Current status of targeted guided intra-stromal radiotherapy for glioma

  Glioblastoma is the most common malignant tumor in the skull, accounting for 33.3% to 58.6% of all intracranial tumors, most of which are highly malignant. Most glioma patients survive less than 2 years after diagnosis despite aggressive surgery, radiotherapy and chemotherapy, and there is no effective treatment for patients who relapse after surgery and radiotherapy. Since the 1980s, radioisotope iodine-125 (125I) seeds have been used for intra-stromal radiotherapy of gliomas, which has been proven to significantly prolong the survival time of patients, and Ryken et al. reported that the effect of this treatment is comparable to palliative tumor cell reduction. Siddiqi et al. found that radioactive 125I reduced the proliferative capacity of cells and that indicators positively associated with cell proliferation, such as cell structural heterogeneity, vascular proliferation, degree of mitosis, and immunolabeling of cell nuclear antigens, were significantly reduced in patients after treatment. Therefore, it has good therapeutic prospect.  1, the physical properties and radiobiological characteristics of 125I seeds 125I is a pure weak γ-ray radiation source, a sealed structure of outsourced titanium alloy, 4.5mm long, 0.8mm in diameter, with a 3.0mm * 0.5mm silver column inside adsorbed 125I , whose outer wall is a titanium shell of 0.05mm thickness. Its half-life is 59.6 days, the average energy is 27-35 KeV, and the tissue penetration capacity is 1.7-2.0 cm, which can be usually kept in the drill jar and removed when used.  Unlike ordinary external radiotherapy and stereotactic radiosurgery, the characteristics of intra-stromal radiotherapy are (i) the radiation source is implanted in the tumor, and the majority of the energy release is absorbed by the tumor tissue, while the irradiated dose to the surrounding brain tissue is very small; (ii) the radiation is released in a continuous low dose, which can be regarded as an infinitely small multiple fractionated dose irradiation, in line with the principle of hyper-segmentation therapy, and the biological effect is obviously improved, so it can kill all stages of (3) The dose distribution in tissues is geometrically decreasing, and there is a steep dose slope distribution in normal tissues around the implanted particles; (4) The cumulative irradiated dose around the target area is high, which is exactly what is required to reduce tumor recurrence and cannot be achieved by other radiation therapy methods. The site of recurrence of high-grade glioma is mostly located within 2cm of the edge of the radiotherapy volume.  2.125I implantation mode and quality verification 125I seed intra-stromal radiotherapy includes two modes: temporary and permanent. Temporary interstitial radiotherapy is to implant the catheter containing the radiation source into the tumor, and remove the catheter and the radiation source after several days to several days of treatment, which has a high activity of 10-20mCi per seed and a total cumulative radiation dose of 100-400Gy. -The total cumulative radiation dose is 60-80Gy, which can significantly reduce the occurrence of serious complications related to radiation damage (including radiation necrosis) due to the slow release of radiation. Permanent low-dose-rate intra-stromal radiotherapy with 125I can be permanently placed in the brain and does not require removal.  The implantation method can be divided into intraoperative implantation, in which the radiation seed source is implanted directly into the residual tumor around the operative cavity after microsurgical resection of the tumor, and targeted implantation, which is further divided into imaging (CT or MRI) guided and stereotactic guided implantation methods. The radiation activity, location, and number of implanted particles are determined by the radiation treatment planning system.  Postoperative quality verification is necessary because the implantation process is influenced by the structure of brain tissue or mechanical errors of stereotactic implantation, and sometimes the tumor texture is too tough (hard) or too soft, which can lead to the implantation position of the particles not matching the preoperative plan. The results showed that the average spatial shift of the implanted seeds in the target area was 2 mm, and the actual dose consistency parameter was 0.64. The possibility of underdose in the target area due to the shift of the radioactive source-containing catheter was much greater than the risk of overdose. It is concluded that stereotactic-guided interstitial radiotherapy has high accuracy, and the displacement of the implanted radiation source is best controlled within 1.5 mm.  3, stereotactic 125I seed interstitial radiotherapy treatment planning system (TPS) The ideal TPS should have the following functions: ① with the functions of a stereotactic surgical planning system, namely: to provide clinicians with interactive cranial tomographic image input and three-dimensional reconstruction tools to identify and establish the geometric description of the skull, lesion (target area) and important intracranial structures; in assisting physicians to develop surgical plans When assisting physicians to develop surgical plans, the