Factors Associated with Cranial Nerve Injury after Radiotherapy for Large Brain Metastases.

This paper mainly studied the correlation factors of cranial nerve injury after radiotherapy for large brain metastases by investigating the influencing factors and predictors of cranial nerve injury, which can provide a good reference and idea for radiotherapy. Through a large number of experiments, it is proved that the research idea proposed in this paper is reasonable and correct.

1. Introduction

Brain Metastasis (BM) is one of the common manifestations of advanced malignancies. The metastases are from malignant tumors in other parts to the intracranial ones, most of them through lymphatic and hematogenous pathways, and some metastases are spread and implanted by cerebrospinal fluid. Cancer cells can often be found in cerebrospinal fluid smear examination of such patients. Among various metastases in the whole body, brain metastases rank third, only second to liver and lung metastases [1]. With the development of multidisciplinary treatment, imaging technology, and the prolongation of patient survival, in recent years, the incidence of brain metastases of malignant tumors has increased significantly. When patients were diagnosed with brain metastases, the clinical stage was stage IV, basically in the advanced stage of tumor. Such patients had rapid pathological changes and high mortality. The average survival time of patients without treatment is only 1.0 months, and the average survival time of patients treated with hormones and dehydrators may be extended to 1.7 months [2]. For a long time, radiotherapy has been the main treatment for BMS. It is mainly suitable for patients with multiple BMS who are not suitable for surgery or stereotactic radiosurgery (SRS), have poor systemic function, and have severe systemic diseases. However, whole brain radiotherapy alone (WBRT) only extended the median survival time to 4–6 months [3]. Intracranial metastases (also known as brain metastases) refer to the tumor cells that are primarily located in other parts of the body, which are transferred to the intracranial area. The incidence rate is 3.5%–10% of intracranial tumors. Both at home and abroad, the most common brain metastases are lung cancer, followed by melanoma, urogenital tumors, and digestive tract tumors. A considerable number of patients cannot find primary tumors, even with brain metastases. The source of the tumor could not be determined after operation.

As the survival time of tumor patients is prolonged, and the sensitivity of imaging diagnosis is improved, the incidence of BMS is increasing in recent years, and it has become the most common intracranial tumor [4]. Literature has reported that 20–40% of patients with malignant tumors, especially lung cancer and breast cancer, will develop BMS, among which more than 90% of patients are brain parenchymal specialties, about 37% to 50% BMS are single, and the rest are multiple. At present, the treatment plan mainly includes local treatment such as radiotherapy, surgery, and integrated treatment combined with systematic treatment. In terms of radiotherapy, the status of stereotactic radiotherapy (SRT) continues to rise, especially in the intracranial control, survival extension, neurological function improvement, and other aspects of large-volume, multiple and other refractory brain metastases [5]. However, the prognosis of these metastases is still poor. On the other hand, stereotactic radiotherapy combined with chemotherapy, targeted therapy, and even immunotherapy has gradually become a research hotspot [6]. In addition to asking whether there are symptoms such as headache, vomiting, blurred vision, hemiplegia or monoplegia, and unclear language, attention should be paid to understand whether there is a history of malignant tumors and surgery in lung, breast, adrenal gland, uterus, gastrointestinal tract, thyroid, and other organs.

The aim of this paper is to identify indicators that influence the response to radiotherapy to optimize the selection of treatment options and identify patients who do not respond to radiotherapy, so as to avoid group cranial nerve injury in patients treated with WBRT.

