Intramedullary Spinal Cord Metastases from Small Cell Lung Cancer: Report of One Case and Review of the Literature


 Purpose

Spinal cord intramedullary metastasis (ISCM) is a rare malignant tumor of the nervous system. Small cell lung cancer (SCLC) accounts for about 15% of lung cancer, and the incidence of brain metastasis is high, but intramedullary spinal cord metastasis is rare. In recent years, the first-line treatment of patients with ISCM from SCLC has been controversial. For these patients with ISCM, the options are usually depending on the progression of the disease.However,the outcom of treatments are not satisfacted.Thus,We try to indentify the use of immunotherapy in ISCM from SCLC.
Methods

In our review, we focused on clinical trials of immunotherapy, especially in relation to ISCM in SCLC.
Results

A patient was diagnosed as ISCM from SCLC. Radiotherapy for ISCM was started on January 11, 2021 Apatinib was taken orally after radiotherapy. The overall survival was almost 8 months, and there was only 1 month after ISCM was diagnosed.
Conclusion

Finding practical treatment options for SCLC is an important goal. Previous trials have shown that immunotherapy with checkpoint inhibitors may be an effective approach for long-term disease control and a new breakthrough in the treatment of ISCM form SCLC.


Introduction
Spinal cord intramedullary metastasis (ISCM) is a rare malignant tumor of the nervous system. Its incidence accounts for 4.2-8.5% of all central nervous system metastases 1, 2 , and nearly 3.5% of spinal metastases, approximately 0.9-2.1% tumor-related deaths are related to ISCM 2, 3 , the incidence of ISCM in lung cancer and breast cancer is higher than other malignant tumor 4 .
Small cell lung cancer (SCLC) accounts for about 15% of lung cancer 5 , and the incidence of brain metastasis is high, but intramedullary spinal cord metastasis is rare. ISCM is one of the rare causes of death in SCLC patients. Japanese scholars reported an elderly patient with ISCM who received radiotherapy combined with systemic corticosteroids and had a poor prognosis 6 ; Professor Gazzeri et al reported 43 patients of intradural spinal cord extramedullary metastases (IESM) surgical related complications and prognosis 7 . ISCM has limited methods and poor prognosis. The main options are surgery, radiotherapy, and drugs, of which radiotherapy is the main option for ISCM. In our case report, we reported a patient who developed ISCM from SCLC after receiving concurrent radiotherapy and chemotherapy. The effect of radiotherapy and systemic treatment was poor, and we reviewed the literature of ISCM research.

Case Presentation
Case presentation A 58-year-old man was admitted to our hospital with numbness and pain in the right lower limb on 2020-04- 10. He was a current smoker. The 5th vertebral body increased metabolism from the Whole-body bone imaging, considering vertebral metastasis, and chest CT scan revealed that right lung space with mediastinum Multiple swollen lymph nodes and pleural effusion on the right side.
The prescribed dose was 95%. PTV 30Gy/10F, and he received rehabilitation treatment at the same time.
Apatinib was taken orally after radiotherapy. After radiotherapy, the symptoms of the right lower limb were improved, but the patient died of respiratory failure due to lung infection on February 1, 2021. The overall survival was almost 8 months, and there was only 1 month after ISCM was diagnosed.

