Combination of Iodine-125 brachytherapy and chemotherapy for locally recurrent stage III non-small cell lung cancer after concurrent chemoradiotherapy

Lung cancer is the leading cause of malignant tumor death. Non-small cell lung cancer (NSCLC) accounts for 80–85 % of lung cancers. For advanced inoperable NSCLC, combined chemoradiotherapy is considered as the standard first-line treatment [1]. Phase III clinical trials have demonstrated that docetaxel is an effective therapeutic agent for recurrent NSCLC after first-line treatment. Nevertheless, for the patients who are treated with docetaxel-based second-line therapy, their overall survival (OS) is usually short and prognosis is poor [2].

Treatment of locally recurrent NSCLC after first-line concurrent chemoradiotherapy poses a great challenge to physicians [3]. Although chemoradiotherapy can be considered as an option for subsequent treatment, its application is strictly limited due to the normal tissue tolerance dose of radiation and the development of severe complications, including chronic basic pulmonary diseases (e.g. chronic obstructive emphysema), radiation pneumonitis, radiation esophagitis, and tracheal necrosis [4].

Currently, implantation of iodine-125 (¹²⁵I) seeds is a treatment option for interstitial brachytherapy in lung cancer [5]. The implanted ¹²⁵I seeds can generate a high dose (140–160 Gy) within target tumor volumes to continuously destroy tumor cells, while the surrounding non-neoplastic tissues only receive a very low dose and subject to little damage. In addition, the low radiation dose rate can induce the reoxygenation and increased blood flow of hypoxic tumor volumes, thus producing radiation-induced bystander effect to kill tumor cells that can overcome the inhomogeneous distribution of radiation dose [6, 7]. Percutaneous CT-guided ¹²⁵I seed permanent implantation can decrease the local recurrence in the treatment of high-risk stage I NSCLC with less tissue injury and few complications [8]. ¹²⁵I seed implantation decrease the local recurrence, especially in those with a positive cytology at the staple line [9]. Therefore, we hypothesized that the combination of ¹²⁵I brachytherapy and second-line chemotherapy may be ideal for the treatment of locally recurrent stage III non-small cell lung cancer after first-line therapy. Nevertheless, this combined therapy is uncommonly used and its efficacy and safety remain unclear. In this study we performed a systematic assessment on the clinical efficacy of the combination of brachytherapy with radioactive iodine-125 (¹²⁵I) seeds and chemotherapy for the treatment of locally recurrent stage III NSCLC.

Of 26 patients who received ¹²⁵I brachytherapy, 15 were male and 11 were female. The median age was 62 years (age range: 48–72 years). Nine patients had squamous cell carcinoma, 16 had adenocarcinoma, and one had large cell carcinoma. Fourteen patients had stage IIIa NSCLC and 12 had stage IIIb NSCLC (Table 1). The number of implanted ¹²⁵I seeds in these patients ranged between 15 and 92, with a median number of 34. The immediate post-operative CT scan demonstrated that the tumor MPD in these patients ranged between 90.2 and 130.6 Gy, with a median dose of 110.0 Gy. The D₉₀ was 103.6–148.2 Gy in these patients, with a median dose of 128.9 Gy (Table 2). After brachytherapy, re-implantation of ¹²⁵I seeds was required in one patient. Three patients had mild pneumothorax, two patients had hemoptysis, two had low-grade fever, and seed migration was observed in one patient. The patients with mild pneumothorax received conservative therapy and finally recovered completely. Another patient with grade III radiation pneumonitis obtained symptom relief after drug therapy (Table 3). There were no grade 4/5 complications in both experimental and control groups. The CT scan images of one representative patient were shown in Fig. 1.

Characteristics		Number of cases		P value
		Experimental group (N = 26)	Control group (N = 26)
Gender	Male	15	17	0.776
	Female	11	9
Stage	IIIA	14	16	0.779
	IIIB	12	10
ECOG score	0–1	22	20	0.726
	2	4	6
Pathology	Squamous cell carcinomas	9	11	0.656
	Adenocarcinomas	16	13
	Large-cell carcinomas	1	2
Differentiation	Well differentiated	7	3	0.291
	Poorly differentiated	19	23
Tumor size (diameter)	3 cm	16	20	0.368
	3–6 cm	10	6

Parameters	Median value	Range
MPD (Gy)	110.0	90.2–130.6
D90 (Gy)	128.9	103.6–148.2
Number of seeds implanted	34	15–92
Activity (mCi per seed)	0.6	0.6–0.9
Dose rate (Gy/h)	0.07	0.05–0.09

Complications	Experimental group (n = 26)	Control group (n = 26)
Grade 4/5 complications	0	0
Mild complications
Mild pneumothorax	3	3
Hemoptysi	2	3
Low-grade fever (38.5 C)	2	5
Radiation pneumonitis	1	0
Seed migration	1	0
Local skin erythema	0	1
No complications	17	14

For patients who received the combined therapy of ¹²⁵I brachytherapy and DP chemotherapy, the time of local control was between 4.5 and 24 months, with a median of 10 months (95 % CI: 8.72–11.28 months). Of the patients in this cohort, three achieved progression free of disease after 24-month follow-up. The median PFS was 8 months (95 % CI: 6.99–9.01 months). The range of PFS was 3–24 months. Three months after ¹²⁵I brachytherapy, the overall response rate (ORR) was 69.2 % (18/26). The rates of CR, PR, SD, and PD in this cohort were 38.5 % (10/26), 30.8 % (8/26), 23.8 % (6/26), and 7.7 % (2/26), respectively. For the control group, the time of local control was 3–15 months, with a median of 6.2 months (95 % CI: 5.27–7.13 months). The median PFS was 5.5 months (95 % CI: 4.43–6.57 months). The range of PFS was 3–10 months. The overall response rate was 57.7 % (15/26). The rates of CR, PR, SD, and PD in this cohort were 7.7 % (2/26), 50.0 % (13/26), 30.8 % (8/26), and 11.5 % (3/26), respectively.

