Clinical Research on Systemic Chemotherapy Combined With Bronchoscopic Seed Implantation in the Treatment of Advanced Lung Cancer.

OBJECTIVE: This study aims to explore the clinical value of systemic chemotherapy combined with bronchoscopic seed implantation in advanced lung cancer treatment.
METHODS: The study enrolled 253 patients with advanced lung cancer in Cangzhou People's Hospital from March 2018 to March 2020, and they were divided into test group and control group. Test group was given systemic chemotherapy combined with bronchoscopic seed implantation, while control group was given systemic chemotherapy. The objective response rate of tumor (ORR), disease control rate (DCR), serum tumor marker level, survival time and adverse reactions of 2 groups were compared.
RESULTS: After treatment, the levels of serum tumor markers including carcino-embryonic antigen, neuro-specific enolase, cytokeratin-19 and pro-gastrin-releasing peptide were markedly decreased in test group compared with those in control group (P < 0.05). Therein, the serum tumor marker level of non-small cell lung cancer (NSCLC) patients was significant decreased compared with that of small cell lung cancer (SCLC) patients in test group. Meanwhile, in test group, the serum tumor marker level of lung adenocarcinoma (LUAD) patients was significant decreased compared with that of lung squamous cell carcinoma (LUSC, P < 0.05). The ORR and DCR in test group were superior to those in control group (63.4%, 92.5% vs 38.7%, 72.3%, P < 0.05), while those were much higher in patients with NSCLC and LUAD relative to those in patients with SCLC and LUSC, respectively (P < 0.05). Furthermore, the progression-free survival (PFS) and overall survival (OS) in test group were significantly greater than those in control group. In test group, the PFS and OS of patients with NSCLC and LUAD were higher than those of patients with SCLC and LUSC.
CONCLUSION: The efficacy of systemic chemotherapy combined with bronchoscopic seed implantation was superior to that of systemic chemotherapy, which is worthy of promoting in clinical practice.

Introduction

Lung cancer is a common pulmonary malignant tumor in clinic, with high incidence rate, mortality rate and poor diagnosis.[1] The most common types of lung cancer are small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), among which NSCLC accounts for about 80%-85%, and lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) are the main types in NSCLC.[2] Regardless of the types of lung cancer, the confirmed cases aged above 60 years.[3] Most patients are often diagnosed in advanced stage or metastatic stage and are ineligible for surgical treatment owing to the insidious onset and unobvious symptoms of the disease in the early stage.[4] Patients who had lost the opportunity of surgical treatment were mostly treated with platinum-based chemotherapy.[5] However, more toxic and side reactions can be caused by chemotherapy, and the 5-year survival rate of postoperative patients remains unsatisfied.[6] Therefore, there is an urgent need to develop an optimal treatment plan.

Iodine-125 (125I) is a low-energy radioactive nuclide that continuously releases radiation and emits X-rays and gamma rays of 27.4-31.5 keV.[7] 125I seeds can kill tumor cells by constantly destroying DNA double strands and disabling their proliferative ability. The radiation can directly function on tumor tissues and its physical half-life period is 59.6 days. The effective duration of tumor exposure can be up to 200 days, which increases the effectiveness of radiotherapy.[8] Meanwhile, the damage to surrounding normal tissues and organs is minimal because radiation penetration is extremely weak at a length of 17 mm[9]. The constant exposure of radiation results in a significant decrease of tumor re-proliferation, while that in a low-dosage can inhibit mitosis of tumor cells and block cells in the G2 phase.[10] Hence, 125I radiotherapy can maximally inactivating the tumor cells, ultimately attaining the treatment purpose.