Review Of Literature
Epidemic analyses of ISCM Spinal cord intramedullary metastasis (ISCM) is a rare malignant tumor of the nervous system. Goyal, A.et al.reported the incidence accounts for 4.2-8.5% of all central nervous system metastases 1, 2 . Payer, S.et al .indicated that the the incidence of ISCM is nearly 3.5% in spinal metastases, and approximately 0.9-2.1% tumor-related deaths are related to ISCM 2, 3 .ISCMs constitute 1-3% of all intramedullary tumors and 0.6% of all spinal cord tumor, which is much lower than soft meningeal metastases 8, 9 .
Among the patients with malignant tumor metastasis, lung cancer and breast cancer have the highest rate of ISCM 4 , the rates are as follows: lung cancer (50%), breast cancer (11%), colorectal cancer (3%), kidney cancer (10%), melanoma (8%) and lymphoma (4%) 10,11 . Studies have shown that there may be three possible ways to cause ISCM. 1. Blood dissemination through arteries and/or veins is the main factor; 2. Meningeal circulation through cerebrospinal uid is another important mechanism; 3. In addition, bone metastasis Causing epidural spinal cord compression and then invading the spinal cord parenchyma through the dura is also an important mechanism leading to ISCM 10,12,13 . Other researcher have con rmed that direct invasion is also an important way of ISCM 14 . We know that the incidence of brain metastases from small cell lung cancer is high, but the incidence of ISCM is low. At present, there is no research that indicate the reason on different incidence, and there is a lack of a large amount of research to support the mechanism, and further studies are needed. In this study, a rare case of intramedullary spinal cord metastasis in a patient from small cell lung cancer was reported, and the difference between brain metastasis of small cell lung cancer and spinal cord intramedullary metastasis was explored.
Treatment options of ISCM ISCM has limited treatment options. It is di cult to compare the results and prognosis of different treatment methods. Therefore, the best treatment plan is currently still Controversial 15 . Generally, individualized treatment is performed according to the patient's tumor burden and the clinician's judgment. Treatment often depends on the severity of symptoms and the physician's clinical experience. Current treatment options include microsurgical resection, radiotherapy, and drugs.

Surgical resection
Microsurgery is the main method of ISCM. Its purpose is to improve symptoms and evaluate tumors from the histological aspect, most patients can undergo surgery after initial treatment 16 . Studies have shown that survival can be prolonged by analyzing 22 cases of ISCM undergoing surgery, whether postoperative radiotherapy or chemotherapy 17 . With the advancement of microsurgery techniques and instruments, ISCM patients' symptoms can be improved after surgery, and survival can be Prolonged 10 . In the comparison of the treatment plan and results of 301 ISCM patients, it was found that 33% of patients' neurological symptoms had been signi cantly improved after surgery 18 . In the subsequent follow-up, 120 patients had a longer survival 18 , obviously, Microsurgery can prevent the deterioration of the nervous system and improve the quality of life. However, the postoperative outcome and survival after resection are largely affected by the scope of resection, and with the increase of the patient's tumor burden, the risk of microsurgery increases, and it is often not as a rst-line treatment option. At present, for microsurgery to ISCM, it is necessary to combine radiotherapy and drug therapy to prolong the survival 19 .

Radiotherapy
Radiotherapy is another main method for ISCM treatment besides surgery. Due to the small number of cases, whether radiotherapy is the rst-line treatment is still controversial. Studies have pointed out that radiotherapy can signi cantly improve the neurological symptoms of ISCM, especially in tumors that are sensitive to radiotherapy. Most patients use 1.8/2.0/2.5/3.0 Gy of conventional fractionated dose, and the symptoms have also been obviously improved. This may be partly due to most patients are radiosensitive tumors such as small cell lung cancer and breast cancer 18, 20 . Radiotherapy can be used as a separate option or as supplementary treatment plan after operation in the treatment of ISCM patients. No research has pointed out the difference in survival and neurological symptoms between radiotherapy and surgery in ISCM. However, when surgery and drug treatment fail to achieve a good effect, radiotherapy can improve the patient's neurological symptoms 19 . Complications of radiotherapy include radiation myelopathy and radiation spinal cord necrosis. The effect or risk of radiotherapy is controversial, because the maximum allowable radiation dose of the spinal cord is limited and often does not meet the criteria for radical ISCM. At present, stereotactic radiotherapy can avoid complications and prolong the survival, which is a new idea for ISCM treatment 21 .