2. Brain Metastases Are Associated with the Treatment Methods and Prognostic Factors

2.1. Pathogenesis and Pathophysiology of Brain Metastases

Brain Metastasis (BM) is one of the common manifestations of advanced malignant tumors. Metastasis from malignant tumors in other parts to the brain is mostly through lymphatic and hematologic pathways, and some metastases are spread and implanted by cerebrospinal fluid. Cancer cells can often be found in cerebrospinal fluid smear examination of such patients [7]. Among the metastases in the whole body, brain metastases rank third, only second to liver and lung metastases. According to data, there are about 150,000 to 200,000 new cases of brain metastases in the United States every year, accounting for 10%–30% of all tumor patients. It has also been reported that the application of various new chemotherapy and targeted therapy drugs leads to the destruction of the blood-brain barrier in patients with BMS to varying degrees, which makes BMS more likely to occur. Single BMS are rare, and more than 65% of patients have multiple BMS. CT scan showed single or multiple abnormal density shadows in the brain, with clear boundaries. Those with large lesions may have low-density necrotic areas or high-density hemorrhagic foci, with severe edema around. After enhancement, the solid part was significantly strengthened. MRI showed low signal on T1 weighted and high signal on T2 weighted. The morphological changes after enhancement were roughly similar to those seen by CT enhancement. MRI is the best diagnostic method for detecting brain metastases.

Generally speaking, tumors have different sizes and imaging features, with bleeding, calcification, cystic change, and so on. Therefore, comprehensive analysis should be made in combination with the general clinical characteristics, medical history, and imaging manifestations of patients in clinical practice to avoid delayed treatment and wrong treatment caused by misdiagnosis and missed diagnosis [8].

Although there are many hypotheses about the pathogenesis of BMS, the available evidence suggests that the dynamic interaction between metastatic cells and the microenvironment leads to the occurrence of BMS.

Despite these limitations, there are still some cells that can migrate to the central nervous system, where the mechanism is yet to be explained, but studies have found that, over the past decade, when there is disturbance after brain homeostasis, part of the loop mononuclear cells through the blood-brain barrier is to deal with related disturbance. The whole body auxiliary examination should look for the primary focus as much as possible. Check whether there are tumor lesions in thyroid, liver, prostate, pelvic organs, stomach, and lung by B-ultrasound, radionuclide scanning, whole gastrointestinal barium meal, gastroscope, chest film, and chest CT.

And the cerebrospinal fluid barrier is formed by veins from epithelial cells, and these cells are closely connected, and the veins have openings and intercellular spaces in the capillaries that allow molecules to move freely through those Spaces. The complement protein C3 of primary tumor can destroy the cerebrospinal fluid barrier and enter the cerebrospinal fluid. This process explains the formation and growth of pia metastases.

At the same time, modern gene analysis links different driver gene mutations with the occurrence of lung adenocarcinoma. However, further studies found that genes, such as tumor suppressor genes LKBl and XI US, not only were related to the formation and growth of lung cancer, but also played a role in the occurrence and development of BMS. The highly active expression of WNT signaling pathway is also associated with the formation of brain and bone metastases of lung adenocarcinoma, through the transcription factor mediators H0xB9 and LEFl to stimulate the invasion and proliferation of tumor cells. The clinical concern is whether these signaling pathways can provide an effective therapeutic target for the prevention of BMS.

2.2. Treatment of Brain Metastases

2.2.1. Surgical Treatment

The regular treatment of BMS includes surgery, radiotherapy, and chemotherapy. The number of BMS is still used as the node of treatment choice. Surgery, whole brain radiotherapy, and SRS are the treatment options for 1–3 resectable BMS. The choice of surgical treatment can be made according to the need for pathological diagnosis, the size of brain metastases (larger than 2 cm in diameter), and whether the location is superficial [9]. However, less than 30% of patients have the opportunity for surgery, and WBRT or SRS is recommended after surgery. Surgery is not appropriate for patients with more than 3 BMS.

