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How to deal with oligometastasis of advanced non-small cell lung cancer?
How to deal with oligometastasis of advanced non-small cell lung cancer? The mortality of non-small cell lung cancer patients with adrenal metastasis is close to 40%.
Oligo metastasis is a concept proposed by Hellman and Weichselbaum  in 1995. It refers to a transitional state between limited period and widespread transfer.
The proposal of oligometastasis has brought new hopes and challenges to patients with advanced non-small cell lung cancer, and with the development of MRI, PET-CT, EBUS and other examination technologies, it can more accurately screen patients with oligometastasis. , And adopt a more individualized active treatment plan to maximize the benefit of patient survival .
Accordingly, Downey et al.  performed a prospective phase II clinical trial for the first surgical treatment of oligometastases in NSCLC and recruited 23 patients (including 14 brain metastases and 13 mediastinal metastases). The metastases were surgically removed, but the surgical R0 resection rate was 43%, and the patient’s median survival time was only 11 months. D
e Ruysscher et al  analyzed the efficacy of non-surgical treatments (chemotherapy and radiotherapy) in NSCLC patients with less than 5 metastases. Among 39 patients, 74% of patients were in stage III, and 44% of patients had For brain metastases, 10% of patients had adrenal metastases, 87% of patients had only one metastasis, and 95% of patients received chemotherapy. The overall median survival time was 13.5 months.
The above two prospective studies confirmed that chemotherapy is still the main treatment for patients with stage IV non-small cell lung cancer when the number of metastases is limited.
Systemic therapy combined with active local therapy can prolong the survival of advanced patients , Niibe
 After reviewing a large number of literatures, they proposed the Niibe-Onishi-Chang classification method, and believed that survival was the criterion for local surgical resection for independent brain or adrenal metastases, especially 1-2 metachronous metastases (recurrence) Of patients are beneficial.
According to the existing analysis of local treatment of oligometastasis and the results of clinical trials, local treatment of selected patients with oligometastasis can benefit patients in terms of survival, N stage, size and number of metastases of simultaneous metastasis The control of the primary tumor is also a factor that affects the overall prognosis of treatment. At present, clinically advanced non-small cell lung cancer oligometastasis mainly manifests in organs such as brain and adrenal glands.
Pathophysiological mechanism of oligometastasis
Several studies by Hellman et al. [7-8] described the pathophysiological mechanism of oligometastasis. They believed that tumor metastasis requires the following steps:
①Have an aggressive phenotype;
②It is aggressive;
③ Suitable microenvironment (such as vascular regeneration and inflammation);
④Invasion like blood vessels;
⑤Adhesion to specific parts of blood vessels due to vascular adsorption and platelet aggregation; ⑥A metastatic environment suitable for growth;
⑦A large number of metastatic cancer cells gather;
⑧Extravascular colonization of metastatic cancer cells (due to cell activity and vascular remodeling);
⑨ Metastatic cancer cells survive at distant metastatic sites;
⑩ Distant metastatic stromal cancer and clonal proliferation.
Lussier et al.  found that there are unique microRNA expression profiles in oligometastatic tumors that are different from those in multi-metastatic tumors.
For specific individuals (microenvironment) and tumors, due to histological classification, organ specificity, etc., they will show different invasion capabilities and time windows. For example, lung cancer has a tendency to metastasize to the brain, lung, adrenal glands, etc., but to the bladder, pancreas, Rectal metastasis is extremely rare.
This tendency to metastasize to specific organs is jointly determined by the primary oncogene, metastatic cancer cells, the microenvironment of the primary tumor and the microenvironment of the distant metastasis .
Local treatment of oligometastasis
Nearly 40% of lung cancer patients will have brain metastases during the course of the disease. Patients with brain metastases from non-small cell lung cancer have a poor prognosis, with a median survival time of only 3-6 months . NCCN and ACCP guidelines recommend surgical treatment for patients with resectable single brain metastases.
In clinical practice, more and more patients with brain metastases whose KPS scores are high and can tolerate surgery, the primary tumor has been resected without recurrence, and the metastasis is located at the resectable site, are being treated with surgery. For patients with non-small cell lung cancer whose primary tumor is in the non-advanced stage, local treatment of brain metastases can benefit patients .
In order to reduce the recurrence of residual tumor tissue, the new occurrence of brain metastases, and to strengthen the control of the primary tumor, a large number of studies have shown that surgery combined with whole brain radiotherapy (WBRT), stereotactic radiotherapy or chemotherapy is the main method for the treatment of oligometastasis. Among them, surgical treatment combined with WBRT is more mature. Compared with WBRT alone, combination therapy can reduce the probability of recurrence and new metastasis, and reduce neurological-related deaths, but the patient’s survival period is not prolonged.
