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Med One 2016;1(3):3; DOI:10.20900/mo.20160012
1Department of Respiratory Medicine, Xiangya Hospital, Central South University, Changsha Hu’nan,410008, China
Correspondence: Huaping Yang, Department of Respiratory Medicine, Xiangya Hospital, Central South University, Changsha Hunan 410008, China. Email:email@example.com
Background: One case of male patient with stage-IV lung cancer was reported here, who had exon 19 deletion mutations in epidermal growth factor receptor (EGFR). The intrapulmonary and extrapulmonary lesions occurred a month after applying the gefitinib and erlotinib in turn. The patient was then switched to the first-line chemotherapy program. The intrapulmonary and extrapulmonary lesions were significantly improved four weeks after the combined therapy with pemetrexed disodium + carboplatin+ bevacizumab (7.5mg/Kg d1), two weeks after the continuous therapy with pemetrexed disodium + bevacizumab (7.5mg/Kg d1), and the short-term efficacy was assessed as PR, without significant adverse effect, which reflects the efficacy of this program and the good tolerance.
The male patient aged 66 years old with a history of smoking was accepted in our Department of Outpatient on September 14, 2015 because of “coughing for more than one month”. His main symptoms included dry cough, a small amount of white phlegm, free from fever, chest pain, bloody sputum, and any other discomforts. It is associated with an anorexia and weight loss of nearly 10 pounds when it develops. He had a poor constitution in the past, with a history of “acute hepatitis”, “type-2 diabetes” and “obsolete pulmonary tuberculosis”. The patient was accepted in our department on September 15. The lung was scanned with CT and the scanning results indicated that “space occupied for posterior basal segment of right inferior lung and enlarged for mediastinal lymph nodes”. The patient was approved to be subjected to the CT-guided transthoracic needle biopsy, immunohistochemistry, EGFR gene mutation detection, and systemic metastases assessment. He was diagnosed as “primary lung cancer, right lung adenocarcinoma, T4N3M1B (lung, pleura and brain), and stage-IV EGFR Exon 19 deletion mutation (Fig. 1A and Fig. 2A) ”.
After the diagnosis, the patient began to take gefitinib (250mg, oral administration and once a day) since September 22, 2015. During the treatment, the cough of the patient was not significantly improved, and the spirit and appetite were not improved, and no new symptom occurred. He returned to our outpatient for review on October 20, 2015 and the review result showed that the targeted lesion in the lung increased from 40.9 mm to 50.9 mm (Fig. 1 A-B), with a growth rate of 24.4%. The progressive disease (PD) was assessed and he was advised to be changed to the chemotherapy for further treatment. He rejected and began to take erlotinib (150mg, oral administration and once a day). The symptom was still not improved during the treatment and he was gradually associated with dizziness, backache, hemiparesthesia in the left side, without malignant vomiting. The patient was reviewed again for his lung with CT (November 16, 2015) one month later, and the reviewed results suggested that the lung lesion further increased (58.3mm for the longest diameter) (Fig. 1C), and the lymphangitis carcinomatosa was significantly progressed. The MRI result of the head showed that the intracranial lesions were increased (Fig.2B), with an obvious edema. The efficacy was assessed as PD and he was recommended again for a chemotherapy treatment.
The patient checked in our department for further treatment on November 23, 2015. The assessment was made again before the chemotherapy and the inspection results showed that multiple bone metastasis and multiple enlarged lymph nodes occurred in left shoulder blade, the fourth lumbar, right iliac bone and other positions of the patient, and the performance status (PS) was only one point. He was administered by Pemetrexed Disodium (500mg/m2 d1) + Carboplatin (AUC 5 d1) + Bevacizumab (7.5mg/Kg d1) since November 26, 2015 for the chemotherapy treatment and meanwhile, the supportive therapy was provided, such as, dehydration, reduction of intracranial pressure, promotion of bone repair, relief of pains, waist protection, etc. After his discharge, the cough symptom of the patients basically disappeared and the dizziness, backache and hemiparesthesia in the left side were significantly improved and the spirit and sleep quality was also significantly improved. It was basically normal after reviewing the blood routine examination. The second chemotherapy treatment was successfully completed on December 18 (the program is idem). The patient checked in the hospital on January 6, 2016 and proposed for the third chemotherapy. The assessment result before the chemotherapy showed that the measurable targeted lesion of right lung decreased (3.2mm, with a decrease rate of 44.8%) (Fig. 1D), lymphangitis carcinomatosa was significantly decreased and right frontal nodulus lesions were reduced significantly (Fig. 2C). No new lesion was found. The efficacy was assessed as the partial relief (PR). The third and fourth chemotherapies were completed on January 9 and January 30, 2016. The efficacy was re-assessed as PR (Fig. 1E) with CT review of lung in the outpatients on February 11. Since then, the patient had been subjected to the combined administration program of pemetrexed disodium (500mg/m2 d1) + bevacizumab (7.5mg/Kg d1) for the further chemotherapy. CT of lung and MRI of head were implemented again on April 16, and the results showed that the control of lung lesions and intracranial lesions were basically the same as before (Fig.1F and Fig. 2D). The symptoms of cough, backache and hemiparesthesia were not found in the patient and the quality of his life significantly improved. PS was decreased to zero.