2.2.2. Radiation Therapy

Radiotherapy plays an extremely important role in nonoperative BMS. According to the NCCN guidelines of the United States, 20 Gy–40 Gy/5–20 doses of total brain irradiation should be given to NSCLC BMS, and 30 Gy/10 times or 37.5 Gy/15 times are the best regimen. The recently published QUARTZ trial is the only randomized controlled study of lung cancer BMS that compared systemic supportive care (hormone) with WBRT and showed no benefit for patients with GPA below 2.5 [10]. However, survival advantage was improved for younger patients with higher GPA. Individualized strategies are more suitable for the treatment of MULTIPLE BMS in NSCLC with WBRT for patients of different ages. However, due to the dose (volume) limitation of normal tissue, WBRT cannot reach the lethal dose of tumor, and the risk of local recurrence is high. Simultaneously integrated boost (WBRT + SIB) is also used as a radiotherapy option for BMS. Tumor radiotherapy is a local treatment of tumor by radiotherapy. Radiation includes radiation produced by radioisotopes α, β, γ X-rays and X-rays, electron lines, proton beams, and other particle beams generated by various X-ray therapeutic machines or accelerators. About 70% of cancer patients need radiotherapy in the process of cancer treatment, and about 40% of cancer patients can be cured by radiotherapy. Radiotherapy plays an increasingly prominent role in tumor treatment and has become one of the main means of treating malignant tumors.

In recent years, the damage of WBRT to neurocognitive function has attracted more and more attention. Most studies believe that cognitive impairment caused by radiation damage is related to the hippocampus, where the subgranular zone (SGZ) is involved in the formation of new memories, memory storage, solidification, and reproduction. Studies have suggested that the hippocampus can be protected during whole brain radiotherapy to reduce the occurrence of cognitive impairment. To this end, several studies have analyzed the risk of tumor lesions in the hippocampus and in 5 to 10 mm expansion.

In recent years, several WBRT + SIR studies have confirmed its feasibility. Related scholars have reported the application of WBRT + SIB in NSCLC brain metastases. A total of 11 patients with lung adenocarcinoma brain metastases (70 lesions) were collected, and the 1-year intracranial control rate was 67%, without grade 3 or higher toxic side effects. Volumetric modulated arc therapy (VMAT) was used in WBRT of 1∼3 brain metastases, which could reduce the dose of hippocampus and ensure that the dose of brain metastases could reach the lethal dose of tumor.

SRS is preferentially recommended for safe, small intracranial tumors, which can give a higher dose of radiation to the lesion without increasing normal tissue damage. Priority should be given to WBRT only in exceptional clinical conditions (e.g., intraventricular metastasis, cerebellar metastasis, meningeal metastasis, non-SRS indication, low PS score, advanced age, etc.). Due to the advantages of SRS, such as accurate localization, high target dose, and small toxicity, multiple studies have confirmed the effectiveness of SRS in NSCLC BMS.

The choice between WBRT and SRS after BMS has also been debated. However, the rate of distant intracranial metastasis after SRS is high, and WBRT and SRS have different focuses. Some scholars have begun to study the combined treatment of the two. A meta-analysis of WBRT + SRS showed that the combined treatment of WBRT and SRS improved the 1-year local control rate of patients with BMS compared with radiotherapy alone [11].

The use of WBRT and SRS in more than three patients with metastases is a continuous discussion. WBRT is a common treatment for multiple nonsmall brain metastases lung cancer, but a series of retrospective studies show that the number of brain metastases is not the subject of SRS recruitment, which indicates that the role of SRS in multiple brain metastases should be improved.

The curative effect of radiotherapy depends on radiosensitivity. The reaction degree of different tissues and organs and various tumor tissues after irradiation is different. Radiosensitivity is related to the proliferation cycle and pathological grade of tumor cells; that is, actively proliferating cells are more sensitive than nonproliferating cells. The higher the degree of cell differentiation, the lower the radiosensitivity, and vice versa. In addition, the oxygen content of tumor cells directly affects the radiosensitivity. For example, the radiosensitivity is low when the early tumor is small and has good blood circulation, the curative effect is good when there are few hypoxic cells, the late tumor is large, the blood circulation in the tumor is poor, and even there is necrosis in the center. The local squamous cell carcinoma has better blood circulation and higher sensitivity than the tumors in the hips and limbs; The tumor was accompanied by local infection, poor blood circulation (more hypoxic cells), and decreased radiosensitivity. Therefore, keeping the irradiation site clean and preventing infection and necrosis are important conditions for improving radiotherapy sensitivity.

