Comparison of efficacy and safety between simultaneous integrated boost intensity-modulated radiotherapy and conventional intensity-modulated radiotherapy in locally advanced non-small-cell lung cancer: a retrospective study

This was a retrospective study. Patients with histologically proven stage III NSCLC (American Joint Committee on Cancer, 7th edition) and receiving thoracic IMRT at our center between January 2014 and December 2016 were included. The procedure of data analysis was shown in Fig. 1. The inclusion criteria were histologically/cytologically confirmed NSCLC, older than age 18 at the time of diagnosis, stage III disease, Karnofsky performance status (KPS) score ≥ 70, and receiving thoracic IMRT. The enrolled patients had to have radiotherapy as a definitive form of treatment. Patients with radiation dose <50Gy, prior thoracic radiotherapy or surgery, or other coexisting primary tumors were excluded. The study was approved by the local institutional review board.

All the patients underwent computed tomograph (CT)-based simulation with 5-mm slice thickness. A head-neck-shoulder mask or chest mask was used to immobilize patients in the supine position during simulation. The scanned area extended from the laryngeal prominence to the bottom of the L2 vertebral body. Four-dimensional simulation was used for selected patients with peripheral or lower lobe lesions. The scanned images were transferred to a three-dimensional (3D) planning system (Philips, Pinnacle 9.0; Netherlands) (Fig. 2).

All of the patients underwent intensity-modulated radiotherapy (IMRT) [4]. The gross tumor volume (GTV) included the primary disease as well as any involved regional lymph nodes, which were defined as those with a short-axis diameter of at least 1 cm on the CT scan or with a short-axis diameter of less than 1 cm but with high fluorodeoxyglucose (FDG) uptake on the Positron emission tomography (PET)-CT scan. The clinical target volume (CTV) was created by expanding the GTV by 0.6–0.8 cm, as well as ipsilateral hilum and mediastinal nodal stations involved. The planning target volume (PTV) was generated by a uniform 0.5 cm expansion around the CTV. For patients treated with SIB-IMRT, the planning gross tumor volume (PGTV) was generated by a uniform 0.5 cm expansion around the GTV.

Radiation therapy was delivered by 6MV X-rays from a linear accelerator (Elekta, Synergy, Sweden; Elekta, VersaHD, Sweden; Varian, Novalis, United States; Varian, Unique, United States). The cone-beam computed tomograph (CBCT) scans was used in most patients for positioning. It was repeated before each treatment in the first week, then performed once a week. Electronic portal imaging device (EPID) was used in a small proportion of patients and it was conducted once a week. For patients treated with conventional IMRT, the median prescribed dose was 60Gy/30f (range: 50.0–70.0Gy, in 25–35 fractions) (Median BED₁₀ 72Gy, range: 60-84Gy) to PTV. As for patients with SIB-IMRT, the median prescribed dose was 59.92Gy/28f (range: 50.0–70.0Gy, in 25–33 fractions) (Median BED₁₀ 72.74Gy, range: 60-84Gy) to PGTV, and 50.4Gy/28f (range, 45–59.4Gy, in 25–33 fractions) (Median BED₁₀ 59.47Gy, range: 53.1–70.1Gy) to PTV. It should be noted that the PTV in the SIB group contain the PGTV. All the patients received concurrent or sequential platinum-based doublet chemotherapy. The mean dose to the lungs (MLD) should optimally be ≤17Gy and not exceed 20Gy; the lung volumes minus GTV receiving more than 20Gy (V20) and 30Gy (V30) were limited to less than 30 and 20%, respectively. The heart volumes receiving more than 30Gy (V30) and 40Gy (V40), were limited to less than 40 and 30%, respectively. The esophageal volume receiving more than 50Gy (V50) was limited to less than 50%. The maximal dose for spinal cord PRV (5 mm) was 45Gy.

Pre-treatment evaluation included full medical histories and physical examinations, laboratory investigations, such as complete blood cell counts (CBC) and chemistries, electrocardiographs (ECGs), and pulmonary function tests. The following examinations were performed to specify the TNM stage of patients: chest and abdominal CTs, brain MRI/CTs, bronchoscopies, and radionuclide bone scans. PET-CTs were recommended but not mandatory.