Seed implantation is one of the novel techniques in current tumor radiotherapy realized by that 125I seeds are implanted into tumor or adjacent tumor infiltrating tissues to conduct brachytherapy, and it belongs to inter-tissue conformal radiotherapy.[11,12] Radioactive 125I seeds are implanted into lung cancer tumors under the bronchoscope, which presents with the characteristics of accurate localization, small trauma and continuous radiation from radioactive sources. It provides a new and effective palliative treatment for patients with advanced lung cancer who cannot or are not suitable for surgery.[13,14] Radioactive 125I seeds have been reported to have a great local control rate and the ability to improve progression-free survival (PFS) of patients,[15] so it has great research values in clinical practice.

In this study, lung cancer patients treated in Cangzhou People’s Hospital were included and grouped according to their treatment plan. The purpose was to explore whether or not conventional chemotherapy combined with seed implantation can provide better treatment effect and prolong the survival time of patients.

Materials and Methods

Patient Enrollment

This study was a retrospective clinical research and was approved by the Institutional Review Boards of Cangzhou People’s Hospital. From March 2018 to March 2020, 253 patients with middle and advanced lung cancer in Cangzhou People’s Hospital were involved. All patients were confirmed with lung cancer by computed tomography imaging and pathological procedures. The 253 patients included 148 men and 105 women aged between 37 and 83 years, with a median age of 61 years. Inclusion criteria: (1) the Karnofsky performance status (KPS) score of patients was above 60; (2) predicted life span >3 months; (3) age > 18; (4) no significant trachea functional failure was observed in heart, kidney, liver, spleen and stomach; (5) patients had not received any chemoradiotherapy or surgical therapy prior to diagnosis; (6) all patients signed the written informed consent. A total of 253 patients were divided into test group (n = 134) and control group (n = 119) according to their in-hospital treatment plans. Test group was given systemic chemotherapy combined with bronchoscopic seed implantation, while control group was given traditional systemic chemotherapy. The general clinicopathological data of all patients including age, gender, smoking history, KPS score, disease stage, classification, metastasis between the 2 groups were well balanced with no significant difference (P > 0.05) but of clinical comparability, as shown in Table 1.

Table 1.

The General Clinicopathological Data of Patients.

Characters	Test group (n = 134)	Control group (n = 119)
Median age, years	63 (37-80)	62 (39-83)
Age group, years
<61	64 (47.8%)	55 (46.2%)
>61	70 (52.2%)	64 (53.8%)
Sex
Man	78 (58.2%)	70 (58.8%)
Woman	56 (41.8%)	49 (41.2%)
Smoking history
Never smoker	18 (13.4%)	19 (16%)
Former smoker	41 (30.6%)	28 (23.5%)
Current smoker	75 (56%)	72 (60.5%)
KPS score
60-75	43 (32.1%)	33 (27.7%)
>75	91 (67.9%)	86 (72.3%)
Metastases
Yes	40 (29.9%)	33 (27.7%)
No	94 (70.1%)	86 (72.3%)
Disease stage
Ⅲb	44 (32.8%)	38 (31.9%)
Ⅳ	90 (67.2%)	81 (68.1%)
Classification
SCLC	35 (26.1%)	30 (25.2%)
NSCLC	99 (73.9%)	89 (74.8%)
NSCLC type
LUAD	76 (76.7%)	69 (77.5%)
LUSC	23 (23.3%)	20 (22.5%)

Treatment Plan

Systematic chemotherapy

For systematic chemotherapy, patients were given 1000-1250 mg/m2 of gemcitabine (Jiangsu Aosaikang Pharmaceutical Co., Ltd., SFDA approval number: HB20093698) through 30 min of intravenous infusion on day 1 and 8 in each course, and then 25 mg/m2 of cisplatin (Yuannan Biovalley Pharmaceutical Co., Ltd., SFDA approval number: H20043888) was administrated through intravenous infusion on day 1 to 3, followed by 250 mg of gefitinib (AstraZeneca Pharmaceutical Co., Ltd., SFDA approval number: J20140471) by oral. All patients were received a treatment course of 21 days, and at least 2 courses of treatment.