2.2.3. Chemotherapy

Chemotherapy is not considered a priority over radiotherapy. Even in the NCCN guidelines for the nervous system, systemic chemotherapy is included as second-line therapy only in recurrent BMS. Poor response to chemotherapy is often attributed to the blood-brain barrier. In fact, when brain metastases grow to a certain size, the blood vessels of the tumor destroy the integrity of the blood-brain barrier. In MRI or CT enhanced scanning, the contrast agent development of brain metastases confirmed this hypothesis [12].

At present, two platinum-containing drugs are the most commonly chosen chemotherapy regimens. The BMS response rate fluctuates between 20 and 40%, especially after pemetrexed emerges. Two recent retrospective studies of pemetrexed in combination with cisplatin in the treatment of nonsmall cell lung cancer brain metastases have shown that intracranial response rate and mean survival time were good. The control rate of extracranial damage to pemetrexed was 34%.

Temozolomide is very controversial. It has been widely used in the chemotherapy of intracranial tumors because of its fat soluble properties and strong blood-brain barrier passability. A phase 3 clinical trial (RTOG0320) included 124 patients with NSCLC with one to three brain metastases. The study was prematurely terminated due to slow enrollment. In a limited data analysis, median survival was 13.4 months, 6.3 months, and 6.1 months, respectively. The authors concluded that radiotherapy combined with temozolomide was not beneficial or even harmful.

The reactions of chemotherapy to digestive system include nausea, vomiting, diarrhea, and constipation. Nausea or vomiting is one of the most common reactions to chemotherapy. In recent years, some powerful and effective antiemetic drugs have been listed, which greatly reduce the nausea and vomiting reaction after chemotherapy. In addition, most of the adverse reactions and side effects of chemotherapy are reversible, and the side effects can be controlled or reduced through the use of some adjuvant drugs. However, chemotherapy is a more intense treatment after all. Therefore, clinicians should strictly grasp the indications of chemotherapy, formulate a standardized and reasonable chemotherapy plan, and take necessary preventive measures.

2.3. Prognostic Factors in Patients with Brain Metastases

Through a retrospective analysis of 318 patients with brain metastases treated by SRS, some scholars did not conclude that age had an impact on the prognosis of patients. However, some literatures have reported that age is a factor affecting the prognosis of patients, but the specific age classification criteria have not been unanimously determined [13]. Currently, scholars generally believe that there is no significant correlation between gender and survival of patients with BMS.

However, there are also some reports that gender has an impact on the prognosis of patients. Some experts concluded that the survival time of female patients was longer than that of male patients [14]. In this study, there was no statistical difference in median survival between patients of different genders, which was consistent with most reported results.

Clinically, once a patient has brain metastases, it is often indicated that the cancer cells have metastasized to the blood and started to spread widely throughout the body with the blood tract. It has been reported that about 30% to 65% of patients with brain metastases may be accompanied by metastasis to other organs outside the skull. Multiple literatures on the prognosis of patients with single brain metastases indicate that it is much better than that in patients with multiple brain metastases, for all of this research is a multiple of patients with brain metastases, so based on the number of metastases, 3 and >3 or less groups were analyzed, and the clinical workers for less than three intracranial metastases patients should take active surgical treatment, prolonging the survival period [15].