Chemotherapy
Drugs as the second choice for ISCM treatment, including chemotherapy, immunotherapy, and targeted therapy. Due to the blood-spinal cord barrier, chemotherapy has almost no effect on the treatment of ISCM, it has been unable to prolong the survival of ISCM patients 13,22 . Chemotherapy is currently used for chemotherapy-sensitive tumors (such as small cell lung cancer and hematological tumors) or as adjuvant treatment of radiotherapy or surgery. Immunotherapy is currently the main program of drug therapy, and it has a good effect on relapsed, metastatic, and refractory ISCM. For cases that no genetic mutations are found, immune checkpoint inhibitors are recommended 23 . In the distant metastasis of nonsmall cell lung cancer caused by oncogenes, such as EGFR, ALK and ROS1 mutations 23,24 . The EGFR tyrosine kinase inhibitors ge tinib, erlotinib or afatinib are very effective and can be used as rst-line drugs. In addition, Anti-angiogenesis such as apatinib can also inhibit tumor growth and reduce patient tumor burden

Anti-angiogenesis
The growth of tumors is vessel-dependent. Large blood vessels provide su cient nutrition and oxygen for tumors. Therefore, there is a hypothesis that anti-vessels of tumor can inhibit the occurrence and development of tumors 25 .
As an Anti-angiogenesis, apatinib is a safe and effective oral drug after the failure of standard chemotherapy for advanced gastric cancer, which can signi cantly prolong the survival of patients 26 . Apatinib as maintenance after chemotherapy in 23 extensive-stage small-cell lung cancer patients,It was found that after taking 250 mg of apatinib, the median PFS after maintenance treatment was 4.1 months (95% con dence interval 3.63-4.57 months). The median OS after maintenance treatment was 12.5 months (95% con dence interval was 5.51-19.49 months). The results of the study suggest that apatinib can make SCLC patients get longer OS and PFS as maintenance treatment after chemotherapy, there were 8 patients with brain metastases, accounting for 34.8% in this study. Although these 8 patients with brain metastases have not been individually analyzed for e cacy, we can speculate that apatinib has a certain anti-tumor activity in patients with small cell brain metastases27.
As a new type of small molecule multi-target tyrosine kinase inhibitor, Anlotinib can strongly inhibit VEGFR, PDGFR, FGFR and other multi-targets 28 . In research of 45 SCLC patients who received Anlotinib, 16 patients of brain metastases were included, accounting for 36%. The median PFS of these patients was 4.1 months, the median OS was 6.1 months, ORR was 11% and DCR was 67%. SCLC patients who received Anlotinib had longer survival 29 . Anti-angiogenic drugs have anti-tumor effects in small cell lung cancer with brain metastases, but there are fewer patients in this study, the evidence is limited, and there is no direct evidence in ISCM. We reported this case. Although apatinib was taken orally after the spinal cord metastasis received radiotherapy, because of the short oral administration time, the effect could not be evaluated. As a PD-1 inhibitor, pembrolizumab can be used for unresectable or metastatic melanoma, and it also has a positive effect on the treatment of small cell lung cancer. In the analysis of 83 cases of SCLC receiving pembrolizumab treatment after two or more lines of therapy, median PFS was 2.0 months, and median OS was 7.7 months, There were 13 brain metastases, accounting for about 15.7%.The sum of the target disease sizes was reduced from baseline in 33 (44%).22 patients (29%) who had at least a 30% reduction in tumor size 33 .
Nivolumab has a positive effect on small cell lung cancer. In the follow-up of 109 SCLC patients treated with nivolumab in third line, it was found that with a median follow-up of 28.3 months (from the rst administration to the database lock), objective response rate was 11.9% (95% con dence interval: 6.5-19.5), and the median duration of response was 17.9 months (range 3.0-42.1). At 6 months, 17.2% of patients had no progression 34 . Phillips reported a patient received Nivolumab to treat ISCM. A 67-year-old female ISCM patient with a 50-year history of smoking was received Nivolumab 3 mg/kg every 2 weeks, combined with surgery and radiotherapy. The patients'clinical manifestations tend to be stable, with no obvious progression of the tumor 35 . Nivolumab may be suitable for ISCM with minimal changes. These studies have con rmed that nivolumab can prolong the survival of patients with small cell lung cancer and can also be used for ISCM from small cell lung cancer.
In a study of 268 SCLC patients treated with durvalumab +platinum + etoposide in rst line, it was found that 28 patients with brain metastases, accounting for about 10%.The median OS was 13.0 months. The 12-month overall survival rate was 54% (47 .4-59.5) and the predicted 18-month overall survival rate was 34% (26.9-41.0), The survival period of the patients was signi cantly longer compared to control group 36 . Durvalumab has positive signi cance for the treatment of SCLC.
Atezolizumab is a monoclonal antibody of PD-L1. Atezolizumab monotherapy is safe and effective for many tumor types. In a retrospective study of 201 SCLC patients who received Atezolizumab in rst line, 35 of the 201 patients had brain metastases. It was found that the median OS was 12.3 months. At the 18th month, 34% of the patients were still alive. ORR in the Atezolizumab+CP/ET group was 60.2% (95% CI, 53.1 to 67.0) and median DOR in the Atezolizumab+CP/ET group was 4.2 months (95% CI, 4.1 to 4.5).
Patients treated with Atezolizumab have a signi cantly prolonged survival 37 . Now, PD-1/PD-L1 checkpoint inhibitors can prolong survival in small cell lung cancer, but there is a lack of head-to-head research data on brain metastases. The e cacy PD-1/PD-L1 checkpoint inhibitors in small cell lung cancer brain metastasis needs more clinical research. Although there are reports on the e cacy of PD-1/PD-L1 checkpoint inhibitor on ISCM, there is a lack of a large amount of research data, and more research is needed.
There are two limitations in our case report.Firstly,the patient had died eventually because of lung infection. Thus,We were unable to assess the effects of chemo-radiotherapy and anti-angiogenesis on ISCM from SCLC. Secondly, our case report need more cases of ISCM to analyse the difference between multiple treatment options for ISCM.

