As we know, primary bronchial lung cancer is remarkable for its high morbidity and mortality which threatens the survival of human and results in general panic. It is a pity that most of people are classified as advanced NSCLC with losing the chance to undergo surgical resection. According to the related guidelines and regulations, chemotherapy and EBRT are recommended as palliative treatment strategies for patients without EGFR or ALK gene mutation. Patients, especially the elderly, are unwilling to choose the chemotherapy because of the severe adverse effects, such as fatigue, myelosuppression, nausea and vomiting, hair loss, cardiotoxicity and hepatorenal function damage. What is more, the low efficacy also hinders patients from adopting to the chemotherapy which brings limited survival benefits. EBRT,as an important local approach, is encumbered by irradiation-related side effects, such as acute radiation pneumonitis, acute esophagitis, and late radiation-induced pulmonary fibrosis which could obviously affect the QOL and survival time (23, 24).
Li et al pointed in his study that it was impossible to deliver enough radiation dose for EBRT aiming at extinguishing tumor without damaging the surrounding normal tissues, especially for tumor measuring > 5 cm (25). However, in clinical practice, physician usually recommend the prescription dose of 60 Gy for primary bronchial lung cancer, when applying EBRT. As a matter of fact, the effective dose of radiotherapy for the diameter of tumor > 5 cm should be more than 100 Gy according to the report of Reveizi (6). As is known to us, radiation pneumonitis is a dose limiting adverse effect which may decline QOL and become life-threatening (26). If patients received so high radiation dose, the adjacent normal tissues would be seriously damaged with increasing the occurrence of severe complications and mortality. In terms of the elderly, they are characterized by poor cardiorespiratory function and physical status. The MILES study had pointed out that QOL was a critical factor for the elderly to decide how to choose a proper treatment (27). Accordingly, it is very necessary to find out proper treatment strategies especially for the elderly which take the QOL evaluation into account.
Fortunately, iodine-125 seed implantation has provided an available approach which can deliver a higher dose (100-170Gy) for doctors. The important point is that the radiation dose could fall off sharply within a short distance, and consequently the adjacent normal tissues would receive a minimal radiation dose, resulting in the reduction of the incidence of irradiation-related pneumonitis and esophagitis (5). Chest wall invasion was defined as soft tissue invasion certified by radiographic evidence and accounted for about 5% in locally advanced NSCLC (28). Owing to the relatively higher mortality of surgical resection for chest wall invasion in perioperative period, many skilled thoracic surgeons suggested it was necessary to look for new strategies(29, 30). Although stereotactic body radiation therapy (SBRT) could deliver a higher radiation dose to tumor lesions, it has been only recommended for small lesions (usually < 5 cm). In addition, patients would suffer from rib fracture or chest wall pain several months after SBRT, especially when tumor lesions were adjacent to the chest wall. Generally speaking, it was improper to perform SBRT for chest wall invasion because of considerable incidence of complications (31, 32). Obviously, the prescription dose of 60 Gy is not sufficient for chest wall invasion and how to improve the dose without damaging to the surrounding tissues has become a hot issue. However, there are few studies about the combined-modality therapy, namely EBRT and iodine-125 seed implantation, applying to the tumor lesions with invading the chest wall. In our study, the data indicated that the combined-modality therapy showed a better local control rate with an ORR of 71.4% and DCR 90.5%, respectively at 1 year, even if there were 15 patients (71.4%) with tumor measuring > 5 cm. What is more, the combined-modality therapy was certified not only to deliver a higher dose for chest wall invasion of NSCLC, but also significantly reduce adverse effect.
There's no denying that iodine-125 seed implantation has its own limitations. Firstly, it is not easy to perform iodine-125 seed implantation aiming at the lesions located in the mediastinum, which may lead to an unsatisfactory disposition of iodine-125 seed. Huang and his colleagues reported that it could carry out artificial pneumothorax for the lymph nodes of mediastinum before seed implantation, which should meet a good cardiorespiratory function. But it also increased the risk of incidence of complications, such as hemoptysis, chest tightness and dyspnea, which was difficult to tolerate for the elderly(10, 32). In addition, when the tumor is larger (especially > 5 cm), the expense of iodine-125 seed implantation will increase which may not be accepted by an ordinary family in developing countries. Therefore, the combined-modality therapy not only had showed superiority in decreasing the expense for tumor measuring > 5 cm, but also provided a new treatment strategy for tumor invading the chest wall.
About 60–90% patients of advanced cancer will suffer from cancer-related pain throughout the process which is a very common clinical issue(20, 33). At the same time, the cancer-related symptoms also bother patients, such as dry cough, hoarseness and hemoptysis. Therefore, how to relieve cancer-related pain and ameliorate cancer-related symptoms to improve QOL has become a critical question for doctors and patients. In our study, all patients suffered from a more or less pain caused by the tumor invading the chest wall. There were 71.4% patients achieving complete pain relief therapy and there were 20 patients, accounting for 95.2%, obtaining evident pain relief after the combined-modality. What is more, patients treated with the combined-modality therapy did not experience rib fracture or intercostal nerve injury in our research which was superior to SBRT (30, 31). After treatment, the caner-related symptoms of patients were obviously improved, so the ECOG performance scores were pronouncedly improved which was observed in 18 patients in our study. Song et al indicated that iodine-125 seed implantation not only showed noteworthy superiority in ameliorating cancer-related symptoms but also significantly improved QOL of patients diagnosed as advanced NSCLC (34). It is remarkable that the combined-modality therapy was able to significantly relieve cancer-related pain and improve ECOG scores which could contribute to improve QOL.
With respect to severe complications in the research, there was no occurrence, consistent with previous reports(3, 10, 11, 16, 32). Except for grade 2 irradiation-related myelosuppression (1 case), there were no other grade 3 or higher toxicity effects. According to the reports of Jiang et al, there were no evident toxicity effects of grade 3 or higher (35). The incidence of radiation pneumonitis with grade ≥ 2 was 7.0 to 32.0% in patients receiving EBRT therapy, while that with grade ≥ 3 was 2.6 to 18.0% according to some authorized studies (36–38). Thereby, it is safe to combine EBRT and iodine-125 seed implantation for locally advanced NSCLC.
Due to lacking prospective randomized controlled trials, it is difficult for clinical physicians to formulate standardized prescription dose for iodine-125 seed implantation. Because of different tumor volume, different treatment strategy, and heterogeneity of tumor, it is impossible to obtain effective information about the prescription dose from previous report which varied from 80 Gy to 170 Gy. Ji and his colleague found that the local control was seemingly positively related to the prescribed dose which indicated the higher prescribed dose, the better local control. In their study, they conducted radioactive iodine-125 seed implantation for solid thoracic malignancies, including the primary lung cancer or metastatic lung cancer. According to their study, the median durations of local control was 11.0 months with the prescription dose < 140 Gy vs. 16.4 months with the dose ≥ 140 Gy, but it did not reach significant difference. Based on their study, they strongly suggested the prescription dose should exceed 140 Gy for solid thoracic malignancies and should be as higher as possible, owing to the higher marginal recurrence of primary lung cancer (10). In our study, the ORR with tumor receiving the prescription dose ≥ 140Gy seemed better than the other, suggesting that the local control rate should be proportional to the delivered dose to the target lesion. Based on our study and pervious other studies, we recommended that the prescription dose for primary lung cancer should exceed 140 Gy, as possible as high, if tolerated. Obviously, the result should be verified by large clinical randomized controlled trial.