Prolonged survival in advanced squamous cell lung carcinoma by rational and standardized treatment: A case report of long‐term survival in a patient with NSCLC

To report the treatment of a long‐term survival case of stage IV lung squamous cell carcinoma (LSCC) patient with multiorgan metastases, including intrapulmonary, brain, liver, bone, and multiple lymph nodes.


| GENERAL INFORMATION
which were considered to be lung cancer in the right lower lung with multiple intrapulmonary metastases. CT also showed multiple enlarged right supraclavicular, mediastinal and right hilar lymph nodes, and compressed trachea and esophagus. In addition, abdomen CT showed a nodular shadow in the right lower lobe of the liver, and the intrahepatic bile duct and common bile duct were dilated. Diagnosis at admission was "Right lung LSCC with multiple lymph node, intrapulmonary, liver, brain and bone metastases, T4N3M1, and stage IV". ECOG was 2 points. The patient had no history of hypertension, diabetes, heart disease, hepatitis, tuberculosis, allergy, and drinking. However, the patient has had gallstone for 5 years and had not received any treatment. The patient had a 10-year smoking history (7-8 cigarettes/day) but had quit smoking for 30 years. The death reason of his parents was unknown; his siblings and children were healthy. Physical examination: temperature: 36.5 C, pulse: 76/min, respiratory rate: 18/min, blood pressure: 105/67 mmHg. The patient was in a good consciousness and spirit, had no dizziness, headache, hoarse voice, and difficult swallowing. Heart rate was 76 beats/min, and had no arrhythmia.
The patient also had no chest pain and tightness, no obvious cough, sputum and dyspnea, and no obvious dry or wet rales in both lungs. The abdomen of the patient was soft and no tenderness as well as no nausea and vomiting. There were no petechiae on the skin and superficial lymph nodes were not enlarged. The physiological reflexes were present, and pathological reflexes were not induced. Numerical rating scale (NRS) score was 6. According to the guideline of lung cancer complicated with brain metastasis, as to the symptomatic NSCLC patients with brain metastases, surgical resection or whole brain + stereotactic radiotherapy can be used when the number of metastases is less than 3. If the number of metastases is more than F I G U R E 1 Brain MRI on May 20, 2013 showed multiple brain metastases (red arrow shown) F I G U R E 2 CT on May 27, 2013 showed a mass shadows in the right lower lobe of liver and multiple nodules in the bilateral lungs (red arrow shown) 3, stereotactic radiotherapy or whole brain radiotherapy can be used. F I G U R E 3 After 2 cycle treatment, the maximum reduction rate was 41%. The lower right lung lesions, the multiple nodules in both lungs, and liver metastases were all smaller than before (red arrow shown) F I G U R E 4 Before May 2013 radiotherapy (left) and after July 2013 radiotherapy (right), brain metastases were reduced (red arrow shown) F I G U R E 5 After 4 cycle treatment, the right lower lung lesions, two lung metastases, and liver metastases were all smaller than before (red arrow shown) showed brain metastases complicated with cerebral edema. Then the patient achieved partial response after 2 cycle treatment by efficacy evaluation and the maximum reduction rate was 41%. One cycle of (b) Gallbladder volume had increased significantly than before. Head MRI showed that metastatic lesions in the bilateral parietal lobes were smaller than before; peripheral cerebral edema reduced considerably than before. Evaluation of efficacy after 4 cycles was stable disease (SD) ( Figure 5). Considering the patient could possibly not tolerate any further treatment after four cycles of chemotherapy and whole brain radiotherapy, the patient was recommended to follow up after discharge.

| Second-line treatment (November 14, 2013 to October 20, 2014)
The patient was followed up after the first-line treatment. Reexamination of head MRI on October 31, 2013 found that brain metastases were further reduced than before, particularly, lesions in the right parietal lobe had basically retracted. Chest CT ( Figure 6) showed: (a) The mass in the right lower lung was smaller than before; however, the number of nodules in both lungs increased and the size of the nodules also grew larger; (b) Lymph nodes in the mediastinum were smaller than before; (c) The nodule in the liver was not observed. To control disease progression, the patients  F I G U R E 8 CT on June 26, 2014 showed the lesions in the right lung were similar than before (red arrow shown); some metastatic lesions in the two lungs were slightly larger than before (yellow arrow shown) was 18.5% and efficacy evaluation was SD. After 6 cycles, reexamination of the chest CT on March 6, 2015 showed that the nodule in the left lower lung further reduced and other signs were similar with before. The patient was in SD and was followed up regularly.
Chest CT on June 12, 2015 showed the nodule in the left lower lung was slightly smaller than before and head MRI did not find obvious   Radiotherapy was given to control the lesion in the right lung (PTV 48 Gy/8 F) from April 17, 2019 to April 26, 2019. Re-examination of chest and abdomen CT on May 28, 2019 found there was a large consolidation shadow in the left lower lung which could not be clearly differentiated from the tumor, which was considered to be radiotherapyassociated adverse effect; the inflammatory changes in the right lung were more obvious. There were also newly occurred inflammatory changes under the left upper lung pleura. Metastasis in the right adrenal gland could not be excluded. Due to low physical performance score, the patient was intermittently treated with multitargeted anrotinib. Efficacy evaluation was SD.

