RESEARCH ARTICLE Clinical Outcome of Helical Tomotherapy for Inoperable NonSmall Cell Lung Cancer: The Kyung Hee University Medical Center Experience

Background: Published studies on clinical outcome of helical tomotherapy for lung cancer are limited. The purpose of this study was to evaluate clinical outcomes and treatment-related toxicity in inoperable non-small cell lung cancer (NSCLC) patients treated with helical tomotherapy in Korea. Materials and Methods: Twenty-seven patients with NSCLC were included in this retrospective study. Radiotherapy was performed using helical tomotherapy with a daily dose of 2.1-3 Gy delivered at 5 fractions per week resulting in a total dose of 62.5-69.3 Gy. We assessed radiation-related lung and esophageal toxicity, and analyzed overall survival, locoregional recurrence-free survival, distant metastasis-free survival, and prognostic factors for overall survival. Results: The median follow-up period was 28.9 months (range, 10.1-69.4). The median overall survival time was 28.9 months, and 1-, 2-, and 3-year overall survival rates were 96.2%, 92.0%, and 60.0%. The median locoregional recurrence-free survival time was 24.3 months, and 1-, 2-, and 3-year locoregional recurrence-free survival rates were 85.2%, 64.5%, and 50.3%. The median distant metastasis-free survival time was 26.7 months, and 1-, 2-, and 3-year distant metastasis-free survival rates were 92.3%, 83.9%, and 65.3%, respectively. Gross tumor volume was the most significant prognostic factor for overall survival. No grade 4 or more toxicity was observed. Conclusions: Helical tomotherapy in patients with inoperable NSCLC resulted in high survival rates with an acceptable level of toxicity, suggesting it is an effective treatment option in patients with medically inoperable NSCLC.

In 2008, the Kyung Hee University Medical Center started treating patients with medically inoperable or locally advanced NSCLC with helical tomotherapy. Helical tomotherapy employs helical intensity-modulated RT in which a 6-megavoltage (MV) linear accelerator gantry rotates continuously 360° around the patient using tens of thousands of narrow beamlets (Mackie et al., 1993). While some planning studies reported dosimetric advantages of helical tomotherapy planning in lung cancer (Scrimger et al., 2003, Kron et al., 2004, Cattaneo et al., 2008, there are no published studies reporting the clinical outcome of helical tomotherapy in lung cancer. Here, we report the results of our retrospective study in which we evaluated the clinical outcomes and treatment-related toxicities in inoperable NSCLC patients treated with helical tomotherapy.

Materials and Methods
Patient eligibility criteria included the presence of pathologically confirmed inoperable NSCLC, receipt of definitive helical tomotherapy with or without chemotherapy, receipt of total RT dose ≥60 Gy, no prior history of thoracic RT and thoracic cancer, no other simultaneous cancer, no distant metastasis, and available follow-up data. From January 2008-January 2013, 57 patients received thoracic helical tomotherapy at Kyung Hee University Medical Center. Of those patients, 27 met the eligibility criteria and were included in this study.
Each patient underwent basic laboratory studies, liver function test, pulmonary function test, chest radiograph, chest computed tomography (CT), brain magnetic resonance imaging, and most patients also had wholebody positron emission tomography (PET). The cancer stage of each patient was assigned based on the American Joint Committee on Cancer (AJCC) staging system (7th edition). For all patients, we retrospectively reviewed hospital records, laboratory results, imaging studies, and extracted dose-volume histogram (DVH) data from computerized treatment planning records. The institutional review board of Kyung Hee University Medical Center approved this study, and all research was carried out in compliance with the Helsinki Declaration.
For CT simulation, all patients were immobilized in the supine position with arms above their head using posterior vacuum bags and anterior vacuum-sealed cover sheets (BodyFix, Medical Intelligence Medizintechnik GmBH, Schwabmünchen, Germany). To reduce movement of the lung by respiration, all patients were instructed to take shallow breaths. All patients received intravenous contrast agents, and axial CT images were acquired with 3-mm slice thickness. The simulation CT data were transferred to the Hi·Art Planning Station (TomoTherapy Inc., Madison, WI) for inverse planning.