In clinical practice, surgery alone for BMS has poor efficacy. Many literatures have reported that WBRT after BMS can significantly improve the local tumor rate and the whole brain control rate and reduce the recurrence of tumors, compared with surgery alone. In the past, it was thought that conventional chemotherapeutic drugs were affected by the blood-brain barrier when entering the intracranial, which made the concentration reaching intracranial tumors extremely low, directly affecting the curative effect of chemotherapy. In recent years, the role of chemotherapy in the treatment of BMS has been significantly improved. Studies have confirmed that the blood-brain barrier in and around BMS has been relatively damaged, and chemotherapy drugs can penetrate the blood-brain barrier into intracranial metastatic lesions and play a role. Some small molecule targeting drugs have higher BBB permeability than traditional drugs and often achieve better efficacy in clinical treatment of PATIENTS with BRAIN metastases with EGFR mutation.

Multiple brain metastases tumor treatment research is slow development, and there is no formation of standardized treatment mode, which needs to make full use of modern neurosurgery clinical and scientific research workers of new technologies, new methods, all experts of the combination of evidence-based medicine, and clinical experience, to carry out multicenter randomized clinical trial, according to the specific situation of the patients, and make reasonable comprehensive treatment scheme, systematic treatment. Under the premise of ensuring the quality of life of patients, the goal is to maximize the improvement of neurological function, reduce neurological symptoms, and prolong survival time. To further improve the therapeutic effect of BMS, efforts should be made in many aspects, such as the molecular mechanism of the occurrence and development of BMS and the search for new and effective therapeutic methods. Under light microscope, at the initial stage of tumor cell metastasis, they first stop in the cerebral vascular cavity and then invade the brain tissue. The tissue of brain metastases is generally the same as that of the primary tumor, sometimes less differentiated than that of the primary tumor, and may be more disordered in structural arrangement, but there are also those with better differentiation than the primary tumor.

3. Animal Experiments on Nerve Injury after Radiation Therapy

3.1. Experimental Animals

Thirty healthy male rats were used, SPF grade, 3 months old, weighed about 220 g before radiation. Animal feed: SPF grade rat feed and maintenance feed. Feeding conditions: school, SPF grade barn, barrier environment, independent isolation cage feeding, environmental control: temperature 20–26°C, humidity 40–70°C, ammonia concentration ≤14 mg/m3, noise ≤60 DM (A), natural light (12 hours A day), free eating and drinking.

3.2. Experimental Methods

In this experiment, 30 rats were randomly divided into short-term normal group (1C), short-term radiotherapy group (1R), medium-term normal group (7C), medium-term radiotherapy group (7R), long-term normal group (28C), and long-term radiotherapy group (28R), with 5 rats in each group. Rats in each group were given standard maintenance feed and purified water for 2 weeks before exposure. Three groups of radiation rats were sent to hospital for radiation therapy.

3.3. Biochemical Indexes of Brain Issue

In this study, the levels of SOD, MDA, TNF-α, IL-6, and other inflammatory factors and caspase-3 and other apoptotic factors were detected to investigate the levels of oxidative stress in mice.

All the above factors were detected by ELISA kit, which was rapid and accurate. Take out a small amount of frozen grinding tissue powder, weigh it, and put it into a 1.5 mL centrifuge tube. RIPA lysate was added in the proportion of 6 μ L/μg. The supernatant was centrifuged at 5000 r/min for 10 min after being placed in ice for 30 min.

3.4. Data Statistics and Analysis

SPSS is the earliest statistical software in the world that uses graphical menu driven interface. Its most prominent feature is that the operation interface is very friendly, and the output results are beautiful. It shows almost all functions in a unified and standardized interface, uses the windows window to show the functions of various data management and analysis methods, and the dialog box shows various function options. As long as users master certain windows operation skills and master the principle of statistical analysis, they can use the software to serve specific scientific research work.

In this paper, SPSS20.0 data statistical software was used to encode and input valid data obtained from the experiment, and further reliability and validity test, descriptive statistics, T test, correlation analysis, and regression analysis were carried out. The t-test formula used in this paper is as follows:

In the formula, X is the sample mean, μ is the population mean, and σ is the sample standard deviation.

