cases of head and neck tumors was 85%, and the quality of life of patients was improved.

In June 2019, the Nantohoku BNCT Research Center in Japan reported the results of the phase II clinical trial of AB-BNCT

. The study included 8 patients with recurrent squamous cell carcinoma of the head and neck who were inoperable and resistant to platinum-based chemotherapy.

There were 13 patients with inoperable, recurrent/locally advanced non-squamous cell carcinoma, and the objective response rates were 75.0% and 69.2%, respectively.

In March 2020, the Japanese National Drug Administration approved BNCT for the clinical treatment of inoperable recurrent head and neck tumors.

3. Melanoma

Melanoma is a malignant skin tumor caused by abnormal hyperplasia of melanocytes.

It has a high degree of malignancy, is prone to recurrence and metastasis, and has a very poor prognosis. Argentina Menéndez et al. reported 7 cases of melanoma patients who received BNCT treatment from 2003 to 2007.

The injection was completed within 90 minutes according to the dose of 14 g/m2 L-BPA. The overall effective rate was 69%, and the grade 3 toxicity (ulcer) rate was 30%. %.

In 2013, the Third Xiangya Hospital of Central South University in some countries launched a “BNCT Clinical Trial on the Effectiveness and Safety of Melanoma Patients”. /kg dose of BPA intravenously, neutron irradiation for 20 min.

The patient developed only mild dandruff at 1 week after BNCT, developed grade 2 dermatitis at 4 weeks, and no tumor was found on biopsy at 9 months and PET scan at 25 months.

4. Other tumors

In addition to the important role of BNCT in the treatment of the above-mentioned tumors, its clinical exploratory research in chest tumors, bone and soft tissue sarcoma, breast cancer, bladder cancer and children’s tumors is also in progress.

(1) Chest tumor

Suzuki et al. reported 2 patients with diffuse pleural tumors (including 1 case of malignant pleural mesothelioma and 1 case of malignant short spindle cell tumor). The follow-up was 6 months after BNCT treatment, the tumors were stable or regressed, and no grade 3 acute or Late toxicity.

This study confirmed that BNCT is an effective treatment for diffuse, unresectable malignant pleural mesothelioma, but for deep thoracic tumors, the therapeutic effect of BNCT remains to be explored.

(2) breast cancer

Studies by Seneviratne et al. have shown that BNCT may be a potential treatment for breast cancer with overexpression of human epidermal growth factor receptor 2 (HER2).

Studies have shown that the use of immunoliposomes (such as trastuzumab-modified liposomes) as a boron carrier can selectively bind to cancer cells expressing HER-2.

In addition, dose analysis shows that BNCT has a significant effect on local recurrence. breast cancer has therapeutic potential. However, its safety and effectiveness need to be verified by further clinical studies.

(3) Bone soft tissue sarcoma

Futamura et al. reported a case of recurrent radiation-induced occipital sarcoma in a patient who was given intravenous BPA at a dose of 500 mg/kg.

The patient had severe walking impairment during diagnostic examination. After 3 weeks of BNCT treatment, he was able to walk stably without assistance.

During the treatment, the patients tolerated it well without skin damage, proving that BNCT is a safe and feasible treatment for osteosarcoma.

Malignant peripheral nerve sheath tumor is a rare and highly invasive soft tissue tumor. There is currently no standard treatment, and surgery is the only sure effective treatment, but the prognosis is poor.

A Japanese scholar reported a case of thoracomediastinal peripheral nerve sheath tumor that recurred after surgery and failed to respond to chemotherapy.

The lesion was located in the right supraclavicular fossa. After receiving two BNCT treatments, there was no recurrence within 2 years.

(4) Extramammary Paget’s disease

For melanoma of the genital region and extramammary Paget’s disease (EMPD), wide surgical excision of the lesion is currently the most commonly recommended treatment, but it is invasive and can lead to functional problems. When surgery is not feasible, new alternative therapies are urgently needed.

Kyoto University in Japan reported 4 patients with genital malignancies (including 1 vulvar melanoma and 3 genital EMPD) who received BNCT treatment, all achieved complete remission within 6 months of treatment.

Therefore, BNCT is a promising treatment for primary vulvar melanoma of the genital region and EMPD.

(5) Malignant brain tumors in children

In the study by Nakagawa et al., a total of 23 patients with malignant brain tumors aged <15 years (including 4 cases <3 years old) received BNCT treatment, including 3 cases of glioblastoma, 6 cases of anaplastic astrocytoma, There were 7 cases of ectodermal tumor, 6 cases of pontine glioma, and 1 case of anaplastic ependymoma, and 4 cases showed no signs of recurrence after treatment. Therefore, BNCT is considered the best treatment for malignant brain tumors in children.

Common side effects of BNCT

The high selectivity of boron drugs to tumor cells makes the incidence and severity of adverse reactions after BNCT treatment lower than that of conventional radiotherapy.

At present, the most common side effect of BNCT treatment for superficial skin tumors is mild skin radiation damage, manifested as dryness and desquamation of the skin at the irradiation site, accompanied by flushing and itching.

Since the same part of the patient only needs to be irradiated once or twice, and the irradiation dose is limited, the skin condition can usually improve on its own within 1 to 4 weeks without special treatment.

Oral mucositis and local hair loss are common side effects in patients with head and neck or other deep tumors treated with BNCT.

These symptoms are mild and can be relieved by themselves. A small number of patients may develop nervous system symptoms such as dizziness and fatigue, or other serious complications of grade III and IV, and active symptomatic treatment is required.

Reference:

14(4): 698-705. d oi: 10.12290/xhyxzz.2023-0120

Boron Neutron Capture Therapy (BNCT): Precisely “blast” cancer cells!

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Boron Neutron Capture Therapy (BNCT): Precisely “blast” cancer cells!

Boron Neutron Capture Therapy (BNCT): Precisely “blast” cancer cells!

Compared with traditional radiotherapy, BNCT has the following characteristics:

1. Central nervous system tumors

2. Head and Neck Tumors

3. Melanoma