Patchell et al.  found that combination therapy has a significant effect on improving the median survival (MST) of patients through clinical trials involving 48 patients (combination therapy for 40 weeks; WBRT alone for 15 weeks; P<0.01), Vecht et al.  A study involving 63 patients came to the same conclusion (P=0.04), and the benefit of stable brain metastases was greater than that of advanced brain metastases.
For recurrent metastases, reoperation can benefit patients, especially patients with disease-free interval ≥ 1 year .
Stereotactic radiotherapy is increasingly used in the treatment of oligometastasis in advanced non-small cell lung cancer. It is generally believed that stereotactic radiotherapy is one of the alternative methods for patients with brain metastases ≤3cm in diameter, brain metastases <5, and metastases located in unresectable sites.
Compared with WBRT, it can reduce the damage to neurocognitive function. For patients with a single brain metastasis, SRS has fewer patient benefits compared with surgical treatment. There is evidence that there is no significant benefit from SRS for patients eligible for surgical treatment.
Compared with the treatment of SRS and SRS combined with WBRT, the two groups are controversial in terms of the survival benefits of patients. Aoyama et al.  conducted a randomized clinical trial that included 132 patients (all ≤ 4 metastases, and metastasis diameter ≤ 3cm), were randomly divided into WBRT treatment group and WBRT combined SRS treatment group. It was found that there was no significant difference in survival benefit between the two groups (7.5 months in the single group; 8 months in the combined group). SRS alone can significantly improve the 1-year survival of patients Rate and 1 year tumor control rate. In the RTOG 9508 clinical trial, the included 333 patients with only 1-3 metastases were randomly divided into the WBRT group and the WBRT combined SRS group. It was found that when the number of metastases is 1, the combined group patients can Benefits (6.5 months in the combined group, 4.9 months in the WBRT group alone; P=0.0393), and the combined treatment reduced the 1-year recurrence rate of brain metastases (46.8%, 76.4%; P<0.001) and 1-year new metastasis rate .
The mortality of non-small cell lung cancer patients with adrenal metastasis is close to 40%, but only some patients with adrenal metastasis have unilateral adrenal metastasis, and local treatment can benefit patients.
ACCP guidelines (recommendation level 1c) and NCCN guidelines (recommendation level 2a) recommend that the primary tumor and metastases should be removed for NSCLC patients with independent unilateral adrenal metastasis.
Multiple retrospective studies have confirmed that surgical treatment is obviously beneficial for a single adrenal metastasis, but there are many factors that affect the prognosis of surgical treatment. Laparoscopy is currently widely used in clinical practice. It has the advantages of small surgical wounds, short time, less bleeding, and short hospital stay. At the same time, its surgery-related mortality is relatively high. A retrospective study by Strong et al.  showed that open surgery and Laparoscopic surgery has no significant difference in survival benefits, but laparoscopic surgery is at a disadvantage when the tumor diameter is greater than 4.5 cm (short survival and high local recurrence rate), so the tumor size is related to prognostic factors. When the tumor diameter is less than 4.5 cm The prognosis is better at this time. Disease-free interval (DFI): Non-small cell lung cancer patients with DFI<6 months are called simultaneous adrenal metastasis, and vice versa, metachronous adrenal metastasis.
Tanvetyanon et al.  included 114 patients with non-small cell lung cancer after renal metastasis. The median survival time of patients with metachronous metastasis was significantly higher than that of concurrent metastases (31 months, 12 months; P=0.02).
Studies have confirmed that the median survival of patients with DFI>12 months is significantly longer than that of patients with DFI<12 months [20,21]. Although many small sample studies did not find the statistical significance of metachronous and simultaneous adrenal metastases affecting the prognosis, the impact of DFI on the prognosis of adrenalectomy is considered to be significant.
Whether the adrenal metastasis is located on the same side as the primary tumor is also one of the prognostic factors. The metastatic cancer cells of the primary tumor directly metastasize to the ipsilateral adrenal gland through the retroperitoneal lymph nodes, so patients with metastases from the contralateral adrenal gland suggest a poor prognosis .
As a non-invasive local treatment method, the development of stereotactic radiotherapy provides another way of local treatment for patients with adrenal metastases who cannot undergo surgery. SBRT treatment has advantages in the local tumor control rate [23, 24], but it also There is controversy. When Milano et al  analyzed patients with oligometastasis of the adrenal gland who received SBRT, they found that the local control rate was only 74%, and the median survival time was 18 months.
A retrospective study by Dasai et al.  showed that the biological effect dose (BED) and histological classification of adrenal metastatic carcinoma may be factors affecting the prognosis of SBRT, and that BEDs>10000cGy can achieve an effective local control rate. For adrenal metastases with tumors >5cm in diameter, SBRT is considered effective, and SBRT combined with chemotherapy can control new distant metastases.
