Radioactive Seed Implantation and Lobaplatin Chemotherapy Are Safe and Effective in Treating Patients with Advanced Lung Cancer

Objecive: To investigate the clinical safety and efficacy of CT-guided 125 iodine (125I) seed implantation combined with percutaneous intra-tumor injection of chemotherapy emulsion of lobaplatin and lipiodol in treating patients with advanced lung cancer. Materials and Methods: Patients with advanced lung cancer and treated with spiral CT-guided 125 I seed implantation combined with percutaneous intra-tumor injection of chemotherapy emulsion of lobaplatin and lipiodol were recruited. Results: Of the 36 patients, there were 40 nidi in total. The contrast-enhanced CT evaluation was conducted 60 d after treatment. Response evaluation suggested that 4 patients achieved complete remission (CR), 24 partial remission (PR), 4 stable disease (SD) and 4 progression disease (PD), with a total response rate of 77.8% (28/36). Conclusions: CT-guided 125 I seed implantation combined with percutaneous intra-tumor injection of chemotherapy emulsion of lobaplatin and lipiodol are safe and effective in treating patients with advanced lung cancer.


Introduction
With the development of industrialization and urbanization, the morbidity of lung cancer increases annually (Li et al., 2005). At present, lung cancer, instead of liver cancer, has become the first cause of malignant tumor-related death. Non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) are the most common lung cancer in clinic, in which NSCLC accounts for >85%. As most NSCLC patients (>85%) are in advanced stage when diagnosed and have lost the opportunity for radical surgery, the therapeutic efficacy is relatively poor (Lu et al., 2013;Liu et al., 2013;Yan et al., 2013;Cui et al., 2014;Huang et al., 2014;Ji et al., 2014). In April, 2012, CT-guided 125 iodine (125I) seed implantation combined with percutaneous intra-tumor injection of chemotherapy emulsion of lobaplatin and lipiodol were applied in our hospital for the treatment of 36 patients with advanced lung cancer, with satisfactory clinical efficacy obtained.
I seeds and the amounts of the therapeutic seeds was calculated. The dosage of chemotherapy emulsion of lobaplatin and lipiodol was selected according to the distribution of the seeds. The patients were well informed of the operative process before operation and were trained how to hold breath. All informed consent forms were signed by the patients and their families.

Instruments, equipments and agents
Philips six-row spiral CT machine; radioactive seed source implantation instruments: domestic 18-G radioactive seed source implantation probes and diskrotating implantation gun and China Atomic Energy Research Institute provided IM 67112 125 I seed [NO: SFDA 2001-034]. The activity of a single seed was 23.31~29.97 MBq. Before the seeds left the factory, leakage test was performed and activity was detected. The qualified seeds were packaged and posted to the hospital as A-type. Lobaplatin (Chang'an International Pharmaceutical Co., Ltd, Hainan, China; specification: 10 mg/piece) was fully mixed with lipiodol to form the emulsion.

Therapeutic methods
The body position was selected and fixed according to the locations of the lesions. The self-made fence locator was placed on the corresponding surface of the lesions in order to conduct CT scan. CT lines of position were opened and the optimal needling surface was selected and marked. The inserting points, angle, direction and depth were then determined. Sterilization was routinely performed and sterile drapes were set up. After local anesthesia, the patients were told to hold their breath and the puncture probes were inserted till the measuring depth. During the puncture, the CT scan was used to regulate the inserting angle and depth. According to the plan, corresponding amount of radioactive seeds were implanted in designated locations. Based on the surgical requirements, multiple puncture points could be set up on the patient's skin surface. After seed implantation, percutaneous intra-tumor injection of chemotherapy emulsion of lobaplatin and lipiodol was applied for multiple times and points on the locations with residual tumors so as to maximally eliminate the blind space. Postoperative re-examination with CT scan was performed to observe the complications and evaluate the recovery area and the therapeutic satisfactory degree of CT-guided 125 I seed implantation combined with percutaneous intratumor injection of chemotherapy emulsion of lobaplatin and lipiodol.

