Patient selection and inclusion
Inclusion criteria were as follows: patients with locally recurrent stage III NSCLC within one year after receiving concurrent chemoradiotherapy; time of survival was estimated to be longer than three months; tumor diameter was less than 6 cm; no severe liver insufficiency or renal insufficiency, heart diseases, diabetes, coagulation dysfunction, and other chronic diseases; no severer chronic obstructive pulmonary diseases; the Eastern Cooperative Oncology Group (ECOG) score was no more than 2; tumor lesion was suitable for brachytherapy, as the location and size of the lesion were confirmed by chest CT scanning; patients intended to receive the treatments; patients did not receive any radiotherapy and chemotherapy within 3 months of this study. Local recurrence was defined as a 20 % increase in the volume of primary tumor mass from the point of maximum tumor regression in the lung without lymph node metastasis. All patients were evaluated by the investigators of this study (including the oncologists, surgical specialists, and radiologists of Huai’an First People’s Hospital Affiliated to Nanjing Medical University) and confirmed to be able to receive the second-line chemotherapy by paclitaxel (135 mg/m2, at day 1) plus cisplatin (75 mg/m2, at day 2) and CT-guided radioactive 125I seed implantation.
Based on pathological conformation, 52 patients with locally recurrent lung cancer within 3–12 months after receiving concurrent chemoradiotherapy were included in this study. Prior to the procedure, all patients received multiple imaging examinations including chest CT, abdominal CT or magnatic resonance imaging (MRI), cranial MRI, and bone emission computed tomography (ECT), blood routine examination, blood coagulation tests, hepatic and renal function tests, pulmonary function tests, and electrocardiogram (ECG). Tumor staging was according to American Joint Committee on Cancer (AJCC) staging manual (7th edition). All patients were previously treated by 6- or 15-MV X-ray beams produced by Siemens ONCOR Expression Linear Accelerator (Siemens AG, Muenchen, Germany). The dose was 2 Gy once daily, 5 times a week, for 6–7 weeks. The total radiation dose received was 66–70 Gy. The concurrent chemotherapy was paclitaxel (135 mg/m2, at day 1) plus cisplatin (75 mg/m2, at day 2), which was intravenously infused prior to radiotherapy and repeated after four weeks, for four cycles. The median time to recurrence was 7.9 months (range: 5.5–11.2 months). The study protocols were approved by Ethics Committee of Huai’an First People’s Hospital Affiliated to Nanjing Medical University and all patients gave signed informed consent.
Study design
This was a prospective study (Trial registration number ChiCTR-IOR-15006560). The 52 patients were divided into two groups using computer-produced digital random method: experimental group, the patients received the combined therapy of 125I seed implantation, docetaxel (60 mg/m2 at day 1), and cisplatin (75 mg/m2 at day 2); control group, the patients received the combination of docetaxel (60 mg/m2 at day 1) and cisplatin (75 mg/m2 at day 2). Chemotherapy cycle length was three weeks and planned duration of chemotherapy was four cycles. Primary endpoints were progression-free survival and time of local control. CT/PET scans were not available during the years of the study due to economic reasons.
CT-guided implantation of 125I seeds
Sixty-four slice spiral CT scanner (SIEMENS Somatom Sensation 64 CT Scanner) was provided by Siemens. Radiotherapy treatment planning system (TPS) HGGR-2000 was provided by Zhuhai Hokai Medical Instruments Co., Ltd (Zhuhai, China). Implantation needle (18 Gauge), implantation gun, and 125I seeds were provided by Ningbo Jun’an Pharmaceutical Technology Co., Ltd (Ningbo, China). The planning target volume (PTV) of lung tumor was defined and outlined after CT scan. Radiotherapy treatment plan for each patient was optimized according to the safety margin around the tumor volume or normal tissues and the radiation dose and radioactivity of 125I seeds. The 125I radioactive seeds used in this study had a length of 4.5 mm and a diameter of 0.8 mm, with an average energy of 27–32 keV, a half life of 59.6 days, and a tissue penetration range of 1.7 cm. The initial dose rate was 7 cGy/h prescribed to 1 cm depth, and the prescription dose was 90–110 Gy. The ideal position for radioactive seed implantation was determined based on pre-operative TPS and physical condition of patients. The correct entry point, the direction of needle advancement, and the space between implanted 125I seeds were determined under CT-guidance. After intramuscular injection of 10 mg diazepam and 100 mg pethidine hydrochloride, 125I seeds were implanted in the tissues via needles. The space between the implanted seeds was 1.5 cm. The activity of 125I seeds was 2.22–2.59 x 107 Bq. Post-operative chest CT examination was performed to monitor the implantation-related complications (e.g. pulmonary hemorrhage, pneumothorax, or migration of radioactive seeds). Acquired CT images were then transferred to TPS for the dosimetry evaluation of implanted 125I seeds. The evaluation indicators included the tumor matched peripheral dose (MPD) and the dose that 90 % of the target volume received (D90). Postoperative monitoring of vital signs was conducted for all patients. Antibiotic prophylaxis was used to prevent post-operative infection. One week after the implatation, hemogram was examined to detect any complications.
Evaluation of efficacy and safety
The efficacy was evaluated three months after interstitial permanent implantation of 125I seeds. Tumor response was evaluated based on imaging findings in accordance with the Response Evaluation Criteria in Solid Tumors (RECIST) criteria: complete response (CR), complete disappearance of target lesions (negative findings or only funicular shadows on imaging evaluation); partial response (PR), at least a 30 % decrease in the sum of the longest diameters of target lesions; progressive disease (PD), at least a 20 % increase in the sum of the longest diameters of target lesions or the appearance of one or more new lesions; stable disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. The response rate (RR) of treatment was calculated using the following formula: RR = (CR + PR)/total number of patients × 100 %. The acute and late radiation toxicities were assessed according to toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC) [10].
Follow-up
All patients were followed up from January 2006 until the time of local recurrence and disease progression. The range of follow-up was 4.5–24 months, with a median of 11 months.
Statistical analysis
Statistical analysis was performed using SPSS 13.0 software. Kaplan-Meier survival curve method was used to estimate local control rate and PFS. The log-rank test was used to compare the difference between two treatment groups. Fisher’s exact test was used to assess the difference in CR rate and short-term efficacy between both groups. P < 0.05 was considered statistically significant.