Patient outcomes of monotherapy with hypofractionated three-dimensional conformal radiation therapy for stage T2 or T3 non-small cell lung cancer: a retrospective study

Three-dimensional conformal radiation therapy (3D-CRT) delivers radiation to tumors while sparing surrounding normal tissue structures. The use of patient-specific 3D images allows for treatment planning in a manner that is distinct from conventional radiotherapy techniques. The complementary use of computed tomography (CT) and magnetic resonance imaging (MRI) of the lungs is performed to define the area of lung tumors. Identifying areas of tumor and normal lung tissue allows for selective and concentrated radiation therapy with less damage to normal lung tissue. Surgical resection is one treatment method for localized non-small cell lung cancer (NSCLC), and good outcomes are achieved with this method in stage I or II NSCLC [1‐3]. While surgery is recommended for some patients with localized NSCLC, the proportion of operable patients declines with age [4, 5]. Radiation therapy is selected if pulmonary function is poor, if surgery is contraindicated due to the patient’s general condition, or if the patient refuses surgery. However, satisfactory results for patients with localized NSCLC have not been obtained with conventional irradiation at a dose of 2 Gy given in a single fraction [6‐9]. In conventional radiation therapy, therapeutic effects are obtained on the basis of differences in the degrees of damage and recovery between normal and cancer cells. Damage to normal cells can be reduced by employing this irradiation method. Also, the treatment duration is prolonged to increase the dose, which may increase the risk of tumor regrowth. Further drawbacks include a low single radiation dose that reduces the anti-tumor effects and changes in the characteristics of cancer cells, especially their sensitivity to radiation, when the treatment duration is prolonged. For this reason, the duration of radiation treatment should be kept short, and the radiation dose should be increased for improved tumor control. Stereotactic body radiotherapy (SBRT) has also been established as a treatment option for localized NSCLC [10, 11]. SBRT results in improved patient outcomes compared with conventional irradiation, with results that rival surgery [12‐14]. However, SBRT requires greater precision and accuracy than conventional radiotherapy, and it should be conducted according to a strict protocol [15]. Furthermore, patient characteristics such as tumor size, site, and general physical condition can make performing SBRT difficult. In such instances, hypofractionated 3D-CRT is an alternative treatment option [16, 17]. Some studies of hypofractionated radiotherapy (HFRT) using various radiation dose schedules have reported improved outcomes beyond those achieved with conventionally fractionated radiotherapy [16‐19]. High-dose irradiation with a biologically effective dose (BED) of 100 Gy or more enables good localized disease control in SBRT, and thus, it may be assumed that not necessarily a mere increase in the total radiation dose, but increasing the BED as well will also lead to good localized control in 3D-CRT [12]. Previous reports indicated that when the radiation dose is increased to 4 Gy delivered in a single fraction, there are no severe adverse events and good localized control can be achieved [20]. There are few reports that describe 3D-CRT to treat patients with localized NSCLC without the use of combined anticancer agents. At our institution, we have recently administered radiation treatment to patients with stage T2 or T3 NSCLC, in whom we increased the radiation dose to more than 5 Gy delivered in a single fraction. In these patients, the radiation field is defined as the tumor plus margin, and the use of 3D-CRT is limited to patients for whom elective nodal irradiation was not conducted. This study investigated the safety and efficacy of 3D-CRT as a monotherapy in patients with T2 or T3 localized NSCLC and examined the factors influencing patient prognosis.

This retrospective study was performed to investigate a possible a role for 3D-CRT as a monotherapy for patients who refuse or could not tolerate surgical therapy with early-stage NSCLC. In this initial study, the 1-year survival rate for patients was 65.8 %, and the 3-year survival rate was 33.8 %. A significant difference in LC was observed with a BED of 80 Gy or more, and the side effects were deemed acceptable. Currently, surgery is the main treatment method for localized NSCLC, and it has achieved favorable outcomes. The Japanese Joint Committee of Lung Cancer Registry investigated prognosis in 6644 patients who underwent resection for NSCLC by histologic type [24]. The 5-year survival rates for patients with clinical stages 1A and 1B NSCLC were 72 and 50 %, respectively. The 3-year survival rates for those with clinical Stages 1A and 1B were 82 and 63 %, respectively [24]. However, a limited number of patients have operable early-stage tumors, and elderly patients are at high risk from complications of surgery. The high long-term costs of surgery and postoperative care justify radiotherapy as a minimally invasive alternative treatment in NSCLC [4]. In our study, the 3D-CRT outcomes for survival was below what would be expected for potentially curative surgery, but none the less, represent an alternative to patients that lack a surgical option.