In this case, the lung biopsy specimens of patients indicated that there existed EGFR exon 19 deletion mutation. According to the recommendations of the Guideline of National Comprehensive Cancer Network (NCCN) in 2015 , we developed the therapy program using EGFR tyrosinekinase inhibitors (TKIs) - Gefitinib administration. However, the intrapulmonary and extrapulmonary lesions occurred after the gefitinib and erlotinib were administered to the patient, which indicates that the patient has the primary resistance against the EGFR Tki.
Under the premise of treatment failure, we re-implemented the combined program of platinum-based doublets + bevacizumab to the patient according to the recommendations of NSCLC guideline of the NCCN in 2015 to ensure the improvement of symptoms and living quality of the patient in a short time, including the contraction and control of primary lesions in lung, spinal, and intracranial lesions. We knew that the new generation of anticancer drugs for molecular targets might become the research and treatment highlights of advanced lung cancer and therefore ensure our current treatment program to be developed towards to “individualization” direction. The genetic locus of EGFR, chinodem microtubule-associated protein-like 4/anaplastic lymphoma kinase (EML4-ALK) fused genes, etc., needs the presence of specific genetic locus mutation to ensure the patient to benefit from their corresponding targeted therapy drugs or medications, and their mutation frequency shall be below 10% in addition to that the EGFR can be up to 50% in the Asian race. Another molecular targeted drug – vascular molecular targeted drug – represented by bevacizumab can inhibit the combination of VEGF with its receptor to degenerate the tumor angiogenesis and normalize the survived blood vessels and inhibit the reproduction of the blood vessels so as to continue to inhibit the growth and metastasis of the tumors. [2,4] Thus, under the condition that the patient has the primary resistance against EGFR Tki in this case, the bevacizumab-based chemotherapy program recommended in the guideline is more suitable for the individualized treatment of this patient and he has indeed benefited from this treatment program.
A total of 878 patients with relapsed or stage III-IV non-squamous NSCLC was included into the stage-III clinical trials (ECOG4599 Trial  conducted by Sandler. They were classified into two groups at random and administered with paclitaxel + carboplatin and paclitaxel + carboplatin +bevacizumab, respectively. The results showed that the overall survival (OS), median PFS and ORR of the bevacizumab-containing group were all superior to the healthy controls (P＜0.05). The OS of the patients with advanced NSCLC was prolonged for over one year for the first time in the history. Therefore, FDA approved the combined program of paclitaxel + carboplatin +bevacizumab for treatment of advanced non-squamous NSCLC. Another stage-III clinical trial (AVAIL Trial ) confirmed the results of ECOG4599 Trial  from the aspects of its efficacy and PFS. The chemotherapy program of combining the bevacizumab with platinum-based doublets was thus approved by European Medicines Evaluation Agency (EMEA) in 2007 for the first-line treatment of metastatic NSCLC. In addition, many studies (SAiL, ARIES) showed that the bevacizumab enabled the OS of the patients with advanced NSCLC to be prolonged for over one year. Among the 314 Asian patients in the study of SAiL, TTP was 8.3 months and median OS was 18.9months, which are all significantly higher than the general population.