Postoperative process
The amount of seeds and the dosage of chemotherapy emulsion of lobaplatin and lipiodol were examined. After being bandaged, spiral CT thin-layer images (layer thickness: 3 mm) were analyzed to observe the presence of the seeds, the metastasis of chemotherapy emulsion lobaplatin and lipiodol and the complications (pneumothorax, hydropneumothorax or pulmonary hemorrhage, etc.). Patients' surveillance: vital signs were closely detected; reptilase 1 Ku was intravenously injected 30 min after operation; antibiotics were routinely applied 3 d after operation to prevent infection; and continuous low-flow oxygen inhalation was conducted to patients with pulmonary hemorrhage or pneumothorax for >24h. For patients with pneumothorax >30%, chest suction or closed drainage was performed.

Clinical efficacy evaluation
The efficacy evaluation of thirty-six patients undergoing CT-guided 125 I seed implantation combined with percutaneous intra-tumor injection of chemotherapy emulsion of lobaplatin and lipiodol mainly depended on the contrast-enhancement spiral CT images. The products of the maximum diameter of the orthogonal tumors detected by spiral CT images before treatment and after the re-examination (60 d after treatment) were compared. The efficacy evaluation referred to the modified Response Evaluation Criteria In Solid Tumors (RECIST) (Yao et al., 2012): Complete remission (CR): the arterial enhancement development of all target nidi disappeared; partial remission (PR): the total diameter of target nidi (arterial enhancement development) shrank ≥30%; stable disease (SD): the total diameter of target nidi shrank <that of PR or increased <that of progression disease (PD); PD: total diameter of target nidi (arterial enhancement development) increased ≥20% or new nidi appeared. Total effective rate=(CR+PR)cases/total cases×100%.

Postoperative complications
All patients finished the treatment of CT-guided 125 I seed implantation combined with percutaneous intratumor injection of chemotherapy emulsion of lobaplatin and lipiodol, with successful rate being 100%. Antiinfection and analgesia therapies were routinely given after operation. All patients had transient moderate and low heat (temperature <38.8℃), which recovered to normal level 3~14 d after treatment. Twelve patients, who had slight pneumothorax, were told to stay in bed quietly without giving any special treatment. Only 1 patient had severe pneumothorax (pulmonary compression: about 75%) that was completely improved 7 d after the closed drainage of chest, according to the re-examined chest X-ray images. Twenty patients, who coughed small amount of dark red blood clot or blood streak during and after operation, were given hemostatic therapies. No

Clinical efficacy
When hospitalized, all patients had different-degree shortness of breath, dyspnea and chest pain, few of whom also had slight hemoptysis, etc. After treatment, all patients had different-degree improvement in clinical symptoms, especially in chest pain and dyspnea. Re-examined chest CT 60 d after treatment showed that 4 patients were with CR, 24 with PR, 4 with SD and 4 with PD, with total effective rate being 77.8% (28/36), as shown in Figures  1~4.

Follow up
The follow-up period was 4~13 months, with median follow-up time and rate being 10 months and 100%, respectively. Moderate-and long-term follow-up results indicated that after 6 months, 28 patients' nidi were stably controlled and 4 died; and after 1 year, only 4 patients' nidi were stably controlled.

Adverse responses
No severe complication was recorded after treatment. However, there were slight gastrointestinal responses and leukopenia, which were recovered rapidly after the end of treatment. No severe adverse response was reported in all patients.