Conclusion
There are few patients with ISCM from SCLC, and no standard treatment plan for ISCM. It is necessary to formulate an individualized plan based on the patient's general conditions, tumor burden, and clinicians 's experience. Surgery, radiotherapy, Immunotherapy and targeted therapy are the main options for ISCM. Although surgery and radiotherapy can prolong survival of ISCM, there are often not as a rst-line treatment option based on risk. stereotactic radiotherapy maybe as a new idea for ISCM treatment. PD-1/PD-L1 checkpoint inhibitors and anti-angiogenesis can make small cell lung cancer achieve longer survival, but this research did not analyze brain metastases. Whether drug treatment can reduce the probability of brain metastases and prolong the survival with brain metastases in SCLC was not analyzed, but the treatment of brain metastases, and the different incidence of ISCM and brain metastases in SCLC is the follow-up goal of this research. In conclusion, nding practical treatment options for SCLC is an important goal. Previous trials have shown that immunotherapy with checkpoint inhibitors may be an effective approach for long-term disease control and a new breakthrough in the treatment of ISCM form SCLC.

Declarations
Funding:The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.
Competing Interests:The authors have no relevant nancial or non-nancial interests to disclose.The authors did not receive support from any organization for the submitted work.
Author Contributions: All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Chenglong Sun, Zhanggui Wang ,Jinfeng Liu,and Huanbing Lu. The rst draft of the manuscript was written by Huanbing Lu and all authors commented on previous versions of the manuscript. All authors read and approved the nal manuscript.

Data Availability statement
The datasets generated during and/or analysed during the current study are available in the Pubmed repository, https://pubmed.ncbi.nlm.nih.gov  Magnetic resonance image (MRI) of the 5th vertebral metastases Magnetic resonance image (MRI) of brain metastases Figure 4 Magnetic resonance image (MRI) of the Spinal cord intramedullary metastasis (ISCM): A sagittal contrast enhanced T1 weighted and T2 weighted MRI of the cervical spine shows intramedullary lesion from the level of T10 to L1 (red arrows).