All patients underwent CBC and blood chemistry examinations once a week during the treatment period. After discharge from the hospital, the patients were followed up every 3 months from hospital medical records and/or by phone. The follow-up evaluations consisted of patient history, a physical examination, and a thoracic CT at intervals of 3 months for 2 years and then 6 to 12 months for 3 years, or earlier if clinically indicated. Other imaging examinations were obtained when recurrence was suspected.

The endpoints included overall survival (OS), progression-free survival (PFS), locoregional recurrence-free survival (LRFS), distant metastasis-free survival (DMFS) and treatment-related toxicity. OS was calculated from the date of initial treatment to death or last follow-up, and PFS was calculated as the time to progression, death from any cause, or the last follow-up. Locoregional failures were defined as recurrences of primary tumor or regional lymph node, and distant metastasis were defined as disease progression excluding locoregional failure. Patients without evidence of progression were censored at the date of last follow-up or death. The treatment response evaluation was based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 [9]. Treatment-related toxicities were evaluated with Common Terminology Criteria for Adverse Events (CTCAE)4.0 criteria.

A total of 426 patients with stage III NSCLC were eligible for analysis, including 128 with SIB-IMRT and 298 with conventional IMRT. Patient and treatment characteristics of the two groups are summarized in Table 1. The median age for the entire cohort was 62 (range: 25–88) years, and 46% underwent concurrent chemoradiotherapy. SIB-IMRT group had more stage IIIB disease (69.5% vs. 53%, P = 0.002), larger planning treatment volumes (median: 504 ml vs. 402 ml, P<0.001), and a larger planning treatment volume/volume of lung ratio (median, 0.18 vs. 0.12, P<0.001). No significant difference was observed between the two groups regarding the distribution of age, gender, smokers, KPS, weight loss, histological classification, percentage of PET-CT staging, treatment modality, and radiation dose towards the PTV/PGTV (Table 1).

The overall response rate was 81% for SIB-IMRT and 76.8% for conventional IMRT(P = 0.404). Locoregional recurrence rates were similar between the two groups (51.6% vs. 44.6%, P = 0.306). More details about failure pattern were shown in Table 2.

One hundred and eighty-two patients died (52 in the SIB-IMRT group; 132 in the conventional IMRT group), and 242 patients were still alive with a median follow-up time of 25 months (8-69 months) (SIB-IMRT group: 24 months; Conventional IMRT group: 26 months). The 1, 2, 3-year OS rate was 85.8, 60.4 and 49.4% for the SIB-IMRT group and 87.2, 59 and 46.9% for the conventional IMRT group. The difference regarding OS between the two arms was not statistically significant (P = 0.797, HR 0.959, 95%CI 0.695–1.322). The 1, 2, 3-year PFS rate was 64.7, 32.1 and 27.2% in the SIB-IMRT group and 68.3, 38.7 and 24.8% in the conventional group (P = 0.425, HR 1.11 95%CI 0.858–1.436). The median OS time (MST) were 34.5 and 31.7 months in the SIB-IMRT and conventional IMRT groups, with median PFS of 16.8 and 17.8 months, respectively. No significant difference was observed regarding LRFS (53% vs 45% at 3 years, P = 0.39) and DMFS (53% vs. 48% at 3 years, P = 0.494) between the two groups (Fig. 3).

The variables of age, gender, KPS, pathology, TNM stage, PET-staging, PTV, concurrent chemoradiotherapy, SIB-IMRT, and RT dose were included for multivariate analysis. The results showed that KPS (HR 0.463, 95%CI [0.269–0.796], P = 0.005), PTV volume (HR 1.627, 95%CI [1.184–2.237], P = 0.003) and concurrent chemoradiotherapy (HR 0.48, 95%CI [0.348–0.660], P<0.001) were independent factors affecting OS (Table 4).

Dose of OARs and treatment-related reactions were collected. Higher lung doses (V5, V20, MLD), Heart dose (mean dose, V30) and spinal cord dose (maximal) were observed in patients receiving SIB-IMRT (Table 3). While patients with conventional IMRT got higher maximal dose of esophageal (P = 0.021). No significant difference was observed in toxicities between the two groups, including radiation pneumonitis, esophagitis, hematologic toxicities and gastrointestinal reactions (Tables 4 and 5).