X1 and X2 are the mean of the two samples, σ X1 and σ X2 are the variance of the two samples, and γ is the correlation coefficient of the relevant samples.

4. Effects of Radiation Therapy on Nerves

4.1. Changes in Oxidative Stress Levels

As shown in Table 1, MDA content in brain tissue increased significantly in a short time after radiation, indicating that brain tissue was attacked by ionizing radiation and produced a large number of free radicals. However, the content of free radicals decreased with the extension of time, and the level of MDA returned to normal at 28 days. This suggests that the short-term effects of radiation are damaged, the body changes a lot, and the long-term damage may be because the body has adapted, so it does not change. Oxidative stress is a state of imbalance between oxidation and antioxidation in the body, which tends to oxidize, leading to neutrophil inflammatory infiltration, increased protease secretion, and the production of a large number of oxidative intermediates. Oxidative stress is a negative effect produced by free radicals in the body and is considered to be an important factor leading to aging and disease.

Table 1

MDA content in brain tissue.

	Short period	Metaphase	Long term
Control group	0.54	0.61	0.53
Radiation group	1.43	1.17	0.57

As shown in Figure 1, SOD activity in brain tissue decreased to the lowest level at the early stage after radiation, which was also the reason why MDA content increased particularly rapidly at the early stage after radiation. However, as time goes by, the brain tissue damage gradually recovers, the body gradually adapts to the radiation damage, and the SOD activity in the brain gradually increases, but the rate of increase is relatively slow.

Figure 1

SOD activity in brain tissue.

4.2. Changes in Levels of Inflammatory Cytokines

As shown in Table 2, the concentration of TNF-α in brain tissue increased significantly over a short period of time, and the difference between the radiotherapy group and the normal group remained significant up to 7 days after radiotherapy. On the 28th day after radiotherapy, the concentration of TNF-α in the radiotherapy group had recovered, and there was no significant difference between the radiotherapy group and the normal group.

Table 2

TNF concentration in brain tissue.

	Short period	Metaphase	Long term
Control group	62	59	66
Radiation group	78	74	61

As shown in Figure 2, like the concentration of TNF-α, the concentration of IL-6 in brain tissue also reached the maximum within a short time after radiation and continued to decrease after radiation, but the decrease was not very large. At the 28th day after radiation, there were still significant differences between the radiation group and the normal group. This is different from the concentrations of TNF-α.

Figure 2

IL-6 concentration in brain tissue.

As shown in Figure 3, the concentration of IFN-γ in brain tissue, like the concentration of TNF-α, peaked for a short time after radiation and then continued to decline, but not to a great extent. At the 28th day after radiation, there were still significant differences between the radiation group and the normal group.

Figure 3

INF concentration in brain tissue.

4.3. Changes of Apoptotic Factor Levels

As shown in Figure 4, the concentration of caspase-3 in brain tissue began to increase after radiation and disappeared 24 hours after radiation, that is, one day after radiation, and the difference between the radiation group and the normal group reached an extremely significant level. This importance did not decrease over time, suggesting that apoptosis continued to occur. This is possible because radioactive radiation is an important means of inducing apoptosis, which does not stop in a short time, which explains why the damaging effects of radiation can last for a long time.

Figure 4

Concentration of caspase-3 in brain tissue.

5. Conclusions

At present, there are many therapeutic methods for intracranial primary tumors and brain metastases, including surgery, radiotherapy, chemotherapy, and targeted drug therapy, but radiation therapy may cause damage and adverse reactions to brain tissues and cranial nerves. In this paper, through the establishment of rat experimental model and experimental scientific research, it is known that patients will have rapid adverse reactions in the short term after radiotherapy, including the production of a large number of free radicals and inflammatory factors. But, over time, the damage will repair itself. This model can be used to investigate the pathogenesis of brain injury or drug efficacy, which has certain reference significance for disease diagnosis and treatment.