Patients
From January 2009 to December 2010, 869 patients with primary non-metastatic, pathologically confirmed NPC were treated with IMRT at Fudan University Shanghai Cancer Center. All patients were re-staged using the 8th edition of the American Joint Committee on Cancer (AJCC) [16]. The details of pretreatment evaluation, treatment, and long-term survival are described in a previous publication [17]. In brief, the 5-year local recurrence-free survival was 89.7% with a median follow-up of 54.3 months [17]. In this study, only patients with solitary local recurrence as well as local and regional recurrence (57 cases) were included. The primary IMRT plans were recovered. Magnetic resonance imaging (MRI) at the time of the first diagnosis of local/locoregional recurrence was traced and imported into the MIM system (7.1.2; MIM Software, Beachwood, OH). This MRI was fused and aligned with the primary computed tomography (CT) of the IMRT plans. The original IMRT plan or MRI of local recurrence was unavailable in five patients because of failure of recovery of IMRT plans and MRI and diagnosis of local relapse in other hospitals. In total, 52 patients with traceable primary radiotherapy plans and MRI for local recurrence were included in this study. A flow diagram of the enrolled patients is shown in Figure A.1. The study protocol was approved by the Institutional Review Board (IRB) of Fudan University Shanghai Cancer Center (2208258-14) according to the principles of the Declaration of Helsinki. The informed consent was waived by the IRB due to the retrospective nature, minimal risk to participants and secondary analysis of previous project. The clinical characteristics of the 52 patients are shown in Table A.1. The median disease-free interval was 35.3 (range: 8.9-60.0) months.
Radiotherapy techniques
Patients were immobilized in the supine position with a thermoplastic mask. CT was performed after immobilization, obtaining 3-mm slices from the calvarium to the hyoid bone and 5-mm slices from the hyoid bone to 2 cm below the sternoclavicular joint. According to the definitions of the ICRU50 and ICRU62 (International Commission on Radiation Units and Measurements), the target volumes were outlined on each layer of the CT images on an IMRT workstation (Pinnacle 3; Philips Healthcare, Best, Netherlands). GTVp included primary tumors and metastatic lymph nodes. The high-risk CTV should cover at least the GTVp with an 8-mm expansion, the entire nasopharynx, parapharyngeal space, at least the anterior two-third of the clivus, the base of the skull, pterygoid fossa, pterygopalatine fossa, inferior sphenoid sinus, and posterior edge of the nasal cavity and maxillary sinuses (at least 5 mm of the posterior part). If the tumor is T3-T4, the entire sphenoid sinus, entire clivus, and bilateral cavernous sinus should be included. The details are outlined in Table 1. The delineation of high-risk CTV of cervical nodes were depicted in our previous publication [18].
A margin of 3–5 mm around the GTV and CTV should be added to account for patient motion and setup error. A smaller margin (at least 1-2 mm and 2-3mm) will be used for the GTV and CTV, which is adjacent to a critical neurological structure.
Radiation was delivered using a simultaneous integrated boost technique. The total dose to the primary tumor was 66 Gy in 30 fractions for T1 or T2 disease, and 70.4 Gy in 32 fractions for T3 or T4 lesions. The total dose delivered to the metastatic lymph nodes was 66 Gy in 30–32 fractions. High- and low-risk CTV received 60 Gy and 54 Gy in 30–32 fractions, respectively. Inverse IMRT plans were optimized using the Pinnacle treatment planning system. Normal tissue contouring, constraints and plan evaluation were in accordance with the Radiation Therapy Oncology Group 0225 protocol [5].
Contouring anatomic structures and GTVr
Primary MRI was fused with primary CT of the IMRT plan using automated rigid alignment with MIM software. An experienced radiation oncologist contoured normal anatomic structures with the guidance of MRI (Figure A.2). The anatomical structures were selected based on the risk assessment of primary tumor extensions, according to the literature [11,12]. The nomenclature of the anatomic structures is listed in Table A.2.
Then, MRI of local recurrence was co-registered with primary CT sets of the IMRT plan using automated rigid alignment by MIM software. The delineation of the GTV of the recurrent tumor (GTVr) was first performed with the help of fused recurrent MRI, after which minor manual modification was permitted, considering the anatomic changes between primary CT and recurrent MRI (Figure A.2).
Two experienced radiology experts (with more than 15 years of practice) reviewed the contouring of the GTVr and anatomic structures. Any disagreement was resolved by discussion and recontouring.
Analysis of anatomic distribution of local recurrence and pathways
The delineation of the GTVr and anatomic structures were exported from MIM with DICOM format. A python script was used to calculate the overlap volume between anatomic structures and GTVr. Then the overlap data for each patient were exported to R project (version 4.0.5; R Foundation, Vienna, Austria) for statistics analysis. The anatomic structure was marked as local recurrence if a certain percentage of the volume overlapped with the GTVr. To select the appropriate threshold to define local recurrence, we compared the proportion of cases with certain anatomic structures involved under various thresholds of overlap with GTVr. As shown in Figure A.3 and Table A.3, the pattern under the threshold of ≥1% was consistent with that of ≥2-5%, whereas the threshold of >0% seemed to be much more sensitive than the other thresholds. To balance the sensitivity and specificity, we selected a threshold of ≥1%; that is, if ≥1% of the volume of a certain anatomic structure overlapped with the GTVr, then this structure was defined as local recurrence in this case.
Sanford et al. [19] summarized the local extension patterns of primary tumor into five common routes. We adopted this classification as the pathway of local recurrence and classified each case into a certain pathway manually if at least two neighboring anatomic structures along this pathway were involved in local recurrence.
Dosimetric analysis
The dose coverage of the entire cohort is presented in Table A.4. The dosimetric parameters of patients with and without local recurrence are compared in Table A.5. The dose coverage of T1,2 was generally better than that of T3,4. However, there were no significant differences in V100, V99, V95[1], and D98[2] of planning tumor volume (PTV) of primary tumor (PTV-G) and V95 and V99 of PTV of high-risk CTV between patients with and without local recurrence in this study.
Statistical analysis
All analyses were performed using R project. The χ2 test or Fisher’s exact test was used to compare categorical variables, and the independent Student’s t-test was used to compare the means of continuous variables. Spearman or Pearson correlation was used to analyze the relationship between the two variables. In all cases, a two-sided p-value of <0.05 was considered statistically significant.
[1] V95: the percent volume that received at least 95% of the prescription dose.
[2] D98: the percent of the prescription dose covering 98% of the volume.