The gross tumor volume (GTV) was delineated according to all detectable tumors and involved lymph nodes as determined from chest CT and PET information. Subsequently, a 6-8 mm margin was added to create the clinical target volume (CTV), and the planning target volume (PTV) was created by adding an additional 8-15 mm margin to the CTV, taking into account the target movement by respiration. Elective nodal irradiation was not performed. Normal structures were also delineated. The ipsilateral and contralateral lungs were delineated separately to attempt to constrain the radiation dose to the contralateral lung. The spinal cord, heart, and esophagus were also delineated.
The prescription dose was decided by the physician's own judgment according to PTV and patients' general condition. A daily dose of 2.1-3 Gy was delivered at 5 fractions per week, resulting in a total dose of 62.5-69.3 Gy. The most commonly prescribed (22 patients, 81.5%) dose fractionation schedules were a total dose of 63-66 Gy with a daily dose of 2.1-2.2 Gy.
We evaluated each treatment plan using a DVH and visually inspecting isodose curves. In general, we considered plans acceptable if the PTV was covered by 95% isodose curves, inhomogeneity of the PTV ranged from 95%-107%, and doses to normal structures were limited in their tolerances. Dose tolerances for normal structures were total lung V20<40%, mean lung dose <20 Gy, maximum dose to spinal cord <45 Gy, heart V40<50%, and esophagus V55<30%. The planners generally attempted to keep radiation doses to the contralateral lung low, although formal dosimetric constraints were not applied to this structure. Planning objectives were prioritized to give the greatest importance to achieving coverage of the PTV and avoiding spinal cord and normal lung, while trying to keep radiation doses in other normal structures as low as possible.
RT was performed using a TomoTherapy (TomoTherapy Inc., Madison, WI). Triangulation marks were used to make sure the patient did not roll and to quickly position the patient into the correct location. Before each treatment, a 3.5-MV fan beam CT image was acquired using a CT detector mounted on a ring gantry and matched to the planning CT image for comparison. Then, if necessary, the patient position was corrected. The implementation of chemotherapy was individualized based on tumor clinical stage, patient general condition and compliance.
Patients were evaluated with weekly chest radiographs during RT. Follow-up visits were scheduled 1 month after completion of RT and every 2-3 months thereafter. Visits were more frequent for those who experienced severe treatment-related complications or disease progression. At the time of follow-up visits, basic laboratory studies, liver function tests, chest radiographs, and chest CT scans were conducted. When needed, PET was also performed.
We assessed the radiation-related lung and esophageal toxicities according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. The worst toxicity grade scored at any time was considered the final grade of toxicity. Because radiation-related toxicities could present during treatment, the time to toxicity was calculated from the date of RT start.
For the purposes of this study, local recurrence was defined as tumor progression within the high-dose radiation treatment volume (PTV). Actuarial survival rates were estimated using the Kaplan-Meier method, and comparisons among groups were performed using logrank tests. Overall survival time and time to locoregional recurrence and distant metastasis were calculated from the date of NSCLC diagnosis. Parameters evaluated as potential prognostic factors for overall survival were age, gender, tumor histology, AJCC stage, GTV, total RT dose, RT interruption, and chemotherapy. For multivariate analysis, the Cox proportional regression hazard model was used. For all analyses, a p value <0.05 was considered statistically significant. All analyses were performed using SPSS version 18.0 (SPCC Inc., Chicago, IL).
Prognostic factors for overall survival were analyzed.