Bronchoscopic seed implantation

Equipment: seed implant needle (MED-TEC company, USA), implant gun and template (Jinxitong Biotech, Inc., Tianjin, China), PQ6000 spiral computed tomography (SCT; Picker company, USA). Seeds: Domestic radioactive 125I seed source with a half-life of 60.2 days and activity of 0.6 mCi (2.00 @107 Bq); the C-ray energy is 27 to 35 keV with the tissue penetration distance of 1.7 cm. Implantation: the tumor location was identified by using a bronchoscope, and a special catheter and guide wire were employed to implant 1 seed per (1-1.5) cm3 of tumor at 4 phases 3, 6, 9, 12. An average of 15 seeds were implanted in each patients. CT scanning was used after the whole implantation procedure. When seeds were found to be scattered or missed, seeds were replanted immediately. See Figure 1 for 125I seed figure and detailed implantation procedures.

Figure 1.

125I seed figure and the detailed implantation procedure. A-C, 125I seed figure. D, Plan for seed implantation. E, Insertion of implant needle. F, Computed tomography imaging after seed implantation.

Evaluation Criteria

Patients in control group were given a 2-cycle chemotherapy, while patients in test group were given a 2-cycle chemotherapy combined with seed implantation. After 2 months of seed implantation, serum tumor markers were detected. Before and after treatment, 4 ml of venous blood was extracted from patients on empty stomach of the 2 groups and placed into an anticoagulative tube, standing for 60 min at 4 °C. After that, the samples were centrifuged at 3000 r/min for 10 min and preserved in a refrigerator at −80 °C. Automatic chemical immunoassay analyzer and the reagent kit (Shenzhen New Industries Biomedical Engineering company, Maglumi2000PLUS) were applied for index detection according to specific operation instructions, including carcino-embryonic antigen (CEA), neuron specific enolase (NSE), cytokeratin fragment 19 (CYFRA21-1), pro-gastrin-releasing peptide (PRO-GRP). Subsequently, chest CT was re-examined for short-term efficacy evaluation, including objective response rate (ORR) and disease control rate (DCR), and for the long-term efficacy evaluation including PFS and overall survival (OS). Short-term efficacy was evaluated according to RECIST 1.1 of 2009 version[16]; (1) Complete Remission (CR): all target lesions had disappeared, and the short diameter of all pathological lymph nodes (both target and non-target) must be reduced to <10 mm; (2) Partial Remission (PR): the sum of target lesions in diameter was reduced by at least 30% from baseline; (3) Stable Disease (SD): the sum of target lesions in diameter was between PR and PD; (4) Progressive Disease (PD): the sum of target lesions in diameter was relatively increased by at least 20% (If the baseline measurements are minimal, the baseline values are used as a reference). In addition, the absolute value of the sum of diameters must be increased by at least 5 mm (the presence of one or more new lesions is also considered as PD).

Follow-Up

All patients were required to follow-up from the day they were hospitalized, including telephone and hospitalization follow-up. By the time of March 31, 2020, a total of 245 patients were followed up for 3 to 24 months, and 8 patients were lost to follow-up, with a total follow-up rate of 96.8%. PFS refers to the time between the beginning of treatment and the onset of disease progression or recurrence. OS refers to the time between the beginning of treatment and the end of death that caused by any reasons or loss of follow-up.

Statistical Analysis

All data were processed by using SPSS 22.0 software, and survival curve was plotted by using GraphPad Prism 7.0. Measurement data were presented as mean ± standard deviation (X ± s) and were verified by t test. The counting data were expressed as rate (%) and were assessed by chi-square test. P < 0.05 was considered statistically significant.

Results

The Level of Serum Tumor Markers of Patients in the 2 Groups

Before treatment, there was no significant difference in the level of serum tumor markers CEA, NSE, CYFRA21-1, PRO-GRP between the 2 groups, which was not considered as statistically significant difference (P > 0.05). After treatment, the levels of serum CEA, NSE, CYFRA21-1, PRO-GRP in test group were remarkably lower than those in control group (P < 0.05), which demonstrated a statistical significance (Table 2). Furthermore, compared with SCLC patients, the levels of serum CEA, NSE, CYFRA21-1, PRO-GRP in NSCLC patients were significant decreased (P < 0.05). Among patients with NSCLC, the levels of CEA, NSE, CYFRA21-1, PRO-GRP in LUAD patients were significantly decreased compared with LUSC patients (P < 0.05, Table 3). These findings indicated that the efficacy of systematic chemotherapy combined with seed implantation was superior to systematic chemotherapy, which was also more effective in patients with NSCLC and LUAD.