The up-to-date NSCLC clinical practice guideline of NCCN in 2016 clearly points out that the first-line chemotherapy program for advanced non-squamous cancer NSCLC has included the doublet chemotherapy as well as bevacizumab + chemotherapy, and the bevacizumb should be administered until the progressive disease PD period. The chemotherapy programs are composed of several combinations, namely, paclitaxel + carboplatin, paclitaxel + cisplatin, vinorelbine + cisplatin, gemcitabine + cisplatin, pemetrexed disodium + cisplatin, and docetaxel + cisplatin. In the United States, the common programs are pemetrexed disodium + cisplatin (carboplatin), and paclitaxel + carboplatin combined (or not combined) with bevacizumb. Forty nine patients with non-squamous NSCLC were included into a stage-II clinical trial conducted by Patel, et al. All patients accepted the first-line chemotherapy of pemetrexed disodium + carboplatin combined with bevacizumb. In the later period, they continuously accepted the chemotherapy of pemetrexed disodium + bevacizumb. The results showed that the median PFS, OS and ORR reached 7.8 months, 14.1 months and 55%, respectively, and no severe adverse events were observed. Similarly, in a similar stage-II clinical trial conducted by Japanese Yokoi T , the same treatment program was implemented to 26 patients with stage IIIB-IV NSCLC. The trial results showed that the median PFS and OS reached 8.6 months and 18.6 months, respectively, which indicates that this treatment program may provide more benefits to the Asian groups. A similar long-term efficacy was obtained in the clinical observation on “first-line treatment of bevacizumb combined with pemetrexed disodium + oxaliplatin for advanced NSCLC” carried out by OLIVIER et al.  At the same time, the trial made by POINTBREAK  showed that the program of pemetrexed disodium + carboplatin + bevacizumb was a reasonable option and it was believed that the paclitaxel-based program had a more toxicity than the pemetrexed disodium based program. This is mainly reflected in neurotoxicity, but there is no significant difference in the aspect of OS between the two programs. Therefore, we can make a more appropriate option according to the specific situation of the patients.
In this case, we provided four cycles of combined chemotherapy program of pemetrexed disodium + carboplatin + bevacizumb (7.5mg/Kg d1) to the patient and continued the chemotherapy with pemetrexed disodium + bevacizumb (7.5mg/Kg d1). In the short-term efficacy assessment, we observe the benefits to the patients. However, the long-term efficacy of the chemotherapy program combined with bevacizumb mainly relies on the maintenance administration of this drug and therefore it is necessary to carry out the closer follow-up observation.
As far as the side effect is concerned, no common myelosuppression, liver and kidney dysfunction, gastrointestinal reaction, hypertension, proteinuria, thrombosis, hemorrhage and other reactions were observed temporarily during the treatment process of this case, which indicates a good tolerance of this combined program for the treatment of advanced NSCLC. However, it may also be such a reason that the related side effect of the bevacizumab is dose-dependent. 
In summary, the combined chemotherapy program of pemetrexed disodium + carboplatin + bevacizumb (7.5mg/Kg d1) was implemented for four cycles to a patient with advanced lung cancer who has EGFR exon 19 deletion mutation and the primary resistance against the EGFR Tki, and it was maintained with pemetrexed disodium + bevacizumb (7.5mg/Kg d1) for two cycles. The short-term efficacy was assessed as PR without obvious adverse effect. It reflects the efficacy and good tolerance of this program, which provides more clinical evidences for clinical application.
1. National Key Scientific & Technology Support Program: Collaborative innovation of Clinical Research for chronic obstructive pulmonary disease and lung cancer, NO.2013BAI09B09; 2. Young Scientists Fund in National Natural Science Foundation of China, Program Number: 81502699.
Figure 1. IL-37 inhibited invasion and migration in HeLa cells. A) Cell invasion assay. B) Cell migration assay. HeLa cells were treated with 400ng/mL or 0 ng/mL of IL-37 for 72 hrs.
Figure 2 A. MRI image of head before the treatment (dated on September 22, 2015); B: MRI image of head a month after administration of gefitinib and erlonat (dated on November 14, 2015), indicating a significant enlargement of intracranial lesions; D. MRI image of head two cycles after using the combined program of Pemetrexed disodium (500mg/m2 d1) + Carboplatin (AUC 5 d1) + Bevacizumab (7.5mg/Kg d1) (dated on January 7, 2016), indicating a decrease of intracranial lesions and a significant contraction of surrounding edema zone; F. MRI image of head after maintaining two-cycle treatment using the program of Pemetrexed disodium (500mg/m2 d1) + Bevacizumab (7.5mg/Kg d1) (dated on April 10, 2016), indicating a stable intracranial lesion as before.