Non-small cell lung cancer (NSCLC) accounts for more than 80% of all lung cancers and is the leading cause of cancer-related deaths worldwide. About 50% of patients have distant metastases at the time of diagnosis, and this article describes the current status of treatment of lung cancer metastases (brain, bone, malignant pleural and pericardial effusions, liver, and adrenal glands).
Treatment of isolated metastases
There is a special type of lung cancer metastasis, namely, single organ and single lesion metastasis, which is called isolated metastasis. isolated metastasis occurring within 3 months is called simultaneous isolated metastasis, and those occurring more than 3 months are called heterogeneous isolated metastasis. common sites of isolated metastasis are brain, bone, adrenal gland and liver. In general, if the primary lesion can be completely resected, local treatment (surgery or radiotherapy) + systemic treatment (chemotherapy or targeted therapy) is recommended for primary and concurrent isolated metastases; if the primary lesion becomes stage III (ipsilateral mediastinum with lymph nodes or subsurface lymph nodes) of NSCLC with resectable isolated metastases, chemotherapy-based combination therapy is recommended; if the primary lesion is evaluated as incomplete If the primary lesion is assessed as not completely resectable, systemic therapy should be the main treatment even if the isolated metastatic lesion is completely resectable. For resectable isolated metastases occurring at a different stage after primary lung cancer surgery, surgical resection + systemic therapy is recommended if the anaplastic interval is >6 months; if the anaplastic interval is <6 months, conformal radiotherapy + systemic therapy is recommended. For isolated metastatic lesions, it should be clarified whether they are true isolated metastases or pseudo-isolated metastases. Enhanced magnetic resonance imaging (MRI) is recommended for intracranial lesions, and positron emission tomography (PET) or PET/CT imaging is recommended for extracranial lesions.
Treatment of brain metastasis
Lung cancer patients are prone to brain metastases, which may occur on the surface of the brain (soft meninges and meninges) or in the parenchyma (brain, cerebellum, brain stem). The distribution of brain metastases mainly reflects the cerebral blood flow, with 80% of the lesions in the brain, 15% in the cerebellum and 5% in the brainstem. About 10-25% of lung cancer patients are found to have brain metastases at the time of diagnosis, and 40-50% of patients have brain metastases at different stages of the disease, and the appearance of brain metastases predicts a poor prognosis for patients. At present, the main treatment for lung cancer brain metastases is palliative treatment, including surgery, radiotherapy, chemotherapy, targeted therapy, etc. The median survival time (MST) of patients with lung cancer brain metastases is only 1 month without treatment, about 2~3 months after adding hormone therapy, and about 6 months after combined with whole brain radiotherapy.
For critically ill patients who cannot tolerate surgery or acute critically ill patients are first given symptomatic treatment with drugs, such as hormones and dehydrating drugs, to relieve the symptoms of intracranial hypertension, and then other treatments are taken after the condition stabilizes. Hormones are the basis of treatment for brain metastases and are effective in 70% of patients, often in combination with other treatments. In addition, drugs such as dehydration and diuretics, seizure control drugs and tranquilizers may be used.
Surgical treatment is mainly indicated for lesions that are isolated intracranially and located in areas that can be reached surgically. For concurrent, symptomatic solitary brain metastases, patients with stable extracranial lesions and good general status can benefit from surgical resection, and the 5-year survival rate (OS) after surgical resection is between 10% and 20%, and whole brain irradiation can be given after surgery, followed by systemic chemotherapy and surgical resection of the primary lesion; for concurrent, asymptomatic isolated brain metastases, if the general status is good, systemic chemotherapy is recommended first. For asymptomatic isolated brain metastases occurring at the same time, if the general condition is good, it is recommended to first administer 3-4 cycles of systemic chemotherapy, followed by surgical resection of the isolated brain metastases + whole brain radiotherapy and then surgical resection of the primary lung lesions. For 1-3 intracranial metastases with a maximum diameter of less than 3CM, which cannot be treated surgically, stereotactic surgery (SRS) is feasible, followed by whole brain radiation therapy or not. For symptomatic multiple brain metastases, whole-brain radiation therapy is the current standard of care. After treatment of brain metastases, for patients with early stage, sequential chemotherapy after surgical resection of pulmonary lesions; or SRS of pulmonary lesions; chemotherapy followed by surgical resection of pulmonary lesions. For patients with late staged NSCLC, systemic therapy is an option. A series of phase II clinical studies have shown the efficacy of chemotherapy for NSCLC brain metastases, such as pemetrexed, nanopaclitaxel, topotecan, etc.; and molecular targeted therapies such as tyrosine kinase inhibitors (TKI), bevacizumab, etc., have also shown some efficacy.
Treatment of bone metastasis
Bone is also a good site for lung cancer metastasis, and the incidence and location are related to the type of lung cancer cases. Adenocarcinoma has the highest incidence of bone metastasis, followed by small cell carcinoma and squamous carcinoma. The most common sites are: ribs, thoracic spine, lumbar spine and pelvis. Bone metastases from lung cancer are mostly osteolytic, while small cell undifferentiated carcinoma and a few adenocarcinomas may show osteogenic destruction. 86% of lung cancer bone metastases are osteolytic, 6.9% are osteogenic and 6.9% are mixed. The current management of lung cancer bone metastases includes: systemic treatment, radiotherapy, and surgery, and these treatments are considered in a comprehensive manner, and the choice of modality depends on the severity of bone metastases and the survival time of patients. The goals of treatment for bone metastases from lung cancer are: to relieve pain, restore function, improve quality of life, and prevent or delay the occurrence of bone-related events (SREs).