Table 2.

Comparison of Serum Tumor Maker Levels in Test and Control Groups.

Project	Test group (n = 134)	Control group (n = 119)	P Value
Before treatment
CEA	95.34 ± 9.61	94.58 ± 9.32	P > 0.05
NSE	88.42 ± 7.50	89.52 ± 7.76	P > 0.05
CYFRA21-1	37.68 ± 5.89	37.66 ± 6.15	P > 0.05
Pro-GRP	165.29 ± 132.16	166.63 ± 133.02	P > 0.05
After treatment
CEA	21.61 ± 3.35	55.13 ± 7.16	P < 0.05
NSE	26.29 ± 4.23	57.87 ± 8.35	P < 0.05
CYFRA21-1	9.29 ± 0.35	20.18 ± 2.21	P < 0.05
Pro-GRP	29.14 ± 9.85	47.25 ± 7.33	P < 0.05

Table 3.

Comparison of Serum Tumor Marker Levels in Patients With Different Subtypes of Lung Cancer in Test Group.

Project	SCLC	NSCLC	P Value	LUAD	LUSC	P Value
Before treatment
CEA	96.28 ± 8.67	94.43 ± 8.70	P > 0.05	93.34 ± 7.61	95.32 ± 7.81	P > 0.05
NSE	88.91 ± 7.01	87.36 ± 6.44	P > 0.05	87.12 ± 6.20	87.38 ± 6.42	P > 0.05
CYFRA21-1	37.71 ± 5.86	37.56 ± 5.85	P > 0.05	36.60 ± 4.81	37.49 ± 5.92	P > 0.05
Pro-GRP	261.63 ± 35.82	40.12 ± 6.99	P < 0.05	40.22 ± 6.89	40.18 ± 7.05	P > 0.05
After treatment
CEA	23.81 ± 1.15	19.15 ± 0.89	P < 0.05	19.12 ± 0.86	19.81 ± 0.24	P < 0.05
NSE	28.63 ± 1.89	24.38 ± 2.32	P < 0.05	22.85 ± 0.79	25.31 ± 1.39	P < 0.05
CYFRA21-1	9.48 ± 0.16	9.06 ± 0.12	P < 0.05	8.98 ± 0.04	9.14 ± 0.04	P < 0.05
Pro-GRP	32.11 ± 6.78	23.57 ± 4.28	P < 0.05	21.28 ± 1.99	26.59 ± 1.26	P < 0.05

Comparison of Short-Term Efficacy in the 2 Groups

As for the curative effects, we compared the difference in short-term efficacy between the 2 treatments. As the results revealed, in test group, CR was observed in 25 cases after the procedure, 60 cases had PR, 39 cases had SD, 10 cases had PD. See Figure 2 for computed tomography imaging after seed implantation. In control group, CR was observed in 10 cases, 36 cases had PR, 40 cases had SD, 33 cases had PD. The ORR and DCR were markedly higher in test group than those in control group (P < 0.05), which showed a statistical significance (Table 4). Taken together, we could conclude that the treatment plan of test group was noticeably better than that of control group. To gain more insight in the therapeutic effects of the treatment plan of test group on different subtypes of lung cancer, we further subdivided them. Similarly, the ORR and DCR of tumor in patients with NSCLC were remarkably higher than those in patients with SCLC. There was no significant difference in the DCR of LUAD and LUSC patients, while the ORR of tumor in LUAD patients was significantly higher than that in LUSC patients (P < 0.05, Table 5).