There was no significant difference in ORR between the experimental group and the control group (χ2 = 0.75, P = 0.57 > 0.05). For the rate of CR, the time of local control, and PFS, there was significant difference between both groups (χ2 = 7.43, P = 0.02 < 0.05 for the rate of CR; χ2 = 8.59, P = 0.003 < 0.01 for the time of local control; χ2 = 4.7, P = 0.04 < 0.05 for PFS) (Figs. 2 and 3). The median time of local control in the experimental group and the control group was 10 and 6.2 months, respectively. There was significant difference in this outcome between two groups (P < 0.05). For PFS, the experimental group had a median of 8.0 months, which was significantly longer than that in the control group (5.5 months) (P < 0.05).

Lung cancer is the most common cancer worldwide. The majority of lung cancer patients are not diagnosed until the disease is at the relatively late stage. The patients with advanced lung cancer usually have a very short survival. Currently, lung cancer therapies are not satisfactory in their efficacy of improving the survival of patients. Clinical studies have proven that concurrent chemoradiotherapy is a standard treatment for locally advanced NSCLC, which can provide a 2-year survival rate of 39.7 %, a median OS of up to 22 months, and a median PFS of 17 months [11]. However, for the patients with locally recurrent stage III NSCLC (stage IIIA and III B) after concurrent chemoradiotherapy, the treatment mainly depends on second-line chemotherapy or molecular targeted therapy, which can provide a median OS of 11.7–12.2 months, a median PFS of 2–3 months, and a one-year survival rate of 30 % [12]. However, these therapies are not yet considered as the standard treatment for locally recurrent stage III NSCLC after concurrent chemoradiotherapy, further investigations are required to explore and optimize possible treatment regimens.

Development of computerized three-dimensional TPS has attracted more attention of physicians on CT-guide brachytherapy with radioactive seeds for treating malignant tumors [13]. The ¹²⁵I radioactive seeds have an effective emission range of 1.7 cm in tissue. During the half-life of ¹²⁵I radioactive seeds (59.6 days), tumor cells at different phases of the cell cycle can be destroyed by the gamma-rays emitted from the radioactive seed. Previous studies have shown that the low radiation dose rate could increase the sensitivity of hypoxic tumor cells to radioactive rays and produce radiation-induced bystander effect to kill tumor cells [7, 14]. In vitro studies have shown that ¹²⁵I radioactive seeds up-regulated apoptosis-related genes, and regulated cell cycle and apoptosis of tumor cells [15]. Taken together, ¹²⁵I radioactive seeds have the advantages including high conformality index and producing high dose in target volumes and low radioactive exposure to surrounding normal tissues, thus having great potential in the treatment of locally recurrent tumors [16].

Currently, brachytherapy with ¹²⁵I seeds are widely used in clinic for the treatment of recurrent and metastatic prostate tumor and head and neck tumors [17–19]. However, this therapy has been rarely reported for treating patients with locally recurrent NSCLC. In this study we investigated the clinical efficacy of the combination of ¹²⁵I brachytherapy and chemotherapy in the patients with locally recurrent stage III NSCLC after concurrent chemoradiotherapy. Our results demonstrated that this combined therapy achieved satisfactory efficacy compared with chemotherapy alone. For the combined therapy, the median time of local control was 10 months. Three patients achieved progression free of disease after 24-month follow-up. The median PFS was 8 months. Three months after ¹²⁵I brachytherapy, ORR was 69.2 % (18/26). The rates of CR and PR were 38.5 % (10/26) and 30.8 % (8/26), respectively, which were significantly higher than those in the control group. Recent studies have indicated that local disease control rate is an important independent prognostic factor for the OS of patients with locally advanced lung cancer [20]. In the present study, ¹²⁵I radioactive seeds were shown to have a good local tumor control. For three patients with well differentiated adenocarcinoma (tumor diameter < 3 cm with single metastatic lesion), the time of local control was longer than two years, suggesting that the degree of tumor differentiation, growth rate, and tumor size could affect the local efficacy in NSCLC patients.

Furthermiore, there was no occurrence of severe complications during the study, indicating that combined therapy of ¹²⁵I brachytherapy and DP regimen is effective and safe for the treatment of locally recurrent stage III NSCLC after concurrent chemoradiotherapy. Further large-sale studies are needed to verify the potential of the combination of ¹²⁵I brachytherapy and second-line chemotherapy for treament of locally recurrent stage III NSCLC.

The combination of ¹²⁵I brachytherapy and second-line chemotherapy is superior to chemotherapy alone and is an effective and safe therapy for this disease.