Systemic treatment depends on the type of tumor and includes chemotherapy, hormone therapy, immunotherapy, stem cell therapy, bone marrow transplantation and phosphate therapy. The choice of chemotherapeutic agents should firstly clarify the pathological type of the primary site and secondly be performed in the absence of pathological fractures in bone metastases. Zoledronic acid can effectively prevent or delay the occurrence of bone-related events caused by bone metastases (including osteolysis and osteogenesis) from lung cancer, and can be used for clinical treatment by intravenous zoledronic acid 4 mg (no less than 15 minutes), repeated every 3-4 weeks.
For patients in good physical condition with limited bone metastases occurring in weight-bearing bone with functional impairment and pain, surgical treatment + radiotherapy followed by systemic therapy is recommended.
External radiation radiotherapy has become the mainstay of bone metastatic disease, and the purpose of radiotherapy is to relieve pain and control local lesions. External radiation radiotherapy can relieve symptoms in 80-90% of patients, and pain can be completely relieved in 50-85% of patients. Whole-body radionuclide therapy with strontium 85, strontium 89, samarium 153, or rhenium 188 can be used as an alternative to hemi-irradiation used in extensive bone metastases, and the most common adverse effect is bone marrow suppression. Therefore, patients should not be treated with whole-body radionuclide therapy after receiving chemotherapy or hemibody radiation therapy.
Indications for surgery for bone metastases from lung cancer are: the need for biopsy, treatment of pathological fractures of long bones, instability of the spine, and use after failure of radiotherapy. The modalities of surgery include: tumor resection. For those with established fractures, conservative treatment is ineffective, and artificial joint replacement and internal fixation can be effective in reducing pain and restoring function. The median survival of untreated patients is 4 to 5 months, and the 1-year survival rate of treated patients is 40% to 50%.
Treatment of thoracic metastases
Pleural or pericardial effusion is a criterion for the diagnosis of stage IV. Although 90-95% of pleural effusions are malignant, it may also be caused by obstructive pneumonia, pulmonary atelectasis, lymphatic or venous obstruction, or pulmonary embolism. Therefore, thoracentesis or pericardiocentesis is recommended to obtain pathologic confirmation. In cases where thoracentesis is inconclusive, thoracoscopy is feasible. Pleural effusions that are exudative or hemorrhagic and have no non-neoplastic etiology (e.g., obstructive pneumonia) are considered malignant regardless of cytologic findings. 95% of patients with pleural effusions (malignant or not) are inoperable because the staging is stage IV and systemic therapy should be the mainstay. Those with malignant pleural or pericardial effusion can be treated with local therapy as stage M1a, such as portable chest tube drainage, pleural fixation and pericardial windowing. Other systemic treatments (including targeted and chemotherapy) are the same as those for stage IV including systemic treatment.
Local treatment of malignant pleural effusion includes pleural drainage and intrathoracic drug therapy, pleural radiotherapy, pleural dissection, palliative drainage (thoracoabdominal shunt and built-in chest drain), commonly performed by thoracentesis aspiration and chest tube placement for drainage. Drugs used in thoracic medicine include sclerosing agents, chemotherapeutic agents, and biological response modifiers.
Intrathoracic chemotherapy is currently the most common method for treating malignant pleural fluid, which can act directly on cancer cells to achieve the purpose of eliminating pleural fluid. It is applicable to cancer cells found in pleural fluid, and is not applicable to pleural fluid caused by primary lesions of tumors or metastases compressing blood vessels and lymph vessels. Intrathoracic chemotherapy can directly stimulate the pleura to cause chemical pleurisy resulting in pleural adhesions and play the role of pleural fixation, and can also directly kill cancer cells through chemotherapeutic drugs to achieve the purpose of eliminating pleural fluid. Commonly used chemotherapeutic drugs include: cisplatin, carboplatin, bleomycin, adriamycin, VP-16, vincristine, etc.
The principle of action of sclerosing agent is mainly to stimulate the pleura to cause inflammatory adhesions, and the commonly used sclerosing agents in recent years include tetracycline, doxycycline, memantine, talcum powder, etc.
Biological immunotherapy is also widely used in the treatment of malignant pleural effusion, and commonly used drugs include interleukin-2, interferon, short rods, pseudomonas aeruginosa, etc.
Pleural fixation is the injection of sclerosing agent into the pleura to cause chemical pleurisy, thus fixing the pleural adhesions and making the pleural effusion grow slowly or stop growing, commonly used are talc, tetracycline and erythromycin.
Total pleural irradiation therapy is effective for malignant pleural fluid; pleurodesis is indicated for recurrent patients who are difficult to control by other less invasive methods and have an expected survival of >3 months. Thoracoabdominal shunt and built-in chest drainage can be used for malignant pleural fluid that is difficult to control.
Treatment of adrenal metastasis
Adrenal gland is one of the common sites of metastasis in patients with NSCLC. About 5-10% of patients have adrenal metastasis at the time of diagnosis, and up to 33% of adrenal metastasis is found at autopsy. The incidence of isolated adrenal-specific metastases is 1.62-3.5%, but in those cases where the primary tumor is resectable, many of the solitary adrenal masses are not malignant. Therefore, lung cancer patients with adrenal masses detected on preoperative CT scans need to be biopsied to rule out benign adenomas. If adrenal metastases are found and the lung lesion is resectable, resection of adrenal metastases may result in long-term survival for some patients. However, experts’ opinions on the resection of adrenal metastases are very diverse, and some panelists believe that resection of the adrenal gland is meaningful only if the coexisting lung lesion is stage I or possibly stage II (i.e., resectable). Another treatment option for adrenal metastases from lung cancer is systemic therapy.
Studies suggest that surgical treatment can result in a relatively good prognosis for patients with controlled or controllable primary foci, no other distant metastases, unilateral adrenal metastases that can be completely resected, and good general condition.