Discussion
Radioactive seed implantation in tumor tissues has a long history of >100 years, and was firstly applied in treating patients with malignant lung cancers by American Craham in 1933 (Yi et al., 2003). In recent years, with the patients' increasing requirement on the disease therapies and the development of micro-invasive techniques, radioactive seed implantation has achieved rapid progression in the treatment of malignant tumors. 125 I seeds can cure patients with lung cancer through killing tumor cells by continuously releasing X-ray with radioactive nucleus (Sider et al., 1998;Martinez-Monge et al., 2008) 125 I seed source is small in size and low in dosage, with half-life period, average photon energy and tissue penetration distance being 59.6 d, 28 KeV and 1.7 cm, respectively. It can also release continuously lowdosage X-and γ-ray and effectively improve the dosage distribution ratio between locally radioactive tissues and normal tissues. The continuous X-ray irradiation can significantly reduce the regeneration of tumors, while continuous low-dosage X-ray irradiation can inhibit the mitosis of tumor cells and the continuous low-dosage conformal irradiation therapy can evenly irradiate the tumor cells, which conforms to the growth rhythm of tumor cells, thus leading to the maximum killing to the tumor cells due to radiation effect so as to achieve the aim of curing the cancer. Seed therapy belongs to the short-distance radiotherapy field, and the initially developed iodine seed implantation had obtained favorable achievements in the treatment of patients with prostate cancer (PC). Multiple literatures at home and abroad reported the availability of radioactive seed implantation in the treatment of malignant tumors, such as brain cancer, mouth and face cancer, lung cancer, liver cancer, colorectal cancer, PC and pancreatic cancer, etc (Horwitz et al., 1996;Martinez-Monge and Nag, 1999;Barkin et al., 2000;Lee et al., 2003;Liu et al., 2005;Nag et al., 2006;Zhou et al., 2006;Bottomley et al., 2007).
Lobaplatin, as the anti-cancer agent of the thirdgeneration cisplatin, is characterized by wide anti-tumor spectrum, strong anti-tumor activity and low toxic responses, etc (Yang et al., 2009;Huang et al., 2013). In certain range, the tumor-cell-killing function of anticancer agents mainly depends on the agent dosage and application time. After being injected into tumor cells, the chemotherapy emulsion of lobaplatin and lipiodol, which showed different-degree dispersion, could prolong the contact time of lobaplatin with the tumor cells. The local injection of lobaplatin and lipiodol could significantly increase the local agent concentration in tumors while decrease that in non-injection area (Editor-in-chief: Li, 2007). The concentration of locally injected chemotherapy emulsion might become 9~23 folds of that by general chemotherapy in unite time (Zhu et al., 2002). Additionally, the local injection of the emulsion could not only directly kill the tumors, but also prevent the dispersion and metastasis of tumor cells, thus becoming an effective supplement for seed implantation.
All patients finished the treatment of CT-guided 125 I seed implantation combined with percutaneous intratumor injection of chemotherapy emulsion of lobaplatin and lipiodol, after which all patients had different-degree improvement in clinical symptoms, especially in chest pain and dyspnea. And the re-examined chest CT 60 d after treatment showed that 4 patients were with CR, 24 with PR, 4 with SD and 4 with PD, with total effective rate being 77.8% (28/36). However, the long-term efficacy of the combined treatment should be further observed due to the short term of follow up.
CT-guided 125 I seed implantation is safe and effective in application, small in trauma, rapid in recovery and slight in postoperative adverse responses, with significant short-term efficacy and short therapeutic duration, so it can be repeatedly applied and has certain clinical efficacy in treating lung cancer patients with various pathological patterns. Therefore, it is believed that CT-guided 125 I seed implantation is a relatively safe and effective therapeutic method for middle and advanced lung cancer patients who are poor in surgeries. In this study, no severe adverse response was reported, suggesting that CT-guided 125 I seed implantation was an ideal therapeutic method for patients with advanced lung cancer, and it was also concluded that CT-guided 125 I seed implantation combined with percutaneous intra-tumor injection of chemotherapy emulsion of lobaplatin and lipiodol could improve the clinical efficacy and prolong the survival time of patients with advanced lung cancer.