Normal tissue complication probability modeling to guide individual treatment planning in pediatric cranial proton and photon radiotherapy

Abstract

Proton therapy (PT) is broadly accepted as the gold standard of care for pediatric patients with cranial cancer. The superior dose distribution of PT compared to photon radiotherapy reduces normal tissue complication probability (NTCP) for organs at risk. As NTCPs for pediatric organs are not well understood, clinics generally base radiation response on adult data. However, there is evidence that radiation response strongly depends on the age and even sex of a patient. Furthermore, questions surround the influence of individual intrinsic radiosensitivity (α/β ratio) on pediatric NTCP. While the clinical pediatric NTCP data is scarce, radiobiological modeling and sensitivity analyses can be used to investigate the NTCP trends and its dependence on individual modeling parameters. The purpose of this study was to perform sensitivity analyses of NTCP models to ascertain the dependence of radiosensitivity, sex, and age of a child and predict cranial side-effects following intensity-modulated proton therapy (IMPT) and intensity-modulated radiotherapy (IMRT). Methods: Previously, six sex-matched pediatric cranial datasets (5, 9, and 13 years old) were planned in Varian Eclipse treatment planning system (13.7). Up to 108 scanning beam IMPT plans and 108 IMRT plans were retrospectively optimized for a range of simulated target volumes and locations. In this work, dose-volume histograms were extracted and imported into BioSuite Software for radiobiological modeling. Relative-Seriality and Lyman-Kutcher-Burman models were used to calculate NTCP values for toxicity endpoints, where TD50, (based on reported adult clinical data) was varied to simulate sex dependence of NTCP. Plausible parameter ranges, based on published literature for adults, were used in modeling. In addition to sensitivity analyses, a 20% difference in TD50 was used to represent the radiosensitivity between the sexes (with females considered more radiosensitive) for ease of data comparison as a function of parameters such as α/β ratio. Results: IMPT plans resulted in lower NTCP compared to IMRT across all models (p < 0.0001). For medulloblastoma treatment, the risk of brainstem necrosis (> 10%) and cochlea tinnitus (> 20%) among females could potentially be underestimated considering a lower TD50 value for females. Sensitivity analyses show that the difference in NTCP between sexes was significant (p < 0.0001). Similarly, both brainstem necrosis and cochlea tinnitus NTCP varied significantly (p < 0.0001) across tested α/β as a function of TD50 values (assumption being that TD50 values are 20% lower in females). If the true α/β of these pediatric tissues is higher than expected (α/β ∼ 3), the risk of tinnitus for IMRT can significantly increase (p < 0.0001).

Radiotherapy with Helium Ions Has the Potential to Improve Both Endocrine and Neurocognitive Outcome in Pediatric Patients with Ependymoma

“…To obtain the endpoint-specific parameters for the calculation, the NTCP models are trained using data with known clinical outcomes after radiotherapy treatment. These data sets are mostly based on largely outdated data of adult patients who received conventional radiotherapy [ 21 ]. With currently available model parameters, NTCP calculations may not be appropriate for pediatric patients or for helium ions.…”

“…In addition, NTCP modulation is very complex. It depends on various factors such as age and sex [ 21 ]. Further research is needed to develop parameters that are more appropriate for specific patient populations.…”

“…In order to compute the LKB for the different radiation modalities, the individual parameter TD 50 , m, n need to be known for the organs/structures of interests and the corresponding endpoint [ 21 , 28 ]. The LKB parameters used in this work are presented in Table 1 .…”

“…The most frequently used models are the Lyman–Kutcher–Burman (LKB) model and the Relative-Seriality model. By inserting parameters which represent the potential biological damage caused by irradiation the patient specific risk for long-term side effects can be calculated [ 21 ]. In fact, NTCPs are expected to become gold standard for identifying the patients likely to benefit most from particle therapy [ 22 ].…”

Helium Ion Therapy for Advanced Juvenile Nasopharyngeal Angiofibroma

“…Potential impacts on the patients' quality of life following radiotherapy were assessed through the estimation of NTCP using different published models, as detailed in Table 2. Computation of NTCP for various OAR were performed with respect to several endpoints, including neurocognition (change in estimated intellectual quotient (IQ) [21,22] or delayed recall on the Wechsler Memory Scale-III Word List [23]), neuroendocrine dysfunctions (e.g., adrenocorticotropic or growth hormone deficiency), central hypothyroidism [24,25], hearing loss or tinnitus [25], ocular toxicity [26], alopecia or erythema [27] or xerostomia [28]. Mahajan [22] Neurocognitive impairment estimation at a long follow-up time (IQ < 85) Dell'Oro [25] adapted from Lee 2015 [29] and De Marzi 2015 [30] Hearing loss (grade ≥ 1-2, 2 years post radiotherapy) Batth 2013 [26] Lens (IL/CL) Cataract (5 years post radiotherapy)…”