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 metastases1, 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 ISCM2, 3.ISCMs constitute 1–3% of all intramedullary tumors and 0.6% of all spinal cord tumor, which is much lower than soft meningeal metastases8, 9.
Among the patients with malignant tumor metastasis, lung cancer and breast cancer have the highest rate of ISCM4, 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 fluid 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 ISCM10, 12, 13. Other researcher have confirmed that direct invasion is also an important way of ISCM14. 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 difficult to compare the results and prognosis of different treatment methods. Therefore, the best treatment plan is currently still Controversial15. 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.
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 treatment16. Studies have shown that survival can be prolonged by analyzing 22 cases of ISCM undergoing surgery, whether postoperative radiotherapy or chemotherapy17. With the advancement of microsurgery techniques and instruments, ISCM patients’ symptoms can be improved after surgery, and survival can be Prolonged10. In the comparison of the treatment plan and results of 301 ISCM patients, it was found that 33% of patients’ neurological symptoms had been significantly improved after surgery18. In the subsequent follow-up, 120 patients had a longer survival18, 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 first-line treatment option. At present, for microsurgery to ISCM, it is necessary to combine radiotherapy and drug therapy to prolong the survival19.
Radiotherapy is another main method for ISCM treatment besides surgery. Due to the small number of cases, whether radiotherapy is the first-line treatment is still controversial. Studies have pointed out that radiotherapy can significantly 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 cancer18, 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 symptoms19. 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 treatment21.
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 patients13, 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 recommended23. In the distant metastasis of non-small cell lung cancer caused by oncogenes, such as EGFR, ALK and ROS1 mutations23, 24. The EGFR tyrosine kinase inhibitors gefitinib, erlotinib or afatinib are very effective and can be used as first-line drugs. In addition, Anti-angiogenesis such as apatinib can also inhibit tumor growth and reduce patient tumor burden
The growth of tumors is vessel-dependent. Large blood vessels provide sufficient nutrition and oxygen for tumors. Therefore, there is a hypothesis that anti-vessels of tumor can inhibit the occurrence and development of tumors25.
As an Anti-angiogenesis, apatinib is a safe and effective oral drug after the failure of standard chemotherapy for advanced gastric cancer, which can significantly prolong the survival of patients26. 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% confidence interval 3.63–4.57 months). The median OS after maintenance treatment was 12.5 months (95% confidence 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 efficacy, 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-targets28. 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 survival29. 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.
The anti-PD-1/PD-L1 pathway
PD-1/PD-L1 can inhibit T cell activation and proliferation, trigger T cell apoptosis, induce and maintain immune function, tumor immune tolerance and escape30, thus blocking PD-1/PD-L1 signal Can promote immune response31. At present, there are mainly pembrolizumab, nivolumab, Durvalumab, Atezolizumab, all of which can inhibit PD-1/ PD-L1, inhibit tumor progression32.
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 size33.
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 first administration to the database lock), objective response rate was 11.9% (95% confidence 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 progression34. 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 tumor35. Nivolumab may be suitable for ISCM with minimal changes. These studies have confirmed 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 first 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 significantly longer compared to control group36. Durvalumab has positive significance 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 first 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 significantly prolonged survival37.
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 efficacy PD-1/PD-L1 checkpoint inhibitors in small cell lung cancer brain metastasis needs more clinical research. Although there are reports on the efficacy 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.