Discussion
This study is the first to report treatment outcomes in patients with inoperable NSCLC treated with helical tomotherapy. Some studies have reported treatment outcomes of linac-based intensity-modulated RT in inoperable NSCLC, and the reported median overall survival time ranged 16.8-29.7 months, and the reported 1-and 2-year overall survival rates ranged 57-71% and 46-58%, respectively (Yom et al., 2007, Sura et al., 2008, Liao et al., 2010, Govaert et al., 2012, Jiang et al., 2012. In our study, the median overall survival time was 28.9 months, and 1-and 2-year overall survival rates were 96.2% and 92.0%, respectively. Compared with previous studies, our study showed comparable median overall survival time, and favorable 1-and 2-year overall survival rates. Because of heterogeneous patient populations and tumor characteristics, various RT dose fractionation schedules and chemotherapy regimens, and different RT techniques and GTVs, it is hard to compare treatment outcomes among published studies. Nevertheless, the overall survival rates of our study seemed to be favorable. Our study also showed favorable locoregional recurrence-free survival rate compared with previous studies. The 2-year locoregional recurrence-free survival rate was 64.5% in our study compared to the 50-58% reported in previously published studies (Yom et al., 2007, Sura et al., 2008, Jiang et al., 2012. The most likely explanation for the favorable results in our study is the high number of patients with early stage cancer. While 51.9% of all patients had stage Ⅰ/Ⅱ NSCLC in our study, patients with stage Ⅰ/Ⅱ NSCLC represented 0-27% of all patients in previously published studies (Yom et al., 2007, Sura et al., 2008, Liao et al., 2010, Govaert et al., 2012, Jiang et al., 2012. To confirm the favorable results of our study, additional studies with larger sample sizes and longer follow-up durations will be required. There are still no randomized trials comparing the clinical outcomes of 3-dimensional conformal RT and intensity-modulated RT in lung cancer. Liao et al. (2010) retrospectively analyzed the treatment outcomes of 318 NSCLC patients treated with 3-dimensional conformal RT and 91 NSCLC patients treated with linac-based intensitymodulated RT. In that study, the median overall survival times were 1.4 years for intensity-modulated RT group and 0.85 years for 3-dimensional conformal RT group, and overall survival was significantly better in patients treated with intensity-modulated RT. Our study showed a longer median overall survival time than those of Liao et al.'s study (2.4 years vs 1.4 years). However, in our study, there was no matched comparison group treated with 3-dimensional conformal RT. In the near future, we plan to conduct additional studies that compare the clinical outcomes of 3-dimensional conformal RT and helical tomotherapy in inoperable NSCLC.
There are some concerns with respect to the use of intensity-modulated RT in lung cancer. One such concern is the low-dose radiation exposure of unaffected ipsilateral and contralateral lung tissues. Because of increasing the number of radiation beams, intensity-modulated RT could expose a larger volume of healthy lung tissue to low-dose radiation. A number of studies have reported potential deleterious effects of low-dose radiation. Gopal et al. (2003) reported losses in the diffusing capacity of carbon monoxide in lung exposed to low-dose radiation. In addition, Hall (Hall, 2006) and Brenner et al. (2003) suggested that more radiation-induced secondary cancers might be expected in long-term survivors treated with intensity-modulated RT. Because of helical radiation delivery method, helical tomotherapy exposes almost all of the lung tissues to low-dose radiation. So, the low-dose radiation exposure of normal tissues is a bigger concern in helical tomotherapy. Our study showed favorable and acceptable acute and late toxicities after thoracic helical tomotherapy with a median follow-up time of 38.1 months. However, a longer follow-up duration will be necessary to detect potential long-term deleterious effects of low-dose radiation after helical tomotherapy in lung cancer patients.
There were some limitations in this study. First, this study was retrospective and may have inherent biases. For example, RT dose fractionation schedules varied widely because they were determined at the discretion of the  attending radiation oncologists rather than a predetermined protocol. In addition, we could not analyze some potential prognostic factors for overall survival, such as changes in body weight. Second, the sample size was small. Third, the patient and tumor characteristics were heterogeneous. However, despite these limitations and some concerns about helical tomotherapy, the clinical outcomes of our study are very promising and the toxicity results are favorable and acceptable. Therefore, we believe that our study provides evidence that helical tomotherapy is a useful treatment modality for the treatment of inoperable NSCLC.
In conclusion, helical tomotherapy in patients with inoperable NSCLC resulted in high survival rates with an acceptable level of toxicity. These findings suggest helical tomotherapy is an effective treatment option in patients with medically inoperable or locally advanced NSCLC.