Conventional methods of administering radiation at a dose of 1.8 or 2 Gy in a single fraction for a total of 60 to 66 Gy results in an LC rate of 50 % and a 3-year survival rate of 20 to 30 %, representing unsatisfactory outcomes [6‐9]. Increasing the dosage prolongs the treatment period, which in turn results in increased patient burden and medical costs. Recent improvements in radiation therapy techniques have led to the widespread popularity of SBRT as an alternative therapy to radical surgery in NSCLC. In a recent systematic review, the 5-year survival rate in patients undergoing SBRT was estimated at 47 % (range, 18–78 %) and the LC rate was 80–100 % [25]. In patients with early-stage NSCLC, it is currently possible to achieve results comparable to those of surgery [13]. Thus, SBRT should be considered for patients with localized NSCLC who are inoperable. SBRT requires greater precision and accuracy than conventional HFRT and 3D-CRT, and it must be performed using a strict protocol that may not be available in all institutions [15]. A recent survey conducted in Japan reported that 44 % of replying institutions did not utilize SBRT [26]. SBRT can be deemed difficult due to varying patient factors, such as when stable respiration is not possible, when the tumor is close to major blood vessels or the hilar region, when respiratory function is poor, and when the patient is in poor general condition. In such instances, 3D-CRT could be an alternative treatment option. Despite the potential role for 3D-CRT in the treatment of NSCLC, there have been few treatment outcome studies. Past reports indicate that the radiation field varies from a field encompassing the tumor plus margin to a field in which elective nodal irradiation is performed, and irradiation techniques and schedules differ between reports [27]. Patients with T2 or T3 NSCLC have a higher incidence of lymph node metastasis, and therefore, many receive concurrent anticancer agents. Thus, irradiation monotherapy is limited to patients with T2 or T3 cancer without lymph node metastasis, and the irradiation field involves the tumor site only. At our institution, a total of 525 patients received radiotherapy for primary lung cancer during the observation period of January 2005 to June 2014. Of these patients, 29 with T2 or T3 localized lung cancer (approximately 5.5 %) underwent 3D-CRT monotherapy with the irradiation field set as the tumor plus tumor margin only. We believe that the results of the present study provide valuable data for future 3D-CRT treatment strategies. In the present study, the 3-year survival period following 3D-CRT for localized lung cancer was comparable with, or better than, those of previous reports [6, 8, 28]. This may be attributed to the difference in radiation distribution. Previous reports described irradiation performed with three to five portals, whereas more than five irradiation portals are used at our institution [6, 8, 28]. The relatively small tumor size in the present study may also have contributed to the findings, with a T staging of T2a in 18 patients and T2b in two patients. Another reason for the findings in this study could be that patients who underwent thorough staging by PET were included. The reason that no difference in survival was observed between T2 and T3 patients is believed to be comparable median tumor diameter in the two groups of patients (T3, 42 mm and T2, 31 mm). It has been reported that patients with T2a (stage IB) disease who underwent SBRT had a 3-year survival rate of 63 % [29]. Based on our results, 3D-CRT appeared to have inferior outcomes to SBRT in patients with early-stage NSCLC. Thus, one conclusion of this present study is that although 3D-CRT may be a second treatment option for patients with early-stage NSCLC who are unable to undergo SBRT, it may not be an alternative treatment. A Japanese multi-institutional, retrospective survey revealed that a BED greater than 100 Gy resulted in significantly improved patient survival and LC than a BED of less than 100 Gy when SBRT was used to control stage I NSCLC [12]. Concerning BED, a radiation dose exceeding 100 Gy resulted in different control rates in T1 and T2 disease, whereas in the event of T2 lung tumors, a BED greater than 120 Gy was required [12]. In this study, LC was significantly improved in patients administered a BED of 80 Gy (range, 67.2–96.0 Gy). Previous reports of the use of 3D-CRT described treatment with a 3–3.5-Gy single fraction [16, 19]. More recently, it has been reported that good LC has been achieved with irradiation using a single 4-Gy fraction, and adverse events were within permissible ranges [20]. The total dosage is also reported to be an important factor [30]. This study has demonstrated that a BED greater than 80 Gy is an independent and significant prognostic factor in LC, using a linear-quadratic model and an α/β ratio of 10 to determine the acute effect on tumor and normal tissues. In a previous study using conventional fractionation, improved local PFS was observed in a subgroup of patients with no nodal disease who were receiving >73 Gy during 3D-CRT [30]. The LC rate in the present study is believed to be comparable with these earlier results. It has previously been reported that radiotherapy toxicities of CTC Grades 3–5 develop in 20 % of patients receiving SBRT with a single fraction that exceeds 20 Gy [31]. This same study concluded that the regimen should not be used for patients with tumors near the central airways because of excessive radiation toxicity [31]. Even for SBRT using approximately 12 Gy delivered in a single fraction, a tumor located near a major vessel or serial organ poses a concern for the occurrence of adverse events. In the present study, no severe adverse events (CTC Grade 2 or more) were observed with 3D-CRT and with irradiation given at a BED of more than 80 Gy. A previous report supports these findings, showing that no severe adverse events developed in 3D-CRT with a BED over 90 Gy [19]. The results of this study support the view that to improve LC in early-stage NSCLC, if the patient’s respiratory function and general physical condition allow, the dose per fraction should be increased, and if possible, the BED should exceed 80 Gy. Furthermore, because this study has confirmed that there are no severe radiation toxicities associated with this regimen, it is possible that the dosage may be increased further. This consideration and other aspects of the role of 3D-CRT as monotherapy in early-stage NSCLC require investigation in further controlled studies with larger patient numbers. Because of current advances in therapy for NSCLC, as well as the increasing numbers of patients treated with combined anticancer agents, the number of patients receiving 3D-CRT within one center will be limited.

Our study limitations include lack of long-term follow up and small number of patients, because of which the results of multivariate analysis were unclear. This limitation may be addressed in the future by studies involving multiple centers in multiple countries.

The retrospective nature of this study and small number of patients who were available within a single center do not detract from the value of these preliminary findings. This study has demonstrated that 3D-CRT may be used as a monotherapy for patients with T2 or T3 NSCLC as a second treatment option for patients unable to receive SBRT. Although the therapeutic efficacy outcomes in this small study were inferior to those reported for SBRT, the safety outcomes were comparable. Furthermore, to improve LC in early-stage NSCLC, this study found that the BED should exceed 80 Gy, and it is possible that this dosage could be increased even further. These findings support a role for 3D-CRT as a treatment option for patients who refuse or could not tolerate surgical therapy with early-stage NSCLC, and they may form the basis for future, larger controlled studies on 3D-CRT as a monotherapy option for early-stage NSCLC.