| DISCUSSION
For patients with early stage LSCC, radical surgery is still the most effective treatment. However, the patient in this case had progressed to stage IV when diagnosis was made, and brain metastases had also developed. Currently, there are few effective treatment measures for advanced patients, and the overall survival of LSCC was lower than that of lung adenocarcinoma. Lung cancer has the highest incidence of brain metastasis. In primary NSCLC, the incidence of brain metastasis at initial diagnosis is 10% and increases to 40%-50% during treatment. 2 The risk of brain metastasis in lung adenocarcinoma, squamous-cell carcinoma and large cell carcinoma are 11%, 6%, and 12%. 2 The median overall survival (mOS) of untreated patients with brain metastasis is about 1-3 months, 3 the 1-year survival rate is about 10%-20%. 4 Brain metastasis not only seriously threatens the lives of patients and reduces the quality of life, but also an important factor leading to poor prognosis. Therefore, for patients with advanced LSCC and multiple brain metastases, it is very important to choose the appropriate high-efficiency and low-toxic treatment plan at the first diagnosis. In addition, according to our experience from this case, paying close attention to patient's symptoms and signs, as well as adopting a full-course management strategy is also vital for their long-term survival.
Treatments of NSCLC brain metastasis include systemic chemotherapy, whole brain radiotherapy (WBRT), stereotactic radiotherapy (SRT), stereotactic radiosurgery (SRS), surgical resection, and molecular targeted therapy. Traditional opinion is that the ability of chemotherapeutic drugs which have a large molecular mass to penetrate blood-brain barrier is low; therefore, the efficacy of chemotherapy in treating brain metastasis is limited. Platinum-based combinational chemotherapy is still the standard treatment for late NSCLC, but the 5-year survival of patients with late NSCLC is less than 5%. 5 Recent studies found that the blood-brain barrier may be destroyed and chemotherapeutic drugs will pass through 7,8 when the diameter of brain metastatic tumor is greater than 0.25 mm. 6 In this case, brain radiotherapy is still an indispensable measure for the treatment of brain metastasis, and also the standard treatment recommended by the NCCN guideline. The treatment is effective for alleviating symptoms of intracranial hypertension and control of local lesions. The overall effective rate of WBRT achieves to 80% and patient's median survival can extend to 3-6 months. 9 Surgical treatment of NSCLC brain metastasis is associated with a high risk of recurrence and complication, and patient's quality of life may reduce after surgery. [10][11][12] The treatment of lung cancer has entered into an era of precision medicine and full-course management. Molecular targeted therapy has been widely used in the treatment of lung cancer and significantly improves patient's prognosis.
This case showed that those LSCC patients with brain metastasis, full-course management is vital for their long-term survival. In addition, emerging novel therapies and treatment regimens will continue to improve patient's survival. The patient in this case was treated with new medicines and investigated treatment plan through participating in multiple clinical trials, which prolonged the patient's survival to a certain extent. Through MDT cooperation, the patient was given local radiotherapy intervention in an appropriate timing, which resulted in him not only obtaining better local control but also increased the quality of life and survival. MDT model can maximize the expertise of various clinical departments, strengthen the collaboration between different disciplines, and promote standardized and personalized treatment. Retrospective studies have indicated that patient's overall survival is improved through MDT cooperation. For patients who have been resistant to first-generation TKI, it is also highly possible to be resistant to other first-generation TKIs. For these patients, combinational treatment including immunotherapy plus multisite radiotherapy, chemotherapy or anti-angiogenesis therapy may bring more benefits.
In conclusion, the treatment mode for advanced lung cancer is becoming more and more diversified. The long-term survival of the reported patient who had multiorgan metastases was benefited from MDT cooperation, comprehensive and personalized treatment, and precise full-course management.