Figure 2.

Computed tomography imaging after seed implantation. A, The time at the end of seed implantation. B, Reexamination result 3 months after seed implantation.

Table 4.

Comparison of Short-Term Efficacy in 2 Groups.

Project	CR (%)	PR (%)	SD (%)	PD (%)	ORR (%)	DCR (%)
Test group (n = 134)	25 (18.6)	60 (44.8)	39 (29.1)	10 (7.5)	63.4	92.5
Control group (n = 119)	10 (8.4)	36 (30.3)	40 (33.6)	33 (27.7)	38.7	72.3
P Value					<0.05	<0.05

Note: ORR = CR+PR; DCR = CR+PR+SD

Table 5.

Comparison of Short-Term Efficacy in Patients With Different Subtypes of Lung Cancer in the Test Group.

Project	CR (%)	PR (%)	SD (%)	PD (%)	ORR (%)	DCR (%)
SCLC (n = 35)	4 (11.4)	12 (34.3)	10 (28.6)	9 (25.7)	45.7	74.3
NSCLC (n = 99)	16 (16.2)	48 (48.5)	31 (31.3)	4 (4)	64.7	96
P Value					<0.05	<0.05
LUAD (n = 76)	13 (17.1)	39 (51.3)	22 (28.9)	2 (2.6)	68.4	97.4
LUSC (n = 23)	3 (13)	9 (39.1)	9 (39.1)	2 (8.7)	52.1	91.3
P Value					<0.05	>0.05

Note: ORR = CR+PR; DCR = CR+PR+SD

Survival Time Comparison

After comparing the short-term efficacy of the 2 groups, we also compared the survival of the 2 groups after treatment. The median survival time of all follow-up patients was 12.3 months, and the median PFS of test group was 7.3 months, while that of control group was 4.2 months. The PFS of patients in test group was significantly higher than that of patients in control group (P < 0.05, Figure 3A). The median OS of test group was 12.8 months, while that of control group was 9.3 months. The OS of test group was significantly increased compared with control group (P < 0.05, Figure 3B). To further explore the OS of patients with different subtypes of lung cancer in test group, we subdivided the patients in test group according to types of lung cancer, and found that the PFS and OS of patients with NSCLC were longer than those of patients with SCLC (P < 0.05, Figure 3C, D). The PFS and OS of LUAD patients were significant increased compared with LUSC patients (P < 0.05, Figure 3E, F).

Figure 3.

Comparison toward PFS and OS. A and B, Comparison of the PFS and OS in patients of test and control groups. C and D, Comparison of PFS and OS in patients with NSCLC and SCLC in test group. E and F, Comparison of PFS and OS in patients with LUAD and LUSC in test group.

Adverse Reactions and Complications

The adverse reactions of all patients induced by systematic chemotherapy mainly included: (1) myelosuppression: leukopenia, anemia, and thrombocytopenia (test group 32%, 22%, 26% vs control group 36%, 21%, 22%); (2) gastrointestinal reactions: nausea, vomiting, and diarrhea (14%, 19%, 9% vs 15%, 21%, 11%); (3) abnormal renal and kidney functions (32% vs 34%). There was no significant difference of adverse reactions in patients of the 2 groups (P > 0.05).

The complications caused by seed implantation in patients of test group were as follows: (1) 21 cases had pneumothorax, among which 14 cases with pulmonary compression of more than 30% were treated with closed thoracic drainage, and 7 cases with pulmonary compression of less than 30% were treated with thoracentesis and aspiration; (2) 13cases had hemoptysis; (3) 11 cases had fever; (4) 5 cases had seed transfer. All the above patients got well after the corresponding treatments. No deaths or treatment termination were caused by the abovementioned complications.

