Patient selection

This retrospective study was conducted on 30 patients with NPC, whose IMRT planning were made using the Eclipse treatment planning system (Eclipse TPS, version 13; Varian Company, USA) following Iranian National Research Ethics Board’s approval. The patients whose tumours ranged from stage I to IV were selected for the study, consisting of 24 males and 6 females with age ranging from 18 to 67 years. All the IMRT plans were carried out using a Varian 6 MV photon beam modulated with 80 pairs of multi-leaf collimator (Varian 600c; Linear Accelerator, USA). All dose calculations were performed with the anisotropic analytical algorithm using a calculation grid of 2·5 mm. The accuracy of the Eclipse TPS has been previously evaluated for the small fields in IMRT. ^{Reference Mesbahi and Dadgar15,Reference Mesbahi and Zergoug16} A team comprising one radiation oncologist and one medical physicist generated the IMRT plans to avoid the variation in IMRT plan quality caused by the operator’s experience and skill.

Treatment planning and modalities

For each patient, in addition to the standard IMRT plans, 11 additional treatment plans were generated using various collimator angles and also non-coplanar fields. Details of various protocols are presented in Table 1.

Table 1.

Details of the extra IMRT treatment planning protocols used for the NPC patients

Abbreviations: IMRT, intensity-modulated radiation therapy; NPC, nasopharyngeal cancer.

The plans were designed for a single treatment course of 33 sessions. Seven coplanar fields were used with an angle of 0, 50, 100, 150, 210, 260 and 310°. A dose of 70 Gy was used for nasopharyngeal primary and gross nodal disease as well as the required margins (planning target volume PTV₇₀. Additionally, a dose of 59·4 and 54 Gy were applied for the high-risk (PTV_59.4) and low-risk lymph nodes (PTV₅₄), respectively. For all the PTVs, a 5-mm margin was added to the clinical target volumes, except in the areas adjacent to the critical structures. The tolerance doses regarded for the normal tissues including brains team, spinal cord, optic nerves, optic chiasm and parotid glands were based on the recommendations proposed by Radiation Therapy Oncology Group (RTOG-0615) as presented in Table 2 ¹⁷ .

Table 2.

The organ at-risk (OAR) constraints used for the dosimetric and radiobiologic assessment

Treatment plan evaluation

The PTV dose coverage, OARs doses and also dose volume histograms were calculated using Eclipse TPS and used for treatment planning evaluation. In addition, extra treatment planning parameters were considered for evaluating the treatment plans, including conformation number (CN) describing the conformation of the dose to the target as defined by Equation (1) ^{Reference Van’t Riet, Mak, Moerland, Elders and Van Der Zee18} :

(1) $${\rm{CN} = {\rm{TV}_{\rm{RI}}\over{\rm{TV}}} \times {{\rm{TV}_{\rm{RI}}}\over{\rm{V}}_{{\rm{RI}}}}}$$

in which TV_RI, TV and V_RI represent the target volume covered by the reference isodose, target volume and volume of the reference isodose, respectively. The CN < 1 indicates that the target volume is not completely covered by the prescribed isodose volume, and CN > 1 indicates liberal coverage. However, a CN value close to 1 does not imply that the two volumes closely coincide spatially unless the PTV is completely contained within the prescription isodose volume. The HI indicates dose homogeneity in the target volumes, as recommended by the International Commission on Radiation Units and Measurements. ^{Reference Landberg, Chavaudra and Dobbs19} This index is defined as the ratio of the dose difference between the greatest dose delivered to 2% of the target volume (D_2%) and the dose to 98% of the target volume (D_98%) to the target median dose (D_median) as described in Equation (2):

(2) $${{\rm{HI}} = ({\rm D}_{2\% } - {\rm D}_{98\% })/{\rm D}_{\rm{median}}}$$

Smaller HI values correspond to more homogenous target volume irradiation, with a value of 0 indicating absolute homogeneity of dose within the target.

