Reducing dose to the lungs through loosing target dose homogeneity requirement for radiotherapy of non small cell lung cancer

Abstract It is important to minimize lung dose during intensity‐modulated radiation therapy (IMRT) of nonsmall cell lung cancer (NSCLC). In this study, an approach was proposed to reduce lung dose by relaxing the constraint of target dose homogeneity during treatment planning of IMRT. Ten NSCLC patients with lung tumor on the right side were selected. The total dose for planning target volume (PTV) was 60 Gy (2 Gy/fraction). For each patient, two IMRT plans with six beams were created in Pinnacle treatment planning system. The dose homogeneity of target was controlled by constraints on the maximum and uniform doses of target volume. One IMRT plan was made with homogeneous target dose (the resulting target dose was within 95%–107% of the prescribed dose), while another IMRT plan was made with inhomogeneous target dose (the resulting target dose was more than 95% of the prescribed dose). During plan optimization, the dose of cord and heart in two types of IMRT plans were kept nearly the same. The doses of lungs, PTV and organs at risk (OARs) between two types of IMRT plans were compared and analyzed quantitatively. For all patients, the lung dose was decreased in the IMRT plans with inhomogeneous target dose. On average, the mean dose, V5, V20, and V30 of lung were reduced by 1.4 Gy, 4.8%, 3.7%, and 1.7%, respectively, and the dose to normal tissue was also reduced. These reductions in DVH values were all statistically significant (P < 0.05). There were no significant differences between the two IMRT plans on V25, V30, V40, V50 and mean dose for heart. The maximum doses of cords in two type IMRT plans were nearly the same. IMRT plans with inhomogeneous target dose could protect lungs better and may be considered as a choice for treating NSCLC.


| INTRODUCTION
Lung cancer is the most frequently diagnosed cancer and the leading cause of cancer death among males. About 85% of lung cancers are NSCLC worldwide. 1 Radiotherapy plays an important role in the treatment of locally advanced, unresectable NSCLC. 2 Treatment outcome of standard radiotherapy for NSCLC patients has not improved much during the past decades, and the 5-year relative survival rate is still no more than 20%. 3 Local failure often occurs in the primary tumor. Doses higher than the standard 60-66 Gy are required to obtain a better local tumor control. 4,5 But this is limited by the protection of organs at risk. Some patients suffered from severe side effects after radiation therapy. 6,7 Radiation pneumonitis (RP) is the main dose-limiting complication in radiation therapy for NSCLC, and occurs in 5%-50% of patients. 8,9 In the case of conventionally fractionated radiotherapy, the traditional strategy for minimizing patients' risk is to follow empirically established dose-volume constraints, such as V20 < 30%-35% and mean lung dose (MLD) <20-23 Gy. However, the relationship between RP risk and dosimetical statistics such as MLD varies among institutions. And it also changes when different treatment techniques (i.e., CRT, IMRT, and VMAT) are applied. 10 IMRT is a common technology for the treatment of lung cancer. 11 The target volume could get higher dose and better conformity index than 3D-CRT. However, the improvement of uniformity of target dose could increase the volume of the low dose area in nearby OARs. As a result the volume of low dose area in the lung could be significantly increased. 12, 13 Shirvani et al found that the proportion of patients under IMRT treatment increased year by year and V20 of lung decreased significantly in IMRT group based on 3986 patients. Compared with 3D-CRT group the adverse reaction of lung occurred at similar rates using IMRT and showed that the lower V20 did not reduce the incidence of RP. 14 The reason may be that V5 of lung would be increased as IMRT applied. 15 To minimize the risk of RP some new techniques were introduced to reduce the lung dose, including respiratory gated PET/CT, Cyber Knife, VMAT, etc. [16][17][18][19] Conventionally, the standard practice is that tumors should be irradiated to an intended uniform, or homogeneous, dose. 20 While this optimizes the tumor control probability in the case of homogenous tumors, this is generally not the optimal dose distribution in tumors with spatial variation in radiation sensitivity. 21 In addition, dose escalation strategies that involve delivery of uniform doses are typically limited by normal tissue dose tolerance. There have been studies indicating that deliberately using nonuniform radiation doses allows for dose escalation of tumor subvolumes without necessarily increasing the dose which is delivered to adjacent critical structures. 22,23 It still remains unclear whether the dose to OARs could be reduced when the dose nonuniformity in the target area is increased.
The goal of this study is to investigate whether it is beneficial to decrease the lung toxicity for NSCLC by increasing target dose inhomogeneity in IMRT plans.