Discussion

Lung cancer, one of the major malignancies worldwide, leads to a high mortality rate in both men and women.[17] In 2012, there were 226,150 cases with lung and bronchus cancer and 160,340 lung cancer related deaths estimated in the United States.[18] Surgery is considered as the standard treatment plan for patients with stage I or II of lung cancer. For patients who cannot receive surgical resection, the third-generation chemotherapeutic agents of gemcitabine, paclitaxel, docetaxel combined with platinum-based drugs are recommended.[19] However, the efficacy of chemoradiotherapy has already hit the bottleneck in the recent years, and the long-term survival rate and quality of life of patients remain unsatisfied. Therefore, it is of great significance to explore a novel therapeutic direction.

In recent years, with the development of nuclear medicine and the improvement of medical equipment, radioactive seed implantation (125I, 131I, 103Pd) has been widely applied in treatment of various tumors. Seed implantation refers to that small radioactive seeds are implanted into the tumor cell to produce the sustain effects. Due to the short radial distance, these radiations can selectively and effectively kill cancer cells without causing any major damage to the adjacent normal cells.[20] Seed implantation has been applied in many types of tumor. For example, some scholars have found that seed implantation contributes to a better survival rate and local control rate in the treatment of unresectable hepatocellular carcinoma and pancreatic cancer.[21,22] Consistent with the previous studies, we found that the local control rate (including ORR and DCR) of patients treated by chemotherapy combined with seed implantation was significantly higher than that of patients treated by chemotherapy alone. The PFS and OS of patients with combination therapy were prolonged. Moreover, compared to the standard treatment group set by us, the levels of serum tumor marker CEA, NSE, CYFRA21-1, PRO-GRP in patients of test group were decreased more significantly than those in control group, which showed that the efficacy of seed implantation is worthy of affirmation.

Seed implantation includes CT-guided implantation and bronchoscopic implantation concerning tumors from different parts of body.[20] These 2 kinds of seed implantation methods can both be adopted for lung cancer. However, the CT-guided percutaneous puncture can be affected by the lung physiological function of patients and anatomical factors with certain difficulty and requires several injections, which increases the possibility for lung injury and complications like bleeding, pneumothorax, seed displacement in clinical practice.[15] Bronchoscopic implantation was employed in this experiment for its ability of reducing these problems to some extent. This study showed that complications (pneumothorax, hemoptysis and fever) caused by seed implantation were relieved in patients after the corresponding treatment, which indicated that the bronchoscopic seed implantation had a good safety. There were no complications developed that led to treatment interruption or termination and no therapy-related deaths.

In our study, we subdivided the types of lung cancer and explored the therapeutic effect of seed implantation on them. The results displayed that the efficacy of seed implantation on NSCLC was better than that on SCLC, whereas similar trend could be observed in LUAD compared with LUSC. Meanwhile, the levels of serum tumor markers in patients with NSCLC or LUAD were remarkably decreased compared with those in patients with SCLC or LUSC, respectively, while the PFS and OS of NSCLC or LUAD patients were also prolonged much significantly. These findings validated that the systemic chemotherapy combined with seed implantation had a better therapeutic effect in patients with NSCLC and LUAD, which was similar to previous findings. The broad classification of SCLC resulted in an unsatisfactory outcome in treatment for SCLC patients.[23,24] Moreover, medical chemotherapy has been reported to be unproductive for advanced LUAD patients.[25] In this study, the addition of seed implantation indicted a great clinical effect on LUAD, which provided a new option for the clinical treatment for LUAD. Therefore, seed implantation is a great option for patients suffering from unresectable malignant lung tumor. Nevertheless, it is necessary to develop uniform dosages and procedures for homogeneity and provide references for clinical practices. Furthermore, certain limitations still exist in this study, and the results might be largely biased attributed to the great variance in sample size of different cancer subtypes. For instance, the sample size of SCLC was far smaller than that of NSCLC, while the sample size of LUSC was also greatly smaller than that of LUAD. Therefore, more precise study should be carried out on lung cancer patients with more diverse subtypes in the future.

Conclusion

To sum up, this study confirmed that systemic chemotherapy combined with seed implantation can improve the clinical treatment effect and prolong the survival time of patients with lung cancer.