For oligometastasis of non-small cell lung cancer with genetic mutations, SBRT combined with TKI inhibitors can increase PFS and OS . Although the dose and side effects of stereoradiation therapy are not very clear, the prospect of SBRT in the treatment of non-small cell lung cancer with adrenal oligometastasis is promising.
For patients with lung metastases of non-small cell lung cancer, it is necessary to distinguish whether they are multiple lung cancers in situ or lung metastases. For a limited number of lung tumors who can tolerate surgery, the survival benefit of surgical treatment is better than palliative Sex therapy.
A small-sample retrospective study conducted by He Jinyuan and others included a total of 21 patients, 11 of whom received surgical treatment for metastases and 10 received nursing care. They found that the prognosis of the surgical group was significantly better than that of the chemotherapy group (the surgical group MST 37 months The 5-year survival rate was 18.2%, the chemotherapy group MST was 11.6 months, the 5-year survival rate was 9.1%; P<0.05), and the patients with single metastasis, N0 and TNM had a better prognosis. SBRT is increasingly used in the treatment of oligometastasis in the lung, and its efficacy may be confirmed. SBRT is also repeated for recurrent lung metastases.
A large-scale retrospective study conducted by Ricco et al.  included a total of 447 patients with lung metastases treated with SBRT. The primary tumors were distributed in:
- Colorectal (25.7%),
- Lung (16.6%),
- Head and neck (11.4%),
- Breast (9.2%),
- Kidney (8.1%),
- Skin (6.5%)
- Other parts (22.1%).
The average OS was 26 months, and the 5-year local control rate was 46.3%. Patients benefited significantly, and the smaller the metastasis, the better the prognosis.
A meta-analysis of non-small cell lung cancer oligometastasis in areas other than the brain and adrenal glands conducted by Salah et al.  included a total of 62 patients, including 13 patients with bone metastases, 9 patients with liver metastases, and 7 patients with renal metastases. Metastasis patients and 6 patients with splenic metastasis analyzed the prognostic factors from the levels of hematological and non-hematological metastasis, simultaneous and metachronous metastasis, and lymph node staging. The results showed that the surgical resection of the metastasis and the primary tumor combined with radiotherapy were effective The 5-year survival rate was 50%, and lymph node staging was a significant factor affecting the prognosis (5-year survival rate was 64% for N0-1 and 0% for N2-3; P<0.001).
Active local treatment of oligometastasis provides new treatment options for patients with oligometastasis in advanced non-small cell lung cancer. According to the eighth edition of lung cancer staging issued by the International Association for the Study of Lung Cancer, local treatment is recommended for patients with T1-2N0-1M1b.
While the local treatment is widely carried out, the screening of patients with oligometastasis has become particularly important, which requires clinicians to master and be able to flexibly apply various new technologies. Strictly screened patients with oligometastatic status can benefit from local treatment.
Stereotactic radiotherapy accurately locates high-dose radiation to the lesion and reduces damage to surrounding tissues. In recent years, it has become a new choice for local treatment of patients with oligometastasis. However, the optimal radiation dose and side effects need to be further studied.
The local treatment of oligometastasis must be based on the combination of effective systemic treatment to benefit the patient’s survival. Appropriate systemic treatment can increase the patient’s local control rate and reduce the rate of new distant metastases. The clinical practice considerations for oligometastasis of advanced NSCLC include:
①Whether the oligometastasis is simultaneous or heterochronous, and the prognosis of local treatment for atypical oligometastasis is better than that of simultaneous;
②The number of metastatic lesions, which is negatively correlated with the prognosis;
③The tumor burden in the thoracic cavity, tumor T and N, the smaller the burden, the more active local treatment is needed for oligometastasis;
④The pathological type of tumor, the local treatment of oligometastasis of adenocarcinoma will benefit greatly;
⑤ Tumor gene mutations, for patients who take molecular targeted therapy, such as EGFR-TKI, ALK-TKI, etc., combined local therapy in the oligometastasis state may have a better effect .
Clinical trials have shown that compared with patients who did not take local intensive treatment, the probability of local recurrence after local intensive treatment is lower and can reach a 15-year survival period .
Systemic therapy, such as the use of molecularly targeted drugs, will affect the efficacy of local therapy. If the systemic therapy is weak or too strong, it will weaken the efficacy of local therapy. On the contrary, if the intensity of systemic therapy is moderate, it can be complementary to local therapy.
In short, for patients with advanced NSCLC with oligometastasis, under effective systemic treatment and active local treatment, the survival benefit of patients has reached a clinical consensus. However, how to accurately screen the benefiting population still requires the basis of tumor molecules and genes. Research and clinical trial verification of large samples.
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