2.A | Patient data
10 NSCLC patients with lung tumor on the right side treated at our institution between July 2014 and October 2015 were selected in this study which had been approved by ethics committee. The patient characteristics are listed in Table 1. The patient-related privacy information (e.g., name, identification number, telephone number) has been removed. All the patients were immobilized in the supine position using a thermoplastic mask. Treatment plans were made based on computed tomography (Philips, Brilliance Big Bore) with slice thickness of 3 mm. Lung cancer Group (DOLG). The planning target volume was created as a patient specific expansion of the CTV with a margin of 5-10 mm. 24,25 The organs at risk included the heart, the spinal cord, the lungs, and the normal tissues. The prescribed dose was 60 Gy in 2.0 Gy daily fractions.

2.B | Plan optimization
The IMRT plans were made on Pinnacle 9.10 workstation and treated on Elekta Synergy accelerator using 6 MV photon beams. The adaptive convolution algorithm provided by Pinnacle was chosen as the dose calculation engine and the calculation grid resolution was set as 2 9 2 9 2 mm 3 . The dose of treatment plans was calculated on free-breathing CT. Two IMRT plans using a static step-and-shoot delivery approach were created for each patient. One was with standard homogeneous dose distribution (IMRT homo ) for target, and the other was with an inhomogeneous dose distribution (IMRT Inho ) for and mean dose for the lungs were set to be as low as possible.
There were no uniform dose constrains for PTV. For each patient, a "Boost" optimization region was constructed by expanding the GTV with the same expansion margin. There were no limitations on the maximum dose to this region. Details of objectives set for the initial optimization were illustrated in Table 2.
The additional contours were as follows: (a) PTV-3 mm, shrink-  Minimum DVH 60/95% coverage: the minimum normalized volume that is radiated by a dose greater than 60 Gy is 95%; Maximum DVH 5/44% coverage: the maximum normalized volume that is radiated by a dose greater than 5 Gy is 44%.
where D eff is the dose that, if given uniformly to the entire volume, will lead to the same NTCP as the actual nonuniform dose distribution, TD 50 is the uniform dose given to the entire organ volume that results in 50% complication risk, m is the slope of the curve repre-

| RESULTS
For all patients, both IMRT homo and IMRT inho plans were accepted for clinical treatment by the radiation oncologist. Figures 1 and 2 were the comparisons of dose distributions and dose-volume histograms between two plans for one patient. They showed that the F I G . 1. Isodose distribution of IMRT inho (a, b, c) and IMRT homo (d, e, f) plans for one patient with six coplanar beams. uniformities of PTV dose of two plans were different. It was also clear that the mean dose of lung in IMRT inho plan was lower than that in IMRT homo plan, while the doses of the other OARs in IMRT inho plans were nearly the same as those in IMRT homo plans.
The dosimetric statistics of PTV in the two IMRT plans were listed in Table 3. IMRT homo exhibited better HI than IMRT inho (P < 0.001). D 2%, Mu and mean dose showed significant difference with P < 0.001, P = 0.001, and P < 0.001 respectively.
There were no significant differences for D 98% (P = 0.876), CI    showed that only MLD, V20 and V30 were predictive of the severe RP. 33 They suggested that a large panel of thresholds from low to high dose could provide advantages.
The result shown in Fig. 3 and Table 4   Besides NSCLC, this method should be valid in other cancers such as esophageal cancer, liver cancer, etc., which will be investigated in the future studies.

| CONCLUSION
It was demonstrated that relaxing the constraints on maximum and uniform dose in the target volume could significantly reduce the dose to lungs from low to high dose region. With this approach, the risk of radiation pneumonitis could potentially be decreased. In addition, it could increase the mean dose to tumor, which might be beneficial to improve local control of tumor by radiotherapy. IMRT plans with inhomogeneous target dose could protect lungs better and may be considered as a choice for NSCLC treatment.

CONFLI CT OF INTEREST
All authors approved the final manuscript, and declared that they have no potential conflicts of interest to this work.