Development and validation of a model for temporal lobe necrosis for nasopharyngeal carcinoma patients with intensity modulated radiation therapy

In patients with nasopharyngeal carcinoma (NPC), an impressive local control rate has been achieved, and as a result, the late toxicities of long-term survival after radiation therapy have become an important concern. Temporal lobe necrosis (TLN) is one major complication observed in NPC patients after radiation therapy. Because of the nearness in the anatomical structure of the TL and nasopharynx, TLs are prone to receiving high doses of radiation, causing cerebral tissue damage. Typical symptoms of TLN include dizziness, lethargy, debilitation, personality change, pressure symptoms, and epileptic attacks. Further failure of cognition can irreversibly impair patients’ quality of life.

Intensity-modulated radiation therapy (IMRT) improves the physical dose distribution compared to two-dimensional RT (2DRT), and with this dose improvement, the corresponding incidence of TLN decreases significantly [1, 2]. Indeed, the incidence of TLN after IMRT from different centers varies from 3 to 14% [3‐8]. QUANTEC suggested that the dose limit for TL D_max ≤ 60 Gy and V_65Gy ≤ 1% are commonly accepted in clinical use. However, the QUANTEC limits are based on past experience from the 3DCRT or 2DRT era and may not be suitable for IMRT. A retrospective analysis performed by Su et al. [9]. revealed that IMRT D_max < 68 Gy or D_1cc < 58 Gy for the TL is relatively safe. Their study covered a series of dosimetric factors. However, following study of Su et al., pointed out rV40 and aV40 (relative and absolute volume receiving dose higher than 40 Gy) could better predict TLN [10]. Sun et al. suggested a dose limitation of D_0.5cc < 69 Gy based on an analysis of 506 patients [11]. A case-controlled study performed by Zhou found that both focal high dose and moderate dose to large volume should be considered [12].

Most previous studies focused on the dose only, and clinical factors have been seldom discussed. In clinical practice, the overall condition of the patient should be taken into consideration. Although there have been several previous publications looking at dosimetric and patient factors in determining a safe dose to the temporal lobes during NPC IMRT treatment. There was no a comprehensive and quantitative analysis.

The purpose of this study was to generate a model to predict TLN occurrence using clinical and dosimetric factors. And to access model performance on a testing data set.

The workflow of this study is presented in Fig. 1. Patients were divided into training set and testing set base on patients’ treatment time. A LASSO modeling method was performed to build a prediction, and the model performance was evaluated by ROC and calibration curve.

In this study, both clinical and dosimetric factors were evaluated. A robust modeling method was implemented to get final model. As we know, this study is the first attempt to derive a quantitative complication model for TLN. This is a logical extension of the previous statistical studies.

The results show that only physical dose parameters were reliable factors for the prediction of TLN. Although, the clinical factor T-stage is strongly correlated with TLN in univariate analysis. It was not selected into final prediction model. This may cause by the strong correlation between dose and T-stage (0.42, Spearman’s correlation of T-stage and TL Mean Dose). The dosimetric factor seem as more direct cause. Moreover, when considering advanced T stage (T3, T4) patients alone, the correlation was weaker (0.335) when the prescription dose was identical.

Diabetes is accompanied by a biological change in the microvascular environment. Its enhancement of TLN supports the hypothesis put forward by Belka that vessel damage is a cerebral toxicity inducing factor [14]. Because of the limited number of patients, further investigation is expected to draw a statistically persuasive conclusion. Concurrent chemotherapy exhibited a similar situation and induction or adjuvant chemotherapy showed no positive effect. These results were consistent with those obtained in Lee’s study [15].

Dosimetric parameters are strongly correlated with each other. In variable selection, collinearity causes competition among predictors and makes arbitrary decisions in choice [16]. The prediction variables were selected via LASSO [17]. LASSO is another approach that can be used to select highly correlated variables for which strongly correlated predictors tend to be in and out together [18]. More advanced modeling strategies, such as random forests, are also alternatives and may achieve more powerful predictions. However, considering the accessibility required for clinical purposes, they may not be a first choice.

Previous studies provided different conclusions regarding dosimetric variables. In addition to various specific cutoff limitation points, a focal high dose [9, 11, 17] or relatively large volume dose [10, 12] are also critical differences. The affecting factors could include TL delineation, treatment strategy, and follow-up period. The posterior and superior margins of the TL are not precisely shown on the CT images, resulting in variances in the dose description of the TL. In our study, although lots dosimetric factors were correlated to TLN, the final selected features were D0.5cc and D10. This result have demonstrated that a hot spot and a small region (10% of the TL) have most effects on the TLN.

The low incidence of TLN makes clinical control difficult. After a median follow-up of 48.8 months, some of the current necrosis-free patients will likely show symptoms of TLN in the future. With an extended follow-up period, more persuasive findings may be obtained. This is the main reason that the TLN incidence rate difference in our training and testing set. This also cause a deviation of the calibration curve. Additionally, although necrosis occurs only within a small region, the dose administered to the entire TL is usually analyzed. A compromise approach is to define a ‘sub-TL’ ROI that delineates only the front TL because nearly all cases of TLN occur in the anterior and lower parts of the TL. Applying this approach might generate a clearer TLN nomogram.

This study presents a prediction model can be conveniently used to facilitate the individualized prediction of TLN in patients with NPC. Clinical factors have no direct impact on TLN.