Radiobiological treatment plan evaluation

The basic dose–response relation used for tumours and normal tissues in our study was based on the Poisson model described in previous reports ^{Reference Komisopoulos, Mavroidis and Rodriguez20–Reference Lind, Mavroidis, Hyödynmaa and Kappas23} as presented in Equation (3):

(3) $${{\rm P(D)} = {\rm exp}\,({{\rm e}^{{\rm e}\gamma - ({{\rm D}_{2{\rm Gy}}}/{{\rm D}_{50}})({\rm e}\gamma - \ln \,\ln 2)}})}$$

where P(D) is the probability of tumour control or normal tissue complication when the tissue is irradiated uniformly with a dose D, D₅₀ is the dose that induces a 50% response and γ is the maximum normalised dose–response gradient. As proposed by other researchers, ^{Reference Monica, Lucullus and Peter14} the values of the D₅₀ and γ parameters are both organ and clinical endpoint dependent and are normally derived from clinical data as presented in Table 3.

Table 3.

The biological functions and additional constraints that are selected for the optimisation of NPC plans

Abbreviations: NPC, nasopharyngeal cancer; PTV, planning target volume.

These are in line with the recommendations from the quantitative analysis of normal tissue effects in the clinic reviews with regard to the clinical endpoints used and the dose–response relations for brainstem, spinal cord, optic nerves, optic chiasm and parotid glands.

As recommended by Monica et al., ^{Reference Monica, Lucullus and Peter14} since the values of the radiobiological parameters are determined for a certain fractionation scheme, to compare the effectiveness of different dose distributions, they must be converted to the corresponding fractionation scheme. This is done in Equation (3) using the D_2Gy (that is also referred as EQD_2Gy in literature), which is a 2-Gy equivalent dose calculated using Equation (4) proposed by Komisopoulos et al. ^{Reference Komisopoulos, Mavroidis and Rodriguez20} :

(4) $${{\rm D}_{2{\rm{Gy}}}} = {\rm D} \cdot (1 + {{d}\over{\alpha /\beta}}\over{1 + {{2}\over{\alpha /\beta }}} )$$

where 2 Gy represents the reference dose level used for the determination of dose–response parameters, D is the physical dose, d is the dose per fraction and α/β is the organ-specific dose that accounts for the fractionation characteristics of the tissue and at which the linear and quadratic components of cell killing are equal. For estimating NTCP from nonuniform dose distribution, the RS model was used. Subsequently, the overall probability of injury, P_I, for a number of OARs was calculated using Equation (5) ^{Reference Kallman, Lind and Brahme24,Reference Mavroidis, Lind and Brahme25} as described below:

(5) $${\rm P}_{\rm I} = 1 - \mathop \prod \limits_{j = 1}^{{{\rm{N}}_{{\rm{organs}}}}} ( 1 - [ 1 - \mathop \prod \limits_{i = 1}^{{\rm M}_j} \bigg( 1 - {\rm P}^j({\rm D}_i )^{{\rm S}_j} \bigg)^{\rm{\Delta}{\rm v}_i} ]^{1/{{\rm S}_j}})$$

where N_organs is the total number of vital OARs and P ^j (D _i ) is the response probability of the organ j having the reference volume irradiated by a dose D_i as given by Equation (3). Furthermore, ${\rm{\Delta}} {{\rm{v}}_i} = {\rm{\Delta}} {{\rm{V}}_i}/{{\rm{V}}_{{\rm{ref}}}}$ is the fractional subvolume of the organ being irradiated compared to reference volume for which D₅₀ and γ have been calculated, M _j is the total number of voxels or subvolumes in organ j and S _j is RS parameter characterising the internal organ structure of organ j. s = 1 indicates a serial structure tissue, whereas s = 0 indicates a tissue of parallel structure. NPC tumours are assumed to have a parallel structure since every clonogenic cell within the tumour volume must be destroyed. Consequently, TCP and the overall probability of benefit, P_B, were quantified using the Poisson model proposed in previous reports, ^{Reference Komisopoulos, Mavroidis and Rodriguez20,Reference Kallman, Lind and Brahme24,Reference Mavroidis, Lind and Brahme25} as described in Equation (6):

(6) $${{\rm P}_{\rm B}} = \mathop \prod \limits_{j = 1}^{{{\rm N}_{{\rm tumors}}}} ( {\mathop \prod \limits_{i = 1}^{{{\rm M}_j}} {{\rm P}^j}{{({{\rm D}_i})}^{\Delta {{\rm v}_i}}}} )$$

where N_tumours is the total number of tumours or targets involved in the clinical case.

Statistical analysis

Statistical analysis was performed with the Statistical Package for Social Science (SPSS), version 17.0, for Windows. All data are expressed as mean ± standard deviation. The analysis of variance with repeated measures was used. p Values less than 0·05 were considered as statistically significant.