analysis of the anatomical structures around the lesion simulates the surgical procedure and simulates the relationship between the surgical path and the vital organs, providing the best path to determine the most optimal and rational surgical plan. It has the planning function of stereotactic intra-stromal radiation therapy, i.e.: guiding physicians to use the least number of puncture source distribution channels, (usually 1~2, at most 3), under the guidance of stereotactic technology, to realize the principle of linear source distribution, placing a certain number of iodine-125 seed radiation sources in different parts of tumor tissues, so that the effective radiation dose curve formed by the combination of each source implanted in different parts and with different radioactivity can be reasonably wrapped. The effective radiation dose curve formed by the combination of the implanted sources with different sites and different radioactivity can reasonably cover the whole tumor target area, achieve the three-dimensional conformal tumor target area, and achieve the best treatment effect, and protect the surrounding normal nerve tissue, especially the important structure or radiation sensitive tissue, so that the irradiated dose is within the safe range. ③Postoperative quality verification function: CT scan of brain is performed immediately after surgery, and the CT scan image is correlated and fused with the intraoperative MRI positioning image, and the plan system automatically picks up each particle shown in CT and forms the actual dose distribution of interstitial radiation, compares the actual dose distribution curve with the preoperative designed dose distribution curve, and calculates the overlap rate of the two dose curves on the target area coverage, if it is found that the actual dose distribution is different from the preoperative design after surgery If it is found that the actual dose distribution has a large gap with the preoperative design and the dose curve does not cover the target area satisfactorily, corresponding remedial measures such as increasing external radiation treatment or reimplanting particles should be carried out.  4.Current clinical application and efficacy 1.Treatment of low malignant glioma: 125I interstitial radiotherapy has achieved significant efficacy in the treatment of low malignant glioma. 27 cases of low grade (grade I-II) glioma, 10 cases of grade III and 6 cases of grade IV glioma were treated by Julow et al. et al. synthesized cases reported in the literature with 239 patients with a mean follow-up of 10.3 years and survival rates of 56%, 37%, and 26% at 5, 10, and 15 years, respectively, with progression-free disease survival rates of 45%, 21%, and 14%, respectively, and malignancy rates of 33%, 54%, and 67%, respectively. peraud et al. applied microsurgical resection combined with postoperative stereotactic 125I seed implantation They treated 11 children with functional hypomalignant gliomas as temporary implants, with a 2-cm scalp incision and 6-mm cranial borehole, and applied 3D planning system software to guide the implantation, and removed the catheter containing hypoactive 125I seeds after an average of 26 days, with a 54 GY dose around the tumor. There was no radiation edema or radiological complications, and no tumor recurrence. Only 5 patients had slight improvement in symptoms of neurological deficits.  2. Treatment of highly malignant glioma Local recurrence or progression of tumor is the main cause of death in highly malignant glioma. Clinical studies have confirmed that either temporary or permanent intra-stromal radiotherapy can achieve ideal tumor control and significantly prolong the survival of most patients, especially for glioblastoma (GBM) and mesenchymal astrocytoma (AA) that recur after surgery and radiotherapy. . The median survival of GBM patients treated with permanent and temporary intrastromal radiotherapy reported in the literature was 10.5 to 12 months and 9.1 to 12.3 months, respectively (see Table 1 for details). Statistical data analysis showed that there was no significant difference in overall survival for recurrent GBM treated by low-dose rate interstitial radiotherapy versus high-dose rate interstitial radiotherapy.Patel et al. followed 40 patients with GBM treated with permanent interstitial radiotherapy at a total radiation dose of 120-160 Gy, with a mean survival of 47 weeks, and none had radionecrosis or radiation damage.Gaspar et al. studied particle implantation in 37 cases of GBM and 22 cases of interstitial AA after surgery or recurrence after radiotherapy, with a peri-tumor radiation dose rate of 0.05 Gy/h and a cumulative dose of 100 Gy, with a mean follow-up of 40 months and 86% death. the 1- and 2-year survival rates for GMB were 44% and 13%, respectively, and the 1-, 2-, and 3-year survival rates for AA were 76%, 55%, and 32%, respectively, with a mean group-wide Leibel et al. reported a group of 95 patients with recurrent glioma who were treated with conventional radiotherapy at 40-72 Gy followed by 125I interstitial radiotherapy at 52.7-150 Gy. The mean survival was 18.7 months for astrocytoma and 12.5 months for GBM. 12.5 months, and 49% of patients were treated with reoperation due to radionecrosis caused by high-dose radiation in the target area.